PRIME Education - PDF TOOL Rheum 11PR193 · 2019-11-21 · PRIME Education, LLC (PRIME®) endorses...

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© 2019 PRIME® Education, LLC. All Rights Reserved..

This activity is provided by PRIME Education. There is no fee to participate. This activity is supported by education grants from AbbVie, Inc., Sanofi Genzyme and Regeneron Pharmaceuticals.

© 2019 PRIME® Education, LLC. All Rights Reserved.. 2

Overview

This fact‐sheet provides a comprehensive look at the evolving landscape of psoriatic arthritis (PsA) and rheumatoid arthritis (RA).

The assessment, treatment, and management strategies included can be implemented in daily practice to support teams in providing

patients with the best treatment aligned with evolving evidence and expert recommendations.

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Disclosure Policy

PRIME Education, LLC (PRIME®) endorses the standards of the ACCME, as well as those of the AANP, ANCC, and ACPE, which require everyone in a position of controlling the content of a CME/CE activity to disclose all financial relationships with commercial interests related to the activity content. CME/CE activities must be balanced, independent of commercial bias, and designed to improve quality in health care. All recommendations involving clinical medicine must be based on evidence accepted within themedical profession. A conflict of interest is created when individuals in a position of controlling the content of CME/CE activities have a relevantfinancial relationship with a commercial interest which therefore may bias his/her opinion and teaching. This may include receiving a salary, royalty, intellectual property rights, consulting fee, honoraria, stocks, or other financial benefits. PRIME® will identify, review, and resolve all conflicts of interest that speakers, authors, course directors, planners, peer reviewers, or relevant staff disclose prior to an educational activity being delivered to learners. Disclosure of a relationship is not intended to suggest or condone bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation. Disclosure information for speakers, authors, course directors, planners, peerreviewers, and/or relevant staff is provided with this activity.Presentations that provide information in whole or in part related to non‐FDA‐approved uses of drugs and/or devices will disclose the unlabeled indications or the investigational nature of their proposed uses to the audience. Participants should refer to theofficial prescribing information for each product for discussion of approved indications, contraindications, and warnings. Participants should verify all information and data before treating patients or employing any therapies described in this educational activity. The opinions expressed in the educational activity are those of the presenting faculty and do not necessarily represent the views of PRIME®, ACCME, AANP, ACPE, ANCC, or other relevant accreditation bodies.


AccreditationIn support of improving patient care, PRIME® is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC) to provide continuing education for the healthcare team.

This activity was planned by and for the healthcare team, and learners will receive 2.5 Interprofessional Continuing Education (IPCE) credits for learning and change.

Physician Credit Designation Statement

PRIME Education, LLC (PRIME®) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.PRIME® designates this Enduring material for a maximum of 2.5 AMA PRA Category 1 Credits. Physicians should claim only credit commensurate with the extent of their participation in the activity.

Physician Assistant Credit Designation Statement

PRIME® has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credits for activities planned in accordance with AAPA CME Criteria. This activity is designated for 2.5 AAPA Category 1 CME credits. PAs should only claim credit commensurate with the extent of their participation..

Nurse Practitioner Credit Designation Statement

PRIME® is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 060815. This activity is approved for 2.5 contact hours of continuing education (which includes 1 hours of pharmacology).

Pharmacist Credit Designation Statement

This Application‐based activity has been approved for 2.5 contact hours (0.25 CEUs) by PRIME® for pharmacists. The Universal Activity Number for this activity is JA0007144‐0000‐19‐086‐H01‐P. Pharmacy CE credits can be electronically submitted to the NABP upon successful completion of the activity. Pharmacists with questions can contact NABP customer service ([email protected]).

Nurse Credit Designation Statement

PRIME Education, LLC (PRIME®) is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.PRIME® designates this activity for 2.5 contact hours.

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Faculty Disclosures

The following individuals have identified relevant financial relationships with commercial interests to disclose:

• Laura K Ferris, MD, PhD (Lead Faculty)

Advisory Board/Panel – Dermavant, JanssenPrincipal Investigator of Research Grant – AbbVie, Amgen, Celgene, Dermavant, Eli Lilly and Company, Janssen, Leo Pharma, Novartis

• Grant W Cannon, MD (Lead Faculty)

Principal Investigator of Research Grant – Amgen

The following individuals have no relevant financial relationships with commercial interests to disclose:

• Heidi Wynn Maloni, PhD, ANP‐BC, CNRN, MSCN (Planner)

• Ryan Burke, PharmD (Planner/Reviewer)

All PRIME staff participating in planning and content development have no relevant financial relationships with commercial interests to disclose.


Learning Objectives

• Identify major barriers to evidence‐based treatment and management in federal and public sectors

• Implement appropriate methods for diagnosis and assessment of disease activity

• Assess current evidence on targeted biologic and small‐molecule therapies to guide treatment decisions for patients with moderate to severe disease

• Monitor treatment responses according to treat‐to‐target principles and methods

• Apply current evidence and guidelines to inform treatment decisions for patients with inadequate responses to initial therapies

• Incorporate patient‐reported outcomes and shared decision‐making into clinical practice

• Apply effective strategies for multidisciplinary care coordination and shared patient management

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PSORIATIC ARTHRITIS


Clinical Features, Classification, & Assessment

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Psoriatic Arthritis (PsA) is a Heterogeneous Disease with a Wide Spectrum of Clinical Manifestations

• Affects <30% of patients with psoriasis 75% of patients develop skin symptoms first

Joint symptoms typically begin at ages 30–55

• PsA more likely to develop in patients with moderate to severe psoriasis (PsO)

• Significant impact on: Disability

Quality of life

Comorbidities

Economic burden

• To achieve best outcomes, guidelines call for collaboration between: Dermatology and rheumatology specialties

Specialists and interprofessional team

PIP = Proximal Interphalangeal; DIP = Distal Interphalangeal.

Image adapted from: Giannelli A. Rheumatol Ther. 2019;6(1):5–21.

Coates LC, et al. Arthritis Rheumatol. 2016;68(5):1060–1071.

Scalp Psoriasis

Psoriatic Lesions

Tender/SwollenSacroiliac Pain

Nail Psoriasis

Plantar FasciitisAchilles Tendon Pain

Dactylitis

PIP/DIP Joint Inflammation

Enthesitis of superior/inferior patella or lateral epicondylar

Grappa Domains of PsA

Peripheral Arthritis Dactylitis

Axial Disease Nails

Enthesitis Skin


What Does PsA Look Like?

DIP joint involvement Symmetric arthritis Asymmetric oligoarthritis

Spondylitis Dactylitis Enthesitis

DIP = Distal Interphalangeal.

Images courtesy of Paul S Yamauchi, MD, PhD.

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Distinguishing Clinical Features of PsA, Rheumatoid Arthritis, and Osteoarthritis (OA)

Features PsA RA OA

Peripheral disease Asymmetric Symmetric Asymmetric

DIP joint involvement Yes No Yes

Sacroiliitis Asymmetric No No

Morning stiffness Peripheral joints,

some spinePeripheral joints

Peripheral or spine joints, especiallyfollowing physical activity

Gender ratio (M:F) 1:1 1:3 1:1

Rheumatoid factor, anti‐CCP

No Yes No

Enthesitis Yes No Yes

Nail lesions Yes No No

Skin involvement Yes No NoMcArdle A, et al. Clin Rev Allergy Immunol. 2017. Epub ahead of print; Mease P, et al. J Am Acad Dermatol. 2005;52(1):1–19.


Classification Criteria for Psoriatic Arthrits (CASPAR)

Symptom Domain Criterion

Clinical

Psoriasis (current*, history, or family history)

Nail changes

Dactylitis (current or history)

Serology Rheumatoid factor negative

Radiology Juxta‐articular new bone formation

*Active psoriasis accounts for two points.

Taylor W, et al. Arthritis Rheum. 2006;54(8):2665‐2673.

Established inflammatory articular disease (joint, spine, entheseal) plus ≥ 3 points from the following criteria:

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Early Diagnosis of PsA is Critical for Long‐Term Outcomes

• PsA is a progressive disease

40–70 % of patients have joint damage within 2 years of disease onset

50% of patients have chronic‐progressive disease

• PsA is underdiagnosed

<40% of PsO patients have undiagnosed PsA

70% of patients have their 1st rheumatologist visit after 2 years of joint symptom onset

Untreated PsA leads to:

Persistent inflammation

Progressive and irreversible joint damage

Severe physical limitations and disability

Onset of related comorbidities

Increased mortality

*Confidence rated on a 5‐point Likert scale (1 = very low; 5 = very high). Percentages shown represent pooled represent pooled ratings of 4 and 5 on this scale.

McArdle A, et al. Clin Rev Allergy Immunol. 2018;55(3):271–294; Mease PJ, et al. J Am Acad Dermatol. 2013;69(5):729–735; Ritchlin CT, et al. N Engl J Med. 2017;376(10):957–970; Menter A, et al. J Am AcadDermatol. 2008;58(5):826–850; Haroon M, et al. Ann Rheum Dis. 2013;72(5):736–740; Haroon M, et al. Ann Rheum Dis. 2015;74(6):1045–1050; Boehncke WH, et al. J Eur Acad Dermatol Venearol. 2014;28(3):264–270.


