COVID-19 Infection in Multiple Sclerosis Patients Treated with Rituximab Compared to Natalizumab and Healthy Controls: A Real-World Multicenter Study

Abstract

Introduction:

The impact of coronavirus disease 2019 (COVID-19) infection on patients with multiple sclerosis (MS) undergoing various immunomodulating therapies can vary. Individuals on B-cell therapy, such as rituximab, may be more susceptible to infection compared to those treated with natalizumab.

Objective:

The objective of this study was to determine the incidence and severity of COVID-19 infection in patients receiving rituximab, natalizumab, and healthy controls.

Methods:

This retrospective multicentric study included data derived from a centralized MS registry of four centers in South India. Data of patients on rituximab and natalizumab recruited between 2020 February and 2022 December were extracted from the registry and analyzed. The outcomes studied were the occurrence of COVID-19 infection, hospitalization, intensive care unit admission, death, post-COVID-19 relapses, and post-vaccine relapses. These outcomes were compared between the treatment groups and the matched controls.

Results:

COVID-19 infection occurred in 49.1% (26/53) of those on rituximab, 19.2% (5/26) of those on natalizumab, and 11.5% (6/52) of healthy controls. In addition, 8/53 (15.1%) in the rituximab group and 1/26 (3.8%) in the natalizumab group were hospitalized. All 6/52 (11.5%) in the control group had mild infection, and none were hospitalized. No deaths occurred in any group. On statistical analysis, the occurrence of COVID-19 infection in the rituximab group was significantly higher when compared to natalizumab (P = 0.0141) and healthy controls (P < 0.001). Hospitalizations were significantly higher in the rituximab group when compared to healthy controls (P < 0.006).

Conclusion:

MS patients treated with rituximab were more likely to experience COVID-19 infection compared to those treated with natalizumab and healthy controls. Hospitalization was more frequently seen in patients treated with rituximab compared to healthy controls.

INTRODUCTION

The impact of coronavirus disease 2019 (COVID-19) infection on people living with multiple sclerosis (PwMS) on different immunomodulating therapies like rituximab and natalizumab is unknown in the Indian population. There is a potential concern that PwMS on B-cell therapy, like rituximab, may exhibit greater susceptibility to infection compared to those receiving natalizumab. Several studies have reported conflicting findings regarding the correlation between COVID-19 infection rates and rituximab treatment. Few similar studies have explored COVID-19 infection rates in PwMS receiving natalizumab. Currently, no studies provide a comparative analysis of the incidence and severity of COVID-19 infection among patients on rituximab, natalizumab, and healthy controls.

The objective of this study was to determine the incidence and severity of COVID-19 infection in PwMS receiving rituximab, natalizumab, and healthy controls.

METHODS

This retrospective study was conducted at the neuroimmunology clinics of four centers in South India. The study was conducted for a period of 6 months from July 2022 to December 2022. The contact details of PwMS on rituximab and natalizumab were extracted from the medical records of the multiple sclerosis (MS) registry from February 2020 to December 2022, during the active phase of the COVID-19 pandemic. The MS registry was maintained in the main center, and patients were referred from the other three centers to the main center. The study was approved by the Institutional Review Board of the coordinating center. Once the diagnosis was confirmed and the therapeutic plan was made, these patients were further followed up in their respective centers. All patients met McDonald’s 2010 or 2017 criteria for diagnosis of MS. The healthy controls recruited for the study were the age- and sex-matched relatives of PwMS. The participants were telephonically interviewed with a detailed questionnaire covering COVID-19 infection, its duration, severity, hospitalization, need for intensive care, death, and MS relapse. The main outcome was the occurrence of COVID-19 infection. The secondary outcomes were hospitalization, intensive care unit (ICU) admission, death, post-COVID-19 relapses, and post-vaccine relapses. Patients who had a definitive diagnosis of COVID-19 infection based on reverse transcription polymerase chain reaction testing or the rapid antigen test on the nasopharyngeal swab were included in the study. Patients requiring hospitalization or having breathlessness were considered to have severe disease. A relapse was considered as post-COVID or post-vaccine related if it occurred within 3 months of COVID infection or vaccination. Data collected was entered into a Microsoft Excel sheet, and IBM Statistical Package for Social Sciences software (version 25) was employed for analysis. Measurements were reported as mean ± standard deviation. The groups were compared for the rates of COVID-19 infection, hospitalization, ICU admission, death, post COVID-19 relapses, and post-vaccine relapses. The statistical methods employed were the Chi-square test and Fisher’s exact test. A Chi-square analysis was conducted to compare among the three groups. In addition, comparisons were made between the two groups receiving disease-modifying therapy (DMT; rituximab and natalizumab) and between each DMT group and healthy controls using Fisher’s exact test. The study proposal was reviewed by the ethical committee of the institution and the approval from the ethics committee was received on the 10^th of December 2020.

