Background/Purpose: Tocilizumab (TCZ) is an effective treatment for Rheumatoid Arthritis (RA) and it is a modifier of B cell subsets in vivo, inducing changes in the distribution of B-cell subpopulations^1-3.  Our purpose was to define whether the combination of clinical parameters and B cell subset analysis at baseline could help to identify the best responders to TCZ, and to examine whether changes after 3 months could predict the occurrence of response to therapy over time.

Methods: 63 RA patients not responder to previous cDMARDs and/or bDMARDS were studied, of which: A) 17 (27.0%) with an early RA (ERA), treated according to a tight control strategy and B) 46 (73.0%) with a long-standing disease (LSRA). All patients were treated with TCZ at a dose of 8 mg/Kg every 4 weeks. At baseline, and every 3 months, demographic and immunological data and the ACR/EULAR core data set  were recorded. At each visit, clinical improvement and remission were evaluated according to ACR/EULAR criteria⁴. At baseline and every 3 months peripheral blood samples were collected and analyzed by flow-cytometry for the distribution of circulating B-cell subsets using IgD-CD27 classification⁵.

Results:  In the whole RA cohort, 16.4% and 17.6% of patients treated with TCZ, reached the ACR/EULAR remission (SDAI≤3.3) at 6^th and 12^thmonths of follow-up (FU), respectively.

The percentage of ACR/EULAR remission after 3, 6 and 12 months of TCZ therapy was higher in male patients compared to female subjects (p<0.05), in ERA compared to LSRA patients (p<0.05), and in subjects with baseline moderate disease activity (SDAI≤26) compared to patients with a high disease activity (p<0.05). Moreover, a lower percentage of RA patients already treated with bDMARDS reached remission over time compared to cDMARDs treated subjects (p<0.05). Autoantibody seropositivity or BMI did not influence the outcome over time. 

A decrease of the percentage of post-switched (IgD-CD27+; p=0.001) and double negative (IgD-CD27-; p=0.004) memory B cells occurred after 12 months of treatment with TCZ, together with an increase of the percentage of naïve (IgD+CD27-; p=0.05) B cells.

A higher percentage of reduction of double negative memory B cells at 3 months of TCZ treatment was observed in RA patients reaching remission (SDAI≤3.3) at 6 months compared to patients not achieving this target (p=0.02).

At the multivariate analysis, a disease duration less than 12 months [OR (95%CI): 24.1 (1.7-341.8)], a moderate disease activity (SDAI≤26) at baseline [OR (95%CI): 18.5 (1.4-250)] and a higher reduction of double negative B cells at 3 months of FU [OR (95%CI): 1.05 (1.001-1.1)] arose as significant independent predictors of ACR/EULAR remission (SDAI≤3.3) at 6^thmonth of TCZ treatment.

Conclusion:  In our cohort of TCZ-treated RA patients, being male, having a disease duration less than 12 months and a moderate disease activity at baseline represent the best clinical matrix to predict remission at 6 months. Furthermore, a significant reduction of DN memory B cells at the 3^th month of FU has emerged as an early biomarker of remission at the 6^thmonth of treatment.

References:

1. Roll P et al. Arthritis Rheum 2011                                   

2. Muhammad K et al. Ann Rheum Dis 2011                                                   

3. Mahmood Z et al. Arth Res Ther 2015                                                          

4. Felson DT et al. Arthritis Rheum 2011

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/clinical-parameters-and-b-cell-subsets-as-biomarkers-of-response-to-tocilizumab-in-rheumatoid-arthritis/