'Difficult to treat' rheumatoid arthritis: current position and considerations for next steps

Yvonne Tan, Maya H Buch, Yvonne Tan, Maya H Buch

Abstract

The European Alliance of Associations for Rheumatology recently defined difficult to treat (D2T) rheumatoid arthritis (RA) and provided points to consider in its management. This review summarises the key concepts of D2T-RA that underpinned this recent guidance. D2T-RA is primarily characterised by failure of at least two different mechanism of action biologic/targeted synthetic disease-modifying antirheumatic drug (DMARDs) with evidence of active/progressive disease. The basis for progressive disease, however, is not limited to clear inflammatory joint pathology, capturing wider contributors to treatment cycling such as comorbidity, obesity and fibromyalgia. This means D2T-RA comprises a heterogeneous population, with a proportion within this exhibiting bona fide treatment-refractory disease. The management points to consider, however, emphasise the importance of checking for the presence of inflammatory pathology before further treatment change. This review suggests additional considerations in the definition of D2T-RA, the potential value in identifying D2T traits and intervening before the development of D2T-RA state and the need for real world evidence of targeted synthetic DMARD in this population to compare to recent trial data. Finally, the review asks whether the presence of D2T-RA implies a failure to treat effectively from the outset, and the need for pharmacological and non-pharmacological management approaches to address the wider D2T-RA population effectively.

Keywords: biological therapy; rheumatoid arthritis; therapeutics.

Conflict of interest statement

Competing interests: MHB is supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre and is in receipt of an NIHR Senior Investigator award.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
EULAR definition of difficult-to-treat rheumatoid arthritis (D2T-RA). EULAR, European Alliance of Associations for Rheumatology.
Figure 2
Figure 2
Postulated opportunity for interventions to address difficult to treat traits early to modify a D2T-RA course. RA, rheumatoid arthritis.
Figure 3
Figure 3
D2T (or challenging) traits, development of a D2T course and the presence of refractory RA.
Figure 4
Figure 4
Factors to consider in the definition of difficult to treat rheumatoid arthritis.
Figure 5
Figure 5
The multiple contributors to a difficult to treat rheumatoid arthritis state.

