Utah Medicaid Pharmacy and Therapeutics Committee Drug Class … · 2019-11-18 · Plaque...

Utah Medicaid Pharmacy and Therapeutics Committee

Drug Class Review

Cytokine Modulators

Abatacept (Orencia) Adalimumab (Humira)

Anakinra (Kineret) Apremilast (Otezla)

Baricitinib (Olumiant) Brodalumab (Siliq)

Canakinumab (Ilaris) Certolizumab Pegol (Cimzia)

Etanercept (Enbrel) Golimumab (Simponi) Guselkumab (Tremfya)

Ixekizumab (Taltz) Risankizumab-rzaa (Skyrizi)

Sarilumab (Kevzara) Secukinumab (Cosentyx)

Tildrakizumab-asmn (Ilumya) Tocilizumab (Actemra)

Tofacitinib (Xeljanz, Xeljanz XR) Upadacitinib (Rinvoq) Ustekinumab (Stelara)

Report finalized: August 2019 Report Presented September 2019

Review prepared by: Valerie Gonzales, Pharm.D., Clinical Pharmacist Elena Martinez Alonso, B.Pharm., Medical Writer Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Joanita Lake, B.Pharm., MSc EBHC (Oxon), Research Assistant Professor, Clinical Pharmacist Joanne LaFleur, PharmD, MSPH, Associate Professor University of Utah College of Pharmacy University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2019 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

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Contents Executive Summary ....................................................................................................................................... 4

Introduction .................................................................................................................................................. 9

Table 1. Disease States Covered by Cytokine Inhibitor Indications ............................................... 10

Table 2. Orphan Disease Approvals ............................................................................................... 12

Methods ...................................................................................................................................................... 13

Disease Overview and Guideline Recommendations ................................................................................. 14

A. Psoriasis ......................................................................................................................................... 14

Table 3. Proposed Definitions for Psoriasis Severity and Treatment Options in Plaque Psoriasis 16

Table 4. FDA-Approved Cytokine Inhibitors for Plaque Psoriasis .................................................. 17

Table 5. Guideline Recommendations for Cytokine Inhibitors in the Treatment of Moderate to Severe Psoriasis .............................................................................................................................. 19

Table 6. Summary of Recommended Options and Strength of Evidence for Monotherapy Treatment of Moderate-to-Severe Psoriasis in Adults (as Reported by the 2019 AAD/NPF Guideline) ....................................................................................................................................... 20

B. Psoriatic Arthritis ........................................................................................................................... 21

Table 7. FDA-Approved Cytokine Inhibitors for Psoriatic Arthritis ................................................ 22

Table 8. Guideline Recommendations for Cytokine Inhibitors in the Treatment of Psoriatic Arthritis .......................................................................................................................................... 25

C. Rheumatoid Arthritis ..................................................................................................................... 28

Table 9. FDA-Approved Cytokine Inhibitors for Rheumatoid Arthritis .......................................... 29

Table 10. Guideline Recommendations for Biologics in the Treatment of Rheumatoid Arthritis . 31

D. Ankylosing Spondylitis ................................................................................................................... 33

Table 11. Cytokine Inhibitors FDA-Approved for Axial Spondyloarthritis...................................... 33

Table 12. Guideline Recommendations for Biologics in the Treatment of Ankylosing Spondylitis and Spondyloarthritis..................................................................................................................... 35

E. Juvenile Idiopathic Arthritis ........................................................................................................... 36

Table 13. FDA-Approved Cytokine Inhibitors for the Treatment of Juvenile Idiopathic Arthritis . 36

Table 14. Guideline Recommendations for Cytokine Inhibitors in the Treatment of Juvenile Idiopathic Arthritis ......................................................................................................................... 38

F. Inflammatory Bowel Disease ......................................................................................................... 39

Table 15. Cytokine Inhibitors Approved for Inflammatory Bowel Disease .................................... 40

F.1 Crohn’s Disease ............................................................................................................................ 41

Table 16. Disease Status Descriptions For Crohn’s Disease ........................................................... 42

Table 17. Treatment Guidelines for the Use of Biologics in Crohn’s Disease ................................ 43

F.2 Ulcerative Colitis ........................................................................................................................... 45

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Table 18. Treatment Guidelines for the Use of Biologics in Ulcerative Colitis .............................. 46

Pharmacology & Special Populations ......................................................................................................... 48

Table 19. Mechanism of Action for Interleukin Inhibitors ............................................................. 50

Table 20. Pharmacokinetic Parameters ......................................................................................... 51

Table 21. Special Population Considerations for Cytokine Inhibitors ............................................ 52

Direct Comparative Evidence for Cytokine Modulators ............................................................................. 56

Figure 1. PRISMA Flow Chart for Publication Screening ................................................................ 56

Section 1. Overview of Key Findings from Head-to-Head Evidence ....................................................... 57

Table 22. Head-to-Head Evidence Identified in the Literature Search .......................................... 58

Section 2. Detailed Information Regarding Head-to-Head Evidence ..................................................... 61

A. Plaque Psoriasis .............................................................................................................................. 61

B. Psoriatic Arthritis ............................................................................................................................ 62

C. Rheumatoid Arthritis ...................................................................................................................... 63

Safety .......................................................................................................................................................... 65

Direct Comparative Evidence ................................................................................................................. 65

Warnings and Precautions ...................................................................................................................... 65

Table 23. Warnings and Precautions for TNF-alpha Inhibitors ...................................................... 68

Table 24. Warnings and Precautions for Interleukin Antagonists ................................................. 69

Table 25. Warnings and Precautions for Selective T Cell Co-stimulator, PDE-4 Inhibitor, and Janus Kinase Inhibitors , ........................................................................................................................... 70

Table 26. Adverse Effects for Cytokine Inhibitors .......................................................................... 71

References .................................................................................................................................................. 73

Appendix A – Additional Product Information for Cytokine Modulators ................................................... 83

Appendix B - Literature Search Strategies .................................................................................................. 86

Appendix C - Excluded References .............................................................................................................. 92

Appendix D - Systematic Reviews and Randomized Controlled Trials ...................................................... 105

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Executive Summary Background: Multiple cytokine inhibitors are currently approved by the U.S. Food and Drug Administration (FDA) for the treatment of chronic, inflammatory, autoimmune conditions including plaque psoriasis (PsO), psoriatic arthritis (PsA), rheumatoid arthritis (RA), axial spondyloarthritis (ankylosing spondylitis [AS] and non-radiographic axial spondyloarthritis), juvenile idiopathic arthritis (JIA), Crohn’s disease (CD), and ulcerative colitis (UC). This report will review the cytokine inhibitors available as self-administered formulations (oral or subcutaneous). These include 11 interleukin (IL) antagonists (anakinra, brodalumab, canakinumab, guselkumab, ixekizumab, risankizumab-rzaa, sarilumab, secukinumab, tildrakizumab-asmn, tocilizumab, and ustekinumab), 4 tumor necrosis factor (TNF) alpha inhibitors (adalimumab, certolizumab pegol, etanercept, and golimumab), 3 janus kinase (JAK) inhibitors (baricitinb, tofacitinib, and upadacitinib), a T-cell co-stimulation modulator (abatacept), and a phosphodiesterase- 4 (PDE4) inhibitor (apremilast). Except for apremilast, baricitinib, tofacitinib, and upadacitinib, which are administered orally, the aforementioned agents are administered by subcutaneous injection, and of this subset, 4 can also be administered intravenously.

There are 2 main subclasses of cytokine modulators including biological therapies (TNF-alpha inhibitors, IL inhibitors, and a T-cell co-stimulation modulator) and the small molecule therapies (JAK inhibitors and a PDE4 inhibitor). The biologics are large, antibody-containing proteins that target extracellular immune signals. The small molecule drugs target signaling pathways inside immune cells. Cytokine inhibitors reduce inflammation and immune responses by directly inhibiting proinflammatory cytokines such as TNF alpha and specific interleukins (eg, IL-6, IL-12, and IL-23), targeting specific enzymes that are involved in cytokine-mediated signaling pathways (eg, JAK and PDE4), or blocking T-cell activation. The indication for some therapies is specific for patients who failed other traditional or conventional disease modifying agents such as methotrexate (MTX), hydroxychloroquine, leflunomide, and sulfasalazine. A few cytokine inhibitors have indications for patients who failed certain TNF inhibitors. Pharmacokinetic parameters differ among the cytokine modulators, with elimination half-lives ranging from 3 hours to 46 days. Dosage recommendations vary depending on the approved indication. Maintenance dosing frequency ranges from twice daily to every 12 weeks.

The aim of this report is to provide evidence from systematic reviews (SRs) and randomized controlled trials (RCTs) of head-to-head efficacy and safety comparisons among the cytokine inhibitors administered orally or subcutaneously for the treatment of PsO, PsA, RA, AS, JIA, CD, and UC. Other FDA-approved indications (eg, hidradenitis suppurativa, panuveitis, periodic fever syndromes, giant cell arteritis, or cytokine release syndrome) are outside the scope of this report.

Comparative Efficacy Evidence and Guideline Recommendations: Following a systematic literature search in Ovid-Medline and Embase for direct head-to-head comparisons among cytokine modulators, few comparative RCTs in psoriasis, psoriatic arthritis, and rheumatoid arthritis populations were identified. In the setting of ankylosing spondylitis, juvenile idiopathic arthritis, Crohn’s disease, and ulcerative colitis, there is an absence of direct head-to-head evidence. Listed below is a summary of the available direct comparative evidence by indication, together with guideline recommendations based on evidence review or expert opinion:

Plaque psoriasis: Three SRs (Sbidian 2017, No 2018, and Loos 2018) including a total of 11 head-to-head RCTs with cytokine inhibitors at FDA-approved dosages were identified. Information is only available for

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certain comparisons in the adult population with moderate to severe PsO and multiple RCTs for the same comparison were rarely found. In terms of the proportion of patients achieving a 75% or 90% improvement in the Psoriasis Area and Severity Index (PASI 75 and PASI 90, respectively) at week 12 or 16, ustekinumab, secukinumab, ixekizumab, and tildrakizumab (interleukin inhibitors) were significantly more efficacious than etanercept (TNF inhibitor). Among interleukin inhibitors, secukinumab, brodalumab, and ixekinumab were significantly more efficacious than ustekinumab. Guselkumab (interleukin inhibitor) was significantly more efficacious than adalimumab (TNF inhibitor).

Regarding the 2019 Joint American Academy of Dermatology (AAD)/National Psoriasis Foundation (NPF) guideline for the treatment of psoriasis with biologics, etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, and risankizumab are recommended as monotherapy for adults with moderate-to-severe plaque psoriasis, based on moderate- to high-quality evidence. Etanercept, infliximab, adalimumab, ustekinumab, secukinumab, and ixekizumab are recommended, based on high-quality evidence, as monotherapy for adults with psoriasis (any severity) associated with psoriatic arthritis. There are no specific recommendations for one biologic agent over another. In the pediatric population there was no head-to-head evidence identified. Only 2 biologic agents are FDA approved for plaque psoriasis in this population. Etanercept is approved for plaque psoriasis in children 4 to 17 years and ustekinumab is approved for plaque psoriasis in adolescents 12 to 17 years.

Psoriatic arthritis: Two SRs (Dressler 2019 and Corbett 2017) reported 4 head-to-head RCTs with cytokine modulators at FDA-approved dosages in patients with PsA. Two RCTs reported differences between cytokine inhibitors. One RCT (Atteno 2010) showed a significantly greater improvement of skin lesions (PASI responses) at year 1 with adalimumab compared to etanercept (at PsA dosage), but significantly better responses in terms of tender joint count and disability with etanercept compared to adalimumab. The other RCT (Langley 2014) included patients with PsO and reported subgroup data for patients with PsO and concomitant PsA. This trial did not evaluate psoriatic arthritis responses (eg, the American College of Rheumatology 20% improvement criteria); only PASI responses measuring the extension of psoriatic skin lesions were reported. There were significantly greater improvements in PASI responses with secukinumab compared to etanercept.

The 2018 American College of Rheumatology (ACR)/NPF guideline on psoriatic arthritis specifies the place in therapy for agents in treatment-naïve and treatment-experienced patients with active psoriatic arthritis; however, most treatment recommendations are based on very low- to low-quality evidence. For treatment-naïve patients, the use of TNF inhibitors is recommended over oral small molecules (OSM; eg, apremilast), an IL-17 inhibitor (secukinumab or ixekizumab), or an IL-12/23 inhibitor (ustekinumab). The use of IL-17 inhibitors is recommended over IL-12/23 inhibitors. For treatment-experienced patients (already treated with OSM or biologics), switching to a TNF inhibitor (or a different one) is recommended over other agents (eg, a different OSM, IL-17 inhibitor, IL-12/23 inhibitor, abatacept, or tofacitinib). Based on expert opinion, the European League Against Rheumatism (EULAR) recommends the use of TNF inhibitors over other biologics for the treatment of PsA. Overall, selection of therapy for the treatment of psoriatic arthritis should be individualized based on disease severity, contraindication to specific agents, patient preferences (oral versus injectable medication), concerns about starting a biologic as the first therapy, convenience, and comorbidities (congestive heart failure, recurrent infections, demyelinating disease, inflammatory bowel disease, or diabetes).

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Rheumatoid arthritis: Five SRs (Choy 2019, Venerito 2019, Ma 2019, Emery 2018, and Kawalec 2013) including head-to-head RCTs with cytokine inhibitors at FDA-approved dosages were identified. A meta-analysis (MA) of 2 RCTs in RA patients with inadequate response to DMARDs showed a significantly greater improvement in terms of the ACR 50% improvement criteria (ACR50 response) with tofacitinib 5 mg twice daily compared to adalimumab 40 mg every 2 weeks; but, no differences in ACR20 and ACR70 responses. One of the limitations of this MA is that the background therapy allowed in each RCT was different (monotherapy in one study vs. background methotrexate therapy in the other). The remaining 4 SRs reported 4 head-to-head RCTs. Only one RCT (Burmester et al) reported significant differences between treatments. Burmester et al included patients who could not receive MTX and showed significantly better results with sarilumab 200 mg every 2 weeks compared to adalimumab 40 mg every other week (both arms as monotherapies) in terms of rheumatoid arthritis activity, ACR 20/50/70 response rates, and disability. Nonetheless, this study did not assess a 40 mg weekly dosage of adalimumab, which is additionally approved for RA patients not receiving MTX. An additional RCT (identified in a secondary PubMed search) demonstrated superiority of upadacitinib compared to adalimumab for the ACR50 response, improvement in disease activity, reduction of pain, and improvement in physical function.

The 2015 American College of Rheumatology (ACR) guideline for RA provides recommendations based on disease duration, disease activity, and comorbidities. For patients with early RA (disease duration of less than 6 months) or established RA (disease duration ≥ 6 months) and moderate or high disease activity despite treatment with a conventional disease modifying antirheumatic drugs (cDMARDs) such as MTX, there is strong recommendation for the use of either a combination of cDMARDs, a TNF inhibitor, or a non-TNF biologic. Tofacitinib may be an additional option for patients with established RA. For patients with comorbidities, specific agents may be preferred (eg, use of a non-TNF biologic or tofacitinib over a TNF inhibitor for patients with congestive heart failure or use of abatacept over TNF inhibitors for patients with serious infections).

For populations with ankylosing spondylitis, juvenile idiopathic arthritis, or inflammatory bowel disease (CD or UC), direct head-to-head evidence is lacking. Guideline recommendations for these disease states are provided below:

Ankylosing spondylitis: The 2015 ACR guideline on AS and nonradiographic axial spondyloarthritis (SpA) recommends the use of TNF inhibitors in patients with active AS and an inadequate response or intolerance to at least 2 different NSAIDs over 1 or 2 months. No recommendations are specified for the IL-17 inhibitor because it was not available at the time of the 2015 ACR guideline publication. Due to the lack of head-to-head evidence, this guideline does not specify a preference for a TNF inhibitor over another in the overall population; however, infliximab or adalimumab are preferred over etanercept for patients with concomitant inflammatory bowel disease or recurrent iritis. Certolizumab pegol is the only biologic agent FDA-approved for non-radiographic axial spondyloarthritis.

Juvenile idiopathic arthritis: The 2019 American College of Rheumatology/Arthritis Foundation guideline for juvenile non-systemic polyarthritis, sacroiliitis, and enthesitis generally recommends biologic treatments (adalimumab, etanercept, golimumab, abatacept, or tocilizumab) in combination with a DMARD for certain children and adolescents with JIA and polyarthritis. TNF inhibitors are recommended for children and adolescents with JIA and active sacroilitis or enthesitis, despite having tried nonsteroidal anti-inflammatory drugs. This guideline does not specifically recommend one biologic over

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another due to the lack of head-to-head comparisons. The 2013 ACR guideline for the treatment of systemic JIA has anakinra, canakinumab, tocilizumab, TNF-alpha inhibitors, and abatacept as treatment options.

Inflammatory Bowel Disease: Based on the American College of Gastroenterology (ACG) 2018 guideline for CD, biologics are recommended for the treatment of moderate-to-severe CD and for patients at high risk of disease progression. The anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) and the IL-12/IL-23 inhibitor (ustekinumab) are considered for patients who have inadequately responded to conventional therapy with thiopurines, methotrexate, or corticosteroids. Adalimumab is additionally approved for adults with loss of response or inadequate response to infliximab, and ustekinumab is additionally approved and recommended for adults who have failed one or more anti-TNF inhibitor. Anti-TNF agents are also recommended for fistulizing and post-operative CD. The ACG notes that data is lacking to support switching patients during the maintenance of stable disease to a biosimilar product.

Options for induction of remission of moderately to severely active UC described in the 2019 ACG guideline include oral systemic corticosteroids; the anti-TNF agents, adalimumab, golimumab, or infliximab; the integrin inhibitor, vedolizumab; and the JAK inhibitor, tofacitinib. For patients who failed anti-TNF therapy, vedolizumab or tofacitinib are recommended. If a biologic or tofacitinib is used for induction, it is recommended that the same agent be continued to maintain remission.

Safety: Only some head-to-head comparisons were evaluated with respect to safety outcomes and found mainly no differences as described in the Safety section of the report. The only significant safety difference reported among these studies was a higher incidence of local injection-site reactions leading to treatment discontinuation with adalimumab therapy versus abatacept.

Cytokine inhibitors may increase the risk of infections and, for most, product labeling warns about serious infections. Agents that have black box warnings pertaining to serious infection include the TNF-alpha blockers, JAK inhibitors, and the IL-antagonists, sarilumab and tocilizumab. Patients should be tested for tuberculosis (TB) infection prior to initiating cytokine inhibitors. TNF-alpha inhibitors, JAK inhibitors, and the IL-antagonists, sarilumab and tocilizumab, have black box warnings regarding TB infection. Labeling for TNF-alpha inhibitors warns of hepatitis B reactivation with treatment.

Hematological reactions (eg, leukopenia, pancytopenia, thrombocytopenia, aplastic anemia) may occur with the TNF-alpha inhibitors, JAK inhibitors, and with the IL-blockers, anakinra, sarilumab, and tocilizumab. Product labeling advises to avoid live vaccines for all the reviewed cytokine inhibitors with the exception of apremilast.

The development of anti-drug antibodies is possible with the biologic agents. In this situation, patients may require higher doses or lose response over time. Therapeutic drug monitoring and measurement of drug-antibodies may be used to determine the reason for inadequate response to biologic therapy.

Black box warnings are included for TNF-alpha inhibitors and JAK inhibitors regarding cases of malignancy. During controlled trials with the TNF-blockers, there were more cases of malignancies observed in the treatment arm compared to control. Cases of malignancy have also be reported with the use of utstekinumab and the JAK inhibitors.

There are thrombosis risk concerns with the JAK inhibitors. A black box warning for baricitinib and upadacitinib notes that thrombosis cases have been reported. The black box warning for tofacitinib is

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specific to increased risk of mortality and thrombosis with the higher dosage of tofacitinib versus the lower dosage in RA patients 50 years or older with at least one cardiovascular risk factor. Some agents were associated with increased lipid parameters during clinical trials (sarilumab, tocilizumab, and the JAK inhibitors); yet, the effect of this elevation on cardiovascular risk has not been determined.

Brodalumab carries a black box warning concerning the risk of suicidal ideation and behavior with the use of this agent and is only available through a Risk Evaluation and Mitigation Strategy (REMS) program.

Summary: Evidence comparing cytokine inhibitors at FDA-approved dosages is available only for populations with plaque psoriasis, psoriatic arthritis, or rheumatoid arthritis, and is limited to only a few comparisons, mostly versus etanercept, adalimumab, or ustekinumab (see table 22 of this report). Head-to-head evidence is currently considered insufficient to guide clinical decision making.

Few significant differences among cytokine inhibitors have been demonstrated with respect to unique populations and short-term treatment. For RA patients, the following studies were identified: 1) a meta-analysis showed a significantly greater improvement in terms of ACR50 response with tofacitinib compared to adalimumab; but no differences in ACR20 and ACR70 responses, 2) a single RCT demonstrated superiority of upadacitinib compared to adalimumab (both in combination with MTX) in terms of ACR50 response, physical function, and pain reduction, and 3) a single RCT in patients unable to take MTX showed improved RA outcomes with sarilumab compared to adalimumab (both as monotherapy); however, authors compared only the every-other-week dosage of adalimumab but not the weekly dosing strategy. In terms of PASI 75 and 90 for adult patients with moderate to severe plaque psoriasis, ustekinumab, secukinumab, ixekizumab, and tildrakizumab were significantly more efficacious than etanercept; secukinumab, brodalumab, and ixekinumab were significantly more efficacious than ustekinumab; and guselkumab was significantly more efficacious than adalimumab. For psoriatic arthritis patients, an RCT showed a significantly greater improvement in PASI responses with adalimumab compared to etanercept (at PsA dosage), but significantly better responses in terms of tender joint count and disability with etanercept compared to adalimumab. Another RCT in PsA patients showed significantly greater improvements in PASI responses with secukinumab compared to etanercept.

The Utah Medicaid Preferred Drug List (PDL) includes, as preferred agents, 2 TNF-alpha inhibitors (Enbrel [etanercept] and Humira [adalimumab]) and an interleukin antagonist (Cosentyx [secukinumab]). Step therapy is required for Costenyx (ie, patients must fail another preferred agent first). Regarding the Medicaid fee-for-service (FFS) pharmacy data for 2018 through June 2019, Humira (adalimumab) and Enbrel (etanercept) are the most frequently utilized agents. For the purposes of the PDL, including at least 2 cytokine inhibitors may be considered. For those agents that are then listed as non-preferred, the panel may recommend the development of drug-specific prior authorization criteria designed to permit utilization for the rare disease-related approved indications.

Introduction The scope of this review encompasses the self-administered cytokine inhibitors that are FDA-approved for one or more of the following indications: rheumatoid arthritis (RA), spondyloarthritis (ankylosing spondylitis [AS] and non-radiographic axial spondyloarthritis), juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), plaque psoriasis (PsO), and the inflammatory bowel disorders (IBD) of Crohn’s disease (CD) and ulcerative colitis (UC).1-20 A few of these conditions, JIA, AS, and pediatric IBD are rare diseases; thus some of the cytokine inhibitors have orphan designations. The more common disease states include RA, PsA, PsO, and IBD in the adult population. Table 1 summarizes the disease states for which self-administered cytokine inhibitors are approved. Detailed information regarding the full labeled indications is provided in upcoming sections of the report that are specific to each disease state. Several cytokine inhibitors reviewed are approved for other rare-diseases as shown in Table 2; however, these disease areas will not be a focus in our review (hidradenitis suppurativa, uveitis, periodic fever syndromes, giant cell arteritis, cytokine release syndrome, and Behcet’s disease).

Cytokine inhibitors work at various points along the inflammation response pathway to ultimately tone down an overly activated immune system that is thought to contribute to disease progression. Most cytokine inhibitors are biologic agents that are large-molecule proteins (TNF inhibitors, interleukin inhibitors, and the selective T-cell costimulation modulator). Others are non-biologic agents that are small molecule proteins (Janus associated kinase [JAK] inhibitors and the phosphodiesterase 4 [PD4] inhibitor). The biologic agents are synthesized in cell lines and are administered as subcutaneous and/or intravenous injections. The small molecule drugs are available as oral formulations. Table 1 of Appendix A includes the available drug formulations for the cytokine inhibitors. Biosimilars are approved for both adalimumab and etanercept; yet, the market launch date of these agents has been delayed due to legal proceedings regarding patent exclusivity. Table 2 of Appendix A lists the brand names of approved biosimilar products that are currently unavailable.

The research objective of this report is to determine whether there are key efficacy or safety differences between the available cytokine modulators listed in Table 1, for their respective FDA-approved indications. The Utah Medicaid Preferred Drug List (PDL) groups these products under the category, Cytokine Modulators, Immunomodulators. Preferred products include an interleukin antagonist, Cosentyx (secukinumab), and 2 TNF-alpha inhibitors, Enbrel (etanercept) and Humira (adalimumab); step therapy is required for Costenyx (ie, patients must fail another preferred agent first).

Regarding the Medicaid fee-for-service (FFS) pharmacy data for 2018 through June 2019, utilization was highest for Humira (adalimumab) followed by Enbrel (etanercept) — PDL preferred status agents. Together these 2 agents made up 86% of the utilization and other cytokine inhibitors, altogether, made up 14% of the utilization from 2018 through June 2019. From the beginning of the year through June 2019, a total of 153 patients received a prescription for one of the reviewed cytokine inhibitors and of these, 13 were pediatric patients. Utilization in the pediatric FFS population (< 18 years) in 2019 included claims for Humira (adalimumab), Enbrel (etanercept), and Actemra (tocilizumab).

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Table 1. Disease States Covered by Self-Administered Cytokine Inhibitor Indications1-20,a Generic name

Brand name (route of administration)

Axial Spondyloarthritis

Crohn’s Disease

Juvenile Idiopathic Arthritis

Plaque Psoriasis

Psoriatic Arthritis

Rheumatoid Arthritis

Ulcerative Colitis

Other approved orphan

indications Selective T cell Co-stimulation Modulator

Abatacept Orencia (SQ, IV) X (PJIA)

(≥ 2 y) X (adults)

X (adults)

TNF-alpha Blockers

Adalimumab Humira (SQ)

X (AS) (adults)

X (adults & peds ≥ 6 y)

X (PJIA) (≥ 2 y)

X (adults)

X (adults)

X (adults)

X (adults)

X (hidradentitis suppurativa,

uveitis)

Certolizumab Pegol Cimzia (SQ)

X (AS and NRA SpA)

(adults)

X (adults) X

(adults) X

(adults) X

(adults)

Etanercept Enbrel (SQ) X (AS) X (PJIA)

(≥ 2 y) X

(≥ 4 y) X X

Golimumab Simponi (SQ)

X (AS) (adults) X

(adults) X

(adults) X

(adults)

Interleukin Antagonists

Anakinra Kineret (SQ) X

(adults) X

(Periodic fever syndromes)

Brodalumab Siliq (SQ) X

(adults)

Canakinumab Ilaris (SQ) X (SJIA)

(≥ 2 y) X

(Periodic fever syndromes)

Guselkumab Tremfya (SQ) X

(adults)

Ixekizumab Taltz (SQ) X X

Risankizumab-rzaa Skyrizi (SQ) X

(adults)

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Table 1. Disease States Covered by Self-Administered Cytokine Inhibitor Indications1-20,a Generic name

Brand name (route of administration)

Axial Spondyloarthritis

Crohn’s Disease

Juvenile Idiopathic Arthritis

Plaque Psoriasis

Psoriatic Arthritis

Rheumatoid Arthritis

Ulcerative Colitis

Other approved orphan

indications Sarilumab Kevzara (SQ) X

(adults)

Secukinumab Cosentyx (SQ)

X (AS) (adults) X

(adults) X

(adults)

Tildrakizumab-asmn Ilumya (SQ) X

(adults)

Tocilizumab Actemra (SQ)

X (PJIA &

SJIA, ≥ 2 y) X

(adults)

X (Giant cell arteritis,

cytokine release syndrome

Ustekinumab Stelara (SQ) X

(adults)

X (adults and adolescents

≥ 12 y)

X (adults)

Phosphodiesterase- 4 Inhibitor Apremilast Otezla (PO) X X

(adults) X Behcet’s disease

Janus Kinase Inhibitors Baricitinib Olumiant (PO) X

(adults)

Tofacitinib Xeljanz (PO) Xeljanz XR (PO)

X (adults)

X (adults)

X (adults)

Upadacitinib Rinvoq (PO) X

(adults)

Abbreviations: AS, ankylosing spondylitis; IV, intravenous; NRA SpA, non-radiographic axial spondyloarthritis; peds, pediatric population; PJIA, polyarticular juvenile idiopathic arthritis; SJIA, systemic juvenile idiopathic arthritis; SQ, subcutaneous; y, years old a Refer to tables in the disease overview area for detailed information about the indication, population covered, and circumstances that must be met.

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Table 2. Orphan Disease Approvals21 Medication (Brand name) Orphan-disease approval Adalimumab (Humira) Moderate to severe hidradenitis suppurativa

Pediatric Crohn's disease Non-infectious intermediate, posterior, or panuveitis, or chronic non-infectious anterior uveitis Treatment of juvenile rheumatoid arthritis (PJIA, ≥ 2 years)

Anakinra (Kineret) Treatment of cryopyrin-associated periodic syndromes Canakinumab (Ilaris) Treatment of TNF-receptor associated periodic syndrome (TRAPS)

Treatment of hyperimmunoglobulinemia D and periodic fever syndrome Treatment of cryopyrin-associated periodic syndromes Treatment of familial mediterranean fever Treatment of pediatric (age >2 years) juvenile rheumatoid arthritis

Etanercept (Enbrel) Reduction in signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs.

Tocilizumab (Actemra) Treatment of chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome Treatment of pediatric patients (age 16 years and younger) with polyarticular and systemic juvenile idiopathic arthritis Giant cell arteritis

Apremilast (Otezla) Treatment of Behcet's disease Abbreviations: PJIA, polyarticular juvenile idiopathic arthritis

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Methods Literature Search

Search strategies were developed in OVID Medline and Embase. Strategies consisted of controlled vocabulary, such as Medical Subject Headings (MeSH), and keyword phrases. A methodological filter was used for SRs and meta-analyses (MAs). In Embase, we excluded conference abstracts. Authors conducted a grey literature search including the websites for the Oregon Drug Effectiveness Review Project (DERP) group and the Agency for Healthcare Research and Quality (AHRQ). Based on the literature searches described in the 2012 DERP report on targeted immune modulators,22 an updated search was carried out in Ovid Medline from January 2011 through June 7, 2019. Following the identification of high-quality SRs from the Ovid Medline results, Embase was then searched with specific date limits according to indication area already addressed in the identified SRs (from 2017 onward for CD and UC, from 2016 onward for PsO and PsA, and from 2011 onward for RA, AS, and JIA). The complete search strategies and terms are available in Appendix B. At the time of the literature search undertaking, upadacitinib was not yet approved so was not included in the search strategy. Following its approval in August, information for this medication was added based on the product labeling information and a non-systematic PubMed search (only using free text for the drug). Authors additionally screened the reference lists of related systematic reviews and other relevant websites for further information:

1. For guidelines addressing PsO, PsA, RA, JIA, AS, CD, and UC: websites of the American Academy of Dermatology, National Psoriasis Foundation, American College of Rheumatology, National Institute for Health and Care Excellence, American College of Gastroenterology, American Gastroenterological Association

2. For FDA-approved prescribing information: the US FDA website, Drugs@FDA: FDA Approved Drug Products

3. Evidence-based drug information databases: Micromedex, Lexicomp, and UpToDate

Screening

At least 2 review authors screened titles and abstracts. Conflicts were resolved via discussion between reviewers. The full texts for all citations receiving 2 inclusion votes were retrieved; inclusion was determined by the lead author. Figure 1 on page 56 shows the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) flow chart23 for the review process.

Inclusion and Exclusion Criteria

Systematic reviews of RCTs providing head-to-head efficacy or safety comparisons among the cytokine inhibitors listed in Table 1 were included. For product comparisons where a systematic review provided robust data, we examined additional systematic reviews published after the search date of the robust systematic review. Network meta-analyses (NMA) including standard pairwise meta-analyses of a cytokine inhibitor vs. another were included; however, the indirect- or mixed-treatment effect summary outcomes from the NMA were not included.

Excluded references met the following criteria: 1) Review articles not using systematic review methodology, 2) Network meta-analyses including indirect comparisons only, or 3) SRs comparing cytokine inhibitors vs. placebo or conventional/traditional non-biologic DMARDs. A list containing the excluded references is provided in Appendix C.

14

Disease Overview and Guideline Recommendations There are many immune-mediated diseases characterized by inflammatory processes and abnormal immune system activity. These may include psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, juvenile idiopathic arthritis, Crohn´s disease, and ulcerative colitis. Following there is information related to the disease states of interest for this drug class review as well as guideline recommendations.

A. Psoriasis Psoriasis is a chronic, immune-mediated, inflammatory disease primarily characterized by skin and joint symptoms.24 Typical skin manifestations include “scaly, erythematous patches, papules, and plaques” that may cause pain, itch, burning sensation, and bleeding.24-26 These signs mainly appear on the scalp, trunk, buttocks, elbows, and knees.24 Psoriasis can cause visible disfiguration that usually affects the patient’s psychological quality of life.24,25

Epidemiology, Risk Factors, and Co-morbidities

In 2013, approximately 7.4 million US adults (3.2% of US adults) had psoriasis.27,28 The estimated prevalence of psoriatic arthritis among patients with psoriasis ranges from 6% to 41%.29 Psoriasis is more common in adults compared to children.30,31 The exact cause of psoriasis is unknown; however, immune system, genetic, and environmental factors play an important role in the development of psoriasis.24,32 T helper cells (eg, IL-17A-secreting T helper cell) have been associated with psoriatic skin inflammation because they release cytokines that cause skin cell growth and redness due to angiogenesis in the psoriatic plaque.33,34 A family history of psoriasis has been identified in approximately 40% of people with psoriasis and psoriatic arthritis.33 Many immune-related genes have been strongly associated with psoriasis.24 Of them, PSORS1, a psoriasis-susceptibility locus on chromosome 6p21, is considered the major genetic risk factor for early-onset psoriasis.24,33 Other triggering factors associated with the development or exacerbation of psoriasis include trauma, obesity, infection (eg, Streptococcal infections), stress, medications (eg, beta-blockers, lithium, and some antibiotics), smoking, and alcohol consumption.26 Medical comorbidities commonly occurring in patients with psoriasis may include psoriatic arthritis, cardiovascular disease, metabolic syndrome, depression, anxiety, suicide, obesity, and inflammatory bowel syndrome.24,26

Classification of Psoriasis

Psoriasis can be classified in different categories based on morphologic descriptions of skin lesions.24 However, based on clinical findings, patients can fall into more than 1 category.24 These major morphological categories include: 1) plaque psoriasis (also called psoriasis vulgaris), 2) inverse psoriasis (ie, intertriginous/flexural psoriasis), 3) erythrodermic psoriasis, 4) pustular psoriasis (eg, palmoplantar pustulosis and generalized pustular psoriasis), 5) guttate psoriasis, 6) nail psoriasis, and 7) psoriatic arthritis.24,26 Plaque psoriasis is the most common type of psoriasis, accounting for approximately 80% to 90% of cases.24,25 It is characterized by “monomorphic, sharply demarcated erythematous plaques covered by silvery lamellar scales” that can affect small parts of the body, large parts of the body, or the entire body surface (also called erythroderma, a potentially life-threatening complication of psoriasis).25 Frequent locations of plaque psoriasis are knee, elbows, scalp, peri-umbilical, perianal, and retro-auricular regions.25 The scalp is generally affected in 75% to 90% of the patients.25

15

Diagnosis

Diagnosis of psoriasis is usually based on family history and physical examination of several body regions such as scalp, nails, and anogenital region.25,26,33 The patient’s new medication and infections should be evaluated for a potential contribution to psoriasis.25,33 Skin biopsy is rarely performed.25

Psoriasis Severity

Severity of the psoriasis and efficacy of psoriasis treatment can be assessed with different rating scales such as the Psoriasis Area and Severity Index (PASI).24 PASI evaluates the severity (thickness, redness, and scaling) of skin lesions and extent of body surface area (BSA) affected.35 PASI score ranges from 0 (no disease) to 72 (maximal disease). This assessment tool is frequently used in clinical trials; however, it is rarely utilized in clinical practice.24,27 The percentage of BSA involved and Physician’s global assessment (PGA) are other frequently utilized assessment tools to evaluate psoriasis severity.24 PGA is an easier-to-use tool developed for clinical practice where the physician ranks 3 severity signs of psoriatic lesions (thickness, redness, and scaling) as cleared, minimal, mild, moderate, or severe.24-26 Impact of psoriasis on quality of life can be measured with several instruments such as the Short-Form 36 Health Survey (SF-36), Psoriasis Quality of Life (PQOL), or Dermatology Life Quality Index (DLQI).24,36

According to the severity of disease, psoriasis is commonly classified into 3 categories as mild, moderate, and severe or into 2 categories (for treatment purposes) as mild psoriasis (“limited” disease that is managed with topical therapies) and moderate to severe psoriasis (“extensive” disease that is managed with phototherapy or systemic therapy).37-39 Disease classification by severity is challenging due to the variety of objective features that should be considered (eg, severity of lesions, areas affected, extension of the area affected, and symptoms) and the subjective impact of psoriasis in each person.26,40

Specific definitions of disease severity vary in the literature; there are no formal definitions.29,40,41 The Medical Advisory Board of the NPF and the American Academy of Dermatology (AAD) propose definitions for the 3 disease categories based on the affected BSA, location of areas involved, and impact on quality of life.27,40 Overall, BSA measurement should not be used alone to evaluate the severity of psoriasis because there may be patients with small BSA affected who have severe psoriasis or patients with large BSA affected who have mild psoriasis.27,40 Table 3 includes definitions for mild, moderate, and severe psoriasis proposed by the NPF, the AAD, a European consensus, and the North American Psoriasis Guidelines. In addition, treatment options for each disease state are included.