RESULTS

During the study period from July 2022 to December 2022, we recruited 53 patients (35 females and 18 males) with MS on rituximab, 26 patients (16 females and 10 males) on natalizumab, and 52 healthy controls (25 females and 27 males). The mean age of rituximab-treated PwMS and natalizumab-treated PwMS was 36.7 ± 9.9 and 36.6 ± 14.1 years, respectively. Table 1 summarizes the demographic details of the patients receiving rituximab and natalizumab and healthy controls. The rituximab regimen used was 500 mg every 6 months in the majority of patients (44/53, 83%), while the remaining patients were on 1 g every 6 months (9/53, 17%). The dose selection between 500 mg and 1 g was based on clinical symptoms and CD19/20 counts. The natalizumab group patients were receiving 300 mg every 28 days. COVID-19 infection occurred in 26/53 (49.1%) rituximab-treated PwMS, 5/26 (19.2%) natalizumab-treated PwMS, and 6/52 (11.5%) healthy controls. Of the 53 PwMS treated with rituximab, eight (15.1%) were hospitalized. Among the nine patients who received 1 g as their last dose, only one (11%) had severe COVID-19 infection and was hospitalized, while seven (15.9%) of the remaining 44 patients who received 500 mg were hospitalized. There was no statistical significance between the groups (P = 0.71). In the natalizumab group, 1/26 (3.8%) was hospitalized. None of the patients hospitalized had any systemic illnesses such as diabetes, hypertension, cancer, or renal disease with or without dialysis. All 6/52 (11.5%) in the control group had a mild infection and none were hospitalized. One patient (1.9%) in the rituximab group required ICU admission. There were no deaths in any group. After COVID-19 infection, one patient in the rituximab group had a relapse, while none on natalizumab relapsed. COVID-19 vaccination was done in 35/53 (66.0%) rituximab patients (24 Covishield and 11 Covaxin), 23/26 (88.5%) natalizumab patients (23 Covishield, 2 Covaxin, and 1 BioNtech), and 37/52 (71.2%) controls (37 Covishield). Post-vaccine, 4/35 (11.4%) rituximab patients had a relapse, while in the natalizumab group, 3/23 (13.0%) had a relapse.

Table 1.

Demographic characteristics of healthy controls and patients with multiple sclerosis receiving rituximab and natalizumab

		Rituximab		Natalizumab		Healthy Controls
Number		53		26		52
Age in Years (mean±SD)		36.7±9.9		36.6±14.1		36.07±9.51
Sex (female: male)		35:18		16:0		25:27
Disease Duration in years (mean±SD)		12.66±7.39		9.47±7.36		-
EDSS (mean±SD)		3.19±2.09		2.67±2.59		-
Presence of Bulbar weakness		None		None		-

The occurrence of COVID-19 infection was significantly higher in the rituximab group compared to the natalizumab group (P < 0.0141) and healthy controls (P < 0.001). Though the natalizumab group had more infections compared to healthy controls, it was not statistically significant (P = 0.49). Hospitalizations were significantly higher in the rituximab group when compared to healthy controls (P < 0.006). There was no significant difference between the rituximab and natalizumab groups in terms of rates of hospitalization (P = 0.258). The number of people who received vaccinations was higher in the natalizumab group when compared to the rituximab group (88.5% vs. 66%, P = 0.056). After COVID-19 vaccination, relapses were more in the natalizumab group compared to the rituximab group, but the difference was not statistically significant (P = 1.00). The results of the study are summarized in Table 2.

Table 2.

Rates and severity of COVID-19 infection and relapses in persons with multiple sclerosis on RTX, NTZ, and HC

		Rituximab n=53		Natalizumab n=26		Healthy Controls n=52		P
COVID-19 infection, n (%)		26 (49.1)		5 (19.2)		6 (11.5)		0.0141 (RTX vs NTZ) <0.001 (RTX vs HC) 0.49 (NTZ vs HC)
Hospitalization, n (%)		8 (15.1)		1 (3.8)		0		0.258 (RTX vs NTZ) 0.006 (RTX vs HC) 0.333 (NTZ vs HC)
ICU, n (%)		1 (1.9)		0		0		-
Death, n (%)		0		0		0		-
Post COVID-19 Relapse, n (%)		1 (1.9)		0		NA		-
Post Vaccine Relapse, n/total* (%)		4/35 (11.4)		3/23 (13.0)		NA		1.00 (RTX vs NTZ)

*Number of patients who received vaccination from each group

DISCUSSION

The impact of COVID-19 infection in MS patients was variable, and one of the factors influencing the prognosis was the type of DMT. In the current study, we compared the impact of COVID-19 infection on PwMS on rituximab and natalizumab and healthy controls and observed that COVID-19 infection was more common in the rituximab group compared to the natalizumab group and healthy controls. During the early phase of the pandemic, an Iranian study showed an increased rate of severe acute respiratory syndrome coronavirus 2 infection in patients receiving rituximab.[1] In the present study, PwMS on rituximab had approximately five times the chance of COVID-19 infection compared to healthy controls and more than twice as much as compared to natalizumab. Our results align with other studies that showed higher rates of COVID-19 infections in rituximab-treated MS patients.[2,3,4] In an Indian study by Iyer et al.,[5] 19.4% (12 out of 62) of MS patients on rituximab developed COVID-19 infection. Patients on B-cell therapies like ocrelizumab were also found to have more severe and prolonged infections by Sormani et al.[4] In the study by Smith et al.,[3] 25.4% (35/138) of patients on rituximab had COVID-19 infection, while 14.7% (36/245) patients on natalizumab were infected; however, there were no healthy controls.

In the current study, the rituximab-treated group showed a significantly higher number of hospitalizations when compared to healthy controls. Though hospitalizations were higher in the rituximab group when compared to the natalizumab group, there were no statistically significant differences. Previous studies on MS patients receiving DMTs have also reported severe and prolonged COVID-19 infections, particularly with B-cell therapies.[3,6] In a comparative study by Simpson-Yap et al.,[7] it was observed that patients treated with rituximab exhibited a higher likelihood of hospitalization (27.8% vs. 11.3%) and mortality (2.8% vs. 1.4%) compared to those receiving natalizumab. When rituximab was contrasted with natalizumab, the former demonstrated elevated risks of hospitalization (adjusted odds ratio [aOR] 2.88, 95% confidence interval [CI] 1.68–4.92), ICU admission (aOR 3.23, 95% CI: 1.17–8.91), and mechanical ventilation (aOR 5.52, 95% CI: 1.71–17.84). However, rituximab did not exhibit a statistically significant increased risk of mortality (aOR 1.34, 95% CI: 0.27–6.56). In the current study, none of the patients died due to COVID-19, but another center in the same city reported one death out of 12 COVID-19–infected cases.[5]

However, in a larger study from California conducted by Langer-Gould et al.[8] involving 1895 PwMS treated with rituximab, a surprisingly lower infection rate was observed among rituximab-treated PwMS compared to the general population, which consisted of approximately 4.8 million non-MS individuals. The proportion of PwMS treated with rituximab who contracted COVID-19 during the study period (n = 24, 1.27%) was comparable to that in the non-MS population (n = 65,520, 1.36%, P = 0.72). This favorable outcome was attributed to several factors, including the adoption of extended dosing intervals of 12 months or more, lower maintenance doses of 500 mg, general advice given to rituximab-treated PwMS to maintain a high degree of precaution, and the infrequent use of rituximab in patients with comorbidities predisposing to serious infections. In addition, the study noted a significant absence of severe COVID-19 infection among PwMS treated with rituximab compared to the general population. Out of the 24 rituximab-treated PwMS with COVID-19 infection, 16 (66.7%) experienced mild symptoms, while eight (33.3%) had a moderate course leading to hospitalization, and no severe infections or deaths were reported. In comparison, among the approximately 65,000 non-MS individuals who contracted COVID-19, 92.8% had mild infections, 5.8% experienced moderate infections, and 1.4% died. The increased risk of a moderate COVID-19 course was observed shortly after the most recent rituximab treatment, with a median of 2.5 months (range: 2 days to 4.5 months). Furthermore, the dose of rituximab administered during the last infusion (more than or equal to 1000 mg) was identified as an independent predictor of COVID-19 severity, while the cumulative lifetime dose did not show such an effect. However, in our study, we could not find any difference in COVID-19 severity between those who received 500 mg and 1 g as their last dose. In Table 3, we have compared our findings with other studies that have analyzed COVID-19 infection in PwMS on rituximab or natalizumab.

Table 3.

Comparison of the present study results with other published studies on COVID-19 infection in PwMS on RTX versus NTZ

Study		Group		n (No. of people)		COVID-19 infection, n/total (%)		Severe/hospitalization n/total (%)		Death n/total (%)
Smith et al.[3]		RTX		138		35/138 (25.4)		5/35 (14)*
		NTZ		245		36/245 (14.7)		1/36 (3)*
Simpson-yap et al.[7]		RTX		2340		258/2340 (11)		70/251 (27.9)		7/251 (2.8)
		NTZ		2340		221/2340 (9.4)		24/209 (11.5)		3/209 (1.4)
Langer-Gould et al.[8]		RTX		1895		24/1895 (1.27)		8/24 (33.30)		0
		NON-MS		4,813,365		65,520/4,813,365 (1.36)		3799/65520 (5.80)		922/655209 (1.40)
Present study		RTX		53		26/53 (49.1)		8/53 (15.1)		0
		NTZ		26		5/26 (19.2)		1/26 (3.8)		0
		HC		52		6/52 (11.5)		0		0

The exact reason for the association between B-cell therapy and an elevated risk of COVID-19 infection remains incompletely understood. While T cells are recognized as primary responders to COVID-19, B cells and antiviral antibodies also play a crucial role in managing the persistent phase of the infection.[9] The heightened severity and longer duration observed in COVID-19 infections among individuals undergoing B-cell therapy may be attributed to the depletion of B cells needed for clearing the virus during the persistent phase of the infection. Other proposed reasons contributing to increased infections in patients treated with rituximab may be the necessity to visit the hospital for infusion sessions, often requiring longer infusion times.[3] Studies on COVID-19–related mortality in MS patients found that deaths occurred in older, nonambulatory, and untreated patients.[4,10,11] The lack of mortality in our rituximab cohort may be due to the younger age, female preponderance, lower cardiovascular risk, and lower neurologic disability (mean Expanded Disability Status Scale of 3.18 in the rituximab group). A study by Nair et al.[12] from South India also noted a decrease in mortality and severe infection in patients of autoimmune rheumatic disease treated with rituximab. One may hypothesize that the lack of severe infections and mortality may also be due to the effect of immune depletion in dampening COVID-19–mediated immune system hyperactivation and cytokine storm. In a recent study by Januel et al.,[13] it was found that in anti -CD20–treated patients with progressive MS, female gender and omicron variant were associated with less-severe COVID-19.

We observed a similar number of relapses post-COVID-19 vaccination in rituximab-treated PwMS and natalizumab-treated PwMS. The association of DMTs with vaccine-associated relapse is not established. One study with 383 vaccinated PwMS did not find any significant association between the use of DMT and COVID-19 vaccine-associated relapse.[14]

In a study looking at predictors of COVID-19 vaccine relapse in PwMS, as per patient-reported data, the extrapolated annualized relapse rate (ARR) was 0.169 (95% CI: 0.107–0.253) in PwMS on anti-CD20 drugs (n = 287) and 0.130 (95% CI: 0.059–0.246) in natalizumab-treated patients (n = 125). These observed ARRs were not different from the prepandemic ARR (0.148; 95% CI: 0.129–0.168) for its registry of 2182 PwMS.[15]

The limitations of the present study include its small sample size, particularly in the natalizumab group, data collection based on telephonic interviews, and its retrospective nature. In addition, we did not analyze the correlation between the timing of rituximab infusion and the levels of CD19/20 with the severity of COVID-19 infection. However, this was the best possible due to the constraints of limited resources and time. The strengths of the study include a healthy control group and the availability of a comparison between rituximab- and natalizumab-treated patients. Moreover, the current study is one of the select few from the Indian subcontinent to systematically analyze COVID-19 infection in patients receiving rituximab and natalizumab.

Based on our observations and findings from other studies, we can infer that patients on B-cell therapies like rituximab face an increased risk of COVID-19 infection and hospitalization. This is particularly crucial considering the occurrence of half a million new COVID cases and 2400 new deaths reported between October 2023 and November 2023 (COVID-19 Epidemiological Update, WHO, November 24, 2023).[16] Therefore, we strongly recommend that all patients undergoing B-cell therapies take additional precautions, such as practicing social distancing, wearing masks, especially in public places, and adhering to hand sanitization recommendations.

CONCLUSION

People with MS receiving B-cell therapies such as rituximab are at an increased risk of COVID-19 infection and hospitalization. These findings offer valuable insights for making informed choices about DMTs during pandemics like COVID-19. Given the persisting COVID-19 pandemic, patients receiving rituximab or natalizumab treatment require continued adherence to preventive measures to minimize the risk of infection.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.