What Measurements Do We Use for Axial Involvement?

Gladman DD. Rheum Dis Clin N Am. 2015;41(4):569–579.

May be detected with:

Finger to floor Tragus to wallSchober’s testLateral flexion of the spineChest expansion

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Tools for Assessing PsA Disease Severity

See appendix for list of abbreviations.

Raychaudhuri SP, et al. J Autoimmun. 2017;76:21–37.

Disease Assessment Tools for Measurement

Peripheral Joint 68/66 tender/swollen joint count, DAS28, CDAI*, DAPSA, cDAPSA, and ACR20/50/70

Composite MDA, VLDA, PASDAS, CPDAI

Axial Joint ASDAS, BASDAI, BASFI, BASMI

Skin PASI, BSA, Target lesion, Physician static global

Enthesitis Leeds, SPARCC, MASES, 4‐point

Dactylitis Leeds, present/absent, DSS (dactyliits severity score)

Patient Global VAS (global, skin + joints)

Physician Global VAS (global, skin + joints)

Pain VAS, NRS

Function / QOL HAQ, SF‐36, PsAQOL, DLQI


Therapeutic Management

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PsA in the US: Quick Statistics

Mease PJ, et al. J Am Acad Dermatol. 2013;69(5):729–735; Armstrong AW, et al. JAMA Dermatology. 2013;149(10):1180–1185; Lebwohl MG, et al. Am J Clin Dermatol. 2016; 17(1):87–97.

• Patients with moderate to severe PsA who report not receiving any form of treatment or topical therapy alone53%

• Patients with PsA who are dissatisfied with their current treatment55%

• Patients with PsA who do not think their current treatment meets their primary goals of therapy40%

• Incremental adjusted direct and indirect costs of PsA as a comorbidity with PsO>$10,000


Targeting Minimal Disease Activity To Achieve Goals of PsA Therapy

Minimal Disease Activity (MDA)

Tender joint count ≤1

Swollen joint count ≤1

PASI ≤1 or BSA ≤3

Patient pain VAS ≤15

Patient global activity VAS ≤20

HAQ ≤0.5

Tender entheseal points ≤1

Coates LC, et al. Arthritis Rheumatol. 2016;68(5):1060–1071; Coates LC, et al. Ann Rheum Dis. 2010;69(1):48–53; Coates LC, et al. Lancet. 2015;386(10012):2489–2498.

Goals of PsA Therapy:

Achieve lowest possible level of disease activity

Improve quality of life and functional status

Minimize or prevent complications

Using a Treat‐to‐Target Approach to Achieve MDA:Results from the TICOPA Study

• 206 patients with early PsA randomized to receive treatment through:

Tight control: review every 4 weeks, escalate treatment if MDA not met

Standard control: review every 12 weeks, treatment according to clinician

Early intervention + tight control of inflammation led to higher ACR20, ACR70, and PASI75 scores after 48 weeks vs standard care

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GRAPPA PsA Treatment Recommendations 2015

*Open‐label data available.

Coates LC, et al. Arthritis Rheumatol. 2016;68(5):1060–1071.

Standard therapeutic route

Expedited therapeutic route

Assess activity, im

pact

and progn

ostic factors

DMARDs (MTX, SSZ, LFN), TNFi

or PDE4i

Biologics (TNFi, IL12/23i IL17i)

or PDE4i

Peripheral arthritis

Switch biologic (TNFi, IL12/23i

or IL17i)

NSA

IDs an

d IA

I corticosteroids as in

dicated

NSAIDs only

TNFi, IL17i or *IL12/23i

Axial disease

Switch biologic (TNFi, IL17i or *IL12/23i)

Physiotherap

y an

d NSA

IDs

No direct evidence for therapies in axial PsArecommendations based on axial SpA literature

NSAIDs

Biologics (TNFiIL12/23i, IL17i)

or PDE4i

Enthesitis

Switch biologic (TNFi, IL12/23i, IL17i) or PDE4i

Physiotherap

y

CS injections: consider on an individual basis due to potential for serious side effects; no clear evidence for efficacy

NSAIDs

DMARDs (MTX, LEF, SSZ) or

PDE4i

Dactylitis

Biologics (TNFi, IL12/23i)

Corticosteroid in

jections as in

dicated


Topicals(keratolytics, steroids, vit. D analogues, emollients, calcineurin i)

Phototherapy or DMARDs (MTX, CSA, acitretin, fumaric acid

esters) or PDE4i

Skin

Biologics (TNFi, IL12/23i, IL17i) or

PDE4i

Topicalsas in

dicated

Switch biologics (TNFi, IL12/23i, IL17i)

or PDE4i

Biologics (TNFi, IL12/23i, IL17i)

or PDE4i

Topical or procedural or DMARDs (CSA,

LEF, MTX, acitretin)

Nails


Which domains are involved?

Consider previous therapy, patient choice, other disease involvement, and comorbidities. Choice of therapy should address as many domains as possible.

Treat, periodically re‐evaluate, and modify therapy as required.


ACR/NPF Guidelines for the Management of Active PsA (2018)

ACR = American College of Rheumatology; OSM = Oral Small Molecules, defined as methotrexate, sulfasalazine, leflunomide, cyclosporine, and apremilast. Does not include tofacitinib or abatacept.

Sing JA, et al. Arthritis Rheumatol. 2019;71(1):5–32.

• Use a treat‐to‐target strategy to make decisions based on individual patient factors: severity or activity of PsA, severity or activity of PsO, comorbidities, contraindications to medications, preferences to route or frequency of administration, concerns over therapies, and others.

• At each point, discuss with the patient, since all recommendations are conditionally based on low/very low quality of evidence: conditional recommendations are preference‐sensitive and always warrant a shared decision‐making approach.

Treatment‐Naïve Active PsA

Start TNFiover OSM, IL 17i, or IL 12/23i

Start OSMover IL 17i or IL 12/23i

Start MTX over NSAIDs

Start IL17iover IL 12/23i

If active despite TNFi monotherapy:• Switch to different TNFi over IL 17i, IL 12/23i, abatacept,

tofacitinib, or adding MTX• Switch to IL 17i over IL 12/23i, abatacept, or tofacitinib• Switch to IL 12/23i over abatacept or tofacitinib

If active despite TNFi + MTX therapy:• Switch to different TNFi + MTX over TNFi monotherapy• Switch to IL 17i monotherapy over IL 17i + MTX• Switch to IL 12/23i monotherapy over IL 12/23i + MTX

If active despite OSM:• Switch to TNFi over another OSM, IL 17i, IL 12/23i,

abatacept, or tofacitinib• Switch to IL 17i over another OSM, IL 12/23i, abatacept,

or tofacitinib• Switch to IL 12/23i over another OSM, abatacept or

tofacitinib

If active despite IL 17i monotherapy:• Switch to TNFi over IL 12/23i, a different IL 17i, or

adding MTX• Switch to IL 12/23i over a different IL 17i, or adding MTX

If active despite IL 12/23i monotherapy:• Switch to TNFi over IL 17i or adding MTX• Switch to IL 17i, adding MTX

ACR/NPF Disclosure: The order of listing of various conditional recommendations or of different treatment choices within a conditional statement does not indicate any sequence in which treatment options would be chosen.

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Conventional DMARDs in PsA

• DMARDs: Decrease pain and inflammation

• Many are used off‐label in PsA Approved for other inflammatory conditions

• Modest effects/efficacy on arthritis and skin disease Minimal effect on preventing radiological progression

No effect on axial disease

• Risk for adverse events

DMARD = Disease‐Modifying Antirheumatic Drug.

Raychaudhuri SP, et al. J Autoimmun. 2017;76:21‐37; Mease PJ, et al. Drugs. 2014;74(4):423‐441; Kingsley GH, et al. Rheumatology. 2012;51(8):1368‐1377.

Methotrexate Leflunomide

Sulfasalazine Cyclosporine


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Biologic and Small Molecule Therapies for PsA

Therapy Target Key Trial Dosing* Considerations*

Abatacept CD 80/86 PsA‐I/PsA‐II IV: weeks 0, 2, 4, then Q4W SC: QW (no loading dose)

• Available as powder for reconstitution, PFS, or autoinjector• Dosing based on patient weight

Apremilast PDE4 PALACE/ACTIVE Oral: titrate‐up over 1 week until 30 mg BID • Adjust dose if renal impairment

Tofacitinib JAK 1/3 OPAL Oral: 5mg BID or 11mg QD• Adjust dose if renal or hepatic impairment; concomitant CYP‐2C19

and/or ‐3A4 inhibitors; or lymphopenia, neutropenia, anemia

Etanercept TNF‐α Ph3 Etanercept in PsA SC: 50mg QW • Available as powder for reconstitution, PFS, or autoinjector

Infliximab TNF‐α IMPACT 2 IV: weeks 0, 2, 6, then Q8W. • Dosing based on patient weight (5 mg/kg)

Adalimumab TNF‐α ADEPT SC: 40mg Q2W or QW • Available as single‐dose vial, PFS, or autoinjector

Golimumab TNF‐α GO‐REVEAL/GO‐VIBRANT SC: 50 mg Q4W • Available as PFS or autoinjector

Certolizumab TNF‐α RAPID‐PsA SC: 400mg at week 0, 2, 4, then 200mg Q2W • Available as powder for reconstitution or PFS

Ustekinumab IL 12/23 PSUMMIT 1 SC: 45mg at week 0, 4, then Q12W• Available as singe‐dose vial or PFS• Double the dose for patients weighing ≥100kg

Secukinumab IL 17A FUTURE 2 SC: 150mg week 0, 1, 2, 3, 4, then Q4W• Available as singe‐dose vial or PFS• Double the dose for patients with active PsO

Ixekizumab IL 17 SPIRIT‐P1 SC: 160mg at week 0, then 80mg Q4W • Different loading dose for patients with active PsO

Phase 3

Upadacitinib JAK 1 SELECT‐PsA Oral

Guselkumab IL 23 DISCOVER SC

*Per prescribing label. Please refer to label for full information on dosing and administration.PFS = Prefilled Syringe.

