In contrast to other studies published during the COVID-19 pandemic (Esmaeili et al. 2021;Klineova et al. 2021༛Reder et al. 2021༛Longinetti et al. 2022༛Smith et al. 2022), we designed a cross-sectional observational study to assess the severity and risk factors associated with COVID-19 infection in PwNIDs treated with a low-dose RTX regimen. Our study yielded three principal findings. Firstly, it is worth noting that we observed no discernible difference in the severity of COVID-19 infections between PwNIDs and their co-residents. Neither group experienced severe infection or death. Secondly, we found that a shorter duration between the last RTX infusion and contracting COVID-19, as well as higher cumulative dosages of RTX, were not risk factors for COVID-19 infection. Lastly, our investigation revealed that COVID-19 infection did not have a significant impact on the underlying neuroimmune diseases in PwNIDs who had contracted COVID-19 and were undergoing low-dose RTX therapy.
The severity of COVID-19 infection was comparable between PwNIDs and their co-residents, with no instances of severe disease or death observed among them. The observed outcomes may be attributed to the individualized low-dose RTX regimen we administered to PwNIDs. This regimen is rarely associated with reduced immunoglobulin levels and increase infection risk, yet it demonstrates comparable efficacy to higher dosages of RTX infusion. The dosages of RTX for autoimmune diseases (AIDs) were primarily derived from the regimen used for non-Hodgkin’s lymphoma (NHL). This includes an induction dose of 1 g per infusion (administered twice consecutively, with a 2-week interval) or 375 mg/m2 per week based on body surface area (for 4 consecutive weeks). Maintenance therapy involves 1 g every 6 months or reinfusion only after recurrence. The efficacy of RTX in eliminating CD20+ B cells was found to have a dose accumulative effect. Higher doses of RTX resulted in a longer duration required for B cell remodeling and had a more pronounced impact in humoral immune function, increasing the risk of hypogammaglobulinemia and subsequent infections, even severe infections(Tieu et al. 2021;Kim et al. 2022). Steve Simpson-Yap(Simpson-Yap et al. 2022) updated data of PwMS from 27 countries revealed a significant association between anti-CD20 therapy and a more severe course of COVID-19. Thamer S Alhowaish(Alhowaish et al. 2023) analyzed 35 PwMS who were infected COVID-19 and had received RTX at a dose of 375 mg/m2 with a median frequency of 4 doses. It was found that more than a third of these individuals developed hypogammaglobulinemia and required hospitalization and treatment in the intensive care unit (ICU). They thought RTX was a potential risk factor for unfavorable outcomes in COVID-19 patients.
Interestingly, D. Baker(Baker et al. 2020) hypothesized that anti-CD20 treatment did not predispose patients to severe COVID-19 due to the reduction in B cells and inflammatory storms following COVID-19 infection. This treatment also may not interfere with the innate immune response and CD8+T cell response. Based on these findings, some studies have indicated that patients undergoing anti-CD20 treatment did not experience severe COVID-19 infections and were able to recover rapidly after being infected with COVID-19(Kim et al. 2022;Longinetti et al. 2022༛Zabalza et al. 2022). Basic research also found that patients who received anti-C20 treatment experienced reduced COVID-19-specific-antibody production due to clearance of B cells. However, their COVID-19-specific T cell response remained robust. This provides a theoretical basis for the belief that anti-CD20 treatment dose not increase the severity of COVID-19 infection in patients(Madelon et al. 2022༛Wolf et al. 2023).