References

    1. Smolen JS, Landewé RBM, Bijlsma JWJ, et al. . EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020;79:685–99. 10.1136/annrheumdis-2019-216655
    1. Nagy G, Roodenrijs NM, Welsing PM, et al. . EULAR definition of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2021;80:31–5. 10.1136/annrheumdis-2020-217344
    1. Roodenrijs NMT, Welsing PMJ, van der Goes MC, et al. . Healthcare utilization and economic burden of difficult-to-treat rheumatoid arthritis: a cost-of-illness study. Rheumatology 2021;60:4681–90. 10.1093/rheumatology/keab078
    1. Roodenrijs NMT, de Hair MJH, van der Goes MC, et al. . Characteristics of difficult-to-treat rheumatoid arthritis: results of an international survey. Ann Rheum Dis 2018;77:77. 10.1136/annrheumdis-2018-213687
    1. Kearsley-Fleet L, Davies R, De Cock D, et al. . Biologic refractory disease in rheumatoid arthritis: results from the British Society for rheumatology biologics register for rheumatoid arthritis. Ann Rheum Dis 2018;77:1405–12. 10.1136/annrheumdis-2018-213378
    1. Li H, Zhu H, Xu L, Xue J, et al. . The characteristics and its contributing factors of refractory rheumatoid arthritis, view of the rheumatologists of China: results of a nationwide cross-sectional survey. Clin Rheumatol 2021;40:4029–38. 10.1007/s10067-021-05687-7
    1. Cuppen BVJ, Welsing PMJ, Sprengers JJ, et al. . Personalized biological treatment for rheumatoid arthritis: a systematic review with a focus on clinical applicability. Rheumatology 2016;55:826–39. 10.1093/rheumatology/kev421
    1. de Hair MJH, Jacobs JWG, Schoneveld JLM, et al. . Difficult-To-Treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology 2018;57:1135–44. 10.1093/rheumatology/kex349
    1. Roodenrijs NMT, van der Goes MC, Welsing PMJ, et al. . Difficult-To-Treat rheumatoid arthritis: contributing factors and burden of disease. Rheumatology 2021;60:3778–88. 10.1093/rheumatology/keaa860
    1. Nagy G, Roodenrijs NMT, Welsing PMJ, et al. . EULAR points to consider for the management of difficult-to-treat rheumatoid arthritis. Ann Rheum Dis 2022;81:20–33. 10.1136/annrheumdis-2021-220973
    1. Ciurtin C, Jones A, Brown G, et al. . Real benefits of ultrasound evaluation of hand and foot synovitis for better characterisation of the disease activity in rheumatoid arthritis. Eur Radiol 2019;29:6345–54. 10.1007/s00330-019-06187-8
    1. Levitsky A, Brismar K, Hafström I, et al. . Obesity is a strong predictor of worse clinical outcomes and treatment responses in early rheumatoid arthritis: results from the SWEFOT trial. RMD Open 2017;3:e000458. 10.1136/rmdopen-2017-000458
    1. Roodenrijs NMT, Kedves M, Hamar A, et al. . Diagnostic issues in difficult-to-treat rheumatoid arthritis: a systematic literature review Informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis. RMD Open 2021;7:e001511. 10.1136/rmdopen-2020-001511
    1. Roodenrijs NMT, Hamar A, Kedves M, et al. . Pharmacological and non-pharmacological therapeutic strategies in difficult-to-treat rheumatoid arthritis: a systematic literature review Informing the EULAR recommendations for the management of difficult-to-treat rheumatoid arthritis. RMD Open 2021;7:e001512. 10.1136/rmdopen-2020-001512
    1. Smolen JS. Update of the EULAR recommendations on the management of rheumatoid arthritis. EULAR congress 2022; 01/06/2022, 2022.
    1. Takanashi S, Kaneko Y, Takeuchi T. Characteristics of patients with difficult-to-treat rheumatoid arthritis in clinical practice. Rheumatology 2021;60:5247–56. 10.1093/rheumatology/keab209
    1. Batko B, Urbański K, Świerkot J, et al. . Comorbidity burden and clinical characteristics of patients with difficult-to-control rheumatoid arthritis. Clin Rheumatol 2019;38:2473–81. 10.1007/s10067-019-04579-1
    1. Buch MH, Eyre S, McGonagle D. Persistent inflammatory and non-inflammatory mechanisms in refractory rheumatoid arthritis. Nat Rev Rheumatol 2021;17:17–33. 10.1038/s41584-020-00541-7
    1. Avina-Zubieta JA, Thomas J, Sadatsafavi M, et al. . Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis 2012;71:1524–9. 10.1136/annrheumdis-2011-200726
    1. Tian Z, Mclaughlin J, Verma A, et al. . The relationship between rheumatoid arthritis and diabetes mellitus: a systematic review and meta-analysis. Cardiovasc Endocrinol Metab 2021;10:125–31. 10.1097/XCE.0000000000000244
    1. Antin-Ozerkis D, Evans J, Rubinowitz A, et al. . Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med 2010;31:451–78. 10.1016/j.ccm.2010.04.003
    1. Hua C, Buttgereit F, Combe B. Glucocorticoids in rheumatoid arthritis: current status and future studies. RMD Open 2020;6:e000536. 10.1136/rmdopen-2017-000536
    1. Crossfield SSR, Buch MH, Baxter P, et al. . Changes in the pharmacological management of rheumatoid arthritis over two decades. Rheumatology 2021;60:4141–51. 10.1093/rheumatology/keaa892
    1. Genovese MC, Kremer J, Zamani O, et al. . Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 2016;374:1243–52. 10.1056/NEJMoa1507247
    1. Genovese MC, Kalunian K, Gottenberg J-E, et al. . Effect of Filgotinib vs placebo on clinical response in patients with moderate to severe rheumatoid arthritis refractory to disease-modifying antirheumatic drug therapy: the finch 2 randomized clinical trial. JAMA 2019;322:315–25. 10.1001/jama.2019.9055
    1. Lee YH, Bae S-C. Comparative efficacy and safety of tocilizumab, rituximab, abatacept and tofacitinib in patients with active rheumatoid arthritis that inadequately responds to tumor necrosis factor inhibitors: a Bayesian network meta-analysis of randomized controlled trials. Int J Rheum Dis 2016;19:1103–11. 10.1111/1756-185X.12822
    1. Singh JA, Hossain A, Tanjong Ghogomu E, et al. . Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis. Cochrane Database Syst Rev 2017;3:CD012591. 10.1002/14651858.CD012591
    1. Ytterberg SR, Bhatt DL, Mikuls TR, et al. . Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med 2022;386:316–26. 10.1056/NEJMoa2109927
    1. Dougados M, Charles-Schoeman C, Szekanecz Z. OP0264 impact of baseline cardiovascular risk on the incidence of major adverse cardiovascular events in the tofacitinib rheumatoid arthritis clinical programme. Annals of the Rheumatic Diseases 2022;81:175.
    1. Rivellese F, Surace AEA, Goldmann K, et al. . Rituximab versus tocilizumab in rheumatoid arthritis: synovial biopsy-based biomarker analysis of the phase 4 R4RA randomized trial. Nat Med 2022. 10.1038/s41591-022-01789-0. [Epub ahead of print: 19 May 2022].

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe