Breakthrough SARS-CoV-2 infections and prediction of moderate-to-severe outcomes during rituximab therapy in patients with rheumatic and musculoskeletal diseases in the UK: a single-centre cohort study
Md Yuzaiful Md Yusof, Jack Arnold, Benazir Saleem, Claire Vandevelde, Shouvik Dass, Sinisa Savic, Edward M Vital, Paul Emery
Abstract
Background: Concerns have been raised regarding the reduced immunogenicity of vaccines against COVID-19 in patients with autoimmune diseases treated with rituximab. However, the incidence and severity of breakthrough infections in unbiased samples of patients with specific rheumatic and musculoskeletal diseases are largely unknown. We aimed to assess the incidence of breakthrough SARS-CoV-2 infection, compare rates of moderate-to-severe COVID-19 with any severe infection event, and evaluate predictors of moderate-to-severe COVID-19 outcomes in patients treated with rituximab. Methods: We did a retrospective cohort study in all rituximab-treated patients with rheumatic and musculoskeletal diseases in a single centre in Leeds, UK between March 1, 2020 (the index date), and April 1, 2022. Adults aged 18 years and older, who fulfilled classification criteria for established rheumatic and musculoskeletal diseases, and received therapy with at least one rituximab infusion between Sept 1, 2019 (6 months before the pandemic in the UK), and April 1, 2022, were eligible for inclusion in the study. SARS-CoV-2 infection was defined by antigen test or PCR. COVID-19 outcomes were categorised as mild (from ambulatory to hospitalised but not requiring oxygen support) or moderate-to-severe (hospitalised and requiring oxygen support or death). The primary outcome was breakthrough COVID-19 infection, which was defined as an infection occurring 14 days or more after the second vaccine dose. Predictors of moderate-to-severe COVID-19 outcomes were analysed using Cox regression proportional hazards. Findings: 25·56 per 100 person-years [9·59-68·10] in those who were partially vaccinated or unvaccinated for moderate-to-severe infections). The rate of moderate-to-severe COVID-19 was broadly similar to other severe infection events in this cohort (5·68 per 100 person-years [95% CI 4·22-7·63]). In multivariable Cox regression analysis, factors associated with an increased risk of moderate-to-severe COVID-19 were the number of comorbidities (hazard ratio 1·46 [95% CI 1·13-1·89]; p=0·0037) and hypogammaglobulinaemia (defined by a pre-rituximab IgG concentration of <6 g/L; 3·22 [1·27-8·19]; p=0·014). This risk was reduced with each vaccine dose received (0·49 [0·37-0·65]; p<0·0001). Other factors, including concomitant prednisolone use, rituximab-associated factors (eg, rituximab dose and time to vaccination since last rituximab dose), and vaccine-associated factors (eg, vaccine type and peripheral B-cell depletion) were not predictive of moderate-to-severe COVID-19 outcomes. Interpretation: This study presented detailed analyses of rituximab-treated patients during various phases of the COVID-19 pandemic. In later stages of the pandemic, the SARS-CoV-2 breakthrough infection rate was high but severe COVID-19 rates were similar to any severe infection event rate in patients who were vaccinated. The risk-benefit ratio might still favour rituximab in vaccinated patients with severe rheumatic and musculoskeletal diseases who have few other treatment options. Increased vigilance is needed in the presence of comorbidities and hypogammaglobulinaemia for all infection types. Funding: Wellcome Trust and Eli Lilly.