Indian Journal of Rheumatology

: 2017  |  Volume : 12  |  Issue : 2  |  Page : 104--109

Recent evidence comparing combination of conventional synthetic disease-modifying antirheumatic drugs with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis

Abhishek Zanwar1, Sakir Ahmed1, Durga Prasanna Misra1, Vikas Agarwal1, Aman Sharma2, Anupam Wakhlu3, Vir Singh Negi4,  
1 Department of Clinical Immunology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
4 Department of Clinical Immunology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

Correspondence Address:
Durga Prasanna Misra
Department of Clinical Immunology, C-Block, 2nd Floor, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow - 226 014, Uttar Pradesh


Rheumatoid arthritis (RA) is a chronic, disabling inflammatory arthritis often treated with a variety of disease-modifying antirheumatic drugs (DMARDs), whether conventional synthetic DMARDs (csDMARDs), targeted synthetic DMARDs (tsDMARDs), or biological DMARDs (bDMARDs). Most patients with RA are seropositive, have significant disease activity at presentation to the Rheumatologist and may have erosions at the time of diagnosis, all of which are poor prognostic factors. Patients with RA are often initially started on methotrexate (MTX), with addition of other DMARDs, the usual practice in the event of failure of/suboptimal response to MTX monotherapy. Since the recent guidelines by the European League against Rheumatism favor the use of bDMARDs over the combination of csDMARDs following the failure of MTX monotherapy in patients with such poor prognostic factors, we decided to review the recent literature comparing combination csDMARDs with bDMARDs. Long-term follow-up of landmark trials such as the Behandel-Strategieëen study (10 years) and NEO-RACo study (5 years) as well as other trials supports similar efficacy of both strategies in terms of clinical and functional outcomes. Whereas some studies have shown a minor but statistically significant progression of radiographic damage in those receiving combination of csDMARDs versus those on bDMARDs, others have not, further confirmed in a recent meta-analysis. Thus, keeping in mind, the similar efficacy and better cost-effectiveness of combination of csDMARDs, this should be the preferred strategy following failure of MTX monotherapy. bDMARDs should be reserved when combination csDMARDs fail, especially in an Indian scenario where most patients are poor and a majority of healthcare is not government-sponsored.

How to cite this article:
Zanwar A, Ahmed S, Misra DP, Agarwal V, Sharma A, Wakhlu A, Negi VS. Recent evidence comparing combination of conventional synthetic disease-modifying antirheumatic drugs with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.Indian J Rheumatol 2017;12:104-109

How to cite this URL:
Zanwar A, Ahmed S, Misra DP, Agarwal V, Sharma A, Wakhlu A, Negi VS. Recent evidence comparing combination of conventional synthetic disease-modifying antirheumatic drugs with biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Indian J Rheumatol [serial online] 2017 [cited 2020 Sep 27 ];12:104-109
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Full Text


Rheumatoid arthritis (RA) is a common, often disabling, inflammatory arthritis which requires therapy with disease modifying anti-rheumatic drugs (DMARDs) to reduce symptoms and retard radiographic progression. Commonly used DMARDs can be classified as conventional synthetic DMARDs (csDMARDs) such as methotrexate (MTX), leflunomide (LEF), sulfasalazine (SSZ) or hydroxychloroquine (HCQ); biologic DMARDs (bDMARDs) such as agents antagonistic to tumor necrosis factor alpha (anti-TNF agents– infliximab, etanercept, adalimumab, golimumab, certolizumab pegol), interleukin-6 receptor antagonist (tocilizumab), inhibitor of T lymphocyte activation (abatacept) or anti-B lymphocyte therapy (rituximab), and targeted synthetic DMARDs (tsDMARDs) such as tofacitinib or baricitinib. Most patients with RA are seropositive for rheumatoid factor or anti-citrullinated peptide antibodies and often have high disease activity at first presentation to the rheumatologist with the presence of erosions on joint radiographs, traditionally considered as poor prognostic factors. The recent recommendations for the management of RA from the European League against Rheumatism (EULAR) suggest initiation of biologic therapy should MTX monotherapy fail in patients with such poor prognostic factors, limiting the use of a combination of csDMARDs to those without poor prognostic factors.[1] Since the utilization of bDMARDs in preference to the combination of csDMARDs is associated with markedly higher costs, and hence, may have lesser feasibility in cost-constrained scenarios such as ours, we decided to review the recent literature addressing the efficacy of combination of csDMARDs versus bDMARDs.

Search strategy

The database MEDLINE was searched for clinical trials published after 2014 addressing treatment strategies comparing combination of csDMARDs with bDMARDs. In addition, few landmark clinical trials which had addressed this issue before and whose longer-term follow-up had been published during this period were included to provide a complete picture. These studies are discussed below and summarized in [Table 1].{Table 1}

 Results and Discussion

The Behandel-Strategieëen study [11] is considered as one of the cornerstone studies guiding the evidence-based management of RA. This study included 508 patients with RA with median disease duration of 23 weeks randomized to four different treatment strategies, i.e., sequential monotherapy (Group 1), step-up combination DMARD therapy (Group 2), upfront combination DMARD therapy with prednisolone (Group 3), and MTX with infliximab (Group 4). The target of therapy was a reduction in DAS44 score to ≤2.4 (low disease activity). Both Group 3 and Group 4 had similar functional status and radiographic progression at 1 year, superior to Groups 1 and 2, suggesting similar efficacy of combination csDMARDs with bDMARD. A 10-year follow-up of this study was recently published.[2] There was no difference between Groups 3 and 4 with respect to the proportion of patients in remission between years 2 and 10. None of the four groups differed from each other in Health assessment questionnaire (HAQ), radiographic progression, or mortality at 10 years. This study with a prolonged follow-up suggested that a strategy of combining csDMARDs was as good as utilizing bDMARDs even in the longer term.

The COBRA trial was one of the first trials to show the superiority of combining SSZ (2 g/day), MTX (7.5 mg/week) with prednisolone (60 mg/day tapered to 7.5 mg/day in 6 weeks) to SSZ monotherapy in terms of radiographic progression (at 28 weeks, 56 weeks and 80 weeks), and earlier attainment of lower disease activity by 28 weeks.[12] A recent trial compared the original COBRA strategy with the COBRA-light strategy (which utilized prednisolone at a lower initial dose of 30 mg/day, tapered to 7.5 mg/day by 9 weeks and MTX hiked to a dose of 25 mg/week by 9 weeks) in an open-label randomized controlled, noninferiority trial including 164 patients with RA.[3] This study revealed that the COBRA light regimen was noninferior to original COBRA regimen in terms of proportion of patients with minimal disease activity (utilizing DAS 44), HAQ scores, ACR20, ACR50, and ACR70 responses and EULAR good response at 26 weeks and 52 weeks. There was no significant difference in radiographic progression between the two groups at 52 weeks. This trial also used the addition of etanercept if patent did not achieve minimal disease activity (DAS 44 < 1.6) by 29/39 weeks inspite of cDMARD therapy. Fewer patients in the COBRA strategy required etanercept when compared to the COBRA-light regime (59% vs. 75%, P = 0.03). Despite the addition of etanercept, at the end of study period (52 weeks), there was reduction of 0.31 and 0.36 points in DAS44 score, which is minimal. In addition, similar DAS44 and HAQ scores were attained by those patients who received etanercept as compared to those who did not. This study highlights limited benefits attributable to addition of anti-TNF therapy after initial the failure of triple DMARDs.

The open-label Swedish SWEFOT study randomized 487 patients with RA (mean disease duration 6.2 months) with moderate disease activity (DAS28 >3.2) after 3–4 months of therapy with MTX 20 mg/week to either triple cDMARD therapy (MTX + SSZ + HCQ) or MTX plus infliximab. Although the proportion of patients attaining EULAR good response was more in the infliximab arm at 1 year,[13] this difference did not exist any more at 2 years.[4] Higher radiographic progression was observed at the end of the first as well as the 2nd year in those patients receiving csDMARDs when compared with infliximab (difference in mean Sharp Van der Heijde score of 3.23). The POPeRA study [14] analyzed the reduction of projected radiographic progression in the same patients. It suggested that the patient in infliximab arm had marginally superior (2.5%) reduction of predicted progression. This small amount of radiographic progression is unlikely to be clinically meaningful although achieving statistical significance. In addition, another analysis of the cost-effectiveness of both SWEFOT strategies [5] suggested that there is significantly higher healthcare and societal cost in the group treated with infliximab compared to that receiving combination of csDMARDs.

The NEO-RACo [6] was a double-blind placebo-controlled study which randomized 99 DMARD naïve patients with RA (median disease duration of 4 months) to receive infliximab or placebo injection in addition to triple therapy (MTX + SSZ + HCQ) for 6 months. When followed up over 5 years, both groups had similar proportion of patients attaining ACR remission and DAS28 remission as well as similar HAQ scores and radiographic progression. This again suggested that an approach utilizing a combination of csDMARDs was as effective as that using bDMARDs.

The TACIT trial [7] was an open-label, pragmatic, randomized multicenter, noninferiority study assessing disability index using HAQ at 12 months. Totally, 205 patients who had persistently high DAS28 score >5.1 twice 1 month apart, inspite of therapy with MTX and another DMARD (thereby fulfilling the NICE guidelines for initiation of anti-TNF therapy in the UK) were randomized to either addition of anti-TNF agents or combination of csDMARDs. There was no difference in median HAQ with anti-TNF agents when compared with triple DMARD therapy at 12 months, with similar results noted in the secondary outcome measures of quality of life and progression of erosions. Moreover, the strategy of combining csDMARDs was associated with significantly lesser costs when compared with anti-TNF agents, indicating the cost-effectiveness of combination csDMARDs versus biologics with similar efficacy.

The IMPROVED study [8] was a randomized single-blinded clinical trial which assessed the efficacy of combination of csDMARDs (MTX, SSZ, HCQ with prednisolone) with MTX and adalimumab in 610 patients (479 with RA and 121 with undifferentiated arthritis) failing to attain DAS44 <1.6 in spite of MTX and oral corticosteroids (60 mg prednisolone/day tapered to 7.5 mg/day by 7 weeks) for 4 months. The proportion of patient achieving remission and drug-free remission at 24 months was similar between the two groups, with similar control of disease activity and retardation of radiographic progression, again suggesting that combining csDMARDs is no less effective than the addition of bDMARDs. Another study secondarily analyzed data of Asian and Latin American patients with RA included in the APPEAL and Latin RA studies [9] to assess whether those receiving a combination of etanercept with MTX (n = 478) fared differently from those receiving one of LEF, SSZ, or HCQ in combination with MTX (n = 245). The approach of using etanercept was better at 16 weeks in those with disease duration more than 2 years and high disease activity (DAS28 >5.1) at study inclusion, but similar in those with disease up to 2 years or with moderate disease activity (DAS28 3.2–5.1). This reiterates the findings of the SWEFOT study wherein those receiving bDMARDs attained earlier control of disease activity. What merits consideration is whether it is really clinically useful to attain such rapid control of disease activity with significantly greater costs when numerous studies discussed above have shown similar longer-term functional and radiologic outcomes irrespective of whether combination of csDMARDs or bDMARDs has been used.

A recently published meta-analyses of randomized controlled trials addressing the utility of csDMARDs with or without anti-TNF agents [15] reaffirmed that either strategy did not differ with respect to radiographic progression at 1 or 2 years. Whereas better clinical outcomes (ACR 50, ACR 70) and lesser radiographic progression at 6 months were observed in those receiving anti-TNF agents, these differences ceased to exist at 2 years. Indeed, another recent study, the OPERA study, which was a randomized, double-blind placebo-controlled study comparing addition of adalimumab versus placebo in 85 patients with RA on a background of MTX and intra-articular triamcinolone, showed similar reduction in modified Sharp Van der Heijde scores in both arms over 12 months. When MRI was assessed using the RAMRIS score, both groups showed a significant reduction in synovitis, tenosynovitis, and osteitis scores over 12 months irrespective of whether adalimumab was added or not.[10]


Our review of the recent literature reaffirms [16] the fact that combination of csDMARDs is not inferior to bDMARDs in terms of control of disease activity and improvement of physical function over the longer term. Whereas some literature may suggest a better retardation of radiographic progression in those receiving bDMARDs, this fact must be tempered by the clinically insignificant, small magnitude of change in radiographic progression as well as the inability to demonstrate a significant difference in this progression after 2 years of treatment in a meta-analysis. Use of csDMARDs in combination is also much more cost-effective than bDMARDs.

Keeping these facts in mind, one must judiciously interpret the recent EULAR recommendations for the management of RA,[1] especially in a resource-constrained scenario like that in India. Using bDMARDs would not only be associated with a huge financial burden on the health-care system in a low/middle-income country but also is associated with higher infection risks.[17] Hence, the authors suggest that the cost-effective yet comparably efficacious strategy of combining csDMARDs should be utilized in those patients with RA failing MTX monotherapy, irrespective of poor prognostic factors. bDMARDs should be reserved for those failing a combination of csDMARDs. Indeed, such a strategy suggesting an equivalence of combination of csDMARDs with bDMARDs following MTX monotherapy has been lent credence by guidelines from other societies worldwide.[18],[19] Our review of literature also exemplifies the need to develop pragmatic guidelines for the management of rheumatic diseases, including RA, which suitably resonate with the biological and socioeconomic diversity of the Indian subcontinent.

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Conflicts of interest

There are no conflicts of interest.


1Smolen JS, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017. pii: Annrheumdis-2016-210715.
2Markusse IM, Akdemir G, Dirven L, Goekoop-Ruiterman YP, van Groenendael JH, Han KH, et al. Long-term outcomes of patients with recent-onset rheumatoid arthritis after 10 years of tight controlled treatment: A randomized trial. Ann Intern Med 2016;164:523-31.
3ter Wee MM, den Uyl D, Boers M, Kerstens P, Nurmohamed M, van Schaardenburg D, et al. Intensive combination treatment regimens, including prednisolone, are effective in treating patients with early rheumatoid arthritis regardless of additional etanercept: 1-year results of the COBRA-light open-label, randomised, non-inferiority trial. Ann Rheum Dis 2015;74:1233-40.
4van Vollenhoven RF, Geborek P, Forslind K, Albertsson K, Ernestam S, Petersson IF, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet 2012;379:1712-20.
5Eriksson JK, Karlsson JA, Bratt J, Petersson IF, van Vollenhoven RF, Ernestam S, et al. Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial. Ann Rheum Dis 2015;74:1094-101.
6Rantalaiho V, Kautiainen H, Korpela M, Hannonen P, Kaipiainen-Seppänen O, Möttönen T, et al. Targeted treatment with a combination of traditional DMARDs produces excellent clinical and radiographic long-term outcomes in early rheumatoid arthritis regardless of initial infliximab. The 5-year follow-up results of a randomised clinical trial, the NEO-RACo trial. Ann Rheum Dis 2014;73:1954-61.
7Scott DL, Ibrahim F, Farewell V, O'Keeffe AG, Walker D, Kelly C, et al. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial. BMJ 2015;350:h1046.
8Heimans L, Akdemir G, Boer KV, Goekoop-Ruiterman YP, Molenaar ET, van Groenendael JH, et al. Two-year results of disease activity score (DAS)-remission-steered treatment strategies aiming at drug-free remission in early arthritis patients (the IMPROVED-study). Arthritis Res Ther 2016;18:23.
9Fleischmann R, Koenig AS, Szumski A, Nab HW, Marshall L, Bananis E. Short-term efficacy of etanercept plus methotrexate vs. combinations of disease-modifying anti-rheumatic drugs with methotrexate in established rheumatoid arthritis. Rheumatology (Oxford) 2014;53:1984-93.
10Axelsen MB, Eshed I, Hørslev-Petersen K, Stengaard-Pedersen K, Hetland ML, Møller J, et al. A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: Results from the OPERA randomised controlled trial. Ann Rheum Dis 2015;74:867-75.
11Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, 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.
12Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:309-18.
13van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Cöster L, Waltbrand E, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet 2009;374:459-66.
14Levitsky A, Forslind K, van Vollenhoven RF; SWEFOT Trial Group. Predicted vs. observed radiographic progression in early rheumatoid arthritis (POPeRA): Results from a randomized trial. Scand J Rheumatol 2015;44:348-53.
15Graudal N, Hubeck-Graudal T, Faurschou M, Baslund B, Jürgens G. Combination therapy with and without tumor necrosis factor inhibitors in rheumatoid arthritis: A meta-analysis of randomized trials. Arthritis Care Res (Hoboken) 2015;67:1487-95.
16Parida JR, Misra DP, Wakhlu A, Agarwal V. Is non-biological treatment of rheumatoid arthritis as good as biologics? World J Orthop 2015;6:278-83.
17Misra DP, Agarwal V, Sharma A, Wakhlu A, Negi VS. 2016 update of the EULAR recommendations for the management of rheumatoid arthritis: A utopia beyond patients in low/middle income countries? Ann Rheum Dis 2017. pii: Annrheumdis-2017-211446.
18Singh JA, Saag KG, Bridges SL Jr., Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2016;68:1-26.
19Pirilä L, Sokka T, Kauppi MJ, Rantalaiho VM, Mervaala E, Puolakka K. Alternative interpretation of data for recommendations on how to manage rheumatoid arthritis. Ann Rheum Dis 2017. pii: Annrheumdis-2017-211505.