Treatment Strategies

Psoriasis is a chronic disease with no cure; however, several treatment strategies are available to control symptoms and improve the patient’s quality of life,25 including topical agents (eg, anthralin, vitamin D derivatives, vitamin A derivatives, and topical steroids), phototherapy, systemic oral therapies (eg, acitretin, apremilast, cyclosporine, methotrexate, and systemic steroids), and injectable biologic agents (eg, the TNF-alpha inhibitors, certolizumab pegol, etanercept, adalimumab, and infliximab; the IL-12/23 inhibitors, ustekinumab; the IL-17 inhibitors, secukinumab, brodalumab, and ixekizumab; and the IL-23 inhibitors, guselkumab, risankizumab-rzaa, and tildrakizumab-asmn).31,42,43 Table 4 contains the FDA-approved indications and dosing recommendations for the self-administered cytokine inhibitors indicated for the treatment of plaque psoriasis.

16

Table 3. Proposed Definitions for Psoriasis Severity and Treatment Options in Plaque Psoriasis

Disease Severity

Definitions by the Medical Advisory Board of the NPF40

Definitions by the AAD27

Definitions by a European

Consensus44

Definitions by the North American Psoriasis Guideline35a

Treatment Options24

Mild plaque

psoriasis

- QoL is not altered - Patient may not require

treatment - Treatment has no known

serious risks to patients - Affected BSA is generally <5%

BSA <3%

BSA ≤10 and PASI ≤10 and DLQI ≤10 (If DLQI >10, psoriasis can be considered as moderate to severe)

- Minimal impact on the patient’s QoL

- Symptomatic control by routine skin care measures and/or topical therapy

Topicals (as monotherapy or in combination)45 If patients do not respond to topical therapy, phototherapy or systemic agents may be needed46

Moderate plaque

psoriasis

- QoL is altered - Patient expects that treatment

will improve quality of life - Affected BSA: 2 to 20% - Treatment options have low

risks; however, they may be inconvenient, expensive, and time-consuming

BSA: 3%-10%

BSA >10 or PASI >10 and DLQI >10 (If DLQI <10, psoriasis can be considered as mild)

- QoL is significantly altered because of the extent of the disease, physical distress, or location (eg, face, hands, feet, or genitals)

- Disease is not controlled to an acceptable degree by routine skin care measures

- Topical agents as adjunct therapy

- Phototherapy (eg, narrow-band UVB)

- Photochemotherapy with PUVA

- Traditional systemic agents (Oral)

- Biologic agents (Injectable)

Severe plaque

psoriasis

- QoL is altered - Affected BSA is generally >10% - Disease does not respond to

treatment with low risks - Patients are willing to accept

more aggressive therapies to improve the disease

- Other factors to consider: disease location (face, feet, hands, etc.), symptoms (pain, intense itching, bleeding, etc.), or presence of arthralgias/arthritis

- BSA >10% - Involvement

of small crucial areas (eg, hands, feet, face, or genitals), OR

- Serious emotional consequences

- Severe reduction of the patients QoL

- Disease is not satisfactorily controlled by topical therapy

Abbreviations: AAD, American Academy of Dermatology; AE, adverse events; BSA, body surface area; DLQI, dermatology life quality index; NPF, National Psoriasis Foundation; PASI, psoriasis area and severity index; PUVA, psoralen plus UVA; QoL, quality of life; UVA, ultraviolet A; UVB, ultraviolet B a Canadian Guidelines updated by the NPF

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Table 4. FDA-Approved Cytokine Inhibitors for Plaque Psoriasis1-6,11,15,16,18,19

Generic Name Brand Name

(Approval Date) MOA

Plaque Psoriasis Labeled Indication Dosing Recommendations for Plaque Psoriasis (SQ & PO)a


(2002)

TNF-alpha blocker

Moderate-to-severe PsO: For the treatment of adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate

80 mg (initial dose) followed by 40 mg every other week (starting one week after the initial dose)

Apremilast Otezla (PO)

(2014)

PDE-4 inhibitor

Moderate-to-severe PsO: For the treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy

To reduce risk of gastrointestinal symptoms, titrate (in a 5-day schedule) to the recommended dose of 30 mg twice daily

Brodalumab Siliq (SQ)

(2017)

IL-17 receptor A antagonist

Moderate to severe PsO in adults who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies

210 mg (SQ) at weeks 0, 1, and 2 followed by 210 mg every 2 weeks

Certolizumab Pegol

Cimzia (SQ) (2008)

TNF-alpha blocker

Moderate-to-severe PsO in adults who are candidates for systemic therapy or phototherapy

400 mg every other week. In patients with body weight ≤ 90 kg, 400 mg can be given initially and at week 2 and 4, followed by 200 mg every other week

Etanercept Enbrel (SQ)

(1998)

TNF-alpha blocker

Chronic moderate to severe PsO in patients 4 years and older who are candidates for systemic therapy or phototherapy

Adults: 50 mg twice weekly for 3 months (starting dose) followed by a maintenance dose of 50 mg once weekly Pediatric patients: ≥ 63 kg 50 mg weekly < 63 kg 0.8 mg/kg weekly

Guselkumab Tremfya (SQ)

(2017)

IL-23 blocker


100 mg at week 0, week 4, and every 8 weeks thereafter

Ixekizumab Taltz (SQ)

(2016)

IL-17A antagonist


160 mg (two 80 mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10 and 12, then 80 mg every 4 weeks

Ixekizumab may be administered with or without conventional DMARDs

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Table 4. FDA-Approved Cytokine Inhibitors for Plaque Psoriasis1-6,11,15,16,18,19 Generic Name Brand Name

(Approval Date) MOA

Plaque Psoriasis Labeled Indication Dosing Recommendations for Plaque Psoriasis (SQ & PO)a

Risankizumab-rzaa

Skyrizi (SQ) (2019)

IL-23 antagonist


150 mg (as two 75 mg SQ injections) at week 0, 4, and every 12 weeks thereafter


(2015)

IL-17A receptor inhibitor

Moderate to severe PsO in adults who are candidates for systemic therapy or phototherapy

PsO: 300 mg at week 0, 1, 2, 3, and 4 followed by 300 mg every 4 weeks

Tildrakizumab-asmn

Ilumya (SQ) (2018)

IL-23 antagonist


100 mg at week 0, 4, and every 12 weeks thereafter

Ustekinumab Stelara (SQ, IV)

(2009)

IL-12 and -23 antagonist

Moderate to severe PsO in adults and adolescents 12 years or older who are candidates for phototherapy or systemic therapy

PsO (adult), SQ Weight ≤100 kg 45 mg initially and 4

weeks later, followed by 45 mg every 12 weeks

Weight > 100 kg 90 mg administered initially and 4 weeks later, followed by 90 mg every 12 weeks

PsO (adolescent, ≥12 years), SQ

Weight < 60 mg 0.75 mg/kg Weight 60 kg to 100 kg

45 mg

Weight > 100 kg 90 mg

Abbreviations: DMARD, disease modifying anti-rheumatic agent; IV intravenous; MOA, mechanism of action; PDE, Phosphodiesterase; PO, oral; PsO, Plaque Psoriasis; MTX, methotrexate; SQ, subcutaneous; TNF, tumor necrosis factor a See Table 1 and product labeling for more information regarding other indications

Guideline Recommendations Evidence-based guidelines on psoriasis management have been developed by several professional organizations including the American Academy of Dermatology (AAD), National Institute for Health and Clinical Excellence, National Psoriasis Foundation (NPF), and Canadian Dermatology Association.

19

According to the American Academy of Dermatology guidelines, topical medications are recommended as first line options for mild-to-moderate plaque psoriasis (eg, corticosteroids, vitamin D analogues, tazarotene).24 Approximately 70% to 80% of patients experience mild to moderate psoriasis and are adequately treated with topical medication.25,47 Moderate to severe disease should be managed with phototherapy (ie, use of ultraviolet radiation) and/or systemic agents (traditional oral systemic agents or biologic agents).45 Topical medication can be added to phototherapy or systemic agents in patients with moderate to severe disease.26,48 Overall, treatment begins with topical therapy and if clinical goals are not met, can progress to phototherapy (as monotherapy or in combination), and then traditional systemic agents or biologic agents (as monotherapy or in combination).24

The 2019 Joint AAD-NPF guideline on biologic agents recommends 3 TNF-alpha inhibitors (adalimumab, etanercept, and infliximab) and 7 interleukin inhibitors (brodalumab, guselkumab, ixekizumab, risankizumab, secukinumab, tildrakizumab, and ustekinumab), as monotherapy, for moderate to severe plaque psoriasis in adult patients. For the treatment of psoriasis (any severity) and concomitant psoriatic arthritis in adults, etanercept, adalimumab, ustekinumab, secukinumab, and ixekizumab are strongly recommended. Specific recommendations for one biologic agent over another are not provided.27

Regarding certolizumab, no specific recommendations are given in this guideline. Apremilast is FDA approved for moderate to severe plaque psoriasis; however, it is not included in this guideline because it is a non-biologic agent.27 Joint AAD-NPF guidelines for the management of psoriasis with non-biologics are expected to be published in the first quarter of 2020.49 In the pediatric population, evidence for the treatment of psoriasis with biologic agents is limited. Only 2 biologic agents are FDA approved for plaque psoriasis in this population. Etanercept is approved for plaque psoriasis in children 4 to 17 years and ustekinumab is approved for plaque psoriasis in adolescents 12 to 17 years.27

Selection of therapy for psoriasis should be individualized based on disease presentation, extent of lesions, response to prior treatments, quality of life concerns, side effects, patient preferences, convenience, and comorbidities (eg, cardiovascular disease, metabolic syndrome, and psychological or psychiatric disorders).24,25,45

Table 5 and 6 summarize guideline recommendations for the treatment of psoriasis with cytokine inhibitors.

Table 5. Guideline Recommendations for Cytokine Inhibitors in the Treatment of Moderate to Severe Psoriasis Professional Organization and Guidelines Recommendationsa American Academy of Dermatology • Joint AAD-NPF Guidelines of Care for the

Management and Treatment of Psoriasis with Biologics, 201927

- Agents recommended as monotherapy for moderate-to-severe plaque psoriasis • Strength of recommendation A: etanercept, adalimumab,

infliximab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, and tildrakizumab

• Strength of recommendation B: risankizumab - Agents recommended as monotherapy for psoriasis (any

severity), if associated with significant psoriatic arthritis (Strength of Recommendation A): etanercept, adalimumab, ustekinumab, secukinumab, and ixekizumab

National Institute for Health and Clinical Excellence • Psoriasis: assessment and management;

2012 (revised in September 2017)50

- Systemic biologic agents (eg, TNF antagonists and interleukin inhibitors) are recommended as third-line after trying topical therapy (first line), phototherapy or systemic non-biological agents (second-line)

20

Table 5. Guideline Recommendations for Cytokine Inhibitors in the Treatment of Moderate to Severe Psoriasis Professional Organization and Guidelines Recommendationsa Canadian Dermatology Association • 2016 Addendum to the Canadian

Guidelines for the Management of Plaque Psoriasis, 200951

• Canadian Guidelines for the Management of Plaque Psoriasis, 200952

- Adalimumab, etanercept, infliximab, and alefacept are recommended for moderate-to-severe plaque psoriasis (Level of Evidence 1++)

- Ustekinumab was added as a new recommended agent (Level of Evidence 1+) in the 2016 update

Abbreviations: AAD-NPF, American Academy of Dermatology/National Psoriasis Foundation aClinical recommendations are as follows: A: Recommendation based on consistent and good quality patient-oriented evidence. B: Recommendation based on inconsistent or limited-quality patient-oriented evidence. 1++, High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias. 1+, Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias.

Table 6. Summary of Recommended Options and Strength of Evidence for Monotherapy Treatment of Moderate-to-Severe Psoriasis in Adults (as Reported by the 2019 Joint AAD/NPF Guideline on Biologic Agents)27,a Drug Name Moderate to

Severe Plaque Psoriasis

Palmoplantarf Scalpg Nailsh Other Subtypes (Pustular or Erythrodermic)

Plaque Psoriasis of any Severity if Associated with Psoriatic Arthritis

Etanercept A - A A B A Adalimumab A A B A B A Ustekinumab A B C B C A Secukinumab A A B A B (pustular)/C

(erythrodermic) A

Ixekizumab A - B B B A Guselkumab A A A A - - Brodalumabb A - - - B (just pustular) - Tildrakizumabc A - - - - - Certolizumabd - - - - - - Risankizumabe B - - - - - Abbreviations: AAD-NPF, American Academy of Dermatology/National Psoriasis Foundation; FDA, U.S. Food and Drug Administration a Clinical recommendations are as follows:

A: Recommendation based on consistent and good quality patient-oriented evidence B: Recommendation based on inconsistent or limited-quality patient-oriented evidence C: Recommendation based on consensus, opinion, case studies, or disease-oriented evidence.

b FDA indication for the treatment of moderate-to-severe psoriasis in adult patients who are candidates for systemic therapy or monotherapy and have failed to respond or lost response to other systemic therapies c FDA approval received 3/21/2018 d Phase III trials completed recently at the time of guideline publication. No specific recommendations concerning certolizumab in the guidelines e FDA approval was still pending at the time of guideline publication. FDA approval received in 4/23/2019 f Plaque psoriasis affecting the palms and soles g Plaque psoriasis affecting the scalp h Plaque psoriasis affecting the nails (-) denotes that the guidelines did not specify a recommendation for a particular indication

21

B. Psoriatic Arthritis Psoriatic arthritis (PsA) is a chronic inflammatory condition affecting joints and skin that may lead to disability and decreased quality of life. It is associated with psoriasis and typically characterized by peripheral arthritis, dactylitis, enthesitis, and spondylitis.53 The estimated prevalence of PsA is 1 to 2 per 1,000 in the overall population.53 According to the American College of Rheumatology/National Psoriasis Foundation (ACR/NPF), approximately 6 to 41% of patients with psoriasis develop PsA.53 The majority of patients with PsA (80-90%) experience nail lesions. Skin symptoms usually occur before the arthritis; however, some patients experience skin and joint symptoms at the same time and some experience arthritis first (10-15%). PsA is a heterogeneous disease that may affect ≤ 4 joints (asymmetric oligoarthritis) or ≥ 5 joints (symmetric polyarthritis). Some patients only experience distal interphalangeal joint damage. Others have axial disease together with peripheral arthritis. Early diagnosis and treatment is key to ameliorate long-term outcomes.53

Treatment options for psoriatic arthritis aim to reduce signs and symptoms, decrease disease activity, and achieve remission of disease.53 They can be broken up into nonpharmacological and pharmacological interventions. Nonpharmacological treatment includes physical therapy, occupational therapy, smoking cessation, weight loss, massage therapy, and exercise. Pharmacotherapies comprise symptomatic treatment for the acute management of symptoms (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], systemic glucocorticoids, and local glucocorticoid injections) and immunomodulatory therapy for long-term management. Immunomodulatory agents include the following:53

• Oral small molecules (OSM): methotrexate, sulfasalazine, cyclosporine, leflunomide, and apremilast

• TNF inhibitors: etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol • IL-12/23 inhibitors: ustekinumab • IL-17 inhibitors: secukinumab, ixekizumab, and brodalumab • Cytotoxic T lymphocyte antigen (CTLA)4-immunoglobulin: abatacept • Janus kinase (JAK) inhibitors: tofacitinib

Regarding the 2018 ACR/NPF guideline for the treatment of psoriatic arthritis, the panel of experts considered the following endpoints as clinically important when comparing therapies: 1) the American College of Rheumatology 20% response criteria (ACR20; primary composite endpoint mostly utilized in PsA clinical trials), 2) the Health Assessment Questionnaire disability index (HAQ-DI; a tool to assess physical functioning), 3) Psoriasis Area and Severity Index 75% response criteria (PASI 75; a measure of skin symptom improvements), and 4) serious infections.54 An ACR20 response represents an improvement of 20% or more in the number of tender and swollen joints, together with an improvement of 20% or more in at least 3 of the following 5 measures: patient’s global assessment of disease activity, patient´s assessment of pain, patient´s assessment of physical function, physician’s global assessment of disease activity, and the erythrocyte sedimendation rate or C-reactive protein (CRP) level.55

Table 7 contains the specific FDA-approved indications and dosing recommendations pertaining to the treatment of psoriatic arthritis for the self-administered cytokine inhibitors.

22

Table 7. FDA-Approved Cytokine Inhibitors for Psoriatic Arthritis3-5,7,9,15-19 Generic Name Brand Name

(Approval Date) MOA

Psoriatic Arthritis Labeled Indication Dosing Recommendations for Psoriatic Arthritis (SQ & PO)a

Abatacept Orencia (SQ, IV)

(2005)

Selective T cell co-stimulation modulator

Active PsA in adults PsA: 125 mg once weekly


(2002)

TNF-alpha blocker

Active PsA

“For reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adults with active PsA

PsA: 40 mg every other week


(2014)

PDE-4 inhibitors

Active PsA in adults To reduce risk of gastrointestinal symptoms, titrate (in a 5-day schedule) to the recommended dose of 30 mg twice daily

Certolizumab Pegol

Cimzia (SQ) (2008)

TNF-alpha blocker

Active PsA in adults

400 mg initially and at week 2 and 4, followed by 200 mg every other week (recommended dose). Maintenance dosing is 400 mg every 4 weeks


(1998)

TNF-alpha blocker

PsA: For reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with PsA (with or without MTX)

Adults: PsA: 50 mg weekly


(2009)

TNF-alpha blocker

Active PsA with or without concomitant MTX 50 mg once monthly with or without MTX


(2016)

IL-17A antagonist


160 mg (two 80 mg injections) at week 0, followed by 80 mg every 4 weeks. If coexistence of PsA and moderate-to-severe PsO, use the dosing regimen for PsO

Ixekizumab may be administered with or without conventional DMARDs

23

Table 7. FDA-Approved Cytokine Inhibitors for Psoriatic Arthritis3-5,7,9,15-19 Generic Name Brand Name

(Approval Date) MOA

Psoriatic Arthritis Labeled Indication Dosing Recommendations for Psoriatic Arthritis (SQ & PO)a


(2015)



PsA in patients with coexistent moderate to severe PsO, dose according to PsO. For PsA in other patients, administer with or without a loading dose:

- Loading dose regimen: 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter

- Without loading dose: 150 mg every 4 weeks

- In non-responding patients, consider a dosage of 300 mg

Tofacitinib Xeljanz (PO)

(2012) Xeljanz XR (PO)

(2016)

Janus Associated Kinase Inhibitor

Active PsA in adults who have had an inadequate response or intolerance to MTX or other DMARDs

PsA (in combination with nonbiologic DMARD): Xeljanz 5 mg twice daily or Xeljanz XR 11 mg once daily Do NOT administer if ALC < 500 cells/mm3, ANC 1000 cells/mm3, or hemoglobin <9 g/dL; dosage adjustment may be necessary for renal/hepatic impairment


(2009)

IL-12 and -23 antagonist

Active PsA in adults (with or without MTX)

45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. Patients with coexisting moderate to severe PsO and weight > 100 kg, use PsO dosage recommendations for adults

Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; DMARD, disease modifying anti-rheumatic agent; IV intravenous; MOA, mechanism of action; PDE, Phosphodiesterase; PsO, plaque psoriasis; MTX, methotrexate; PO, oral; PsA, psoriatic arthritis; SQ, subcutaneous; TNF, tumor necrosis factor a See Table 1 and product labeling for more information regarding other indications

Guideline Recommendations

Evidence-based guidelines on the management of psoriatic arthritis (PsA) have been developed by several professional organizations including the American College of Rheumatology (ACR), National Psoriasis Foundation (NPF), European League Against Rheumatism (EULAR), and American Academy of Dermatology (AAD).

The 2018 ACR/NPF guideline on PsA specifies the place in therapy for agents in treatment-naïve and treatment-experienced patients with active psoriatic arthritis; however, most preferences are based on very low to low-quality evidence. Active psoriatic arthritis is defined as “disease causing symptoms at an unacceptably bothersome level as reported by the patient, and judged by the examining clinician to be due to PsA based on ≥1 of the following: swollen joints, tender joints, dactylitis, enthesitis, axial disease, active skin and/or nail involvement, and extraarticular inflammatory manifestations such as uveitis or inflammatory bowel disease (IBD).”53

24

In patients treatment-naïve to oral small molecules (OSMs), TNF inhibitors, IL-17 inhibitors, or IL-12/23 inhibitors, low-quality evidence suggests the use of a TNF inhibitor (etanercept, infliximab, adalimumab, golimumab, or certolizumab pegol) over OSMs (methotrexate, sulfasalazine, cyclosporine, leflunomide, or apremilast) as first-line. OSMs may be used in specific situations (eg, patients without severe PsA and PsO, preference for oral therapy, or contraindication to TNF inhibitors). Based on very low-quality evidence (expert opinion), TNF inhibitors or OSMs are recommended over IL-17 inhibitors (eg, secukinumab and ixekizumab) or IL-12/23 inhibitors (ustekinumab). IL-17 or IL-12/23 inhibitors may be used over TNF inhibitors if severe psoriasis or a contraindication to TNF inhibitors exists. IL-17 or IL-12/23 inhibitors may be used over OMSs if severe psoriasis or severe PsA. Based on very low-quality evidence (expert opinion), IL-17 inhibitors are recommended over IL-12/23 inhibitors, unless concomitant IBD or a preference for less frequent administration exists.53

In treatment-experienced patients, multiple switching options are provided. In OMS-experienced patients, low- to moderate-quality evidence suggests switching to a TNF inhibitor over a different OSM, IL-17 inhibitor, IL-12/23 inhibitor, abatacept, or tofacitinib. Based on low- to moderate-quality evidence, switching to IL-17 inhibitors over a different OSM, IL-12/23, abatacept, or tofacitinib is recommended. Based on low-quality evidence, switching to IL-12/23 inhibitors over a different OSM, abatacept, or tofacitinib is recommended. In TNF inhibitor-experienced patients, low to very low-quality evidence suggests switching to a different TNF inhibitor over IL-17 inhibitor, IL-12/23 inhibitor, abatacept, tofacitinib, or adding methotrexate. Switching to IL-17 inhibitors is preferred over switching to IL-12/23, abatacept, or tofacitinib. Switching to IL-12/23 inhibitors is preferred over abatacept or tofacitinib. In IL-17 inhibitor-experienced patients, very low-quality evidence suggests switching to a TNF inhibitor over an IL-12/23 inhibitor, a different IL-17 inhibitor, or adding methotrexate. In IL-12/23 inhibitor-experienced patients, very low-quality evidence suggests switching to a TNF inhibitor over an IL-17 inhibitor or adding methotrexate. Alternative options may be considered in certain situations (eg, severe psoriasis, contraindication to TNF inhibitors, concomitant IBD, or a preference for oral therapy or less frequent subcutaneous administration).53

Evidence suggesting the efficacy of potential combination therapies of these drug categories versus monotherapy is limited and no strong recommendations are stated.53

The European League Against Rheumatism (EULAR) recommends the use of TNF inhibitors over other biologics for the treatment of psoriatic arthritis, based on expert opinion. Authors highlight the lack of consistent, supporting head-to-head data among biologics.56

Overall, selection of therapy for psoriatic arthritis should be individualized based on disease severity, contraindications, patient preferences (oral versus injectable medication), concerns about starting a biologic first-line, convenience, and comorbidities (congestive heart failure, recurrent infections, demyelinating disease, IBD, or diabetes).53

Table 8 summarizes guideline recommendations for cytokine inhibitors in the treatment of psoriatic arthritis.

25

Table 8. Guideline Recommendations for Cytokine Inhibitors in the Treatment of Psoriatic Arthritis Professional

Organization and Guidelines

Statementsa

American College of Rheumatology and National Psoriasis Foundation (ACR/NPF) • 2018 American

College of Rheumatology/ National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis53

Active PsA in Treatment-Naïve Patients All of the following recommendations supporting one drug class (eg, TNFi, IL-12/IL-23, IL-16, or OSM) over another are conditional recommendations based on low- to very low-quality evidence: • Treat with a TNFi over an OSM (LOE low). An OSM may be considered first in specific

situations (patient without severe PsA or severe psoriasis, preference for oral therapy, concerns regarding the use of biologics first, contraindications to TNFi such as congestive heart failure, recurrent or prior serious infections, and demyelinating disease)

• Treat with a TNFi over an IL-17i (LOE Very low). An IL-17i may be considered first in specific situations (patient with severe psoriasis or contraindications to TNFi)

• Treat with a TNFi over an IL-12/23i (LOE Very low). An IL-12/23i may be considered first in specific situations (patient with severe psoriasis, preference for less frequent administration, or contraindications to TNFi)

• Treat with an OSM over an IL-17i (LOE Very low). An IL-17i may be considered if severe psoriasis or severe PsA is present

• Treat with OSM over an IL-12/23i (LOE Very low). An IL-12/23i may be considered if the patient has concomitant IBD and/or severe psoriasis and/or severe PsA, or prefers less frequent administration

• Treat with an IL-17i over an IL-12/23i (LOE Very low). An IL-12/23i may be considered if the patient has concomitant IBD or prefers less frequent administration

Active PsA Despite Treatment with an OSM All of the following are conditional recommendations based on moderate- to very low-quality evidence: • Switch to TNFi over a different OSM, IL-17i, or IL-12/23i (LOE Moderate) • Switch to an IL-17i over an IL-12/23i (LOE Moderate) • Switch to a TNFi over abatacept or tofacitinib (LOE Low) • Switch to an IL-17i over a different OSM, abatacept, or tofacitinib (LOE Low) • Switch to an IL-12/23i over a different OSM, abatacept, or tofacitinib (LOE Low) • Add APR to current OSM therapy over switching to APR (LOE Low) • Switch to another OSM (except APR) over adding another OSM (except APR) to current

treatment (LOE Low) • Switch to a TNFi monotherapy over MTX and a TNFi combination therapy (LOE Low) • Switch to IL-17i monotherapy over MTX and an IL-17i combination therapy (LOE Very

Low) • Switch to IL-12/23i monotherapy over MTX and an IL-12/23i combination therapy (LOE

Very Low) Active PsA Despite Treatment with a TNFi as Monotherapy or Combination Therapy All of the following are conditional recommendations based on low- to very low-quality evidence: Active PsA despite treatment with TNFi monotherapy • Switch to a different TNFi over an IL-17i, IL-12/23i, abatacept, or tofacitinib (LOE Low) • Switch to a different TNFi over adding MTX to current therapy (LOE Very Low) • Switch to an IL-17i over an IL-12/23i, abatacept, tofacitinib (LOE Low) • Switch to an IL-12/23i over abatacept, tofacitinib (LOE Low) • Switch to a different TNFi over switching to a different TNFi and MTX combination

therapy (LOE Very Low)

26



Statementsa

• Switch to an IL-17i over switching to an IL-17i and MTX combination therapy (LOE Very Low)

• Switch to an IL-12/23i monotherapy over an IL-12/23i band MTX combination therapy (LOE Very Low)

Active PsA despite TNFi plus MTX combination therapy • Switch to a different TNFi plus MTX over a different TNFi monotherapy (LOE Very Low) • Switch to an IL-17i monotherapy over IL-17i and MTX combination therapy (LOE Very

Low) • Switch to an IL-12/23i monotherapy over IL-12/23i biologic and MTX combination

therapy (LOE Very Low) Active PsA Despite Treatment with an IL-17i as monotherapy All of the following are conditional recommendations based on very low-quality evidence: • Switch to a TNFi over an IL-12/23i or different IL-17i (LOE Very Low) • Switch to a TNFi over adding MTX to an IL17i (LOE Very Low) • Switch to an IL-12/23i over a different IL-17i (LOE Very Low) • Switch to an IL-12/23i over adding MTX to an IL-17i (LOE Very Low)

Active PsA Despite Treatment With an IL-12/23i as monotherapy All of the following are conditional recommendations based on very low-quality evidence: • Switch to a TNFi over an IL-17i (LOE Very Low) • Switch to a TNFi over adding MTX to an IL-12/23i (LOE Very Low) • Switch to an IL-17i over adding MTX to an IL-12/23i (LOE Very Low)

Active PsA and concomitant IBD Despite Treatment with an OSM • Strong recommendation to switch to a monoclonal antibody TNFi over a TNFi biologic

soluble receptor (etanercept) (LOE Moderate) • Strong recommendation to switch to a TNFi monoclonal antibody over an IL-17i (LOE

Moderate) • Strong recommendation to switch to an IL-12/23i over an IL-17i (LOE Moderate)

Active PsA and Frequent Serious Infections in Patients Who are Both OSM and Biologic Treatment Naïve • Strong recommendation to start an OSM over a TNFi biologic (LOE Moderate) • Conditional recommendation to start an IL-12/23i biologic over a TNFi biologic (LOE

Very Low) • Conditional Recommendation to start an IL-17i biologic over a TNFi biologic (LOE Very

Low) National Institute for Health and Care Excellence (NICE) • Spondyloarthritis in

over 16s: diagnosis and management; 201757

• Biological DMARDs (etanercept, infliximab, adalimumab, and golimumab) are recommended for active and progressive PsA in adults who have not responded adequately to at least 2 standard DMARDs. Treatment should usually begin with the least expensive agent

• Ustekinumab is recommended (as monotherapy or in combination with MTX) in adults for active PsA when TNFis are contraindicated

European League Against Rheumatism (EULAR) • European League

Against Rheumatism

• In patients with peripheral arthritis and an inadequate response to at least one csDMARD, therapy with a bDMARD, usually a TNFi, should be commenced (LOE 1b) o If TNFi are not appropriate, bDMARDs targeting IL12/23 or IL17 pathways may

be considered (LOE 1b) o If bDMARDs are not appropriate, a targeted synthetic DMARD such as a PDE4-

inhibitor may be considered (LOE 1b)

27



Statementsa

(EULAR) Recommendations for the Management of Psoriatic Arthritis with Pharmacological Therapies: 2015 Update, 201556

• In patients with active enthesitis and/or dactylitis and insufficient response to NSAIDs or local glucocorticoid injections, therapy with a bDMARD should be considered, which according to current practice is a TNFi (LOE 1b)

• In patients with predominantly axial disease that is active and has insufficient response to NSAIDs, therapy with a bDMARD should be considered, which according to current practice is a TNFi (LOE 1b)

• In patients who fail to respond adequately to a bDMARD, switching to another bDMARD should be considered, including switching between TNFi (LOE 1b)

British Society of Rheumatology (BSR) • The 2012 BSR and

BHPR guideline for the treatment of psoriatic arthritis with biologics, 201258

Peripheral Arthritis • Anti-TNF therapy should be considered for those patients with active arthritis who

have failed treatment with at least two conventional DMARDs. (Grade C) • Anti-TNF therapy may be considered for patients who have failed only one DMARD,

especially where there is evidence of any of the following adverse prognostic factors (Grade C)

• All of the licensed anti-TNF therapies are recommended for use in patients eligible for treatment and the choice of therapy should be left to the treating physician after considering concomitant medical problems, patient preference and cost-effectiveness. (Grade A)

• Anti-TNF therapies should be considered in patients with severe persistent oligoarthritis (fewer than three tender/swollen joints), which has a major demonstrable influence on well-being and who have failed treatment with at least two conventional DMARDs and appropriate intra-articular therapy (Grade C).

Axial Arthritis • Anti-TNF therapy should be considered for those patients with active axial PsA

In the case of failure of an anti-TNF treatment either due to inefficacy or adverse events, an alternative anti-TNF therapy should be considered and response to treatment assessed as for the first anti-TNF agent. (Grade B)

Abbreviations: APR, apremilast; bDMARD, biological agent DMARD; CSA, cyclosporine; csDMARD, conventional synthetic DMARD; DMARD, disease modifying antirheumatic drug (MTX, SSZ, LEF); IL-17i, interleukin 17 inhibitor; IL-23i, interleukin 23 inhibitor; IL-12, interleukin 12 inhibitor; JAK, janus kinase; LEF, leflunomide; LOE, level of evidence; MTX, methotrexate; NSAID, nonsteroidal anti-inflammatory drug; OSM, oral small molecule (refers to MTX, SSZ, LEF, CSA and APR); PDE, phosphodiesterase inhibitor; PsA, psoriatic arthritis; SSZ, sulfalazine; TNFi, tumor necrosis factor inhibitor; tsDMARD, targeted synthetic DMARD (PDE/JAK inhibitors) a Recommendation descriptions are as follows:

- ACR/NPF guideline: Level of Evidence (LOE): Moderate = Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low = Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low = Any estimate of effect is very uncertain.

- EULAR guideline - Level of Evidence (LOE): 1A - From meta-analysis of randomised controlled trials. 1B - From at least one randomised controlled trial.

