Rheumatoid Arthritis

“Treat-to-target”

Dr Li-Ching Chew

Consultant,

Department of Rheumatology & Immunology, Singapore General Hospital

Introduction: What is RA?

Choy EHS, Panayi GS. N Engl J Med. 2001;344(12):907–916.

Photos: Copyright © American College of Rheumatology

RA Disease Progression

Introduction: Who is affected?

Introduction: What are the symptoms?

Articular Systemic Extra-articular

• Polyarticular arthritis,

often symmetrical

• Joint swelling and

tenderness

• Limitation of motion

• Malalignment of joints

• Pain at rest, improves

with activity

• Morning stiffness

• Diffuse aching

• Fever

• Weight loss

• Anemia

• Fatigue

• Malaise

• Depression

• Rheumatoid nodules

• Vasculitis

• Pulmonary disease

• Ocular disease (sicca,

episcleritis)

• Carditis (pericarditis,

myocarditis)

Lipsky PE. Rheumatoid Arthritis. In: Harrison’s Principles of Internal Medicine. 15th ed. 2001:1928–1937.

Grassi W, et al. Eur J Radiol. 1998;27(suppl 1):S18–S24.

Clinical Presentation of RA

Introduction: What is the impact on economy?

Introduction: What is the Impact on the Individual?

Introduction: What is the Impact on the Individual?

– Premature mortality

– Increased morbidity

– Impact on quality of life

• Pain with associated functional disability

• Fatigue

– 71% of patients experience mild fatigue

– 42% experience substantial fatigue

• Depression

– Up to 40% of patients suffer depression that impacts personal and

family life

– Loss of productivity

– Increased incidence of work disability

– Average earnings loss—35% reduction of family income

Wolfe F, et al. J Rheumatol. 1996;23:14071417; Goldbach-Mansky R, et al. Annu Rev Med. 2003;54:197216;

Wolfe F and Hawley DJ. J Rheumatology. 1998;25:2108-2117.

3 Major Advances in RA Management

1. Window of Opportunity – recognising disease early in the course, during which intervention may prevent or limit functional loss, joint deformities and improve health-related quality of life.

2. Treat to Target – tight clinical control using disease activity-guided treatment strategies, to aid in making therapy adjustments, which are associated with higher rates of remission.

3. Improvements in disease control using Biological and/or Combination Disease Modifying Anti-Rheumatic Drugs (DMARD) therapy.

“Window of Opportunity”

There is acknowledgment that RA is best treated

by early intervention with medication, aimed at

reducing joint swelling and preventing joint

destruction and therefore long term disability,

reducing the long term cost of care and improving

the quality of life.

This has resulted in the treatment paradigm in

general, use of methotrexate (MTX) as the

‘anchor drug’.

“Window of Opportunity”

The major goal of management in RA is to suppress

disease activity using medication, so as to prevent or retard

joint damage, and to prevent loss of function.

In patients with established disease where joint damage or

disability have occurred, treatment is less effective than in

patients with early disease.

1-3This has lead to the concept of a “window of opportunity”

(< 12 weeks symptoms).

1. Anderson JJ, Wells G, Verhoeven AC, Felson DT. Factors Predicting Response To Treatment In Rheumatoid

Arthritis: The Importance of Disease Duration. Arthritis Rheum 2000;43:22-29.

2. M.A. Quinn, P. Emery. Window of opportunity in early rheumatoid arthritis: Possibility of altering the disease

process with early intervention. Clin Exp Rheumatol 2003; 21 (Suppl. 31):S154-S157.

3. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and Radiographic Outcomes of Four

Different Treatment Strategies in Patients With Early Rheumatoid Arthritis (the BeSt Study): a randomized, controlled

trial. Arthritis Rheum. 2005;52:3381-90.

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van der Heijde DM, et al. J Rheumatol. 1995;22:1792–1796; Fuchs HA, et al. J Rheumatol. 1989;16:585–591.

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Joint Erosions Occur Early in RA

– Up to 93% of patients with 2 years of RA may have radiographic abnormalities

– Rate of progression is significantly more rapid in the first year than in the second and third years

– Radiographic changes in the feet are important indicators of disease progression in RA

Total

Hand

“Treat-To-Target”

A well known initiative designed to improve

care in RA

Extensive literature review

Consensus conference

Mirrors concepts used in Diabetes and CVD

“Treat-To-Target”

Recommendations of an international task force

(J Smolen, et al. ARD 2010 )

Overarching Principles

(A) The treatment must be based

on a shared decision between

patient and rheumatologist.

