First exposure to rituximab is associated to high rate of anti-drug antibodies in systemic lupus erythematosus but not in ANCA-associated vasculitis

Abstract

Background Anti-drug antibodies (ADAs) can impact on the efficacy and safety of biologicals, today used to treat several chronic inflammatory conditions. Specific patient groups may be more prone to develop ADAs. Rituximab is routinely used for ANCA-associated vasculitis (AAV) and as off-label therapy for systemic lupus erythematosus (SLE), but data on occurrence and predisposing factors to ADAs in these diseases is limited. Objectives To elucidate the rate of occurrence, and risk factors for ADAs against rituximab in SLE and AAV. Methods ADAs were detected using a bridging electrochemiluminescent (ECL) immunoassay in sera from rituximab-naïve (AAV; n = 41 and SLE; n = 62) and rituximab-treated (AAV; n = 22 and SLE; n = 66) patients. Clinical data was retrieved from medical records. Disease activity was estimated by the SLE Disease Activity Index-2000 (SLEDAI-2 K) and the Birmingham Vasculitis Activity Score (BVAS). Results After first rituximab cycle, no AAV patients were ADA-positive compared to 37.8% of the SLE patients. Samples were obtained at a median (IQR) time of 5.5 (3.7–7.0) months (AAV), and 6.0 (5.0–7.0) months (SLE). ADA-positive SLE individuals were younger (34.0 (25.9–40.8) vs 44.3 (32.7–56.3) years, p = 0.002) and with more active disease (SLEDAI-2 K 14.0 (10.0–18.5) vs. 8.0 (6.0–14), p = 0.0017) and shorter disease duration (4.14 (1.18–10.08) vs 9.19 (5.71–16.93), p = 0.0097) compared to ADA-negative SLE. ADAs primarily occurred in nephritis patients, were associated with anti-dsDNA positivity but were not influenced by concomitant use of corticosteroids, cyclophosphamide or previous treatments. Despite overall reduction of SLEDAI-2 K (12.0 (7.0–16) to 4.0 (2.0–6.7), p < 0.0001), ADA-positive individuals still had higher SLEDAI-2 K (6.0 (4.0–9.0) vs 4.0 (2.0–6.0), p = 0.004) and their B cell count at 6 months follow-up was higher (CD19 + % 4.0 (0.5–10.0) vs 0.5 (0.4–1.0), p = 0.002). At retreatment, two ADA-positive SLE patients developed serum sickness (16.7%), and three had infusion reactions (25%) in contrast with one (5.2%) serum sickness in the ADA-negative group. Conclusions In contrast to AAV, ADAs were highly prevalent among rituximab-treated SLE patients already after the first course of treatment and were found to effect on both clinical and immunological responses. The high frequency in SLE may warrant implementations of ADA screening before retreatment and survey of immediate and late-onset infusion reactions.

Anti-rituximab antibodies in patients with refractory autoimmune nodopathy with anti-neurofascin-155 antibody

“…Specifically, there was a significant association between ARAs’ presence and titers and incomplete B-cell depletion in MS, and the ARA-positive group had a faster B-cell reconstitution in SDNS and MN ( 14 , 22 ). The count of CD19 + B cells after rituximab infusion in the ARAs group in SLE varied as Chris Wincup showed that no difference was found in CD19 + lymphocyte counts at the early and six-month time points between ARAs persistently positive and negative patients and Francesca Faustini reported that a higher proportion of CD19 + lymphocytes was seen in ARA-positive patients compared to ARA-negative patients ( 31 , 36 ). Moreover, most patients with MOGAD had a B-cell counts <1% at the time of disease activity ( 37 ) and B-cell counts have been found to be unrelated to clinical relapse in NMOSD ( 38 ).…”

Association Between Plasma Rituximab Concentration and the Risk of Major Relapse in Antineutrophil Cytoplasmic Antibody–Associated Vasculitides During Rituximab Maintenance Therapy

“…The time‐dependent formation of antidrug antibodies (ADA) is known to accelerate the clearance of anti‐TNFα therapies and impair their efficacy in patients treated for inflammatory bowel disease (25). Regarding RTX, Faustini et al reported the lack of ADA in AAV patients (n = 41) while ADA presence was observed in 37.8% of patients treated for systemic lupus erythematosus (n = 62) (26). Given that the risk of immunogenicity seems very low in AAV patients with RTX, we decided not to investigate the formation of ADA as a determinant of PK variability as well as its association with relapse.…”

Rituximab in Systemic Lupus Erythematosus: Transient Effects on Autoimmunity Associated Lymphocyte Phenotypes and Implications for Immunogenicity

“…The presence of ADA was determined with an in-house validated electrochemiluminescence bridging assay (ECL) according to a previously described protocol (27,28).…”

“…The 15 patients analyzed in this study were also included in a recently published paper investigating the prevalence of antidrug antibodies (ADA) in our SLE cohort (28). In the mentioned paper, ADA positive SLE individuals showed higher B-cell counts at about six months follow-up with respect to ADA negative individuals.…”