- GRADE: A, Further research is very unlikely to change our confidence in the estimate of effect; several high-quality studies with consistent results. B, Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; one high-quality study or several studies with some limitations. C, Further research is very likely to have an important on our confidence in the estimate of effect and is likely to change the estimate; one or more studies with severe limitations

28

C. Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is a systemic autoimmune disease that causes inflammation and damage of the lining of joints in hands, wrists, and knees. RA also affects other organ tissues (eg, lungs, heart, and eyes), producing severe complications.59 The estimated number of American adults with RA is 1.3 million.60 Signs and symptoms of RA include joint pain, inflammation, stiffness, and tenderness, fever, fatigue, weight loss, and weakness. Diagnosis consists of symptom evaluation, physical examination, imaging (eg, X-ray or magnetic resonance imaging), and laboratory tests.59 According to the 2010 ACR and EULAR classification criteria, a patient is diagnosed with “definite RA” if there is “confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0–5), serologic abnormality (score range 0–3), elevated acute-phase response (score range 0–1), and symptom duration (2 levels; range 0–1).”61

The American College of Rheumatology classifies rheumatoid arthritis according to the duration of the disease or symptoms as early RA (less than 6 months) or established RA (6 months or longer).62 Disease activity is classified as low, moderate, or high based on validated scales such as patient activity scale (PAS), routine assessment of patient index data 3 (RAPID-3), clinical disease activity index (CDAI), and disease activity score 28 (DAS28). These scales can also be used to define disease remission.62 Common efficacy outcomes evaluated in clinical trials include the proportion of patients with at least 20%, 50%, or 70% improvement in the American College of Rheumatology criteria (ACR20, ACR50, or ACR70, respectively), disease activity score in 28 joints using the C-reactive protein level (DAS28-CRP), and Health Assessment Questionnaire–Disability Index (HAQ-DI). Radiographic damage progression, which correlates with disease activity, long-term disability, and efficacy of treatment, is occasionally evaluated.63

The goal of RA treatment is to improve signs, symptoms and physical function, achieve disease remission, and reduce disease activity and progression. Treatment approaches include agents to delay disease progression and prevent joint damage (ie, disease-modifying antirheumatic drugs [DMARDs]) and agents for symptom control such as non-steroidal anti-inflammatory drugs (NSAIDs). DMARDs indicated for RA include conventional synthetic DMARDs (methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide), targeted biologic DMARDs (TNF inhibitors such as etanercept, adalimumab, certolizumab pegol, golimumab, and infliximab; abatacept, rituximab, and the interleukin inhibitors, anakinra, sarilumab, secukinumab, and tocilizumab), and targeted oral small molecule DMARDs (baricitinib, tofacitinib, and upadacitinib).62 Table 9 provides the labeled indications and dosing recommendations pertaining to the treatment of RA for the self-administered cytokine inhibitors.

29

Table 9. FDA-Approved Cytokine Inhibitors for Rheumatoid Arthritis7-10,12,13,15-18,20 Generic Name Brand Name

(Approval Date) MOA

RA Labeled Indication Dosing Recommendations for RA (SQ & PO)a


(2005)


Moderately to severely active RA in adults (with or without DMARDs other than TNF antagonists)

RA: 125 mg once weekly


(2002)

TNF-alpha blocker

For reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adults with moderately to severely active RA

RA: 40 mg every other week; for RA without concomitant MTX, may increase dosage to 40 mg weekly

Anakinra Kineret (SQ)

(2001)

IL-1 receptor antagonist

Reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active RA, in adults who have failed 1 or more DMARDs

100 mg daily

Baricitinib Olumiant (PO)

(2018)

Janus kinase inhibitor

Moderately to severely active RA in adults who have had an inadequate response to one or more TNF antagonist therapies

2 mg once daily, with or without MTX or other DMARDs. Do NOT administer if ALC < 500 cells/mm3, ANC < 1000 cells/mm3, or Hgb < 8 g/dL; dosage adjustment may be necessary for renal/hepatic impairment


(2008)

TNF-alpha blocker

Moderately to severely active RA in adults

400 mg (as 2 SQ injections of 200 mg) initially and at week 2 and 4, followed by 200 mg every other week. Maintenance dosing: 400 mg every 4 weeks


(1998)

TNF-alpha blocker

For reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active RA (with or without MTX)

Adults: 50 mg weekly


(2009)

TNF-alpha blocker

For the treatment of adults with moderately to severely active RA (with concomitant MTX)

50 mg once monthly in combination with MTX

Sarilumab Kevzara (SQ)

(2017)

IL-6 receptor inhibitor

For treatment of adults with moderately to severely active RA who have had an inadequate response or intolerance to one or more DMARDs

200 mg every 2 weeks, with or without MTX or other conventional DMARDs. Do not start sarilumab in patients with an ANC < 2000/mm3, PLC < 150,000/mm3, or liver transaminases > 1.5 times the ULN

30

Table 9. FDA-Approved Cytokine Inhibitors for Rheumatoid Arthritis7-10,12,13,15-18,20 Generic Name Brand Name

(Approval Date) MOA

RA Labeled Indication Dosing Recommendations for RA (SQ & PO)a

Tocilizumab Actemra (SQ, IV)

(2010)


Moderate to severely active RA in adults who have had an inadequate response to one or more DMARDs

RA (SQ dosage with or without MTX or other non-biologic DMARDs) Weight < 100 kg

162 mg every other week, followed by an increase to every week based on clinical response

Weight ≥ 100 kg

162 mg every week

Tofacitinib Xeljanz (PO)

(2012) Xeljanz XR (PO)

(2016)

Janus associated kinase inhibitor

Moderately to severely active RA in adults who have had an inadequate response or intolerance to MTX. It may be used alone, with MTX, or with other nonbiologic DMARDs

Xeljanz: 5 mg twice daily Xeljanz XR: 11 mg once daily Do NOT administer or interrupt dosing if ALC < 500 cells/mm3, ANC < 1000 cells/mm3, or Hgb <8 g/dL; dosage adjustment may be necessary for renal/ hepatic impairment or drug-drug interactions

Upadacitinib Rinvoq XR (PO)

(2019)

Janus associated kinase

inhibitor

Moderately to severely active RA in adults who have had an inadequate response or intolerance to MTX. It may be used alone, with MTX, or with other nonbiologic DMARDs.

15 mg once daily Avoid initiation or interrupt dosing if ALC is <500 cells/mm3, ANC is <1000 cells/mm3, or Hgb is <8 g/dL

Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; DMARD, disease modifying anti-rheumatic drug; Hgb, hemoglobin; IL, interleukin; IV intravenous; MOA, mechanism of action; MTX, methotrexate; PLC, platelet count; PO, oral; RA, rheumatoid arthritis; SQ, subcutaneous; TNF, tumor necrosis factor; ULN, upper limit of normal; XR, extended release a See Table 1 and product labeling for more information regarding other indications


A wide variety of agents are available for the treatment of rheumatoid arthritis (RA). Guidelines recommend initiation of treatment as soon as RA is diagnosed. The 2015 American College of Rheumatology (ACR) guideline for RA provides recommendations based on disease duration, disease activity, and comorbidities. For patients with early RA or established RA and moderate or high disease activity despite treatment with a conventional disease modifying antirheumatic drugs (cDMARDs) such as methotrexate, it is strongly recommended the use of either a combination of cDMARDs, a TNF inhibitor, or a non-TNF biologic. Tofacitinib may be an additional option for patients with established RA. For patients with comorbidities, specific agents may be preferred (eg, use of a non-TNF biologic or tofacitinib over a TNF inhibitor for patients with congestive heart failure or use of abatacept over TNF inhibitors for patients with serious infections).62

31

Table 10. Guideline Recommendations for Biologics in the Treatment of Rheumatoid Arthritis Professional Organization

and Guidelines Recommendations

American College of Rheumatology (ACR) • 2015 American College

of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis62

Patients with symptomatic early RA (disease duration < 6 months) • For patients with moderate or high disease activity despite DMARD therapy

(with or without glucocorticoids), it is strongly recommended treatment with a combination of DMARDs (double or triple traditional/conventional DMARD therapy) OR a TNFi (adalimumab, certolizumab pegol, etanercept, golimumab, or infliximab) OR a non-TNF biologic (abatacept, rituximab, or tocilizumab [excludes anakinra]), with or without methotrexate (MTX) in no particular order of preference, rather than continuing DMARD monotherapy alone (Strong recommendation, LoE low)

• If disease activity remains moderate or high despite conventional DMARDs: - use a TNFi monotherapy over tofacitinib monotherapy (Strong

recommendation, LoE low) - use a TNFi plus MTX over tofacitinib plus MTX (Strong recommendation,

LoE low) Patients with established RA (disease duration ≥ 6 months) • For patients with moderate or high disease activity despite DMARD

monotherapy including methotrexate, it is strongly recommended using combination DMARDs or adding a TNFi or a non-TNF biologic or tofacitinib (all choices with or without methotrexate) in no particular order of preference, rather than continuing DMARD monotherapy alone (Strong recommendation, LOE moderate to very low)

• If disease activity is moderate or high despite single TNFi biologic therapy, we conditionally recommend:

- using a non-TNF biologic over another TNFi (Conditional recommendation, low to very low LOE)

- using a non-TNF biologic over tofacitinib (Conditional recommendation, LOE very low)

• If disease activity is moderate or high despite the use of multiple (2+) TNFi therapies (in sequence, not concurrently), non-TNF biologic therapy and then conditionally treating with tofacitinib when a non-TNF biologic is not an option (Conditional recommendation, LOE low)

• In patients with low disease activity but not remission, it is strongly recommended to:

- continue DMARD therapy - continue TNFi, non-TNF biologic, or tofacitinib rather than discontinuing

respective medication (Strong recommendation, LOE high to very low) Patients with congestive cardiac failure • In patients with moderate or high disease activity and New York Heart

Association (NYHA) class III or IV congestive heart failure (CHF), combination DMARD therapy, a non-TNF biologic, or tofacitinib rather than a TNFi is recommended (Conditional recommendation, LOE moderate to very low)

Patients with hepatitis B receiving/received effective antiviral treatment • Same recommendations as in patients without this condition (Strong

recommendation, LOE very low)

Patients with hepatitis C receiving/received effective antiviral treatment • Same recommendations as in patients without this condition (Conditional

recommendation, LOE very low)

32

Table 10. Guideline Recommendations for Biologics in the Treatment of Rheumatoid Arthritis Professional Organization

and Guidelines Recommendations

Patients previously treated for lymphoproliferative disorder • Use rituximab over TNFi (Strong recommendation. LOE - very low) • Use combination DMARD OR abatacept OR tocilizumab over TNFi

(Conditional recommendation, LOE very low)

Patients with previous serious infection • Use combination DMARD over TNFi. Use abatacept over TNFi (Conditional

recommendation, LOE very low) National Institute for Health and Care Excellence (NICE)

• Drug treatment for rheumatoid arthritis (last updated: July 2019)64

• Rheumatoid arthritis in adults: management (July 2018)43

• Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed (January 2016)65

• For patients with inadequate response to a combination of conventional DMARDs (oral methotrexate, leflunomide, sulfasalazine or hydroxychloroquine) and with severe RA (DAS28 > 5.1), a biologic agent (abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, sarilumab, or tocilizumab) or a targeted synthetic DMARD (baricitinib, tofacitinib) in combination with methotrexate is recommended. Adalimumab, etanercept, certolizumab pegol, sarilumab, tocilizumab, baricitinib, or tofacitinib can be used as monotherapy if methotrexate is contraindicated or due to intolerance.64

• Based on cost-effectiveness concerns, anakinra is not recommended for the treatment of RA, except in the context of a controlled, long-term clinical study64,66

• For adult patients with severe active RA who failed other DMARDs, including at least one TNFi, rituximab + MTX is recommended. If rituximab is not tolerated or contraindicated, adalimumab, etanercept, infliximab, sarilumab, or abatacept, each in combination with methotrexate, is recommended64

• The Committee concluded that the evidence did not suggest differential effectiveness between the biological DMARDs65

European League Against Rheumatism (EULAR) • EULAR

recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update67

• If the treatment target is not achieved with the first conventional synthetic DMARD (csDMARD) strategy (eg, methotrexate, leflunomide, sulfasalazine, hydroxychloroquine), when poor prognostic factors are present, addition of a biologic DMARD (bDMARD) or a targeted synthetic DMARD (tsDMARD; eg, tofacitinib, baricitinib) should be considered; current practice would be to start a bDMARD

• bDMARDs and tsDMARDs should be combined with a csDMARD; in patients who cannot use csDMARDs as comedication, IL-6 pathway inhibitors and tsDMARDs may have some advantages compared with other bDMARDs

• If a bDMARD or tsDMARD has failed, treatment with another bDMARD or a tsDMARD should be considered; if one TNF-inhibitor therapy has failed, patients may receive another TNF-inhibitor or an agent with another mode of action

Abbreviations: bDMARD, biologic DMARD; csDMARD, conventional DMARD; DAS, disease activity score; DMARD, disease modifying antirheumatic drug; TNF, tumor necrosis factor; tsDMARD, targeted synthetic DMARD

33

D. Ankylosing Spondylitis

Spondyloarthritis (SpA) includes several types of rheumatoid conditions characterized by inflammation and pain of different parts of the body (eg, back, extremities, entheses, and uvea).68-70 SpA is currently classified based on the clinical presentation as (1) axial SpA, if the spine, pelvis, and thoracic cage are predominantly affected or (2) peripheral SpA, if extremities are predominantly affected.57,71,72 Axial SpA is further classified into (1) non-radiographic axial SpA characterized by the absence of radiographic sacroiliitis (ie, inflammation of sacroiliac joints) and (2) radiographic axial SpA (also known as classic ankylosing spondylitis) characterized by the presence of radiographic variations in the sacroiliac joints.57,71-73 The estimated prevalence of axial SpA in adult Americans is between 0.9% and 1.4%.68 Ankylosing Spondylitis (AS) is the most common and widely studied type of SpA.69,74 It primarily affects the spine, particularly the sacroiliac joints;71,73,74 however, it can also affect other parts of the body such as shoulders, hips, ribs, hands, feet, eyes, bowel, heart, and lungs.75 Typical symptoms usually start in adolescence or early adulthood and include chronic back pain, inflammation, and stiffness.70,75 Disease progression may result in new bone formation and vertebral fusion, causing stiffness and loss of spinal mobility (ankylosis).70,71,74,75 The etiology of the disease is unknown. It is thought to relate to genetic factors. Around 70-90% of patients with either non-radiographic axial SpA or AS express the genetic marker, human leukocyte antigen B27 (HLAB27).71

Treatment strategies focus on relieving pain and stiffness, retaining spinal mobility, improving functional disability, reducing the risk of complications, and improving quality of life.76 Table 11 includes labeled indications and dosing recommendations for cytokine inhibitors FDA-approved for axial spondyloarthritis (ankylosing spondylitis and/or non-radiographic axial spondyloarthritis).

Table 11. Cytokine Inhibitors FDA-Approved for Axial Spondyloarthritis4,15-18 Generic Name Brand Name

(Approval Date) MOA

Spondyloarthritis Labeled Indication

Dosing Recommendations for Spondyloarthritis (SQ & PO)a


(2002)

TNF-alpha blocker

Reducing signs and symptoms in adults with active AS 40 mg every other week


(2008)

TNF-alpha blocker

Active AS in adults

Active non-radiographic axial spondyloarthritis with objective signs of inflammation in adults

AS and non-radiographic axial spondylarthritis: 400 mg (as 2 SQ injections of 200 mg) initially and at week 2 and 4, followed by 200 mg every other week or 400 mg every 4 weeks


(1998)

TNF-alpha blocker

For reducing signs and symptoms in patients with active AS Adults: 50 mg weekly


(2009)

TNF-alpha blocker

For the treatment of adults with active AS

50 mg once monthly with or without MTX or other DMARDs

34

Table 11. Cytokine Inhibitors FDA-Approved for Axial Spondyloarthritis4,15-18 Generic Name Brand Name

(Approval Date) MOA

Spondyloarthritis Labeled Indication

Dosing Recommendations for Spondyloarthritis (SQ & PO)a


(2015)


For the treatment of adults with active AS

Administer with or without a loading dose:

• Loading dose regimen: 150 mg at week 0, 1, 2, 3, and 4, and every 4 weeks thereafter

• Without a loading dose: 150 mg every 4 weeks

Abbreviations: AS, ankylosing spondylitis; IL, interleukin; MOA, mechanism of action; MTX, methotrexate; SQ, subcutaneous; TNF, tumor necrosis factor a See Table 1 and product labeling for more information regarding other indications


Evidence-based guidelines on the management of spondyloarthritis have been developed by several professional organizations including the American College of Rheumatology, the Assessments in Ankylosing Spondylitis International Society (ASAS), and the European League Against Rheumatism (EULAR). NSAIDs are the mainstay of pharmacological therapy for pain and stiffness relief in patients with AS.71,76 Biologic DMARDs such as the TNF inhibitors (adalimumab, certolizumab pegol, etanercept, and golimumab) or the IL-17A receptor inhibitor (secukinumab) are suggested as second-line therapy for AS.77 The 2015 ACR guideline on AS and nonradiographic axial SpA recommends the use of TNF inhibitors in patients with an inadequate response or intolerance to at least 2 different NSAIDs over 1 or 2 months.76 No recommendations are specified for the IL-17 inhibitor (secukinumab) because it was not available at the time of the 2015 ACR guideline publication. Due to the lack of head-to-head evidence, authors do not specify a preference for one TNF inhibitor over another in the overall population; 76 however, infliximab or adalimumab are preferred over etanercept for patients with concomitant inflammatory bowel disease or recurrent iritis. Certolizumab pegol is the only biologic agent FDA-approved for non-radiographic axial spondyloarthritis.16

The 2016 ASAS/EULAR guideline recommends the use of a TNF inhibitor over an IL-17 inhibitor for patients with persistently high disease activity who have not responded to conventional treatments. This recommendation is based on the volume and long-term efficacy and safety data available regarding the use of TNF inhibitors in axial SpA.77

35

Table 12. Guideline Recommendations for Biologics in the Treatment of Ankylosing Spondylitis and Spondyloarthritis

Professional Organization and Guidelines Recommendations

American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network • 2015 Recommendations

for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis76

Patients with active AS despite treatment with NSAIDs: • TNFi over no treatment with TNFi is strongly recommended • No particular TNFi is preferred, except infliximab or adalimumab that are

preferred over etanercept for patients with concomitant IBD or recurrent iritis • If AS remains active despite treatment with the first TNFi, switch to a different

TNFi (conditional recommendation) Patients with stable AS receiving treatment with TNFi and NSAIDs • TNFi monotherapy is recommended over continuing both treatments

(conditional recommendation)

Assessments in Ankylosing Spondylitis International Society (ASAS)/European League Against Rheumatism (EULAR) • 2016 update of the

ASAS-EULAR management recommendations for axial spondyloarthritis77

• bDMARDs (TNFi: adalimumab, certolizumab pegol, etanercept, golimumab, and infliximab; and IL-17i: secukinumab) are recommended for patients with persistently high disease activity despite conventional treatments (non-pharmacological treatment and NSAIDs in all patients, and injectable glucocorticoids and sulfasalazine in patients with peripheral arthritis). Current practice is to begin treatment with a TNFi, based on volume and time of follow-up of evidence available for TNFi compared to IL-17i

• There is a lack of head-to-head evidence supporting a difference in efficacy (musculoskeletal symptoms) of the various TNFis on axial SpA. However, some agents have demonstrated efficacy for certain extra-articular manifestations (infliximab, adalimumab, certolizumab, and golimumab are efficacious in patients with concomitant IBD and infliximab, adalimumab, and certolizumab are efficacious in preventing the recurrence of uveitis). Etanercept has no clear efficacy in IBD or uveitis

• If a patient has not responded to the first TNFi, switching to a second TNFi or IL-17i may be an option

National Institute for Health and Care Excellence (NICE) • Spondyloarthritis in over

16s: diagnosis and management; 201757

TNF-alpha inhibitors • Biological DMARDs (adalimumab, certolizumab pegol, etanercept, golimumab,

and infliximab) are recommended for treating severe active AS in adults who have not responded adequately or are intolerant to NSAIDs

• Adalimumab, certolizumab pegol, and etanercept are recommended for the treatment of severe non-radiographic axial SpA in adults who has not responded adequately or are intolerant to NSAIDs

• Selection of a TNFi should be made after discussion between the clinician and the patient about the benefits and risks of the treatments available

Interleukin inhibitors • Secukinumab is recommended for the treatment of AS when patients have not

responded adequately to NSAIDs or TNF-alpha inhibitors Abbreviation: AS, ankylosing spondylitis; bDMARD, biological disease-modifying antirheumatic drug; DMARD, disease modifying antirheumatic drug; IBD, inflammatory bowel disease; IL-17i, interleukin-17 inhibitor; NSAID, non-steroidal anti-inflammatory drug; SpA, spondyloarthritis; TNFi, tumor necrosis factor inhibitor

36

E. Juvenile Idiopathic Arthritis

Juvenile idiopathic arthritis (JIA), also called juvenile rheumatoid arthritis (JRA) or juvenile chronic arthritis (JCA), is one of the most frequently diagnosed form of childhood arthritis but overall is a rare disease.60,78,79 JIA is an umbrella term that includes all types of arthritis that start before the child is 16 years, last more than 6 weeks, and are of unknown origin.79-81 The estimated number of people in the US with juvenile arthritis is 294,000.60 Childhood arthritis may result in irreversible joint damage, disability, and reduced quality of life.78,80 Symptoms include joint pain, inflammation, fever, stiffness, rash, fatigue, loss of appetite, eye swelling, and difficulty in walking, playing, and dressing.78 According to the International League of Associations for Rheumatology (ILAR) classification criteria, there are 7 subtypes of JIA based on the number of joints affected, extraarticular manifestations (eg, uveitis), and markers such as rheumatoid factor (RF) and HLA-B27: (1) systemic arthritis, (2) oligoarthritis, (3) polyarthritis (RF negative), (4) polyarthritis (RF positive), (5) psoriatic arthritis, (6) enthesitis related arthritis, and (7) undifferentiated arthritis.81 Systemic JIA is defined by the ACR as “arthritis in ≥1 joint for at least 6 weeks' duration in a child age <16 years with or preceded by fever of at least 2 weeks' duration that is documented to be daily (“quotidian”) for at least 3 days and accompanied by one or more of the following: evanescent erythematous rash, generalized lymphadenopathy, hepatomegaly or splenomegaly, and serositis.”82 Polyarthritis (RF negative or positive) is defined as arthritis involving at least 5 joints during the first 6 months of disease.81 Diagnosis consists of symptom evaluation, physical examination, imaging (eg, X-ray or magnetic resonance imaging), and laboratory tests.39

The objective of pharmacological therapy in patients with JIA is to induce and preserve remission of symptoms, prevent irreversible joint damage, and improve the child´s quality of life.80 Treatment options are NSAIDs, oral and intraarticular glucocorticoids, non-biologic DMARDs, and biologic DMARDs.80 Five biologic DMARDs are currently available in the US for the treatment of JIA, including a T-cell costimulation modulator (abatacept), 2 TNF-alpha inhibitors (adalimumab and etanercept), and 2 interleukin inhibitors (canakinumab and tocilizumab). Abatacept, adalimumab, and etanercept are only approved for polyarticular JIA. Canakinumab is only approved for systemic JIA. Tocilizumab is approved for both polyarticular and systemic JIA. Table 13 includes labeled indications and dosing recommendations for the biologic agents FDA-approved for JIA.

Table 13. FDA-Approved Cytokine Inhibitors for the Treatment of Juvenile Idiopathic Arthritis9,13-15,18 Generic Name Brand Name

(Approval Date) MOA

JIA Labeled Indication Dosing Recommendations for JIA (SQ & PO)a


(2005)


Moderately to severely active polyarticular JIA in patients ≥ 2 years of age with or without MTX

JIA: 50 mg to 125 mg once weekly based on weight

37

Table 13. FDA-Approved Cytokine Inhibitors for the Treatment of Juvenile Idiopathic Arthritis9,13-15,18 Generic Name Brand Name

(Approval Date) MOA

JIA Labeled Indication Dosing Recommendations for JIA (SQ & PO)a


(2002)

TNF-alpha blocker

For reducing signs and symptoms of moderately to severely active polyarticular JIA in patients ≥ 2 years

JIA dosing weight based 10 kg to < 15 kg 10 mg every other week 15 kg to < 30 kg 20 mg every other week ≥30 kg 40 mg every other week

Canakinumab Ilaris (SQ)

(2009)

IL-1 β blocker

Active systemic JIA in patients ≥ 2 years

Patients with body weight ≥ 7.5 kg: 4 mg/kg every 4 weeks (maximum dosage 300 mg)


(1998)

TNF-alpha blocker

For reducing signs and symptoms of moderately to severely active polyarticular JIA in patients ≥ 2 years

Pediatric patients with JIA: ≥ 63 kg 50 mg weekly < 63 kg 0.8 mg/kg weekly

Tocilizumab Actemra (SQ, IV)

(2010)

IL-6 Receptor inhibitor

Active polyarticular JIA in patients ≥2 years

Active systemic JIA in patients ≥ 2 years

PJIA (SQ dosage with or without MTX) Weight < 30 kg 162 mg once every 3 weeks Weight ≥ 30 kg 162 mg once every 2 weeks SJIA (SQ dosage with or without MTX) Weight < 30 kg 162 mg every 2 weeks Weight ≥ 30 kg 162 mg every week

Abbreviations: IL, interleukin; IV intravenous; JIA, juvenile idiopathic arthritis; MOA, mechanism of action; MTX, methotrexate; PJIA, polyarticular JIA; SJIA, systemic JIA; SQ, subcutaneous; TNF, tumor necrosis factor a See Table 1 and product labeling for more information regarding other indications


The 2019 American College of Rheumatology/Arthritis Foundation guideline for juvenile non-systemic polyarthritis, sacroiliitis, and enthesitis generally recommends biologic treatments (adalimumab, etanercept, golimumab, abatacept, or tocilizumab) in combination with a DMARD for certain children and adolescents with JIA and polyarthritis.80 Initial therapy with biologics in JIA and polyarthritis may be considered for “patients with risk factors and involvement of high-risk joints (eg, cervical spine, wrist, or hip), high disease activity, and/or those judged by their physician to be at high risk of disabling joint damage.”80 TNF inhibitors are recommended for children and adolescents with JIA and active sacroilitis or enthesitis, despite having tried nonsteroidal anti-inflammatory drugs.80 This guideline does not specifically recommend one biologic agent over another due to the lack of head-to-head comparisons.80 The 2013 ACR guideline for the treatment of systemic JIA has anakinra, canakinumab, tocilizumab, TNF-alpha inhibitors, and abatacept as treatment options.82

38

Table 14. Guideline Recommendations for Cytokine Inhibitors in the Treatment of Juvenile Idiopathic Arthritis Professional Organization and Guidelines Recommendations

American College of Rheumatology/ Arthritis Foundation • 2019 American College of

Rheumatology/ Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis80

Children and adolescents with JIA and active polyarthritis, sacroiliitis, or enthesitis Initiation of treatment with a biologic in combination with a DMARD is conditionally recommended over biologic monotherapy • etanercept or golimumab (very low LOE) • abatacept (low LOE) • adalimumab or tocilizumab (moderate LOE) Children and adolescents with JIA and active sacrolitis despite treatment with NSAIDs • adding TNFi is strongly recommended over continued NSAID

monotherapy Children and adolescents with JIA and active enthesitis despite treatment with NSAIDs • using TNFi is conditionally recommended over MTX or sulfasalazine Authors highlight the lack of head-to-head comparisons among the biologic treatments (eg, TNFis, abatacept, or tocilizumab)

American College of Rheumatology • 2013 Update of the 2011 American

College of Rheumatology Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for the Medical Therapy of Children With Systemic Juvenile Idiopathic Arthritis and Tuberculosis Screening Among Children Receiving Biologic Medications82

Patients with active systemic features and varying degrees of synovitis: • Anakinra, glucocorticoids, or NSAIDs are recommended for initial

therapy • Therapy may be continued with biologics (canakinumab,

tocilizumab, TNF-alpha inhibitors, and anakinra), methotrexate, leflunomide, or glucocorticoids

Patients without active systemic features and varying degrees of synovitis: • Methotrexate, leflunomide, glucocorticoids, or NSAIDs are

recommended for initial therapy • Therapy may be continued with biologics (abatacept, anakinra, and

TNF-alpha inhibitors), methotrexate, or leflunomide

American College of Rheumatology/ Arthritis Foundation • 2019 American College of

Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis–Associated Uveitis83

• Starting a TNFi, starting a monoclonal antibody TNFi is conditionally recommended over etanercept

• Failed a first monoclonal antibody TNFi at above-standard dose and/or frequency, changing to another monoclonal antibody TNFi is conditionally recommended over a biologic in another category

• Failed methotrexate and 2 monoclonal antibody TNFi at above-standard dose and/or frequency, abatacept or tocilizumab are conditionally recommended as biologic DMARD options, and mycophenolate, leflunomide, or cyclosporine as alternative nonbiologic options

National Institute for Clinical Excellence (NICE) • Abatacept, adalimumab, etanercept,

and tocilizumab for treating juvenile idiopathic arthritis, 201584

• Abatacept, adalimumab, etanercept, and tocilizumab are recommended for polyarticular-onset JIA, polyarticular-course JIA, and extended oligoarthritis,

• Adalimumab and etanercept are recommended for enthesitis-related JIA

• Etanercept is recommended for psoriatic JIA Abbreviations: DMARD, disease modifying antirheumatic drug; JIA, juvenile idiopathic arthritis; LOE, level of evidence; MTX, methotrexate; NSAID, non-steroidal anti-inflammatory drug; TNFi, tumor necrosis factor inhibitor

39

F. Inflammatory Bowel Disease Inflammatory bowel disease (IBD) encompasses Crohn’s disease and ulcerative colitis which are idiopathic, chronic, immune-mediated inflammatory disorders. While the precise etiology is not fully understood, it is thought to involve genetic, immunologic, and environmental factors.85,86 The Centers for Disease Control and Prevention estimated from a national household survey (2015 National Health Interview Survey) that 3.1 million of US adults (1.3%) are diagnosed with IBD.3 About a quarter of IBD patients are diagnosed before adulthood and the natural history of pediatric disease is typically more severe compared to cases diagnosed later in life.87 Features that distinguish CD from UC include inflammation that may permeate all layers or thickness of the bowel wall (ie, transmural), discontinuous appearance (ie, skip areas), and deep linear serpiginous ulcers of the colon, strictures, fistulas, or granulomas.85 UC is “…usually confined to the mucosa,” most often involving the rectum.88

IBD is a relapsing disease with periods of exacerbation that dramatically reduce patient quality of life.88 Assessment and management of stress, depression, and anxiety—which are common in IBD— should be included in the comprehensive treatment approach to improve health-related quality of life and prescription adherence.85,86 While there are a variety of medications available for the treatment of IBD, the disease is not curable despite maintenance of remission or surgical intervention.

Biologics are generally used to induce and maintain clinical remission of moderately to severely active or high risk IBD and are thought to exert their effect on the entire gastrointestinal (GI) tract. There are 8 cytokine inhibitors FDA-approved for the treatment of IBD. Four are available as subcutaneous (SQ) injectable products (adalimumab, certolizumab pegol, golimumab, and ustekinumab) and 1 as an oral (PO) formulation (tofacitinib). Three cytokine inhibitors for IBD are intravenous products: infliximab (an anti-TNF agent indicated for CD and UC), and the integrin/adhesion inhibitors natalizumab (indicated for CD) and vedolizumab (indicated for CD and UC).

Table 15 details the IBD indications of the SQ and PO administered cytokine inhibitors. Adalimumab is approved for both CD and UC; whereas, the other products are approved for only one IBD subtype (cetolizumab and ustekinumab for CD; and golimumab and tofacitinib for UC). Adalimumab has a pediatric indication for CD (patients ≥6 years old); others are only indicated for adults. With the exception of certolizumab, each product is approved for induction and maintenance of remission respective to the IBD-subtype indication. Certolizumab is approved for maintenance of remission (not induction)89 for moderately to severely active CD non-responsive to conventional therapy.

If response to therapy is inadequate, dose adjustments or a change of medication must be made. Therapeutic drug monitoring and measurement of drug-antibodies may be used to determine the reason for inadequate response to biologic therapy (particularly in UC). The body may produce antibodies to an employed monoclonal antibody drug that hastens the drug’s elimination. When drug efficacy is diminished because of this mechanism, it is called immune-mediated failure (ie, patients have high levels of drug-antibodies present and subtherapeutic drug levels). Non-immune-mediated drug failure may occur due to rapid drug clearance during high inflammatory burden (ie, patients lack drug-antibodies but have subtherapeutic drug levels). Mechanistic failure is when patients have therapeutic drug levels with no drug-antibodies; these patients must be switched to a drug with different mechanism of action (eg, patient on anti-TNF therapy may switch to an anti-interleukin 12/23 therapy or anti-integrin agent).

40

Table 15. Cytokine Inhibitors Approved for Inflammatory Bowel Disease3,7,15-17 Active Agent

(approval date) MOA

IBD Indications and Dosinga


(2002)

TNF-alpha blocker

Reducing signs and symptoms and inducing and maintaining clinical remission in moderately to severely active CD - for pediatric patients (≥6 yrs old) inadequately responding to CCS or

immunomodulators - for adults inadequately responding to conventional therapy or who lost response to

or are intolerant to infliximab Inducing and sustaining clinical remission in moderately to severely active UC - for adults inadequately responding to immunosuppressants (eg, CCS, AZA, 6-MP) - Not established in patients who lost response or were intolerant to TNFα blockers Dosing

Adult CD and UC: Day 1 give 160 mg Day 15 give 80 mg Day 29 and thereafter 40 mg every other week Pediatric CD (≥6 years and older)

Weight Induction Dose Day 29 Onward 17 kg to <40 kg

Day 1 give 80 mg Day 15 give 40 mg 20 mg every other wk

≥40 kg Day 1 give 160 mg (on day 1 or divided over 2 consecutive days) Day 15 give 80 mg

40 mg every other wk


(2008)

TNF-alpha blocker

Reducing signs and symptoms and maintaining response in moderately to severely active CD - for adults inadequately responding to conventional therapy

Dosing: 400 mg initially and at week 2 and 4. If a response occurs, continue with 400 mg every 4 weeks


(2009)

TNF-alpha blocker

Inducing and maintaining clinical response/remission and improving endoscopic appearance of the mucosa in moderate to severely active UC

- for adults inadequately responding to or intolerant to prior treatment, or who require continuous steroids

Dosing: 200 mg SQ week 0, followed by 100 mg at week 2 and then maintenance therapy with 100 mg every 4 weeks.


