Background/Purpose: The most widely used B cell targeted therapies in auto-immune diseases (AID) is Rituximab (RTX), a murine chimeric monoclonal antibody. Among RTX’s side effects, immunization and anti-drug antibodies to RTX (RTX-ADA) production have been reportedbut their consequences are poorly described. The immunization rate against RTX in rheumatoid arthritis (RA) is 2.7-9.2% and data is lacking in sAID.

We aimed to evaluate the frequency, consequences and predictive factors of RTX-ADA in RA and sAID, as well as the use of an alternative B-cell targeted therapy, ofatumumab (OFA).

Methods: All patients with RA or sAID treated with RTX from 2012 to 2017 in our tertiary reference centre for RA and sAIDwere retrospectively studied. All patients who were tested for RTX-ADA were identified. Clinical and biological characteristics of RTX immunized patients were compared to those of non-immunized patients. For patients treated with OFA, clinical and biological efficacy was obtained before and after treatment.

Results: 199 patients were treated with RTX (RA: 124, sAID: 75 including 38 primary Sjögren’s Syndrome (pSS), 15 systemic lupus erythematous, 7 myositis, 6 overlap syndrome, 5 ANCA-associated vasculitides and 4 other sAID). 62/199 (31.1%) patients were tested for RTX-ADA because of a loss of clinical efficacy or absence of B-cell depletion (43.4%), a long delay between cycles (13.2%), a reaction during the first infusion (7.5%) or at subsequent infusions (35.8%). 14 were positive: 3/35 RA (8.6%) and 11/27 (40.7%) other sAID, (p=0.0025). None of the patients who experienced a reaction to the first RTX infusion were positive for RTX-ADA. Among the whole RTX-treated patients, the frequency of RTX-ADA was 2.4% and 14.7% in RA and in other sAID, respectively (p=0.003). Most of the immunized patients experienced delayed infusion reactions (11/14 [78.5%]). Delayed reactions were observed within the first 15 days after the infusion, and after a median 2 cycles [range; 1-2]. They were mainly rash (72.7%), fever (54.5%) and/or abdominal pain (36.3%). Predictive factors of immunization were a sAID compared to RA (40.7% vs 8.6%, p=0.0025) and African origin (57.1% vs 4.2%, p< 0.001). Neither hypergammaglobulinemia, rheumatoid factor, disease activity, nor associated immunosuppressive therapy were associated with RTX-ADA. Among 23 tested patients with SLE or pSS, anti-SSA antibodies were positive in 9/10 (90%) immunized patients versus in only 8/13 (61.5%) non immunized patients (p=0.18). Three pSS patients immunized against RTX were treated with OFA because of associated cryoglobulinemic vasculitis or MALT lymphoma. All 3 experienced complete remission of their disease without any recurrence of infusions reactions. No other adverse event was reported.

Conclusion:
Immunization against RTX is an event leading to loss of efficacy, absence of B-cell depletion and infusion reactions at the 2^nd or subsequent infusions. Testing for RTX-ADA must be realized in patients presenting one of these three features, especially if they are of African origin and treated for a sAID. Our results suggest that immunized patients can be treated safely with OFA although OFA should be further evaluated in sAID.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/risk-of-immunization-to-rituximab-in-systemic-autoimmune-diseases-and-rheumatoid-arthritis-frequency-and-risk-factors-analysis-of-the-efficacy-of-an-alternative-treatment-by-ofatumumab/