OP0021 PREDICTING SEVERE INFECTION IN REPEAT CYCLES OF RITUXIMAB AND EFFECTS OF HYPOGAMMAGLOBULINAEMIA FOR THE TREATMENT OF RHEUMATIC AND MUSCULOSKELETAL DISEASES
Authors: Md Yuzaiful Md Yusof, Edward Vital, Damien M. Mcelvenny, Elizabeth Hensor, Sudipto Das, Shouvik Dass, Andy C. Rawstron, Maya Buch, Paul Emery, Sinisa Savic
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rituximab (RTX) is effective in treating various rheumatic and musculoskeletal diseases (RMDs). Repeat cycles are often required for disease control but may lead to hypogammaglobulinaemia. Low IgG at baseline has been associated with increased risk of severe infection event (SIE) post-RTX. However, there are limited data on predictors of SIEs in repeat cycles including immunoglobulin levels and B-cell numbers as well as outcomes of hypogammaglobulinaemia. <h3>Objectives</h3> To assess predictors of SIEs in repeat RTX cycles and effects of hypogammaglobulinaemia in terms of SIEs rates, humoral response and its persistence post-cessation of RTX. <h3>Methods</h3> A retrospective study was conducted in the first 700 consecutive ARD patients treated with at least a cycle of RTX in Leeds. IgM, IgA and IgG levels were measured at baseline and 4-6 months after each cycle. For cycles 2-4 (C2-4), predictors for SIEs were analysed using mixed-effects logistic regression analysis. <h3>Results</h3> 550 patients were female, mean(SD) age 56(16) years and median (IQR) disease duration 7.9(3.4-15.0) years. 507(72%) had RA, 94(13%) SLE, 49(7%) AAV, 14(2%) inflammatory myopathies, 9(1%) pSS, 5(1%) APS, 6(1%) SSc and 16(3%) other CTDs. 364(52%) were biologic-naïve and 514(73%) were on concomitant DMARDs. Total follow-up: 2880 patient-years (PY). 281 SIEs were recorded in 176 patients (9.8/100 PY). In C1, we had validated that low IgG was predictive of SIE within 12 months of C1. For cycles 2-4, in multivariable analysis, non-RTX-specific comorbidities [chronic lung OR (95% CI) 2.4 (1.3-4.4), diabetes 2.9 (1.2-6.9), heart failure 6.3 (1.4-28.1), previous cancer 3.0 (1.3-6.7) and severe infection 6.3 (3.0-13.4)] and RTX-specific variables [higher corticosteroid dose 1.08 (1.02-1.14), higher IgM 1.3 (1-1.7) and longer retreatment time 1.01 (1-1.02)] were associated with increased odds of SIEs, but not B-cell numbers or depletion status. Higher IgG reduced the risk 0.88 (0.8-0.96). Of 103 patients with low IgG for at least 4 months duration, SIEs rates were higher in those with low baseline IgG (16.4 PY) or acquired it during/post-RTX (21.3 PY) versus those with normal IgG (9.7 PY), 5/8(64%) had impaired humoral response to pneumococcal and haemophilus following vaccination challenge and only 4/11(36%) had IgG normalised after switching therapies. Overall, 7(1%) of the patients required Ig replacement based on recurrent sino-pulmonary SIEs and/or low IgG. <h3>Conclusion</h3> Immunoglobulin should be monitored at baseline and before each RTX cycle to identify patients at risk of SIEs. Vigilance is needed for those with lower IgG as this is a consistent predictor of SIE and may affect infection outcomes when patients are switched to a different bDMARD. For those at risk of SIEs, reduction of corticosteroid dose could reduce risk. Low B-cell numbers were not predictive of SIEs. <h3>Acknowledgement</h3> This research was supported by Octapharma and NIHR (DRF-2014-07-155). The views expressed are those of the author(s) &amp; not necessarily the NHS, NIHR or DOH. <h3>Disclosure of Interests</h3> Md Yuzaiful Md Yusof: None declared, Edward Vital Grant/research support from: He has received honoraria and research grant support from Roche, GSK and AstraZeneca., Damien M McElvenny: None declared, Elizabeth Hensor: None declared, Sudipto Das: None declared, Shouvik Dass Grant/research support from: Roche and GSK, Andy C Rawstron: None declared, Maya Buch Grant/research support from: Pfizer LTD, UCB, Consultant for: AbbVie, Eli Lilly, EMD Serono, Pfizer Ltd., Sanofi, Paul Emery Grant/research support from: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, Roche, Consultant for: Pfizer, MSD, AbbVie, Bristol-Myers Squibb, UCB, Roche, Novartis, Gilead,Samsung, Sandoz and Lilly, Sinisa Savic Grant/research support from: Novartis and Sobi