(2009)

Interleukin-12 and -23 antagonist

For the treatment of moderately to severely active CD (clinical trials showed induction and maintenance of response and remission benefits) - for adults who are naïve to TNFα blockers that failed or were intolerant to immunomodulators or CCS

- for adults who failed or were intolerant to treatment to TNFα blockers Dosing

Initial IV dosage: Weight up to 55 kg 260 mg Weight > 55 kg to 85 kg 390 mg Weight > 85 kg 520 mg

Maintenance SQ dosage: 90 mg administered 8 weeks after the initial IV dose, then every 8 weeks thereafter

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Table 15. Cytokine Inhibitors Approved for Inflammatory Bowel Disease3,7,15-17 Active Agent

(approval date) MOA

IBD Indications and Dosinga

Tofacitinib Xeljanz, Xeljanz XR (PO)

(2012)

Janus Kinase Inhibitor

For the treatment of adults with moderately to severely active UC (clinical trials showed induction and maintenance of response and remission benefits)

o concomitant use with biologics or immunosuppressants (eg, AZA and cyclosporine) is not recommended

Dosing: 10 mg twice daily for at least 8 weeks; then 5 or 10 mg twice daily; discontinue after 16 weeks of 10 mg twice daily, if adequate therapeutic benefit is not achieved

a See table 1 and product labeling for more information regarding other indications Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; CCS, corticosteroids; CD, Crohn’s disease; IV, intravenous; MOA, mechanism of action; SQ, subcutaneous; PO, oral; TNF, tumor necrosis factor; UC, ulcerative colitis

F.1 Crohn’s Disease Crohn's disease is most often destructive of the lower GI-tract, but not confined to this location as it may emerge anywhere from the mouth to the anus.6,85,90 Patients usually experience chronic diarrhea, fatigue, and abdominal pain usually in the lower right quadrant that may worsen after eating.85 Weight loss, fever, reduced bone mass, and linear growth in children can occur. Intra-intestinal manifestations include recurrent fistulas, strictures, and abscesses. The integrity and function of the intestine becomes compromised causing vitamin and mineral deficiencies. Extra-intestinal manifestations are numerous: those considered classic are arthropathy and dermatological, ocular, and hepatobiliary abnormalities (eg, pyoderma gangrenosum, erythema nodosum, uveitis, scleritis, sclerosing cholangitis). Other complications may involve clotting disorders, metabolic bone diseases, and nephrolithiasis. Those with proximal GI, ileal, or ilealcolonic disease are at higher risk of intestinal complications than those with disease isolated to the colon. The cumulative 10-year risk of the need for a major abdominal surgery in Crohn’s disease is about 30%.85

CD is diagnosed using a combination of endoscopy, biopsy, and imaging studies, while taking into account signs/symptoms of gut inflammatory markers (eg, fecal calprotectin) and ruling out fecal pathogens.85 Once CD diagnosis is established, the patient’s disease burden is assessed to discern low or high risk of disease progression and the severity of disease activity. The determination relies on the provider’s overall impression without strict definitions for classifying patients. Table 1685,91 includes descriptions provided from treatment guidelines regarding the patient’s disease status or classification.

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Table 16. Disease Status Descriptions For Crohn’s Disease85,91 2018 American College of Gastroenterology Guideline Descriptions 2014 American Gastroenterological

Association Care Pathway Descriptions Disease Activity

High Risk for Progressive Disease

Disease Burden

Low Risk High Risk Mild to moderate disease

Moderate to severe disease

- Patient is ambulatory and can eat/drink normally

- <10% weight loss - No complications such

as obstruction, fever, abdominal mass, or dehydration

- May have diarrhea and abdominal pain and elevated serum C-reactive protein

- Minimal impact on quality-of-life

- Correlates to a Crohn’s disease activity index score of 150–220

- Significant weight loss

- Possible complications such as obstruction or intra-abdominal abscess

- Symptoms persist despite aggressive therapy

- Frequently hospitalized

- Crohn’s activity index score of >450

- Young age at diagnosis

- Initial extensive bowel involvement

- Ileal/ileocolonic involvement

- Perianal/severe rectal disease

- Presenting with a penetrating or stenosis disease phenotype

- Visceral adiposity may be a marker for increased risk of penetrating disease

- Age at initial diagnosis >30 years

- Extensive anatomic involvement

- Perianal and/or severe rectal disease

- Superficial ulcers - No prior surgical

resection - No stricturing

and/or penetrating behavior

- Age at initial diagnosis <30 years

- Extensive anatomic involvement

- Perianal and/or severe rectal disease

- Deep ulcers - Prior surgical

resection - Stricturing

and/or penetrating behavior

Authors of the 2018 American College of Gastroenterology (ACG) guideline for adult CD describe that their recommendations should be interpreted with flexibility. By providing a recommended option, this does not mean it is only acceptable treatment approach.85 The choice of therapy should be guided by patient preferences and depends on the disease location, disease activity, and severity of disease (ie, complications and prognosis). Goals of therapy include controlling disease flare within 3 months, maintaining control thereafter, and ultimately preventing further tissue damage (stricture and fistulas) or need for surgical intervention. Response to pharmacotherapy should be objectively evaluated by endoscopic or cross-sectional imaging; onset of clinical improvement and maximal improvement is expected within 2–4 weeks and 12–16 weeks, respectively.85

Biologics are employed for the treatment of moderate-to-severe CD and for patients at high risk of disease progression.85 Based on the ACG 2018 guideline, the anti-TNF agents (infliximab, adalimumab, and certolizumab pegol) and interleukin-12 and -23 (IL-12/IL-23) inhibitor, ustekinumab, are considered for patients who have inadequately responded to conventional therapy with thiopurines, methotrexate, or corticosteroids. Adalimumab is additionally approved for adults with lost or inadequate response to infliximab,15 and ustekinumab is additionally approved and recommended for adults who have failed one or more anti-TNF inhibitor.85,92 Other IV agents (natalizumab and vedolizumab) are also recommended for induction therapy.

For maintenance of luminal disease, when an anti-TNF agent is used to induce remission, the anti-TNF agent should be continued for maintenance of remission; the addition of a thiopurine or methotrexate should be considered to reduce immunogenicity. Similarly, ustekinumab should be continued for maintenance of remission of ustekinumab-induced response. TNF-inhibitors may be added to a thiopurine or MTX for patients dependent on corticosteroids. Anti-TNF agents are also recommended for fistulizing and post-operative CD.85 The ACG notes that biosimilars of infliximab and adalimumab are

43

effective in moderate to severe CD for induction and maintenance therapy; however, data is lacking to support switching patients during the maintenance of stable disease to the biosimilar product.

Table 1785,89,93 summarizes the 2018 ACG treatment recommendations regarding the biological therapies for CD in addition to those by the 2013 American Gastroenterology Association guideline and the 2019 guidance by a Canadian expert consensus panel.

Table 17. Treatment Guidelines for the Use of Biologics in Crohn’s Disease Professional Organization Guideline

Excerpts

American College of Gastroenterology Guidelines ACG Clinical Guideline: Management of Crohn's Disease in Adults, 201885

Recommendations are provided using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system Pharmacologic Therapy for Crohn’s Disease in Adults Mild-to-moderately severe disease/Low-risk disease

Recommended for use: • Sulfasalazine for treating symptoms of colonic CD (conditional recommendation, low

LOE) • Controlled ileal release budesonide, 9 mg once daily for induction of symptomatic

remission of ileocecal CD (strong recommendation, low LOE) Moderate-to-severe disease/Moderate-to-high-risk disease • Non-Biologics: Azathioprine, and 6-mercaptopurine can be used for steroid sparing

in CD and for maintenance of remission, but should not be used to induce short-term symptomatic remission; MTX (up to 25 mg once weekly IM or SC) for alleviating signs/symptoms in steroid-dependent CD and for maintaining remission

• Anti-TNF agents (infliximab, adalimumab, certolizumab pegol) for CCS-resistant CD or for thiopurine- or MTX-refractory CD (strong recommendation, moderate LOE). o Combination therapy of infliximab and immunomodulators (thiopurines) is

more effective than these monotherapies in patients naive to those agents (strong recommendation, high LOE)

• Anti-integrin therapy (with vedolizumab) with or without an immunomodulator for induction of symptomatic remission of active CD (strong recommendation, high LOE)

• Natalizumab for induction of symptomatic response and remission of active CD (strong recommendation, high LOE); use natalizumab for maintenance of natalizumab-induced remission of CD only if serum antibody to John Cunningham virus is negative (strong recommendation, moderate LOE)

• Ustekinumab for patients who failed CCS, thiopurines, MTX, or TNFα inhibitors or who are naïve to anti-TNF inhibitors (strong recommendation, high LOE)

For short-term use only • Oral CCS for alleviating signs and symptoms of active CD (strong recommendation,

moderate LOE); conventional corticosteroids are to be used sparingly Severe/fulminant disease • Intravenous CCS (conditional recommendation, moderate LOE) • Anti-TNF agents (infliximab, adalimumab, certolizumab pegol) for severely active

CD (strong recommendation, moderate LOE) • Infliximab to treat fulminant CD (conditional recommendation, LOE)

Use of biologics in perianal or fistulizing disease Note: One-quarter of CD patients experience perianal fistulizing disease • Infliximab for perianal, enterocutaneous, or rectovaginal fistulas (strong

recommendation, moderate LOE) • Adalimumab and certolizumab pegol for perianal fistulas (strong recommendation,

low LOE)

44


Excerpts

Use of biologics for maintenance therapy of luminal disease • CCS-induced remission should be followed with thiopurine or methotrexate for

maintenance therapy (strong recommendation, moderate LOE); anti-TNF therapy can be added as a third agent in steroid dependent patients (strong recommendation, moderate LOE).

• Anti-TNF therapy, specifically infliximab, adalimumab, and certolizumab pegol, should be used to maintain remission of anti-TNF-induced remission (strong recommendation, high LOE). o Anti-TNF monotherapy is effective at maintaining anti-TNF induced remission,

but because of the potential for immunogenicity and loss of response, combination with AZA, 6-MP or MTX should be considered (strong recommendation, moderate LOE).

• Vedolizumab should be used for maintenance of remission of vedolizumab-induced remission (conditional recommendation, moderate LOE).

• Natalizumab should be considered for maintaining remission of natalizumab-induced remission if John Cunningham (JC) virus is negative (conditional recommendation, moderate LOE)

• Ustekinumab should be use for maintenance of ustekinumab-induced remission (conditional recommendation, moderate LOE)

Use of Biologics in Post-operative Crohn’s Disease • In high-risk patients, start anti-TNF agents within 4 weeks of surgery to prevent CD

recurrence (conditional recommendation, low LOE) • Anti-TNF therapy combined with an immunomodulator to decrease immunogenicity

and decrease loss of response (conditional recommendation, very low LOE) American Gastroenterological Association Clinical Care Pathway for Crohn’s Disease derived from the AGA Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti–TNF-α Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn's Disease, 201389

Authors note that these guidelines do not address treatment in children Low risk patients with none to minimal systemic symptoms • Budesonide 9 mg once daily +/- AZA for ileum and/or proximal colon involvement • Prednisone (taper) +/- AZA for diffuse or left colon involvement or for ileum and/or

proximal colon involvement • Maintenance options: stop therapy and observe, budesonide 6mg/day may prolong

relapse, or consider azathioprine, 6-mercaptourine or methotrexate For patient not in remission, assess patient’s drug levels and consider adding anti TNF therapy Moderate to high risk patients (Moderately severe CD) For Induction of Remission Standard therapies include melamine, antibiotics and steroids; this guideline focuses on the use of immunomodulators. Initial treatment for moderate/severe risk patients to induce remission despite the use of standard therapies: • Use anti TNF monotherapy over no therapy or thiopurine alone • Use anti TNF with thiopurine over thiopurine or anti-TNF monotherapy • Use methotrexate for patients intolerant to purine analog combination with anti TNF

Maintenance Therapy • For steroid induced remission use of thiopurine, methotrexate, or anti TNF +/-

thiopurine is recommended

45


Excerpts

- If patient doesn’t remain in remission for 6 months try combination therapy, anti TNF with a thiopurine

• For anti TNF +/- thiopurine induced remission • Use anti TNF monotherapy over no therapy or thiopurine monotherapy • Use anti TNF + thiopurine over thiopurine or anti TNF monotherapy

- Remains in remission 6 months: may define resolution of inflammation and ulcers, re-assess inflammatory markers every 3 months

- Not in remission: determine reason for failed response and consider a change to patient’s regimen

Determine reason for failed response: low drug concentration/low anti-drug antibody (increase drug dose), low drug concentration/high anti-drug antibody (switch within drug class), therapeutic drug concentration/low anti-drug antibody (assess inflammation)

Clinical Consensus of Expert Practitioners in Canada Clinical Practice Guideline for the Management of Luminal Crohn’s Disease: The Toronto Consensus, 201993

Select recommendations regarding the subcutaneously administered biologics • For moderate to severe luminal CD with risk factors of poor prognosis, use anti-TNF

therapy (infliximab, adalimumab) as first-line therapy to induce complete remission (Strong recommendation, moderate-quality evidence)

• For patients with moderate to severe CD not achieving complete remission with CCS, thiopurines, or MTX, use anti-TNF therapy (infliximab, adalimumab) to induce complete remission (Strong recommendation, high-quality evidence) o If symptomatic response with anti-TNF induction therapy occurs, continue anti-

TNF therapy to achieve and maintain complete remission. (Strong recommendation, high-quality evidence)

o Combine anti-TNF therapy with a thiopurine to induce complete remission or with a thiopurine or MTX to improve pharmacokinetic parameters

o Evaluate for symptomatic response to anti-TNF induction therapy between 8 and 12 weeks to determine the need to modify therapy

• Avoid switching between anti-TNF therapies if the patient is doing well on anti-TNF therapy (Conditional recommendation, low-quality evidence). It is also noted that “…there is insufficient evidence to support routine switching to biosimilar anti-TNF agents in patients with stable CD…”

• In patients not achieving complete remission with corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, ustekinumab is recommended to induce complete remission. (Strong recommendation, moderate-quality evidence). Evaluate for symptomatic response between 6 and 10 weeks. o If symptomatic response is achieved with ustekinumab induction therapy, it

should be continued to achieve and maintain complete remission. (Strong recommendation, moderate-quality evidence)

Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; CCS, corticosteroids; CD, Crohn’s disease; LOE, level of evidence; TNF, tumor necrosis factor

F.2 Ulcerative Colitis Ulcerative colitis affects the large intestine, most often involving the rectum in adults. Symptoms include bleeding, urgency, and tenesmus (a sense of pressure). Complications include dysplasia and colorectal cancer thought to result from long-standing inflammation. Goals of therapy include maintaining steroid-

46

free remission, improvement in quality of life, and prevention of hospitalization, surgery, and cancer. Classification of disease severity is based on patient-reported bleeding and bowel habits, inflammatory burden per endoscopic assessment and markers of inflammation, disease course, and disease impact on daily function and quality of life. The greater number of poor prognostic factors, the greater likelihood of colectomy: age <40 at diagnosis, extensive colitis, severe endoscopic disease (Mayo endoscopic subscore 3 or Ulcerative Colitis Endoscopic Index of Severity ≥7), elevated C-reactive protein, low serum albumin.86

Options for induction of remission of moderately to severely active UC described in the 2019 ACG guideline for UC include oral systemic corticosteroids; the anti-TNF agents including adalimumab, golimumab, or infliximab; the integrin inhibitor vedolizumab; and the JAK inhibitor, tofacitinib. For patients who failed anti-TNF therapy, vedolizumab or tofacitinib are recommended for induction of remission. If a biologic or tofacitinib is used for induction, it is recommended that the same agent be continued to maintain remission. Patients with mildly active disease who are at a high risk of hospitalization or surgery may also be treated with the medications appropriate for moderately to severely active disease. Table 1886,94 summarizes the 2019 ACG treatment recommendations regarding the cytokine inhibitors for UC in addition to guidance outlined by the American Gastroenterology Association and a Canadian expert consensus panel.

Table 18. Treatment Guidelines for the Use of Biologics in Ulcerative Colitis Professional Organization Guideline

Excerpts

American College of Gastroenterology Guidelines ACG Clinical Guideline: Ulcerative Colitis in Adults, 201986

Recommendations are provided using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system Pharmacologic Therapy for Ulcerative Colitis in Adults Moderately to severely active UC or at high risk of hospitalization/surgery Induction of remission • Patients with mildly active UC at increased risk of hospitalization or surgery should be

treated with therapies for moderately to severely active disease • For moderately active UC, oral budesonide multi-matrix for induction of remission is

recommended (strong recommendation, moderate quality of evidence) • For moderately to severely active UC

o Oral systemic CCS to induce remission can be considered (strong recommendation, moderate quality of evidence)

o Monotherapy with thiopurines or methotrexate for induction of remission is recommended against (strong recommendation, low quality of evidence)

o Anti-TNF therapy using adalimumab, golimumab, or infliximab for induction of remission is recommended (strong recommendation, high quality of evidence) - Do not add 5-ASA to anti-TNF therapy if patients already failed 5-ASA

previously; supportive evidence for combination anti-TNF and immunomodulator therapy in moderately to severely active disease exist only for infliximab and thiopurines

- For responders to anti-TNF therapy who start losing response, serum drug level and drug-antibodies assessment is recommended; if patients are found to have adequate drug levels, they should be tried on a drug with a different mechanism of action; if patients had an initial response to anti-TNF therapy but lost efficacy, cycling to another anti-TNF therapy can be tried.

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Excerpts

o Anti-integrin therapy with vedolizumab for induction of remission is recommended (strong recommendation, moderate quality of evidence); vedolizumab is also recommended in patients who failed anti-TNF therapy for induction of remission (strong recommendation, moderate quality of evidence).

o Tofacitinib is recommended for inducing remission (strong recommendation, moderate quality of evidence); tofacitinib is also recommended for patients with previous failure to anti-TNF therapy for the induction of remission (strong recommendation, moderate quality of evidence).

Consider colectomy in patients with moderately to severely active UC who are refractory or intolerant to medical therapy Maintenance of Remission Most clinical trials and available data demonstrate a benefit of using the steroid-sparing therapy that induces remission to maintain that remission

o Continue anti-TNF therapy using adalimumab, golimumab, or infliximab to maintain remission after anti-TNF induced remission (strong recommendation, moderate quality of evidence)

o Continue vedolizumab to maintain remission after vedolizumab induced remission (strong recommendation, moderate quality of evidence)

o Continue tofacitinib for maintenance of remission after tofacitinib-induced remission (strong recommendation, moderate quality of evidence)

• Systemic CCS or MTX for maintenance of remission is recommended against o Following corticosteroid-induced remission, it is recommended to use

thiopurines for maintenance of remission compared with no treatment or corticosteroids

American Gastroenterological Association Clinical Care Pathway, 201595

Anti-TNF therapy is an option among the AGA clinical care outpatient pathway for the following: • Induction and continued maintenance therapy for high risk outpatient with or

without a thiopurine • For maintenance therapy following CCS + thiopurine indication of remission of high

risk outpatient • For lost response to vedolizumab therapy for high risk outpatient not in remission

Clinical Consensus of Expert Practitioners in Canada Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus, 201594

Recommendations regarding anti-TNF therapy • Use an anti-TNF if patients fail a thiopurines or corticosteroids to induce CCS-free

remission (strong recommendation, high-quality evidence); combine with a thiopurine or methotrexate, over monotherapy (strong recommendation)

• In CCS-dependent patients, use an anti-TNF to induce and maintain CCS-free remission (strong recommendation, very low-quality evidence)

• Evaluate for lack of symptomatic response to anti-TNF induction therapy in 8 to 12 weeks (strong recommendation, low-quality evidence)

- Responders to anti-TNF induction therapy should continue therapy to maintain complete remission (strong recommendation, very low-quality evidence for infliximab and adalimumab and high-quality evidence for golimumab)

Statements regarding other agents • If unable to achieve CCS-free complete remission with anti-TNF therapy despite dose

optimization, switch to vedolizumab over switching to another anti-TNF therapy to induce complete CCS-free remission (Strong recommendation, very low-quality evidence)

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Excerpts

• If unable to maintain CCS-free complete remission with anti-TNF therapy despite symptomatic response, switch to another anti-TNF therapy or vedolizumab based on therapeutic drug monitoring results to induce complete corticosteroid-free remission (Strong recommendation, very low quality evidence)

• For moderate to severe active UC with response failure to CCS, thiopurines, or anti-TNF therapies, vedolizumab is recommended for induction of complete CCS-free remission (Strong recommendation, moderate-quality evidence); continue vedolizumab therapy to maintain complete CCS-free remission

Abbreviations: 6-MP, 6-mercaptopurine; AZA, azathioprine; CCS, corticosteroids; TNF, tumor necrosis factor; UC, ulcerative colitis

Pharmacology & Special Populations

A. Oral Cytokine Inhibitors

Four cytokine inhibitors among the list of products reviewed are small molecule drugs that are administered orally: apremilast, baricitinib, tofacitinib, and upadacitinib. The phosphodiesterase 4 enzyme (PD4E) inhibitor, apremilast, increases intracellular cyclic adenosine monophosphate (cAMP).96 This is thought to decrease pro-inflammatory mediators and increase anti-inflammatory mediators (eg, IL-10) to ultimately help downregulate inflammation contributing to plaque psoriasis and psoriatic arthritis.97 Baricitinib, tofacitinib, and upadacitinib are janus associated kinase (JAK) inhibitors. Janus kinases interact with the intracellular portion of transmembrane cytokine receptors, activating a signaling pathway and regulating intracellular activity. JAK inhibitors impede phosphorylation of Signal Transducers and Activators of Transcription [STATs] in the pro-inflammatory signaling cascade normally activated by cytokines.98,99

The usual dosing frequency of apremilast is twice daily and the elimination half-life is 6 to 9 hours.96 Apremilast is primarily metabolized by CYP3A4, with minor contributions from CYP1A2 and CYP2A6. The drug is cleared via urine and feces. Dose adjustment for hepatic impairment is not necessary; however, the dose should be reduced to 30 mg once daily for persons with severe renal impairment.96

Baricitinib is administered daily, with a half-life of 12 hours.99 The drug is primarily (75%) cleared hepatically (via CYP3A4) and 20% eliminated in the urine. Use is not recommended in severe hepatic impairment or with a glomerular filtration rate <60 mL/min/1.73m2.99

The half-life of tofacitinib is 3 and 6 hours for the immediate- and extended-release formulations, respectively. The usual dosing frequency is twice daily for the IR tablet and once daily for the XR tablet.98 Clearance of the parent molecule is 70% via hepatic metabolism (CYP3A4 primarily and CYP2C19) and 30% by renal excretion. Dose reductions are recommended for patients receiving CYP2C19 and/or CYP3A4 inhibitors; in patients with moderate or severe renal impairment or moderate hepatic impairment; and patients with lymphopenia, neutropenia, or anemia. Use in severe hepatic impairment is not recommended.98

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Upadacitinib is available as an extended-release product, dosed once daily with its half-life about 8 to 12 hours. Metabolism occurs mainly through CYP3A4 and to a lesser extent via CYP2D6. There are no dose adjustment recommendations for renal or hepatic impairment; however, it is advised not to use the medication in severe hepatic impairment.

B. Monoclonal Antibody Cytokine Inhibitors, Injectables

B.1. Selective T cell Co-stimulation Modulator

Abatacept is a fusion protein containing the extracellular domain of human cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) linked to the modified Fc portion of immunoglobulin G1 (IgG1). 100 It inhibits the interaction of CD80 and CD86 with CD28 to downregulate the costimulatory signal that contributes to activation of T lymphocytes. T lymphocytes are involved in the pathogenesis of RA and PsA and elevated in synovium of RA and PsA patients. Decreases in the serum levels of interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and TNFα were observed in clinical trials with abatacept treatment. The maintenance SC dosing interval is once weekly and corresponding terminal half-life is about 2 weeks.100

B.2. TNF-alpha Blockers

TNF is a pro-inflammatory cytokine that interacts with the p55 and p75 cell surface TNF receptors. Elevated levels of TNF are found in synovial fluid of patients with RA, JIA, PsA, and AS and in psoriatic plaques. TNF is involved in promotion of adhesion molecules responsible for leukocyte migration.15 Inhibitors of TNF induce the lysis of various immune cells by either activation of complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC; mediated by Fc receptors).101

Full length, bivalent IgG monoclonal antibodies include adalimumab and golimumab. Certolizumab is a monovalent Fab-antibody fragment attached to polyethylene glycol. Adalimumab, certolizumab, and golimumab selectively bind soluble and transmembrane forms of TNF-alpha, blocking its interaction with the cell surface TNF receptors. Etanercept contains a dimer of the p75 TNF (TNFR2) receptor that binds TNF-alpha (soluble and transmembrane forms) and TNF-beta (lymphotoxin), inhibiting the stimulation of cell surface TNF receptors.101,102

Half-lives of adalimumab, golimumab, and certolizumab are approximately 2 weeks; SQ administration intervals for maintenance dosing are once monthly for golimumab, every 4 weeks or every other week for certolizumab, and every other week for adalimumab.15-17 The half-life for etanercept is about 5 days and the maintenance SQ administration interval is once weekly.102

B.3. Interleukin Antagonists

Interleukin (IL) antagonists are monoclonal antibodies produced by recombinant DNA technology.10 They inhibit the release and activity of proinflammatory cytokines and chemokines by blocking the action of specific interleukins (eg, IL-17 or IL-23) or inhibiting interleukin receptors (eg, IL-6 receptor).1-

6,11-13 Interleukin production is triggered by inflammatory stimuli.10 Abnormally elevated levels of specific ILs are identified in synovium and synovial fluid and psoriatic plaques of patients with RA, psoriasis, PsA, and AS, which may cause cartilage damage and inflammation.1,4,10 Table 19 describes the mechanism of action of each interleukin inhibitor.

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Interleukin antagonists are administered by subcutaneous injection and include an IL-1β inhibitor (canakinumab), three IL-23 inhibitors (guselkumab, risankizumab, and tildrakizumab), two IL-17 A inhibitors (ixekinumab and secukinumab), and an IL-12 and IL-23 inhibitor (ustekinumab). The recommended maintenance dosing frequency is every 4 weeks for canakinumab, ixekinumab, and secukinumab (half-lives ranging from 13 days to 31 days), every 8 weeks for guselkumab (half-life of 15 to 18 days), every 8 to 12 weeks for ustekinumab (half-life of 15 to 46 days), and every 12 weeks for risankizumab and tildrakizumab (half-lives ranging from 23 to 28 days).2-6,11,14

Interleukin receptor antagonists include anakinra (IL-1 receptor antagonist), brodalumab (IL-17 receptor A inhibitor), sarilumab (IL-6 receptor inhibitor), and tocilizumab (IL-6 receptor inhibitor). The half-life of anakinra is around 6 hours and is administered daily. The recommended maintenance dosing frequency for brodalumab and sarilumab is every 2 weeks. The half-life for sarilumab is 8 to 10 days and 11 days for brodalumab. Tocilizumab is administered every week or every 3 weeks (maintenance dosing), with a half-life ranging from 5 to 14 days.1,10,12,13

The effect of interleukin inhibitors in patients with renal or hepatic impairment has not been studied, except for Anakinra. Anakinra is significantly excreted the kidney and dosage adjustments are required in patients with severe renal impairment or end stage renal disease.10

Table 19. Mechanism of Action for Interleukin Inhibitors1-6,10-14 Agent MoA Description of MoA

Interleukin Antagonists

Canakinumab Ilaris IL-1β inhibitor

Human monoclonal anti- IL-1β antibody of the IgG1/κ isotype. Canakinumab binds to the pro-inflammatory IL-1β cytokine, preventing its binding and action at IL-1 receptors

Guselkumab Tremfya IL-23 inhibitor Human monoclonal IgG1λ antibody that targets the p19 subunit of IL-23,

preventing its binding to IL-23 receptor Ixekizumab Taltz

IL-17A inhibitor

Humanized IgG4 monoclonal antibody that selectively binds to IL-17A, preventing its binding with the IL-17A receptor

Risankizumab Skyrizi IL-23 inhibitor Humanized IgG1 monoclonal antibody that targets the p19 subunit of IL-23,

preventing its binding to IL-23 receptor Secukinumab Cosentyx

IL-17A inhibitor

Human IgG1 monoclonal antibody that targets IL-17A, preventing its binding to IL-17 receptor

Tildrakizumab Ilumya IL-23 inhibitor Humanized IgG1/k monoclonal antibody that targets the p19 subunit of IL-

23, preventing its binding to IL-23 receptor

Ustekinumab Stelara

IL-12 and IL-23 inhibitor

Human IgG1κ monoclonal antibody that binds to p40 protein subunit of IL-12 and IL-23 cytokines. Ustekinumab ultimately disrupts the signaling cascade of these inflammatory cell mediators

Interleukin Receptor Antagonists Anakinra Kineret


Recombinant, nonglycosylated human interleukin-1 receptor antagonist that binds competitively to the IL-1 receptor. This blocks IL-1 activity

Brodalumab Siliq

IL-17 receptor A inhibitor

Human monoclonal IgG2 antibody that selectively binds to the cell-surface IL-17 receptor A and prevents interaction and activation of cytokines IL-17A, IL-17F, IL-17C, IL-17A/F heterodimer and IL-25. Higher levels of IL-17A, IL-17C and IL-17F are identified in psoriatic plaques

Sarilumab Kevzara


Human monoclonal IgG1 antibody that targets both soluble and membrane-bound IL-6 receptor and blocks IL-6 mediated pro-inflammatory signaling pathway

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Table 19. Mechanism of Action for Interleukin Inhibitors1-6,10-14 Agent MoA Description of MoA

Tocilizumab Actemra


Recombinant humanized anti-human IL-6 receptor monoclonal antibody of the IgG1κ subclass. It binds to soluble and membrane-bound IL-6 receptors and inhibits the IL-6-mediated pro-inflammatory signaling cascade

Abbreviations: Ig, immunoglobulin; IL, interleukin; MoA, mechanism of action Table 20 summarizes select pharmacokinetic parameters for the cytokine inhibitors.

Table 20. Pharmacokinetic Parameters1-20 Active Ingredient Brand Name (route)

Bio-availability

Tmax Terminal half-life Maintenance dosing (dependent on indication)

Abatacept Orencia (SQ)

79% NR 14.3 days Once weekly


64% 131 ± 56 hours ~2 weeks (range 10-20 days)

Every other week to once weekly

Anakinra Kineret (SQ)

95% 3-7 hours ~5.7hrs (range 4-6 hours)

Daily


73% 2.5 hours 6-9 hours Twice daily

Baricitinib Olumiant (PO)

80% 1 hour

12 hours Daily

Brodalumab Siliq (SQ)

55% ~3 days (non-linear pharmacokinetics)

NR Every 2 weeks

Canakinumab Ilaris (SQ)

66% 7 days 26 days Every 4 weeks


80% 54-171 hours 14 days

Every 4 weeks to every other week


60%103 69 ± 34 hours 102 ± 30 hours Once weekly


53% 2-6 days ̴2 weeks Once monthly

Guselkumab Tremfya (SQ)

49% ~5.5 days 15-18 days Every 8 weeks


60-81% ~4 days 13 days Every 4 weeks

Risankizumab Skyrizi (SQ)

89% 3-14 days 28 days Every 12 weeks

Sarilumab Kevzara (SQ)

NR 2-4 days Concentration dependent: 200 mg every 2 weeks = up to 10 days At 150 mg every 2 weeks = up to 8 days

Every 2 weeks


55-77% 6 days 22-31 days Every 4 weeks

Tocilizumab Actemra (SQ)

80%-96% 3 days (with weekly dosing); 4.7 days (with

Concentration-dependent

RA (SQ):

Every week or every 3 weeks

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Table 20. Pharmacokinetic Parameters1-20 Active Ingredient Brand Name (route)

Bio-availability

Tmax Terminal half-life Maintenance dosing (dependent on indication)

every other week dosing)

13 days for 162 mg every week and 5 days for 162 mg every other week.

At steady state with SQ dosing:

PJIA: 10 days SJIA: 14 days

Tofacitinib Xeljanz (PO) Xeljanz XR (PO)

74%

0.1 to 1 hour 4 hours

3 hours 6 hours

Twice daily for IR form Once daily for XR form

Ustekinumab Stelara (SQ)

NR Psoriasis: 13.5 days for 45 mg SQ and 7 days for 90 mg SQ

Psoriasis: 15-46 days Crohn’s disease: 19 days

Every 8 to 12 weeks

Upadacitinib Rinvoq (PO)

NR 2 - 4 hours 8-14 hours Once daily

Abbreviations: IR, immediate release; NR, not reported; PJIA, polyarticular juvenile idiopathic arthritis; PO, oral; RA, rheumatoid arthritis; SJIA, systemic juvenile idiopathic arthritis; SQ, subcutaneous; XR, extended release

Table 21 summarizes select special population considerations for the cytokine inhibitors.

Table 21. Special Population Considerations for Cytokine Inhibitors1-20 Generic Name Brand Name

Dose adjustments Pregnancy Breast feeding

Pediatric Indications

Abatacept Orencia

Renal and hepatic impairment: not studied

Pregnancy: Evidence is insufficient about the risks during pregnancy (use caution)

Lactation: Unknown whether drug is excreted into human milk (use caution)

Moderately to severely active PJIA in patients ≥ 2 years of age

Adalimumab Humira


Pregnancy: An association between adalimumab and major birth defects is not reliably established

Lactation: Distributes in small amounts to milk (consider benefit/risk)

- Moderately to severely active PJIA in patients ≥ 2 years

- Moderate to severely active pediatric Crohn’s disease in patients ≥ 6 years

- Hidradenitis suppurativa in patients ≥ 12 years

- Uveitis in patients ≥ 2 years

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Anakinra Kineret

Renal impairment: If CrCL <30 mL/min, 100 mg every other day (RA) Hepatic impairment: not studied


Lactation: Unknown whether drug is excreted into human milk (use caution)

Neonatal-onset multisystem inflammatory disease

Apremilast Otezla

Renal impairment: If CrCl <30 mL/min, 30 mg once daily in AM Hepatic impairment: No dose adjustment

Pregnancy: Category C (consider benefit/risk); animal studies showed harm at supratherapeutic doses

Lactation: Human data insufficient, In lactating mice, apremilast was found in milk (use caution)

Efficacy and safety not established

Baricitinib Olumiant

Renal impairment: Not recommended for use with GFR < 60 mL/min/1.73 m2

Hepatic impairment: No dose adjustment necessary in mild/moderate impairment. Not recommended for use with severe hepatic impairment

Pregnancy: Evidence is insufficient about the risks during pregnancy (use caution); animal studies showed harm at exposures 20 to 84 times greater than the maximum human dose

Lactation: Human data insufficient; in lactating rats, found to distribute at 45-fold the amount in plasma. Labeling recommends women to not breastfeed while taking this medication


Brodalumab Siliq



Lactation: Human data insufficient. Drug detected in milk of lactating cynomolgus monkeys (consider risk/benefit)


Canakinumab Ilaris



Lactation: Human data insufficient (consider risk/benefit)

- CAPS, TRAPS, HIDS/MKD, and FMF

- Efficacy and safety

not established in SJIA

Certolizumab Pegol Cimzia


Pregnancy: Evidence is insufficient about the risks during pregnancy (use caution); animal studies revealed no harm to fetus

Lactation: Human data insufficient (consider risk/benefit); minimal tranfer into milk has been observed


Etanercept Enbrel


Pregnancy: Available observational evidence does not support a strong

- In children with moderately to

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association with major birth defects; animal studies revealed no harm to fetus

Lactation: Human data insufficient (consider risk/benefit); present in low levels in breast milk

severely active polyarticular juvenile idoiopathic arthritis aged 2 to 17 years

- In patients with moderate to severe plaque psoriasis ages 4 to 17 years

Golimumab Simponi


Pregnancy: Evidence is insufficient about the risks during pregnancy (use caution); animal studies revealed no harm to fetus

Lactation: Human data insufficient (consider risk/benefit); it is unknown if drug is tranfered into human


Guselkumab Tremfya





Ixekizumab Taltz



Lactation: Human data insufficient. Drug detected in milk of lactating cynomolgus monkeys (consider risk/benefit)


Risankizumab Skyrizi





Sarilumab Kevzara

No dose adjustment in mild to moderate renal impairment Not studied in severe renal impairment and hepatic impairment




Secukinumab Cosentyx





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Tildrakizumab-asmn Ilumya



Lactation: Human data insufficient. Drug detected in milk of lactating monkeys (consider risk/benefit)


Tocilizumab Actemra

No dose adjustment in mild to moderate renal impairment Not studied in severe renal impairment or hepatic impairment



SQ administration: - Active PJIA in

patients ≥ 2 years - Active SJIA in patients

≥ 2 years

Tofacitinib Xeljanz

The recommended dosage in patients with RA or PA and who have moderate or severe renal impairment or moderate hepatic impairment is 5 mg once daily; for those with UC, the dose adjustment is half the normal dosage. Avoid use in severe hepatic impairment.

