Background: RITAZAREM [1, 2] was an international randomized-controlled trial comparing rituximab (RTX) and azathioprine (AZA) for maintenance of remission in relapsing ANCA-associated vasculitis (AAV). All patients received initial treatment with glucocorticoids (GC) and RTX. GC regimens were not randomized, and investigators selected either a high-dose or a reduced-dose regimen for each patient.

Objectives: Identify factors associated with risk of infection among patients with AAV receiving rituximab to induce remission.

Methods: The association of patient characteristics at enrolment with infections of any severity were analyzed by Cox regression models. Variables included age, sex, ANCA type (anti-proteinase 3, anti-myeloperoxidase), co-morbidities, organ involvement (based on BVAS/WG), chronic organ damage (per the Combined Damage Assessment, CDA), and immunoglobulin levels. Stepwise backward selection was used to create multivariate models of static variables with a P-value < 0.1 in univariate analysis. Use of trimethoprim-sulfamethoxazole (TMS) and GC doses were added to the models as time-varying covariates. Results are reported as hazard ratios (HR) with 95% confidence intervals (CIs). Two models were created: i) for the induction of remission phase of the trial (Month 0 to 4), and ii) for the maintenance of remission and follow-up phase (Month 4 to last visit, between Months 36 and 48).

Results: 187 subjects that received treatment for induction with RTX for relapsing AAV were included in the analysis. 62 (33%) had at least one infectious event in the induction phase. Factors associated with infection risk in the final model were chronic lung disease (HR 1.79, 95% CI 1.01 to 3.18, P=0.048), active nodules or cavities on BVAS/WG (HR 2.04, 95% CI 1.14 to 3.65, P=0.016), IgM concentration (g/L) at Baseline (HR 0.56, 95% CI 0.32 to 0.98, P=0.044), and time-varying use of TMS prophylaxis (binary variable of on/off: HR 0.56, 95% CI 0.33 to 0.97, P=0.040). Time-varying GC dose (continuous) in mg/day (HR 0.99, 95% CI 0.97 to 1.02, P=0.496) was also retained in the final model. 170 subjects were subsequently randomized to RTX or AZA at Month 4 and were included in the maintenance and follow-up phase analysis. 128 (75%) patients had infectious events. Infectious events during remission induction treatment were associated with subsequent infections during the maintenance phase (HR 2.35, 95% CI 1.61 to 3.44, P<0.001). Pulmonary fibrosis (HR 2.46, 95% CI 1.05 to 5.74, P=0.038) and large airway obstruction (HR 2.78, 95% CI 1.17 to 6.62, P=0.021) on CDA were also associated with infections. TMS prophylaxis (HR 0.71, 95% CI 0.50 to 1.03, P=0.070) and IgM level at Month 4 (HR 0.67, 95% CI 0.37 to 1.22, P=0.192) were retained in the maintenance and follow-up model. Risk of infection did not differ between subjects assigned to maintenance treatment with RTX or AZA. Chronic kidney disease was not significantly associated with infection risk.

Conclusion: Pre-existing chronic lung disease and chronic lung damage (large airway obstruction and pulmonary fibrosis) are important factors associated with risk of infection in AAV. Infectious events during treatment to induce remission were associated with subsequent events during maintenance treatment. TMS prophylaxis was associated with lower infection rates during remission induction treatment, but this effect was reduced during the maintenance/follow-up phase. Being randomized to either RTX or AZA for remission maintenance treatment did not significantly change risk of infection.

REFERENCES: [1] Smith RM, Jones RB, Specks U, et al. Rituximab versus azathioprine for maintenance of remission for patients with ANCA-associated vasculitis and relapsing disease: an international randomized controlled trial. Ann Rheum Dis. 2023 Jul;82(7):937-944.

[2] Smith RM, Jones RB, Specks U, et al. Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis. Ann Rheum Dis. 2020 Sep;79(9):1243-1249.

Acknowledgements: NIL.

Disclosure of Interests: Jan H. Schirmer: None declared, Ellen Romich: None declared, Carol McAlear: None declared, Peter Merkel Kyverna, Q32, Lifordi, Sparrow, AbbVie, Alpine, Amgen, ArGenx, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, CSL Behring, GlaxoSmithKline, iCell, Interius, Kinevant, Kyverna, Metagenomia, Neutrolis, Novartis, NS Pharma, Q32, Quell, Regeneron, Sanofi, Sparrow, Takeda, Vistera, AbbVie, Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Eicos, Electra, GlaxoSmithKline, Neutrolis, Takeda, David R. W. Jayne CSL Vifor, Otsuka, Amgen, Alentis, Astra-Zeneca, BMS, CSL vifor, Novartis, Roche, Takeda, CSL Vifor, Roche, Rona M. Smith Vifor Pharma, Vifor Pharma, GSK, Union Therapeutics.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.