key: cord-1030662-yf5e71hu
authors: Iyer, Rajesh B; S, Raghavendra; M, Javeria Nooraine; R, Jaychandran
title: COVID-19 outcomes in Persons with Multiple Sclerosis treated with Rituximab
date: 2021-11-10
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2021.103371
sha: b47c76752d3d418c8f1264e2a009c619449416b6
doc_id: 1030662
cord_uid: yf5e71hu

BACKGROUND: Outcomes of COVID-19 in PwMS (persons with Multiple Sclerosis) on immunosuppressive therapies, particularly B-cell depletors, can be unpredictable. There has been a concern for postponing or avoiding use of Rituximab (RTX) during the COVID-19 pandemic. We report the course and outcomes of COVID-19 in PwMS receiving RTX. METHODS: PwMS receiving RTX who contracted COVID-19 were closely monitored by tele-consultation and/or evaluated during hospital visits. Those requiring hospitalization for oxygen therapy or admission to ICU or expiring due to COVID-19 were considered to have severe disease. Those without desaturation and manageable at home were considered to have mild disease. Disease course and outcomes were noted. RESULTS: Twelve out of 62 (19.4%) PwMS on RTX therapy developed COVID-19. Four (age 35-49 years; mean 43.5) had severe COVID; three of whom had Secondary Progressive MS (SPMS). One PwMS expired. Two had prolonged fever lasting >1 month. One demonstrated features of SARS-CoV-2 reactivation. Interval from last RTX infusion (average dose 750mg) to COVID-19 onset ranged 1-4 (mean 3.7) months. Eight PwMS had mild COVID-19 (age 26-54 years; mean 37.7); six had RRMS and two SPMS. RTX dose was lower (average dose 625 mg) and infusion to COVID-19 onset duration was longer, ranging 4-20 (mean 9.5) months. Four patients, two each from mild and severe COVID-19 groups had neurological deterioration, but none had true relapses. CONCLUSION: RTX treated PwMS may have unpredictable disease outcomes if they contract COVID-19, but may be at risk of severe disease and persistent infection. In our series higher age, SPMS, shorter interval from RTX infusion to COVID-19 onset and higher dose of RTX were noted amongst those developing severe disease. RTX should be use cautiously during the COVID-19 pandemic and if unavoidable, less frequent and lower doses should be considered. Patients receiving RTX must be counselled to follow strict COVID-19 preventive measures.

Rituximab (RTX), an anti-CD20 B-cell monoclonal antibody, is commonly used in neuroimmunological disorders. RTX acts by depleting the B-cells and suppresses the humoral immune response. It is a relatively inexpensive disease modifying therapy (DMT) for persons with multiple sclerosis (PwMS) and has been found effective in Remitting Relapsing MS (RRMS) and useful in Progressive MS (Chisari et al., 2021) . RTX has however been associated with an increased risk of infections (Luna et al., 2020) .

The natural course and outcomes of SARS-CoV-2 infection ranges from asymptomatic infection to severe disease, leading to death. PwMS on RTX therapy may be expected to have increased risk of severe COVID-19 disease, should they get infected by the SARS CoV-2 virus. However, COVID-19 outcomes in subjects receiving B-cell therapies have been nonuniform, ranging from mild course to severe disease and death (Esmaeili et al., 2021; Langer-Gould et al., 2021; Möhn et al., 2020; Montero-Escribano et al., 2020) . We observed a high incidence of severe COVID-19 disease in our PwMS on RTX when compared to the general prevalence of severe disease. We analysed the course and outcomes of COVID-19 in our PwMS receiving RTX and discuss the safety aspects of its use during the pandemic.

Data was prospectively collected from August 2020 to July 2021. PwMS treated at our institute who reported getting COVID-19 infection were included for this study. Diagnosis of COVID-19 was based on a positive SARS-CoV-2 RT-PCR report. Patients were closely monitored by tele-consultation and/or evaluated during hospital admission or subsequent hospital visits. Patients developing increase in disability (SPMS) or new deficits (RRMS) after clinical examination were considered to have worsening of MS. MRI scans were generally avoided and were done only if an acute relapse was suspected.

Those developing oxygen desaturation on pulse-oximetry and requiring hospitalization for either oxygen therapy or admission to ICU or those who expired due to COVID-19 were considered to have severe disease. Those who did not develop oxygen desaturation or breathlessness and were manageable at home were considered to have a mild disease. Disease course and outcomes were noted.

RTX had been prescribed in patients with SPMS, those transiting from RRMS to SPMS and some RRMS patients. RTX was typically initiated after baseline investigations for complete blood counts, CD19 and CD20 cell counts, Liver function tests, Kidney functions tests and exclusion of HIV, HCV and HBV viral infections. Subsequent RTX doses were guided by repopulation of CD19/20 cells. Tests were repeated after six to eight months. In patients with CD 19/20 counts < 1%, RTX was deferred for 2-3 months and the tests repeated. RTX was infused once repopulation was >1%. In patients receiving RTX for > two years, S.

Immunoglobulin-G level was additionally done to decide the dose. After an initial dose of 1000-2000 mg, subsequent doses were usually 500-1000 mg.

Sixty-two PwMS were on RTX infusions at our institute. Twelve PwMS (19.4%), five males and seven females reported having contracted COVID-19. Their demographic and clinical characteristics are given in Table- 1. and had developed bed sores during hospitalization for COVID-19. He expired three days after discharge from hospital. The exact cause of death was not clear but was likely a complication of COVID-19 pneumonia. The other two had mild walking disability with EDSS 2.5 and 3, one of whose deficits worsened. These two PwMS also had persistent fever for more than four weeks. Both had undetectable CD19/CD20 cells done about six-eight weeks after COVID-19 diagnosis. One of these subjects, a 49-year-old male (Table-1, patient no.1) contracted COVID-19 two months after RTX infusion. He showed progressive COVID-19 lung changes in CT scans done at three weeks, five weeks and ten weeks from symptom onset, characterized by development of new viral pneumonitic lesions. RT-PCR repeated by nasopharyngeal swab was positive at five weeks. He also had low immunoglobulin-G levels. Anti SARS-CoV-2 antibodies were not detectable at five weeks after initial COVID diagnosis and after 10 weeks, were found in very low titres (0.03 U/ml).

His fever and cough persisted despite symptomatic treatment and abated after re-treating with Favipiravir.

Among eight PwMS with mild COVID-19 (age 26-54yrs; mean 38.8yrs), five had RRMS and two SPMS (Table-1) . Interval from last dose of RTX to COVID onset was 4-20 months with a mean of 9.5 months. Subjects who had mild COVID-19 had received a lower dose of RTX (average 625mg) when compared to those with severe COVID-19 (mean 750mg). One patient was pregnant and had asymptomatic infection detected during routine testing prior to hospital admission for confinement.

Four PwMS had neurological deterioration after COVID-19 onset. But none shad true relapses. One patient with RRMS (Table 1 , patient no.10) developed paraparesis following two days of fever. MRI brain and spinal cord did not show any new or gadolinium enhancing lesions or increase in T2 lesion size. She improved rapidly after intravenous steroids. Three SPMS patients (Table-1 , patient no.1, 4 and 6) had worsening of existing disabilities after onset of COVID-19 symptoms. This was attributed to fever and not considered as relapses.

One of these patients expired while the other two recovered and attained their baseline EDSS scores after fully recovering from COVID-19.

The characteristics of PwMS developing mild and severe COVID-19 are summarized in RTX is a widely used DMT in PwMS. It is cost effective and has a high efficacy with a reasonable safety profile (Chisari et al., 2021) . But amongst DMTs, RTX was associated with the highest rate of serious infections (Luna et al., 2020 The incidence of severe COVID-19 in PwMS on RTX seems higher than the general population. In the general population, amongst 44415 subjects who contracted COVID-19, it was observed that 81% had mild disease, 14% had severe disease, and 5% became critically ill (Wu and McGoogan, 2020 (Sormani et al. 2021) . Use of methylprednisolone in the month preceding COVID-19 infection was also associated with a worse outcome (Sormani et al., 2021) . One of our PwMS had diabetes mellitus as a comorbidity but had a mild COVID-19 course. None of the other subjects including those with severe COVID-19 were obese or had any other comorbid illnesses. These observations implicate an independent association of RTX with severe COVID-19.

RTX has been reported to be associated with prolonged COVID-19 course, with fever lasting for more than a month and delayed worsening after an initial recovery (Leipe et al., 2020 ). Bose and Galetta reported a case of RTX associated reactivation of COVID-19 after three weeks and one of our cases confirms this potential risk (Bose and Galetta., 2021) . Two of our subjects had prolonged COVID-19 course with fever lasting more than one month after initial recovery from mild COVID-19, requiring subsequent hospitalization due to worsening of symptoms and oxygen desaturation. Ten weeks after disease onset, one of these subjects had new COVID-19 patches in lungs suggesting viral reactivation. He had undetectable CD 19+ B cells, reduced immunoglobulin-G levels and very low SARS-CoV-2 antibody titres.

The other subject also had undetectable CD+19 cells.

Our sample size was small to run statistical tests. Nevertheless, we noted shorter infusion to infection interval (mean 3.7 months), higher dosages (mean 750mg), higher age (mean 43 years), and SPMS with severe COVID-19. Rituximab causes sustained B-cell depletion. Although the half-life of rituximab is about one-week, active levels persist in the blood for about 3 months (Ghielmini., 2005) . In another study, median serum levels of RTX were found to be 20.3 ug/ml after three months of infusion which declined to 1.3 ug/ml after six months (Berinsten et al., 1998) . SPMS is associated with increasing age, duration of MS and worsening disability (Fambiatos et al 2020) . Advancing age is also a risk factor for severe COVID infections and fatality. Several reasons have been hypothesised for this including "immunosenescence"the aging of the immune system and "inflammaging"the increased systemic inflammation due to an overactive, but ineffective immune system. (Mueller et al., 2020) . These dynamics may be responsible for our observation of higher age and SPMS with severe COVID-19.

