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• Re:Re:EULAR advice against DMARD combination therapy, a major flaw.
  Niels A Graudal
  Published on: 22 November 2010
• Re:EULAR advice against DMARD combination therapy, a major flaw.
  Josef S. Smolen
  Published on: 7 September 2010
• EULAR advice against DMARD combination therapy, a major flaw.
  Niels A Graudal
  Published on: 15 July 2010

• Published on: 22 November 2010

  Re:Re:EULAR advice against DMARD combination therapy, a major flaw.

  • Niels A Graudal, Senior consultant
  • Other Contributors:
    • Gesche Jurgens

  Dear Editor,

  We thank Dr. Smolen for commenting our criticism. As Dr. Smolen correctly states we did not pay attention to the fact that the EULAR recommendations (1) are based on 5 different systematic reviews. However, we assumed that the authors of the recommendations would attempt to reach an unambiguous position on the basis of the different reviews. Comparing the 15 recommendations in Table 1 with the treatment al...

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  Dear Editor,

  We thank Dr. Smolen for commenting our criticism. As Dr. Smolen correctly states we did not pay attention to the fact that the EULAR recommendations (1) are based on 5 different systematic reviews. However, we assumed that the authors of the recommendations would attempt to reach an unambiguous position on the basis of the different reviews. Comparing the 15 recommendations in Table 1 with the treatment algorithm in Figure 1 we agree that there is not full accordance between the two. This is in itself a problem, especially as the object for the conflicting recommendations, the combination DMARD therapy, potentially could save a significant proportion of biologic treatment. Still, for the reader, the more obvious of the two conflicting recommendations is the one given in Table 1, which has the headline "Final set of 15 recommendations for the management of RA".
  We are not ignoring recommendation no. 6, in which we agree. We do not object to the combination of DMARDs with glucocorticoids, but to the lack of recommendation of two or more DMARDs.
  Dr. Smolen indicates that our meta-analysis (2) is less complete, because we only include one outcome measure. However, the outcome measures of RA are not mutually independent, on the contrary. If a study shows a difference in ACR 50, it will almost invariably also show a difference in ACR 20, ACR 70, ESR, CRP, number of swollen joints, DAS28 etc.

  Consequently, one measure would generally be enough to decide whether there is a difference between treatments in randomised trials. Although most rheumatologists probably may recall exceptional patient cases where inflammation and joint destruction may run separately, several studies have shown that on the average there is a very high association between integrated measures of inflammatory variables (i.e. CRP, swollen joint count etc.) and the radiographic score. Therefore, the radiographic score has the advantage that it not only shows the present status of the patient, but also reflects the preceding disease course including joint swelling, pain and fatigue. Furthermore, we were able to standardize the radiographic outcome measure to the same scale, which made it possible to make comparisons across all 70 studies. This is in contrast to the Cochrane analysis by Katchamart et al (3), which include 19 combination studies of methotrexate + DMARD vs. methotrexate. They were not able to find one single common outcome variable, and therefore this analysis consists of many small meta-analyses each investigating a separate outcome and each including very few studies with a low statistical power. In spite of this and in spite of the fact that the majority of studies included in this meta-analysis are short-term studies, almost all efficacy variables are in favour of combination treatment, many of them statistically significant. Dr. Smolen states the conclusion of the Cochrane review to be "no statistically significant advantage of the MTX combination versus monotherapy". However, the full conclusion of the authors is as follows:
  "When the balance of efficacy and toxicity is taken into account, the moderate level of evidence from our systematic review showed no statistically significant advantage of the MTX combination versus monotherapy." Accordingly, the conclusion is that the increased toxicity in the combination group outbalances the increased efficacy. In their analysis (3) the withdrawal rate due to adverse reactions in the combination group was 14% and in the methotrexate group it was 9%. In DMARD naive patients, the ACR 50 response in the combination group was 51% (similar to biologic + methotrexate in biologic studies) and in the methotrexate group 29% (similar to methotrexate single therapy in biologic studies). This clinically significant difference was not statistically significant because only 127 patients were included in the analysis.

