The use of disease-modifying antirheumatic drugs (DMARDs) and the adoption of an early and aggressive treatment strategy have transformed the outcomes of patients with rheumatoid arthritis (RA). These immunosuppressive and immunomodulatory agents are essential to the comprehensive RA treatment strategy, with an objective of achieving disease remission or sustained minimal disease activity, to prevent radiographic progression.1
The DMARDs currently available are broadly categorized as conventional synthetic DMARDs (csDMARDs) and biologic DMARDs (bDMARDs). Conventional synthetic DMARDs typically include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide, and are generally used in the first-line setting.2 Several bDMARDs are approved for RA in 6 therapeutic classes, including tumor necrosis factor inhibitors (etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab); T-cell costimulatory blocking agent (abatacept); B-cell depleting agents (rituximab); interleukin-1 receptor antagonists (anakinra); interleukin(IL)-6 inhibitors (tocilizumab and sarilumab); and Janus kinase inhibitors (JAK; tofacitinib, baricitinib, and upadacitinib).3 Biosimilars, a highly similar copy of the original approved biologic agent, with no clinically meaningful differences in safety, purity, and potency, has expanded the options of bDMARDs.4 In general, bDMARDs are prescribed after the failure of first-line csDMARD therapy.
The most commonly used csDMARD in the first-line setting is methotrexate. When RA progresses despite treatment with csDMARDs, a bDMARD may be introduced as monotherapy, typically in combination with a csDMARD, such as methotrexate. In cases of disease progression, despite treatment with methotrexate and bDMARDs, clinicians are faced with an increasingly challenging choice of treatment selection to achieve optimal disease management. Over time, 2 key questions have emerged: the comparative effectiveness of bDMARD monotherapy vs the combination of a bDMARD with methotrexate, and the comparative effectiveness of the available bDMARD either as monotherapy or in combination with methotrexate. The importance of these questions may be related to treatment efficacy and safety, given the diverse RA patient population among whom approximately one-third are treated with bDMARD monotherapy, primarily because of intolerance or noncompliance with methotrexate.5
Biologic DMARD Monotherapy vs Combination With Methotrexate
The comparative effectiveness of bDMARD vs methotrexate monotherapy has been addressed in several studies. Overall, the superiority of bDMARD vs methotrexate monotherapy has been established for all 6 classes of bDMARDs, particularly in the setting of disease progression with methotrexate.6-9
With respect to the comparative effectiveness of bDMARD monotherapy vs combination with methotrexate, available studies have shown that some bDMARDs were more efficacious in combination with methotrexate, others as efficacious as either monotherapy or in combination, and the evidence for other DMARDs were less clear.
Specifically, the superiority of the efficacy of bDMARDs in combination with methotrexate compared to bDMARD monotherapy has been evident for tumor necrosis factor inhibitors (TNFis), but not non-TNFis.5,8 Both abatacept and tocilizumab have showed effectiveness whether combined with methotrexate or used as monotherapy.5,8,10 The effectiveness of rituximab as monotherapy compared to combination with methotrexate has been less clear, with some studies reporting superior efficacy as a combination,11-13 although the effectiveness either as monotherapy or in combination with methotrexate has also been reported.14 The use of tofacitinib in RA has been inconclusive because of lack of available data.5,15 Taken together, the evidence suggests that the currently available bDMARDs vs methotrexate monotherapy achieve greater control of disease activity. However, the combination of a bDMARD with methotrexate may be more efficacious than bDMARD monotherapy for anti-TNF agents, comparable for tocilizumab and abatacept, and inconclusive for rituximab, tofacitinib, and anakinra because of paucity of studies and data.
Choice of bDMARD Therapy: Overcoming the Limitations of Clinical Data
While it has been established that bDMARDs vs methotrexate may be more efficacious in disease control, the choice of available bDMARDs can be challenging because of the lack of head-to-head comparative studies and the limited data for use of these agents. The majority of the studies that have evaluated the comparative effectiveness of bDMARDs have concluded that anakinra may be the least efficacious.16 Furthermore, the American College of Rheumatology (ACR) response was found to be higher with tocilizumab compared to a TNFi or the JAK inhibitor tofacitinib.5 Among the TNFi agents, etanercept has been reported to be the most efficacious and infliximab the least.16,17 In combination with methotrexate, excluding anakinra, available data suggest comparable efficacy across the bDMARDs evaluated.10,18
A meaningful comparative effectiveness analysis of bDMARDs has been challenged by several limitations that question the accuracy of the comparisons.3 In many cases, there are variations in study design and clinical end points. Furthermore, available data may not be comparable for all agents; for example, there is fewer data for the newer approved agents such as the JAK inhibitors. Data has typically included heterogeneous, selected patient populations, with outdated definitions of clinical end points of clinical remission and low disease activity. Furthermore, in the absence of head-to-head studies, an indirect comparison of trial findings has often resulted in inconclusive analyses challenging clinical decision-making.
A recent systematic review and network meta-analysis by Janke et al provides a more rigorous comparative effectiveness analysis of the approved bDMARDs, using a method that included data from clinical study reports and reanalyses from individual patient data on key outcomes for RA, adopting the current definitions of clinical end points.3 This approach enabled a more homogeneous patient population for comparative analysis. The 34 studies that met the criteria for comparative effectiveness analyses included 10,869 patients and investigated 8 different biologic agents in combination with methotrexate (etanercept, adalimumab, infliximab, certolizumab pegol, golimumab, anakinra, abatacept, and tocilizumab). However, the analysis did not include rituximab, or the more recently approved agents such as sarilumab, tofacitinib, baricitinib, and upadacitinib. Overall, as reported in previous studies, there were few statistically significant differences between the bDMARDs in combination with methotrexate in terms of benefits and harms.
