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ACR/ARP 2020: New Data on Optimizing Use of IL-6 Inhibitors

William F. C. Rigby, MD

Vice Chair, Department of Medicine
Professor of Medicine, Microbiology and Immunology
Rheumatology Section
The Geisel School of Medicine at Dartmouth
Lebanon, New Hampshire

William F. C. Rigby, MD, has disclosed that he has received funds for contracted research from AbbVie, BMS, Gilead, and Lilly; and consulting fees from AbbVie, BMS, and Gilead.

View ClinicalThoughts from this Author

Released: December 4, 2020

At the 2020 virtual ACR/ARP Convergence, the international rheumatology community shared new data with important clinical implications for treating patients with rheumatoid arthritis (RA). In this commentary, I focus on 2 key studies of IL-6 inhibitors—tocilizumab and sarilumab—that shed new light on our understanding of RA and its treatment.

Tocilizumab Responses by Pathotype
In the last 3 decades, there has been tremendous growth in our understanding and treatment of RAThe recognition of anti-citrullinated protein antibodies as an autoantibody that is strongly linked to the onset of RA has brought about recognition that RA does not arise in the synovial joints that are the ultimate targets of morbidity.

Rather, the best evidence suggests that the breaking of immune tolerance occurs in the respiratory tract due to genetic (shared epitope) and environmental (tobacco smoking) factors. Systemic autoimmunity results, but synovial disease occurs years, if not decades, later.

What has troubled many investigators for years has been the unpredictable nature of the onset of synovial inflammation. This lack of understanding is heightened by the recognition that synovial inflammation has at least 3 different histologic and transcriptomic patterns. The clinical significance of these “pathotypes,” which include diffuse myeloid, lympho-myeloid, and pauci-immune, is only now being tested. 

To this end, at ACR/ARP 2020, Rivellese and colleagues reported findings from an assessment of histopathologic cellular markers of treatment response in the R4RA trial. In this analysis, 164 patients with RA and an inadequate response to TNF-inhibitors underwent synovial biopsy prior to being randomized 1:1 to rituximab or tocilizumab. After 16 weeks of treatment, 65 patients had repeat biopsies.

Following treatment with tocilizumab, patients with a diffuse myeloid pathotype were significantly more likely to achieve a CDAI response > 50% compared with those with lympho-myeloid or pauci-immune pathotypes (81% vs 48%). In contrast, responses with rituximab were equivalent across all 3 pathotypes.

Follow-up synovial biopsies showed that rituximab and tocilizumab selectively reduced CD20+ B cells/plasma cells and CD68+ sublining macrophages, respectively. These data establish the utility of synovial biopsy in guiding treatment strategies

Sarilumab and Methotrexate
With the advent of biologics and targeted therapies, attention has focused on whether supplementary methotrexate enhances these newer treatments and provides clinically significant benefit. To be sure, data for the TNF inhibitors infliximab and adalimumab have demonstrated the need for methotrexate as background therapy to prevent the development of antidrug antibodies. In the case of the TNF inhibitor etanercept, where antidrug antibodies are not a clinically significant problem, background methotrexate clearly enhances responses compared with etanercept alone. Similar results have been observed with the anti-CD20 agent rituximab.

An outstanding question was whether antiIL-6 receptor therapy also requires background methotrexate for optimal outcomes. Several studies of tocilizumab have demonstrated insignificant differences between tocilizumab monotherapy and combination therapy with methotrexate.

Sarilumab, which also blocks IL-6 receptor signaling, has shown clinically significant efficacy in the treatment of RA. In pivotal phase III studies, sarilumab demonstrated superiority as monotherapy vs adalimumab (MONARCH), and as combination therapy with methotrexate vs methotrexate alone (MOBILITY).

At ACR/ARP 2020, Burmester and colleagues reported results from a post hoc analysis of the MONARCH and MOBILITY studies to compare the efficacy of sarilumab with vs without methotrexate in patients with RA who were intolerant of or had an inadequate response to methotrexate.

The investigators measured continuous change from baseline as a dependent variable, and variations in patient characteristics were set as covariates in a mixed-effect model for repeated measures. After adjusting for these differences, the least-square mean change from baseline at Week 24 was similar for all endpoint comparisons, including CDAI, DAS28-CRP, CRP levels, hemoglobin levels, pain on a visual analog scale, and fatigue.

These finding suggest that the efficacy of sarilumab does not require background methotrexate, which aligns with previous observations with tocilizumab. These data extend the use of IL-6 receptor blockade to those patients who are intolerant of methotrexate or for whom methotrexate is contraindicated.

Your Thoughts?
How will new data on IL-6 inhibitors in RA influence your practice? Answer the polling question and join the conversation by posting a comment in the discussion section. And for more from ACR 2020, download capsule summaries of all the key data.

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