Article In Brief
Most therapies for multiple sclerosis and neuromyelitis optica spectrum disorder should be continued and not stopped during the COVID-19 pandemic, MS experts agree. But there are also pros and cons of starting certain B-cell depleting and other therapies.
For most patients with multiple sclerosis (MS), the benefits of staying on therapy will outweigh the risks of stopping due to concerns over COVID-19, according to new guidelines for treating MS during the pandemic.
Even in those with a documented mild case of COVID-19, continued treatment with most MS medications may be reasonable, the guidelines recommend. However, they emphasize: “Neurologists should have a lower threshold for stopping treatment in people taking therapies with greater immunosuppressive effects and those with risk factors for a more severe disease (older age, comorbidities), or if COVID-19 symptoms are deteriorating.”
Published online in Neurology on April 2 by a team of MS neurologists from the United States, Australia, The Netherlands, and the United Kingdom, the new guidelines cover both MS and neuromyelitis optica (NMO) spectrum disorder. The guidelines differ only slightly from guidelines previously released by the National Multiple Sclerosis Society, the Italian Society of Neurology, and other groups.
Even so, MS neurologists not involved in preparing the recommendations welcomed their publication.
“Kudos to the authors for taking the time to do this when we're all under so much pressure,” said Annette Langer-Gould, MD, PhD, the regional lead for clinical and translational neuroscience for the Southern California Permanente Medical Group/Kaiser Permanente.
Based on prior experience with other viral infections in people with MS, the recommendations will likely need to be updated as data emerges from actual cases of patients who develop COVID-19.
“New data are emerging quickly from clinical experience and from registries that have been established for MS patients with COVID-19,” said the first author of the paper, Wallace Brownlee, MD, PhD, a neurologist with the Queen Square MS Centre and the National Hospital for Neurology and Neurosurgery in London.
Indeed, one recommendation in the paper is already out of date. “Face masks are only recommended for people who are coughing or sneezing, or for those caring for a patient with suspected COVID-19 infection,” the guidelines stated. By now, of course, most public health recommendations call for wearing face masks whenever people are in public and are unable to stay at least six feet away from others.
Otherwise, MS neurologists told Neurology Today that they had few if any disagreements with the guidelines as published. In particular, they all agreed that IV treatments with drugs known to cause significant declines in immune function should be avoided or delayed as long as possible.
Dr. Brownlee and other MS neurologists urged any neurologist treating a patient with MS who develops a COVID-19 infection to submit data to one of the patient registries that have been established. In North America, the National MS Society and the Consortium of MS Centers have established the Coronavirus and MS Reporting Database at www.covims.org.
The Guideline Recommendations
For MS patients who are just beginning treatment, Dr. Brownlee said, “We recommend that neurologists take a cautious approach to initiating patients on treatments that can be associated with periods of significant immune suppression, including autologous hematopoietic stem cell transplantation, alemtuzumab and cladribine.”
Although acute MS relapses are often treated with a short course of high-dose IV methylprednisolone, such treatments should be avoided during the pandemic, the guidelines stated. “High-dose steroids hasten the recovery from MS relapses, but do not influence the final degree of recovery,” the paper noted. Because steroids can increase the risk of infection, neurologists should have a higher threshold for offering them during the COVID-19 pandemic, according to the guidelines.
A few disease-modifying therapies (DMTs), including interferon-beta and glatiramer acetate, do not increase the risk of systemic infections. Other DMTs, however, “do have immunosuppressive effects with alterations in lymphocyte number, trafficking, proliferation and function, with an increased risk of infections, including viral infections and respiratory infections,” the guidelines stated.
“People with MS who are profoundly lymphopenic, for example, after treatment with alemtuzumab or less commonly during treatment with cladribine, fingolimod or dimethyl fumarate, may be at higher risk.”
As reasonable as such concerns appear to be at this time, the paper noted that no data specific to MS patients with COVID-19 has yet emerged supporting them.
For patients scheduled for routine treatment with alemtuzumab or cladribine, “We recommend delaying treatment with these therapies,” the paper stated. Likewise, standard every six-month dosing with ocrelizumab or rituximab can also be delayed in most cases.