Pregnancy: Evidence is insufficient about the risks during pregnancy (use caution); harm has been observed in animal studies at supratherapeutic doses

Lactation: Human data insufficient (consider risk/benefit); however, transfer into rat milk has been observed. Product labeling advises women not to breastfeed for at least 18 hours post tofacitinib IR dose and 36 hours post an XR dosage


Ustekinumab Stelara

Not reported Pregnancy: Evidence is insufficient about the risks during pregnancy (use caution)

Lactation: Human data insufficient. Drug detected in milk of lactating monkeys (consider risk/benefit)

- Moderate to severe PsO in children 12 to 17 years

- Efficacy and safety not established for patients < 12 years of age

Upadacitinib Rinvoq

No clinically relevant effect on exposure was seen with renal impairment or with mild or moderate hepatic impairment; not recommended with severe hepatic impairment

Pregnancy: Evidence is insufficient about the risks during pregnancy (use caution); harm has been observed in animal studies at supratherapeutic doses

Lactation: advise not to breastfeed per labeling


Abbreviations: CAPS, cryopyrin-associated periodic syndromes, creatinine clearance; FMF, familial mediterranean fever; GFR, glomerular filtration rate; HIDS/MKD, hyperimmunoglobulin D syndrome/ mevalonate kinase deficiency; IR, immideate release; PA, psoriatic arthritis; PsO, plaque psoriasis; RA, rheumatoid arthritis; SJIA, systemic juvenile idiopathic arthritis; TRAPS, tumor necrosis factor receptor associated periodic syndrome; UC, ulcerative colitis; XR, extended release

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Direct Comparative Evidence for Cytokine Modulators The literature search for systematic reviews yielded 2343 unique records, of which 11 SRs including head-to-head RCTs of cytokine modulators for the rheumatoid arthritis, psoriasis, and psoriatic arthritis populations met inclusion criteria for the qualitative synthesis. There were no direct comparative RCTs found for the cytokine inhibitors in populations with ankylosing spondylitis, juvenile idiopathic arthritis, Crohn’s disease, and ulcerative colitis. Figure 1 shows the PRISMA flow diagram for the review process of SRs.

Figure 1. PRISMA Flow Chart for Publication Screening

Abbreviations: DERP, Drug Effectiveness Review Project; SRs, systematic reviews a See Appendix C for descriptions b Eleven SRs were included (10 SRs reporting efficacy and safety outcomes and 1 SR reporting safety outcomes only)

The following 2 sections address the clinical evidence identified in the literature search. Section 1 contains a summary of the reported head-to-head RCTs among systematic reviews and Section 2 includes detailed information regarding the trials and the comparative outcomes (ie, key findings for comparative efficacy and safety).

Records excluded (2113)

Full-text articles assessed for eligibility

(230)

Scre

enin

g In

clud

ed

Elig

ibili

ty

Iden

tific

atio

n • Records identified in Ovid Medline: 1780 SRs

• Records identified in Embase: 1511 SRs

Records after duplicates removed (1771+572= 2343)

Full-text articles excluded, with reasonsa

(219) Wrong comparator (63) Wrong study design (57)

More up-to-date SR available (47) SRs reporting an absence of comparative evidence (41)

Completed report unavailable (11)

Publications (SRs) included in qualitative synthesis (11)b

Additional records identified through other sources: 1 DERP report conducted by the Pacific Northwest Evidence-based Practice Center

Records screened (2343)

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Section 1. Overview of Key Findings from Head-to-Head Evidence For the management of moderate-to-severe plaque psoriasis in adults, 3 SRs (Sbidian 2017, No 2018, and Loos 2018) containing a total of 11 head-to-head RCTs with cytokine modulators at FDA-approved dosages were identified.104-106 In terms of the proportion of patients achieving a 75% or 90% improvement in the Psoriasis Area and Severity Index (PASI 75 and PASI 90, respectively), ustekinumab, secukinumab, ixekizumab, and tildrakizumab (interleukin inhibitors) were significantly more efficacious than etanercept (TNF inhibitor). Among interleukin inhibitors, secukinumab, brodalumab, and ixekinumab were significantly more efficacious than ustekinumab. Guselkumab was significantly more efficacious than adalimumab. For all the aforementioned comparisons, no differences in safety outcomes were reported.

For the management of psoriatic arthritis or plaque psoriasis with concomitant psoriatic arthritis, 2 SRs (Dressler 2019 and Corbett 2017) reporting 4 head-to-head RCTs with cytokine modulators at FDA-approved dosages were identified.107,108 Studies measured skin improvements (PASI scores) and/or joint involvement (eg, American College of Rheumatology [ACR] improvement criteria). One low-quality RCT (Mease 2017) showed no differences between ixekizumab and adalimumab in terms of ACR 20% response criteria (ACR20). This study was not powered to assess equivalency or non-inferiority versus adalimumab. Another RCT (Atteno 2010) showed a significantly greater improvement of skin lesions (PASI responses) at year 1 with adalimumab compared to etanercept (at PsA dosage), but significantly better responses in terms of tender joint count and disability with etanercept compared to adalimumab. The remaining 2 RCTs in psoriasis (Langley 2014 and Thaçi 2015) included subgroup data for patients with PsO and concomitant PsA. These trials did not evaluate psoriatic arthritis responses (eg, ACR20); only responses pertaining to skin lesions (ie, PASI) were reported. Secukinumab induced significantly greater PASI responses compared to etanercept and there were no differences compared to ustekinumab.

For the management of rheumatoid arthritis, 5 SRs (Choy 2019, Venerito 2019, Ma 2019, Emery 2018, and Kawalec 2013) reporting head-to-head RCTs with cytokine inhibitors at FDA-approved dosages were identified.109-113 A meta-analysis (MA) of 2 RCTs (Fleischmann 2012 and van Vollenhoven 2012) showed a significantly greater improvement in ACR50 at week 12 with tofacitinib 5 mg twice daily compared to adalimumab 40 mg every 2 weeks, but no differences in terms of ACR20 and ACR70 at week 12. One of the limitations of this MA is that the background therapy allowed in each study was different (monotherapy in one study and background methotrexate therapy in the other). The remaining 4 SRs reported 4 head-to-head RCTs (Burmester 2017, Fleischmann 2017, Weinblatt 2013, and Jobanputra 2012). Burmester et al included patients who could not receive methotrexate and showed significantly better results with sarilumab 200 mg every 2 weeks compared to adalimumab 40 mg every other week (both arms as monotherapies) in terms of rheumatoid arthritis activity and disability. Nonetheless, this study did not assess a 40 mg weekly dosage of adalimumab, which is additionally approved for RA patients without concomittant methotrexate. Fleischmann et al showed tofacitinib is non-inferior to adalimumab (both in combination with methotrexate) with respect to ACR50. Weinblatt et al support non-inferiority of abatacept vs. adalimumab (both in combination with methotrexate) in terms of ACR20 at year 1. Jobanputra et al support non-inferiority of adalimumab vs. etanercept with respect to the percentage of patients continuing therapy over 52 weeks.

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An additional RCT (Fleischmann 2019) was identified from the secondary PubMed search. This trial included RA patients with inadequate response to methotrexate and reported significantly greater improvements in terms of ACR50, physical function, and pain reduction at week 12; and significantly more patients achieving low disease activity or remission at week 26 with upadacitinib 15 mg daily compared to adalimumab 40 mg every other week (both in combination with methotrexate).114

For the management of ankylosing spondylitis, juvenile idiopathic arthritis, Crohn’s disease, or ulcerative colitis, no SRs reporting head-to-head RCTs were found.

Table 22 includes the head-to-head studies reported in SRs. Most studies compared cytokine inhibitors at FDA-approved dosing. Some trials (eg, Langley 2014, Griffiths 2015, and Reich 2017) included patients receiving FDA and non-FDA approved dosages. The most common active comparators were the TNF inhibitors adalimumab and etanercept, and the interleukin inhibitor, ustekinumab. The following section describes these studies in further detail and Appendix D includes a table of key findings reported in the SRs.

Table 22. Head-to-Head Evidence Identified in the Literature Search Population Systematic

Reviews RCTs with Cytokine Inhibitors Resultsa,b

PsO Sbidian 2017106 (Cochrane Review)

12 RCTs in 10 publications with at least 1 arm containing an FDA-approved dose: 1. SEC vs. ETA

Langley 2014 (FIXTURE study, 12-week primary assessment)115: SEC 150 mg or 300 mg at weeks 0,1,2,3,4, then every 4 weeks vs. ETA 50 mg twice weekly (SEC 150 mg dose is not FDA-approved)

2. SEC vs. UST Thaçi 2015 (CLEAR, 16-week primary assessment)116: SEC 300 mg at baseline and weeks 1, 2, and 3, then every 4 weeks from week 4 vs. UST 45 mg to 90 mg (based on body weight) at baseline and week 4, then every 12 weeks

3. IXE vs. ETA Griffiths 2015 (UNCOVER-2 and UNCOVER-3, 12-week primary assessment)117: IXE 160 mg at week 0, then 80 mg monthly or every other week vs. ETA 50 mg twice weekly (IXE 80 mg monthly is not an FDA-approved dosing)

4. BRO vs. UST Lebwohl 2015 (AMAGINE-2 and AMAGINE-3, 12-week primary assessment)118: BRO 140 mg or 210 mg at weeks 0, 1, 2, 4, 6, 8, and 10, then every other week vs. UST 45 mg to 90 mg (based on body weight)

5. UST vs. ETA Griffiths 2010 (ACCEPT, 12-week primary assessment)119: UST 45 mg to 90 mg (based on body weight) at week 0 and 4 vs. ETA 50 mg twice weekly

6. GUS vs. ADA Gordon 2015 (X-PLORE, Phase II 16-week primary assessment)120: GUS 15 to 200 mg at week 0, 4, and 16 [non-FDA approved doses] vs. ADA at FDA approved dosing

7. GUS vs. ADA Blauvelt 2017 (VOYAGE-1, 16 week primary assessment)121: GUS 100 mg at weeks 0, 4, 12, and every 8 weeks vs. ADA 80 mg at week 0, 40 mg at week 1, and 40 mg every 2 weeks

PASI 90: SEC > ETA SEC > UST IXE > ETA BRO > UST UST >ETA GUS > ADA ETA = APR ETA = TOF SAEs: SEC = ETA SEC = UST IXE = ETA BRO = UST UST = ETA GUS = ADA ETA = TOF ETA = APR

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8. GUS vs. ADA Reich 2017 (VOYAGE-2, 16-week primary assessment)122: GUS 100 mg at weeks 0, 4, 12 vs. ADA 80 mg week 0, then 40 mg week 1, and every 2 weeks

9. ETA vs. TOF Bachelez 2015, 12-week primary assessment123: ETA 50 mg twice weekly vs. TOF [off-label] 10 mg twice daily for 12 weeks

10. ETA vs. APR Reich 2017 (LIBERATE, 16-week primary assessment)124: ETA 50 mg weekly [non-FDA approved dosing] vs. apremilast 30 mg twice daily

PsO No 2018105 10 RCTs in 8 publications already reported in Sbidian 2017 (Langley 2014, Thaçi 2015, Griffiths 2015, Lebwohl 2015, Griffiths 2010, Gordon 2015, Blauvelt 2016, and Reich 2017)

Results similar to those reported in Sbidian 2017

2 additional publications (2 phase II RCTs) not reported in Sbidian 2017: 1. TIL vs. ETA:

Reich 2017 (reSURFACE 2 study)125: TIL 100 mg or 200 mg at week 0, 4, 12, and 16 weeks vs. etanercept 50 mg (twice weekly for 12 weeks; then once weekly)

2. RIS vs. UST Papp 2017 (NCT02054481) - phase II study126: RIS at non-FDA approved doses (18 to 180 mg) vs. UST at approved doses

PASI 75/90/100 (Reich 2017): TIL > ETA PGA 0/1 and quality of life (Reich 2017): TIL 100 mg = ETA PASI 50/75/90/100 and PGA 0/1 (Papp 2017): RIS > UST

Loos 2018104

7 RCTs in 5 publications already reported in Sbidian 2017 (Langley 2014, Thaçi 2015, Griffiths 2015, Lebwohl 2015, and Griffiths 2010)

Results similar to those reported in Sbidian 2017

1 additional publication (1 RCT) not reported in Sbidian 2017 IXE vs. UST: Reich 2017 (IXORA-S): IXE 160 mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks vs. UST 45 mg or 90 mg at weeks 0, 4, 16, 28 and 40

PASI 75/90/100 and sPGA: IXE > UST

PsA, or PsO with PsA

Dressler 2019108

1 RCT in 1 publication: IXE vs. ADA: Mease 2017 (SPIRIT-P1)127: IXE 160 mg at baseline, then 80 mg every 2 or 4 weeks vs. ADA 40 mg every other week

ACR20, ACR50 and HAQ-DI: IXE=ADA

Corbett 2017107

3 RCTs in 3 publications: 1. SEC vs. ETA

Langley 2014 (FIXTURE study): SEC vs. ETA, both at FDA-approved dosing (predefined subgroup data for patients with PsO and concomitant PsA)

2. SEC vs. UST Thaçi 2015 (CLEAR study): SEC vs. UST, both at FDA-approved dosing (predefined subgroup data for patients with PsO and concomitant PsA)

3. ADA vs. ETA Atteno 2010128: ADA 40 mg every other week vs. ETA 25 mg twice weekly vs. INF

Langley 2014 or Thaci 2015: PsA arthritis response (ie, ACR) was not evaluated; only PASI responses were reported: PASI 75/90 (Langley): SEC > ETA PASI 90 (Thaci): SEC = UST Atteno 2010: PASI: ADA > ETA Joint Symptoms: ETA > ADA

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RA Choy 2019,109 Venerito 2019,110 and Emery 2018112

3 RCTs in 4 publications: 1. SAR vs. ADA (as monotherapy)

Burmester 2017 (MONARCH study)129: SAR 200 mg every 2 weeks vs. ADA 40 mg every 2 weeks

2. ABA vs. ADA (plus MTX) Weinblatt 201363 and Schiff 2014130 (AMPLE study – 1 and 2 year results): ABA 125 mg once weekly vs. ADA 40 mg every other week (plus MTX)

3. TOF vs. ADA (plus MTX) Fleischmann 2017131 (ORAL strategy): TOF 5 mg twice daily vs. ADA 40 mg every other week (plus MTX)

DAS28-ESR (Burmester 2017): SAR > ADA ACR20 (Weinblatt 2013 and Schiff 2014): ABA = ADA ACR50 (Fleischmann 2017): TOF = ADA

Ma 2019111

1 publication (1 RCT) ADA vs. ETA Jobanputra 2012 (RED SEA study)132: ADA 40 mg every other week vs. ETA 50 mg weekly

Patients continuing treatment after 52 weeks: ADA = ETA

Kawalec 2013113

1 publication (1 MA of 2 RCTs – Fleischmann 2012 and van Vollenhoven 2012) TOF vs. ADA: TOF 5 mg twice daily vs. ADA 40 mg once every 2 weeks

ACR 20/70: TOF = ADA ACR 50: TOF > ADA SAEs and discontinuations due to AE: TOF = ADA

Abbreviations: ABA, abatacept; ACR20, American College of Rheumatology 20% response criteria; ACR50, American College of Rheumatology 50% response criteria; ACR70, American College of Rheumatology 70% response criteria; ADA, adalimumab; APR, apremilast; BRO, brodalumab; DAS28-ESR, Disease Activity Score 28-erythrocyte sedimentation rate; ETA, etanercept; FDA, U.S. Food and Drug Administration; GUS, guselkumab; HAQ-DI, Health Assessment Questionnaire Disability Index; IXE, ixekinumab; MA, meta-analysis; MTX, methotrexate; PASI, Psoriasis Area and Severity Index; PGA 0/1, proportion of patients with cleared or minimal disease according to the physician´s global assessment; PsA, psoriatic arthritis; PsO, plaque psoriasis; RA, rheumatoid arthritis; RCT, randomized controlled trials; RIS, risankizumab; SAE, serious adverse events; SAR, sarilumab; SEC, secukinumab; sPGA, static physician´s global assessment; TIL, tildrakizumab; TOF, tofacitinib; UST, ustekinumab a “>” means a product is significantly better that other b “=” means no significant differences between treatment groups or non-inferiority demonstrated

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Section 2. Detailed Information Regarding Head-to-Head Evidence

A. Plaque Psoriasis

Three SRs evaluated the comparative efficacy and safety among cytokine modulators in patients with moderate to severe plaque psoriasis.

Sbidian el al106 (2017) performed a Cochrane review to assess the comparative efficacy and safety among systemic cytokine modulators for the treatment of moderate to severe plaque psoriasis or psoriatic arthritis in adults. This systematic review included pair-wise meta-analyses and network meta-analyses of RCTs. Primary outcomes were the proportion of patients achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) and the proportion of patients with serious adverse events (SAEs). Secondary endpoints included PASI 75, the proportion of patients with cleared or minimal disease according to the physician´s global assessment (PGA 0/1), and quality of life. Twelve head-to-head RCTs were identified. Results are described as follows:

• In terms of PASI 90 response at week 12 (end of induction phase), direct head-to-head studies showed ustekinumab, secukinumab, and ixekizumab were significantly more efficacious than etanercept. Secukinumab and brodalumab were significantly more efficacious than ustekinumab at weeks 16 and 12, respectively. Guselkumab was significantly more efficacious than adalimumab in 2 studies that compared FDA-approved dosages at week 16 and in the meta-analysis with 3 studies, one of which used non-approved dosages. Regarding PASI 75 and PGA 0/1 responses, results were consistent with the results for PASI 90.

• When comparing etanercept to small molecule drugs (tofacitinib, apremilast), no significant differences were shown in the PASI 90 response.106 However, apremilast was compared to etanercept at non-FDA approved dosing (50 mg weekly). Tofacitinib is currently not approved for psoriasis.

• Regarding the percentage of patients with SAEs, no significant differences were found when comparing ustekinumab, secukinumab, or ixekinumab versus etanercept; secukinumab or brodalumab vs. ustekinumab; guselkumab vs. adalimumab; or etanercept vs. tofacitinib or apremilast.106

No et al (2018) found 12 head-to-head RCTs (10 RCTs already identified by Sbidian 2017 and 2 phase II RCTs, re-SURFACE 2 and NCT02054481). Efficacy results from individual studies were consistent with the results reported by Sbidian 2017. No traditional meta-analyses were conducted.105 Results for the 2 phase II studies are as follows:

• Re-SURFACE 2 (Reich 2017) compared subcutaneous tildrakizumab (100 mg or 200 mg) at week 0, 4, 12, and 16 weeks versus etanercept 50 mg (twice weekly for 12 weeks; then once weekly) for the treatment of plaque psoriasis. At week 12, a significantly greater proportion of patients achieved a 75%, 90%, and 100% improvement in psoriasis severity (PASI 75/90/100 response) with tildrakizumab (100 mg or 200 mg) compared with etanercept. The proportion of patients with cleared or minimal disease according to the physician´s global assessment (PGA 0/1) and Dermatology Life Quality Index (DLQI 0/1) was significantly higher with tildrakizumab 200 mg (non-FDA approved dose) versus etanercept at week 12; however, this statistical significance was not achieved with tildrakizumab 100 mg (FDA-approved dose) versus etanercept. Serious adverse events were low and comparable between treatment groups.105,125

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• NCT02054481 phase II study (Papp 2017) compared risankizumab at non-approved doses (18 mg, 90 mg, or 180 mg) versus ustekinumab (45 mg or 90 mg, depending on weight) for the treatment of plaque psoriasis. Significantly greater improvements in psoriasis in terms of PASI 50/75/90/100 and PGA 0/1 were reported with risankizumab versus ustekinumab.105,126

Loos et al (2018) conducted an SR and network meta-analysis of immunomodulators for the treatment of patients with moderate to severe psoriasis.104 Eigth head-to-head RCTs were reported in this SR (7 RCTs already identified by Sbidian et al and one new RCT published in 2017- IXORA-S trial133). Efficacy results from individual studies were consistent with the results reported by Sbidian 2017. Results for IXORA-S trial are as follows:

• IXORA-S trial (Reich 2017) showed superiority of ixekizumab at the FDA-approved dosage (160 mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks) compared to ustekinumab at the FDA-approved dosage (45 mg or 90 mg at weeks 0, 4, 16, 28 and 40) in terms of PASI 90 response at week 12. PASI 75, PASI 100, and static PGA responses at week 12 were significantly greater with ixekizumab compared to ustekinumab. Efficacy results at 12 weeks were maintained up to 24 weeks. No significant differences were reported regarding the overall incidence of adverse events.133

B. Psoriatic Arthritis Two SRs comparing cytokine inhibitors in patients with psoriatic arthritis were identified (Dressler 2019 and Corbett 2017).

Dressler et al (2019) performed an SR concerning the efficacy and safety of systemic treatments for the treatment of psoriatic arthritis in adult patients. One head-to-head RCT (Mease 2017: SPIRIT-P1) evaluating ixekizumab versus adalimumab, both at FDA-approved dosages, was identified. Results indicated no differences between these agents in terms of the American College of Rheumatology 20% response criteria (ACR20), American College of Rheumatology 50% response criteria (ACR50), adverse events, and Health Assessment Questionnaire Disability Index (HAQ-DI) after 16-24 weeks.108 This trial was under-powered to assess equivalency or non-inferiority versus adalimumab, as the primary objective was superiority assessment versus placebo.127

Corbett et al (2017) identified 3 head-to-head RCTs in adult patients with active psoriatic arthritis:

• Two RCTs included patients with psoriasis (Langley 2014 and Thaci 2015). Authors reported subgroup data regarding skin symptom response (ie, PASI) for those patients with concomitant PsA. In Langley 2014, secukinumab had significantly better PASI 75 and PASI 90 responses than etanercept at week 12. In Thaçi 2015, no significant differences were reported between secukinumab and ustekinumab with respect to PASI 90 at week 16. These 2 RCTs did not have data for joint symptom response in patients with PsA.

• The third RCT (Atteno 2010) compared adalimumab and etanercept, both at approved dosages for PsA, and showed different results depending on the outcome measured. In terms of PASI, adalimumab had significantly better skin responses compared to etanercept; however, in terms of tender joint count and disability, etanercept had significantly better responses vs. adalimumab.128 Of note, etanercept was used at the approved dosage for psoriatic arthritis (50 mg weekly), a lower dosage than that approved for plaque psoriasis (50 mg twice weekly).

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C. Rheumatoid Arthritis Five SRs providing head-to-head evidence in patients with active RA were identified (Choy 2019, Venerito 2019, Ma 2019, Emery 2018, and Kawalec 2013).109-113

Kawalec et al (2013) conducted a systematic review and meta-analysis of 2 RCTs (Fleischman 2012 and van Vollenhoven 2012) to compare the efficacy and safety of tofacitinib 5 mg twice daily versus adalimumab 40 mg once every 2 weeks. Regarding the percentage of patients achieving a 20% and 70% improvement response based on the ACR criteria (ACR20 and ACR70, respectively) at week 12, no significant differences were reported between both agents. With respect to the ACR50 response at week 12, tofacitinib was significantly better than adalimumab. No differences were reported between groups regarding the incidence of serious adverse events and discontinuations due to adverse events.113 One of the limitation of this meta-analysis is the use of different background therapy in each RCT. Based on data from Fleischman 2012 (patients on monotherapy), Kawalec et al reported no significant differences between agents with respect to ACR50 response. Based on data from van Vollenhoven 2012 (patients receiving methotrexate), Kawalec et al showed a significantly greater improvements with tofacitinib vs. adalimumab in terms of ACR50 response.113

Choy 2019, Venerito 2019, Ma 2019, and Emery 2018 reported 4 RCTs. Key findings for individual RCTs are described below:

Fleischmann 2017 conducted a 1-year RCT to compare the efficacy and safety of tofacitinib 5 mg twice daily versus adalimumab 40 mg every other week (both in combination with methotrexate [MTX]). Tofacitinib plus MTX was non-inferior to adalimumab plus MTX in term of ACR50 responses at month 6. No differences were reported between groups regarding ACR20, ACR70, and the number of patients with low disease activity or remission.131

Burmester et al (2017) conducted a 24-week RCT (superiority trial – MONARHC study) to compare the efficacy and safety of sarilumab monotherapy (200 mg every 2 weeks) versus adalimumab monotherapy (40 mg every 2 weeks) in RA adult patients with intolerance or inadequate response to methotrexate. The primary efficacy endpoint was the change from baseline in the severity of RA measured by the Disease Activity Score-28 using erythrocyte sedimentation rate (DAS28-ESR) at week 24. Sarilumab showed superiority over adalimumab for the primary endpoint. Regarding secondary endpoints, sarilumab showed significantly better results compared to adalimumab in terms of ACR 20/50/70 response rates, Health Assessment Questionnaire Disability Index, Clinical Disease Activity Index remission, and low disease activity. Safety profiles of both agents were comparable, with similar rates of adverse events, serious adverse events, discontinuations between treatment groups.129 Although this study assessed differences with adalimumab dosed every other week, it is unknown how the treatments would compare if adalimumab was dosed at 40 mg weekly, an additional dosing frequency approved for RA patients not receiving methotrexate.

Weinblatt et al (2013) conducted a 2-year, non-inferiority RCT (AMPLE study) to evaluate the efficacy and safety of subcutaneous abatacept (125 mg once weekly) plus MTX compared to subcutaneous adalimumab (40 mg every other week) plus MTX in patients with active RA who had inadequate response to methotrexate and had not received biologic therapy. This publication reports the results at year 1. Abatacept was non-inferior to adalimumab regarding ACR20 response at year 1.63 Regarding secondary efficacy endpoints, comparable results were reported between groups in terms of ACR50 response, ACR70 response, Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) score, and radiographic damage progression. Similar safety

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profiles between both agents were reported, except for the incidence of local injection-site reactions that was significantly higher with adalimumab therapy vs. abatacept and led to treatment discontinuation.63 Schiff et al (2014) published the final results of the 2-year AMPLE study.130 A non-inferiority evaluation for efficacy was not formally assessed at year 2, nor were safety outcomes statistically compared.130 At the end of year 2, ACR 20, ACR50, ACR70, and radiographic outcomes were similar between both treatment groups and compared to year 1 results. There were similar adverse events and serious adverse events between abatacept and adalimumab. Numerically more serious infections were reported with adalimumab compared to abatacept. Lower discontinuation rates due to adverse events (including serious adverse events and serious infections) and fewer injection site reactions were reported in the abatacept group compared to adalimumab.

Jobanputra et al (2012) conducted an unblinded, pragmatic non-inferiority trial (RED SEA study) to compare subcutaneous adalimumab 40 mg every other week versus etanercept 50 mg weekly in RA patients with inadequate response to 2 DMARDs (eg, MTX).132 Adalimumab was non-inferior to etanercept with respect to the percentage of patients continuing therapy over 52 weeks. DAS28 response, treatment satisfaction, and adverse events (key secondary outcomes) were similar between groups after 52 weeks. Some limitations of this study include the absence of blinding, pragmatic design, and wide non-inferiority margin.132

An additional RCT (Taylor 2017) in adult patients with active RA was reported in the SR by Choy 2019. In this trial, patients received baricitinib 4 mg once daily, adalimumab 40 mg every other week, or placebo.134 Since baricitinib 4 mg is a non-FDA-approved dosage, we do not focus on results since the effects of the 4 mg can not be automatically extrapolated to the lower 2 mg approved dosage.134

At the time of the literature search undertaking, upadacitinib was not yet approved so was not included in the search strategy. Based on the product labeling information and a secondary search in PubMed after its approval in August, a head-to-head RCT was identified (Fleischmann 2019).114 This trial compared upadacitinib 15 mg once daily versus adalimumab 40 mg every other week (both in combination with MTX) in adults with RA and an inadequate response to MTX. Upadacitinib was superior to adalimumab regarding the ACR50 response rate, percentage of patients achieving a DAS28-CRP score of ≤3.2, pain reduction (as measured by the 0-100 mm visual analog scale), and improvement in physical function (as measure by HAQ-DI). A significantly higher number of patients on upadacitinib achieved low disease activity or remission compared to adalimumab.114 Adverse events and serious adverse events were similar between both agents, with the exception of a numerically higher incidence of herpes zoster and creatine phosphokinase elevations with upadacitinib.114

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Safety

Direct Comparative Evidence

A systematic review (Desai 2016) of 10 RCTs and 51 observational studies showed comparative safety results based on head-to-head studies with cytokine inhibitors in RA, PsO, and PsA population.135 With respect to overall adverse events and/or serious adverse events, 4 RCTs in 5 publications (Weinblatt 2013, Schiff 2014, Jobanputra 2012, van Vollenhoven, and Fleischmann 2012) including RA patients showed no significant differences for adalimumab versus abatacept, etanercept, or tofacitinib. Authors stated that the strength of evidence for these outcomes was low or insufficient. Two RCTs in PsO patients reported no significant differences in terms of overall adverse events and serious adverse events for etanercept versus ustekinumab. Regarding treatment discontinuation due to adverse events, no significant differences were observed among cytokine inhibitors; however, 1 RCT (Schiff 2014) in RA patients showed less risk of discontinuation due to adverse events with abatacept compared to adalimumab at FDA-approved dosages. Based on observational data, a lower risk for drug discontinuation due to AEs, serious infections, and tuberculosis was reported with etanercept compared to adalimumab in RA patients. With respect to the incidence of mortality, malignancies, and herpes zoster, evidence was insufficient to demonstrate any difference between adalimumab and etanercept in RA patients.135 In non-RA patients, comparative safety evidence was very limited.135

In the setting of plaque psoriasis, a Cochrane review (Sbidian et al) assessed safety outcomes and showed no significant differences in terms of serious adverse events (primary safety outcome) with ustekinumab, secukinumab, or ixekinumab versus etanercept; secukinumab or brodalumab vs. ustekinumab; and guselkumab vs. adalimumab.106 Similarly, Loos et al reported an RCT showing no significant differences regarding the overall incidence of adverse events between ixekizumab vs. ustekinumab.104

Regarding psoriatic arthritis, Dressler et al reported an RCT showing no differences in adverse events between ixekizumab versus adalimumab.108

In the setting of rheumatoid arthritis, a meta-analysis of 2 RCTs (Kawalec 2013) reported no differences between tofacitinib 5 mg and adalimumab 40 mg every 2 weeks regarding the incidence of serious adverse events and discontinuations due to adverse events.113 An RCT (Weinblatt et al) reported similar safety profiles between adalimumab and abatacept, except for the incidence of local injection-site reactions leading to treatment discontinuation, which was significantly higher with adalimumab therapy vs. abatacept.63 Another RCT (Fleischmann 2019) reported similar adverse events and serious adverse events between upadacitinib and adalimumab, with the exception of a numerically higher incidence of herpes zoster and creatine phosphokinase elevations with upadacitinib.114

Warnings and Precautions

Immunogenicity

Biologic agents are efficacious in the treatment of autoimmune diseases such as RA, SpA, and IBD. However, some patients receiving biologics require higher doses or lose response over time due to the formation of antibodies against biologic agent. Anti-drug antibodies may reduce or inhibit the effect of the monoclonal antibody. When drug efficacy is diminished through this mechanism, it is called

66

immune-mediated failure. In this scenario, patients have elevated levels of drug-antibodies present and subtherapeutic drug levels. Therapeutic drug monitoring and measurement of drug-antibodies may be used to determine the reason for inadequate response to biologic therapy (particularly in UC).86

Infection Potential, Screening for Latent Infections, and Hematological Abnormalities

A main concern with immunosuppressive therapies is the increased risk of infection. Cytokine inhibitors may increase the risk of infections and most have warnings about risk of serious infections. Several agents have black box warnings pertaining to serious infection; this group includes TNF-alpha blockers, JAK inhibitors, and 2 IL-antagonists, sarilumab and tocilizumab.7,8,12,13,15-18,20 Patients should be tested for tuberculosis (TB) infection prior to initiating cytokine inhibitors. TNF-alpha inhibitors, JAK inhibitors, and the IL-antagonists, sarilumab and tocilizumab, have black box warnings regarding TB infection.7,8,12,13,15-

18,20 To minimize the risk for TB reactivation, positive cases of latent TB should be started on prophylaxis therapy before initiating treatment with a cytokine inhibitor. Cytokine inhibitors should not be started with active TB infection or any other serious infection. Labeling for TNF-alpha inhibitors warns of hepatitis B reactivation with treatment.15-18 Other possible infections should be considered according to clinical guideline recommendations before initiating treatment with these agents. For example, the ACG recommends screening for TB and viral hepatitis prior to initiating ant-TNF therapy in all CD patients and considering whether other latent opportunistic infections (eg, histoplasmosis and blastomycosis) are present based on patient risk factors.85

Hematological reactions (eg, leukopenia, pancytopenia, thrombocytopenia, aplastic anemia) may occur with the TNF-alpha inhibitors, JAK inhibitors, and with the IL-blockers, anakinra, sarilumab, and tocilizumab.7,8,10,13,15-18,20

Product labeling advises to avoid live vaccines for all the reviewed cytokine inhibitors with the exception of apremilast.1-20 Current CDC immunization schedules should be referred to for additional instructions regarding use of vaccines in patients with planned iatrogenic immunosuppression.

Malignancies

Black box warnings are included for TNF-alpha inhibitors and JAK inhibitors regarding cases of malignancy.7,8,15-18,20 During controlled trials of the TNF-blockers, there were more cases of malignancies observed in the treatment arm compared to control. Cases of malignancy have also been reported with the use of utstekinumab and the JAK inhibitors.

Cardiovascular Concerns

Thrombosis cases (eg, deep venous thrombosis and pulmonary embolism) have been reported with the use of JAK inhibitors; this is a black box warning for baricitinib and upadacitinib.8,20 The black box warning for tofacitinib specifically refers to a higher incidence of thrombosis and all-cause mortality with the use of tofacitinib 10 mg twice daily compared to tofacitinib 5 mg twice daily or TNF inhibitors in RA patients 50 years and older with at least 1 cardiovascular risk factor.7

There are some uncertainties concerning the use of JAK inhibitors at higher doses and the association of a higher incidence of cardiovascular events. A 2019 SR and MA of RCTs comparing JAK inhibitors versus placebo for adult patients with RA showed no association between tofacitinib or baricitinib, individually, and cardiovascular events (all cardiovascular events, major cardiovascular events, and venous

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thromboembolism events). When various JAK inhibitor doses were compared, no significant differences in cardiovascular safety were observed with tofacitinib 5 mg versus tofacitinib 10 mg; however, baricitinib 2 mg (the single FDA-approved dose) showed a significantly better cardiovascular safety profile compared to baricitinib 4 mg. Authors suggest that further post-marketing studies are needed to clarify the cardiovascular risk/benefit profile of these agents.136 Data from a large, ongoing postmarketing study in RA patients 50 years or older with at least one cardiovascular risk factor showed an increased risk of all-cause mortality, pulmonary embolism, deep venous thrombosis, and arterial thrombosis with tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily or versus TNF inhibitors.7 Consequently, this year, the FDA included a black box warning for Xeljanz (tofacitinib) regarding this risk.7 8

Some agents were associated with increases in lipids (LDL, HDL cholesterol, or triglycerides) during clinical trials (sarilumab, tocilizumab, and the JAK inhibitors); yet, the effect of this elevation on cardiovascular risk has not been determined. Lipid levels should be monitored during treatment and elevations can be managed according to clinical guidelines as necessary. 7,8,12,13,20

Suicidal Ideation

Brodalumab carries a black box warning concerning the risk of suicidal ideation and behavior with the use of this agent.1 Four completed suicides were reported in psoriasis clinical trials with brodalumab. This medicine is only available through the Siliq Risk Evaluation and Mitigation Strategy (REMS) program.1

The warnings discussed thus far in addition to others are summarized in Tables 23, 24 and 25.

