Severe SARS‐CoV‐2 infection in rituximab‐treated patients with autoimmune cytopenia: A multicenter observational study

Résumé fourni par la source

Rituximab (RTX), a monoclonal anti-CD20 antibody targeting B cells, is one of the main therapies for many autoimmune diseases, including immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA). During the first waves of the COVID-19 pandemic, exposure to RTX was rapidly identified as a risk factor for severe COVID-19 and COVID-19-related death, mainly in patients with inflammatory rheumatologic diseases.1, 2 In addition, several studies have shown that the immune response after anti-SARS-CoV-2 vaccine is impaired in patients receiving B-cell-depleting agents including RTX.3 Nevertheless, the risk of severe COVID-19 in RTX-treated patients has remained poorly studied since the occurrence of new variants and the development of new therapies for COVID-19. Notably, there are no data, to date, on the risk of severe COVID-19 in RTX-treated patients with autoimmune cytopenia (AIC) including ITP and AIHA. We conducted a retrospective multicenter nationwide study to evaluate the incidence and risk factors of severe COVID-19 in patients receiving RTX for an AIC during the COVID-19 pandemic. Methods are detailed in the Supplementary Methods. We included 308 patients in 11 centers over the French territory (Supplementary Figure 1). Main clinical data are reported in Table 1 and Supplementary Table 1. In total, 186 (60%) patients were female, the median age at first RTX injection during the study was 59 years (interquartile range [IQR] 38–75), 164 (53%) patients had ITP, 138 (45%) had AIHA and 6 (2%) had a combination of ITP and AIHA (Evans syndrome). Median time between the diagnosis of the AIC and the initiation of RTX therapy was 20 months (IQR 4–80). Prevalence of risk factors and protective factors for severe COVID-19 are detailed in Table 1 and Supplementary Table 2. The median number of risk factors was 2 (IQR 1–4): 267 (87%) patients had at least 1 risk factor, 205 (67%) had at least 2 risk factors and 146 (47%) had at least 3 risk factors. The most frequent risk factors were age (150 [49%] patients >60 years), immune deficiency of another cause (103 [33%] patients; 98 received immunosuppressive therapy during the pandemic, and 10 had a primary immune deficiency), high body mass index (62 [20%] with body mass index ≥30 kg/m2), chronic cardiovascular disease (67 [22%] patients) and cancer (65 [21%] patients). Vaccination status was available for all patients: during the study period, 266 (86%) had received at least one anti-SARS-CoV-2 vaccine dose and the median number of vaccine doses was 3 (2–4) (before or after RTX infusion). Overall, 92 (30%) patients were fully vaccinated before RTX infusion and 27 (9%) received anti SARS-CoV-2 pre-exposure prophylaxis. The median follow-up after RTX infusion was 20 months (IQR 11–29) (Table 1). During follow-up, 16 patients died with no link to COVID-19 or anti-SARS-CoV-2 vaccination. During follow-up, 87 COVID-19 cases were reported in 79 (26%) patients: 11 (4%) had severe COVID-19 (i.e., COVID-19 requiring hospitalization and oxygen therapy or leading to death), including two patients who died of severe COVID-19, and 68 (22%) had non-severe COVID-19. The incidence of severe COVID-19 overall was 2.25 infections per 100 patient-years (95% confidence interval [CI] 1.13–3.99), and that of non-severe COVID-19 was 15.54 infections per 100 patient-years (95% CI 12.44–19.06). The incidence of severe and non-severe COVID-19 during each pandemic period according to the predominant SARS-CoV-2 variant in France are reported in Supplementary Table 3. The rate of severe COVID-19 was 27% (3 out of 11) during the "alpha" period (before June 28, 2021), 40% (4 out of 10) during the "delta" period (between June 28, 2021 and December 27, 2021) and 6% (4 out of 66) during the "omicron" period (after December 27, 2021). Characteristics of patients with all-severity COVID-19 are summarized in Supplementary Table 4 and those of patients with severe COVID-19 are