In rheumatoid arthritis (RA), early use of disease-modifying anti-rheumatic drugs (DMARDs), intensive follow-up and ‘treating to target’ to achieve low disease activity produce significant improvements in measures of disease activity, functional impairment and retard erosive radiographic progression. Step-up, parallel and step-down regimens are all significantly more effective than sequential monotherapy; although the most effective regimen has not been established. Minimising the period of exposure to synovitis, by including a rapidly acting agent (e.g., corticosteroids or tumour necrosis factor α (TNFα) inhibitor), may slow radiographic progression further. Biologic therapies, especially TNFα inhibitors, are effective in early RA; however, their exact role is unclear. Current measures may overestimate the number of patients in clinical remission; therefore, musculoskeletal ultrasound and/or novel biomarkers may also have a role. Pre-clinical immunological markers could possibly be used to trigger pre-emptive treatment in asymptomatic, ‘at risk’ individuals. Potential treatment developments include combining biologic agents or targeting alternative immunological pathways.
Over the past few years, there has been a radical change in the approach to the management of the early stages of rheumatoid arthritis (RA). Erosive joint damage becomes evident in the very early stages of the disease process and, as a sufficient burden accumulates, is associated with deformity, loss of function and disability. It is now broadly accepted that, as soon as the diagnosis of RA is made, disease modifying anti-rheumatic drug (DMARD) therapy should be started and used aggressively (singly or in combination) to suppress the nascent inflammatory process to retard erosive progression . Thereafter, therapy should aim to minimise persisting synovitis, whilst maintaining an acceptable risk–benefit ratio. This article aims to summarise the core principles underpinning the management of early RA, the role of different biologic and non-biologic DMARD treatment regimens, the clinical targets at which therapy should aim and will finally speculate about possible future developments.
Core treatment principles
Many cases of early RA run an apparently indolent course though spontaneous remission is relatively rare . Therefore, early referral for specialist rheumatological opinion and consideration of DMARD therapy is essential whenever RA is suspected. Early DMARD therapy is consistently associated with lower disease activity measures; a greater likelihood of achieving clinical remission , reduced radiographic progression rates , lower levels of long-term functional and work disability and lower mortality rates . Why, then, do delays in initiating therapy have such a deleterious effect on long-term outcomes?
The ‘window of opportunity’
It has been postulated that, in the early stages of RA, there exists a period when the immune dysregulation is potentially reversible. Beyond this period, a settled trajectory of abnormal inflammation and auto-immune dysfunction develops, which is often less responsive to immunomodulatory therapy . Histologically, this transition from immune plasticity to rigidity coincides with the development of established pannus and erosive joint damage. This period has been termed the ‘window of opportunity’ during which therapy may have the capability to fundamentally alter the disease process and influence its long-term course (and prognosis). What is the evidence that such a ‘window of opportunity’ exists?
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Longer disease duration before therapy is associated with a worse prognosis.
Disease duration has consistently been shown to be the strongest predictor of likelihood of response to therapy, with delayed DMARD therapy (i.e., out with the window) being associated with lesser treatment responses and poorer functional status . A longitudinal study of 63 patients with early inflammatory arthritis demonstrated that those whose disease duration was greater than 12 weeks were 5 times less likely to achieve disease remission compared with those with a shorter disease duration . Subgroup analysis of the Finnish rheumatoid arthritis combination therapy (FIN-RACo) trial demonstrated that even a comparatively short delay in starting DMARD monotherapy (>4 months’ disease duration) reduced the likelihood of achieving clinical remission after 2 years’ follow-up . Interestingly, this effect was not observed in patients randomised to initial combination DMARD therapy suggesting that the ‘window’ may not have sharp edges – short delays may have an impact upon prognosis but might be overcome by combination therapy, at least for a while.
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Short-term delays in therapy have long-term effects on radiographic progression.
Several clinical trials have studied the impact of delaying DMARD therapy. A randomised controlled trial comparing immediate with delayed DMARD therapy demonstrated that, in the short term, patients did better with immediate therapy. More importantly, the benefits of early intervention extended well beyond the duration of the trial, such that patients with delayed therapy had a faster rate of radiographic progression . These findings were confirmed in a meta-analysis of 12 clinical trials, which concluded that the benefits of early DMARD therapy on radiographic progression persisted for up to 5 years after treatment initiation; whereas delaying DMARD therapy (up to 9 months’ disease duration) was associated with sustained radiographic deterioration .
The concept of ‘tight control’
Parallels can be drawn between RA and type 1 diabetes mellitus: both are auto-immune disorders in which end-organ damage develops over many years. The Diabetes Control and Complications Trial demonstrated that tight glycaemic control was associated with lower rates of microvascular disease and therefore minimised long-term complications. Could this paradigm be applied to RA? First, longitudinal magnetic resonance imaging (MRI) studies have demonstrated that it is the volume and persistence of synovitis which correlates most strongly with the development of erosions . Second, persistent, cumulative exposure to inflammation (i.e. the area under the curve) correlates with radiographic progression . Thus, a therapeutic strategy that attempts to minimise the period of exposure to synovitis might reduce long-term radiographic damage. The tight control of rheumatoid arthritis (TICORA) trial tested an intensive management strategy – comprising frequent review, formal disease activity assessment, liberal use of intra-articular/intra-muscular steroids and a step-up DMARD regimen – aiming to reduce each participants’ disease activity score (DAS) to below 2.4 (i.e. low disease activity score (LDAS) Fig. 1 ). TICORA demonstrated that substantial improvements in signs, symptoms, physical function, health-related quality of life and radiographic progression accrue when an intensive follow-up strategy is compared with routine outpatient care .
The computer-assisted management in early rheumatoid arthritis (CAMERA) trial confirmed the benefits of regular assessment and escalation of treatment following an inadequate initial response. Patients were randomised to either intensive (4-weekly) or routine (3-monthly) follow-up. In the intensive group, methotrexate, and later ciclosporin, doses were escalated aggressively using decision-making software, which analysed pre-defined response criteria at each consultation. Patients in the intensive group achieved higher doses of methotrexate, an earlier clinical response and experienced longer, more frequent periods of remission .
Aiming for remission?
Integral to the TICORA strategy was the ethos of ‘treating to target’ whereby DMARD therapy was intensified whenever the DAS44 exceeded 2.4 (i.e., moderate-to-high disease activity). Subsequent trials, employing similar strategies, have also consistently reported high rates of remission . This suggests that the target for intensive treatment strategies ought to be clinical remission, rather than LDAS. The FIN-RACo study was the first to target clinical remission and compared combination DMARD therapy (plus oral corticosteroids) with DMARD monotherapy in an open randomised controlled trial. Treatment was tailored to achieve a 50% improvement in two of four variables (swollen and tender joint counts, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)). If patients reached remission, their drug therapy was tapered but, if remission was lost, treatment was re-escalated . However, to date, there have been no strategy trials that have targeted remission throughout. This may reflect the difficulty clinicians have perceived in changing treatment in patients with minimal disease activity (but not yet clinical remission). In conclusion, current evidence strongly supports an intensive ‘treat to target’ strategy that aims for LDAS since this strategy also substantially increases the proportion of patients achieving clinical remission.
Risk–benefit of aggressive therapy
Clinicians have been rightly concerned about the balance of risks and benefits of increasingly complex DMARD regimens. It is possible that combinations of DMARDs might achieve not only superior clinical outcomes but also more drug-related toxicity. A meta-analysis of 36 combination therapy trials concluded that combination therapy not only was more effective than monotherapy, but was also associated with a higher risk of toxicity . However, trials of intensive management in early RA have not borne out this initial concern. The combinatie therapie bij reumatoide arteritis (COBRA) and FIN-RACo trials both compared combination DMARD therapy (including prednisolone) with sulphasalazine monotherapy. Superior short-term outcomes for disease activity , remission induction and radiographic progression were demonstrated but without any increase in toxicity. In the TICORA trial, there were fewer adverse events recorded with intensive therapy than with routine care . Nonetheless, care does need to be taken since randomised clinical trials rarely have the statistical power to identify any increase in the risk of serious or long-term toxicities.
Conventional DMARD therapy in early RA
The next issue to be addressed is how clinicians can best achieve their target of LDAS as quickly as possible, and with the least risk. In most parts of the world, initial treatment is restricted to conventional DMARD therapy and there are some important questions to be answered about the optimal strategy for these drugs.
DMARD monotherapy – Does it matter which drug is used?
Treatment with a single DMARD remains a common first choice because a significant proportion (∼40%) of patients will respond adequately to monotherapy. A systematic review concluded that there were no clinically significant differences in efficacy or adverse event rates between methotrexate, sulphasalazine or leflunomide monotherapy ; therefore, any of these drugs may reasonably be chosen. However, methotrexate is usually regarded as the first-choice DMARD for two reasons: first, a greater proportion of patients remain on methotrexate in the medium term and second, the majority of trials that have studied DMARD combinations have included methotrexate. Consequently, methotrexate is the preferred ‘anchor drug’ if a step-up combination strategy is to be pursued following a suboptimal response to monotherapy . Moreover, unlike alternative agents, there is some evidence that a good response to methotrexate is associated with a mortality benefit .
