key: cord-0871453-6y54tgtw
authors: Smith, Tyler E; Madhavan, Maya; Gratch, Daniel; Patel, Aneek; Saha, Valerie; Sammarco, Carrie; Rimler, Zoe; Zuniga, Guadalupe; Gragui, Dunia; Charvet, Leigh; Cutter, Gary; Krupp, Lauren; Kister, Ilya; Ryerson, Lana Zhovtis
title: Risk of COVID-19 infection and severe disease in MS patients on different disease-modifying therapies
date: 2022-03-11
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2022.103735
sha: be3bd7e0f10a91a74106911815f94ec4d3c1b879
doc_id: 871453
cord_uid: 6y54tgtw

Background: The risk of SARS-CoV-2 infection and severity with disease modifying therapies (DMTs) in multiple sclerosis (MS) remains unclear, with some studies demonstrating increased risks of infection with B-cell-depleting (anti-CD20) therapies and severity, while others fail to observe an association. Most existing studies are limited by a reliance on ‘numerator’ data (i.e., COVID-19 cases) only. Objective: To assess the risks of COVID-19 by DMT, this study aimed to assess both ‘numerator’ (patients with SARS-CoV-2 infection) and ‘denominator’ data (all patients treated with DMTs of interest) to determine if any DMTs impart an increased risk of SARS-CoV-2 infection or disease severity. Methods: We systematically reviewed charts and queried patients during clinic encounters in the NYU MS Comprehensive Care Center (MSCCC) for evidence of COVID-19 in all patients who were on the most commonly used DMTs in our clinic (sphingosine-1-phosphate receptor (S1P) modulators (fingolimod/siponimod), rituximab, ocrelizumab, fumarates (dimethyl fumarate/diroximel fumarate), and natalizumab). COVID-19 status was determined by clinical symptoms (CDC case definition) and laboratory testing where available (SARS-CoV-2 PCR, SARS-CoV-2 IgG). Multivariable analyses were conducted to determine predictors of infection and severe disease (hospitalization or death) using SARS-CoV-2 infected individuals per DMT group and all individuals on a given DMT as denominator. Results: We identified 1,439 MS patients on DMTs of interest, of which 230 had lab-confirmed (n = 173; 75.2%) or suspected (n = 57; 24.8%) COVID-19. Infection was most frequent in those on rituximab (35/138; 25.4%), followed by fumarates (39/217; 18.0%), S1P modulators (43/250; 17.2%), natalizumab (36/245; 14.7%), and ocrelizumab (77/589; 13.1%). There were 14 hospitalizations and 2 deaths. No DMT was found to be significantly associated with increased risk of SARS-CoV-2 infection. Rituximab was a predictor of severe SARS-CoV-2 infection among patients with SARS-CoV-2 infection (OR 6.7; 95% CI 1.1-41.7) but did not reach statistical significance when the entire patient population on DMT was used (OR 2.8; 95% CI 0.6-12.2). No other DMT was associated with an increased risk of severe COVID-19. Conclusions: Analysis of COVID-19 risk among all patients on the commonly used DMTs did not demonstrate increased risk of infection with any DMT. Rituximab was associated with increased risk for severe disease.

Risk of SARS-CoV-2 infection and severe disease in MS patients on different disease-modifying therapies

Whether any disease modifying therapy (DMT) for multiple sclerosis (MS) increases the risk for SARS-CoV-2 infection or severe disease (hospitalization/death) has not been resolved to date . Some studies show increased risk of infection or severe COVID-19 with anti-CD20 therapies [5, 7, 8, 12-14, 17, 18, 16, 20, 23-26] while others fail to detect an increased risk [6, 1-4, 9-11, 15, 19, 21, 22] . The discrepant conclusions between these studies may be due in part to methodological limitations. Studies that examined COVID-19 risk across DMTs frequently relied on numerator data only, i.e., did not account for the frequency with which each DMT is used in the respective MS population. To properly assess the risks per DMT, one needs both numerator data (the number of COVID-19 cases occurring on a given DMT) as well the denominator data (total number of patients on that DMT).