Besides, we did not find any risk factors (including recent low-dose RTX infusion, higher cumulative RTX dosages and so on) for COVID-19 infection. Rajesh B Iyer(Iyer et al. 2022) enrolled 62 PwMS who received RTX infusion with an initial dose typically ranging from 1000 to 2000 mg, and subsequent doses averaging between 500 and 1000 mg. Their finding indicated that factors such as older age, secondary progressive MS(SPMS), a shorter duration between RTX infusion and COVID-19 onset, and receiving a higher dose at the last RTX infusion were associated with an increased risk of severe disease, which aligned with findings from other studies. Annette Langer-Gould(Langer-Gould et al. 2021) enrolled 1895 PwMS who were treated with RTX. Out of these, 24 patients contracted COVID-19. Compared to patients who either did not contract COVID-19 or experienced a mild of the disease, 8 out of 24 patients developed moderate disease. Among these patients, the median cumulative RTX dose was higher (3250 mg versus 2000 mg), and median time since last infusion was shorter (2.5 m versus 7.8 m). They also observed that the duration in months since the last infusion and receiving a dose of 1000 mg compared to lower doses at the last infusion were independent factors predicting the severity of COVID-19. This indicates that PwNIDs who have a shorter median time since their last infusion and a higher cumulative RTX dose remain vulnerable to COVID-19 and are at an increased risk of severe infection(Landtblom et al. 2021;Spelman et al. 2022). Our study found that low-dose RTX effectively cleared CD20+ B cell without causing a decrease in immunoglobulin levels and had minimal impact on adaptive immune responses.
Numerous reviews have highlighted that the most prevalent symptom of COVID-19 infection is an upper respiratory tract infection, typically presenting with symptoms such as fever, followed by dry cough, fatigue, and so an(Furlan et al. 2021;Ochani et al. 2021༛Salter et al. 2021). Some patients with COVID-19 infection may be accompanied by muscle soreness, loss of smell and taste, nasal congestion, runny nose, diarrhea, conjunctivitis, etc. In our study, fever was the most common frequently reported symptom among PwNIDs who had COVID-19 infection. This was followed by systemic symptoms like myalgia, fatigue, as well as less uncommon symptoms such as rash and conjunctivitis, pharyngodynia, and decreased sense of smell and taste. In controls with COVID-19 infection, the most common symptom was also fever, followed by upper respiratory tract infections and systemic symptoms such as fatigue, dry cough, pharyngodynia, nasal congestion, headache, runny nose, and phlegm. There were statistically significant differences in systemic, gastrointestinal and less common symptoms between the two groups. We took into account that the immune system composition in PwNIDs receiving RTX might differ from that of the general population(Winkelmann et al. 2016). After COVID-19 infection, varying immune responses can occur, resulting in different symptom presentations or syndromes.
It is widely recognized that virus infections can act as triggers for patients with AIDs. A cohort in Iranian focusing on MS reported that 17% of patients experienced a relapse after contracting COVID-19(Paybast et al. 2023). In order to clarify the impact of SARS CoV-2 on NIDs, we used the self-assessment questionnaire to investigate the underlying diseases in PwNIDs after COVID-19 infection. The results showed that the majority of PwNIDs who received a low-dose RTX regimen did not experience any significant impact on their primary diseases after COVID-19 infection. Fewer patients reported that their previous neurological symptoms and signs worsened, although this did not require hospitalization. The worsened clinical manifestations experienced by some individuals improved upon full recovery from COVID-19. Importantly, none of these patients developed new-onset neurological symptoms that required acute-phase treatment. Up to date, PwNIDs who have been followed up for more than one and a half years in our study have not reported any disease relapse. Furthermore, some of them are still undergoing regular low-dose RTX infusion as part of their treatment regimen. It appears that COVID-19 infection did not have any discernible impact on the underlying disease in PwNIDs who were receiving an individualized low-dose RTX regimen.
The study has certain limitations: firstly, it is a single-center retrospective survey study with a small sample size. To reduce bias, we conducted a questionnaire survey on all patients with NIDs who received low-dose RTX treatment before the enrollment deadline. We also conducted a case-control study to investigate the infection status of co-residents and compare the infection status between groups. Secondly, this study used a questionnaire survey instead of face-to-face interviews. To minimize errors resulting from data entry, all completed questionnaires were cross-checked against EMRS. Any discrepancies or unclear responses were addressed through followed-up phone calls to ensure the accuracy of the data collected.