(B) The primary goal is to

maximise long-term health-related

quality of life through control of

symptoms, prevention of structural

damage, normalisation of function

and social participation.

(C) Abrogation of inflammation is

the most important way

to achieve these goals.

(D) Treatment-to-target by

measuring disease activity and

adjusting therapy accordingly

optimises outcomes.

(A) The treatment must be based on a shared decision

between patient and rheumatologist.

“Treat-To-Target”

Recommendations of an international task force

(J Smolen, et al. ARD 2010 )

Overarching Principles

(A) The treatment must be

based on a shared decision

between patient and

rheumatologist.

(B) The primary goal is to maximise

long-term health-related quality of life

through control of symptoms,

prevention of structural damage,

normalisation of function and social

participation.

(C) Abrogation of

inflammation is the most

important way

to achieve these goals.

(D) Treatment to target by measuring

disease activity and

adjusting therapy accordingly optimises

outcomes.

Overarching Principles

(A) The treatment must be based

on a shared decision between

patient and rheumatologist.

(B) The primary goal is to maximise long-term

health-related quality of life through control of

symptoms, prevention of structural damage,

normalisation of function and social

participation.

(C) Abrogation of inflammation is

the most important way

to achieve these goals.

(D) Treatment to target by measuring disease

activity and

adjusting therapy accordingly optimises

outcomes.

(C) Abrogation of inflammation is the most important way to achieve these goals.

“Treat-To-Target”

Recommendations of an international task force

(J Smolen, et al. ARD 2010 )

Overarching Principles

(A) The treatment must be

based on a shared decision

between patient and

rheumatologist.

(B) The primary goal is to maximise long-

term health-related quality of life through

control of symptoms, prevention of

structural

damage, normalisation of function and

social participation.

(C) Abrogation of

inflammation is the most

important way

to achieve these goals.

(D) Treatment to target by measuring

disease activity and adjusting therapy

accordingly optimises outcomes.

Monitoring Outcomes in Routine Care

• Disease Activity Scores

• Patient Functional Outcomes

• Radiographic Outcomes

• Others

Co-morbidities eg

» Cardiovascular

» Malignancy (lymphoma)

» Mortality

Disease Activity Score (DAS) 28

Simplified Disease Activity Index (SDAI)

Clinical Disease Activity Index (CDAI)

Routine Assessment of Patient Index Data

(RAPID)

Patient Activity Scale II (PAS-II)

ACR score (ACR20, 50, 70)

“Treat-to-Target”: RA in 2011

Phenotype Serology/Immunology Imaging Treatment

Swollen Joints ESR/CRP X-ray Individualisation of therapy

Tender Joints RF US Scan Tight control (DAS-driven)

Systemic Symptoms anti CCP MRI Rapid adjustment of therapy

Smoking Shared epitope (DAS-driven)

(HLA-DR1 typing)

Factors that may predict poor prognosis

What is DAS?

Tight control Rapid adjustment of therapy

• Disease Activity Score 28 (DAS28) or Disease Activity Score 44 (includes feet & hips)

• Useful tool used to measure disease activity to measure disease activity and define remission in RA

• 1,2DAS28 has been widely used in RA clinical trials and is a validated measure of disease activity in RA in

clinical practice

• Can be measured during rheumatology outpatient to document and compare patients’ disease status

1.Van der Heijde DMFM, et al. Ann Rheum Dis, 1990

2. Prevoo MLL, et al. Arthritis Rheum, 1995.

DAS-driven

DAS28 Activity Scores

The following parameters are

Included in the calculation:

a) Number of joints tender to

the touch (TEN)

b) Number of swollen joints

(SW)

c) Erythrocyte sedimentation

rate (ESR)

d) Patient assessment of

disease activity (VAS; mm)

1. Van der Heijde DMFM, van't Hof MA, van Riel

PLCM, van der Putte LBA. Development of a

disease activity score based on judgement in

clinical practice by rheumatologists. J.

