Rheumatoid arthritis (RA), a progressive and painful systemic inflammatory disease that preferentially attacks the synovium of the joint, affects approximately 1% of the adults around the world.1 In the last several decades, the availability of targeted biological and synthetic disease-modifying antirheumatic drugs (DMARDs), along with an emphasis on early intensive therapy and tight disease control, has led to remarkable reductions in RA disease severity, extra-articular manifestations, RA-related joint surgeries, and radiographic progression.2,3 In the current guidelines-based RA treatment paradigm, a conventional synthetic (cs) DMARD (preferably methotrexate) is used in the first line, and biological (b) DMARDs and targeted synthetic (ts) DMARDs are used in patients who continue to experience moderate or high disease activity despite csDMARD treatment.4,5 The vast majority of patients who require targeted therapy after csDMARD failure receive a tumor necrosis factor (TNF) inhibitor.6 However, an estimated 30% to 40% of patients treated with TNF inhibitors do not respond adequately, do not sustain response over time, or experience adverse events leading to discontinuation.7 Strategies for addressing treatment failure with TNF inhibitors include switching to an alternate TNF inhibitor (known as “switching” or “cycling”) or moving to a different class of targeted agents with an alternative mechanism of action (“swapping”).8 Although using another TNF inhibitor may seem counterintuitive, randomized controlled trials have demonstrated that this strategy is effective in producing a clinical response.5,9,10

Despite numerous studies and meta-analyses examining differences in outcomes, uncertainty remains as to whether cycling or swapping is optimal. In the first clinical trial to compare the efficacy of these approaches, patients who did not respond adequately to a TNF inhibitor were randomly assigned to receive a nonTNF-targeted biologic agent or a TNF inhibitor that differed from their previous treatment.

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Results demonstrated that patients who were swapped to a nonTNF biologic agent had greater improvement in disease activity than those switched to another TNF inhibitor.9 In addition, several analyses have evinced that among patients with RA who were using a TNF inhibitor and then required a switch in therapy, switching to a targeted agent with a different mechanism was associated with better treatment persistence than cycling to another TNF inhibitor.7,11,12 However, some studies have found equivalence between the strategies, using other measures.7

Recommendations from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) on what to do after treatment failure with TNF inhibitors diverge. The ACR recommends swapping to an agent with an alternative mechanism if the disease remains active despite the use of a single TNF inhibitor, whereas EULAR states that after failure of a single TNF inhibitor, treatment can be switched to a nonTNF-targeted agent or a second TNF inhibitor.4,5 In an interview with Rheumatology Advisor, Aliza Karpes Matusevich, BSN, MPH, PhD, outcomes research fellow at the University of North Texas Health Science Center at Fort Worth and coauthor of a recent meta-analysis that concluded that both strategies were equally effective in improving patient-reported functional disability,13 noted that the evidence supporting each organization’s recommendations differs. “The ACR guidelines are based on evidence from registry data, but they acknowledge that the strength of the evidence is of low quality and that further research will likely impact the confidence of the results,” she noted. “The EULAR guidelines are based on evidence from prospective studies in which no differences were found between the 2 types of strategies, and they also acknowledge the limitations of registry data.”

In a recent review, Andrea Rubbert-Roth, MD, from the University of Cologne, Germany, and colleagues evaluated the pros and cons of choosing a second TNF inhibitor after the failure of the first vs moving on early to a bDMARD or tsDMARD with an alternate mechanism of action. The authors concluded that although switching or swapping both represent reasonable options of treating patients with RA who are resistant to or intolerant of anti-TNF agents, most observational studies suggest that swapping represents a superior strategy. However, the researchers noted that switching to a second TNF inhibitor is generally successful in patients who have experienced loss of efficacy as a result of anti-drug antibodies, and that a second TNF inhibitor might be considered when other agents are contraindicated because of comorbidities.7

Dr. Matusevich told Rheumatology Advisor that further research is needed to determine optimal approaches. “There is still uncertainty regarding how the different reasons for discontinuation of the first TNF inhibitor, for example, adverse events, primary failure or secondary failure, may impact responses to different second biologic or targeted agents. The effects of agent-specific neutralizing antibodies could also influence response. Also, more data regarding the patient-level characteristics that may influence subsequent treatment outcomes, such as biomarkers or specific comorbidities, are needed.”

References

1. Gibofsky A. Epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis: A Synopsis. Am J Manag Care. 2014;20:s128-145.

2. Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320(13):1360-1372.

3. Minichiello E, Semerano L, Boissier M-C. Time trends in the incidence, prevalence, and severity of rheumatoid arthritis: A systematic literature review. Joint Bone Spine. 2016;83(6):625-630.

4. Singh JA, Saag KG, Bridges SL, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol (Hoboken, NJ). 2016;68(1):1-26.

5. Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.

6. Jin Y, Desai RJ, Liu J, Choi N-K, Kim SC. Factors associated with initial or subsequent choice of biologic disease-modifying antirheumatic drugs for treatment of rheumatoid arthritis. Arthritis Res Ther. 2017;19(1):159.

7. Rubbert-Roth A, Szabó MZ, Kedves M, Nagy G, Atzeni F, Sarzi-Puttini P. Failure of anti-TNF treatment in patients with rheumatoid arthritis: The pros and cons of the early use of alternative biological agents. Autoimmun Rev. 2019;18(12):102398.

8. Favalli EG, Biggioggero M, Marchesoni A, Meroni PL. Survival on treatment with second-line biologic therapy: a cohort study comparing cycling and swap strategies. Rheumatology. 2014;53(9):1664-1668.

9. Gottenberg J-E, Brocq O, Perdriger A, et al. Non-TNF-targeted biologic vs a second anti-tnf drug to treat rheumatoid arthritis in patients with insufficient response to a first anti-TNF drug: a randomized clinical trial. JAMA. 2016;316(11):1172-1180.

10. Schiff MH, von Kempis J, Goldblum R, Tesser JR, Mueller RB. Rheumatoid arthritis secondary non-responders to TNF can attain an efficacious and safe response by switching to certolizumab pegol: a phase IV, randomised, multicentre, double-blind, 12-week study, followed by a 12-week open-label phase. Ann Rheum Dis. 2014;73(12):2174-2177.

11. Chastek B, Chen C-I, Proudfoot C, Shinde S, Kuznik A, Wei W. Treatment persistence and healthcare costs among patients with rheumatoid arthritis changing biologics in the USA. Adv Ther. 2017;34(11):2422-2435.

12. Bonafede MMK, McMorrow D, Proudfoot C, Shinde S, Kuznik A, Chen C-I. Treatment persistence and healthcare costs among patients with rheumatoid arthritis after a change in targeted therapy. Am Health Drug Benefits. 2018;11(4):192-202.

13. Lopez-Olivo MA, Matusevich A, Cantor SB, Pratt G, Suarez-Almazor M. The comparative effectiveness of cycling tumor necrosis factor inhibitor (TNFi) versus swapping to a nontnfi on patient-reported functional ability of patients with rheumatoid arthritis [abstract]. Arthritis Rheumatol. 2018;70(suppl 10). Abstract 626.