Abstract
The use of biological disease-modifying antirheumatic drugs (bDMARDs) has changed the face of rheumatoid arthritis (RA). Achieving remission, normal function and prevention of joint damage are now possible for many patients with RA. In clinical practice, however, particularly with cost considerations, bDMARDs are usually prescribed after failure of one or more conventional synthetic DMARDs. With evidence that early treatment has a greater impact than later on, the question regarding initial bDMARD therapy and their potential role within a window of opportunity to influence disease outcomes remain. The increasing emphasis on early diagnosis and research into the preclinical phase of the disease also heralds the question, ‘Can bDMARDs prevent the development of RA?’
The aim of this review is to review randomised controlled trials with bDMARDs as initial therapy in early RA and to discuss their role in early disease.
Introduction
Since the introduction of the first tumour necrosis factor alpha inhibitor (TNFi), infliximab, for the treatment of RA in the 1990s , there has been a rapid expansion of biological disease-modifying antirheumatic drugs (bDMARDs) in this area. Within the TNFi class of agents, these include the monoclonal TNFi, adalimumab and the soluble recombinant TNF receptor fusion protein, etanercept, as well as two newer agents, golimumab (another fully human antibody) and certolizumab-pegol (a humanised recombinant antibody conjugated with a polyethylene glycol chain). Two other bDMARD cytokine inhibitors are the interleukin (IL)-1 receptor antagonist, anakinra and the IL-6 receptor blocking monoclonal antibody, tocilizumab. Those targeting alternative pathways include the anti-CD20 B-cell depleting agent, rituximab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) fusion protein, abatacept.
The use of these bDMARDs has changed the face of rheumatoid arthritis (RA) with remission and prevention of joint damage progression being an achievable goal in a large proportion of patients. For many rheumatologists, the use of bDMARD therapy has become part of routine clinical practice. The cost of these drugs, however, remains an important point of consideration and many guidelines place them after failure of one or more conventional synthetic DMARDs (csDMARDs) . However, the question, ‘Is there a place for initial treatment with biological DMARDs in the early phase of RA?’ still remains.
This review will aim to
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address the rationale for early DMARD therapy,
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review randomised controlled trials (RCTs) with bDMARDs in early RA as first-line therapy compared to csDMARD and as part of different treatment strategies,
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address RCTs aiming at the potential to step down or stop DMARD therapy following remission induction and
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review RCTs with bDMARDs in early inflammatory arthritis.
A. Rationale for early therapy
The concept of the ‘window of opportunity’ suggests that there is a phase early in the disease during which there may be the opportunity to potentially alter the course of the disease or possibly even reverse this with a complete return to normality . Treatment during this period is thought to have a much more profound effect in terms of halting disease progression and achieving remission than therapy at a later stage.
From clinical studies, the disease duration at the time of DMARD initiation has been found to be a significant predictor of response to treatment . A meta-analysis of 12 trials examined the effect of early synthetic DMARD therapy on the long-term radiographic progression in patients with early RA (<2 years at presentation). The average delay between early and late therapy was 9 months. After a median of 3 years of observation, those patients who received early treatment had 33% less radiographic progression compared to those with delayed treatment .
It has been suggested that the window for early treatment is much shorter than this, possibly within the first 12 weeks of symptom onset . In a study by Green et al. in which a single dose of corticosteroid was administered to patients with mild early inflammatory arthritis, a disease duration <12 weeks at the time of therapy was noted to be the strongest predictor of remission at 6 months . A systematic literature review by Nies et al. has also shown radiographic progression to be lower with shorter symptom duration. In addition, a meta-analysis of three early arthritis data sets showed symptom duration to be independently associated with DMARD-free sustained remission (the outcome chosen as deemed the closest proxy of cure in (RA) with a hazard ratio (HR) 0.989 (95% CI 0.983–0.995)) and an HR 0.88 using 12 weeks at treatment initiation. In a sub-analysis of the COMET study, an RCT of 417 early RA patients, etanercept + methotrexate (MTX) use in patients with disease duration <4 months was associated with significantly higher proportions reaching remission and low disease activity (LDA) than when the same treatment was used with a longer disease duration . Interestingly, this increased remission rate with very early treatment was not seen in the MTX monotherapy group although radiographic non-progression was higher in the group that was treated early.
B. Clinical trials with biological DMARDs as first-line therapy in early RA
Early DMARD therapy is therefore one of the key principles in the treatment of RA . Whilst this recommendation is widely agreed upon, initial treatment strategies particularly those which include bDMARDs are still a matter of debate.
B.1. RCTs of first-line biological DMARDs + MTX vs. MTX monotherapy
The placebo-controlled RCT by Quinn et al. was one of the first studies addressing the use of TNFi therapy in DMARD-naïve RA, introducing the concept of induction with bDMARDs and maintenance with csDMARDs. In this study of 20 RA patients with poor prognostic factors, treatment with infliximab and MTX results in less magnetic resonance imaging (MRI)-detected erosions at 12 months than treatment with MTX alone. Function and quality of life benefits achieved with infliximab after 1 year were sustained at 2 years without further infliximab therapy.