  The problem with the many analyses of this Cochrane review is that they are of small size with no power. However one might pose the question: Does an extra withdrawal of 5% (14%-9%) outbalance an extra effect on ACR 50 of 22% (51%-29%)? This is a matter of opinion, but if we had made this meta-analysis we would have concluded that the fact that 15 % of the patients had to leave the treatment because of side effects should not stop the remaining 85% of patients from getting the benefit from the better combination treatment. We think that the weak signal in this underpowered meta-analysis is in accordance with the results of our meta-analysis of studies of DMARD combinations, which has a very significant power, including 1384 patients (2).
  It is correct that we mislabelled one of our studies in the online version of our meta-analysis. We did, however, discover this mistake, and it has been changed in the final published version (2). It is also correct that 8 of 12 DMARD combination studies are not statistically significant.
  However, 11 of 12 studies have a trend towards a reducing effect on radiographic progression. Furthermore, these studies are in general much smaller than studies of biologic drugs, which may reflect that DMARDs are less profitable than biologic agents. The idea of a meta-analysis is to increase the power of the conclusion by integrating many small studies into one large study. Doing this we find that the average effect of DMARD combination studies is highly significant (p = 0.001) and almost as good as the one of studies combining a biologic agent with methotrexate.

  We still think that the authors of the EULAR guidelines should consider a quick revision of the guidelines and give combination DMARD treatment a definite place in the treatment algorithm.

  References

  (1) Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69(6): 964-975.

  (2) Graudal N, Jurgens G. Similar effects of disease modifying anti rheumatic drugs, glucocorticoids and biologics on radiographic progression in rheumatoid arthritis: meta-analysis of 70 randomised placebo or drug controlled studies including 112 comparisons. Arthritis Rheum 2010;62:2852-2863.

  (3) Katchamart W, Trudeau J, Phumethum V, et al. Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis. Cochrane Database Syst Rev 2010;4:CD008495.

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  Conflict of Interest:
  None declared.

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• Published on: 7 September 2010

  Re:EULAR advice against DMARD combination therapy, a major flaw.

  • Josef S. Smolen, Rheumatologist
  • Other Contributors:
    • Robert Landewe, Laure Gossec, Simone Gorter, Cecile Gaujoux-Viala,

  Dear Editor,

  When writing their comment on the recent EULAR recommendations for the management of RA (1), Drs. Graudal and Jurgens must have overlooked several important aspects related to these recommendations. First, the set of recommendations was based on five separate systematic literature reviews (SLRs) and, indeed, items 5, 7 and 8 quoted by them are largely based on two of these 5 SLRs (2;3) rather than,...

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  Dear Editor,

  When writing their comment on the recent EULAR recommendations for the management of RA (1), Drs. Graudal and Jurgens must have overlooked several important aspects related to these recommendations. First, the set of recommendations was based on five separate systematic literature reviews (SLRs) and, indeed, items 5, 7 and 8 quoted by them are largely based on two of these 5 SLRs (2;3) rather than, as they suggest, on a past review article (4). Second, the recommendations were not the work of a few individuals, but were the result of consensus finding by a large task force that included authors of studies on combination therapy, and all had ample opportunity to review the SLRs and discuss the text of individual recommendations. Third, within the task force, the agreement with these points was high.

  Fourth, combination of synthetic DMARDs is still proposed as an option (see also the Figure presenting the algorithm on the recommendations), although it is not regarded as more effective than monotherapy based on the SLRs performed. Finally, they disregard the fact that recommendation number 6 clearly addresses the superiority of combining synthetic DMARDs with glucocorticoids (GC), while stating that there is insufficient evidence for a superiority of starting GC with combinations of synthetic DMARDs versus starting GC with DMARD monotherapy.

