Conventional disease-modifying anti-rheumatic drugs (DMARDs) are the main tool to treat any form of rheumatoid arthritis (RA). Over the years, treatment strategies and use of DMARDs have changed. ‘Tight control’ and ‘treat-to-target’ are now the present paradigms. Combining DMARDs and adapting their dosages to obtain the best (clinical) result in individual RA patients with the least amount of medication has been and is studied worldwide. Literature results are mainly on early RA however, and they do not necessarily also apply to patients with established RA. Methotrexate (MTX) is the key conventional DMARD also for the treatment of established RA, and MTX often has to be combined with other DMARDs to reach low disease activity. However, there is lack of data on combination DMARD strategies and on how to treat best individual patients with established RA. In this review, we address these uncertainties and give an overview of available data.
Rheumatoid arthritis (RA) is a progressively disabling chronic disease with severe symptoms of pain and stiffness, in which persistent inflammation often leads to joint destruction, deformity and loss of function . Therapy is aimed not only at alleviation of symptoms, but also at prevention of joint damage – the disease-modifying effect. We have come a long way with strategies with disease-modifying anti-rheumatic drugs (DMARDs); see Fig. 1 . In the middle of the past century, because of their feared potential toxicity, the use of DMARDs was based on the principle of “primum non nocere”; a DMARD was only given if “milder” non-steroidal anti inflammatory drugs (NSAIDs) therapy had failed: the pyramid strategy . With this approach, patients experienced severe joint damage and physical disability in the long term . Whether earlier start of DMARDs would lead to better outcome was the item of the first study of the Utrecht Arthritis Cohort study group and this proved to be the case, in agreement with results of other studies . The strategy shifted to early start with a DMARD, preferentially methotrexate (MTX), because this drug had better efficacy and tolerability compared with other conventional DMARDs used at that time . Since then also sulphasalazine (SSZ) became more applied, leflunomide (LEF) entered the market and glucocorticoids (GCs) proved to be DMARDs in early RA. Combination treatment with DMARDs gradually was more frequently applied, and MTX became the anchor DMARD. Although effects and outcomes improved, the aim of remission only became realistic for larger groups of patients with the implementation of biological next to conventional DMARDs. This led to the present paradigms of tight control and treat-to-target . Tight control relates to a treatment strategy with dose adjustments tailored to the disease activity of an individual patient, aimed at achieving a preset level of low disease activity or remission within a certain limited period of time . Treating-to-target refers to this preset level . Guidelines and recommendations on how to treat RA have been updated. Amongst others, the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR) and National Institute for Health and Clinical Excellence (NICE) give their views on how best to treat RA . However, these guidelines and recommendations are centred on the treatment of early RA although the ACR guidelines also address RA patients with a disease duration >2 years. If there is a window of opportunity for treatment of RA, effective treatment of early RA with DMARDs would have a prolonged effect when administered in this period . This indicates that RA could react differently to DMARDs in different stages of the disease.
The ultimate goal of treatment is to achieve a drug-free remission . Until recently, consensus on a particular definition of remission did not exist . In 2011, the EULAR and ACR combined efforts created workable definitions that can be applied uniformly as an outcome measure in clinical trials . For established RA however, there is an extra hurdle to achieve remission and that is the presence of irreversible damage in the joints . This could fuel low-grade synovitis irresponsive to DMARDs and joint damage might influence the tender joint count and patient global assessment, which would make it difficult to meet the remission criteria. So, often, a more realistic goal of treatment in established RA is low disease activity. As treatment options and possibilities develop and progress in early RA, the aim of remission could eventually be a realistic goal in established RA too, if indeed the long-term course of RA is more beneficial when treated early in a tight control way.
This paper will review treatment possibilities and strategies in established RA, here defined as RA with a duration ≥2 years, with conventional DMARDs.
Literature search
For this review, we used published meta-analyses, systematic reviews and randomised controlled trials (RCTs), if available. We based our search on ‘established RA’ and ‘conventional (synthetic) DMARDs’, including GCs and ‘DMARD strategies’.
Because of the lack of recent high-level literature addressing established RA, we have chosen to use literature addressing early RA as well where there is no high-graded literature available on established RA. Although the magnitude of effects and frequency of adverse effects of DMARDs might be different in established RA compared with in early RA (quantitative differences), there is no reason in our view to assume that if a certain combination of DMARDs would have a positive or negative effect in early RA, this would not be the case in established RA (qualitative differences). It will be made clear in this paper when we are referring to information obtained only from early RA studies. We here report the most relevant data in our view; the lack of data in established RA precluded a more systemic review.
Currently available conventional DMARDs
As all available conventional DMARDs are used in all phases of RA, also established RA, we (in short) describe these drugs. The most common and dominant DMARD on the market is MTX . Among the available conventional DMARDs, MTX is also one of the most effective and best tolerated . Because of its favourable characteristics, MTX should be regarded as anchor DMARD; it has several benefits over other DMARDs; see Box 1.
In placebo-controlled trials, also the efficacy of SSZ has been proven . SSZ is often used for treating RA because of its positive risk/benefit ratio. It starts to work relatively quickly (short lag-time), but time is lost stepping up – to avoid intolerability – to the effective dose. Many rheumatologists prescribe SSZ because of considerations of safety, convenience and cost . It has been described that SSZ has only a small effect on joint damage. Because of this and because of the lack of proven differences between MTX and SSZ, SSZ is often seen as less favourable compared with MTX .
The antimalarial agents hydrochloroquine (HCQ) and chloroquine are structurally similar, although HCQ is prescribed more often because of lower toxicity. Compared with other DMARDs, they are clinically less effective, have a long lag time before the beneficial effect is evident and they do not seem to have a clear slowing-down effect of radiographic progression of joint damage .
LEF has similar clinical efficacy and inhibiting effect on radiographic damage as MTX, both in early and established RA . Patients who do not respond to MTX sufficiently could use LEF as an alternative . Recent studies addressing tolerability and toxicity of LEF (compared with MTX) have been conflicting.
Cyclosporin (CSA) is an effective DMARD, but its toxic side effects, though mostly reversible, have prevented CSA from becoming widely used. At present, it is only administered in patients with non-responsive RA and few other options .
GCs for the treatment of RA are effective, cheap and available all over the world . GCs not only have impressive symptomatic effects on pain and stiffness, but also delay the forming and progression of joint erosions, proven at least in early RA . Because of these disease-modifying characteristics, GCs are considered as DMARD and are often used as part of an early RA treatment strategy . However, a DMARD effect of GCs on established RA has not yet been proven, that is, whether GCs started in patients with disease duration >2 years also protect joints. Although, according to a Cochrane systematic review, it is likely that the positive effect of GC treatment during the first 2 years extends at least for 1–2 additional years .
Less frequently used DMARDs nowadays are azathioprine, intramuscular gold – although mentioned in the EULAR recommendations –, minocycline and d-penicillamine. In this review, we will not elaborate on these DMARDs.
Currently available conventional DMARDs
As all available conventional DMARDs are used in all phases of RA, also established RA, we (in short) describe these drugs. The most common and dominant DMARD on the market is MTX . Among the available conventional DMARDs, MTX is also one of the most effective and best tolerated . Because of its favourable characteristics, MTX should be regarded as anchor DMARD; it has several benefits over other DMARDs; see Box 1.
In placebo-controlled trials, also the efficacy of SSZ has been proven . SSZ is often used for treating RA because of its positive risk/benefit ratio. It starts to work relatively quickly (short lag-time), but time is lost stepping up – to avoid intolerability – to the effective dose. Many rheumatologists prescribe SSZ because of considerations of safety, convenience and cost . It has been described that SSZ has only a small effect on joint damage. Because of this and because of the lack of proven differences between MTX and SSZ, SSZ is often seen as less favourable compared with MTX .
The antimalarial agents hydrochloroquine (HCQ) and chloroquine are structurally similar, although HCQ is prescribed more often because of lower toxicity. Compared with other DMARDs, they are clinically less effective, have a long lag time before the beneficial effect is evident and they do not seem to have a clear slowing-down effect of radiographic progression of joint damage .
LEF has similar clinical efficacy and inhibiting effect on radiographic damage as MTX, both in early and established RA . Patients who do not respond to MTX sufficiently could use LEF as an alternative . Recent studies addressing tolerability and toxicity of LEF (compared with MTX) have been conflicting.
Cyclosporin (CSA) is an effective DMARD, but its toxic side effects, though mostly reversible, have prevented CSA from becoming widely used. At present, it is only administered in patients with non-responsive RA and few other options .
GCs for the treatment of RA are effective, cheap and available all over the world . GCs not only have impressive symptomatic effects on pain and stiffness, but also delay the forming and progression of joint erosions, proven at least in early RA . Because of these disease-modifying characteristics, GCs are considered as DMARD and are often used as part of an early RA treatment strategy . However, a DMARD effect of GCs on established RA has not yet been proven, that is, whether GCs started in patients with disease duration >2 years also protect joints. Although, according to a Cochrane systematic review, it is likely that the positive effect of GC treatment during the first 2 years extends at least for 1–2 additional years .
Less frequently used DMARDs nowadays are azathioprine, intramuscular gold – although mentioned in the EULAR recommendations –, minocycline and d-penicillamine. In this review, we will not elaborate on these DMARDs.
DMARD: monotherapy or combination therapy?
When starting to treat RA, treatment with a single DMARD as monotherapy remains a common first choice and is still considered by most rheumatologists the gold standard in treating DMARD-naive patients . For established RA patients in developed countries however, it is not very common to be DMARD naive. If the wanted effect of the treatment is not reached with monotherapy in a preset time frame, combination therapy is initiated . Most established RA patients need combination therapy. Monotherapy could be an option only for a subgroup that has not been experiencing very active RA.
In 2005, five systematic reviews were identified addressing combination therapy in established RA, of which the two oldest were inconclusive or negative towards combination therapy compared with mono-DMARD therapy. However, the three more recent systematic reviews and the clinical trial by Choy et al. reported positive evidence regarding combination therapy .
Combination therapy with conventional DMARDs
Combination strategies
There are different strategies to address combination DMARD therapy. A switch in strategies can be necessary if disease activity changes or if it flares. Although the approaches described below are mainly studied in early RA populations, they might also apply to the individual established RA patient; see Fig. 2 .
Step-down approach
For established RA patients with severe flares, a rapid reduction of disease activity is needed; often a major switch to another combination therapy might be necessary. A step-down approach could then be used when the RA is no longer active. The advantage of this approach is the quick symptom relief for patients and, if effective, use of limited number of drugs in the longer term. The drawback is that tailoring the medication to disease activity early in this approach is not possible.
Step-up approach
The step-up approach can be useful when the response to the previously administered DMARD(s) is no longer meeting the preset goal, but there is no major flare. Adding another DMARD then is indicated. The advantage of this step-up strategy is the possibility to tailor the DMARDs to disease activity; consequently, chances of overmedicating the patient are slim. The drawback of this approach is the relatively slow symptom relieve for patients, thus losing time before individual patient improvement occurs.
Step-up or step-down?
What the best treatment strategy for treating RA could be is still under debate. In early RA, clinicians who are in favour of a step-up approach are using the possible overmedication by step-down strategies as an argument . The ones who believe in the favourability of the step-down approach in early RA raise the argument that the supposed window of opportunity is used to the fullest. The analysis that evaluated the two strategies head-to-head in early RA found better and quicker results following the step-down strategy .
For the treatment of established RA, in our view it depends on the individual patient and the level of disease activity as to which approach is best applicable.
Which DMARDs to combine?
Most recent literature on combining conventional DMARDs is addressing early RA. As stated before, there is no good reason to assume these results would not apply to established RA at all.
MTX–LEF
In a randomised, double-blind, placebo-controlled trial, the effect of addition of LEF or a placebo to a stable dose of MTX in a patient group that still had active RA after receiving MTX for 6 months was studied. The addition of LEF resulted in clinical improvement . In an extension of the trial, the placebo group started to use LEF as well, either with a regular dose or with a loading dose; there was a similar positive clinical effect in both subgroups. However, the loading dose was associated with more frequent and more severe adverse effects; the loading dose of LEF has since then been abandoned . The ACR recommends the MTX–LEF combination for established RA patients with high disease activity .
MTX–CSA
A study was performed in 1995 on established RA patients with severe RA and suboptimal response to MTX . The patients received either MTX–CSA or MTX–placebo. After 24 weeks, the patients receiving the combination therapy of MTX–CSA had significantly better response compared with the MTX–placebo group. After another additional 24 weeks in which the MTX–placebo combination also was changed to MTX–CSA, the improvement was maintained in the original MTX–CSA group and was also seen in the group previously on MTX–placebo .
More recently, the Ciclosporine, Methotrexate, Steroid in RA (CIMESTRA) Study Group investigated if remission in early RA patients could be achieved by administering MTX and intra-articular GCs (betamethasone) and if extra administration of CSA had any additional effect. The trial period was 2 years. After 52 weeks, the addition of CSA improved the ACR20 and ACR-N responses, but did not show any effect on ACR50 and -70 responses, remission rates and radiographic changes . After 68 weeks, HCQ was added and from week 76 to 104 CSA (or the placebo–CSA) was reduced to 0. After 2 years (104 weeks), again CSA had no altered effect on ACR50 and -70 responses, remission rates and radiographic changes . After 5 years of follow-up, no effect of initial CSA-added therapy was seen . The Utrecht Arthritis Cohort study group published in 2010 that adding CSA to MTX (with a simultaneous reduction of the MTX dose), in case of adverse events or insufficient effect in early RA) was found to be ineffective . In all, the MTX–CSA combination has limited added value, but it could be used for patients with active established RA and few other options.
MTX-HCQ
The combination of MTX–HCQ resulted in better outcomes than MTX monotherapy in early RA patients . It also showed a significant improvement following a suboptimal response to MTX monotherapy . The ACR recommends this combination for established RA patients with moderate- to-high disease activity .
MTX–SSZ
In three double-blind clinical trials, no significant or clinically relevant differences between the effects of starting combination therapy of MTX–SSZ versus those of starting monotherapy with either one of these two DMARDs were found in early RA . More recently, Capell did find a significant improvement in disease activity in response to adding MTX therapy to that of SSZ in patients with a suboptimal response to SSZ . However, this could be just or predominantly the positive effect of the added MTX only. The ACR does however recommend the use of MTX–SSZ for established RA patients with high disease activity and poor prognostic features in its guidelines .
MTX–SSZ–HCQ
The ACR recommends as triple-DMARD combination MTX–HCQ–SSZ . This is based on an article showing that combination therapy with MTX, SSZ and HCQ is more effective than MTX alone in early RA patients . A few years later, the same author also reported that this triple combination is superior to the dual combination of MTX–SSZ and marginally superior to the combination of MTX–HCQ, following a suboptimal response to MTX monotherapy . Another study confirmed that the triple combination of the three appears to be more effective than the individual components also in established RA patients .
GCs–any DMARD
GCs are very frequently added to MTX or MTX-combination therapy, treating early RA, in low, medium and high dosages, see Box 2 for definitions , according to, for instance, the Low-dose Prednisolone Therapy Study Group (LDP) study with 5 mg prednisolone per day , the Utrecht study and the Computer Assisted Management for Early Rheumatoid Arthritis trial-II (CAMERA-II) studies with 10 mg prednisolone per day and the Combinatietherapie Bij Reumatoïde Artritis (COBRA) study, starting with 60 prednisolone mg per day . The NICE guidelines even state that combination therapy should always include GCs . A recently published review summarised the arguments for including GCs in combination therapy with conventional DMARDs: the long-lasting benefits even after withdrawal of GCs, the reduction in the need for non-steroidal anti-inflammatory drugs (NSAIDs) and GC-intra-articular injections, reduction in DMARD-induced adverse events and the improvement in the tolerance of biologicals GCs also have a positive effect on remission rates in early RA patients and can increase the survival time of DMARDs: the time until stopping because of adverse events and loss of efficacy . Evaluating radiographic outcomes in a Cochrane review on GCs, it was noted that, even in the most conservative estimate, GCs given in addition to standard therapy can substantially reduce the rate of erosion progression .
Related posts:
Precipitating and perpetuating factors of rheumatoid arthritis immunopathology – linking the triad of genetic predisposition, environmental risk factors and autoimmunity to disease pathogenesis
Co-morbidities in established rheumatoid arthritis
What is the outcome of RA in 2011 and can we predict it?
Quality of life and the outcome of established rheumatoid arthritis
Anti-TNF therapy
Imaging in rheumatoid arthritis
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