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Table 23. Warnings and Precautions for TNF-alpha Inhibitors 15-18 ,a

Warning/Precaution ADA CER ETA GOL

Serious infections leading to hospitalization or death have occurred while receiving the drug

X X X X

The risk/incidence of infections may be increased X X X X

Do not start during an active infection X X X X

Discontinue if serious infection develops and until resolved X X X X

Screen for tuberculosis infection prior to initiating therapy X X X X

Hepatitis B virus reactivation: test before starting and monitor carriers X X X X

Consider empiric antifungal therapy for patients that develop a systemic illness during treatment and who reside or travel to regions where mycoses are endemic

X X X X

Avoid concurrent use of live vaccines X X X X Increased risk of serious infection when a TNF alpha inhibitor is combined with anakinra or abatacept

X X

(and RIT, and NAT)

X X (and RIT)

Hypersensitivity, anaphylaxis, anaphylactoid reactions X X X X

Reported cases of malignancies X (cases of lymphoma and other malignancies)

Exacerbation or new onset demyelinating disease may occur X X X X

Cytopenia potential (eg, pancytopenia, leukopenia, thrombocytopenia, or aplastic anemia)

X X X X

Heart failure, worsening or new onset X X X X

Lupus-like syndrome X X X X

Autoimmune hepatitis X Abbreviations: ADA, adalimumab; CER, certolizumab; ETA, etanercept; GOL, golimumab; NAT, natalizumab; RIT, rituximab; TNF, tumor necrosis factor a Boxes outlined black and with a bolded X means that it is with respect to a black box warning for the product

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Table 24. Warnings and Precautions for Interleukin Antagonists1-6,10,12-14,a

Warning/Precaution ANA BRO CAN GUS IXE RIS SAR SEC TOC TIL UST

Serious infections leading to hospitalization or death have occurred

X X X X X X X X X

Risk/incidence of infections may be increased X X X X X X X X X

Do not start during active infection X X X X X X X X

Discontinue if serious infection develops and until resolved

X X X X X X X X X X X

Screen for tuberculosis prior to initiating therapy X X X X X X X X X X X

Avoid concurrent use of live vaccines X X X X X X X X X X X

Concomitant use is not recommended with TNF antagonists

X

Hypersensitivity/ anaphylaxis X X X X X X X X X

Reported cases of malignancies

X

Decreased neutrophil counts; monitor prior, during, and after treatment

X

Neutropenia, thrombocytopenia, elevated liver enzymes, lipid abnormalities: monitor laboratory parameters

X

X

Suicidal ideation and behavior, including completed suicides, have occurred

X (REMS

program)

Reported cases of GI perforation; use with caution with other risk factors (eg, diverticulitis or NSAID use)

X

X

Caution with comorbid IBD X X Non-infectious pneumonia cases reported

X

One case of Reversible Posterior Leukoencephalopathy Syndrome reported

X

Abbreviations: ANA, anakinra; BRO, brodalumab; CAN, canakinumab; GUS, guselkumab; IXE, ixekizumab; RIS, risankizumab; SAR, sarilumab; SEC, secukinumab; TIL, tildrakizumab; TOC, tocilizumab; UST, ustekinumab a Boxes outlined black and with a bolded X means that it is a black box warning

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Table 25. Warnings and Precautions for Selective T Cell Co-stimulator, PDE-4 Inhibitor, and Janus Kinase Inhibitors , a

Warning/Precaution ABA APR BAR TOF UPA

Serious infections leading to hospitalization or death have occurred while receiving the drug X

X X X

Do not start during an active infection X X X

Discontinue if serious infection develops and until resolved X

X X X

Screen for tuberculosis infection prior to initiation X

X X X

Avoid concurrent use of live vaccines X X X X

Patients with juvenile idiopathic arthritis should be brought up to date with all immunizations prior to therapy X

Concomitant use is not recommended with TNF antagonists X

Hypersensitivity, anaphylaxis, anaphylactoid reactions X X COPD pts may develop more frequent respiratory adverse events X

Reported cases of malignancies

X (cases of lymphoma and

other malignancies)

Thrombosis cases reported (eg, DVT, PE and arterial thrombosis)

X X X

Higher risk of all-cause mortality and thrombosis in rheumatoid arthritis patients 50 years of age or older who had at least one cardiovascular risk factor and were treated with TOF 10 mg twice daily versus 5 mg twice daily or TNF blockers

X

Monitor for potential abnormalities in neutrophils, lymphocytes, lipids, hemoglobin, and liver enzymes

X X X

Worsening of depression, suicidal thoughts or other mood changes

X

Reported cases of GI perforation; use with caution in patients with other risks (eg, concurrent diverticulitis or NSAID use)

X X X

May cause significant weight loss X

May cause fetal harm based on animal studies X X X X

Potential for severe diarrhea, nausea and vomiting; dose reduce or stop if this occurs

X

Use with strong CYP450 enzyme inducers (rifampin, phenobarbital, carbamazepine, phenytoin) not recommended

X

Abbreviations: ABA, abatacept; APR, apremilast; BAR, baricitinib; TOF, tofacitinib; UPA, upadacitinib a Boxes outlined black and with a bolded X means that it is a black box warning

71

The most common adverse events reported with cytokine inhibitors include headache, upper respiratory tract infections, gastrointestinal adverse events, injection-site reactions, herpes simplex, herpes zoster, and tinea infections. Table 26 lists the most common adverse events reported in the product labeling for cytokine inhibitors.

Table 26. Adverse Effects for Cytokine Inhibitors1-20 Generic Name Adverse Effects Reported in the Package Insert Abatacept Most common AE (≥ 10%):

- Headache, upper respiratory tract infection, nasopharyngitis, and nausea Adalimumab Most common AE (≥ 10%):

- Infections (e.g. upper respiratory, sinusitis), injection site reactions, headache and rash Anakinra Most common AE (≥ 5%):

- Injection site reaction, worsening of rheumatoid arthritis, upper respiratory tract infection, headache, nausea, diarrhea, sinusitis, arthralgia, flu like-symptoms, and abdominal pain

Apremilast Most common AE (≥ 5%): - PsA: diarrhea, nausea, and headache - Psoriasis: diarrhea, nausea, upper respiratory tract infection, and headache, including

tension headache Baricitinib AEs ≥ 1%:

- Upper respiratory tract infections, nausea, herpes simplex, and herpes zoster Brodalumab AEs ≥ 1%:

- Arthralgia, headache, fatigue, diarrhea, oropharyngeal pain, nausea, myalgia, injection site reactions, influenza, neutropenia, and tinea infections

Canakinumab Most common AE (≥ 10%): - Infections (nasopharyngitis and upper respiratory tract infections), abdominal pain and

injection-site reactions Certolizumab pegol

Most common AE (≥ 7%): - Upper respiratory tract infection, rash, and urinary tract infection

Etanercept Most common AE (> 5%): - Infections and injection site reactions

Golimumab Most common AE (> 5%): - Upper respiratory tract infection, nasopharyngitis, injection site reactions

Guselkumab Most common AE (≥ 1%): - Upper respiratory infections, headache, injection site reactions, arthralgia, diarrhea,

gastroenteritis, tinea infections, and herpes simplex infections Ixekizumab Most common AE (≥ 1%):

- Injection site reactions, upper respiratory tract infections, nausea, and tinea infections Risankizumab-rzaa

Most common AE (≥ 1%): - Upper respiratory infections, headache, fatigue, injection site reactions, and tinea

infections Sarilumab Most common AE (≥ 3%):

- Neutropenia, increased ALT, injection site erythema, upper respiratory infections and urinary tract infections.

Secukinumab Most common AEs (> 1%): - Nasopharyngitis, diarrhea, and upper respiratory tract infection

Tildrakizumab-asmn

Most common AEs (≥1%): - Upper respiratory infections, injection site reactions, and diarrhea

Tocilizumab Most common AEs (≥5%): - Upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased

ALT, and injection site reactions

72

Table 26. Adverse Effects for Cytokine Inhibitors1-20 Generic Name Adverse Effects Reported in the Package Insert Tofacitinib AEs (≥ 2%):

- RA and PsA: upper respiratory tract infection, nasopharyngitis, diarrhea, and headache AEs (≥ 5%): - Nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection,

increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster Ustekinumab AEs (≥ 3%):

- Psoriasis: nasopharyngitis, upper respiratory tract infection, headache, and fatigue - Crohn’s Disease (induction): vomiting - Crohn’s Disease (maintenance): nasopharyngitis, injection site erythema, vulvovaginal

candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, and sinusitis Upadacitinib AEs (≥ 10%):

- headache, upper respiratory tract infection, nasopharyngitis, and nausea Abbreviations: AE, adverse effect; ALT, alanine aminotransferase; PsA, psoriatic arthritis; RA, rheumatoid arthritis

73

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80

125. Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet (London, England). 2017;390(10091):276-288.

126. Papp KA, Blauvelt A, Bukhalo M, et al. Risankizumab versus Ustekinumab for Moderate-to-Severe Plaque Psoriasis. The New England journal of medicine. 2017;376(16):1551-1560.

127. Mease PJ, van der Heijde D, Ritchlin CT, et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Annals of the rheumatic diseases. 2017;76(1):79-87.

128. Atteno M, Peluso R, Costa L, et al. Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drugs. Clin Rheumatol. 2010;29(4):399-403.

129. Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Annals of the rheumatic diseases. 2017;76(5):840-847.

130. Schiff M, Weinblatt ME, Valente R, et al. Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Annals of the rheumatic diseases. 2014;73(1):86-94.

131. Fleischmann R, Mysler E, Hall S, et al. Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet (London, England). 2017;390(10093):457-468.

132. Jobanputra P, Maggs F, Deeming A, et al. A randomised efficacy and discontinuation study of etanercept versus adalimumab (RED SEA) for rheumatoid arthritis: a pragmatic, unblinded, non-inferiority study of first TNF inhibitor use: outcomes over 2 years. BMJ Open. 2012;2(6).

133. Reich K, Pinter A, Lacour JP, et al. Comparison of ixekizumab with ustekinumab in moderate-to-severe psoriasis: 24-week results from IXORA-S, a phase III study. The British journal of dermatology. 2017;177(4):1014-1023.

134. Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. The New England journal of medicine. 2017;376(7):652-662.

135. Desai RJ, Thaler KJ, Mahlknecht P, et al. Comparative Risk of Harm Associated With the Use of Targeted Immunomodulators: A Systematic Review. Arthritis care & research. 2016;68(8):1078-1088.

136. Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Annals of the rheumatic diseases. 2019(0372355, 62w).

137. Europe Sees Its First Adalimumab Biosimilar Launches. https://www.centerforbiosimilars.com/news/europe-sees-its-first-adalimumab-biosimilar-launch. Accessed September 4, 2019.

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https://www.centerforbiosimilars.com/news/europe-sees-its-first-adalimumab-biosimilar-launch

https://www.boehringer-ingelheim.us/press-release/boehringer-ingelheim-announces-resolution-cyltezo-patent-litigation

https://www.boehringer-ingelheim.us/press-release/boehringer-ingelheim-announces-resolution-cyltezo-patent-litigation

https://www.sandoz.com/news/media-releases/sandoz-announces-global-resolution-biosimilar-adalimumab-patent-disputes

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announces-global-resolution-biosimilar-adalimumab-patent-disputes. Accessed September 4, 2019. .

140. Mao EJ, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN. Systematic review with meta-analysis: comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn's disease and ulcerative colitis. Aliment Pharmacol Ther. 2017;45(1):3-13.

141. Cholapranee A, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN. Systematic review with meta-analysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcerative colitis controlled trials. Aliment Pharmacol Ther. 2017;45(10):1291-1302.

142. Bonovas S, Fiorino G, Allocca M, et al. Biologic Therapies and Risk of Infection and Malignancy in Patients With Inflammatory Bowel Disease: A Systematic Review and Network Meta-analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2016;14(10):1385-1397.e1310.

143. Mocko P, Kawalec P, Pilc A. Safety Profile of Biologic Drugs in the Therapy of Ulcerative Colitis: A Systematic Review and Network Meta-Analysis. Pharmacotherapy. 2016;36(8):870-879.

144. Mocko P, Kawalec P, Pilc A. Safety profile of biologic drugs in the therapy of Crohn disease: A systematic review and network meta-analysis. Pharmacol Rep. 2016;68(6):1237-1243.

145. Mocko P, Kawalec P, Pilc A. Safety Profile of Biologic Drugs in the Treatment of Inflammatory Bowel Diseases: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials. Clin Drug Investig. 2017;37(1):25-37.

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147. Bakouny Z, Yared F, El Rassy E, et al. Comparative Efficacy of Anti-TNF Therapies For The Prevention of Postoperative Recurrence of Crohn's Disease: A Systematic Review and Network Meta-Analysis of Prospective Trials. Journal of clinical gastroenterology. 2019;53(6):409-417.

148. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease. Aliment Pharmacol Ther. 2018;48(4):394-409.

149. Singh S, Garg SK, Pardi DS, Wang Z, Murad MH, Loftus EV, Jr. Comparative efficacy of biologic therapy in biologic-naive patients with Crohn disease: a systematic review and network meta-analysis. Mayo Clinic proceedings. 2014;89(12):1621-1635.

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151. MacDonald JK, Nguyen TM, Khanna R, Timmer A. Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. The Cochrane database of systematic reviews. 2016;11:Cd007572.

152. Hazlewood GS, Rezaie A, Borman M, et al. Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn's disease: a network meta-analysis. Gastroenterology. 2015;148(2):344-354.e345; quiz e314-345.

153. Da W, Zhu J, Wang L, Lu Y. Efficacy and safety of certolizumab pegol for Crohn's disease: a systematic review and meta-analysis. Advances in therapy. 2013;30(5):541-553.

154. Kawalec P, Mikrut A, Wisniewska N, Pilc A. Tumor necrosis factor-alpha antibodies (infliximab, adalimumab and certolizumab) in Crohn's disease: systematic review and meta-analysis. Archives of medical science : AMS. 2013;9(5):765-779.

155. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Aliment Pharmacol Ther. 2018;47(2):162-175.

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83

Appendix A – Additional Product Information for Cytokine Modulators

Table 1. Available Drug Preparations of Cytokine Modulators1-20 Generic Name Brand Name

(Approval Date) SQ and PO Preparations Route of

Administration

Abatacept

Orencia (2005)

- Single-dose prefilled syringe for SQ use: 50 mg/0.4 mL 87.5 mg/0.7 mL 125 mg/mL

- Single-dose prefilled ClickJect autoinjector for SQ use 125 mg/mL

- Single-use vial with 250 mg lyophilized powder for IV use

SQ or IV

Adalimumab

Humira (2002)

- Single-dose, 1 mL prefilled glass syringe: 80 mg/0.8 mL 40 mg/0.4 mL 40 mg/0.8 mL 20 mg/0.2 mL 20 mg/0.4 mL 10 mg/0.1 mL 10 mg/0.2 mL

- Single-dose 1 mL prefilled pens: 80 mg/0.8 mL 40 mg/0.4 mL 40 mg/0.8 mL

- Single-dose, glass vials: 40 mg /0.8 mL

SQ

Anakinra

Kineret (2001)

Single-use, Preservative free, 0.67mL prefilled glass syringe: 100mg/0.67mL SQ

Apremilast

Otezla (2014)

Tabs: 10 mg 20mg 30mg

Oral

Baricitinb

Olumiant (2018)

Tabs: 2mg Oral

Brodalumab

Siliq (2017)

Single-dose prefilled syringe containing 210 mg/1.5 mL solution SQ

Canakinumab

Ilaris (2009)

- Single-dose vials of 150 mg lyophilized powder for reconstitution

- Single-dose vials of 150 mg/mL solution SQ

Certolizumab Pegol

Cimzia (2008)

- Single-use, 1 mL prefilled glass syringe containing 200 mg/mL

- Single-use vial of 200 mg lyophilized powder for injection SQ

84



Administration

Etanercept

Enbrel (1998)

- Single-use prefilled syringe containing 50 mg or 25 mg etanercept

- SureClick autoinjector containing 50 mg etanercept - Multiple-use vial containing 25 mg etanercept

(recommended for weight-based dosing) - Enbrel Mini® single-dose prefilled cartridge containing

50 mg (for use with the AutoTouch® reusable autoinjector only)

SQ

Golimumab

Simponi (2009)

Single-dose prefilled syringe or SmartJect autoinjector containing 50 mg/0.5 mL or 100 mg/mL SQ

Guselkumab

Tremfya (2017)

Single-dose prefilled syringe or One-Press patient-controlled injection containing 100 mg/mL SQ

Ixekizumab

Taltz (2016)

- Single-dose prefilled autoinjector of 80 mg/mL - Single-dose prefilled syringe of 80 mg/mL SQ

Risankizumab-rzaa

Skyrizi (2019)

Single-dose prefilled syringe of 75 mg/0.83 mL SQ

Sarilumab

Kevzara (2017)

Single-dose prefilled syringe of 150 mg/1.14 mL or 200 mg/1.14 mL solution SQ

Secukinumab

Cosentyx (2015)

- Single-use Sensoready pen solution for injection containing 150 mg/mL

- Single-use prefilled syringe for injection containing 150 mg/mL

- Single-use vial for reconstitution containing 150 mg of lyophilized powder

SQ

Tildrakizumab-asmn

Ilumya (2018)

Single-dose prefilled syringe containing 100 mg/mL SQ

Tocilizumab

Actemra (2010)

- Single-use prefilled syringe containing 162 mg/0.9 mL solution

- Single-dose vial for IV administration: 80 mg/4 mL 200 mg/10 mL 400 mg/20 mL

SQ, IV

85



Administration

Tofacitinib

Xeljanz (2012)

Xeljanz XR (2016)

Tablets: 5 mg, 10 mg XR Tablets: 11 mg Oral

Ustekinumab

Stelara (2009)

- Single-dose prefilled syringe of 45 mg/0.5 mL or 90 mg/mL for SQ injection

- Single-dose vial of 45 mg/0.5 mL for SQ injection - Single-dose vial of 130 mg/26 mL (5 mg/ml) solution for

IV injection

SQ, IV

Abbreviations: IV, intravenous; SQ, subcutaneous

Table 2. Approved Biosimilars Originator (Brand name)

Biosimilars (Brand name)

FDA Approval Date Online information for future launch date

Adalimumab (Humira) Brand product Dec 2002 (Adalimumab-atto) Amjevita

Sep 2016 After Sept 2023137

Adalimumab- abdm (Cyltezo)

Aug 2017 After Sept 2023138

Adalimumab-adaz (Hyrimoz)

Oct 2018 After Sept 2023139

Adalimumab-bwwd (Hadlima)

July 2019 Unknown

Etanercept (Enbrel)

Brand product 1998 Etanercept-szzs (Erelzi)

Aug 2016 Unknown

Etanercept-ykro (Eticovo)

April 2019 Unknown

86

Appendix B - Literature Search Strategies 1. Ovid Medline Search Strategy Database(s): Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily 1946 to June 07, 2019

# Searches Results

1 Abatacept/ or abatacept.ti,ab,kw,kf,rn. 3482

2 Adalimumab/ or adalimumab.ti,ab,kw,kf,rn. 7515

3 Anakinra.ti,ab,kw,kf,rn. 1553

4 Apremilast.ti,ab,kw,kf,rn. 486

5 Baricitinib.ti,ab,kw,kf,rn. 184

6 Brodalumab.ti,ab,kw,kf,rn. 219

7 Canakinumab.ti,ab,kw,kf,rn. 567

8 Certolizumab Pegol/ or certolizumab.ti,ab,kw,kf,rn. 1153

9 Etanercept/ or etanercept.ti,ab,kw,kf,rn. 8055

10 Golimumab.ti,ab,kw,kf,rn. 1073

11 Guselkumab.ti,ab,kw,kf,rn. 127

12 Ixekizumab.ti,ab,kw,kf,rn. 375

13 Risankizumab.ti,ab,kw,kf,rn. 44

14 Sarilumab.ti,ab,kw,kf,rn. 80

15 Secukinumab.ti,ab,kw,kf,rn. 757

16 Tildrakizumab.ti,ab,kw,kf,rn. 77

17 Tocilizumab.ti,ab,kw,kf,rn. 2635

18 Tofacitinib.ti,ab,kw,kf,rn. 1064

19 Ustekinumab/ or ustekinumab.ti,ab,kw,kf,rn. 1609

20 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 22846

21 (((Interleukin* or IL*) adj4 (blocker* or inhibitor* or antagonist*)) or anti-interleukin*).ti,ab,kw,kf. 20306

22 (((tumor necrosis factor* or tumour necrosis factor* or TNF*) adj2 (blocker* or inhibitor* or

antagonist*)) or anti-TNF* or antiTNF*).ti,ab,kw,kf. 19697

23 Janus Kinase Inhibitors/ or (JAK* or (janus adj3 (inhibitor* or blocker* or antagonist*))).ti,ab,kw,kf. 28563

87

24 Phosphodiesterase 4 Inhibitors/ or ((Phosphodiesterase or phosphodiesterase type 4 or

phosphodiesterase 4 or PDE4) adj2 (inhibitor* or blocker* or antagonist*)).ti,ab,kw,kf. 11384

25 (T-cell adj2 (blocker* or modulator* or inhibitor* or antagonist*)).ti,ab,kw,kf. 1158

26 Interleukin 1 Receptor Antagonist Protein/ 4881

27 Antirheumatic Agents/ or (Antirheumatic* or DMARD* or antipsoriatic*).ti,ab,kw,kf. 27217

28 Antibodies, Monoclonal/ or Antibodies, Monoclonal, Humanized/ or (monoclonal antibod* or

biologic*).ti,ab,kw,kf. 1065123

29 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 1145056

30 Psoriasis/ or psoria*.ti,ab,kw,kf. 50516

31 Arthritis, Psoriatic/ or psoriatic arthritis.ti,ab,kw,kf. 9219

32 Arthritis, Rheumatoid/ or rheumatoid arthritis.ti,ab,kw,kf. 129003

33 Spondylitis, Ankylosing/ or Spondylarthritis/ or Spondylarthropathies/ or (Ankylosing spondylitis or

Spondyloarthritis or Spondylarthropath*).ti,ab,kw,kf. 21425

34 Arthritis, Juvenile/ or (juvenile adj2 arthritis).ti,ab,kw,kf. 12628

35 Inflammatory Bowel Diseases/ or Colitis, Ulcerative/ or Crohn Disease/ or (inflammatory bowel

disease* or IBD* or ulcerative colitis or Crohn* or regional ileitis or regional enteritis).ti,ab,kw,kf. 108223

36 30 or 31 or 32 or 33 or 34 or 35 298813

37

meta-analysis/ or (metaanaly$ or meta-analy$).ti,ab,kw,kf. or "Systematic Review"/ or ((systematic

adj3 review$) or (systematic adj2 search$) or cochrane$ or (overview adj4 review)).ti,ab,kw,kf. or

(cochrane$ or systematic review?).jw.

293397

38 (MEDLINE or systematic review).tw. or meta analysis.pt. 242338

39 37 or 38 324503

40 (20 or 29) and 36 and 39 2340

41 limit 40 to yr="2011 -Current" 1780

88

2. Embase Search Strategy No. Query

Results 1,511

#44 #38 OR #43

1,284 #43 #39 OR #41

1,511 #42 #38 OR #39 OR #41

1,078 #41 #29 AND #37 AND #40 AND [2011-2019]/py

250,447 #40 #32 OR #33

303 #39 #29 AND #31 AND #37 AND [2016-2019]/py

272 #38 #29 AND #30 AND #37 AND [2017-2019]/py

267,753 #37 #34 OR #35 OR #36

29,088 #36 (systematic NEAR/2 search*):ti,ab,kw

254,135 #35 (cochrane*:jt OR 'systematic review*':jt OR 'meta analysis'/mj OR 'systematic review'/mj OR ((systematic NEAR/3 review*):ti,ab,kw) OR 'meta analys*':ti,ab,kw OR metaanalys*:ti,ab,kw OR ((overview NEAR/4 (review OR reviews)):ti)) NOT ('conference abstract'/it OR 'conference review'/it) AND [english]/lim

1,071 #34 'network meta-analysis'/exp NOT ('conference abstract'/it OR 'conference review'/it) AND [english]/lim

226,189 #33 'rheumatoid arthritis':ti,ab,kw OR 'rheumatoid arthritis'/exp OR 'juvenile rheumatoid arthritis'/exp OR ((juvenile NEXT/2 arthritis):ti,ab,kw)

36,803

89

#32 'ankylosing spondylitis':ti,ab,kw OR spondyloarthritis:ti,ab,kw OR spondylarthritis:ti,ab,kw OR spondylarthropath*:ti,ab,kw OR 'ankylosing spondylitis'/exp OR 'spondylarthritis'/exp

98,040 #31 psoria*:ti,ab,kw OR 'psoriatic arthritis':ti,ab,kw OR 'psoriasis'/exp OR 'psoriatic arthritis'/exp OR 'spondyloarthropathy'/exp OR spondyloarthropath*:ti,ab,kw

182,604 #30 'inflammatory bowel disease*':ti,ab,kw OR ibd*:ti,ab,kw OR 'ulcerative colitis':ti,ab,kw OR crohn*:ti,ab,kw OR 'regional ileitis':ti,ab,kw OR 'regional enteritis':ti,ab,kw OR 'inflammatory bowel disease'/exp OR 'crohn disease'/exp OR 'ulcerative colitis'/exp

3,292,074 #29 #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28

1,971,218 #28 (((interleukin* OR il*) NEXT/4 (blocker* OR inhibitor* OR antagonist*)):ti,ab,kw) OR 'anti interleukin*':ti,ab,kw OR 'cytokine receptor antagonist'/de OR 'interleukin 1 receptor blocking agent'/exp

21,045 #27 (((phosphodiesterase OR 'phosphodiesterase type 4' OR 'phosphodiesterase 4' OR pde4) NEXT/2 (inhibitor* OR blocker* OR antagonist*)):ti,ab,kw) OR 'phosphodiesterase inhibitor'/de OR 'phosphodiesterase iv inhibitor'/de

74,271 #26 'immunosuppressive agent'/de

1,300,546 #25 'monoclonal antibod*':ti,ab,kw OR biologic*:ti,ab,kw OR 'monoclonal antibody'/de

37,627 #24 antirheumatic*:ti,ab,kw OR dmard*:ti,ab,kw OR antipsoriatic*:ti,ab,kw OR 'antipsoriasis agent'/de OR 'antirheumatic agent'/de OR 'disease modifying antirheumatic drug'/de OR 'disease modifying therapy'/de OR 'disease modifying drug'/de OR 'disease modifying agent'/de

949 #23 ('t cell' NEXT/2 (blocker* OR modulator* OR inhibitor* OR antagonist*)):ti,ab,kw

44,986 #22 ((('tumor necrosis factor*' OR 'tumour necrosis factor*' OR tnf*) NEXT/2 (blocker* OR inhibitor* OR antagonist*)):ti,ab,kw) OR 'anti-tnf*':ti,ab,kw OR antitnf*:ti,ab,kw OR 'tumor necrosis factor inhibitor'/de

45,280 #21

90

jak*:ti,ab,kw OR ((janus NEXT/3 (inhibitor* OR blocker* OR antagonist*)):ti,ab,kw) OR 'janus kinase inhibitor'/de 70,361

#20 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19

5,913 #19 'ustekinumab'/exp OR 'ustekinumab':ti,ab,kw

3,736 #18 'tofacitinib'/exp OR tofacitinib:ti,ab,kw

10,549 #17 'tocilizumab'/exp OR tocilizumab:ti,ab,kw

300 #16 'tildrakizumab'/exp OR tildrakizumab:ti,ab,kw

2,788 #15 'secukinumab'/exp OR secukinumab:ti,ab,kw

397 #14 'sarilumab'/exp OR sarilumab:ti,ab,kw

217 #13 'risankizumab'/exp OR risankizumab:ti,ab,kw

1,313 #12 'ixekizumab'/exp OR ixekizumab:ti,ab,kw

439 #11 'guselkumab'/exp OR gulselkumab:ti,ab,kw

6,160 #10 'golimumab'/exp OR golimumab:ti,ab,kw

30,152 #9 'etanercept'/exp OR etanercept:ti,ab,kw

6,407 #8 'certolizumab pegol'/exp OR certolizumab:ti,ab,kw

2,704 #7 'canakinumab'/exp OR canakinumab:ti,ab,kw

850

91

#6 'brodalumab'/exp OR brodalumab:ti,ab,kw

822 #5 'baricitinib'/exp OR baricitinib:ti,ab,kw

1,605 #4 'apremilast'/exp OR apremilast:ti,ab,kw

7,850 #3 'anakinra'/exp OR anakinra:ti,ab,kw

30,929 #2 'adalimumab'/exp OR adalimumab:ti,ab,kw

8,505 #1 abatacept:ti,ab,kw OR 'abatacept'/exp

92

Appendix C - Excluded References Wrong comparator

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2. Acosta Felquer ML, Coates LC, Soriano ER, et al. Drug therapies for peripheral joint disease in psoriatic arthritis: a systematic review. The Journal of rheumatology. 2014;41(11):2277-2285.

3. Adegbola SO, Sahnan K, Tozer PJ, et al. Review of local injection of anti-TNF for perianal fistulising Crohn's disease. International journal of colorectal disease. 2017;32(11):1539-1544.

4. Albert DA. Are All Biologics the Same? Optimal Treatment Strategies for Patients With Early Rheumatoid Arthritis: Systematic Review and Indirect Pairwise Meta-Analysis. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2015;21(8):398-404.

5. Almeida C, Choy EHS, Hewlett S, et al. Biologic interventions for fatigue in rheumatoid arthritis. The Cochrane database of systematic reviews. 2016(6):CD008334.

6. Amarilyo G, Tarp S, Foeldvari I, et al. Biological agents in polyarticular juvenile idiopathic arthritis: A meta-analysis of randomized withdrawal trials. Seminars in arthritis and rheumatism. 2016;46(3):312-318.

7. Ash Z, Gaujoux-Viala C, Gossec L, et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Annals of the rheumatic diseases. 2012;71(3):319-326.

8. Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D. Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: Meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiology and Drug Safety. 2011;20(2):119-130.

9. Baker EL, Coleman CI, Reinhart KM, et al. Effect of Biologic Agents on Non-PASI Outcomes in Moderate-to-Severe Plaque Psoriasis: Systematic Review and Meta-Analyses. Dermatology and therapy. 2012;2(1):9.

10. Balsa A, Lula S, Marshall L, Szczypa P, Aikman L. The comparative immunogenicity of biologic therapy and its clinical relevance in psoriatic arthritis: a systematic review of the literature. Expert opinion on biological therapy. 2018;18(5):575-584.

11. Bergrath E, Gerber RA, Gruben D, Lukic T, Makin C, Wallenstein G. Tofacitinib versus Biologic Treatments in Moderate-to-Severe Rheumatoid Arthritis Patients Who Have Had an Inadequate Response to Nonbiologic DMARDs: Systematic Literature Review and Network Meta-Analysis. International journal of rheumatology. 2017;2017(101519204):8417249.

12. Bilal J, Riaz IB, Kamal MU, Elyan M, Sudano D, Khan MA. A Systematic Review and Meta-analysis of Efficacy and Safety of Novel Interleukin Inhibitors in the Management of Psoriatic Arthritis. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2018;24(1):6-13.

13. Busard C, Zweegers J, Limpens J, Langendam M, Spuls PI. Combined use of systemic agents for psoriasis: a systematic review. JAMA dermatology. 2014;150(11):1213-1220.

14. CADTH Common Drug Review Report. Certolizumab pegol (Cimzia). Canadian Agency for Drugs and Technologies in Health, 2017. https://cadth.ca/sites/default/files/cdr/clinical/SR0385_CimziaAS_CL_Report_e.pdf. Accessed August 8, 2019.

15. CADTH Common Drug Review Report. Canakinumab (Ilaris). Canadian Agency for Drugs and Technologies in Health, 2016. https://cadth.ca/sites/default/files/cdr/clinical/SR0463_Ilaris_sJIA_CL_Report.pdf. Accessed August 8, 2019.

16. CADTH Common Drug Review Report. Ustekinumab (Stelara). Canadian Agency for Drugs and Technologies in Health, 2016. https://cadth.ca/sites/default/files/cdr/clinical/SR0359_Stelara_CL_Report.pdf. Accessed August 8, 2019.

17. Cai W, Gu Y, Cui H, et al. The Efficacy and Safety of Mainstream Medications for Patients With cDMARD-Naive Rheumatoid Arthritis: A Network Meta-Analysis. Frontiers in pharmacology. 2018;9(101548923):138.

18. Chen C, Zhang X, Xiao L, Zhang X, Ma X. Comparative Effectiveness of Biologic Therapy Regimens for Ankylosing Spondylitis: A Systematic Review and a Network Meta-Analysis. Medicine. 2016;95(11):e3060.

19. Corbett M, Soares M, Jhuti G, et al. Tumour necrosis factor-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis: a systematic review and economic evaluation. Health technology assessment (Winchester, England). 2016;20(9):1-vi.

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21. Daien CI, Hua C, Combe B, Landewe R. Non-pharmacological and pharmacological interventions in patients with early arthritis: a systematic literature review informing the 2016 update of EULAR recommendations for the management of early arthritis. RMD open. 2017;3(1):e000404.

22. Desai RJ, Hansen RA, Rao JK, et al. Mixed treatment comparison of the treatment discontinuations of biologic disease-modifying antirheumatic drugs in adults with rheumatoid arthritis. The Annals of pharmacotherapy. 2012;46(11):1491-1505.

23. Donahue KE, Gartlehner G, Schulman ER, et al. AHRQ Comparative Effectiveness Reviews. In: Drug Therapy for Early Rheumatoid Arthritis: A Systematic Review Update. Rockville (MD): Agency for Healthcare Research and Quality (US); 2018.

24. Geng Z, Yu Y, Hu S, Dong L, Ye C. Tocilizumab and the risk of respiratory adverse events in patients with rheumatoid arthritis: a systematic review and meta-analysis of randomised controlled trials. Clinical and experimental rheumatology. 2019;37(2):318-323.

25. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Annals of the rheumatic diseases. 2016;75(3):499-510.

26. Gulacsi L, Zrubka Z, Brodszky V, et al. Long-Term Efficacy of Tumor Necrosis Factor Inhibitors for the Treatment of Methotrexate-Naive Rheumatoid Arthritis: Systematic Literature Review and Meta-Analysis. Advances in therapy. 2019;36(3):721-745.

27. Hughes CD, Scott DL, Ibrahim F, Investigators TP. Intensive therapy and remissions in rheumatoid arthritis: a systematic review. BMC musculoskeletal disorders. 2018;19(1):389.

28. Jansen JP, Buckley F, Dejonckheere F, Ogale S. Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs--a systematic review and network meta-analysis. Health and quality of life outcomes. 2014;12(101153626):102.

29. Kemper AR, Van Mater HA, Coeytaux RR, Williams JW, Jr., Sanders GD. Systematic review of disease-modifying antirheumatic drugs for juvenile idiopathic arthritis. BMC pediatrics. 2012;12(100967804):29.

30. Kawalec P, Mocko P. An indirect comparison of ustekinumab and vedolizumab in the therapy of TNF-failure Crohn's disease patients. Journal of comparative effectiveness research. 2018;7(2):101-111.

31. Lee MJ, Parker CE, Taylor SR, et al. Efficacy of Medical Therapies for Fistulizing Crohn's Disease: Systematic Review and Meta-analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2018;16(12):1879-1892.

32. Lee YH, Bae S-C. Comparative efficacy and safety of tocilizumab, rituximab, abatacept and tofacitinib in patients with active rheumatoid arthritis that inadequately responds to tumor necrosis factor inhibitors: a Bayesian network meta-analysis of randomized controlled trials. International journal of rheumatic diseases. 2016;19(11):1103-1111.

33. Lee YH, Bae SC. Comparative efficacy and safety of baricitinib 2 mg and 4 mg in patients with active rheumatoid arthritis : A Bayesian network meta-analysis of randomized controlled trials. Zeitschrift fur Rheumatologie. 2018;77(4):335-342.

34. Lethaby A, Lopez-Olivo MA, Maxwell L, Burls A, Tugwell P, Wells GA. Etanercept for the treatment of rheumatoid arthritis. The Cochrane database of systematic reviews. 2013(5):CD004525.

35. Lethaby A, Lopez-Olivo MA, Maxwell L, Burls A, Tugwell P, Wells GA. Etanercept for the treatment of rheumatoid arthritis. Cochrane Database of Systematic Reviews. 2013;2013(5).

36. Liu W, Wu Y-H, Zhang L, et al. Efficacy and safety of TNF-alpha inhibitors for active ankylosing spondylitis patients: Multiple treatment comparisons in a network meta-analysis. Scientific reports. 2016;6(101563288):32768.

37. Liu Y, Wu EQ, Bensimon AG, et al. Cost per responder associated with biologic therapies for Crohn's disease, psoriasis, and rheumatoid arthritis. Advances in therapy. 2012;29(7):620-634.

38. Lucka TC, Pathirana D, Sammain A, et al. Efficacy of systemic therapies for moderate-to-severe psoriasis: a systematic review and meta-analysis of long-term treatment. Journal of the European Academy of Dermatology and Venereology : JEADV. 2012;26(11):1331-1344.

39. Maneiro JR, Souto A, Gomez-Reino JJ. Risks of malignancies related to tofacitinib and biological drugs in rheumatoid arthritis: Systematic review, meta-analysis, and network meta-analysis. Seminars in arthritis and rheumatism. 2017;47(2):149-156.

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40. Messori A, Fadda V, Maratea D, et al. Biological drugs for the treatment of moderate-to-severe psoriasis by subcutaneous route: determining statistical equivalence according to evidence-based methods. Clinical drug investigation. 2014;34(8):593-598.

41. Nam JL, Takase-Minegishi K, Ramiro S, et al. Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2016 update of the EULAR recommendations for the management of rheumatoid arthritis. Annals of the rheumatic diseases. 2017;76(6):1113-1136.

42. Orme ME, Macgilchrist KS, Mitchell S, Spurden D, Bird A. Systematic review and network meta-analysis of combination and monotherapy treatments in disease-modifying antirheumatic drug-experienced patients with rheumatoid arthritis: analysis of American College of Rheumatology criteria scores 20, 50, and 70. Biologics : targets & therapy. 2012;6(101321511):429-464.

43. Panaccione R, Steinhart AH, Bressler B, et al. Clinical Practice Guideline for the Management of Luminal Crohn's Disease: The Toronto Consensus. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2019(101160775).

44. Poiroux L, Allanore Y, Kahan A, Avouac J. All-cause mortality associated with TNF-α inhibitors in rheumatoid arthritis: A meta-analysis of randomized controlled trials. American Journal of Medicine. 2015;128(12):1367-1373e1361.

45. Schoels M, Aletaha D, Smolen JS, Wong JB. Comparative effectiveness and safety of biological treatment options after tumour necrosis factor α inhibitor failure in rheumatoid arthritis: Systematic review and indirect pairwise meta-analysis. Annals of the rheumatic diseases. 2012;71(8):1303-1308.

46. Sepriano A, Regel A, van der Heijde D, et al. Efficacy and safety of biological and targeted-synthetic DMARDs: a systematic literature review informing the 2016 update of the ASAS/EULAR recommendations for the management of axial spondyloarthritis. RMD open. 2017;3(1):e000396.

47. Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Tugwell P, Wells GA. Biologic or tofacitinib monotherapy for rheumatoid arthritis in people with traditional disease-modifying anti-rheumatic drug (DMARD) failure: a Cochrane Systematic Review and network meta-analysis (NMA). The Cochrane database of systematic reviews. 2016;11(100909747):CD012437.

48. Singh JA, Hossain A, Mudano AS, et al. Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis. The Cochrane database of systematic reviews. 2017;5(100909747):CD012657.

49. Singh JA, Hossain A, Tanjong Ghogomu E, et al. Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis. The Cochrane database of systematic reviews. 2017;3(100909747):CD012591.

50. Song GG, Choi SJ, Lee YH. Comparison of the efficacy and safety of tofacitinib and upadacitinib in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials. International Journal of Rheumatic Diseases. 2019((Song G.G.; Choi S.J.; Lee Y.H., [email protected]) Department of Rheumatology, Korea University College of Medicine, Seoul, South Korea).

51. Song GG, Lee YH. Comparison of the Efficacy and Safety of Tofacitinib and Apremilast in Patients with Active Psoriatic Arthritis: A Bayesian Network Meta-Analysis of Randomized Controlled Trials. Clinical drug investigation. 2019;39(5):421-428.

52. Song GG, Lee YH. Correction to: Comparison of the Efficacy and Safety of Tofacitinib and Apremilast in Patients with Active Psoriatic Arthritis: A Bayesian Network Meta-Analysis of Randomized Controlled Trials (Clinical Drug Investigation, (2019), 39, 5, (421-428), 10.1007/s40261-019-00765-w). Clinical Drug Investigation. 2019;39(7):701.

53. Strand V, Elaine Husni M, Betts KA, et al. Network meta-analysis and cost per responder of targeted Immunomodulators in the treatment of active psoriatic arthritis. BMC rheumatology. 2018;2(101738571):3.

54. Tam LS, Wei JC-C, Aggarwal A, et al. 2018 APLAR axial spondyloarthritis treatment recommendations. International journal of rheumatic diseases. 2019;22(3):340-356.

55. Tarp S, Tarp U, Andersen LS, et al. Serious adverse events associated with using biological agents to treat rheumatic diseases: Network meta-analysis from a national guideline panel. Arthritis and rheumatism. 2013;65((Herlin T.) Aarhus University Hospital, Aarhus, Denmark):S997-S998.

56. Tarp S, Furst DE, Dossing A, et al. Defining the optimal biological monotherapy in rheumatoid arthritis: A systematic review and meta-analysis of randomised trials. Seminars in arthritis and rheumatism. 2017;46(6):699-708.

57. Thaler KJ, Gartlehner G, Kien C, et al. Drug Class Reviews. In: Drug Class Review: Targeted Immune Modulators: Final Update 3 Report. Portland (OR): Oregon Health & Science University, Portland, OR; 2012.

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58. Thomas SS, Borazan N, Barroso N, et al. Comparative Immunogenicity of TNF Inhibitors: Impact on Clinical Efficacy and Tolerability in the Management of Autoimmune Diseases. A Systematic Review and Meta-Analysis. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2015;29(4):241-258.

59. Wang Y, Wang H, Jiang J, Zhao D, Liu Y. Comparative Efficacy and Acceptability of Anti-TNF-Alpha Therapy in Ankylosing Spondylitis: A Mixed-Treatments Comparison. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology. 2016;39(5):1679-1694.

60. Wei M, Duan D. Efficacy and safety of monoclonal antibodies targeting interleukin-17 pathway for inflammatory arthritis: a meta-analysis of randomized controlled clinical trials. Drug design, development and therapy. 2016;10(101475745):2771-2777.

61. Wu D, Yue J, Tam L-S. Efficacy and safety of biologics targeting interleukin-6, -12/23 and -17 pathways for peripheral psoriatic arthritis: a network meta-analysis. Rheumatology (Oxford, England). 2018;57(3):563-571

62. Xie W, Huang Y, Xiao S, Sun X, Fan Y, Zhang Z. Impact of Janus kinase inhibitors on risk of cardiovascular events in patients with rheumatoid arthritis: systematic review and meta-analysis of randomised controlled trials. Annals of the rheumatic diseases. 2019(0372355, 62w).

63. Yang Z, Ye X, Wu Q, Wu K, Fan D. A network meta-analysis on the efficacy of 5-aminosalicylates, immunomodulators and biologics for the prevention of postoperative recurrence in Crohn's disease. International journal of surgery (London, England). 2014;12(5):516-522.

64. Zong HX, Xu SQ, Tong H, Wang XR, Pan MJ, Teng YZ. Effect of anti-tumor necrosis factor α treatment on radiographic progression in patient with ankylosing spondylitis: A systematic review and meta-analysis. Modern Rheumatology. 2019;29(3):503-509.

Wrong study design

65. Ai J-W, Zhang S, Ruan Q-L, et al. The Risk of Tuberculosis in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor-alpha Antagonist: A Metaanalysis of Both Randomized Controlled Trials and Registry/Cohort Studies. The Journal of rheumatology. 2015;42(12):2229-2237.

66. Al Sawah S, Foster SA, Burge R, et al. Cost per additional responder for ixekizumab and other FDA-approved biologics in moderate-to-severe plaque psoriasis. Journal of medical economics. 2017;20(12):1224-1230.

67. Albaghdadi A. Current and Under Development Treatment Modalities of Psoriasis: A Review. Endocrine, metabolic & immune disorders drug targets. 2017;17(3):189-199.

68. Allocca M, Fiorino G, Gilardi D, et al. Biologic Therapies in Ulcerative Colitis: Primi Inter Pares? Current drug targets. 2018;19(7):748-756.

69. Amarilyo G, Tarp S, Foeldvari I, et al. Efficacy and safety of biologic agents in patients with poly-articular juvenile idiopathic arthritis: Network meta-analysis of randomized controlled withdrawal trials. Arthritis and rheumatism. 2013;65((Woo J.M.P.) Mattel Children's Hospital, University of California, Los Angeles, CA, United States):S922-S923.

70. Bae S-C, Lee YH. Comparison of the efficacy and tolerability of tocilizumab, sarilumab, and sirukumab in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Clinical rheumatology. 2018;37(6):1471-1479.

71. Baji P, Pentek M, Szanto S, et al. Comparative efficacy and safety of biosimilar infliximab and other biological treatments in ankylosing spondylitis: systematic literature review and meta-analysis. The European journal of health economics : HEPAC : health economics in prevention and care. 2014;15 Suppl 1(101134867):S45-52.

72. Barra L, Ha A, Sun L, Fonseca C, Pope J. Efficacy of biologic agents in improving the Health Assessment Questionnaire (HAQ) score in established and early rheumatoid arthritis: a meta-analysis with indirect comparisons. Clinical and experimental rheumatology. 2014;32(3):333-341.

73. Betts KA, Griffith J, Song Y, et al. Network Meta-Analysis and Cost Per Responder of Tumor Necrosis Factor-alpha and Interleukin Inhibitors in the Treatment of Active Ankylosing Spondylitis. Rheumatology and therapy. 2016;3(2):323-336.

74. Bewley A, Barker J, Mughal F, et al. Cost-effectiveness of apremilast in moderate to severe psoriasis in the United Kingdom. Cogent Medicine. 2018;5(1):1-23.

75. Bonovas S, Pantavou K, Evripidou D, et al. Safety of biological therapies in ulcerative colitis: An umbrella review of meta-analyses. Best practice & research Clinical gastroenterology. 2018;32-33(dhw, 100894206, d5w, 101120605):43-47.

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77. CADTH Common Drug Review Report. Golimumab (Simponi). Canadian Agency for Drugs and Technologies in Health, 2014. https://cadth.ca/sites/default/files/cdr/clinical/SR0341_Simponi_CL_Report_e.pdf. Accessed August 8, 2019.

78. Camean-Castillo M, Gimeno-Ballester V, Rios-Sanchez E, Fenix-Caballero S, Vazquez-Real M, Alegre-Del Rey E. Network meta-analysis of tofacitinib versus biologic treatments in moderate-to-severe rheumatoid arthritis patients. Journal of clinical pharmacy and therapeutics. 2019;44(3):384-396.

79. Cameron C, Druchok C, Hutton B, et al. Guselkumab for the Treatment of Moderate-to-Severe Plaque Psoriasis During Induction Phase: A Systematic Review and Network Meta-Analysis. Journal of Psoriasis and Psoriatic Arthritis. 2019;4(2):81-92.

80. Cantini F, Niccoli L, Nannini C, et al. Second-line biologic therapy optimization in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Seminars in arthritis and rheumatism. 2017;47(2):183-192.

81. Choi M, Hyun MK, Choi S, et al. Comparative efficacy of biological agents in methotrexate-refractory rheumatoid arthritis patients: a Bayesian mixed treatment comparison. The Korean journal of internal medicine. 2017;32(3):536-547.

82. Choy E, Freemantle N, Proudfoot C, et al. Evaluation of the efficacy and safety of sarilumab combination therapy in patients with rheumatoid arthritis with inadequate response to conventional disease-modifying antirheumatic drugs or tumour necrosis factor alpha inhibitors: systematic literature review and network meta-analyses. RMD open. 2019;5(1):e000798.

83. Christensen R, Tarp S, Furst DE, Kristensen LE, Bliddal H. Efficacy and safety of infliximab or adalimumab, versus abatacept, in patients with rheumatoid arthritis: ATTEST-AMPLE network randomized trial. International Journal of Clinical Rheumatology. 2013;8(6):647-655.

84. Daien C, Hua C, Gaujoux-Viala C, et al. Update of French society for rheumatology recommendations for managing rheumatoid arthritis. Joint, bone, spine : revue du rhumatisme. 2019;86(2):135-150.

85. Deodhar A. Mirror, mirror, on the wall, which is the most effective biologic of all? Journal of Rheumatology. 2018;45(4):449-450.

86. Diener C, Horneff G. Comparison of adverse events of biologicals for treatment of juvenile idiopathic arthritis: a systematic review. Expert Opinion on Drug Safety. 2019((Horneff G.) Department of Paediatric and Adolescents Medicine, Medical Faculty, University Hospital of Cologne, Cologne, Germany).

87. Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease - algorithm for practical management. Alimentary pharmacology & therapeutics. 2016;43(1):30-51.

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89. Fiorino G, Bonovas S, Cicerone C, et al. The safety of biological pharmacotherapy for the treatment of ulcerative colitis. Expert opinion on drug safety. 2017;16(4):437-443.

90. Girolomoni G, Altomare G, Ayala F, et al. Safety of anti-TNFα agents in the treatment of psoriasis and psoriatic arthritis. Immunopharmacology and Immunotoxicology. 2012;34(4):548-560.

91. Hodgson R, Walton M, Biswas M, Mebrahtu T, Woolacott N. Ustekinumab for Treating Moderately to Severely Active Crohn's Disease after Prior Therapy: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. PharmacoEconomics. 2018;36(4):387-398.

92. Huoponen S, Blom M. The Cost-Effectiveness of Biologics for The Treatment of Inflammatory Bowel Diseases: A Systematic Review. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2015;18(7):A668.

93. Hutfless S, Lau BD, Wilson LM, Lazarev M, Bass EB. AHRQ Future Research Needs Papers. In: Pharmacological Management of Crohn's Disease: Future Research Needs: Identification of Future Research Needs From Comparative Effectiveness Review No. 131. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014.

94. Kawalec P, Holko P, Mocko P, Pilc A. Comparative effectiveness of abatacept, apremilast, secukinumab and ustekinumab treatment of psoriatic arthritis: a systematic review and network meta-analysis. Rheumatology international. 2018;38(2):189-201.

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96. Kawalec P, Mocko P, Pilc A, Radziwon-Zalewska M, Malinowska-Lipien I. Vedolizumab Compared with Certolizumab in the Therapy of Crohn Disease: A Systematic Review and Indirect Comparison. Pharmacotherapy. 2016;36(8):861-869.

97. Kawalec P, Pilc A. An indirect comparison of infliximab versus adalimumab or golimumab for active ulcerative colitis. Archives of medical science : AMS. 2016;12(5):1097-1109.

98. Mandema JW, Salinger DH, Baumgartner SW, Gibbs MA. A dose-response meta-analysis for quantifying relative efficacy of biologics in rheumatoid arthritis. Clinical pharmacology and therapeutics. 2011;90(6):828-835.

99. McInnes IB, Nash P, Ritchlin C, et al. Secukinumab for psoriatic arthritis: comparative effectiveness versus licensed biologics/apremilast: a network meta-analysis. Journal of comparative effectiveness research. 2018;7(11):1107-1123.

100. Miligkos M, Papamichael K, Vande Casteele N, et al. Efficacy and Safety Profile of Anti-tumor Necrosis Factor-alpha Versus Anti-integrin Agents for the Treatment of Crohn's Disease: A Network Meta-analysis of Indirect Comparisons. Clinical therapeutics. 2016;38(6):1342-1358.e1346.

101. Navarro-Compan V, Plasencia-Rodriguez C, de Miguel E, Diaz Del Campo P, Balsa A, Gratacos J. Switching biological disease-modifying antirheumatic drugs in patients with axial spondyloarthritis: results from a systematic literature review. RMD open. 2017;3(2):e000524.

102. Neubauer AS, Minartz C, Herrmann KH, Baerwald CGO. Cost-effectiveness of early treatment of ACPA-positive rheumatoid arthritis patients with abatacept. Clinical and experimental rheumatology. 2018;36(3):448-454.

103. Park SK, Lee MY, Jang EJ, Kim HL, Ha DM, Lee EK. comparison of discontinuation rates of tofacitinib and biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis: A systematic review and Bayesian network meta-analysis regression. Clinical and Experimental Rheumatology. 2017;35(4):689-699.

104. Pillai N, Dusheiko M, Burnand B, Pittet V. A systematic review of cost-effectiveness studies comparing conventional, biological and surgical interventions for inflammatory bowel disease. PloS one. 2017;12(10):e0185500.

105. Qiu Y, Chen BL, Mao R, et al. Systematic review with meta-analysis: loss of response and requirement of anti-TNFα dose intensification in Crohn’s disease. Journal of Gastroenterology. 2017;52(5):535-554.

106. Ruemmele FM, Turner D. Differences in the management of pediatric and adult onset ulcerative colitis--lessons from the joint ECCO and ESPGHAN consensus guidelines for the management of pediatric ulcerative colitis. Journal of Crohn's & colitis. 2014;8(1):1-4.

107. Sawyer LM, Cornic L, Levin LA, Gibbons C, Moller AH, Jemec GB. Long-term efficacy of novel therapies in moderate-to-severe plaque psoriasis: a systematic review and network meta-analysis of PASI response. Journal of the European Academy of Dermatology and Venereology : JEADV. 2019;33(2):355-366.

108. Simpson EL, Ren S, Hock ES, et al. Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis. International journal of technology assessment in health care. 2019;35(1):36-44.

109. Singh S, Garg SK, Pardi DS, Wang Z, Murad MH, Loftus EV, Jr. Comparative efficacy of pharmacologic interventions in preventing relapse of Crohn's disease after surgery: a systematic review and network meta-analysis. Gastroenterology. 2015;148(1):64-e14.

110. Singh S. Network meta-analysis to inform positioning of biologics in patients with Crohn's disease: Promise and perils. Best Practice and Research: Clinical Gastroenterology. 2019;38-39((Singh S., [email protected]) Division of Biomedical Informatics, University of California San Diego, La Jolla, CA, United States).

111. Strand V, Balsa A, Al-Saleh J, et al. Immunogenicity of Biologics in Chronic Inflammatory Diseases: A Systematic Review. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 2017;31(4):299-316.

112. Tarp S, Furst DE, Luta G, et al. Risk of serious adverse effects associated with different biological and targeted synthetic disease-modifying anti-rheumatic drugs in patients with rheumatoid arthritis: A systematic review and meta-analysis of randomised trials. Annals of the rheumatic diseases. 2015;74((Thirstrup S.) Institute for Pharmacology and Pharmacotherapy, University of Copenhagen, Copenhagen, Denmark):176-177.

98

113. Uttley L, Bermejo I, Ren S, et al. Tofacitinib for Treating Rheumatoid Arthritis After the Failure of Disease-Modifying Anti-rheumatic Drugs: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. PharmacoEconomics. 2018;36(9):1063-1072.

114. van Bezooijen JS, Prens EP, Pradeepti MS, et al. Combining biologics with methotrexate in psoriasis: a systematic review. The British journal of dermatology. 2015;172(6):1676-1680.

115. Voulgari PV, Kaltsonoudis E, Papagoras C, Drosos AA. Adalimumab in the treatment of rheumatoid arthritis. Expert opinion on biological therapy. 2012;12(12):1679-1686.

116. Wade R, Grosso A, South E, et al. Brodalumab for the Treatment of Moderate-to-Severe Plaque Psoriasis: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal. PharmacoEconomics. 2019;37(2):131-139.

117. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis & rheumatology (Hoboken, NJ). 2016;68(2):282-298.

118. Wells AF, Jodat N, Schiff M. A critical evaluation of the role of subcutaneous abatacept in the treatment of rheumatoid arthritis: patient considerations. Biologics : targets & therapy. 2014;8(101321511):41-55.

119. Wheat CL, Ko CW, Clark-Snustad K, Grembowski D, Thornton TA, Devine B. Inflammatory Bowel Disease (IBD) pharmacotherapy and the risk of serious infection: a systematic review and network meta-analysis. BMC gastroenterology. 2017;17(1):52.

120. Xu G, Xia M, Jiang C, et al. Comparative efficacy and safety of thirteen biologic therapies for patients with moderate or severe psoriasis: A network meta-analysis. Journal of pharmacological sciences. 2019;139(4):289-303.

121. Zhang D, Liu H, Zhou D, Chen Y. Anti-TNFα agents and interleukin-17A inhibitor secukinmuab have similar effects in improvement of ASAS20, ASAS40, and safety: A meta-analysis. International Journal of Clinical and Experimental Medicine. 2016;9(11):20668-20673.

A more recent systematic review or a higher-quality systematic review is available

122. Alfonso-Cristancho R, Armstrong N, Arjunji R, et al. Comparative effectiveness of biologics for the management of rheumatoid arthritis: systematic review and network meta-analysis. Clinical rheumatology. 2017;36(1):25-34.

123. Aly AM, Furst DE. Update of sarilumb to treat rheumatoid arthritis based on randomized clinical trials: a systematic review. Expert review of clinical immunology. 2017;13(8):741-752.

124. Bae SC, Lee YH. Comparison of the efficacy and safety of tofacitinib and baricitinib in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials. Zeitschrift fur Rheumatologie. 2018(y0v, 0414162).

125. CADTH Common Drug Review Report. Ixekinumab (Taltz). Canadian Agency for Drugs and Technologies in Health 2018. https://cadth.ca/sites/default/files/cdr/clinical/SR0558_TaltzPsA_CL_Report.pdf. Accessed August 8, 2019.

126. CADTH Common Drug Review Report. Guselkumab (Tremfya). Canadian Agency for Drugs and Technologies in Health 2018. https://cadth.ca/sites/default/files/cdr/clinical/SR0530_Tremfya_CL_Report.pdf. Accessed August 8, 2019.

127. CADTH Common Drug Review Report. Sarilumab (Kevzara). Canadian Agency for Drugs and Technologies in Health, 2017. https://cadth.ca/sites/default/files/cdr/clinical/SR0503_Kevzara_CL_Report.pdf. Accessed August 8, 2019.

128. CADTH Common Drug Review Report. Apremilast (Otezla). Canadian Agency for Drugs and Technologies in Health, 2017. https://cadth.ca/sites/default/files/cdr/clinical/SR0478_Otezla_CL_Report_e.pdf. Accessed August 8, 2019.

129. Cawson MR, Mitchell SA, Knight C, et al. Systematic review, network meta-analysis and economic evaluation of biological therapy for the management of active psoriatic arthritis. BMC musculoskeletal disorders. 2014;15(100968565):26.

130. Chi C-C, Wang S-H. Efficacy and cost-efficacy of biologic therapies for moderate to severe psoriasis: a meta-analysis and cost-efficacy analysis using the intention-to-treat principle. BioMed research international. 2014;2014(101600173):862851.

131. Donahue KE, Jonas DE, Hansen RA, et al. AHRQ Comparative Effectiveness Reviews. In: Drug Therapy for Rheumatoid Arthritis in Adults: An Update. Rockville (MD): Agency for Healthcare Research and Quality (US); 2012.

99

132. Fenix-Caballero S, Alegre-del Rey EJ, Castano-Lara R, Puigventos-Latorre F, Borrero-Rubio JM, Lopez-Vallejo JF. Direct and indirect comparison of the efficacy and safety of adalimumab, etanercept, infliximab and golimumab in psoriatic arthritis. Journal of clinical pharmacy and therapeutics. 2013;38(4):286-293.

133. Giacomelli R, Afeltra A, Alunno A, et al. International consensus: What else can we do to improve diagnosis and therapeutic strategies in patients affected by autoimmune rheumatic diseases (rheumatoid arthritis, spondyloarthritides, systemic sclerosis, systemic lupus erythematosus, antiphospholipid syndrome and Sjogren's syndrome)?: The unmet needs and the clinical grey zone in autoimmune disease management. Autoimmunity reviews. 2017;16(9):911-924.

134. Gilbert KE, Manalo IF, Wu JJ. Efficacy and safety of etanercept and adalimumab with and without a loading dose for psoriasis: A systematic review. Journal of the American Academy of Dermatology. 2015;73(2):329-331.

135. Gomez-Garcia F, Epstein D, Isla-Tejera B, Lorente A, Velez Garcia-Nieto A, Ruano J. Short-term efficacy and safety of new biological agents targeting the interleukin-23-T helper 17 pathway for moderate-to-severe plaque psoriasis: a systematic review and network meta-analysis. The British journal of dermatology. 2017;176(3):594-603.

136. Guyot P, Taylor P, Christensen R, et al. Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate: a network meta-analysis. Arthritis research & therapy. 2011;13(6):R204.

137. Igarashi A, Kuwabara H, Fahrbach K, Schenkel B. Cost-efficacy comparison of biological therapies for patients with moderate to severe psoriasis in Japan. The Journal of dermatological treatment. 2013;24(5):351-355.

138. Jabbar-Lopez ZK, Yiu ZZN, Ward V, et al. Re: Quantitative Evaluation of Biologic Therapy Options for Psoriasis: A Systematic Review and Network Meta-Analysis. The Journal of investigative dermatology. 2017;137(12):2644-2646.

139. Launois R, Avouac B, Berenbaum F, et al. Comparison of certolizumab pegol with other anticytokine agents for treatment of rheumatoid arthritis: a multiple-treatment Bayesian metaanalysis. The Journal of rheumatology. 2011;38(5):835-845.

140. Lin VW, Ringold S, Devine EB. Comparison of Ustekinumab With Other Biological Agents for the Treatment of Moderate to Severe Plaque Psoriasis: A Bayesian Network Meta-analysis. Archives of dermatology. 2012;148(12):1403-1410.

141. Lv J, Zhou D, Wang Y, et al. Quantitative evaluation to efficacy and safety of therapies for psoriasis: A network meta-analysis. Molecular pain. 2018;14(101242662):1744806918762205.

142. Machado MAdA, Barbosa MM, Almeida AM, et al. Treatment of ankylosing spondylitis with TNF blockers: a meta-analysis. Rheumatology international. 2013;33(9):2199-2213.

143. Malottki K, Barton P, Tsourapas A, et al. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a tumour necrosis factor inhibitor: a systematic review and economic evaluation. Health technology assessment (Winchester, England). 2011;15(14):1-278.

144. Messori A, Fadda V, Maratea D, et al. Biological drugs for the treatment of rheumatoid arthritis by the subcutaneous route: interpreting efficacy data to assess statistical equivalence. Therapeutic advances in musculoskeletal disease. 2014;6(6):207-216.

145. Messori A, Trippoli S, Fadda V, Maratea D, Marinai C. Subcutaneous Biological Treatments for Moderate to Severe Psoriasis: Interpreting Safety Data by Network Meta-Analysis. Drugs - real world outcomes. 2015;2(1):23-27.

146. Migliore A, Bizzi E, Egan CG, Bernardi M, Petrella L. Efficacy of biological agents administered as monotherapy in rheumatoid arthritis: a Bayesian mixed-treatment comparison analysis. Therapeutics and clinical risk management. 2015;11(101253281):1325-1335.

147. Migliore A, Broccoli S, Bizzi E, Lagana B. Indirect comparison of the effects of anti-TNF biological agents in patients with ankylosing spondylitis by means of a mixed treatment comparison performed on efficacy data from published randomised, controlled trials. Journal of medical economics. 2012;15(3):473-480.

148. Naik GS, Ming WK, Magodoro IM, et al. Th17 Inhibitors in Active Psoriatic Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Clinical Trials. Dermatology (Basel, Switzerland). 2017;233(5):366-377.

149. Nam JL, Winthrop KL, Van Vollenhoven RF. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: A systematic literature review informing the EULAR recommendations for the management of RA (Annals of the Rheumatic Diseases (2010) 69, (976-986)). Annals of the rheumatic diseases. 2011;70(8):1519.

100

150. Nast A, Jacobs A, Rosumeck S, Werner RN. Efficacy and Safety of Systemic Long-Term Treatments for Moderate-to-Severe Psoriasis: A Systematic Review and Meta-Analysis. The Journal of investigative dermatology. 2015;135(11):2641-2648.

151. Pham PA, Dressler C, Eisert L, Nast A, Werner RN. Time until onset of action when treating psoriatic arthritis: meta-analysis and novel approach of generating confidence intervals. Rheumatology international. 2019;39(4):605-618.

152. Reich K, Burden AD, Eaton JN, Hawkins NS. Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta-analysis of randomized controlled trials. The British journal of dermatology. 2012;166(1):179-188.

153. Ryoo JY, Yang H-J, Ji E, Yoo BK. Meta-analysis of the Efficacy and Safety of Secukinumab for the Treatment of Plaque Psoriasis. The Annals of pharmacotherapy. 2016;50(5):341-351.

154. Sandoval LF, Pierce A, Feldman SR. Systemic therapies for psoriasis: an evidence-based update. American journal of clinical dermatology. 2014;15(3):165-180.

155. Sawyer L, Fotheringham I, Wright E, Yasmeen N, Gibbons C, Holmen Moller A. The comparative efficacy of brodalumab in patients with moderate-to-severe psoriasis: a systematic literature review and network meta-analysis. The Journal of dermatological treatment. 2018;29(6):557-568.

156. Schmitt J, Rosumeck S, Thomaschewski G, Sporbeck B, Haufe E, Nast A. Efficacy and safety of systemic treatments for moderate-to-severe psoriasis: meta-analysis of randomized controlled trials. The British journal of dermatology. 2014;170(2):274-303.

157. Shu T, Chen GH, Rong L, et al. Indirect comparison of anti-TNF-alpha agents for active ankylosing spondylitis: mixed treatment comparison of randomized controlled trials. Clinical and experimental rheumatology. 2013;31(5):717-722.

158. Singh JA, Hossain A, Tanjong Ghogomu E, et al. Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. The Cochrane database of systematic reviews. 2016(5):CD012183

159. Stevenson M, Archer R, Tosh J, et al. Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation. Health technology assessment (Winchester, England). 2016;20(35):1-610.

160. Tausend W, Downing C, Tyring S. Systematic review of interleukin-12, interleukin-17, and interleukin-23 pathway inhibitors for the treatment of moderate-to-severe chronic plaque psoriasis: ustekinumab, briakinumab, tildrakizumab, guselkumab, secukinumab, ixekizumab, and brodalumab. Journal of cutaneous medicine and surgery. 2014;18(3):156-169.

161. Turkstra E, Ng SK, Scuffham PA. A mixed treatment comparison of the short-term efficacy of biologic disease modifying anti-rheumatic drugs in established rheumatoid arthritis. Current medical research and opinion. 2011;27(10):1885-1897.

162. Tvete IF, Natvig B, Gasemyr J, Meland N, Roine M, Klemp M. Comparing Effects of Biologic Agents in Treating Patients with Rheumatoid Arthritis: A Multiple Treatment Comparison Regression Analysis. PloS one. 2015;10(9):e0137258.

163. Ungprasert P, Thongprayoon C, Davis JM, 3rd. Indirect comparisons of the efficacy of biological agents in patients with psoriatic arthritis with an inadequate response to traditional disease-modifying anti-rheumatic drugs or to non-steroidal anti-inflammatory drugs: A meta-analysis. Seminars in arthritis and rheumatism. 2016;45(4):428-438.

164. Van SS, Diels J, Van LJ, Hemels M. Network Meta-Analysis With Baseline Risk Adjustment To Assess The Relative Efficacy Of Ustekinumab In Adult Patients With Active Psoriatic Arthritis. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2014;17(7):A373.

165. Wu Y, Feng X, Li J, Wang X, Yang C, Zhao L. Model-Based Meta-Analysis in Ankylosing Spondylitis: A Quantitative Comparison of Biologics and Small Targeted Molecules. Clinical pharmacology and therapeutics. 2019;105(5):1244-1255.

166. Yamauchi PS, Bissonnette R, Teixeira HD, Valdecantos WC. Systematic review of efficacy of anti-tumor necrosis factor (TNF) therapy in patients with psoriasis previously treated with a different anti-TNF agent. Journal of the American Academy of Dermatology. 2016;75(3):612-618.e616.

167. Yiu ZZN, Exton LS, Jabbar-Lopez Z, et al. Risk of Serious Infections in Patients with Psoriasis on Biologic Therapies: A Systematic Review and Meta-Analysis. The Journal of investigative dermatology. 2016;136(8):1584-1591.

101

168. Zhang X, Liang F, Yin X, et al. Tofacitinib for acute rheumatoid arthritis patients who have had an inadequate response to disease-modifying antirheumatic drug (DMARD): a systematic review and meta-analysis. Clinical rheumatology. 2014;33(2):165-173.

Systematic reviews reporting an absence of head-to-head evidence

169. Albrecht K, Kruger K, Wollenhaupt J, et al. German guidelines for the sequential medical treatment of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. Rheumatology international. 2014;34(1):1-9.

170. Archer R, Tappenden P, Ren S, et al. Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): clinical effectiveness systematic review and economic model. Health technology assessment (Winchester, England). 2016;20(39):1-326.

171. Bakouny Z, Yared F, El Rassy E, et al. Comparative Efficacy of Anti-TNF Therapies For The Prevention of Postoperative Recurrence of Crohn's Disease: A Systematic Review and Network Meta-Analysis of Prospective Trials. Journal of clinical gastroenterology. 2019;53(6):409-417.

172. Bonovas S, Fiorino G, Allocca M, et al. Biologic Therapies and Risk of Infection and Malignancy in Patients With Inflammatory Bowel Disease: A Systematic Review and Network Meta-analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2016;14(10):1385-1397.e1310.

173. Bonovas S, Lytras T, Nikolopoulos G, Peyrin-Biroulet L, Danese S. Systematic review with network meta-analysis: comparative assessment of tofacitinib and biological therapies for moderate-to-severe ulcerative colitis. Alimentary pharmacology & therapeutics. 2018;47(4):454-465.

174. CADTH Common Drug Review Report. Ustekinumab (Stelara). Canadian Agency for Drugs and Technologies in Health, 2017. https://cadth.ca/sites/default/files/cdr/clinical/SR0501_Stelara_CL_Report.pdf. Accessed August 8, 2019.

175. CADTH Common Drug Review Report. Adalimumab (Humira). Canadian Agency for Drugs and Technologies in Health, 2016. https://cadth.ca/sites/default/files/cdr/clinical/SR0450_Humira_UC_CL_Report.pdf. Accessed August 8, 2019.

176. Cholapranee A, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN. Systematic review with meta-analysis: comparative efficacy of biologics for induction and maintenance of mucosal healing in Crohn's disease and ulcerative colitis controlled trials. Alimentary pharmacology & therapeutics. 2017;45(10):1291-1302.