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Anti‐TNF Therapies in PsA: ACR and PASI Responses

Mease PJ, et al. Arthritis Rheum. 2005;52(10):3279–3289; Mease PJ, et al. Ann Rheum Dis. 2014;73(1):48–55; Mease PJ, et al. Lancet. 2000;356(9227):385–390; Mease PJ, et al. Arthritis Rheum. 2004;50(7):2264–2272; Kavanaugh A, et al. Arthritis Rheum. 2009;60(4):976–986; Antoni C, et al. Ann Rheum Dis. 2005;64(8):1150–1157; Antoni CE, et al. Arthritis Rheum. 2005;52(4):1227–1236.

57

39

23

5958

36

25

47

73

50

13

26

59

38

11

23

48

32

18

5858

36

15

6465

46

29

68

0

10

20

30

40

50

60

70

80

ACR20 ACR50 ACR70 PASI75

Adalimumab (n = 405) ‐14 wks

Certolizumab (n = 409) ‐12 wks

Etanercept (n = 60) ‐12 wks

Etanercept (n = 205) ‐24 wks

Golimumab (n = 405) ‐14 wks

Infliximab (n = 200) ‐14 wks

Infliximab (n = 104) ‐16 wks

1

2

3

4

5

6

7

Patient Response (%)

Please note: data presented in this graph come from different trials and are not directly comparable.


Impact of Switching on PsA Outcomes

• 30–40% of patients switch to a second or third therapy mainly due to lack of effect or adverse events

• Data from observational studies show a trend toward poorer responses to and lower drug survival for 2nd TNFi compared with 1st TNFi No difference found between TNFi

• GRAPPA recommendations: Switch to either an alternative biologic within a

drug class or to a drug with a different mechanism of action

Add conventional DMARDs (e.g., methotrexate) to biologic therapy, but there is little evidence of added benefit

DANBIO Registry 10‐year Observational Cohort

D’Angelo S, et al. Open Access Rheumatol. 2017;9:21–28; Glintborg B, et al. Arthritis Rheum. 2013;65(5):1213–1223; Coates LC, et al. Arthritis Rheumatol. 2016;68(5):1060–1071; Fagerli KM, et al. Ann Rheum Dis. 2013;72(11):1840–1844; Lubrano E, et al. J Rheumatol. 2016;43(5):918–923.

TNF therapy # of Switches

Patients (%)

47%

22%18%

0%

10%

20%

30%

40%

50%

1st 2nd 3rd

57%

47%

None Any

ACR20 Response by Anti‐TNF Switch

3–6 Months 2 Years

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Efficacy of Apremilast (PDE4) in PsA Patients with Prior Biologic‐Therapy Exposure or Failure

24

5 6

31 31

21

43

2823

0

10

20

30

40

50

60

Biologic‐Naïve Patients Biologic‐Experienced Patients Biologic Failures

Placebo Apremilast 20 mg twice a day Apremilast 30 mg twice a day

†P <0.007.

Kavanaugh A, et al. Ann Rheum Dis. 2014;73(6):1020–1026.

Results from PALACE‐1 TrialACR20 Response by Biologic Experience

Responders (%)

n = 118 125 120 40 36 39 18 14 13

†

††


0

20

40

60

80

0 1 2 3 4 5 6

Efficacy of Tofacitinib (JAK 1/3 inhibitor) in PSA Patients with Prior Anti‐TNF Treatment Failure: OPAL‐Beyond Phase 3 Results

ACR20 Response PASI‐75 Response

At 3 Months

Placebo(n = 131)

Tofacitinib5 mg

(n = 131)

Tofacitinib10 mg

(n = 132)

12/86 (14%) 17/80 (21%) 35/81 (43)

At 6 MonthsPbo → Tofa

5 mg(n = 66)

Pbo → Tofa10 mg(n = 65)

Tofacitinib5 mg

(n = 131)

Tofacitinib10 mg

(n = 132)

11/42 (26%) 14/44 (32%) 27/80 (34%) 37/81 (46%)

Tofa = Tofacitinib

Gladman D, et al. N Engl J Med. 2017;377(16):1525–1536.

Month

Responders (%)

PlaceboTofacitinib 10mg

Tofacitinib 5mg

Placebo Tofacitinib 10mg

Placebo Tofacitinib 5mg

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0

20

40

60

80

0 4 8 12 16 20 24 28 32 36 40 44 48 52

n = 62n = 60n = 58

Efficacy of Ustekinumab (Anti‐IL12/23) in PsA Patients with Prior Anti‐TNF Exposure: PSUMMIT 2 Trial

*Ustekinumab was administered at week 0, week 4 and every Q12W thereafter.

†Among randomized patients with ≥3% body surface area with PsO skin involvement at baseline.

‡For pa ents who qualified for early escape, data at or prior to Week 16 were carried forward through Week 24. A er Week 24, observed data were used.

Ritchlin C, et al. Ann Rheum Dis. 2014;73(6):990–999.

10

7058

79

63

82

0

25

50

75

100

2

434636

49 50

0

25

50

75

100

Responders (%)

Responders (%)

n = 30 36 40 27 33 33

n = 50 44 41 30 36 40

Week 24 Week 52

0

20

40

60

80

0 4 8 12 16 20 24 28 32 36 40 44 48 52

n = 42

n = 43

n=47

Prior Anti‐TNF

Exposure

† ‡

Week 24 Week 52Weeks

Weeks

No Prior Anti‐TNF

Exposure

† ‡

Responders (%)

Responders (%)

ACR20

ACR20

PASI75

PASI75

Placebo Ustekinumab 45mg Ustekinumab 90mg


Efficacy of Secukinumab (Anti‐IL17A) in PsA Patients With or Without Prior Anti‐TNF Exposure

*Secukinumab was given QW from week 0–4, then Q4W thereafter.

IR = Inadequate Response.

McInes IB, et al. Lancet. 2015;386(9999):1137–1146.

58%

45%

63%

30%

16% 14%

0%

20%

40%

60%

80%

Anti‐TNF Naïve Anti‐TNF IR

Secukinumab 300mg Secukinumab 150mg Placebo

63% 64%

56%

36%

19%

8%

Anti‐TNF Naïve Anti‐TNF IR

ACR20 Response PASI75 Response

FUTURE 2: Phase 3 Trial

Patients (%)

n = 67 63 63 33 37 35 30 36 31 11 22 12

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Efficacy of Ixekizumab (Anti‐IL17A) in PsA Patients with Prior Anti‐TNF Treatment Failure: SPIRIT‐P2 Phase 3 Results

*P <0∙0001

Patients in both ixekizumab treatment groups received a loading dose of 160 mg at week 0, then 80 mg per dose thereafter.

Nash P, et al. Lancet. 2017;389(10086):2317–2327.

ACR20 Scores ACR70 Scores

0 4 8 12 16 20 24

19%

53%*

48%*

Patients with ACR‐20 (%)

Week

Placebo (n = 118)Ixekizumab Q4W (n = 122)Ixekizumab Q2W (n = 123)

0 4 8 12 16 20 240%

22%*

12%*

Patients with ACR‐70 (%)

Week


Interdisciplinary Collaboration and Management

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PPACMAN: National Initiative to Improve Collaboration Between Dermatologists and Rheumatologists

Combined Clinic Model

Cross training between specialties

One‐stop‐shop for patient education and support

Cohesive management ofpatients with psoriatic disease

Development of validated tools and measures between specialties

Perform observational and interventional trials activities

GoalsResearch

• Barriers and facilitators• Patient perspectives and attitudes• Improved diagnosis

Education

• Build networks and relationshipso Referral practiceso Tele‐management o EMR links, forms, templateso Community outreach o Provider database (NPF)o Education partnership (GRAPPA/PRIME)

• Best practices toolkit for building clinics and assessing patients


Initial Findings from PPACMAN’s Research Projects

Demographics:

• 25 clinics across the US

• 32 physician responses 16 dermatologists

14 rheumatologists

2 dual‐trained physicians

• 1 in private practice

• 5 collaborated virtually

• 25 reported having trainees

Okhovat JP, et al. J Rheumatol. 2017;44(5):693–694.

