High SARS-COV-2 Infection Death Rate for Some MS Patients

How disease modifying therapies might interact with COVID-19 vaccines first given emergency use authorization by the Food & Drug Administration has made the situation confusing for MS pateints. Current information advises that timing of COVID-19 vaccination can better optimize effectiveness in some multiple sclerosis patients on DMTs.

The prevalence of multiple sclerosis has shown an upward trend among veterans treated at the VHA, and those patients have found the COVID-19 outbreak especially challenging. One reason is that MS increases risk of infection overall. The other difficulty is that, in some cases, disease modifying theaters appear to curb the effectiveness of novel coronavirus vaccines and immunization has to be carefully timed with MS treatment.

LEXINGTON, MA — While the COVID-19 pandemic has been difficult for everyone, multiple sclerosis patients have faced special challenges for at least two reasons: They are at increased risk of infection, in general, and common therapies affect how and when they can be vaccinated against the novel coronavirus.

That has special significance for the VA, where prevalence of MS increased over a five-year period from about 141 per 100,000 veterans in 1999 to 262 per 100,000 in veterans in 2014, according to most-recent statistics. While the rate among active-duty military personnel is only 14.9 per 100,000 and generally declining, the rate goes up significantly when retired servicemembers and other MHS beneficiaries are included.

One issue raised during the pandemic was the higher likelihood of infection among those diagnosed with MS. An article in Multiple Sclerosis & Related Disorders discussed efforts to quantify incidence of infections in patients with MS compared with a matched sample of patients without MS (non-MS).1

The study led by the Boston Collaborative Drug Surveillance Program in Lexington, MA, and including participation from the Naval Medical Center Portsmouth, VA, used two separate electronic medical databases: the U.S. DoD Military Health System and the U.K.’s Clinical Practice Research Datalink GOLD (UK-CPRD).

The focus was on patients with a first-recorded diagnosis of MS between 2001 and 2016 (UK-CPRD) or 2004 and 2017 (US-DoD) and matched non-MS patients. Researchers identified infections recorded after the MS diagnosis date (or the matched date in non-MS patients) and calculated incidence rates (IRs) and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) by infection site and type.

Results indicated that, compared with non-MS patients, MS patients had higher rates of any infection (US-DoD IRR 1.76; 95% CI 1.72-1.80 and UK-CPRD IRR 1.25; 95% CI 1.21-1.29) and a twofold higher rate of hospitalized infections (US-DoD IRR 2.43; 95% CI 2.23-2.63 and UK-CPRD IRR 2.00; 95% CI 1.84-2.17).

In fact, incidence rates of any infection were higher in females than males in both MS and non-MS patients, while IRs of hospitalized infections were similar between sexes in both MS and non-MS patients.

Especially significant was that the IR of first urinary tract or kidney infection was nearly twofold higher in MS compared with non-MS patients (US-DoD IRR 1.88; 95% CI 1.81-1.95 and UK-CPRD IRR 1.97; 95% CI 1.86-2.09) with higher rates in females than males.

“IRs for any opportunistic infection, candidiasis and any herpes virus were increased between 20 and 52% among MS patients compared with non-MS patients,” the authors wrote. “IRs of meningitis, tuberculosis, hepatitis B and C were all low.”

A report in JAMA Neurology noted that some MS patients fared especially poorly. In a registry-based cross-sectional study, Washington University St. Louis-led researchers determined that increased disability was independently associated with worse clinical severity, including death, from COVID-19. Among the risk factors that worsened outcomes were older age, Black race, cardiovascular comorbidities and recent treatment with corticosteroids.2

“Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment,” the authors suggested.

Of 1,626 patients in the study, most had laboratory-positive SARS-CoV-2 infection (1,345 [82.7%]), were female (1,202 [74.0%]), and had relapsing-remitting MS (1,255 [80.4%]). Most participants, 61.5%, were non-Hispanic White, 20.8% were Black, and 11.7% were Hispanic/Latinx; the mean age was 47.7, and nearly half (49.5%) had one or more comorbidity.

The overall mortality rate among the MS patients was calculated at 3.3% (95% CI, 2.5%-4.3%). Of those who died, 79.6% were hospitalized, 53.7% were admitted to the ICU, and 46.3% required ventilator support. As with non-MS patients, mortality increased with age, with no deaths in those younger than 35 years. The mortality rate was 1.2% for patients aged 35 to 44 years, 2.1% for those aged 45 to 54 years, 4.9% for those aged 55 to 64 years, 11.7% for those age 65 to 74 years, and 22.6% for those 75 years or older.

In terms of the nexus between race/ethnicity and death, the mortality rate was 3.5% (95% CI, 2.5%-4.9%) for white patients with MS, 4.2% (95% CI, 2.3%-6.9%) for Black patients with MS, and 1.1% (95% CI, 0.1%-3.8%) for Hispanic/Latinx patients with MS.

“Higher proportions of younger-aged Black patients with MS had worse outcomes vs. younger white patients,” researchers noted. “Clinical severity in 190 Hispanic/Latinx patients with MS was generally similar to those of White patients with MS across age levels.”

DMTs and COVID-19 Vaccines

Complicating matters is how disease modifying therapies might interact with COVID-19 vaccines first given emergency use authorization by the Food & Drug Administration. Current information advises that timing of COVID-19 vaccination can better optimize effectiveness in some multiple sclerosis patients on DMTs.

The issue of COVID-19 vaccines in MS patients was raised at the recent Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) annual meeting, Forum 2021, held virtually.3

“With the rollout of vaccines to the SARS-CoV-2 virus (aka COVID vaccines) aimed at protecting from COVID complications and viral spread, important questions have been raised with respect to individuals living with MS and particularly those on different MS DMTs,” according to an abstract for a presentation by Amit Bar-Or, MD, of the Perelman School of Medicine at the University of Pennsylvania.

Bar-Or raised several questions, including whether there is likely to be a risk of immune activation with the mRNA vaccines that might trigger MS relapse. Bar-Or also put forth concerns about use of the vaccines on patients taking DMTs and whether the therapy could affect the effectiveness of responses to COVID-19 vaccines. He further mentioned advice on timing of vaccines relative to administration of specific DMTs.

“While direct data is lacking, it is expected that different DMTs will have different impact on COVID vaccine responses, and that these differences will depend on the particular DMT mechanism of action and, when relevant, the timing of vaccination relative DMT administration,” Bar-Or noted.

The abstract pointed out that vaccine-induced neutralizing antibodies to the SARS-CoV-2 spike protein are probably important for effective protection, going on to explain, “Cell-depleting therapies, including those that deplete B-cells (egaCD20, cladribine, alemtuzumab) are likely not to impact pre-existing humoral immunity, but expected to attenuate vaccine induced antibody responses.”

In line with that, the National Multiple Sclerosis Society recently recommended dosing adaptations for some DMTs in an effort to improve novel coronavirus vaccine effectiveness. At the time of the guidance’s release, two COVID-19 vaccines were being distributed in the United States—the Pfizer-BioNTech and the Moderna vaccines—both of which are mRNA-based and require two doses. At press time, the group had not yet developed recommendations on the Johnson & Johnson vaccine, which also received an EUA from the FDA.

Based on their mechanism of action, these vaccines are expected to be safe for MS patients, regardless of the use of DMTs, according to the National MS Society, which strongly urged vaccination. It advised that patients about to start on Avonex, Betaseron, Copaxone, Extavia, glatiramer acetate, Glatopa, Plegridy, Rebif, Aubagio, Bafiertam, dimethyl fumarate, Tecfidera, Tysabri and Vumerity should not delay initiation for a COVID-19 shot, and those already taking one of these DMTs will require no adjustments. (See sidebar for other recommendations.).

“The science has shown us that the COVID-19 vaccines are safe and effective. Like other medical decisions, the decision to get a vaccine is best made in partnership with your healthcare provider,” guidance from the society stated. “Most people with relapsing and progressive forms of MS should be vaccinated. The risks of COVID-19 disease outweigh any potential risks from the vaccine.”

It also especially encouraged high-risk patients to be vaccinated as soon as possible, including those with progressive MS, those who are older, those who have a higher level of physical disability, those with certain medical conditions (e.g., diabetes, high blood pressure, obesity, heart and lung disease, pregnancy) and Black and Hispanic populations.

Awareness of Risks

Based on a survey conducted by New York City’s Icahn School of Medicine at Mount Sinai and the University of Alabama Birmingham, MS patients are well aware of their risks.

Researchers emailed a survey to patients from a large MS center in New York City during the local peak of the pandemic to assess perceptions of infection risk and adherence to MS care including appointments, laboratory studies, MRIs, and taking disease-modifying therapies (DMT).

With 529 patients responding during two weeks in April 2020, results were published in Multiple Sclerosis & Related Disorders.4

“Patients collectively showed concern about becoming infected with COVID-19 (88%) and perceived a higher infection risk due of having MS (70%) and taking DMTs (68%),” the authors reported.

On the other hand, the pandemic affected their ability to manage their disease. The study noted that patients frequently postponed appointments (41%), laboratory studies (46%) and MRIs (41%), yet noncompliance with DMTs was less common (13%).

“Decisions to alter usual recommendations for care were made by the patient more often than by the provider regarding adherence to appointments (68%), laboratory studies (70%), MRI (67%), and DMT (65%),” the study said. “Degree of concern for infection was associated with adherence to appointments (p=0.020) and laboratory studies (p=0.016) but not with adherence to MRI and DMTs.”

Among survey respondents, 35 patients reported being tested for COVID-19, of whom 14 reported a positive test.

“Patients with MS were highly concerned about becoming infected during the local peak of the COVID-19 pandemic,” researchers concluded. “Behaviors that deviated from originally recommended MS care were common and often self-initiated, but patients were overall compliant with continuing DMTs.”

While, in many cases, getting the vaccine as soon as possible might be more important than timing it with a DMT, according to the Multiple Sclerosis Society, the group suggested that timing or adjustments might be desirable, if possible, for the following disease-modifying therapies:

 

  • Gilenya, Mayzent, Zeposia — Patients about to start Gilenya, Mayzent or Zeposia should consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so the second vaccine injection is done four weeks or more prior to starting Gilenya, Mayzent or Zeposia. Those already taking Gilenya, Mayzent or Zeposia, should continue taking the medication as prescribed and get vaccinated as soon as the vaccine is available.
  • Lemtrada and Mavenclad — Those about to start Lemtrada or Mavenclad should consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so the second vaccine injection is done four weeks or more prior to starting Lemtrada or Mavenclad. Those already taking Lemtrada or Mavenclad should consider having vaccine injections starting 12 weeks or more after the last Lemtrada or Mavenclad dose, with the optimal timing of the vaccine 24 weeks or more after the last DMT dose. When possible, Lemtrada or Mavenclad should be resumed four weeks or more following the second vaccine injection.
  • Ocrevus and Rituxan (and biosimilars) — Patients about to start Ocrevus or Rituxan should consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so that the second vaccine injection is four weeks or more prior to starting Ocrevus or Rituxan. Patients already taking Ocrevus or Rituxan should consider getting the vaccine injections 12 weeks or more after the last DMT dose. When possible, Ocrevus or Rituxan should be resumed four weeks or more following the second vaccine injection.
  • Kesimpta—Patients about to initiate this DMT should consider getting the Pfizer BioNTech or Moderna COVID-19 vaccine so that the second vaccine injection is four weeks or more prior to starting. Those already taking Kesimpta should consider getting the vaccine injections four weeks after their last Kesimpta injection. When possible, Kesimpta injections should be resumed four weeks or more following the second vaccine injection.
  • High-dose steroids — Patients on this therapy should consider getting the vaccine injections three-to-five days after the last dose of steroids.

 

  1. Persson R, Lee S, Ulcickas Yood M, Wagner Usn Mc CM, Minton N, Niemcryk S, Lindholm A, Evans AM, Jick SS. Infections in patients diagnosed with multiple sclerosis: A multi-database study. Mult Scler Relat Disord. 2020 Jun;41:101982. doi: 10.1016/j.msard.2020.101982. Epub 2020 Feb 4. PMID: 32070858.
  2. Salter A, Fox RJ, Newsome SD, Halper J. Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis. JAMA Neurol. doi:10.1001/jamaneurol.2021.0688 Published online March 19, 2021.
  3. Bar-Or, A. Vaccination Responses in Settings of Different Types of MS DMTs. [Conference presentation]. ACTRIMS 2021 Forum Virtual, Feb. 25-27, 2021. https://www.abstractsonline.com/pp8/#!/9245/presentation/16
  4. Zhang Y, Staker E, Cutter G, Krieger S, Miller AE. Perceptions of risk and adherence to care in MS patients during the COVID-19 pandemic: A cross-sectional study. Mult Scler Relat Disord. 2021 Feb 23;50:102856. doi: 10.1016/j.msard.2021.102856. Epub ahead of print. PMID: 33662858; PMCID: PMC7899915.
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