177. Da W, Zhu J, Wang L, Lu Y. Efficacy and safety of certolizumab pegol for Crohn's disease: a systematic review and meta-analysis. Advances in therapy. 2013;30(5):541-553.

178. Danese S, Fiorino G, Peyrin-Biroulet L, et al. Biological agents for moderately to severely active ulcerative colitis: a systematic review and network meta-analysis. Annals of internal medicine. 2014;160(10):704-711.

179. Davies R, Gaynor D, Hyrich KL, Pain CE. Efficacy of biologic therapy across individual juvenile idiopathic arthritis subtypes: A systematic review. Seminars in arthritis and rheumatism. 2017;46(5):584-593.

180. Hazlewood GS, Rezaie A, Borman M, et al. Comparative effectiveness of immunosuppressants and biologics for inducing and maintaining remission in Crohn's disease: a network meta-analysis. Gastroenterology. 2015;148(2):344-345.

181. Huang X, Lv B, Jin H-F, Zhang S. A meta-analysis of the therapeutic effects of tumor necrosis factor-alpha blockers on ulcerative colitis. European journal of clinical pharmacology. 2011;67(8):759-766.

182. Hutfless S, Almashat S, Berger Z, et al. AHRQ Comparative Effectiveness Reviews. In: Pharmacologic Therapies for the Management of Crohn's Disease: Comparative Effectiveness. Rockville (MD): Agency for Healthcare Research and Quality (US); 2014.

183. Jeong DY, Kim S, Son MJ, et al. Induction and maintenance treatment of inflammatory bowel disease: A comprehensive review. Autoimmunity reviews. 2019;18(5):439-454.

184. Kawalec P, Mocko P, Malinowska-Lipien I, Brzostek T. Efficacy and safety of ustekinumab in the induction therapy of TNF-alpha-refractory Crohn's disease patients: a systematic review and meta-analysis. Journal of comparative effectiveness research. 2017;6(7):601-612.

185. Kemper AR, Coeytaux R, Sanders GD, et al. AHRQ Comparative Effectiveness Reviews. In: Disease-Modifying Antirheumatic Drugs (DMARDs) in Children With Juvenile Idiopathic Arthritis (JIA). Rockville (MD): Agency for Healthcare Research and Quality (US); 2011.

186. Khanna R, Preiss JC, MacDonald JK, Timmer A. Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. The Cochrane database of systematic reviews. 2015(5):CD007572.

102

187. Lu C, Wallace BI, Waljee AK, Fu W, Zhang Q, Liu Y. Comparative efficacy and safety of targeted DMARDs for active psoriatic arthritis during induction therapy: A systematic review and network meta-analysis. Seminars in Arthritis and Rheumatism. 2019((Fu W.) Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China).

188. Lv R, Qiao W, Wu Z, et al. Tumor necrosis factor alpha blocking agents as treatment for ulcerative colitis intolerant or refractory to conventional medical therapy: a meta-analysis. PloS one. 2014;9(1):e86692.

189. MacDonald JK, Nguyen TM, Khanna R, Timmer A. Anti-IL-12/23p40 antibodies for induction of remission in Crohn's disease. The Cochrane database of systematic reviews. 2016;11(100909747):CD007572.

190. Mao EJ, Hazlewood GS, Kaplan GG, Peyrin-Biroulet L, Ananthakrishnan AN. Systematic review with meta-analysis: comparative efficacy of immunosuppressants and biologics for reducing hospitalisation and surgery in Crohn's disease and ulcerative colitis. Alimentary pharmacology & therapeutics. 2017;45(1):3-13.

191. Mocko P, Kawalec P, Pilc A. Safety Profile of Biologic Drugs in the Therapy of Ulcerative Colitis: A Systematic Review and Network Meta-Analysis. Pharmacotherapy. 2016;36(8):870-879.

192. Mocko P, Kawalec P, Pilc A. Safety profile of biologic drugs in the therapy of Crohn disease: A systematic review and network meta-analysis. Pharmacological reports : PR. 2016;68(6):1237-1243.

193. Mocko P, Kawalec P, Pilc A. Safety Profile of Biologic Drugs in the Treatment of Inflammatory Bowel Diseases: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials. Clinical drug investigation. 2017;37(1):25-37.

194. Paschos P, Katsoula A, Giouleme O, et al. Tofacitinib for induction of remission in ulcerative colitis: systematic review and meta-analysis. Annals of gastroenterology. 2018;31(5):572-582.

195. Paschos P, Katsoula A, Salanti G, Giouleme O, Athanasiadou E, Tsapas A. Systematic review with network meta-analysis: the impact of medical interventions for moderate-to-severe ulcerative colitis on health-related quality of life. Alimentary pharmacology & therapeutics. 2018;48(11-12):1174-1185.

196. Ruiz Garcia V, Burls A, Cabello JB, Vela Casasempere P, Bort-Marti S, Bernal JA. Certolizumab pegol (CDP870) for rheumatoid arthritis in adults. Cochrane Database of Systematic Reviews. 2017;2017(9).

197. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review with network meta-analysis: first- and second-line pharmacotherapy for moderate-severe ulcerative colitis. Alimentary pharmacology & therapeutics. 2018;47(2):162-175.

198. Singh S, Fumery M, Sandborn WJ, Murad MH. Systematic review and network meta-analysis: first- and second-line biologic therapies for moderate-severe Crohn's disease. Alimentary pharmacology & therapeutics. 2018;48(4):394-409.

199. Singh S, Garg SK, Pardi DS, Wang Z, Murad MH, Loftus EV, Jr. Comparative efficacy of biologic therapy in biologic-naive patients with Crohn disease: a systematic review and network meta-analysis. Mayo Clinic proceedings. 2014;89(12):1621-1635.

200. Stidham RW, Lee TCH, Higgins PDR, et al. Systematic review with network meta-analysis: the efficacy of anti-tumour necrosis factor-alpha agents for the treatment of ulcerative colitis. Alimentary pharmacology & therapeutics. 2014;39(7):660-671.

201. Tarp S, Amarilyo G, Foeldvari I, et al. Efficacy and safety of biological agents for systemic juvenile idiopathic arthritis: A systematic review and meta-analysis of randomised trials. Annals of the rheumatic diseases. 2015;74((Woo J.M.; Pope T.D.; Furst D.E.) David Geffen School of Medicine, University of California, Los Angeles, United States):391-392.

202. Thorlund K, Druyts E, Toor K, Mills EJ. Comparative efficacy of golimumab, infliximab, and adalimumab for moderately to severely active ulcerative colitis: a network meta-analysis accounting for differences in trial designs. Expert review of gastroenterology & hepatology. 2015;9(5):693-700.

203. Trigo-Vicente C, Gimeno-Ballester V, Garcia-Lopez S, Lopez-Del Val A. Systematic review and network meta-analysis of treatment for moderate-to-severe ulcerative colitis. International journal of clinical pharmacy. 2018;40(6):1411-1419.

204. Vickers AD, Ainsworth C, Mody R, et al. Systematic Review with Network Meta-Analysis: Comparative Efficacy of Biologics in the Treatment of Moderately to Severely Active Ulcerative Colitis. PloS one. 2016;11(10):e0165435.

205. Vieira MC, Wallenstein G, Bradley J, et al. Tofacitinib versus biologic treatments in patients with active rheumatoid arthritis who have had an inadequate response to tumour necrosis factor inhibitors-a network meta-analysis. Annals of the rheumatic diseases. 2013;72((Koncz T.) Pfizer Inc, New York, United States).

206. Wang R, Dasgupta A, Ward MM. Comparative Efficacy of Tumor Necrosis Factor-alpha Inhibitors in Ankylosing Spondylitis: A Systematic Review and Bayesian Network Metaanalysis. The Journal of rheumatology. 2018;45(4):481-490.

103

207. Wang R, Dasgupta A, Ward MM. Comparative efficacy of tumor necrosis factor-α inhibitors in ankylosing spondylitis: A systematic review and Bayesian network metaanalysis. Journal of Rheumatology. 2018;45(4):481-490.

208. Wu Y, Chen J, Li Y-H, et al. Treatment of psoriasis with interleukin-12/23 monoclonal antibody: a systematic review. European journal of dermatology : EJD. 2012;22(1):72-82.

Only abstract or protocol available

209. Choi M, Hyun MK, Choi S, et al. Comparative effectiveness of biological agents with diseases modifying anti-rheumatic drugs for methotrexate failure rheumatoid arthritis patients: A baysian mixed treatment comparison. Value in Health. 2014;17(7):A373-A374.

210. González Álvarez A, Gómez Barrera M, Borrás Blasco J, Giner Serret EJ. Efficacy and cost effectiveness of anti-TNF drugs for reumatoid arthritis treatment. Atencion Farmaceutica. 2013;15(4):244-254.

211. Hindryckx P, Zou GY, Feagan BG, et al. Biologic drugs for induction and maintenance of remission in Crohn's disease: A network meta-analysis. Cochrane Database of Systematic Reviews. 2017;2017(8).

212. Hochberg M, Janssen K, Broglio K, Walsem AV, Nadkarni A. Comparison of abatacept and other biologic dmards for the treatment of rheumatoid arthritis patients: A systematic literature review and network meta-analysis. Annals of the rheumatic diseases. 2014;73((Nadkarni A.) Bristol-Myers Squibb, Plainsboro, United States).

213. Jenkins D, Martina R, Bujkiewicz S, Dequen P, Abrams K. Network Meta-Analysis of Biological Response Modifiers in Rheumatoid arthritis Including real World Evidence at Multiple time Points. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2015;18(7):A343.

214. Kim D, Kim H, Cho S, Park MC. Secukinumab versus adalimumab for the treatment of ankylosing spondylitis: A cost per responder analysis from Korean perspective. Arthritis and Rheumatology. 2018;70((Kim H.; Cho S.) Patient Access Team, Novartis Korea, Seoul, South Korea):1307-1308.

215. Murray E, Butylkova Y, Ellis A, Skup M, Kalabic J, Garg V. A systematic review and meta-analysis of comparative efficacy of biologics in treating patients with rheumatoid arthritis: Assessment of long-term radiographic progression from published clinical trials. Arthritis and Rheumatology.

216. Oton T, Loza E, Sanmarti R, Tornero Molina J. Efficacy and safety of interleukin 6 inhibitors in rheumatoid arthritis: A systematic literature review. Annals of the rheumatic diseases. 2018;77((Tornero Molina J.) Rheumatology, Hospital De Guadalajara, Guadalajara, Spain):1396.

217. Strand V, Ahadieh S, DeMasi R, et al. Meta-analysis of serious infections with baricitinib, tofacitinib and biologic DMARDs in rheumatoid arthritis. Annals of the rheumatic diseases. 2017;76((Gomez-Reino J.J.) Fundacion Ramon Dominguez, Hospital Clinico Universitario, Santiago De Compostela, Spain):284.

218. Tarp S, Amarilyo G, Foeldvari I, et al. Short term efficacy of biologic agents in patients with systemic juvenile idiopathic arthritis: Network meta-analysis of randomized trials. Arthritis and rheumatism. 2013;65((Woo J.M.P.) Mattel Children's Hospital, University of California, Los Angeles, CA, United States):S924-S925.

219. Vieira MC, Wallenstein GV, Bradley JD, et al. Tofacitinib versus biologic treatments with and without methotrexate in patients with active rheumatoid arthritis who have had an inadequate response to traditional disease modifying anti-rheumatic drugs-a network meta-analysis. Annals of the Rheumatic Disease. 2013;71((Koncz T.) Pfizer Inc, New York, NY, United States).

104

The following table lists examples of systematics reviews that searched for comparative RCTs but that did not locate any available for the treatment of IBD

Table X. Disease

Area First Author and Publication Year SR Information

No head to head RCTs were found for the following populations or outcomes:

Infla

mm

ator

y Bo

wel

Dis

ease

a) Mao 2017140

b) Cholapranee 2017141

c) Bonovas 2016142 d) Mocko; 3 SRs,

2016143,144, 2017145 e) Thaler 2012146

a) Biologics or immunosuppressants for reducing hospitalization or surgery b) Biologics for induction and maintenance of mucosal healing in IBD c) Biological therapies and risk of infection or malignancy outcomes in IBD d) Biologics and the incidence of AEs, SAEs, or study discontinuation due to

AEs e) Therapies for IBD, RCTs of at least 12 weeks duration evaluating efficacy

or safety

Croh

n Di

seas

e

a) Bakouny 2019147 b) Singh 2018148 c) CADTH Health

Technology assessment 201730

d) (Singh 2014)149 e) Khanna 2015150

and MacDonald 2016151

f) Hazlewood 2015152 g) Da 2013153 h) Kawalec 2013154

a) Anti-TNF agents (INF, ADA, CERT, GOL, ETA) in adults for prevention of postoperative recurrence of CD

b) First and second line biologics for moderate to severe CD; literature search through May 2017

c) Ustekinumab versus biological comparator trials in CD d) Biological agents for the treatment of biologic-naive patients with CD e) Ustekinizumab for induction of remission in CD f) Immunosuppressants or biologics for induction or maintenance of

remission g) Certolizumab versus active comparators h) Anti-TNF (ADA or CERT) for CD

Ulc

erat

ive

Colit

is

a) Singh 2017155

b) Trigo 2018156

c) Bonovas 2017157

d) Paschos 2018158

e) Paschos 2018159

f) Vickers 2016160

g) Archer 2016161

h) CADTH 2016162

i) Danese 2014163

j) Stidham 2014164

k) Lv 2014165

a) First and second line pharmacotherapy for moderate to severe UD; literature search through May 2017

b) Biologics and small molecule drugs for moderate to severe UC c) Biologicals and tofacitinib for moderate to severe UC in patients naiive

to anti-TNF therapy d) Tofacitinb versus active comparator for induction of remission in

ulcerative colitis e) Health related quality of life in moderate to severe UC f) Biologics for treatment of moderate to severely active UC g) Biologics (ADA, INF, GOL) in children, adolescents, or adults with

moderately to severely active ulcerative colitis who have had an inadequate or intolerant response, or are with contraindications to conventional therapy (eg, CSS, 6-MP, AZA)

h) Adalimumab versus GOL, INF, or VED (note, did not include tofacitinib) i) Biologics for moderate to severely active UC j) Anti-TNF agents for the induction or maintenance of response or

remission in UC k) Anti-TNF agents in UC patients refractory to conventional therapy

105

Appendix D - Systematic Reviews and Randomized Controlled Trials

Table 1. Characteristics and Results of Included Systematic Reviews (from the Literature Search)

First author,

year, study design

Population Intervention

Number of head-to-

head trials of interest

identified by the SR

Literature search databases

(search dates) Efficacy and safety endpoints/results

Plaque Psoriasis No 2018105 SR of RCTs

Patients with moderate-to-severe psoriasis

Secukinumab vs. etanercept Secukinumab vs.ustekinumab Ixekizumab vs. etanercept Brodalumab vs. ustekinumab Ustekinumab vs. etanercept Guselkumab vs. adalimumab Tildrakizumab vs. etanercept Risankizumab, vs. ustekinumab

12 RCTs (RCTs were included if at least 2 biologic treatments of differing mechanisms were compared)

PubMed, Google Scholar, and ClinicalTrials.gov (Jan 1, 2010 to Jun 26, 2017)

• Secukinumab 150 mg or 300 mg vs. etanercept 50 mg (FIXTURE study) PASI 75 (%) at week 12:

- SEC 300 mg 77.1% vs. ETA 44.0% (p < 0.001) - SEC 150 mg 67.0% vs. ETA 44.0% (p < 0.001)

PASI 90 (%) at week 12: - SEC 300 mg 54.2% vs. ETA 20.7% (p < 0.001) - SEC 150 mg 41.9% vs. ETA 20.7% (p < 0.001)

PASI 100 (%) at week 12: - SEC 300 mg 24.1% vs. ETA 4.3% (p < 0.001) - SEC 150 mg 14.4% vs. ETA 4.3% (p < 0.001)

IGA 0/1 response at week 12: p<0.001 (favors SEC) • Secukinumab 300 mg vs. ustekinumab 45 mg or 90 mg depending on

the weight (CLEAR study) PASI 75 (%) at week 16:

- SEC 300 mg 93.1% vs. UST (45 mg/90 mg) 82.7% (p < 0.0001) PASI 90 (%) at week 16:

- SEC 300 mg 79% vs. UST (45 mg/90 mg) 57.6% (p < 0.0001) PASI 100 (%) at week 16:

- SEC 300 mg 44.3% vs. UST (45 mg/90 mg) 28.4% (p = 0.0003) IGA 0/1 and DLQI 0/1: p<0.0001 (favors SEC)

• Ixekinumab 80 mg every 2 or 4 weeks vs. etanercept 50 mg (UNCOVER-2 and UNCOVER-3 studies)

- PASI 75, PASI 90, PASI 100, sPGA 0/1, and DLQI 0/1 at week 12: p<0.0001 (favors IXE)

106


First author,

year, study design


Number of head-to-





• Brodalumab 140 mg or 210 mg vs. ustekinumab 45 mg or 90 mg (AMAGINE-2 and AMAGINE-3 studies)

- AMAGINE 2: PASI 100, sPGA 0, and sPGA 0/1 response rates at week 12: P≤0.001 (favors BRO 210 mg vs. UST) PASI 75 response: NSS

- AMAGINE 3: PASI75, PASI100, sPGA 0, and sPGA 0/1 response at week 12: p ≤0.007 (favors BRO 210 mg vs. UST)

• Ustekinumab 45 mg or 90 mg vs. etanercept 50 mg (ACCEPT study) - PASI 75, PASI 90, and PGA 0/1 responses at week 12: p ≤0.01

(favors UST) • Guselkumab vs. adalimumab (XPLORE Phase II study)

- GUS showed superior clinical efficacy vs. ADA • Guselkumab 100 mg vs. adalimumab 40 mg (VOYAGE-1 and

VOYAGE-2 studies) - PASI 75, PASI 90 and PASI 100, and IGA 0/1 responses at

week 16: p<0.001 (favors GUS) • Tildrakizumab 100 mg or 200 mg vs. etanercept 50 mg (reSURFACE 2

study) - PASI 75/90/100 responses at week 12 were significantly

greater with TIL vs. ETA - PGA 0/1 and DLQI at week 12: NSS between TIL 100 mg and

ETA • Risankizumab 18 mg, 90 mg, or 180 mg (non-approved doses) vs.

ustekinumab 45 mg or 90 mg (NCT02054481 - phase II) - PASI 50/75/90/100 and sPGA 0/1 at week 12: p<0.001

Loos 2018104

Adults with moderate-to-

Approved targeted immune-

8 RCTs Medline, Embase, and Cochrane (from

Head to head RCTs identified: - Griffiths 2010: ACCEPT study - Langley 2014: Fixture study

107


First author,

year, study design


Number of head-to-





SR and NMA of RCTs

severe chronic plaque psoriasis

modulators vs. placebo or active comparator

Jan 1, 1996 to Jun 28, 2016)

- Griffiths: UNCOVER 2 and 3 studies - Reich 2017: IXORAS-S: Ixe vs. USTE - Thaci 2015: CLEAR study - Lebwohl 2015: AMAGINE 2 and 3 studies

Sbidian 2017106 SR, NMA, and MA of RCTs

Patients over 18 years of age, at any stage of treatment with: -moderate to severe plaque psoriasis OR -psoriatic arthritis whose skin had been clinically diagnosed with moderate to severe psoriasis

Ustekinumab vs etanercept Secukinumab vs etanercept Ixekizumab vs etanercept Secukinumab vs ustekinumab Brodalumab vs ustekinumab Guselkumab vs adalimumab Etanercept vs tofacitinib Etanercept vs apremilast

10 RCTs Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS (Dec 2016)

Direct Evidence Primary outcomes Proportion of patients achieving PASI 90 (clear or almost clear skin) - UST vs. ETA (1 trial: Griffiths ACCEPT, 2010):

RR 1.80, 95% CI (1.45, 2.24) (favors biologic 1) - SEC vs ETA (1 trial: Langley FIXTURE, 2014):

RR 2.32, 95% CI (1.85, 2.92) (favors biologic 1) - IXE vs ETA (2 trials: Griffiths UNCOVER-2 and-3, 2015):

RR 2.98, 95% CI (2.24, 3.98) (favors biologic 1) - SEC vs USTE (1 trial: Thaci CLEAR 2015):

RR 1.38, 95% CI (1.23, 1.53) (favors biologic 1) - BRO vs UST (2 trials: Lebwohl AMAGINE-2 and -3, 2015):

RR 1.27, 95% CI (1.16, 1.39) (favors biologic 1) - GUS vs ADA (3 trials: Blauvelt VOYAGE-1, 2016, Gordon X-PLORE,

2015, and Reich VOYAGE-2, 2017): RR 1.41, 95% CI (1.25, 1.60) (favors biologic 1)

- ETA vs TOF (1 trial: Bachelez 2015): NSS - ETA vs APR (1 trial: Reich LIBERATE, 2017): NSS Proportion of patients with serious adverse events - UST, SEC, or IXE vs. ETA: NSS - SEC or BRO vs. UST: NSS - GUS vs. ADA: NSS - ETA vs. TOF or APR: NSS Secondary outcomes Proportion of patients achieving PASI 75 at induction phase - UST vs. ETA (1 trial): RR 1.26, 95% CI (1.13, 1.40) (favors biologic 1) - SEC vs ETA (1 trial): RR 1.64, 95% CI (1.44, 1.88) (favors biologic 1)

108


First author,

year, study design


Number of head-to-





- IXE vs ETA (2 trials): RR 1.79, 95% CI (1.43, 2.24) (favors biologic 1) - SEC vs UST (1 trial): RR 1.13, 95% CI (1.06, 1.20) (favors biologic 1) - BRO vs UST (2 trials): RR 1.10, 95% CI (1.04, 1.17) (favors

biologic 1) - GUS vs ADA (3 trials): RR 1.21, 95% CI (1.13, 1.30) (favors

biologic 1) - ETA vs TOF (1 trial): RR 1.14. 95% CI (1.02, 1.28) (favors biologic 1) - ETA vs. APR (1 trial ): NSS Proportion of patients achieving a PGA value of 0 or 1 - UST vs. ETA (1 trial): RR 1.40, 95% CI (1.24, 1.58) (favors biologic 1) - SEC vs. ETA (1 trial): RR 2.09, 95% CI (1.73, 2.53) (favors biologic 1) - IXE vs. ETA (2 trials): RR 2.01, 95% CI (1.74, 2.31) (favors biologic 1) - SEC vs. UST (1 trial): RR 1.23, 95% CI (1.13, 1.35) (favors biologic 1) - BRO vs. UST (2 trials): RR 1.17, 95% CI (1.07, 1.27) (favors

biologic 1) - GUS vs. ADA (3 trials): RR 1.24, 95% CI (1.17, 1.32) (favors

biologic 1) - ETA vs TOF (1 trial): RR 1.15, 95% CI (1.04, 1.27) (favors biologic 1) - ETA vs. APR (1 trial): NSS Quality of life - IXE vs. ETA (2 trials): MD -1.99, 95% CI (-2.39, -1.59) (favors

biologic 1) - GUS vs. ADA (2 trials): MD -1.73, 95% CI (-2.50, -0.97) (favors

biologic 1) - ETA vs. TOF (1 trial): NSS Proportions of participants with adverse effects - UST, SEC, or IXE vs. ETA: NSS - SEC or BRO vs. UST: NSS - GUS vs. ADA: NSS - ETA vs. TOF or APR: NSS - ETA vs. APR (1 trial): RR 1.32, 95% CI (1.03, 1.69) (favors APR)

109


First author,

year, study design


Number of head-to-





Psoriatic Arthritis Dressler 2019108 SR of RCTs

Adult patients with PsA or psoriasis with PsA; naïve to bDMARDs

Ixekizumab vs. adalimumab

3 RCTs (only 1 RCT of interest)

MEDLINE Ovid, EMBASE Ovid and CENTRAL (September 2017)

SPIRIT-P1: Ixekizumab 80 mg Q2W for 12 weeks, then 80 mg every 4 weeks vs. adalimumab 40 mg Q2W: - Patients achieving ACR20 after 16-24 weeks:

RR 1.08; 95% CI (0.86–1.36) (Very low quality of evidence) - Patients achieving ACR50 after 16-24 weeks:

RR 1.21; 95% CI (0.88–1.66) (Low quality evidence) - Patients with at least 1 adverse event after 16-24 weeks:

RR 1.02; 95% CI (0.83–1.25) (Moderate quality of evidence) - HAQ-DI:

MD 0.13 lower; 95 % CI (0.27 lower to 0.01 higher) (low quality evidence)

Corbett 2017107 SR and economic evaluation

Adult patients with active PsA and inadequate response to DMARDs

Secukinumab vs. etanercept Secukinumab vs. ustekinumab Adalimumab vs. etanercept vs. infliximab

3 RCTs 14 databases (including Medline and Embase) (From inception to April 2016)

2 RCTs including patients with plaque psoriasis and reporting subgroup data for patients with concomitant PsA: FIXTURE study (data for PsA subgroup) - PASI 75 response at week 12: SEC 300 mg vs. ETA 50 mg twice

weekly (dosing for psoriasis) (RR 1.86, 95% CI 1.24 to 2.81) (favors SEC)

- PASI 90 response at week 12: SEC 300 mg vs. ETA 50 mg twice weekly (dosing for psoriasis) (RR 2.42, 95% CI 1.20 to 4.88) (favors SEC)

CLEAR study (data for PsA subgroup) - PASI 90 at week 16: SEC 300 mg (80%) vs. UST 45-90 mg (65%)

(NSS) - HAQ-DI at week 16: SEC 300 mg showed a higher improvement in

HAQ-DI score vs. UST 45-90 mg 1 RCT including patients with active PsA: Atteno et al (2010)

110


First author,

year, study design


Number of head-to-





- Improvements in psoriasis severity (PASI) at week 52: ADA 40 mg every other week showed significantly better results vs. ETA 50 mg weekly

- Tender joints count (TJC) and HAQ-DI at week 52: ETA 50 mg weekly showed significantly greater improvements in TJC and HAQ-DI vs. ADA 40 mg every other week

Rheumatoid Arthritis Choy 2019109 SR and NMA

Adult RA patients with moderately to severely active RA and with inadequate response to cDMARDs or TNFi

Sarilumab vs. adalimumab (both as monotherapy)

2 RCTs MEDLINE, Embase, and Cochrane databases (Dec 2016)

Head-to-head RCTs identified: • Burmester 2017 (MONARCH trial): Sarilumab vs. adalimumab (as

monotherapy) Other head-to-head RCTs mentioned in this SR: • Weinblatt 2013 and Schiff 2014 (AMPLE trial): Abatacept vs.

adalimumab (both in combination with MTX) See Table 2 of Appendix D for further information

Venerito 2019110 SR and MTC

Adult RA patients with a disease duration of < 1 year

Biologic agents and small molecules in combination with MTX

2 RCTs MEDLINE, Embase, Cochrane Library, and Clinicaltrials.gov (Sept 2017)

Head-to-head RCTs identified: • Schiff 2014 (AMPLE trial): abatacept vs. adalimumab (both in

combination with MTX) • Fleischmann 2017 (ORAL strategy): Tofacitinib vs. adalimumab

(both in combination with MTX) See Table 2 of Appendix D for further information

Ma 2019111 SR and NMA

Patients with RA

Biologics vs. any comparator (placebo, other biologic, or cDMARDs)

2 RCTs PubMed, Embase and Cochrane Library (from 1997 to 2016)

Head-to-head RCTs identified: • Jobanputra 2012 (RED-SEA study): adalimumab vs. etanercept • Weinblatt 2013 and Schiff 2014 (AMPLE trial): Abatacept vs.

adalimumab (both in combination with MTX) See Table 2 of Appendix D for further information

111


First author,

year, study design


Number of head-to-





Emery 2018112 SR

Adult RA patients

Biological and targeted DMARDs (as monotherapy)

1 RCT MEDLINE, Embase, and the Cochrane database (April 2017)

Head-to-head RCTs identified: • Burmester 2017 (MONARCH trial): Sarilumab vs. adalimumab (as

monotherapy). See Table 2 of Appendix D for further information

Kawalec 2013113 SR and MA

Adult RA patients with inadequate response to MTX or other DMARDs

Tofacitinib 5 mg twice daily vs. placebo or adalimumab 40 mg every 2 weeks

2 RCTs PubMed, EMBASE, CENTRAL, and Clinicaltrials.gov (May 2013)

MA results for tofacitinib vs. adalimumab: • ACR50 at week 12: tofacitinib was superior to adalimumab

(relative benefitfixed=0.65; 95 % CI, 0.49 to 0.87; p=0.003) • ACR20 at week 12: no differences between groups • ACR70 at week 12: no differences between groups • SAE and discontinuations due to adverse events: no differences

between groups Abbreviations: ACR20, American College of Rheumatology 20% response rate; ACR50, American College of Rheumatology 50% response rate; ACR70, American College of Rheumatology 70% response rate; ADA, adalimumab; APR, apremilast; bDMARD, biologic disease modifying antirheumatic drug; BRO, brodalumab; cDMARD, conventional disease modifying antirheumatic drug, CENTRAL, Cochrane Central Register of Controlled Trials; CI, confidence interval; DMARD, Disease-Modifying Antirheumatic Drugs; ETA, etanercept; GUS, guselkumab; HAQ-DI, Health Assessment Questionnaire-Disability Index; IXE, ixekinumab; MA, meta-analysis; MD, mean difference, MTC, mixed treatment comparisons; MTX, methotrexate; NMA, network meta-analysis; NSS, non-statistically significant; PASI, Psoriasis Area and Severity Index; PGA, Physician Global Assessment; PsA, psoriatic arthritis; Q2W, once every 2 weeks; RCT, randomized controlled trial; RR, risk ratio; SAE, serious adverse events; SEC, secukinumab; TNFi, tumor necrosis factor inhibitor; TOF, tofacitinib; UST, ustekinumab

112

Table 2. Characteristics and Results of Randomized Controlled Trials Reported in Systematic Reviews for the Rheumatoid Arthritis Population First author, year, study

design Population Intervention Efficacy and safety endpoints/results

Burmester, 2017129 (MONARCH study) Multicentre, randomised, active-controlled, double-blind, double-dummy, phase III superiority trial

Adult patients with active RA who are intolerant or had inadequate response to MTX. Disease duration ≥ 3 months

SARI 200 mg every 2 weeks vs. ADA 40 mg every 2 weeks

Primary endpoint at week 24: - Change from baseline in DAS28-ESR at week 24: SAR −3.28 vs. ADA

−2.20; p<0.0001 (superiority of SARI vs. ADA was demonstrated) Secondary endpoints at week 24:

- ACR20 response rate: SAR 71.7% vs. ADA 58.4% (p≤0.0074) - ACR50 response rate: SAR 45.7% vs. ADA 29.7% (p≤0.0074) - ACR70 response rate: SAR 23.4% vs. ADA 11.9% (p≤0.0074) - Health Assessment Questionnaire-Disability Index (HAQ-DI): greater

improvements with SAR vs. ADA (p=0.0037) - Clinical Disease Activity Index (CDAI): SAR 7.1% vs ADA 2.7%; (nominal

p=0.0468) Safety:

- AEs: SAR 64.1% vs. ADA 63.6% - Incidence of infections: SAR 28.8% vs. ADA 27.7% - Serious infections 1.1% (both groups)

Taylor, 2017134 52-week, phase 3, double-blind, placebo- and active-controlled trial

Adult patients with active RA who have an inadequate response to MTX

BAR 4 mg once daily (oral) [non FDA-approved dose] ADA 40 mg (SC) every other week PLA

Primary endpoint: BAR vs. PLA Secondary endpoints:

- ACR20 response rate at week 12: 70% with BARI vs. 61% with ADA (P=0.014); ADA is non-inferior to BARI. The superiority analysis showed significantly greater improvements with BARI vs. ADA

- Mean change in DAS28-CRP at week 12: BARI was superior to ADA (P>0.001)

Fleischmann, 2017131 (ORAL Strategy) 1 year, double-blind, triple-dummy, phase 3b/4, active comparator, head-to-head controlled trial

Adult patients with active RA who have an inadequate response to MTX

TOF 5 mg twice daily vs. ADA 40 mg every other week (both in combination with MTX)

Primary endpoint: Proportion of patients achieving ACR50 at month 6 - TOF+MTX was non inferior compared to ADA+MTX.

Treatment difference: 2% (98·34% CI −6 to 11) Secondary endpoints:

- ACR20 and ACR70 at month 6: similar results between groups - Percentage of patients with low disease activity or remission at

month 6: similar between groups Weinblatt, 201363 (AMPLE study) [Results at year 1]

Adult patients with active RA for ≤ 5 years who had an inadequate

SC ABA vs. SC ADA (plus MTX)

Primary endpoint: Percentage of patients achieving ACR20 response at year 1: - SC ABA group: 64.8% - SC ADA group: 63.4%

(Estimated difference between groups: 1.8% [95% CI 5.6%, 9.2% - Non-inferiority demonstrated)

113

Table 2. Characteristics and Results of Randomized Controlled Trials Reported in Systematic Reviews for the Rheumatoid Arthritis Population First author, year, study

design Population Intervention Efficacy and safety endpoints/results

Phase IIIb, 2-year, randomised, investigator-blinded, non-inferiority study

response to MTX, and had not received previous bDMARD therapy (Patients not blinded due to logistic issues of masking Humira)

Secondary endpoints: similar results between groups for ACR50, ACR70, DAS28-CRP score, and radiographic non-progression rates Safety: SAE:

- SC ABA: 10.1% - SC ADA: 9.1%

Serious infections: - SC ABA: 2.2% - SC ADA: 2.7%

Discontinuation due to AE: - SC ABA: 3.5% - SC ADA: 1.3%

Injection site reactions: - SC ABA: 3.8% - SC ADA: 9.1% (P= 0.006)

Schiff, 2014130 (AMPLE study) [Results at year 2]

Same as above Same as above Efficacy endpoints: - ACR20: 59.7% with ABA vs. 60.1% with ADA - ACR50: 44.7% with ABA vs. 46.6% with ADA - ACR70: 31.1% with ABA vs. 29.3% with ADA

Jobanputra, 2012132 (RED SEA study) 52-week pragmatic, randomized, parallel group, multicenter, unblinded and non-inferiority trial

Adult patients with active RA despite treatment with 2 DMARDs, including MTX

ADA 40 mg every other week vs. ETA 50 mg weekly

Primary endpoint: - Proportion of patients continuing treatment after 52 weeks:

ADA 65% vs. ETA 56.7% (non-inferiority demonstrated at the 15% margin) Secondary endpoints: - DAS28-C responder status: NSS - Patient global assessment, tender and swollen joint count scores: NSS - Change in EQ5D Utility Score from baseline to 12 months: significantly

greater in patients treated with ADA vs. ETA over 1 year (p=0.046) Abbreviations: ABA, abatacept; ACR, American college of Rheumatology; ADA, adalimumab; BAR, baricitinib; bDMARD, biologic disease modifying antirheumatic drug; CI, confidence interval; DAS28-CRP, Disease activity score in 28 joints using the C-reactive protein level; DAS28-ESR, 28-joint disease activity score using erythrocyte sedimentation rateEQ5D; DMARD, disease modifying antirheumatic drug; Euroqol-5D (health status); ETA, etanercept; HAQ DI, Health Assessment Questionnaire Disability Index; MTX, methotrexate; NSS, non-statistically significant; PLA, placebo; RCT, randomized controlled trials; SAR, sarilumab; SC, subcutaneous; TOF, tofacitinib

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