The few studies that used both numerator and denominator data to estimate relative risk of SARS-CoV-2 infection by DMT are limited by incomplete data capture. For example, the analysis of the IBM Explorys database (>72 million patients in the US) identified an increased risk of infection with anti-CD20 therapies, but could not yield "strong conclusions" about the effect of DMT on hospitalization and deaths due to the very low incidence of severe disease, as well as cases in general (likely an undercount of mildly symptomatic, asymptomatic, or unconfirmed SARS-CoV-2infections) [18] . Moreover, only 20% of MS patients in this dataset had an open DMT prescription, which is a surprisingly low percentage for MS patients and underscores gaps in the data [18] . An Iranian study from an early phase of the pandemic that utilized numerator and denominator data had a small total number of COVID cases (n=68), likely due to the requirement of positive SARS CoV-2 PCR or lung CT scan supporting the diagnosis of COVID-19, and showed an increased rate of SARS-CoV-2infection in patients on rituximab [8] .

To overcome some of these methodologic limitations, we set out to systematically collect both numerator (number of COVID-19 cases on DMTs of interest including both clinician-diagnosed and lab-confirmed cases) and denominator (number of patients on DMTs of interest) data for the most common DMTs prescribed in the NYU Multiple Sclerosis Comprehensive Care Center (NYU MSCCC). We present the adjusted risks of SARS-CoV-2 infection and of severe disease per DMT among our MS patients receiving fumarates, sphingosine-1-phosphate receptor (S1P) modulators, natalizumab, and two anti-CD20 therapies (rituximab and ocrelizumab) during the first 15 months of the COVID-19 pandemic (February 2020 to May 2021).

Inclusion criteria for the denominators were: clinician-diagnosed MS; actively followed at the NYU MSCCC (at least 2 clinic visits in the past 2 years); and on treatment with a commonly used DMT during the period between February 2020 and May 2021. The commonly used DMTs in our practice were: 1. fumarates (FUM: dimethyl fumarate and diroximel fumarate), 2.

Sphingosine-1-phosphate receptor modulators (S1P modulators: fingolimod and siponimod), 3. natalizumab (NAT), 4. ocrelizumab (OCR), and 5. rituximab (RTX). Fumarates and S1P modulators were each analyzed as a medication class, because the number of patients on siponimod and diroximel fumarate were too small for separate analysis. Patients on rituximab and ocrelizumab were analyzed separately since adequate number of patients were available.

Patients on other DMTs (e.g., platform injectables, teriflunomide, alemtuzumab, cladribine) were not included in this study as the number of patients on these therapies in our practice was too small to enable meaningful statistical comparisons.

Patients who contacted the center or were seen during routine clinic visits between February 2020 and May 2021 were queried regarding SARS-CoV-2 infection using a standardized instrument that included questions regarding common COVID-19 symptoms (per CDC clinical case definition criteria), such as fever, cough, chills, loss of taste and smell, and dyspnea, and if they had been formally diagnosed with COVID-19 either clinically by a medical professional and/or underwent laboratory testing for SARS CoV-2 (a copy of the lab report was required for the case to be defined as 'laboratory-confirmed'). Additionally, we undertook a systematic chart review of all actively followed MS patients receiving DMTs of interest to identify patients with was defined as hospitalization and/or death. Comorbidities relevant to COVID-19 severity were collected for COVID-19 cases (numerators) only: cancer; cardiovascular disease; cerebrovascular disease; chronic kidney disease; chronic liver disease; chronic lung disease; diabetes; hypertension, and obesity [28] . For hospitalized patients, inpatient records were reviewed when available. Vaccination status was not collected, as no vaccines were available at the start of the study period.

Descriptive statistics (frequency distribution for categorical variables and mean, SD, median, interquartile range, minimum, and maximum for continuous variables) were calculated for both numerator and denominator data. Descriptive statistics and Chi-Square/Fisher Exact tests were used for exploratory analyses. Univariate logistic regression was used to screen variables with a p-value criterion of p < 0.05 for entry into the model selection procedure. Multivariable logistic regression model was performed with the following variables as predictors: age, race/ethnicity, and DMT to calculate risk of infection. The risk of severe COVID-19 was calculated for the entire sample (severe COVID-19 on a given DMT per all individuals on given DMT) as well as for those with any SARS-CoV-2 infection (severe COVID-19 on a given DMT per all COVID-19 cases on a given DMT). Age, race/ethnicity, DMT, and BMI where available (BMI was only collected for COVID-19 cases), were used as predictors to assess risk of severe disease. Analysis of maximum likelihood estimates was also done. A sensitivity analysis was conducted for "laboratory-confirmed COVID-19" cases only. Fumarates were used as a reference group, similar to prior studies, because fumarates have not been identified to impart an increased risk of infection and are frequently used in clinical practice [29, 30, 18, 16] .

