PO.6.126 Anti-rituximab antibodies demonstrate neutralising capacity, associate with lower circulating drug levels and early relapse in patients undergoing treatment for systemic lupus erythematosus. (27th September 2022)

• Record Type: Journal Article
• Authors: Wincup, C; Dunn, N; Ruetsch-Chelli, C; Manouchehrinia, A; Kharlamova, N; Naja, M; Seitz-Polski, B; Isenberg, D; Fogdell-Hahn, A; Ciurtin, C; Jury, E
• Is Part Of: Lupus science & medicine. Volume 9(2022)Supplement 2
• Page Start: A95
• Page End: A96
• Publication Date: 2022-09-27
• Subjects: Systemic lupus erythematosus -- Periodicals; 616.772005
• DOI: 10.1136/lupus-2022-elm2022.147
• Languages: English
• ISSNs: 2398-8851

Abstract

Abstract : Purpose: A major limitation of biologic therapy is formation of anti-drug antibodies (ADA). We have demonstrated ADA to Rituximab (RTX) predict subsequent infusion related reactions. However, little is known regarding the longterm dynamics of ADA to RTX in patients undergoing treatment for SLE. In this study we evaluated the longitudinal impact of ADA positivity with particular focus on; 1) Risk factors for the development of ADA. 2) The impact of ADA on treatment response. 3) Influence of ADA on RTX drug kinetics over time. 4) The capacity of ADA to neutralise RTX. Methods: Patients with SLE undergoing treatment with RTX were recruited to this study from the UCLH Lupus Clinic, England (n=35). Serum samples were collected at the following intervals post-treatment; 1–3 months (early post-treatment), 6 months, 12 months, 36 months (n=114). Clinical and laboratory data was collected pretreatment and at each time point. ADA were detected using an electrochemiluminescent immunoassay. Serum RTX levels were measured via ELISA. ADA status was defined according to the following patterns over time as either persistently negative, persistently positive (<15 AU/ml) and persistently positive at a high titre (≥16 AU/ml, upper quartile). A complement dependent cytotoxic assay was used to determine neutralizing capability of ADA in vitro. Results: ADA to RTX were found to be persistently positive in 64.3% of patients over the 36-month follow-up period with no significant difference in baseline disease activity (BILAG/SLEDAI-2K) between those who were subsequently ADA positive vs negative observed. ADA positive patients were younger at diagnosis of SLE compared with ADA negative (mean 22.50 ± 9.10 vs 37.29 ± 11.31 years, p=0.002, Fig A). Multivariate logistic regression found a 22% decrease in risk of ADA positivity for each addition year after diagnosis (p=0.03). ADA titres peaked earlier and remained higher over 36-month following in those who had been treated with rituximab previously (n=16) when compared with those who were rituximab naïve at entry to the study (n=19, Fig B). ADA positive patients had a significantly lower C3 at baseline (mean 0.61 ± 0.23 vs 0.87 ± 0.30, p=0.026), which remained lower at each subsequent time point up to 12 months post-treatment (Fig C). At 1–3- and 6-months post-RTX, patients who were ADA positive had a significantly lower circulating drug level than ADA negative (p<0.001, Fig D). In terms of BILAG defined response (Fig E), at six months post-treatment ADA positive patients (33%) showed a higher rate of relapse than those who were ADA negative (in which there were no cases of relapse). At 12-months post-RTX, a higher rate of BILAG defined Major Response was seen in those who were ADA negative (80%) when compared with ADA positive (36%). Finally, all ADA positive samples (38/38) were found to neutralise RTX in vitro. Conclusion: ADA to RTX were common and persisted over the 36-month period of this study. ADA associated with earlier serum drug elimination, increased relapse rates and demonstrated neutralising capacity suggesting that ADA could be a significant limitation to sustained response to treatment in clinical practice.