The role of combination DMARD therapy
Whilst a significant minority of patients will respond adequately to DMARD monotherapy, most patients will not achieve LDAS. For example, in the TICORA trial, 56% of patients in the intensive group eventually required triple therapy (methotrexate, sulphasalazine and hydroxychloroquine). A variety of DMARD combinations have been studied, and whilst not all combinations have been proven to be effective a meta-analysis has shown that overall, combination therapy is more effective than monotherapy, albeit with a modest increase in adverse event rates . The National Institute for Clinical Excellence guidelines on the management of RA conclude that the use of combination DMARD therapy should be the norm whilst recognising that this may not be appropriate for all patients with mild disease and good prognostic features . There is, however, no consensus about the optimal strategy for using combinations of DMARDs and, so far, successful clinical trials have used either step-up (TICORA), step-down (COBRA) or parallel (FinRACo) strategies.
Step-up DMARD combination therapy strategy
Step-up regimens introduce additional DMARDs if there has been an inadequate response to initial monotherapy and will avoid overtreatment of patients who respond satisfactorily to monotherapy. Trials have demonstrated that stepping up from methotrexate monotherapy by adding hydroxychloroquine, hydroxychloroquine/sulphasalazine, sulphasalazine , ciclosporin , leflunomide or parenteral gold can be effective. However, this approach will still expose some patients to several months of uncontrolled disease activity until their lack of response to monotherapy becomes evident. This delay runs contrary to the underpinning principle of achieving tight control as quickly as possible.
Parallel DMARD combination therapy strategy
Parallel regimens commence two or more DMARDs simultaneously since theoretically, combining drugs with different modes of action might deliver synergistic benefits. Not all trials of parallel strategies have had positive results – for instance, two randomised controlled trials have shown that methotrexate and sulphasalazine double therapy produced no significant advantage over monotherapy with either agent . In contrast, the FIN-RACo study demonstrated that initial parallel triple therapy (methotrexate, sulphasalazine and hydroxychloroquine) and low-dose prednisolone allowed significantly more patients to attain clinical remission and response targets (American College of Rheumatology (ACR) 50 response) than those treated with sequential monotherapy (initially sulphasalazine). Both groups demonstrated radiographic progression, which was significantly less in the combination group . Once again, follow-up analyses demonstrated the longer-term benefits of initial aggressive therapy with the combination group experiencing lesser rates of radiographic progression and work disability after 5 years and higher rates of remission (ACR) and minimal disease activity after 11 years .
Methotrexate and ciclosporin double therapy is an alternative, less commonly prescribed strategy. Compared to initial methotrexate monotherapy, the CIMESTRA study showed that the combination of methotrexate, ciclosporin and regular intra-articular steroid injections produced a significantly higher rate of ACR20 responses after 1 year of treatment and a higher rate of ACR20 and 50 responses after 2 years . However, there were no additional benefits in terms of remission rates or radiographic progression, and a greater proportion of the combination group experienced hypertrichosis and increases in serum creatinine. An earlier randomised trial had shown that whilst methotrexate and ciclosporin double therapy was not associated with significantly better clinical outcomes than methotrexate monotherapy, it did appear to slow radiographic progression after 1-year follow-up .
Step-down combination therapy strategy
The first example of a step-down regimen was seen in the COBRA trial. Patients were initially prescribed sulphasalazine, methotrexate and high-dose oral prednisolone. The prednisolone dose was tapered over 28 weeks and methotrexate was stopped after 40 weeks. Compared with monotherapy, this approach resulted in significantly faster improvements in disease activity, though the clinical benefit was lost after the prednisolone was tapered and eventually stopped. Radiographic progression was reduced in the step-down group , and this benefit persisted for more than 5 years .
Which is the most effective combination strategy?
Two trials have compared different combination strategies within a ‘treat-to-target’ context:
• The BeST study compared four DMARD strategies in a protocol which adjusted therapy every 3 months, aiming to achieve LDAS. The treatment groups comprised: group 1 – sequential monotherapy; group 2 – step-up combination therapy; group 3 – combination therapy (methotrexate and sulphasalazine) with high-dose tapering prednisolone; and group 4 – methotrexate and infliximab. Over 12-months’ follow-up, patients who received initial combination therapy (group 3 or 4) experienced a more rapid improvement in DAS44, although final DAS44 scores were similar for all treatment groups. Both combination therapy groups experienced greater (and faster) improvements in functional ability, reduced rates of radiographic progression and a greater likelihood of achieving LDAS or DAS remission. After 2-years’ follow-up, the observed clinical responses were similar among all treatment groups ; however, patients in groups 1 and 2 had required more treatment adjustments to achieve the same outcome. Thus, whilst combination therapy produced a modest clinical benefit, which dwindled over time, it was associated with sustained superiority in radiographic outcomes. It is likely that the rapidity of control of disease activity is important but it is impossible to disentangle this from the direct disease-modifying effects of oral corticosteroid and anti-TNF therapy.
• The TEAR study returned results which differed from the BeST study by suggesting that a step-up (sulphasalazine → sulphasalazine/methotrexate → sulphasalazine/methotrexate/hydroxychloroquine) strategy was at least as effective as initial parallel therapy (all three agents). Similar to the BeST study, treatment was tailored to achieve LDAS, but (1) more frequent reviews (monthly) were undertaken; and (2) there was liberal use of intra-articular and/or intramuscular, rather than oral, steroids. Patients in both groups experienced significant improvements in disease activity scores and after 12 months’ follow-up, there were no significant differences between either group’s change in disease activity measures, remission rates or degree of radiographic progression. However, despite the substantial clinical responses, both groups had significant radiographic progression.
No study has specifically compared the parallel DMARD regimen and oral corticosteroids of the BeST study with the intensive step-up regimen and parenteral corticosteroids of TICORA/TEAR. Both studies report similar 12-month ACR20 and ACR70 response rates; however, clinical remission rates were higher in TICORA/TEAR whilst the BeST regimen had a greater influence on radiographic progression. Until a direct head-to-head study has been performed, it is probable that each rheumatologist’s preference for a particular regimen will be influenced by prior experience and local prescribing traditions.
Conventional DMARD therapy in early RA
The next issue to be addressed is how clinicians can best achieve their target of LDAS as quickly as possible, and with the least risk. In most parts of the world, initial treatment is restricted to conventional DMARD therapy and there are some important questions to be answered about the optimal strategy for these drugs.
DMARD monotherapy – Does it matter which drug is used?
Treatment with a single DMARD remains a common first choice because a significant proportion (∼40%) of patients will respond adequately to monotherapy. A systematic review concluded that there were no clinically significant differences in efficacy or adverse event rates between methotrexate, sulphasalazine or leflunomide monotherapy ; therefore, any of these drugs may reasonably be chosen. However, methotrexate is usually regarded as the first-choice DMARD for two reasons: first, a greater proportion of patients remain on methotrexate in the medium term and second, the majority of trials that have studied DMARD combinations have included methotrexate. Consequently, methotrexate is the preferred ‘anchor drug’ if a step-up combination strategy is to be pursued following a suboptimal response to monotherapy . Moreover, unlike alternative agents, there is some evidence that a good response to methotrexate is associated with a mortality benefit .
The role of combination DMARD therapy
Whilst a significant minority of patients will respond adequately to DMARD monotherapy, most patients will not achieve LDAS. For example, in the TICORA trial, 56% of patients in the intensive group eventually required triple therapy (methotrexate, sulphasalazine and hydroxychloroquine). A variety of DMARD combinations have been studied, and whilst not all combinations have been proven to be effective a meta-analysis has shown that overall, combination therapy is more effective than monotherapy, albeit with a modest increase in adverse event rates . The National Institute for Clinical Excellence guidelines on the management of RA conclude that the use of combination DMARD therapy should be the norm whilst recognising that this may not be appropriate for all patients with mild disease and good prognostic features . There is, however, no consensus about the optimal strategy for using combinations of DMARDs and, so far, successful clinical trials have used either step-up (TICORA), step-down (COBRA) or parallel (FinRACo) strategies.
Step-up DMARD combination therapy strategy
Step-up regimens introduce additional DMARDs if there has been an inadequate response to initial monotherapy and will avoid overtreatment of patients who respond satisfactorily to monotherapy. Trials have demonstrated that stepping up from methotrexate monotherapy by adding hydroxychloroquine, hydroxychloroquine/sulphasalazine, sulphasalazine , ciclosporin , leflunomide or parenteral gold can be effective. However, this approach will still expose some patients to several months of uncontrolled disease activity until their lack of response to monotherapy becomes evident. This delay runs contrary to the underpinning principle of achieving tight control as quickly as possible.