Rheumatol 1993; 20:579-81

2. Prevoo MLL, van't Hof MA, Kuper HH, et al.

Modified disease activity scores that include

twenty-eight-joint counts. Arthritis Rheum 1995;

38:44-8

3. EULAR response criteria:

Van Gestel AM, Prevoo MLL, van't Hof MA, et al.

Development and validation of the European

League Against Rheumatism response criteria

for rheumatoid arthritis. Arthritis Rheum 1996;

39:34-40

DAS28 calculation

Example 1

a) Number of joints tender to the touch (TEN) = 2

b) Number of swollen joints (SW) = 1

c) Erythrocyte sedimentation rate (ESR) = 20

d) Patient assessment of disease activity (VAS; mm) = 30

DAS28 = 3.6 (Moderate Disease Activity)

Example 2

a) Number of joints tender to the touch (TEN) = 4

b) Number of swollen joints (SW) = 4

c) Erythrocyte sedimentation rate (ESR) = 50

d) Patient assessment of disease activity (VAS; mm) = 50

DAS28 = 5.12 (High Disease Activity)

ACR-EULAR 2011Definition of Remission

For clinical practice

• Boolean

– SJC, TJC, PtGA all ≤1

• Index-based

– CDAI ≤2.8

CDAI*=SJC+TJC+PhGA+PtGA

*Clinical Disease Activity Index

For clinical trials

• Boolean

– SJC, TJS, PtGA, CRP all ≤1

• Index-based

– SDAI ≤3.3

SDAI=SJC+TJC+PhGA+PtGA+ CRP (mg/dl)

“Treat-to-Target”

Recommendations of an international task force

(J Smolen, et al. ARD 2010 )

“Treat-to-Target”

Recommendations of an international task force

(J Smolen, et al. ARD 2010 )

• The process

– modified Delphi technique

– voted on anonymously

• Round 1 75% = a winner

• Round 2 67% = a winner

• Round 3 50% = a winner

Recommendations of an international task force

1. The primary target for treatment of rheumatoid arthritis should be

a state of clinical remission.

2. Clinical remission is defined as the absence of signs and

symptoms of significant inflammatory disease activity.

3. While remission should be a clear target, based on available

evidence low disease activity may be an acceptable alternative

therapeutic goal, particularly in established long-standing disease.

Recommendations of an international task force

4. Until the desired treatment target is reached, drug therapy should be

adjusted at least every 3 months.

5. Measures of disease activity must be obtained and documented

regularly, as frequently as monthly for patients with high/moderate

disease activity or less frequently (such as every 3–6 months) for patients

in sustained low disease activity or remission.

6. The use of validated composite measures of disease activity, which

include joint assessments, is needed in routine clinical practice to guide

treatment decisions.

7. Structural changes and functional impairment should be considered when

making clinical decisions, in addition to assessing composite measures of

disease activity.

Recommendations of an international task force

8. The desired treatment target should be maintained throughout the course

of the disease.

9. Multiple factors will influence the choice of the (composite) measure of

disease activity and the level of the target value may be influenced by

consideration of co-morbidities, patient factors and drug-related risks.

10. The patient has to be appropriately informed about the treatment target

and the strategy planned to reach this target under the supervision of the

rheumatologist.

“Treat-to-Target”

Strategy Studies - Evidence in the literature

•The TICORA study was the first to

examine this question specifically and

provided important information.

•Simply stated, if physicians treat to a

target, patients do better, than

‘conventional therapy’

•Using a clinical target of Disease

Activity Score (DAS) <2.4, patients

receiving intensive therapy reached a

mean DAS of 1.4 compared with a

mean DAS of 2.4 in the ‘conventional’

therapy group.

•Importantly, patients receiving

intensive therapy not only improved

clinically but had significantly less

radiographic progression (median

change in Sharp score 0.5 vs 3.9).

“Treat-to-Target” Strategy Studies –

Evidence in the literature

Trial Summary CAMERA (Netherlands)

90% sero (+) early RA

Better clinical outcomes

No radiological difference

No difference in function

TICORA

Sero (+) early RA (mean 19 months)

75% reduced erosions

FRANSEN (Netherlands)

Established disease

STENGER (Netherlands)

Group 1: routine =

NSAID , HCQ/oral gold/SSZ, IMI gold,

D-penicillamine, azathioprine/MTX

Group 2: intensive =

SSZ , add MTX, increase MTX, IMI gold,

azathioprine

Less radiological progression in group 2

Evidence for treating rheumatoid arthritis to target: results of a

systematic literature search (M Schoels, et al. ARD 2011).

Objectives :

To summarise existing evidence on a target oriented approach for

rheumatoid arthritis (RA) treatment.

Search covered Medline, Embase and Cochrane databases until

December 2008 and also conference abstracts (2007, 2008).

Conclusion :

Only few studies RCTS. However, they provided unanimous evidence

for benefits of targeted approaches.

Role of Imaging in addressing

“Tight Control” in RA

Tight Control

a) US is useful to show subclinical disease or occult synovitis not detected by blood

tests/bedside examination. This predicts further erosive disease even when patient

is asymptomatic

b) MRI is useful in showing bone marrow oedema/osteitis, which also predicts

erosions (Hetland, 2009; McQueen, 2003)

Phenotype Serology/Biomarkers Imaging Treatment

Swollen Joints ESR/CRP X-ray Individualisation of therapy

Tender Joints RF US Scan Tight control

Systemic Symptoms anti CCP MRI Rapid adjustment of therapy

Smoking

“Treat-to-Target”

Summary

• Example of other diseases that embraces this principle: DM, CVD, Hyperlipidaemia

• Primary aim in RA = Remission (Benchmark = DAS28 <2.6) / Low Disease Activity

• Level of target may be influenced by Patient-related Factors, eg. co-morbidities, toxicities

• Recommendation for monitoring = 1-3 monthly

• Therapy be adjusted every 3 months until goal achieved

• Measurements of disease activity must be obtained and documented regularly

• Structural assessments - annual radiographs

• Use validated Disease Activity Scores in routine clinical practice (DAS28, CDAI, etc.)

• Patient should be informed about treatment target and strategy

RA Treatment

History over time (1)

1950s 1960s 1970s Prolonged Steroids Gold Therapy Immunosuppresants

Boland, BMJ, 1951 Empire Rheumatism Council Currey

ARD 1960 Mod Trends

Rheumatol, 1971

RA Treatment

History over time (2)

1980s 1990s 2000 Methotrexate Combination DMARD Infliximab+MTX

Pilot study, Paulus, A & R 1990 Lipsky et al.

Wilke et al. NEJM 2000

Cleveland Clinic

RA TREATMENT:

THERAPEUTIC STRATEGIES

1“Discussion of therapeutic strategies by necessity should not concern specific drugs but rather focus

on overarching therapeutic principles of treating to target (i.e. achieving remission / low disease

activity), within the shortest possible time”.

2Landmark Study:

In the BeSt study 51 the key design feature was that clinicians treat to a target (DAS <2.4) by

therapeutic adjustment. While there were differences among groups early in the trial, arguably the

most important finding of the BeSt study was that 79% of patients achieved target DAS scores <2.4

at 2 years regardless of group.

1.State-of-the-art: rheumatoid arthritis Iain B McInnes and James R O'Dell ARD, 2010.

2. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and Radiographic Outcomes of Four Different Treatment Strategies in

Patients With Early Rheumatoid Arthritis (the BeSt Study): a randomized, controlled trial. Arthritis Rheum. 2005;52:3381-90.

TREATMENT PARADIGM

a) Emphasise the sequential use of therapeutic agents driven by measurement of disease activity.

b) The empirical nature of decision-making - the precise choice and order of DMARD use in the initial

treatment of RA remains an individualised decision between patient and physician; however, early

commencement of a DMARD should be considered optimal.

RA Treatment

Tight control DAS-driven Rapid adjustment of therapy

RA TREATMENT:

CONVENTIONAL DMARDs

Step 1: Monotherapy +/- oral glucocorticoids

– Monotherapy, usually MTX, as anchor drug

– If contraindicated, consider Sulfasalazine or Leflunomide

+/- low dose steroids, taper rapidly.

– MTX is also the key drug in successful combinations

– Folic Acid given concomitantly

– MTX should be rapidly escalated from 10mg/wk to 20-25mg/wk and

given a minimum of 3 months to work.

– With this approach, approximately 30% of patients will achieve a DAS28

of <3.2 after 3–6 months

RA TREATMENT:

CONVENTIONAL DMARDs

Step 2: Patients with active disease despite MTX

– Hydroxychloroquine (reduces lipid/DM), sulfasalazine and

leflunomide remain important (albeit often underused) components of the armamentarium.

– In general, these conventional DMARDs are used in combination with other DMARDs, frequently MTX.

– Used as 1st line if MTX contraindicated.

– Landmark study comparing the addition of SFZ or HCQ to MTX: SFZ+HCQ was better than either alone (O’Dell, 2002)

– Infliximab was better than SFZ+HCQ at 12 months (Swefot Trial, Lancet, 2009); Adalimumab (OPTIMA Trial).

– EULAR recommendations based on systematic review (2010):

If poor prognostic markers present (erosion, anti CCP, RF, high disease activity)

Benefit of Combination Therapy with TNF inhibitor in

ERA / VERA?

• Should combination therapy—and, in particular, combination therapy with a

TNF inhibitor be used at the outset, OR is it sufficient to step up to these

therapies only in those patients who demonstrate the clinical need for them.

Currently available data are equivocal.

RA Treatment: Biological and/or combination Disease Modifying Anti-Rheumatic Drugs (DMARD)

therapy (A & R, 2010. Graudal & Jurgens).

-Meta-analysis of 70 Randomised Placebo controlled or Drug-controlled Studies, including 112 Comparisons.

-Similar effects of DMARDS, Glucocorticoids, and Biologic Agents on Radiographic Progression in RA.

-Treatment with DMARDS, GC, Biologics, and Combination agents significantly reduce radiographic

progression at 1-year.

-Direct comparison between combination of Biologic, & MTX AND combination of 2 DMARDs and GC revealed

NO DIFFERENCE.

OPTIMA 2011: Global study looking at different treatment strategies to achieve positive outcomes in early

rheumatoid arthritis (RA), comparing MTX and Adalimumab Combination Therapy.

Results of the OPTIMA study demonstrated the value of targeted treatment strategies, which resulted in

improved disease control and reduced disease progression (including Sharp score) in a significantly greater

number of patients treated with a combination of HUMIRA (adalimumab) and methotrexate (MTX) vs. MTX

alone.

BIOLOGICAL THERAPY

b) BEYOND TNF INHIBITORS

Golimumab

Infliximab Abatacept – CTLA4Ig

Adalimumab Monoclonal Ab

Certolizumab –

PEGylated anti-TNF

Tocilizumab- anti IL-6

Etanercept - Soluble receptor fusion protein

Rituximab – anti CD20

a) TNF INHIBITORS

a) TNF inhibitors

i) TNF inhibitors have been approved for clinical use for a decade

iii) Efficacy in RA is remarkably similar among these products across many trials, often summarised as the ‘60–40–20’ rule, when using the ACR20, 50 and 70, regardless of the preparation used

iii) All have been shown to substantially retard radiographic progression.

b) Biological agents beyond TNF blockade

Patients with inadequate response to combination therapy (including a TNF inhibitor) :

i) Switch to another TNF inhibitor

ii) Changing to rituximab, abatacept, or tocilizumab

BIOLOGICAL THERAPY

Risk/benefit trade-offs of TNF agents

TNF agent Toxicities Advantages

ALL Reactivation of latent TB,

soft tissue and joint infections,

lymphoma, solid tumours, skin cancers,

exacerbations of CCF,

multiple sclerosis

ALL Bacterial infections

Infliximab /

Adalimumab

Reactivation of tuberculosis

Granulomatous diseases e.g.

histoplasmosis & coccidioidomycosisas

Listeria infections

Varicella zoster virus

Etanercept Demyelinating disease

Infliximab IBD

Inflammatory eye disease

Concluding Remarks

• Progress in RA treatment accelerated remarkably from the late 1990s with

the introduction of an ever-increasing array of biological agents. Given the

prohibitive cost of biologics, more scientific work is needed to identify

individuals that could benefit from biologicals early in the disease.

Optimal treatment allocation depends on the determination of prognostic &

predictive factors

• However, that the most important paradigm shifts have been in

recognising the importance of

(a) early treatment (“window of opportunity”)

(b) remission or very low disease activity (“treat to a target”)

• Paradigm of intensive or complex treatment regimens is most feasible in a

clinical setting in an academic centre, where rheumatologists work together

with other health-care professionals, such as APNs within a MDT.

“Thank you for your attention!”