detailed in Supplementary Table 5. We compared the 11 patients with severe COVID-19 (Group A) to other patients including those with non-severe COVID-19 and those who did not have COVID-19 (Group B; Table 1). The median number of risk factors was 4 (IQR 3–5) in Group A and 2 (1–4) in Group B. Most risk factors were more frequent in Group A than in Group B including male sex, age ≥ 60 years, diabetes mellitus, chronic cardiovascular disease, chronic pulmonary disease, cancer, and liver cirrhosis. None of the patients in Group A had fewer than three risk factors versus 55% of patients in Group B. None of the patients in Group A were fully vaccinated before RTX versus 31% in Group B. In addition, full vaccination was achieved at least 2 weeks before COVID-19 in 6 (54%) patients who had severe COVID-19 versus 56 (82%) patients who had non-severe COVID-19. The number of vaccine doses before COVID-19 was 2 (IQR 0–3) in patients who had severe COVID-19 and 3 (IQR 2, 3) in patients who had non-severe COVID-19. The median time between last RTX infusion and COVID-19 was 392 days (IQR 118–550) in patients who had severe COVID-19 and 302 (IQR 151–545) in patients who had non-severe COVID-19; it was inferior to 6 months in 3 (27%) patients who had severe COVID-19 and in 18 (26%) patients who had non-severe COVID-19; it was inferior to 12 months in 5 (45%) patients who had severe COVID-19 and in 38 (56%) patients who had non-severe COVID-19. We performed univariate regression analysis with a Cox proportional-hazards model to evaluate the impact of each factor on the risk of severe COVID-19 in our population (Group A vs. Group B). Hazard ratios (HRs) with 95% CIs for each variable tested are reported in Supplementary Figure 2. Risk of severe COVID-19 was associated with age: as compared with patients <60 years old, for patients 60–70 years, the HR was 1.70 (95% CI 0.15–18.77), 70–80 years 6.88 (95% CI 1.33–35.5) and ≥80 years 6.77 (95% CI 1.13–40.63). The HR for AIHA versus ITP was 1.57 (95% CI 0.48–5.16). The HR for secondary AIC versus primary AIC was 1.36 (95% CI 0.41–4.45). Cumulative probability of severe COVID-19 after RTX infusion according to the number of risk factors is shown in Supplementary Figure 3. In this multicenter nationwide observational study, we evaluated the incidence and studied risk factors of severe COVID-19 in patients receiving RTX for an AIC. In our study, the incidence of severe COVID-19 was low: among 308 patients, only 11 had COVID-19 requiring oxygen therapy and two died. As expected, the prevalence of most known risk factors of severe COVID-19 were higher in patients with severe COVID-19 than in others. Although the impact of these factors on the risk of severe COVID-19 was statistically significant for some factors only, possibly because of an insufficient population size in our study, the risk of severe COVID-19 increased with the number of risk factors. No severe COVID-19 was reported in patients with three or fewer risk factors. Hence, our study shows that RTX use is safe in patients with few risk factors. In addition, no severe COVID-19 was reported in patients fully vaccinated before RTX infusion. This observation highlights the need to adapt RTX infusions to vaccine status and notably to plan vaccinations before RTX infusion if possible. Six patients had severe COVID-19 despite anti-SARS-CoV-2 vaccination initiated after RTX, including five who had received between one and three vaccine doses before severe COVID-19. This observation agrees with studies showing an impaired immune response after anti-SARS-CoV-2 vaccination in patients receiving RTX, even after three vaccine doses.4 Despite multiple risk factors of severe COVID-19, five patients had not received any vaccine dose before they had severe COVID-19. This is possibly explained for three of them by the date of infection that was before mid-February 2021, when the French national vaccination campaign had just begun and only 2.9% of the population had received at least one dose of vaccin

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.