NPC Archive Item: Combination therapy with DMARDs is BeSt

NOTE – This is an archive post from the NPC and has not been updated since first publication. Therefore, some hyperlinks may no longer be working.
MeReC Rapid Review NPC Logo

5th February 2009

Four different DMARD treatment strategies in people with recent onset rheumatoid arthritis significantly improved patient-orientated outcomes after two years. Earlier improvements were seen in those initially treated with combination strategies.

The early introduction of disease-modifying antirheumatic drugs (DMARDs) can improve symptoms and quality of life for patients with rheumatoid arthritis (RA). Often more than one agent or a combination of agents is required. However, all DMARDs are associated with significant adverse effects and frequent monitoring is needed to assess the need for continuing, changing and/or to plan for reduction of therapy for maintenance. Early introduction of combination therapy, including methotrexate, may have advantages.

Health professionals should follow the recommendations for DMARDs in the recently published NICE clinical guideline for the management of RA in adults . With regard to DMARDs, this states that:

  • in people with newly diagnosed active RA offer a combination of DMARDs (including methotrexate plus short-term glucocorticoids) as first-line treatment as soon as possible, ideally within 3 months of the onset of persistent symptoms.
  • Where combination DMARD therapy is not appropriate, start DMARD monotherapy, placing greater emphasis on fast escalation to a clinically effective dose rather than on the choice of DMARD.
  • In people with recent-onset RA already receiving combination DMARD therapy and in whom sustained and satisfactory levels of disease control have been achieved, cautiously try to reduce drug doses to levels that still maintain disease control.

What is the background to this?
Analgesics or anti-inflammatory drugs (corticosteroids or NSAIDs) can be used for pain relief, and reduction of stiffness and swelling for patients with RA, although DMARDs (e.g. methotrexate [MTX], sulfasalazine [SSA]) also play an important role in controlling symptoms. The new NICE guideline recommends that patients with RA should be established on disease-modifying therapy as soon as possible after a diagnosis of RA is established. However, the optimal sequencing of DMARDs has been a source of debate, as has whether patients should be started on combinations of therapies or single DMARDs.

The BeSt study was a Dutch, single-blind, randomised controlled trial of 508 patients with recent-onset RA. It evaluated four different DMARD treatment strategies for the treatment of new-onset RA, all of which included methotrexate initially (alone or in combination). The strategies were: 1) sequential monotherapy; 2) step-up combination therapy, i.e. initially MTX monotherapy; 3) initial combination therapy, including a tapered high-dose prednisone; or 4) initial combination therapy with MTX and infliximab▼. All therapies were adjusted according to the Disease Activity Score (DAS) evaluated. The study reviewed here considered patient-reported outcomes of the BeSt study.

What does this study claim?
After 3 months there were clinically important improvements in HRQOL compared with baseline in all subscales of the Medical Outcomes Study Short Form 36 (SF-36) for all four different treatment strategies tested, with the exception of improvements in general health for groups 1 and 2. After two years, all SF-36 scores approached population norms for three physical components, and achieved population norms for bodily pain and four mental components. Functional ability assessed by the McMaster Toronto Arthritis Patient Preference Disability Questionnaire (MACTAR) improved markedly in all groups, as did patient-reported visual analogue scale (VAS) scores for pain, global health and disease activity. However, improvements in MACTAR, VAS, and physical items of the SF-36 occurred significantly earlier in the patients initially treated with combination treatments (groups 3 and 4) compared with the other two groups.

How does this fit with other evidence?
There is some evidence from randomised controlled trials that combination therapy with DMARDs, at least for those combinations involving methotrexate, is more effective than monotherapy alone (Choy 2004). The review carried out for NICE full Clinical Guideline for RA showed similar improvements with a variety of DMARD monotherapies and combination therapies, and suggested that the type and combination of drug used was less important than the speed and intensity of the DMARD introduction. However, health economic analysis demonstrated clear benefits of a combination strategy, compared with monotherapy, and the Guideline Development Group (GDC) felt that combination therapy should be the first-line treatment strategy unless specifically contraindicated.

The GDC also felt that methotrexate should be included as the first DMARD therapy, either as monotherapy or as part of a combination of other therapies. Furthermore, the most successful and cost-effective step-down and combination therapy regimes had all used steroids in one form or another (either orally in a tapered dose, intra-articularly, intra-muscularly or a combination of these approaches) and it was therefore felt that steroids should be specifically mentioned in combination regimes.

So what?
A previous publication of the BeSt study reported favourable outcomes with regard to functional ability and radiographic progression for initial combination therapy compared with monotherapy. The secondary analysis of the study reviewed here provides additional information on outcomes that are of most importance to patients, i.e. the effect of treatment on improving daily activities and quality of life, and gives valuable support to these findings. The results generally support the recommendations in the NICE RA guideline for early intervention with a combination DMARDs, one of which is methotrexate.

Patients in the BeSt dtudy were typical of patients with recent onset RA, who would be referred to a specialist, and had not previously received DMARDs, although they were being assessed clinically far more frequently (at least every three months) and would probably have been more motivated than would normally be the case in routine clinical practice.

There are a number of other limitations to the study. It was single blind, with the investigators being aware of the study treatments, and as no placebos were included it is not known how much of the improvement seen was due to the treatment strategies per se. The outcomes may also have been influenced by patient expectations of certain treatment strategies.

Although carried out in the Netherlands, the study used treatment regimens that are available and commonly used in the UK. However, initial therapy with methotrexate plus infliximab (group 4) is not a recommended option for first-line therapy. According to NICE Technology Appraisal 130, infliximab, should only be considered after trials of two (non-biological) DMARDs, and would not normally be used initially (as per group 4).

Further information on the management of rheumatoid arthritis is available on the rheumatoid arthritis section of NPC.

Study details
van der Kooij SM, de Vries-Bouwstra JK, Goekoop-Ruiterman YP, et al. Patient-reported outcomes in a randomized trial comparing four different treatment strategies in recent-onset rheumatoid arthritis. Arthritis Rheum 2009;61:4–12.

Patients: The study included 508 adults (mean age 54 years; 68% female) with recent-onset RA (<2 years) diagnosed according to American College of Rheumatology 1987 criteria, who had not previously received DMARDS.
Treatments: Patients were randomly allocated to one of four treatment groups: 1) sequential monotherapy (MTX, then SSA, then leflunomide, then MTX plus infliximab); 2) step-up combination therapy, initially monotherapy with MTX, then MTX plus SSA, then MTX plus SSA plus hydroxychloroquine [HDQ], then MTX plus SSA plus HDQ plus prednisone, then MTX plus infliximab); 3) initial combination therapy, including a tapered high-dose prednisone (MTX plus SSA plus prednisone [tapered from 60mg  to 7.5mg/day], then MTX plus cyclosporine A plus prednisone 7.5mg/day, then MTX plus infliximab; or 4) initial combination therapy with MTX and infliximab, then SSA, then leflunomide. Therapy was adjusted according to Disease Activity Score (DAS) evaluated by research nurses who were blind to the treatment strategy. Clinicians and patients were aware of the treatments received.
Outcomes: These were pre-specified secondary outcomes of the BeSt study, which were assessed by the patients themselves, under supervision. Functional ability was assessed by the MACTAR. HRQOL was assessed by the Medical Outcomes Study Short Form 36 (SF-36). Patients assessed pain, disease activity and global health on a 100mm VAS.
Results: After 3 months, improvements in MACTAR score in groups 1, 2, 3 and 4 were 10.6, 9.5, 16.7 and 17.3, respectively, (P<0.001 for groups 1 and 2 vs. 3 and 4). After one year the differences from baseline were 15.2, 16.3, 16.9 and 19.3, respectively (P<0.02 for group 1 vs. group 4).

After 3 months all groups achieved clinically relevant improvements of at least 5 to 10 points in all subscales of the SF-36, except for improvements in general health in groups 1 and 2. After 2 years values approached those of the age- and sex-matched Dutch population for bodily pain, vitality, social functioning, role-emotional, and mental health. However, this was not the case for physical functioning, role-physical and general health across the four groups. Greater improvements in the physical health component scores was seen at three months for groups 3 and 4 (11.2 and 9.6, respectively) compared with groups 1 and 2 (5.8 and 3.9, respectively) (P<0.001), although there were differences at six month also, there were no significant differences between groups after one and two years. There were no significant differences in the mental health component scores between groups throughout the study.

Improvements in VAS scores for pain (mean changes 15.1, 13.4, 29.2, 26.6, for groups 1, 2, 3 and 4, respectively), VAS scores for disease activity (18.7, 18.2, 35.9, 34.2, respectively) were significantly less in groups 1 and 2 compared with groups 3 and 4 at 3 months. Significant differences between groups 1 and 2 vs. group 4, and between groups 2 and 3, were identified for VAS scores for global health at 3 months (10.8, 11.8, 22.0, 28.9, respectively). There were no significant differences between groups for any of the VAS scores after two years.

Sponsorship: The study was sponsored by the Dutch College of Health Insurances, with additional funding by Centocor Inc. and Schering-Plough BV.

Sponsorship:  Supported by grants from the National Heart, Lung and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics

Please comment on this blog in the NPC discussion rooms, or using our feedback form