Serum IL-33, a new marker predicting response to rituximab in rheumatoid arthritis

Jérémie Sellam, Elodie Rivière, Alice Courties, Paul-Olivier Rouzaire, Barbara Tolusso, Edward M Vital, Paul Emery, Gianfranco Ferraccioli, Martin Soubrier, Bineta Ly, Houria Hendel Chavez, Yassine Taoufik, Maxime Dougados, Xavier Mariette, Jérémie Sellam, Elodie Rivière, Alice Courties, Paul-Olivier Rouzaire, Barbara Tolusso, Edward M Vital, Paul Emery, Gianfranco Ferraccioli, Martin Soubrier, Bineta Ly, Houria Hendel Chavez, Yassine Taoufik, Maxime Dougados, Xavier Mariette

Abstract

Background: Recent works have suggested a possible link between interleukin (IL)-33 and B-cell biology. We aimed to study the possible association between serum IL-33 detection and response to rituximab (RTX) in rheumatoid arthritis (RA) patients in different cohorts with an accurate enzyme-linked immunosorbent assay (ELISA).

Methods: Serum IL-33, rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP), and high serum immunoglobulin (Ig)G levels were assessed in 111 RA patients receiving a first course of 2 g RTX (cohort 1) in an observational study and in 74 RA patients treated with the same schedule in routine care (cohort 2). Univariate and multivariate analyses identified factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks.

Results: At week 24, 84/111 (76%) and 54/74 (73%) patients reached EULAR response in cohorts 1 and 2, respectively. Serum IL-33 was detectable in only 33.5% of the patients. In the combined cohorts, the presence of RF or anti-CCP (odds ratio (OR) 3.27, 95% confidence interval (CI) 1.13-9.46; p = 0.03), high serum IgG (OR 2.32, 95% CI 1.01-5.33; p = 0.048), and detectable serum IL-33 (OR 2.40, 95% CI 1.01-5.72; p = 0.047) were all associated with RTX response in multivariate analysis. The combination of these three factors increased the likelihood of response to RTX. When serum IL-33 detection was added to seropositivity and serum IgG level, 100% of the patients with the three risk factors (corresponding to 9% of the population) responded to RTX (OR versus patients with none of the three risk factors 29.61, 95% CI 1.30-674.79; p = 0.034).

Conclusion: Detectable serum IL-33 may predict clinical response to RTX independently of, and synergistically with, auto-antibodies and serum IgG level.

Trial registration: NCT01126541 ; 18 May 2010.

Keywords: B-cell; Interleukin 33; Personalized medicine; Rheumatoid arthritis; Rituximab.

Figures

Fig. 1
Fig. 1
Serum IL-33 levels in patients from cohort 1, cohort 2, and the combined cohorts. Dosage performed with Quantikine ELISA IL-33 kit (R&D Systems). Each dot represents one patient; means are presented. IL interleukin
Fig. 2
Fig. 2
Association between the four explanatory variables and EULAR response at 24 weeks after the first rituximab infusion in the combination of cohorts 1 and 2. Results from the multivariate analysis are presented as odds ratios (OR) (95% confidence intervals (CI)) for each factor. anti-CCP anti-cyclic citrullinated peptide antibody, DAS28-CRP Disease Activity Score in 28 joints by C-reactive peptide, IL interleukin, RF rheumatoid factor
Fig. 3
Fig. 3
Frequency of EULAR response according to the presence of auto-antibodies, the detectability of serum IL-33, and a serum IgG above the upper limit of normal in cohort 1, cohort 2, and the combined cohorts. Results are presented for patients having auto-antibodies and/or elevated serum IL-33 level and/or elevated serum IgG level compared with patients having no auto-antibodies, a non-elevated serum IL-33 and a non-elevated IgG level (referent). anti-CCP anti-cyclic citrullinated peptide antibody, Ig immunoglobulin, IL interleukin, RF rheumatoid factor

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