Interleukin (IL)-33 may play a role in rheumatoid arthritis (RA) pathophysiology as shown by human studies and murine models [
1]. Previously, we demonstrated that detectable serum IL-33 predicts clinical response to rituximab independently of auto-antibody status [
2].
Here, we aimed to investigate whether the prediction of therapeutic response using serum IL-33 level is generalizable to all biologic agents, including TNF inhibitors (TNFi) and non-TNFi in RA.
We set up an ancillary study of the ROC (Rotation or Change of Biotherapy After First Anti-TNF Treatment Failure for RA) trial (NCT01000441) which compared the efficacy of TNFi vs non-TNFi in patients with insufficient response to a first TNFi [
3]. Three hundred patients were randomized, and treatment efficacy was evaluated at 24 weeks according to EULAR response, showing that a non-TNFi was more effective in achieving EULAR response than a TNFi. Serum IL-33 level was assessed before treatment using an accurate enzyme-linked immunosorbent assay (ELISA IL-33, Quantikine, R&D Systems) [
4]. Statistical analyses used Prism (Mann-Whitney and Fisher tests for quantitative and qualitative values, respectively). Serum IL-33 level was defined as detectable when > 6.25 pg/mL (lower threshold).
Results were analyzed for 267 patients with available serum and clinical data (Table
1). Serum IL-33 level was detectable for 109/267 (40.8%) patients (mean ± standard deviation serum level was 49.7 ± 61.0 pg/mL when detectable) (Table
2). IL-33 detection was associated with auto-antibody positivity: rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (anti-CCP), either combined or analyzed separately (Table
3). Auto-antibody positivity was not associated with response to the different treatment: TNFi (
N = 132, odds ratio (OR) = 1.1, 95% confidence interval (CI) = 0.39–3.16), non-TNFi (
N = 130, OR = 1.5, 95% CI = 0.40–5.62), or different sub-groups of non-TNFi (data not shown). There was no association between IL-33 detection and response to TNFi as well as to non-TNFi drugs overall or analyzed separately (Table
2). Likewise, there was no difference when comparing the levels of serum IL-33 between responders and non-responders in TNFi and non-TNFi groups (data not shown).
Table 1
Characteristics of the patients included in the ancillary study of the ROC trial
Number of women (%) | 114 (85.7) | 110 (82.1) | 224 (83.9) |
Mean age (SD) | 55.9 (13.0) | 58.4 (11.2) | 57.2 (12.1) |
Number rheumatoid factor-positive (%) | 108 (82.4) | 101 (76.5) | 209 (79.8) |
Number anti-CCP-positive (%) | 102 (79.7) | 105 (82.7) | 207 (81.2) |
Mean DAS28-CRP (SD) | 4.7 (0.9) | 4.8 (1.1) | 4.8 (1.0) |
Table 2
EULAR response, IL-33 detectability rates and association between IL-33 detection and response to tumor necrosis factor inhibitor (TNFi; including adalimumab, certolizumab, etanercept and infliximab) and non-TNFi (including abatacept, rituximab, and tocilizumab) in patients from the ROC study
TNFi | Adalimumab | 53 | 30 (56.6) | 23 (43.4) | 14 (46.7) | 1.4 [0.5–4.1] |
Etanercept | 49 | 29 (59.2) | 20 (40.8) | 13 (44.8) | 1.5 [0.5–5.0] |
Certolizumab | 23 | 10 (43.5) | 10 (43.5) | 5 (50.0) | 1.6 [0.3–8.5] |
Infliximab | 8 | 1 (12.5) | 3 (37.5) | 1 (100) | 6.6 [0.2–226] |
Total TNFi | 133 | 70 (52.6) | 56 (42.1) | 33 (47.1) | 1.6 [0.8–3.1] |
Non-TNFi | Rituximab | 37 | 20 (54.0) | 10 (27.0) | 6 (30.0) | 1.4 [0.3–6.1] |
Abatacept | 30 | 18 (60.0) | 11 (36.6) | 8 (44.4) | 2.4 [0.5–11.9] |
Tocilizumab | 67 | 53 (79.1) | 32 (47.8) | 25 (47.2) | 0.9 [0.3–2.9] |
Total non-TNFi | 134 | 91 (67.9) | 53 (39.6) | 39 (42.9) | 1.6 [0.7–3.3] |
Table 3
Association between IL-33 detection and auto-antibody positivity
RF+ and/or anti-CCP+ vs RF− and anti-CCP− | 262 | 21.1 | 2.8-158.3 |
RF+ vs RF− | 263 | 9.7 | 3.7-25.3 |
Anti-CCP+ vs anti-CCP− | 255 | 2.7 | 1.3- 5.7 |
Thus, this new study confirms the association between serum IL-33 detection and seropositivity in RA patients. However, it did not replicate the association between IL-33 detection and response to rituximab. This may be due to a lack of power related to the number of patients who received this treatment (
N = 37), but it may also reflect the difficulty of studying IL-33 as a possible predictor of response given its association with seropositivity, which is a well-known factor associated with response to some biologics such as rituximab or abatacept [
5].
In conclusion, we confirm that serum IL-33 detection is associated with auto-antibody positivity but is not a predictive marker for response to TNFi and non-TNFi in RA.
Acknowledgements
The authors thank all patients for participating in this study and all investigators who included patients in the ROC study : Olivier Brocq, MD; Aleth Perdriger, MD; Slim Lassoued, MD; Jean-Marie Berthelot, MD; Daniel Wendling, MD, PhD; Liana Euller-Ziegler, MD; Martin Soubrier, MD; Christophe Richez, MD, PhD; Bruno Fautrel, MD, PhD; Arnaud L. Constantin, MD, PhD; Jacques Morel, MD, PhD; Melanie Gilson, MD; Gregoire Cormier, MD; Jean Hugues Salmon, MD; Stephanie Rist, MD; Frederic Lioté, MD, PhD; Hubert Marotte, MD, PhD; Christine Bonnet, MD; Christian Marcelli, MD, PhD; Olivier Meyer, MD, PhD; Elisabeth Solau-Gervais, MD, PhD; Sandrine Guis, MD, PhD; Jean-Marc Ziza, MD; Charles Zarnitsky, MD; Isabelle Chary-Valckenaere, MD, PhD; Olivier Vittecoq, MD, PhD; Alain Saraux, MD, PhD; Yves-Marie Pers, MD, PhD; Martine Gayraud, MD; Gilles Bolla, MD; Pascal Claudepierre, MD, PhD; Marc Ardizzone, MD; Emmanuelle Dernis, MD; Maxime A. Breban, MD, PhD; Olivier Fain, MD, PhD; Jean-Charles Balblanc, MD; Ouafaa Aberkane, PhD; Marion Vazel, PhD; Christelle Back, PhD; Sophie Candon, MD, PhD; Lucienne Chatenoud, MD, PhD; Elodie Perrodeau, MSc; Jean Sibilia, MD
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