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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10
20
30
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MTP
van der Heijde DM, et al. J Rheumatol. 1995;22:1792–1796; Fuchs HA, et al. J Rheumatol. 1989;16:585–591.
Year
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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!”