Cross‐sectional survey of 25 participating centers with dual rheumatology‐dermatology clinics

Benefits:• Improved communication among healthcare teams• Excellent training opportunities• Prompt and accurate diagnosis of PsA• Frequent monitoring of symptoms and medication• Increased professional development/satisfaction

Challenges:• Scheduling the right mix of patients• Filling both specialists’ schedules appropriately• Demonstrating value to the institution

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Real‐World Evaluation of Multidisciplinary Care in PsA: The NEXUS Project in Spain

Queiro R, et al. Reumatol Clin. 2017;13(2):85–90.

Interviews with 24 clinicians (12 rheumatologists and 12 dermatologists) to characterize the different multidisciplinary care units currently functioning in Spain

Key Steps for Success:

Enlist involved specialist and staff with experience and interest in PsA who get along well

Define collectively the type of model that best fits the center/professionals, referral criteria and access, visit intervals,method of communication, office location, and other logistics

Develop templates and formulas to facilitate visits, discharge, and follow up

Share visit reports with patient and with other attending physicians

Evaluate model and make adjustments every 3–6 months for the first 2 years

Face‐to‐Face Approach (n = 9)

• Same office

• Attend patients simultaneously

• Make decisions together

• “One stop shop” for patients

Parallel Approach (n = 1)

• Different but contiguous offices

• Attend patients in separate but successive appointments

• Discuss cases by phone or attend patients jointly when needed

Preferential Circuits (n = 2)

• Different offices in corresponding department

• Attend patients separately

• Highly trained in PsA with specific referral criteria

• Discuss cases by phone or attend patients jointly when needed


Comorbidities and Extra‐Articular Manifestations of PsA

Incidence of Comorbidities of Interest among PsO Patients ± PsA (PSOLAR Registry)

Most Common Comorbidities

*Self‐reported PsA, established by a HCP; **Self‐reported PsA.

Kavanaugh A, et al. BMC Rheumatol. 2018;29(2):29; Kaine J, et al. J Manag Care Spec Pharm. 2019;25(1):122–132; Merola JF, et al. Clin Rheumatol. 2018;37(10):2751–2761.

• Cardiovascular/Metabolic Hypertension

Hyperlipidemia

Coronary artery disease

Fatty liver disease

Diabetes

Obesity

• Immune/Inflammatory Psoriasis

Inflammatory bowel disease

Uveitis

• Psychiatric Anxiety

Fatigue

Depression

47%

27%

3%

44%

26%

3%

35%

18%

1%0%

10%

20%

30%

40%

50%

Cardiovascular Psychatric IBD

PsO + PsA* (n = 1,719)

PsO + PsA** (n = 4,315)

PsO only (n = 7,775)P < 0.001 vs patients with psoriasis only

18


Management Considerations for Patients with Comorbidities

Husni ME. Rheum Dis Clin North Am. 2015;41(4):677–698; Husni ME, et al. Curr Rheumatol Rep. 2010;12(4):281–287; Ogdie A, et al. Curr Opin Rheumatol. 2015;27(2):118–126.

Comorbidity Practice Tips

CVD

• Check blood pressure, lipid panel• Encourage smoking cessation• Assess risk‐benefit of NSAIDs use • Identify high‐risk patients

Depression/Anxiety

• Ask about symptoms of depression and anxiety • May impact adherence to treatment • Refer to psychosocial support • Certain medications may worsen depression

Diabetes • Check fasting glucose or hemoglobin A1c

IBD• Ask about gastrointestinal symptoms• Certain medications may exacerbate disease• Not all targeted therapies approved or effective in IBD

Liver/Kidney Disease• Check serologies before starting therapy• Certain medications may exacerbate function

Malignancy • Consider periodic skin check for patients

Obesity• Council patients on the benefits of weight loss • Certain medications can help with weight loss• Certain medications are not as effective in heavier patients

Ophthalmic Disease• Ask about ophthalmic symptoms• Certain medications may aggravate symptoms


Interprofessional Collaboration and Co‐Management of PsA

QoL = Quality of Life

• Engage entire interprofessional team and establish roles for:

Monitoring, treatment decisions, adherence, patient education, etc.

• Improve communication between specialists, primary care, and others

Share patient notes

Call provider to discuss

• Create workflow process for:

Timely and appropriate referrals

Ensuring patient follow‐up and monitoring

Dermatology

RheumatologySupport

QoLPain

DisabilityFunctioningComorbidities

Joint symptoms

Skin symptomsScreening

Co‐managementMonitoring

Primary CarePsychology

Physical therapyCounseling Pharmacy

19


Patient Perspectives on PsA Treatment and Disease Burden

Kavanaugh A, et al. Rheumatol Ther. 2016. 3(1):91–102; Mease PJ, et al. J Am Acad Dermatol. 2013;69(5):729–735; Armstrong AW, et al. JAMA Dermatology. 2013;149(10):1180–1185; Lebwohl MG, et al. Am J Clin Dermatol. 2016; 17(1):87–97.

• Patients who report that PsA has either prevented them from going to work in the past year or impacted ability to work full time32%

• Patients with moderate to severe PsA who do not think their current treatment meets their primary goals of therapy40%

• Patients with moderate to severe PsA who report not receiving any form of treatment or topical therapy alone53%

• Patients with PsA who are dissatisfied with their current treatment 55% • Patients with PsA who are concerned about health risks with long‐term therapy64%


Eliciting Patient‐Reported Outcomes

Validated Tools•Patient Global Assessment (PGA)

•Routine Assessment of Patient Index Data (RAPID‐3)

•Work Productivity/Activity Impairment Questionnaire (WPAI)

•Functional Assessment of Chronic Illness Therapy (FACIT)

Pain and Function

•Health Assessment Questionnaire (HAQ)

•Study Short Form 36 (SF‐36)

•Psoriatic Arthritis Quality of Life (PsAQoL)

•Dermatology Life Quality Index (DLQI)

•Psoriatic Arthritis Impact of Disease (PsAID)

Quality of Life

•Patient Health Questionnaire (PHQ)‐2 or ‐9

•Generalized Anxiety Disorder‐7 Tool (GAD‐7)

•Center for Epidemiological Studies Depression Scale(CES‐D)

•Beck Depression Inventory‐II (BDI‐II)

Mental Health

Interview Questions • Assessing Disease Activity

Do you have trouble in performing daily tasks?

Do you wake up at night because of low back pain?

Have you ever experienced pain in your heel, knee, or elbow?

Have you ever noticed pain and complete swelling of a single finger/toe?

Have you ever had red, itchy, and scaly patches on your skin?

Do your fingernails or toenails have holes or pits?

• Monitoring Treatment Response

Have you noticed reduced pain or swelling in your wrists or finger joints?

Are you now able to sleep through the night?

Has your ability to climb stairs improved?

Have you noticed a reduction in swelling of the enlarged finger/toe?

Has there been improvement to areas of your skin affected by psoriasis?

Has the appearance of your fingernails/toenails improved?

Giannelli A. Rheumatol Ther. 2019 Mar;6(1):5–21; Wong PC, et al. Int J Rheumatol. 2012;2012:839425.

20


Strategies for Engaging Patients in Shared Decision‐Making

Needs

• Ask about disease impact, personal circumstances, and therapy preferences

• Assess health literacy and knowledge gap

Support

• Share and encourage use of NPF resources

• Provide patient education literature and tools

• Define treatment needs and goals

Quality

• Use patient decision aids

• Empower patients for active participation in care

• Guide decision‐making with clinical expertise

Outcomes

• Improve communication

• Increase likelihood of patient adherence to and satisfaction with therapy

NPF. For Your Patients. https://www.psoriasis.org/health‐care‐providers/for‐your‐patients. Accessed 9/21/17. Tan J, et al. Br J Dermatol. 2016;175(5):1045–1048; Strohal R, et al. J Eur Acad Dermatol Venereol. 2015; 29(12):2390–2398.


RHEUMATOID ARTHRITIS

21


Overview of Paradigms and Challenges


Disease and Economic Burden of Rheumatoid Arthritis (RA) in US

CDC. Arthritis. Available at https://www.cdc.gov/arthritis/index.htm. Accessed 6/8/18; Arthritis Foundation. Arthritis By The Numbers: 2018. Available at: https://www.arthritis.org/Documents/Sections/About‐Arthritis/arthritis‐facts‐stats‐figures.pdf Accessed 6/11/2018; Birnbaum H, et al. Curr Med Res Opin. 2010;26(1):77–90; Hresko A, et al. Arthritis Care Res (Hoboken). 2018. Epub ahead of print; Cooper NJ. Rheumatology (Oxford). 2000;39(1):28–33; Sokka T. Clin Exp Rheumatol. 2003;21(5 Suppl 31):S71–S74; Strand V, et al. Ann Rheum Dis. 2012;71(7):1143–1150.

$39 billion in medical costs, including direct and indirect costs (2010)

About 1.3 million Americanssuffer from RA

Women are 2–3 times more likely to get RA than men

High incidence of co‐morbidities andextra‐articular manifestations:

Underlying inflammation leads to cardiovascular disease, interstitial lung disease, and depression

Significant burden in QoL, which can be improved by effective treatment

If left untreated, 20–30% of RA patients become work‐disabled within 3 years

Total direct medical costs range from $12,000–$52,000 per patient (2015)

22


Therapeutic Window of Opportunity in Early RA

Image on the right courtesy of Peng T Fan, MD.