  The authors of the letter relate their critique to their own SLR in which they presented an indirect comparison of the effects of DMARD monotherapy, DMARDs plus GC and combinations of DMARDs on radiographic progression (5). Aside from methodological concerns regarding this paper and from the fact that our SLRs looked at all aspects of response rather than just radiographic progression, their results actually fully confirm our conclusions - they just interpret their data differently. In their paper, the vast majority of the studies on combinations of synthetic DMARDs (8 of 12) did not show superiority of the combination. Moreover, of the remaining 4 studies, one is mislabelled and examined cyclosporine A plus methotrexate (MTX) vs cyclosporine A monotherapy (rather than, as they stated, MTX monotherapy) and thus lacked MTX monotherapy as comparator, and another one employed MTX at a dose of 11mg/week and thus at about half of the usually most effective dose (6) that we likewise have recommended. Also regarding recommendation 6 we feel endorsed by their publication, since the majority of the studies on GC plus synthetic DMARDs versus synthetic DMARDs alone which they had assessed (7 of 11) showed superiority of this particular combination, pointing towards the importance of GC in combination regimens.

  Last but not least, a recent Cochrane analysis compared MTX monotherapy with MTX combination therapy with non-biologic DMARDs and concluded that there was "no statistically significant advantage of the MTX combination versus monotherapy" (7), fully in line with our SLRs and recommendations1-3 and opposed to Graudal's and Jurgens' contention.

  Thus, we do not agree with Graudal's and Jurgens' suspicion of a flaw in the EULAR recommendations - on the many accounts detailed above. Nevertheless, this does not preclude that combinations of certain synthetic DMARDs may, indeed, be superior to DMARD monotherapy - it is just that the currently available data are too meagre to support such a conclusion and, therefore, addressing this question with the proper controls is an important part of the research agenda we have brought forward.

  Reference List

  (1) Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux -Viala C et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69(6):964-975.

  (2) Gaujoux-Viala C, Smolen JS, Landewe R, Dougados M, Kvien TK, Mola EM et al. Current evidence for the management of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2010; 69(6):1004-1009.

  (3) Gorter SL, Bijlsma JW, Cutolo M, Gomez-Reino J, Kouloumas M, Smolen JS et al. Current evidence for the management of rheumatoid arthritis with glucocorticoids: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2010; 69(6):1010-1014.

  (4) Smolen JS, Aletaha D, Keystone E. Superior efficacy of combination therapy for rheumatoid arthritis. Fact or Fiction? Arthritis Rheum 2005; 52:2975-2983.

  (5) Graudal N, Jurgens G. Similar effects of disease modifying anti rheumatic drugs, glucocorticoids and biologics on radiographic progression in rheumatoid arthritis: meta-analysis of 70 randomised placebo or drug controlled studies including 112 comparisons. Arthritis Rheum 2010.

  (6) Visser K, van der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis 2009; 68(7):1094-1099.

  (7) Katchamart W, Trudeau J, Phumethum V, Bombardier C. Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis. Cochrane Database Syst Rev 2010; 4:CD008495.

  Conflict of Interest:

  Authors

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  Conflict of Interest:
  None declared.

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• Published on: 15 July 2010

  EULAR advice against DMARD combination therapy, a major flaw.

  • Niels A Graudal, senior consultant
  • Other Contributors:
    • Niels Graudal, Gesche Juergens

  Dear Editor,

  In point 5 and 7-8 of the EULAR recommendations for the management of rheumatoid arthritis (1) the following statements are listed:
  1) In DMARD naive patients, irrespective of the addition of GCs, synthetic DMARD monotherapy rather than combination therapy of synthetic DMARDs may be applied.
  2) If the treatment target is not achieved with the first DMARD strategy, addition of a biological DMARD s...

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  Dear Editor,

  In point 5 and 7-8 of the EULAR recommendations for the management of rheumatoid arthritis (1) the following statements are listed:
  1) In DMARD naive patients, irrespective of the addition of GCs, synthetic DMARD monotherapy rather than combination therapy of synthetic DMARDs may be applied.
  2) If the treatment target is not achieved with the first DMARD strategy, addition of a biological DMARD should be considered when poor prognostic factors are present; in the absence of poor prognostic factors, switching to another synthetic DMARD strategy should be considered.
  3) In patients responding insufficiently to MTX and/or other synthetic DMARDs with or without GCs, biological DMARDs should be started; current practice would be to start a TNF inhibitor (adalimumab, certolizumab, etanercept, golimumab, infliximab) which should be combined with MTX.

  Furthermore, in the explanatory details of point 5 it is concluded that neither a start with combinations of synthetic DMARDs nor a step up combination therapy are better than monotherapies or switching DMARDs for the major outcomes.
  Consequently the use of combination DMARD therapy for rheumatoid arthritis is more or less dissuaded in these recommendations. The evidence for this advice against combination DMARD therapy is given in a review article from 2005 (2). However, substantial evidence in favour of combination DMARD therapy has appeared since then (3-6).

  In the BEST study (3) a direct comparison showed that infliximab combined with methotrexate was better than step-up combination of DMARDs during the first year period in which the treatment was stepped-up to full-dose treatment (difference: -0.68% [-1.01, -0.35], p<0.0001).
  However, during the second year after attainment of the full doses there was no longer a difference between infliximab combined with methotrexate and conventional combination DMARD therapy (difference: 0.03 [-0.34, 0.40] p =0.87).(4). Consequently this study is in favour of an initial combination DMARD therapy in full doses in order to reach maximum effect as soon as possible, a maximum effect which corresponds to the effect of a biologic with methotrexate. In the BEST study these data are confirmed by the fourth arm of the study showing that initial combination of DMARDs with glucocorticoid is as effective as infliximab with methotrexate already during the first year (difference: -0.07 [-0.25, 0.11] p = 0.44) (3).
  In addition to this evidence in favour of combination DMARD with or without glucocorticoid treatment, our recent meta-analysis of 70 randomised trials using blindly assessed progression in radiographic scoring as outcome (5) shows that 1 DMARD vs. placebo reduces radiographic progression with a relative effect of 74% per year, that 2 DMARDs vs. one DMARD reduce radiographic progression with additionally 52% and that 3 DMARDs vs. one DMARD reduce radiographic progression with additionally 78%. The last effect corresponds to the effect of a biologic with methotrexate. An independent meta-analysis finds results comparable to ours (6).
  Some may argue that there are more, better and bigger studies of the effects of biologics than the effects of DMARDs and that the evidence for biologics therefore is better. However, with the exception of the BEST study (3,4) all biologic studies are insufficiently designed as they only compare combination therapy vs. monotherapy. They should, of course have compared combination therapy vs. combination therapy. It is unreasonable to base treatment recommendations on wrongly designed studies on the expense of the conventional DMARDs (and the tax payers) just because they are bigger.
  In our opinion, the new EULAR recommendations are favouring unreasonably expensive treatments by excluding a cheap and effective treatment principle and should be changed to include combination DMARD therapy in the line before the biologics.
  All that said, the authors of the present letter are happy that we have the possibility to use biologics when they are indicated, that is when combination DMARD treatment is not sufficient to control the disease activity of rheumatoid arthritis.

  References

  1. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69:964-75.

  2. Smolen JS, Aletaha D, Keystone E. Superior efficacy of combination therapy for rheumatoid arthritis: fact or fiction? Arthritis Rheum 2005;52:2975-83.

  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.

  4) Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007;146:406-15.

  5) Graudal N, Juergens G. Similar effects of disease modifying anti rheumatic drugs, glucocorticoids and biologics on radiographic progressionin rheumatoid arthritis: meta-analysis of 70 randomised placebo or drug controlled studies including 112 comparisons. Arthritis Rheum. 2010 Jun 17. [Epub ahead of print]

  6) Ma MH, Kingsley GH, Scott DL. A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis.Rheumatology (Oxford). 2010;49:91-8.

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  Conflict of Interest:
  None declared.

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