“B-cell depletion frequently lasts much longer than the scheduled dosing interval,” the recommendations noted. “Extended interval dosing should be considered, especially in patients who are B-cell depleted...or [in] those with low levels of immunoglobulin-G. Extended interval dosing is already widely used in patients treated with natalizumab because of observational data showing a reduced risk of progressive multifocal leukoencephalopathy. Whether this approach reduces the risk of other infections is unknown but should be considered during the COVID-19 pandemic to reduce hospital visits.
For MS patients who are hospitalized with a severe COVID-19 infection, “consideration should be given to stopping treatment,” the guidelines state. “Treatment can be restarted after four weeks, or when symptoms have fully resolved, keeping in mind the risk of rebound MS activity with S1P modulators and natalizumab. Neurologists should alert intensive care physicians to the importance of fever management in people with MS.”
Patients with neuromyelitis optica spectrum disorder who do not have a COVID-19 infection should be encouraged to continue attack-prevention therapies, because relapses of NMOSD can be devastating. If the need to stop or delay treatment in such patients arises, “then moderate dose corticosteroids (e.g. prednisolone 20mg) can be used to prevent relapses in the short to medium term,” the guidelines recommended.
Experts Endorse the Guidelines
Dr. Langer-Gould echoed the guidelines' concern about MS drugs associated with lymphopenia.
“With COVID-19, we're seeing something very unusual—that in the people who do poorly, almost all of them have lymphopenia when they're admitted,” she said. “Any drug you're on that is causing T-cell lymphopenia is more likely to increase your risk of getting a severe case of COVID. So they have correctly identified the ones to stay away from, including alemtuzumab and cladribine, but I would add fingolimod, dimethyl fumarate and other S1P modulators to that list.”
Starting in early March, she said, “We actively reached out to patients on dimethyl fumarate and S1P inhibitors and are switching them, depending on their disease severity, either to interferon and glatiramer acetate, or if they had active disease, then we switched them to either rituximab or natalizumab.”
But for all her patients other than those on interferon-beta or glatiramer acetate, she said, “We're telling them to consider themselves immune-suppressed. They should immediately get themselves tested for COVID-19 if they develop fever or shortness of breath.”
Her practice recently had an MS patient who had been stable on natalizumab until suddenly developing a high titer positive antibodies against JC Virus. “The patient is now at increased risk of progressive multifocal leukoencephalopathy,” Dr. Langer-Gould said.
“Our plan had been to switch them to rituximab, but then they developed a COVID-19 infection and are mildly symptomatic. That's a big problem, because you need to pre-treat for rituximab with steroids, potentially increasing the risk of a more severe case of COVID-19, and the infusion is long, which raises the risk of infecting the nursing staff at the infusion center. We've decided to give her another dose of natalizumab eight weeks after her last dose. It's a short infusion, and we don't have to pre-treat with steroids. But what's the right decision?”
Timothy L. Vollmer, MD, FAAN, professor of neurology at the University of Colorado Health Sciences Center and medical director of the Rocky Mountain MS Center, said that most of his group's patients are on ocrelizumab.
“We probably didn't need to be dosing patients every six months,” he said. “As a result of COVID-19, we're reevaluating the dosing strategy. We're checking their B cells and antibody levels, and if they are still depleted, we wait another two months. It will take some patients a year or more before they begin to normalize their B cells. Dosing less frequently will also decrease costs substantially and make the drug more attractive for patients to use.”
One clear effect of the COVID-19 pandemic is that many MS patients are reaching out to their neurologists about what it means for them.
“My colleagues and I have been receiving many phone calls and messages about our recommendations,” said Bardia Nourbakhsh, MD, assistant professor of neurology at Johns Hopkins. “We try to extrapolate the information that we have from other viral infections.”
Dr. Nourbakhsh said he had been contacted the week of April 13 by a community neurologist whose patient had developed a severe, disabling, demyelinating relapse that did not improve after IV steroids.
“My recommendation was for the neurologist to set up a plasma exchange,” he said. “I would not delay the treatment of a serious relapse that could affect the mobility or vision of the patient. Treating an actual condition takes precedence over the possibility of coming into contact with coronavirus.”
Bianca Weinstock-Guttman, MD, director of the Jacobs MC Center at the University of Buffalo and director of its Pediatric MS Center of Excellence, said she recommends that all MS patients should be reminded, now more than ever, to follow basic daily health recommendations.
“Supportive recommendations for patients include keeping interactions with friends and relatives through video, exercising via YouTube, maintaining a healthy diet, and vitamin supplementation, especially vitamin D,” she said.
Is There an Unexpected Benefit?
Joseph Berger, MD, FAAN, professor and associate chief of the Multiple Sclerosis Division at the University of Pennsylvania School of Medicine, noted that the very same tendency of some MS drugs to suppress immune function could in fact benefit COVID-19 patients who develop acute respiratory distress syndrome (ARDS).
“Individuals who end up developing ARDS are not dying because of unsuppressed viral replication,” Dr. Berger said. “Rather, it's an overly robust immune response, a cytokine storm, that appears to give rise to the ARDS. Many of the drugs we use may actually have a beneficial effect on the phase of the illness that results in high morbidity and mortality.”
He pointed out that a non-randomized, open-label trial is underway in China to test the effect of giving fingolimod to 30 patients with COVID-19 in order to prevent ARDS.
Dr. Weinstock-Guttman said another drug that might block the cytokine storm is tocilizumab, approved to treat moderate to severe rheumatoid arthritis.
“IL-6 blockade was shown beneficial recently also for NMO patients, so it will be interesting to see COVID-19 patients' outcome when treated with anti–IL-6 products for a previous underlying disease,” Dr. Weinstock-Guttman said.
Dr. Langer-Gould expressed caution about the approach. “There's a big difference between using a drug like fingolimod for a few days to reduce a cytokine storm versus having someone on it as a long-term therapy, which results in chronic T-cell suppression and, in rare instances, fatal viral infections,” she said.
“If your T-cells are markedly diminished and you are infected with COVID-19, your body would have a hard time clearing that virus and you would potentially be at higher risk of developing pneumonia, ARDS, and, potentially, multisystem organ failure.”
She added that none of the immunologists she works with are recommending a T-cell-depleting therapy for COVID-19. “Most of the patients we're seeing already have low lymphocytes,” she said. “The virus is taking down the CD4 and CD8 cells. I don't think anyone would feel comfortable giving a drug that further suppresses CD4 and CD8.”
Dr. Brownlee agreed that while the potential benefit of fingolimod as an acute treatment to prevent ARDS is interesting, “we need to be careful about being too quick to translate hypotheses into treatment. It's not enough to inform patient care at the moment.”
Ultimately, such questions can only be answered as more experience is gained in treating MS patients who develop a COVID-19 infection, Dr. Berger said. “Time will tell,” he said. “It's going to be important to get real-world data from the registries to see whether or not what we think is correct. Is there a signal for any of these MS drugs? We'll know when the registries reveal their data. It's going to take the participation of neurologists around the world to distill out the treatments with one or another drug.”
Dr. Brownlee has accepted speaker honoraria and/or participated in advisory boards for Biogen, Merck, Mylan, Novartis, Roche and Sanofi-Genzyme. Dr. Vollmer has received compensation for lectures and consultancy with Biogen IDEC, Genentech/Roche, Siranax, Celgene, EMD Serono, and Novartis. He has received research support from Rocky Mountain MS Center, Biogen,Actelion, Roche/Genentech;, F. Hoffman-La Roche, Ltd., and TG Therapeutics, Inc. Dr. Berger has received honoraria and an institutional grant from Biogen, and Genentech/Roche. He has received honoraria as a consultant for Celegene, Millennium/Takeda, Novartis, Inhibikase, Excision Biom Amgen, Shire, Dr. Reddy, Serono, Morphic, Encycle, Merck, and MAPI. Dr. Nourbarkhsh served on the advisory board for Jazz Pharmaceutical. Dr. Langer-Gould had no disclosures.