Singh JA, et al. Arthritis Care Res. 2012;64(5):625–639.

Early Established End StageDiseaseOnset

Critical Window of Opportunity

Functional impairment

Work disability

Radiographic damage

50–70% of patients have radiographic damage within the first 2 years of onset of symptoms

Intervention

RA Untreated

Disease Duration (time)

Prevents Progression

Natural Course

Population X‐Ray Score


Core Principles in RA Management

DMARDs = Disease‐Modifying Antirheumatic Drugs.

Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1–26; Singh JA, et al. Arthritis Care Res. 2016;68(1):1–25; Smolen JS, et al. Ann Rheum Dis. 2014;73(3):492–509; Smolen JS, et al. Ann Rheum Dis. 2010;69(4):631–637; Smolen JS, et al. Ann Rheum Dis. 2016;75(1):3–15.

Early recognition and

diagnosis

Early use of DMARDs

Treat‐to‐target (T2T)

Target of remission or low disease activity

Frequent monitoring of disease activity

Individualized treatment

Shared decision‐making

23


Evolving RA Treatment Landscape: Pre‐Biologic Era

ASA = acetylsalicylic acid; AZA, azathiopine; Ig, immunoglobulin; HCQ, hydroxychloroquine; LEF, leflunomide; SSZ, sulfasalazine.

Treat signs and symptoms• Aggressive MTX dosing• Combination therapy• Disease modification

1930s

Injectablegold

1950s

HCQ,Steroids

1970s

D‐Pen,AZA

1980s

MTX,Oral gold

1990s

Leflunomide

1960s

SSZ

ASA

1900

Biologic DMARDs(see next slide)

2000s


The Evolving RA Treatment Landscape:The Rise of Biologic and Small Molecule Agents

MTX = Methotrexate; LEF = Leflunomide; JAK = Janus Kinase

1988 2001 2005 2012

MTXLEF

(ARAVA)

Etanercept(ENBREL) TNF‐α

Infliximab(REMICADE)

TNF‐α

Anakinra(KINERET)

IL‐1R

1998

Adalimumab(HUMIRA)

TNF‐α

Abatacept(ORENCIA)CD80/86

2008

Certolizumab(CIMZIA)TNF‐α

2010

Golimumab(SIMPONI)

TNF‐α

Rituximab(RITUXAN)

CD‐20

Tocilizumab(ACTEMRA)

IL‐6R

Tofacitinib(XELJANZ)JAK 1/3

FDA APPROVED

Phase 3

MTX

2013

Tocilizumab(ACTEMRA)

IL‐6R

Oral

Infusion

Injection

Golimumab(SIMPONI)

TNF‐α

Infliximab‐dyyb*(INFLECTRA)

TNF‐ α

2016

Adalimumab‐atto*(AMJEVITA)

TNF‐α

Etanercept‐szzs*(ERELZI) TNF‐α

2017

Sarilumab(KEVZARA)

IL‐6R

Adalimumab‐adbm*(CYLTEZO) TNF‐α

Infliximab‐qbtx*(IXIFI)TNF‐ α

Infliximab‐abda*(RENFLEXIS)

TNF‐ α

Baricitinib

(OLUMIANT)JAK 1/2

Filgotinib

JAK 1

OlokizumabIL‐6

Peficitinib

JAK 1/3

2019

Upadacitinib

(RINVOQ)JAK 1/2

* Biosimilar

24


The “Problem of Choice” in RA Treatment Decision‐Making

Karaca‐Mandic P, et al. Health Serv Res. 2010;45(5 Pt 1):1227–1250; Gleason P, et al. J Manag Care Pharm. 2013;19(7):542–548; Schneider CK. Ann Rheum Dis. 2013;72(3):315–318; CVS Caremark. Insights 2013 Specialty Trend Management. Retrieved from www.info.cvscaremark.com/sites/default/files/Insights%202013.pdf. Accessed 3/9/16.

Need for personalized treatment approach

RA disease

Patient factors

Drugs

• Complex and evolving treatment armamentarium:

New and emerging therapies with novel mechanisms

Increasing number and cost of specialty drugs

Utilization of biologics & biosimilars

• Marked heterogeneity of RA disease

• Numerous patient‐specific factors


Disease Assessment andInitial Treatment

25


Patient Global Assessment

Components of Different RA Disease Activity Measures

DAS28=disease activity score using 28 joint counts. SDAI=simplified disease activity index. CDAI=clinical disease activity index. RAPID3=. Routine Assessment of Patient Index Data CRP= C‐reactive protienESR=erythrocyte sedimentation rate (in mm). HAQ = Health Assessment Questionnaire

Patient Reported Outcomes

Laboratory Measures

Provider Reported Outcomes

HAQ

CRP

ESRTender Joint Count

Swollen Joint Count

Patient Pain Score

Provider Global Assessment

RAPID3

DAS28

CDAI

SDAI


ACR‐Recommended Instruments and Measures for Assessing Disease Activity

DAS28 = Disease Activity Score Using 28 Joint Counts; SDAI = Simplified Disease Activity Index; CDAI = Clinical Disease Activity Index; TJC28 = Tender Joint Count (Of 28); SJC28 = Swollen Joint Count (Of 28); ESR = Erythrocyte Sedimentation Rate (In Mm); GH = Global Health.

Anderson JK, et al. Arthritis Care Res (Hoboken). 2012;64(5):640–647; Singh JA, et al. Arthritis Care Res. 2012;64(5):625–639.

Instrument/

Measure

Administration

Method

Measurement

Scale

Disease Activity Levels

Remission Low ActivityModerate Activity

High Activity

Patient‐Driven Composite Tools

PAS or PASII Patient questionnaire Scale: 0–10 0–0.25 0.26–3.7 3.71– <8 >8

RAPID3 Patient questionnaire Scale: 0–30 0–1.0 >1.0–2.0 2.0–4.0 4.0–10

Patient and Provider Composite Tool

CDAIProvider item; patient

itemScale: 0–76 <2.8 > 2.8–10.0 >10.0–22.0 >22

Patient, Provider, and Laboratory Composite Tools

DAS28

(ESR or CRP)

Provider assessment;

patient item; labScale: 0–9.4 <2.6 > 2.6 – <3.2 >3.2 – <5.1 >5.1

SDAIProvider item; patient

item; labScale: 0–86 <3.3 >3.3 – <11.0 >11.0 – <26 >26

26


EULAR 2017 RA Recommendations: Prognostic Factors for Poor Disease

EULAR = European League Against Rheumatism; csDMARD = Conventional, Synthetic DMARD; RF = Rheumatoid Factor; ACPA = Anticitrullinated Protein Antibody.

Smolen JS, et al. Ann Rheum Dis. 2017;0:1–18.

Unfavorable Prognostic Factors

• Moderate to high disease activity after csDMARD therapy

• High acute phase reactant levels

• High swollen joint counts

• Presence of RF and/or ACPA, especially at high levels

• Presence of erosions

• Failure of ≥2 csDMARDS


52

TICORA Study: Treatment Strategy of Tight Control for RA

Grigor C et al. Lancet. 2004;1(9430):263‐269.

Single‐blind, randomized controlled trial in 111 patients allocated toeither intensive management or routine care

A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity, radiographic disease progression,physical function, and quality of life at no additional cost

Sulfasalazine, increasing every week to target

dose of 40 mg/kg per day

• Sulfasalazine• Methotrexate• Folic acid• Hydroxychloroquine

Triple therapy with monthly increments of methotrexate followed by weekly increments of

sulfasalazine

Addition of prednisolone

Change triple therapy to:• Ciclosporin• Methotrexate• Folic acid

Change to alternative DMARD (leflunomide or sodium aurothionalate)

0

1

2

3

4

5

6

0 3 4 5 12 15 18Month

Disease activity score

Intensive Routine

27


53

64

18 16

91

7165

0

20

40

60

80

100

ACR20 ACR70 Remission

Patients (%)

Routine Care (n = 55) Intensive Management‡ (n = 55)

TICORA Study: Combination of Non‐Biologic DMARDs

*With protocol-based escalation of DMARDs: SSZ, MTX, hydroxychloroquine; †P <0.0001; ‡P = 0.02.SSZ = sulfasalazine; TSS = Total Sharp Score.

Grigor C et al. Lancet. 2004;1(9430):263–269.

Single‐blind, randomized controlled trial in 111 patients allocated toeither intensive management or routine care

Disease Activity Score Radiographic Progression

†

†

†

8.5

4.5

0

1

2

3

4

5

6

7

8

9

Increase in

Median TSS From

Baselin

e

Routine Care (n = 55) Intensive Management‡ (n = 55)


54

Treat‐to‐Target (T2T) in RA

• Treat to desired goal: REMISSION For long‐standing disease, goal may be

low disease activity

• Measure disease activity High/moderate disease activity: monthly

Remission/low disease activity: x6 months

• Adjust therapy At least x3 months until target is reached

• Personalize treatment strategy Consider all factors (comorbidities and

other patient factors)

*2010 T2T recommenda ons updated in 2014 to reflect be er suppor ve evidence; †Shared decision‐making criteria not applied to visits that did not address changing targets or treatment; ‡Treatment decision based on target and disease ac vity measure.