Several larger RCTs have also addressed the use of bDMARDs in MTX-naïve RA. With MTX often used as first-line DMARD therapy, a large proportion of patients in these studies were also DMARD naïve providing further information to address the role of bDMARDs as first-line TNFi therapies. These include studies on adalimumab (PREMIER , PROWD and OPTIMA ), etanercept (COMET) , golimumab (GO-BEFORE) and infliximab (ASPIRE) . There are also RCTs on the other bDMARDs: abatacept (Westhovens 2009) , rituximab (IMAGE) and tocilizumab (FUNCTION) . All have shown higher proportions of patients achieving clinical remission and less radiographic progression with combination bDMARD + MTX compared to methotrexate alone ( Table 1 a and b).
| a | ||||||||
|---|---|---|---|---|---|---|---|---|
| Biological DMARD | Trial (reference) | Treatment group | No. of patients evaluated | Time-point evaluated (months) | DAS28 remission (DAS 28 < 2.6) (%) | p | LDAS28 (DAS28 < 3.2) (%) | p |
| ABT | Westhovens 2009 | Placebo + MTX | 253 | 12 | 23.3 | |||
| ABT 10 mg/kg + MTX | 256 | 41.4 | <0.001 | |||||
| ADA | Detert 2013 (HIT HARD) | Placebo + MTX | 85 | 6 | 29.5 | |||
| ADA 40 mg every 2 weeks + MTX | 87 | 47.9 | 0.021 d | |||||
| Breedveld 2006 (PREMIER) | Placebo + MTX | 257 | 12 | 21 | Referent | |||
| ADA 40 mg every 2 weeks | 274 | 23 | Referent | |||||
| ADA 40 mg every 2 weeks + MTX | 268 | 43 | <0.001 | |||||
| Placebo + MTX | 257 | 24 | 25 | Referent | ||||
| ADA 40 mg every 2 weeks | 274 | 25 | Referent | |||||
| ADA 40 mg every 2 weeks + MTX | 268 | 49 | <0.001 | |||||
| Bejarano 2008 (PROWD) | Placebo + MTX | 73 | 12 | 36.1 | Referent | |||
| ADA 40 mg every 2 weeks + MTX | 75 | 48.0 | 0.145 e | |||||
| Kavanaugh 2013 (OPTIMA) | Placebo + MTX | 517 | 6 | 17 | Referent | 26 a | Referent | |
| ADA 40 mg every 2 weeks + MTX | 515 | 34 | <0.001 | 47 a | <0.001 | |||
| ETN | Emery 2008 (COMET) | Placebo + MTX | 263 | 12 | 28 | Referent | 41 | Referent |
| ETN 50 mg weekly + MTX | 265 | 50 | <0.0001 f | 64 | <0.0001 g | |||
| GLM | Emery 2009(GO-BEFORE) | 1. Placebo + MTX | 160 | 6 | 28.1 a | Referent | ||
| 2. GLM 100 mg every 4 weeks + Placebo | 159 | 25.2 a | ||||||
| 3. GLM 50 mg every 4 weeks + MTX | 159 | 38.4 a | 0.050 | |||||
| 4. GLM 100 mg every 4 weeks + MTX | 159 | 37.7 a | 0.069 | |||||
| 3 + 4 (GLM + MTX) | 318 | 38.1 a | 0.031 | |||||
| Emery ACR 2011 (GO-BEFORE) | 1. Placebo + MTX | 160 | 12 | 26.3 a | Referent | |||
| 3. GLM 50 mg every 4 weeks + MTX | 159 | 35.8 a | b | |||||
| 4. GLM 100 mg every 4 weeks + MTX | 159 | 39.6 a | c | |||||
| IFX | St. Clair 2004 (ASPIRE) | Placebo + MTX | 240 | 12 | 15.0 | Referent | ||
| IFX 3 mg/kg + MTX | 302 | 21.2 | 0.065 | |||||
| IFX 6 mg/kg + MTX | 300 | 31.0 | <0.001 | |||||
| RTX | Tak 2011 (IMAGE) | Placebo + MTX | 232 | 12 | 13 | Referent | 20 | Referent |
| RTX 2 × 500 mg +MTX | 239 | 25 | <0.001 | 40 | <0.0001 | |||
| RTX 2 × 1000 mg +MTX | 244 | 31 | <0.0001 | 43 | <0.0001 | |||
| Tak 2012 (IMAGE) | Placebo + MTX | 249 | 24 | 13 | Referent | |||
| RTX 2 × 500 mg +MTX | 249 | 34 | <0.0001 | |||||
| RTX 2 × 1000 mg + MTX | 250 | 32 | <0.0001 | |||||
| TCZ | Burmester EULAR 2013 (FUNCTION) | Placebo + MTX | 287 | 6 | 15.0 | Referent | ||
| TCZ 4 mg/kg every 4 weeks + MTX | 288 | 31.9 | <0.0001 | |||||
| TCZ 8 mg/kg every 4 weeks | 292 | 38.7 | ≤0.0001 | |||||
| TCZ 8 mg/kg every 4 weeks + MTX | 290 | 44.8 | ≤0.0001 | |||||
| b | ||||||||
|---|---|---|---|---|---|---|---|---|
| Biological DMARD | Trial (reference) | Treatment group | N of patients evaluated | Time-point evaluated (months) | ΔmTSS (Mean (SD)) | p | ΔmTSS < 0.5 (%) | p |
| ABT | Westhovens 2009 | Placebo + MTX | 218 | 12 | 1.06 | Referent | 52.9 h | Referent |
| ABT 10 mg/kg + MTX | 234 | 0.63 | 0.040 | 61.2 h | j | |||
| ADA | Breedveld 2006 (PREMIER) | Placebo + MTX | 257 | 12 | 5.7 | Referent | 37 | Referent |
| ADA 40 mg every 2 weeks | 274 | 3 | <0.001 | 51 | Referent | |||
| ADA 40 mg every 2 weeks + MTX | 268 | 1.3 | <0.001 | 64 | <0.01 | |||
| Placebo + MTX | 257 | 24 | 10.4 | Referent | 34 | Referent | ||
| ADA 40 mg every 2 weeks | 274 | 5.5 | <0.001 | 45 | Referent | |||
| ADA 40 mg every 2 weeks + MTX | 268 | 1.9 | <0.001 | 61 | <0.01 | |||
| Kavanaugh 2013 (OPTIMA) | Placebo + MTX | 514 | 6 | 0.96 | Referent | |||
| ADA 40 mg every 2 weeks + MTX | 508 | 0.15 | <0.001 | |||||
| ETN | Emery 2008 (COMET) | Placebo + MTX | 263 | 12 | 2.44 | 59 | Referent | |
| ETN 50 mg weekly + MTX | 265 | 0.27 | 80 | <0.0001 k | ||||
| GLM | Emery 2011 (GO-BEFORE) | 1. Placebo + MTX | 160 | 6 | 1.11 (3.88) | Referent | ||
| 2. GLM 100 mg every 4 weeks + Placebo | 159 | 0.61 (3.55) | 0.054 | |||||
| 3. GLM 50 mg every 4 weeks + MTX | 159 | 0.71 (3.77) | 0.065 | |||||
| 4. GLM 100 mg every 4 weeks + MTX | 159 | 0.01 (1.47) | 0.003 | |||||
| 3 + 4 (GLM combined) | 318 | 0.36 (2.89) | 0.005 | |||||
| 1. Placebo + MTX | 160 | 12 | 1.37 (4.56) | Referent | ||||
| 2. GLM 100 mg every 4 weeks + Placebo | 159 | 1.25 (6.16) | 0.266 | |||||
| 3. GLM 50 mg every 4 weeks + MTX | 159 | 0.74 (5.23) | 0.015 | |||||
| 4. GLM 100 mg every 4 weeks + MTX | 159 | 0.07 (1.83) | 0.025 | |||||
| 3 + 4 (GLM combined) | 318 | 0.41 (3.93) | 0.060 | |||||
| Emery ACR 2011 (GO-BEFORE) | Placebo + MTX | 141 | 59.3 h | |||||
| GLM 50 mg every 4 weeks + MTX | 140 | 71.4 h | ||||||
| GLM 100 mg every 4 weeks + MTX | 139 | 61.2 h | ||||||
| IFX | St. Clair 2004 (ASPIRE) | Placebo + MTX | 240 | 12 | 3.7 (9.6) | Referent | 89.0 i | Referent |
| IFX 3 mg/kg + MTX | 302 | 0.4 (5.8) | <0.001 | 96.1 i | <0.001 | |||
| IFX 6 mg/kg + MTX | 300 | 0.5 (5.6) | <0.001 | 98.1 i | <0.001 | |||
| RTX | Tak 2011 (IMAGE) | Placebo + MTX | 232 | 12 | 1.079 | Referent | ||
| RTX 2 × 500 mg + MTX | 239 | 0.646 | NS | |||||
| RTX 2 × 1000 mg + MTX | 244 | 0.359 | <0.001 | |||||
| TCZ | Burmester EULAR 2013 (FUNCTION) | Placebo + MTX | 287 | 12 | 1.14 | Referent | ||
| TCZ 4 mg/kg every 4 weeks + MTX | 288 | 0.42 | <0.05 | |||||
| TCZ 8 mg/kg every 4 weeks | 292 | 0.26 | <0.05 | |||||
| TCZ 8 mg/kg every 4 weeks + MTX | 290 | 0.08 | ≤0.0001 | |||||
Related posts:
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Can rheumatoid arthritis be prevented?
To screen or not to screen: How to find and identify very early arthritis
Imaging in early rheumatoid arthritis
What is the best treatment strategy for early RA?
Outcomes of early rheumatoid arthritis – The WHO ICF framework
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