NYU Grossman School of Medicine Institutional Review Board approved the study. Informed consent was not required for this retrospective study.

Anonymized data can be made available upon request for research purposes by submitting a request to the corresponding author.

We identified 1,439 MS patients on DMTs of interest (mean age: 41.2 ± 12.1 years; 71% female, 54% non-White). Demographics and disease characteristics of patients on each of the five DMT groups are shown in Table 1 . We identified 230 patients in our sample with SARS-CoV-2 infection -173 (75%) were laboratory-confirmed and 57 (25%) clinically-suspected . The average age of patients with SARS-CoV-2 infection was 39.9 ± 12.3 years, 75% were female, and 57% were non-White.

Demographics and disease characteristics of COVID-19 cases by DMT group are shown on Table 2 . The proportion of infected patients was highest for rituximab (25%), followed by fumarates (18%), S1P modulators (17%), natalizumab (15%), and ocrelizumab (13%). The proportion of lab-confirmed cases was lower in patients on anti-CD20 (69% for ocrelizumab and 60% for rituximab) than in patients on other therapies (87% fumarates, 84% S1P modulators, and 81% natalizumab). The proportion of patients with at least one COVID-19 relevant comorbidity was lowest in the rituximab group (20%) and highest in the fumarate group (38%). Mean duration on the current therapy was approximately 4.5 years for all DMT except for ocrelizumab, for which the mean duration on current therapy was 1.8 years. age group as shown in Figure 1 . Sensitivity analysis for predictors of SARS-CoV-2infection

using only laboratory-confirmed COVID-19 cases yielded similar results (data not shown). Characteristics of severe COVID-19 cases by DMT group are shown in Table 3 . [31, 32] , infection [33] , and hospitalization from infections [25] .

Alternatively, rituximab may cause a more pronounced immune defect than ocrelizumab per dose, in which case we would expect difference in risk of COVID-19 severity between RTX and OCR to persist independent of treatment duration. It is also possible that differences between RTX and OCR are unrelated to treatment and were unaccounted for in the multivariable analysis (i.e., unknown confounders).

There are several other potential explanations for why the effect of anti-CD20 therapies are more evident in some studies than others. Ascertainment bias is an important potential source of influence in both the present and prior similar studies. Patients on DMTs that are regarded to be more immunosuppressive and therefore considered 'high risk' for COVID-19 complications (e.g., anti-CD20 therapies) may be more prone to get testing for their symptoms and to report COVID-19 diagnosis to their provider than patients who are on presumably 'lower risk' DMT (e.g., fumarates). There may be some evidence for ascertainment bias in our data as there was a higher proportion of suspected (but not lab-confirmed) infections with the two anti-CD20 therapies compared to other DMTs (33.9% for anti-CD20 versus 15.3% for other DMTs; p = 0.001). However, it is also possible that anti-CD20-treated patients, which are much less likely to generate SARS CoV-2 specific antibodies following infection [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] , are therefore more likely to remain 'suspected but not confirmed given the lack of detectable antibody results with commercially available tests following infection. Furthermore, patients on infusion therapies tend to have more frequent contact with the physicians and therefore more opportunities to report an infection. In our study, we sought to mitigate against this bias by systematically reviewing all active patients on all DMTs independent of DMTs' presumed risk for COVID-19 complications.

A limitation of our study is that we did not systematically assess the incidence of SARS-CoV-2 infection in our patient population. As this was not our clinical practice, we are not able to report on the seroprevalence of asymptomatic infections in our patient populations. However, we have encountered asymptomatic patients who had positive SARS-CoV-2 antibody tests, either because they requested this test, were tested by outside providers, or were tested as part of unrelated research studies. These incidentally discovered asymptomatic cases were included in the analyses. However, it was not the aim of our study to comprehensively assess rate of asymptomatic infection, and our numbers almost certainly reflect an undercount of asymptomatic cases.

The crude death rate in our study, 0.87%, is among the lowest reported for MS cohorts [1-6, 9-12, 17, 18, 8, 20, 22, 24, 25, 37, 44, 45] . This may be due to the fact that we excluded untreated patients, who tend to be older, more disabled, and to have a higher number of comorbidities and more frequently developed severe disease [5, 16, 23] . Another possible reason may be related to anti-CD20 dosing adjustments implemented in our clinic at the onset of the pandemic. Due to concern for increased severity of COVID-19 with anti-CD20 therapies at the start of the pandemic, we delayed infusions in stable patients, sometimes extending the interval between doses by up to a year or, on occasion, even longer. As time from infusion may be an independent predictor of COVID-19 severity [14] , it is possible that the practice of delaying infusions may have led to better outcomes in patients on anti-CD20 therapies in our clinic than would be expected with the standard 6-month dosing intervals.

Improvement in COVID-19 management over the course of this study such as introduction of monoclonal antibodies to reduce hospitalization and use of dexamethasone in hospitalized patients, may also account for lower severity and fatality rates [17, 19] . In addition, increased accessibility to testing led to improved detection of mild cases, which was not possible during the early phase of pandemic.An estimated 78% of cases in the United States were undocumented in 2020, so non-hospitalized cases were mostly undetected [46] . Finally, three vaccinations for COVID-19 received emergency use authorization (EUA) during the latter half of this study period [47] [48] [49] , and patients on anti-CD20 therapies in particular were encouraged to vaccinate early. Of the 39 SARS-CoV-2 infections occurring between January 2021 (when SARS-CoV-2 vaccines started to become available to select patients) to May 2021 (end of our study period), a total of only 10 individuals reached fully-vaccinated status (defined as 2 weeks after completion of primary vaccine series), and only 3 of these individuals had breakthrough infections after becoming fully vaccinated. Given these small numbers, it is difficult to draw conclusions as to whether vaccination may have preferentially protected patients on some DMTs more than others.

It is unlikely that vaccination had impacted our analyses, as patients who were infected with SARS CoV-2 were overwhelmingly infected during pre-vaccination period or did not reach fully-vaccinated status during this early phase of vaccination period.

Among limitations of our study is a relatively small sample size, which may have precluded detection of statistically significant differences for severe outcomes on anti-CD20 agents and other DMTs (type 2 errors). We would need a sample size of 1,141 per each DMT group to detect an increase in likelihood of death from 2% to 4%, with an α of 0.05, a β of 0.2 and a power of 0.8 [50] . Ultimately, relatively low fatality and hospitalization rates across all DMTs in our study is reassuring. Another limitation was the lack of access to gold standard PCR SARS-CoV-2 testing in the early phases of the pandemic, which we sought to mitigate by assessing We also examined other patient characteristics as risk factors for SARS-CoV-2 infection or severe disease. Hispanic ethnicity and younger age were predictors of infection in our study, which may be a reflection of the difficulty with which younger and Hispanic patients, many of whom may be 'essential workers,' live in more crowded conditions, and were unable to socially isolate to limit their exposure to the SARS-CoV-2 virus compared to older and more resourcerich patients. Hispanic ethnicity was also a risk factor for SARS-CoV-2 infection and complications in other studies from our area [51, 52] and in the United States [53] . Older age, obesity, and worse ambulation status are known risk factor for severe disease, and these findings were generally reflected in our sample as well [1, 4, 20, 17, 54] . Some risk factors for COVID-19 severity such as presence of certain comorbidities and insurance status (as a proxy for socioeconomic status) [55, 56] were not observed in our study, likely due to a limited sample size and a relatively young population. Due to lack of resources, we limited in-depth chart review for relevant comorbidities to the 230 'numerator cases' and did not collect these data on all 1,439 'denominator' patients in our practice.

In conclusion, our single-center analysis of SARS-CoV-2 infection and severe disease in MS patients, does not suggest that any DMT increases the risk of infection. We did observe an association between severe infection and rituximab in some of our analyses. We did not observe increased risk of COVID-19 complications with ocrelizumab, which may be due to differences in the extent of B-cell depletion under different therapies, or due to duration of therapy, or other factors. Given the fact that anti-CD20 therapies have been identified as a risk factor for worse outcomes in other studies [5, 7, 8, 12-14, 17, 18, 16, 20, 23-26] , it is prudent to recommend extra precautions in B-cell depleted individuals, including booster vaccinations as recommended by federal health authorities, maintaining work-from-home conditions when feasible during times of local surges in COVID-19 cases, as well as extending dosing intervals between infusions or switch to non-anti-CD20 DMTs. .

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Funding: This work was supported by an investigator-initiated grant from The Consortium of Multiple Sclerosis Centers.