Smolen JS, et al. Ann Rheum Dis. 2010;69(4):631–637; Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1–26; Singh JA, et al. Arthritis Care Res. 2016;68(1):1–25; Smolen JS, et al. Ann Rheum Dis. 2017;0:1–18; Solomon DH, et al. Arthritis Care Res. 2018 [ePub ahead of print].

ACR 2015 Guidelines: Use a T2T strategy in all patients regardless of disease activity level

TRACTION Trial11 rheumatology sites participated in a Learning Collaborative to implement

best practices that support the T2T approach in RA.

T2T Implementation Score Phase I Intervention Phase II Intervention

Months 0 9 18Change(09) 0 9 18

Change(918)

Primary Outcome

Implementation score 11% 57% 52% 46% 11.0% 13% 58% 45%

Visits with components present

Treatment Target <1% 46% 51% 45% 0% 1% 52% 51%

Disease Activity 20% 89% 71% 69% 30% 34% 85% 51%

Shared Decision‐Making 51% 86% 43% 35% 25% 30% 67% 37%

Treatment Decision‐Making <1% 28% 37% 27% 0% 1% 37% 36%

28


Established RA†

Early RA‡

Biologic and Small Molecule Agents Are a Mainstayin RA Patients with Moderate to High Disease Activity

* According to the 2015 ACR RA treatment recommendations, combination therapy with MTX is recommended, when possible, due to superior efficacy of this combination over biologic monotherapy (no particular order or preference of treatment options).

† Dura on of disease/symptoms ≥6 months of mee ng 1987 ACR RA criteria.

‡ Dura on of disease/symptoms <6 months.

Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1–26; Singh JA, et al. Arthritis Care Res. 2016;68(1):1–25; Smolen JS, et al. Ann Rheum Dis. 2017;0:1–18.

Combination DMARD Therapy

Anti‐TNF Biologic+/‐ MTX

Non‐TNF Biologic+/‐ MTX

JAK Inhibitor+/‐ MTX

After Failure with DMARD Monotherapy in RA Patients with Moderate or High Disease Activity*

EULAR 2017 RA Recommandations:In patients with poor prognostic factors, add a biologic or small‐molecule therapy


Real‐World Response to csDMARDs and bDMARDsAfter 1 year of Treatment

*Includes patients on tocilizumab, certolizumab pegol, golimumab, etanercept, adalimumab, and rituximab.

Boyadzhieva V, et al. EULAR 2019. Madrid, Spain. Abstract AB0233.

Prospective assessment of 344 patients with RA starting treatment with csDMARDS and/or corticosteroids vs bDMARDs* for 1 year

The bDMARD group had higher disease activity at BL vs the csDMARD group

11%

1%

13.50%

71%

16%

27%

0%

10%

20%

30%

40%

50%

60%

70%

80%

ACR50 ACR70 MDA

6‐Month Follow Up

csDMARDs (n = 220) bDMARDs (n = 124)

P = 0.002

P <0.001

20%

10%13%

36%

52%

30%

0%

10%

20%

30%

40%

50%

60%

ACR50 ACR70 MDA

12‐Month Follow Up

csDMARDs (n = 220) bDMARDs (n = 124)

P <0.001

P = 0.0102

P = 0.0186

P = 0.0025

29


Approved & Emerging Targeted Therapies for RA

Status Therapy Target Key Trials RouteDose

Frequency*

Approved

Rituximab CD‐20 IMAGE, DANCER, REFLEX IV Q6M (2 doses)

Abatacept CD80/CD86 AGREE, AIM, ATTAIN SC/IV QW/Q4W

Adalimumab TNF‐α ARMADA, DE019, DE011, ReAct SC Q2W

Certolizumab TNF‐α RAPID (1, 2), FAST4WARD SC Q2W/Q4W

Etanercept TNF‐α TEMPO, COMET, ERA SC QW

Golimumab TNF‐α GO (BEFORE, FORWARD, AFTER) SC/IV Q4W/Q8W

Infliximab TNF‐α ATTRACT IV Q8W

Anakinra IL ‐1R TRACK SC QD

Sarilumab IL‐6R SARIL‐RA (ONE, TARGET, ASCERTAIN, EXTEND, MONARCH, MOBILITY, EASY) SC Q2W

Tocilizumab IL‐6R FUNCTION, OPTION, RADIATE SC/IV QW/Q4W

Upadacitinib* JAK 1 SELECT (NEXT, BEYOND, EARLY, MONOTHERAPY, CHOICE, COMPARE) Oral QD

Baricitinib JAK 1/2 RA (BEGIN, BEYOND, BEACON, BUILD, BEAM) Oral QD

Tofacitinib JAK 1/3 ORAL (START, STANDARD, STEP) Oral BID/QD

Phase 3(Completed or ongoing)

Filgotinib JAK 1 FINCH 1‐3 Oral QD

Peficitinib JAK 1/3 NCT02305849, NCT01638013, NCT02308163 Oral QD

Olokizumab IL‐6 CREDO1‐4 SC Q2W/Q4W

*Not accounting for a loading dose; **Submitted for FDA approval. Estimated approval: Q3 2019.R = Receptor; SC = Subcutaneous; IV = intravenous; BID = Twice a Day.US Food and Drug Administration (FDA). www.accessdata.fda.gov. Accessed 6/7/18.


Head‐to‐Head Comparison of TNF Inhibitorsin MTX‐IR and TNF‐IR Patients

Schiff M, et al. Ann Rheum Dis. 2014;73(1):86–94; Smolen JS, et al. Lancet. 2016;388(10061):2763–2774.

EXXELERATE: Certolizumab (TNF) vs Adalimumab (TNF)

Week

• Certolizumab vs adalimumab show comparable long term (2 years) efficacy and safety• In some patients, after primary failure of each of the two TNF therapies, the switch to the other therapy was associated with a potential

response

MTX Failure First TNF Failure

Patients (%)

100

80

60

40

20

0

0 8 16 24 32 40 48 56 64 72 80 88 96 104

Non‐responders switch treatment at week 12

ACR20

ACR50

ACR70

Primary responders to certolizumab pegol plus methotrexate (n = 353)

Primary responders to adalimumab plus methotrexate (n = 361)

Week

Patients (%)

100

80

60

40

20

0

0 8 16 24 32 40 48 56 64 72 80 88 96 104


Double non‐responders withdrawn at week 24

30


Blocking Signaling by Cytokine Receptors: Anti‐IL and ‐JAK Therapies

Figure adapted from Schwartz DM, et al. Nat Rev Drug Discov. 2017;16(12):843–862; Nakayamada S, et al. BioDrugs. 2016;30(5):407–419.

• T‐cell differentiation• Lymphocyte effector function• Macrophage activation

• T‐cell proliferation •T cell memory •T regulatory cell function • B cell function

JAK1JAK3

IFN‐γ

IL‐2, ‐4, ‐7‐9, ‐15, ‐21

IL‐6, ‐11

IL‐12, ‐23

• Acute phase response• Lymphocyte growth/differentiation• Catabolic metabolism • Lipid metabolism• Bone resorption• T‐cell differentiation • Lymphocyte effector function

• T‐cell differentiation • Lymphocyte effector function

IL‐3, ‐5,GM‐CSF

• Myeloid/lymphoid differentiation• T‐cell prolideration/survival •Lymphocyte effector function

JAK2JAK2JAK2JAK2

JAK2

JAK1

TYK2

TYK2 TYK2JAK1 JAK1JAK2 JAK2

EPO, TPO, C‐CSF, GH, Leptin

• Growth • Anabolic metabolism

IFN‐α / β

• Anti‐viral responses


Efficacy and Safety of Tocilizumab (IL‐6R) in MTX‐IR RA Patients

ACT‐RAY Phase 3b Trial ADACTA Phase 4 Trial

*An open‐label csDMARD other than MTX was added after Wk 24 for patients who did not achieve DAS28 <3.2 by 24 wks.

Dougados M, et al. Ann Rheum Dis. 2014;73(5):803–809; Gabay C, et al. Lancet. 2013;381(9877):1541–1550; Mohan S, et al. ACR 2017. San Diego, CA. Abstract 550.

3537

40

46

0

10

20

30

40

50

Week 24 Week 52*

Patients (%)

Tocilizumab (n = 229) Tocilizumab + MTX (n = 243)

P = 0.21 P = 0.03

DAS28‐ESR <2.6

8

7

6

5

4

3

2

1

0

Mean change = ‐1.8

Mean change = ‐3.3

0 4 8 12 16 20 24

DAS2

8

Time (Weeks)

Adalimumab (n = 162)Tocilizumab (n = 163)

Long‐term safety results across 12 RA clinical trials + global post‐marketing safety database (~600,000 patients) indicate that there is no increased safety risk with increasing exposure to tocilizumab.

31


Efficacy and Safety of Sarilumab (IL‐6R) in MTX‐IR RA Patients

MOBILITY Phase 3 Trial

33 32

17 18

7 9

58 54

37 40

20 25

66 59

46 43

25 27

‐

20

40

60

80

Week 24 Week 52 Week 24 Week 52 Week 24 Week 52

Patients

Placebo + MTX (n = 398) Sarilumab 150 mg + MTX (n = 400) Sarilumab 200 mg + MTX (n = 399)

MONARCH Phase 3 Trial

*P <0.0001

LS = Least Square.