Researchers found that anakinra was the least efficacious in clinical remission or low disease activity3; compared to anakinra, adalimumab, certolizumab pegol, and golimumab had statistically significant advantages for RA remission, and abatacept, adalimumab, infliximab, and tocilizumab were found to have statistically significant advantages for low disease activity.3 Regarding safety, certolizumab pegol had a higher risk for serious adverse events (compared to abatacept, adalimumab, anakinra, etanercept, and infliximab) and infections (compared to abatacept, anakinra, etanercept, golimumab, tocilizumab, and infliximab). The risk for serious infections was higher with infliximab compared to golimumab and tocilizumab. The discontinuation rate due to adverse events was higher for anakinra compared to abatacept, adalimumab, etanercept and infliximab, and higher for abatacept compared to tocilizumab.3 Despite the rigorous methodology of this study, the authors acknowledged the limited data for long-term direct comparisons between the bDMARDs, with a recommendation for routine availability of individual patient data.
Implications for Clinical Practice
Although the expansion of bDMARDs provides improved treatment options, selecting treatment for the optimal disease management has been challenging because of the limited robust comparative effectiveness studies available.
The recent rigorous study by Janke and colleagues suggest a small but statistically significant differences in disease remission, and serious adverse events between the biologic agents. From a clinical decision standpoint, it is important to individualize treatment, taking into consideration disease activity, comorbidities, and patient treatment preferences, while weighing the significance of the differences between the bDMARDs for disease management and outcomes.
- Nikiphorou E, Norton SJ, Carpenter L, et al. Remission vs low disease activity: function, quality of life and structural outcomes in the Early Rheumatoid Arthritis Study and Network. Rheumatology (Oxford). 2020;59(6):1272-1280.
- Benjamin O, Bansal P, Goyal A, et al. Disease modifying anti-rheumatic drugs (DMARD). In: StatPearls [Internet]. StatPearls Publishing; 2020.
- Janke K, Biester K, Krause D, et al. Comparative effectiveness of biological medicines in rheumatoid arthritis: Systematic review and network meta-analysis including aggregate results from reanalysed individual patient data. BMJ. 2020;370:m2288.
- Arthritis Foundation. Biosimilars: What you should know. Accessed August 2, 2020. https://www.arthritis.org/drug-guide/medication-topics/biosimilars-an-alternative-to-biologics
- Buckley F, Finckh A, Huizinga TW, Dejonckheere F, Jansen JP. Comparative efficacy of novel DMARDs as monotherapy and in combination with methotrexate in rheumatoid arthritis patients with inadequate response to conventional DMARDs: a network meta-analysis. J Manag Care Spec Pharm. 2015;21(5):409-423.
- Taylor A, Jones G. Biologic monotherapy for the treatment of rheumatoid arthritis. Clin. Invest. 2011;1(9): 1291-1300.
- Alfonso-Cristancho R, Armstrong N, Arjunji R, et al. Comparative effectiveness of biologics for the management of rheumatoid arthritis: systematic review and network meta-analysis. Clin Rheumatol. 2017;36(1):25-34.
- Donahue KE, Schulman ER, Gartlehner G, et al. Comparative effectiveness of combining mtx with biologic drug therapy versus either mtx or biologics alone for early rheumatoid arthritis in adults: a systematic review and network meta-analysis. J Gen Intern Med [published correction in J Gen Intern Med; May 2020]. 2019;34(10):2232-2245.
- Cohen SB, Moreland LW, Cush JJ, et al. A multicentre, double blind, randomised, placebo controlled trial of anakinra (Kineret), a recombinant interleukin 1 receptor antagonist, in patients with rheumatoid arthritis treated with background methotrexate. Ann Rheum Dis. 2004;63(9):1062-1068.
- Choy E, Aletaha D, Behrens F, et al. Monotherapy with biologic disease-modifying anti-rheumatic drugs in rheumatoid arthritis. Rheumatology (Oxford). 2017;56(5):689-697.
- Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004;350(25):2572-2581.
- Cohen MD, Keystone E. Rituximab for rheumatoid arthritis. Rheumatol Ther. 2015; 2(2): 99-111.
- Mok CC. Rituximab for the treatment of rheumatoid arthritis: an update. Drug Des Devel Ther. 2013;8:87-100.
- Wendler J, Burmester GR, Sörensen H, et al. Rituximab in patients with rheumatoid arthritis in routine practice (GERINIS): six-year results from a prospective, multicentre, non-interventional study in 2,484 patients. Arthritis Res Ther. 2014;16(2):R80.
- Emery P, Pope JE, Kruger K, et al. Efficacy of monotherapy with biologics and JAK inhibitors for the treatment of rheumatoid arthritis: a systematic review. Adv Ther. 2018;35(10):1535-1563.
- Silvagni E, Bortoluzzi A, Carrara G, Zanetti A, Govoni M, Scirè CA. Comparative effectiveness of first-line biological monotherapy use in rheumatoid arthritis: a retrospective analysis of the RECord-linkage On Rheumatic Diseases study on health care administrative databases. BMJ Open. 2018;8(9):e021447.
- Yun H, Xie F, Delzell E, et al. The comparative effectiveness of biologics among older adults and disabled rheumatoid arthritis patients in the Medicare population. Br J Clin Pharmacol. 2015;80(6):1447-1457.
- Jansen JP, Buckley F, Dejonckheere F, Ogale S. Comparative efficacy of biologics as monotherapy and in combination with methotrexate on patient reported outcomes (PROs) in rheumatoid arthritis patients with an inadequate response to conventional DMARDs–a systematic review and network meta-analysis. Health Qual Life Outcomes. 2014;12:102.