Parallel DMARD combination therapy strategy
Parallel regimens commence two or more DMARDs simultaneously since theoretically, combining drugs with different modes of action might deliver synergistic benefits. Not all trials of parallel strategies have had positive results – for instance, two randomised controlled trials have shown that methotrexate and sulphasalazine double therapy produced no significant advantage over monotherapy with either agent . In contrast, the FIN-RACo study demonstrated that initial parallel triple therapy (methotrexate, sulphasalazine and hydroxychloroquine) and low-dose prednisolone allowed significantly more patients to attain clinical remission and response targets (American College of Rheumatology (ACR) 50 response) than those treated with sequential monotherapy (initially sulphasalazine). Both groups demonstrated radiographic progression, which was significantly less in the combination group . Once again, follow-up analyses demonstrated the longer-term benefits of initial aggressive therapy with the combination group experiencing lesser rates of radiographic progression and work disability after 5 years and higher rates of remission (ACR) and minimal disease activity after 11 years .
Methotrexate and ciclosporin double therapy is an alternative, less commonly prescribed strategy. Compared to initial methotrexate monotherapy, the CIMESTRA study showed that the combination of methotrexate, ciclosporin and regular intra-articular steroid injections produced a significantly higher rate of ACR20 responses after 1 year of treatment and a higher rate of ACR20 and 50 responses after 2 years . However, there were no additional benefits in terms of remission rates or radiographic progression, and a greater proportion of the combination group experienced hypertrichosis and increases in serum creatinine. An earlier randomised trial had shown that whilst methotrexate and ciclosporin double therapy was not associated with significantly better clinical outcomes than methotrexate monotherapy, it did appear to slow radiographic progression after 1-year follow-up .
Step-down combination therapy strategy
The first example of a step-down regimen was seen in the COBRA trial. Patients were initially prescribed sulphasalazine, methotrexate and high-dose oral prednisolone. The prednisolone dose was tapered over 28 weeks and methotrexate was stopped after 40 weeks. Compared with monotherapy, this approach resulted in significantly faster improvements in disease activity, though the clinical benefit was lost after the prednisolone was tapered and eventually stopped. Radiographic progression was reduced in the step-down group , and this benefit persisted for more than 5 years .
Which is the most effective combination strategy?
Two trials have compared different combination strategies within a ‘treat-to-target’ context:
• The BeST study compared four DMARD strategies in a protocol which adjusted therapy every 3 months, aiming to achieve LDAS. The treatment groups comprised: group 1 – sequential monotherapy; group 2 – step-up combination therapy; group 3 – combination therapy (methotrexate and sulphasalazine) with high-dose tapering prednisolone; and group 4 – methotrexate and infliximab. Over 12-months’ follow-up, patients who received initial combination therapy (group 3 or 4) experienced a more rapid improvement in DAS44, although final DAS44 scores were similar for all treatment groups. Both combination therapy groups experienced greater (and faster) improvements in functional ability, reduced rates of radiographic progression and a greater likelihood of achieving LDAS or DAS remission. After 2-years’ follow-up, the observed clinical responses were similar among all treatment groups ; however, patients in groups 1 and 2 had required more treatment adjustments to achieve the same outcome. Thus, whilst combination therapy produced a modest clinical benefit, which dwindled over time, it was associated with sustained superiority in radiographic outcomes. It is likely that the rapidity of control of disease activity is important but it is impossible to disentangle this from the direct disease-modifying effects of oral corticosteroid and anti-TNF therapy.
• The TEAR study returned results which differed from the BeST study by suggesting that a step-up (sulphasalazine → sulphasalazine/methotrexate → sulphasalazine/methotrexate/hydroxychloroquine) strategy was at least as effective as initial parallel therapy (all three agents). Similar to the BeST study, treatment was tailored to achieve LDAS, but (1) more frequent reviews (monthly) were undertaken; and (2) there was liberal use of intra-articular and/or intramuscular, rather than oral, steroids. Patients in both groups experienced significant improvements in disease activity scores and after 12 months’ follow-up, there were no significant differences between either group’s change in disease activity measures, remission rates or degree of radiographic progression. However, despite the substantial clinical responses, both groups had significant radiographic progression.
No study has specifically compared the parallel DMARD regimen and oral corticosteroids of the BeST study with the intensive step-up regimen and parenteral corticosteroids of TICORA/TEAR. Both studies report similar 12-month ACR20 and ACR70 response rates; however, clinical remission rates were higher in TICORA/TEAR whilst the BeST regimen had a greater influence on radiographic progression. Until a direct head-to-head study has been performed, it is probable that each rheumatologist’s preference for a particular regimen will be influenced by prior experience and local prescribing traditions.
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