Genovese MC, et al. Arthritis Rheumatol. 2015;67(6):1424–1437; Burmester GR, et al. Ann Rheum Dis 2017;76:840–847; Genovese MC, et al. Rheumatology (Oxford). 2018;57(8):1423–1431;

Genovese MC, et al. ACR 2018. Chicago, IL. Abstract 2509; Curtis JR, et al. EULAR 2019. Madrid, Spain. Abstract FRI0081.

‐1.88‐2.2

‐2.77*

‐3.28*‐4

‐3

‐2

‐1

0

0 12 24

LS M

ean

Chan

geFrom Baselin

e

Adalimumab (n = 185)

Sarilumab (n = 184)

DAS28‐ESR

ACR20 ACR50 ACR70

*

*

**

*

**

*

** * *

• Safety: neutropenia, injection site erythema, increased alanine aminotransferase, and URTI. Efficacy and safety profile of sarilumab remained consistent over 4 years.

• Post‐hoc analysis of EXTEND open‐label extension study: sarilumab monotherapy shows similar efficacy as sarilumab + csDMARDs


62

ORAL Strategy Phase 3b/4 Trial

Clinical Outcomes at Month 6

Efficacy and Safety of Tofacitinib (JAK 1/3) in MTX‐IR Patients

38

18

10

46

25

12

44

21

12

0

10

20

30

40

50

ACR 50* ACR 70 DAS28‐4(ESR) < 2.6

Patients (%)

Tofacitinib (n = 384) Tofacitinib + MTX (n = 376) Adalimumab + MTX (n = 386)

*Primary endpoint.

Fleischmann R, et al. Lancet. 2017;390(10093):457–468; Cohen S, et al. ACR 2018. Chicago, IL. Abstract 963; Dikranian A, et al. EULAR 2019. Madrid, Spain. Abstract AB0454.

• Long‐term safety analysis with up to 9.5 years of follow‐up and 22,875 patient years of tofacitinib exposure indicate that incidence rates for AEs did not increase with prolonged tofacitinib exposure

• Non‐infectious non‐serious AEs were mild/moderate and the majority were self‐limiting (pooled analysis of 6 ORAL trials in 2,657 pts)

32


Efficacy and Safety of Peficitinib (JAK 1/3) in MTX‐IR Patients

Phase 3 Trial: Clinical Outcomes at Weeks 28 and 52/ET

ET = Early Termination.

*P <0.001 vs PBO; **For the calculation of mTSS, patients who discontinued at or before week 28/52 or were switched from PBO to peficitinib at week 12/28 due to lack of efficacy, week 28/ET was extrapolated using a linear extrapolation method based on the mTSS at BL and ET or week 12/28 (before switching).

Genovese MC, et al. Arthritis Rheumatol. 2017;69(5):932–942; Kivitz AJ, et al. Arthritis Rheumatol. 2017;69(4):709–719; Takeuchi T, et al. ACR 2018. Chicago, IL. Abstract 888; Takeuchi TT, et al. EULAR 2019. Madrid, Spain. Abstract OP0026; Tanaka YT, et al. EULAR 2019. Madrid, Spain. Abstract FRI0134.

• For weeks 0–12 there was similar overall incidence of AEs between PBO and peficitinib groups. For the overall study period (52 weeks), the incidence rate of serious infections per 100 patient years was higher with peficitinib than PBO.

• Peficitinib is also effective at reducing RA symptoms in DMARD‐IR patients

29

116

74

51

27

79

59

40

0

20

40

60

80

ACR20 ACR50 ACR70

Placebo (n = 170)Peficitinib 100mg QD (n = 174)Peficitinib 150mg QD (n = 174)

Patients (%)

* *

**

*

*

ACR20/50/70 at Wk 28 Modified Total Sharp Score (mTSS) at Wks 28 & 52

Mean (SD) mTSSchange from baseline

Placebo Peficitinib100 mg QD

Peficitinib150 mg QD

Week 28/ET(primary outcome)**

3.37 (5.46) 1.62 (4.23)* 1.03 (2.86)*

Week 52/ET 6.27 (10.18) 2.12 (5.83)* 1.54 (4.11)*


Efficacy and Safety of Baricitinib (JAK 1/2) in MTX‐IR Patients

*P ≤0.001 vs PBO; †P ≤0.05 vs adalimumab; ‡P ≤0.01 vs adalimumab

HAQ‐DI = Health Assessment Questionnaire Disability Index; PtGA = Patient Global Assessment of Disease Activity; FACIT = Functional Assessment of Chronic Illness Therapy; SF‐36 = Short Form Health Survey;

WPAI = Work Productivity and Activity Impairment; RTC = Renal Tubular Acidosis

Taylor PC, et al. N Engl J Med. 2017;376(7):652–662; Keystone EC, et al. Ann Rheum Dis. 2017;76(11):1853–1861; Dougados M, et al. Ann Rheum Dis. 2017;76(1):88–95; Kunwar S, et al. ACR/ARHP 2017. San Diego, CA. Abstract 530; Genovese MC, et al. EULAR 2019. Madrid, Spain. Abstract THU0078.

40

17 5

37

19 8

70

45

19

74

50

30

61

35

13

66

46

22

0

20

40

60

80

ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

PBO + MTX (n = 488) Baricitinib + MTX (n = 487) Adalimumab + MTX (n = 330)

RA‐BEAM Phase 3 Results

Week 12 Week 24* †

*

* ‡

*

* †

*

* †

*

**

* †

*

• At week 52, baricitinib groups demonstrated significant improvements (P ≤0.05) in HAQ‐DI, PtGA, pain, FACIT, SF‐36, EQ‐5D and WPAI‐RA scores vs PBO and adalimumab groups.

• In the RA‐BUILD Phase 3 Trial, baricitinib monotherapy also showed significant improvements in clinical and patient‐reported outcomes.• In a meta‐analysis of 5 RTC, baricitinib:

– Demonstrated greater efficacy in improving clinical outcomes vs PBO– Increased AEs, but not severe or serious infections, vs PBO

• Integrated safety analysis demonstrated that baricitinib maintained safety profile for up to 7 years

33


Efficacy and Safety of Upadacitinib (JAK 1) in MTX‐IR Patients

¶ Indicates multiplicity‐controlled comparisons of upadacitinib vs placebo

UPA = Upadacitinib; ADA = Adalimumab; IR = Inadequate Response; PBO = Placebo; AE = Adverse Event; MTX = Methotrexate.

Burmester GR, et al. Lancet (London, England). 2018;391(10139):2503–2512; Fleischmann R, et al. Arthritis Rheumatol. 2019:art.41032. Epub ahead of print; Buch M, et al. EULAR 2019. Madrid, Spain. Abstract THU0165; Kremer L, et al. EULAR 2019. Madrid, Spain. Abstract FRI0155.

• Overall safety profile of upadacitinib was similar to that of adalimumab. The proportions of patients with serious AEs and AEs leading to discontinuation were highest for adalimumab; the proportion with herpes zoster and creatine phosphokinase elevations was highest for upadacitinib.

• Efficacy of UPA was comparable when administered as monotherapy or when given in combination with MTX or non‐MTX csDMARDS.

SELECT‐COMPARE Phase 3 (vs Adalimumab)

**P ≤0.01 vs PBO***P ≤0.001 vs PBO#P ≤0.05 vs ADA##P ≤0.05 vs ADA###P ≤0.001 vs ADAWeek

% Responders: ACR20

% Responders: DAS2

8CRP<2

.6

2 4 8 12 14 18 22 262 4 8 12 14 18 22 26

100

80

60

40

20

0

100

80

60

40

20

0

Week


Efficacy and Safety of Filgotinib (JAK 1) in MTX‐IR Patients

FINCH1 Phase 3 Trial

Combe B, et al. EULAR 2019. Madrid, Spain. Abstract LB001; Genovese MG, et al. EULAR 2019. Madrid, Spain. Abstract FRI0092; Kalunian K, et al. EULAR 2019. Madrid, Spain. Abstract FRI0154;

Westhovens R, et al. EULAR 2019. Madrid, Spain. Abstract LB0003.

Efficacy at Week 24

Patient with event, %FIL 200 mg(n = 475)

FIL 100 mg(n = 480)

ADA 40 mg(n = 325)

PBO(n = 475)

Serious AEs 4.4 5 4.3 4.2

Serious infections 1.7 1.7 2.5 0.8

Herpes zoster 0.4 0.4 0.6 0.4

Adjudicated MACEs 0 0.2 0.3 0.4

Venous thrombotic events

0.2 0 0 0.4

Malignancies 0 0.2 0.3 0.6

Deaths 0.4 0.2 0 0.4

Safety through Week 24

• Filgotinib was similarly safe and effective in younger and older (>65 yrs) patients (subanalysis of FINCH2)• Filgotinib + MTX therapy was effective and well tolerated in early RA patients naïve to MTX (FINCH 3)• Additional studies are being conducted to assess testicular safety of filgotinib

78

36

48

78

29

35

75

30

36

59

15 16

0

20

40

60

80

100

ACR20 ACR70 DAS28‐CRP≤2.6

FIL 200 mg (n = 475) FIL 100 mg (n = 480)ADA 40 mg (n = 325) PBO (n = 475)

34


ACR 2015 Recommendations for RA Patients with High‐Risk Comorbidities

*Consider using csDMARDs other than MTX or leflunomide.

TNF = Tumor Necrosis Factor; CHF = Congestive Heart Failure; HBV = Hepatitis B Virus; HCV = Hepatitis C Virus.

Singh JA, et al. Arthritis Rheumatol. 2016;68(suppl 1):1–26; Singh JA, et al. Arthritis Care Res. 2016;68(suppl 1):1–25.

High‐Risk Condition Recommendation(s) Evidence Type

CHF, including worsening on current TNF inhibitorUse combination DMARDs, non‐TNF biologic, or tofacitinib over anti‐TNF

Very low/moderate

Conditional

Active HBV infection, and receiving/received effective antiviral RxSame recommendations as in patients without HBV

Very low Strong

HCV infection, and receiving/received effective antiviral Rx Same recommendations as in pts without HCV Very low Conditional

HCV infection, and NOT receiving or requiring effective antiviral Rx Use csDMARDs* over anti‐TNF Very low Conditional

Previously treated or untreated skin cancer Use csDMARDs over biologics and tofacitinib Very low Conditional

Previously treated lymphoproliferative disorder Use rituximab over anti‐TNF Very low Strong

Previously treated lymphoproliferative disorderUse combination csDMARDs or abatacept or tocilizumab over anti‐TNF

Very low Conditional

Previously treated solid organ malignancySame recommendation as in patients without this malignancy


Previous serious infection(s)Use combination csDMARDs over anti‐TNFUse abatacept over anti‐TNF



Management Following TNF Failure

35


After TNFi Failure – Cycle or Swap?

• Optimal treatment after TNFi failure remains unclear

Mostly registry studies and observational research

• Switching to another TNFi

May offer clinical benefit in some RA patients

Antidrug antibodies and seropositivity/negativity may guide choice of second biologic

• Switching to non‐TNFi biologic with different mode of action

Sarilumab, tocilizumab, tofacitinib, rituximab, abatacept effective after TNFi‐IR

• Choice may be driven by contraindications and safety factors

Nam JL, et al. Ann Rheum Dis. 2014;74(3):516–528; Schoels M, et al. Ann Rheum Dis. 2012;71(8):1303–1308; Favalli EG, et al. Rheumatology. 2014;53(9):1664–1668; Sullivan SD, et al. J Med Econ. 2013;16(3):391–396; Chatzidionysiou K, et al. Ann Rheum Dis. 2015;74(5):890–889; Emery P, et al. Ann Rheum Dis. 2015;74(6):979–984; Smolen JS, et al. Ann Rheum Dis. 2017;0:1–18; Smolen JS, et al. Lancet. 2016;388(10061):2763–2774.


2015 ACR RA Treatment Recommendations for After Biologic Therapy Failure

*e.g., If patient declines non‐TNF biologic therapy due to inefficacy or side effects.

Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1–26; Singh JA, et al. Arthritis Care Res. 2016;68(1):1–25.

Failure Type Conditional Recommendation ± MTX

• Single TNFi or non‐TNF biologic failure • Non‐TNF biologic

• ≥1 TNFi and ≥1 non‐TNF biologic failure • ≥2 TNFi failures

• Non‐TNF biologic • Tofacitinib if non‐TNF biologic is not an option*

• ≥2 non‐TNF biologic failures and patient is TNFi‐naive • TNFi

Failure defined as patients with moderate or high disease activity despite biologic DMARD therapy

36


Head‐to‐Head Comparison of TNF Inhibitorsin MTX‐IR and TNF‐IR Patients

Schiff M, et al. Ann Rheum Dis. 2014;73(1):86–94; Smolen JS, et al. Lancet. 2016;388(10061):2763–2774.

EXXELERATE:Certolizumab (TNF) vs Adalimumab (TNF)

Week

• Certolizumab vs adalimumab show comparable long term (2 years) efficacy and safety• In some patients, after primary failure of each of the two TNF therapies, the switch to the other therapy was associated with a potential

response

MTX Failure First TNF Failure

Patients (%)

100

80

60

40

20

0

0 8 16 24 32 40 48 56 64 72 80 88 96 104


ACR20

ACR50

ACR70

Primary responders to certolizumab pegol plus methotrexate (n = 353)

Primary responders to adalimumab plus methotrexate (n = 361)

Week

Patients (%)

100

80

60

40

20

0

0 8 16 24 32 40 48 56 64 72 80 88 96 104


Double non‐responders withdrawn at week 24


70%

60%52%

43%

0%

20%

40%

60%

80%

24 Weeks 52 Weeks

Non‐TNF Biologic Group (N=146) Second Anti‐TNF Group (N=146)

Non‐TNF vs TNF Treatment Efficacy After 1st TNF Failure*

HAQ = Health Assessment Questionnaire .

Gottenberg JE, et al. JAMA. 2016;316(11):1172–1180.

• HAQ Scores did not differ between the two groups at week 12, 24, and 52• ~50% of patients with insufficient response to a TNF‐α inhibitor might respond to a second anti‐TNF agent• However, a therapeutic response was more frequent with non–TNF‐targeted biologics

Response Criteria in the Non‐TNF Biologic and Second Anti‐TNF Groups

45%41%

28%23%

24 Weeks 52 Weeks

EULARGood or Moderate Response

Low Disease ActivityDAS28‐ESR <3.2

27% 27%19%

14%

24 Weeks 52 Weeks

DAS28 RemissionDAS28‐ESR <2.6

Patients (%)

37


Considerations for Payer & Provider Collaboration


Payers’ and Providers’ Perceptions in RA Management

Greenaple R. Am Health Drug Benefits. 2012;5(2):83–92.

2011 parallel‐structure online surveys of 100 rheumatologists and 50 health plan payers representing >80 million covered lives

Ranked Order of Importance for Choosing Preferred Biologics

Question: Please rank in order of importance (from highest to lowest) the reasons for your choice of preferred biologic(s).

Rheumatologists (n = 53) Rank Payers (n = 28)

Efficacy profile 1 Efficacy profile

Safety profile 2 Contracting/rebating

My personal experience 3 Safety profile

Mode of administration 4 Mode of administration

Frequency of dosing 5 Market share

Reimbursement easier to obtain on most health plans

6Utilization rate among plan’s

in‐network physicians

38


Actions to Improve Payer‐Provider Collaboration

With payers…

• Develop positive working relationships with key decision‐makers

• Ensure both parties are working under the same expectations and timelines

• Become familiar with the terminology and buzzwords used by payers

• Ask to speak with peers within the organization

Within your practice…

• Document patient and clinical information thoroughly

• Verify patient coverage before prescribing therapy or service

• Enlist team members to take the lead on the PA process and other payer‐related processes

• Use electronic methods for completing and submitting PAs


Supporting Patient Navigation of and Access to Care

PSP = Patient Support Program; PA = Prior Authorization.

Rubin DT, et al. J Manag Care Spec Pharm. 2017;23(8):859–867.

Patient Support Programs

• Available through patient advocacy organizations and pharmaceutical companies

• Offer nurse navigators, financial assistance, educational resources, adherence support, and others

• Participation in PSPs increases adherence and persistence to TNF therapy by while reducing medical costs

Case Management

• Offered through insurance companies, health‐care systems, or patient support programs

• Instrumental in assisting both providers and patients navigate clinical care and managed care processes

• They build relationship with patients, and can identify adherence or socio‐economic issues that impact clinical outcomes

Specialty Pharmacy

• Key player in the management of patients with chronic illnesses (e.g., medication reconciliation and patient education)

• Support practices on PA‐related processes like submission and appeals,

• Triage between practices and insurance companies to improve communication and comply with required processes

39


Benefits of Involving an NP/PA Within Rheumatology Care

Observational Cohort Study in 7 Rheumatology Practices in the US

APP = Advanced Practice Provider.

van Eijk‐Hustings Y, et al. Ann Rheum Dis. 2012;71(1):13–19; Solomon DH, et al. Arthritis Care Res (Hoboken). 2015;67(12):1664–1670.

RA patients seen in practices with NP/PAs had lower disease activity over 2 years vs those in rheumatologist‐only practices

For APPs, the scope of practice (practice autonomy and prescriptive authority) varies

state to state and is often defined by a practice agreement with the leading specialist.

• Rheumatology nurse care for people with these conditions has been shown to: Better education and improve psychosocial support for

patients

Reduce delays in access to specialist care

Improve care coordination and continuity of care

Reduce health system costs in primary and secondary care

Improve patient outcomes and satisfaction with care

With NP/PAs MD Only P

Patient Load 158 143 ‐

Total Visits 1,168 814 ‐

Visits per Patient 7.4 ± 2.6 5.7 ± 1.9 <0.0001

Laboratory Test 950 (81%) 501 (62%) <0.001

Radiology Tests 232 (20%) 110 (14%) <0.001

High Disease Activity 15 (15%) 27 (44%) <0.0001

DMARD Starts 103 (9%) 62 (8%) 0.01

Patients on Synthetic DMARDs 135 (85%) 105 (73%) 0.01

Patients on Biologic DMARDs 126 (80%) 67 (47%) <0.0001


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