It will be of interest to know the outcomes of COVID-19 in patients on other immunosuppressive medications. The incidence of developing COVID-19 was similar in PwMS and patients with Systemic lupus erythematosus (SLE). In analysis of large data bases, (1.19%) patients with SLE contracted COVID-19 (Reder et al., 2021) . The COVID-19 Global Rheumatology Alliance (GRA) physician-reported registry observed that exposure to DMARDs and NSAIDs were not associated with hospitalisation risks in patients with rheumatic disease (Gianfrancesco et al., 2020) . But in a follow-up study, the GRA raised concerns regarding higher risk of poor outcomes with rituximab, sulfasalazine, and certain immunosuppressants and expressed caution in their use (Strangfeld et al., 2021) . Avouac et al. compared the outcomes of COVID-19 in patients with inflammatory rheumatic and musculoskeletal diseases receiving RTX (n=63) and those not on RTX (n=1027) and

observed that RTX was associated with more severe COVID-19 (Avouac et al., 2021) .

In our series, the COVID-19 course ranged from asymptomatic disease to death. The majority of available literature and our study do suggest a risk for severe COVID-19 course in subjects on RTX. Therefore, it may be desirable to explore alternate DMTs in PwMS otherwise deemed suitable for initiating on RTX.

RTX induced depletion of B-cells may be responsible for prolonged and severe disease course and indicates the importance of humoral immunity in COVID-19 recovery.

Since the initial antiviral response is primarily T-cell mediated, subjects on RTX with intact T-cells can be expected to have an initial mild disease like most general population. This might be misleading as there could be subsequent worsening and progression of disease.

The performance of the COVID-19 vaccines in B-cell depleted patients will be known in near future. In a study on five subjects on RTX who were vaccinated with BNT162b2

(Pfizer/BioNTech) vaccine, antibodies against SARS-CoV-2 were detected only in patients (n=2) who had measurable CD19+ B cells at the time of vaccination, suggesting the development of a humoral immune response only after the peripheral B cells are repopulated ( Bonelli et al., 2021) . The timing of vaccination in relation to RTX administration is critical in the immune response. Patients can be vaccinated about four-six weeks before administering RTX or after five to six months of RTX infusion after confirming the commencement of repopulation of CD19/20 cells.

The outcomes of COVID-19 infections in PwMS on RTX can range from asymptomatic disease to death, but RTX does carry an increased risk for severe disease and persistent infection. A thorough risk-benefit consideration must be carried out before prescribing RTX during the present pandemic scenario. We recommend caution in prescribing RTX during the present pandemic. If there are no other suitable treatment options available, then choosing the lowest possible RTX dose, younger patients with lesser disability and those without other systemic comorbidities could be potential considerations. Patients receiving RTX must be counselled to strictly adhere to all protective measures to prevent COVID-19 infection.

All health care professionals involved in COVID-19 care

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

COVID-19 outcomes in patients with inflammatory rheumatic and musculoskeletal diseases treated with rituximab: a cohort study

Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent lowgrade or follicular non-Hodgkin"s lymphoma

SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response

Reactivation of SARS-CoV-2 after Rituximab in a Patient with Multiple Sclerosis

Rituximab for the treatment of multiple sclerosis: a review

Coronavirus disease 2019: Favourable outcome in an immunosuppressed patient with multiple sclerosis

Rituximab and risk of COVID-19 infection and its severity in patients with MS and NMOSD

Mild Course of COVID-19 and Spontaneous Virus Clearance in a Patient With Depleted Peripheral Blood B Cells Due to Rituximab Treatment

Rituximab-associated infections

COVID-19 Global Rheumatology Alliance. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19

Global Rheumatology Alliance physician-reported registry

Multimodality therapies and optimal schedule of antibodies: rituximab in lymphoma as an example

Effect of different rituximab regimens on B cell depletion and time to relapse in children with steroid-dependent nephrotic syndrome

Multiple sclerosis, rituximab, and COVID-19

Long, relapsing, and atypical symptomatic course of COVID-19 in a B-cell-depleted patient after rituximab

Infection Risks Among Patients With Multiple Sclerosis Treated With Fingolimod, Natalizumab, Rituximab, and Injectable Therapies

COVID-19 in 7 multiple sclerosis patients in treatment with ANTI-CD20 therapies

B-cell depletion with rituximab in the COVID-19 pandemic: where do we stand?

The prevalence of COVID-19 infection in patients with multiple sclerosis (MS): a systematic review and meta-analysis

Experience in Multiple Sclerosis Patients with COVID-19 and Disease-Modifying Therapies: A Review of 873 Published Cases

Anti-CD20 and COVID-19 in multiple sclerosis and related disorders: A case series of 60 patients from

Why does COVID-19 disproportionately affect older people?

COVID-19 in Patients with Multiple Sclerosis: Associations with Disease-Modifying Therapies

Evaluation of the rate of COVID-19 infection, hospitalization and death among Iranian patients with multiple sclerosis

COVID-19 and diseasemodifying therapies in patients with demyelinating diseases of the central nervous system: A systematic review

Musc-19 Study Group. Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

COVID-19 Global Rheumatology Alliance. Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry

Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention