What’s New in MS Research: November 2019
Reviewed by MSAA Chief Medical Officer Barry A. Hendin, MD
ECTRIMS Annual Meeting Highlights
This edition of MSAA’s “What’s New in MS Research” provides highlights from this year’s European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) annual meeting. Experts from throughout the world gathered in Stockholm, Sweden in mid-September to share and discuss the latest research into the causes, diagnosis, course, and treatment of multiple sclerosis. Those investigators and clinicians were gathered for the 35th annual Congress of ECTRIMS, a key forum for presenting the findings that help advance evidence-based management of MS.
This article focuses on more than a dozen studies with significance for people living with MS. The studies featured obviously constitute a very small sampling of the research unveiled in Stockholm. However, they provide a good sense of the depth, breadth, and innovation that mark the current state of research into multiple sclerosis.
Ofatumumab: Favorable Phase III results set stage for seeking FDA approval
Ofatumumab is a monoclonal antibody that people with relapsing-remitting MS could inject at home once a month. This experimental medication demonstrated positive Phase III study results, which were announced at the ECTRIMS 2019 meeting.
Based on those results, the pharmaceutical company Novartis said it will file paperwork with the FDA by the end of this year seeking approval for use of ofatumumab in relapsing-remitting MS.1 The medication is already approved for the treatment of certain forms of leukemia under the brand name Arzerra®.
Two identically designed Phase III trials, ASCLEPIOS I and ASCEPLIOS II, compared ofatumumab to Aubagio® (teriflunomide). More than 1,800 patients from 37 countries were enrolled in the trials. Those people were randomized on a 1:1 basis to receive either 20 mg of ofatumumab injected subcutaneously every four weeks, or daily, oral doses of 14 mg of Aubagio, for up to 30 months. The primary endpoint of both trials was impact on the annualized relapse rate, or ARR. 2
In both studies, the ARR for patients receiving ofatumumab was less than half that of those receiving Aubagio.3 Ofatumumab also demonstrated greater suppression of gadolinium-enhancing T1 lesions on MRI – an indication of inflammatory activity – compared with Aubagio, and reduced the risk of three-month and six-month confirmed disability progression by roughly one-third relative to Aubagio. Meanwhile, safety data in the trial were comparable with that seen in earlier studies of the agent.3
Mayzent® and delay in time to disability progression in secondary-progressive MS
Mayzent® (siponimod) helps patients with secondary-progressive multiple sclerosis (SPMS) delay the time until they need to use a wheelchair, according to a team of international researchers.
In March 2019, the FDA approved Mayzent as the first oral drug to treat SPMS with active disease.4 The FDA’s approval was based on results of the Phase III EXPAND trial. Researchers drew on data from that trial to assess the impact that Mayzent had on people reaching an Expanded Disability Status Scale (EDSS) score of 7.0, which reflects an inability to walk beyond a few steps and the need for wheelchair use.
Analysis of data on more than 1,100 study participants found that, compared to placebo, Mayzent lengthened the median time to reaching an EDSS score of 7 or greater by 4.3 years (12.0 years for placebo vs 16.3 years for Mayzent). The reduction in risk of need for a wheelchair was greatest in people with more significant disability. In more than 400 study participants with an EDSS score of 6.5 at the study’s start, Mayzent cut the risk of needing a wheelchair by 28% to 36%, depending on the type of analysis employed. 5
Impact of extending Tysabri® dosing interval on relapse rates
Tysabri (natalizumab) has demonstrated its efficacy in treating relapsing-remitting MS, but the standard dosing schedule of a 300-mg infusion every four weeks is associated with increased risk for progressive multifocal leukoencephalopathy (PML), a serious and potentially life-threatening disease.
In an effort to continue providing people with MS with the benefits of Tysabri while reducing their risk for PML, researchers have explored whether extending the period between infusions can preserve the disease-modifying effects of the drug while diminishing the chances of developing PML. With earlier research showing that extended interval dosing (EID) lowers the risk of PML compared to standard interval dosing (SID), a large, long-term observational study presented at ECTRIMS 2019 examined the differences in effectiveness when extending the time between treatments.
Investigators drew on data from the Tysabri Observational Program (TOP) to compare 135 pairs of patients. One patient in each pair had received Tysabri on the standard-interval schedule, while the other had extended-interval dosing. 6
The researchers found no significant difference in annualized relapse rate (ARR) or risk of relapse between the two groups. They added that a randomized, prospective study comparing the two treatment approaches is needed to provide more-definitive evidence.
What’s the risk of “rebound” disease activity after stopping Gilenya®?
People with MS may decide to stop a disease-modifying therapy (DMT) for any number of reasons, ranging from side effects or a perceived lack of effectiveness to a desire to switch to another agent or to be “treatment-free” for a period of time. The importance of consulting with a clinician before stopping treatment is underscored by the risk for rebound disease activity, or RDA, which can occur once a medication that is taken to control MS is discontinued.
Investigators recently examined the records of 117 patients to determine the risk for RDA after stopping Gilenya, and to see if any factors made people more prone to experiencing “rebound.”7 The group included 86 women and 31 men.
Nine of the 117 patients, or 7.7%, had RDA after stopping Gilenya, with the rebound activity marked by severe clinical relapses with exaggerated MRI lesions compared to their level of disease activity before starting the DMT. Compared to patients who did not experience RDA upon stopping treatment, those who did have rebound activity had a higher annualized relapse rate (ARR) before initiating Gilenya, and also had a shorter interval between their last relapse and their first dose of the medication. The duration of Gilenya treatment did not appear to affect the likelihood of rebound.
The researchers added that eight of the nine people experiencing RDA had stopped treatment abruptly. In an observation that again reinforces the importance of working closely with a clinician when considering any change to treatment approach, the investigators concluded, “Our results indicate that [a] fingolimod every-other-day cessation strategy may help to prevent RDA.”
Assessing Ocrevus® beyond clinical trials
Patients at the Cleveland Clinic’s Mellen Center for Multiple Sclerosis had lower rates of adverse events (AEs) with Ocrevus® (ocrelizumab) than did patients in the Phase III clinical trials that led to the disease-modifying therapy’s approval in March 2017, according to Mellen Center researchers.8
In the Mellen Center cohort, 3.3% had a serious adverse event, while 21% had an infection – typically a urinary tract infection or upper respiratory infection – and 18% had an infusion-related reaction. By contrast, in the OPERA I and OPERA II trials of Ocrevus in RRMS, 6.9% and 7.0%, respectively, of patients receiving Ocrevus had a serious adverse event, 56.9% and 60.2% had an infection, and 30.9% and 37.6% had at least one infusion-related reaction.9 Similarly, in the ORATORIO trial of Ocrevus in PPMS, 20.4% of Ocrevus patients had a serious adverse event, and 39.9% had one or more infusion-related reactions.10
The Mellen Center researchers noted that the lower rates of adverse events that they recorded may have been due to differences in reporting. They also observed that patients at their institution had longer average disease duration and fewer enhancing lesions at baseline than clinical trial participants. The real-world findings are, nonetheless, welcome and reassuring.
FDA approves Vumerity™, a fumarate medication designed to address GI tolerability
Clinicians know that the medications that work best are those that patients take regularly. For this reason, the tolerability of an agent can be as important as its effectiveness. In a nod to this reality, Biogen and Alkermes developed Vumerity™ (diroximel fumarate) to provide the efficacy already demonstrated by Biogen’s disease-modifying therapy Tecfidera® (dimethyl fumarate), but with fewer of the gastrointestinal (GI) side effects reported with the latter medication.11
In late October, a few weeks after MS researchers returned from ECTRIMS 2019, the FDA announced that it had approved Vumerity for use in relapsing forms of MS, including clinically isolated syndrome and relapsing-remitting MS.11
In pursuing FDA approval for Vumerity, Biogen provided data from the EVOLVE-MS-1 study, an ongoing, Phase III, single-arm, open-label, two-year safety study enrolling patients with relapsing-remitting MS. Interim results from the study submitted to the FDA showed that 6.3% of patients had stopped Vumerity due to adverse events, with fewer than 1% stopping because of gastrointestinal events. In the clinical trials leading to approval of Tecfidera, 18% of patients reported abdominal pain, 14% reported diarrhea, 12% cited nausea, and 9% reported vomiting.12
A tilt toward monoclonal antibody therapy as first-line MS treatment
Neurologists’ top choice of an initial multiple sclerosis (MS) treatment has shifted from interferon-based medications to monoclonal antibodies.13
That was the main finding of an analysis of data on more than 1,000 people with MS who began their first disease-modifying therapy (DMT) in late 2018 or early 2019. In December 2018 and January 2019, investigators drew on records from 213 U.S. neurologists to examine those physicians’ prescribing of MS medications over the prior three months. They then compared that 2018-2019 information with comparable data on the first medications prescribed to more than 1,000 “treatment-naïve” patients (individuals who had never taken a DMT previously) in early 2018, and another 1,020 patients who received their first DMT in 2017.
Researchers found that in late 2018-early 2019, 18% of treatment-naïve patients started a monoclonal antibody medication as their first DMT, compared with 8% in 2017. Conversely, the proportion of newly treated patients receiving an interferon-based medication declined from 26% in 2017 to 17% in 2019.
The investigators noted that greater prescribing of Ocrevus® (ocrelizumab) drove much of the increase in monoclonal antibody use, and was accompanied by a quantitatively measured increase in neurologists’ comfort level with using Ocrevus for relapsing-remitting forms of MS. They added that the 2017 approval of a generic version of Copaxone® (glatiramer acetate, or GA) also had significantly affected neurologists’ choice of a first-line DMT, with branded GA seeing its share of first-line prescriptions declining from 27% in 2017 to 18% in 2019, while generic GA went from accounting for 4% of first-line prescriptions in 2017 to 13% in 2019.
Further evidence supporting early initiation of disease-modifying therapy
Increasing age, duration of multiple sclerosis (MS), and greater disability detract from the effectiveness of disease-modifying therapies, according to an analysis of data on more than 14,000 patients. While those findings may seem intuitive, the researchers went further and quantified the extent to which medication therapy was diminished per year, per 1-point change in Expanded Disability Status Scale (EDSS) score, and other measures.14
The study drew on the MSBase Registry, examining data for 14,717 people who had been followed for at least one year. Seventy-two percent of the patients were female. The mean age at first visit was 36 years, and the patients had a mean duration of disease of 5.7 years and a median EDSS score of 2. Roughly three-quarters had clinically definite MS, while 20% had a clinically isolated syndrome (CIS).
The researchers found that patients receiving treatment were 39% more likely to experience confirmed improvement of disability than their untreated counterparts. However, this effect of therapy declined with age (-2% per year), disease duration (-6% per year), and disability (-8% per EDSS step). In an observation that reinforces the value of early initiation of treatment, the investigators concluded, “Immunotherapies exert their maximum effect in young patients with shorter disease course, mild disability and a previous stability on treatment.”
Tracking changes in use of DMTs as well as complementary and alternative interventions
People with MS are drawing on both disease-modifying therapies (DMTs) and complementary and alternative medicine (CAM) interventions in managing their health, according to a recent survey of more than 1,100 patients in Oregon and southwest Washington.15
Fielded from September 2018 to April 2019, the survey identified respondents’ use of both prescription medications for MS and interventions such as herbs and supplements, cannabis, dietary plans, and yoga. In addition to assessing current approaches to MS, researchers compared results from the 2018-2019 questionnaire with answers to a similar survey conducted in 2001.
Those investigators found that the proportion of people taking a DMT at the time they were surveyed increased from 47% in 2001 to 69% now. Use of CAM at time of survey response also increased during that period, from 68% to 93%.
Eighty-six percent of respondents to the 2018-2019 survey reported having employed exercise in managing their MS, with the proportion of people who have tried yoga increasing from 23% in 2001 to 46% in the recent survey. The proportion of people reporting having used meditation also increased, 16% to 39%. A majority of respondents to both surveys reported having used diet to manage their MS, with a slight increase from 59% in 2001 to 66% more recently. Low-carbohydrate and anti-inflammatory diets were the most commonly followed approaches in both surveys.
Researchers noted that they will further analyze their data to explore differences in perceived benefit of DMTs between CAM users and nonusers. Three key take-aways emerge from this research. First, more people are doing more than ever before to take a pro-active approach to dealing with their MS. Second, many people have rejected the false dichotomy of either using only a prescription medication or rejecting such agents in favor of exclusive reliance on alternative approaches. Third, as use of alternative approaches grows, it is important for patients to talk openly with their clinicians about all interventions they are employing or considering, particularly given the potential for interaction between herbs and some supplements and prescription medications.
Mixed news on stem-cell transplantation
Ninety-three percent of the 81 MS patients to undergo stem-cell transplantation at a Swedish center between 2004 and February 2019 remained progression free over an average follow-up period of 3.9 years, and none have died since undergoing the procedure.16 The investigators presenting that heartening news at the 2019 ECTRIMS meeting added that 87% of the patients had not experienced a relapse since transplantation, and that the annualized relapse rate (ARR) for the entire group was 0.022. By comparison, the group’s mean ARR for the year prior to the procedure was 2.2. The patients consisted of 56 women and 25 men. Their median age was 29 years, and 95% had relapsing-remitting MS.
Conversely, stem-cell transplantation did not reduce the number of active lesions seen on MRI after 24 weeks of treatment in a major international study, but did show promise in reducing the relapse rate, one of the investigation’s lead researchers told the press in discussing preliminary results presented at the 2019 ECTRIMS meeting.17 The MESEMS trial (MEsenchymal StEm cells for Multiple Sclerosis) was a randomized, double-blind, cross-over phase II trial examining the impact of autologous mesenchymal stem cells (MSC). Most of the 144 patients randomized for treatment had relapsing-remitting MS, while roughly 20% had secondary-progressive MS, and a little over 10% had primary-progressive MS. The study’s authors noted that the results presented at ECTRIMS were preliminary, and that further analysis is needed.
Assessing the impact of plasma exchange when steroids don’t help with relapses
Therapeutic plasma exchange – or plasmapheresis – is a technique clinicians sometimes employ when steroids aren’t helping to resolve an MS relapse. The process involves withdrawing whole blood from a vein, separating the plasma – or liquid portion of the blood – from the red and white blood cells, and then transfusing the red and white blood cells back into the patient, along with plasma replacement fluid. This “blood cleansing” approach is fairly uncommon, so Austrian and German researchers recently analyzed 14 years’ worth of data on 133 patients at their MS clinics to better understand its effectiveness.18
The investigators assessed clinical response to plasma exchange, with a marked clinical response defined as ≥1 step improvement in the Expanded Disability Status Scale (EDSS) and mild clinical improvement – which was characterized by improvement in neurological examination with change of EDSS <1 step. They also identified patients who had no improvement. Seventy-six percent of patients undergoing therapeutic plasma exchange (TPE) saw improvement, with 36% having marked improvement and 40% experiencing mild improvement. In general, TPE was more effective in younger patients, those with a shorter duration of disease, and with a shorter interval between relapse and receiving TPE. By exploring how often and to what extent TPE helps patients who have not benefited sufficiently from steroids during relapses – and by identifying which patients are likely to have the best response to the treatment – the researchers have provided clinicians with valuable insights on a less commonly employed treatment option.
Emerging methods of predicting MS disease course
A team of Canadian researchers showed in a small study that blood levels of a protein called serum neurofilament light chain (NfL) measured in the first five years after onset of symptoms can provide important insights on a patient’s likely course over the next 15 years.19
In analyzing data on 64 people with MS, they found that patients with a serum NfL level greater than 7.62 pg/mL had a nine-times greater risk of developing secondary-progressive MS over the following several years than people with lower blood levels of the protein. Similarly, when they divided patients into three groups, based on whether they had low, medium, or high NfL levels, they found that those with the highest level had more aggressive disease progression, with their Expanded Disability Stats Scale (EDSS) score increasing by 0.16 per year, reflecting greater impairment. Similarly, patients in the lowest NfL levels were 5.3-times less likely than others to reach an EDSS of 4.0 or greater.
The researchers noted that their findings were consistent across the adult age range and in both men and women. They concluded that their study “demonstrates an association between early disease serum NfL and long term clinical outcomes over the longest follow-up to-date. Whether the course of such patients can be altered by earlier treatment will require further study.”
In another study, a Spanish investigator has developed evidence indicating that the presence and prevalence of certain types of bacteria in the gastrointestinal tract can serve as predictive factors in assessing the long-term course of relapsing-remitting multiple sclerosis (RRMS).20
The gut microbiome – the milieu of bacteria and other molecules found in the gastrointestinal tract – is a major component of the body’s immune system, and in recent years has emerged as a focus of intense study in MS. Earlier research indicates that people with MS or at heightened risk for MS have imbalances in the mix of bacteria normally found in the GI tract of healthy people.
The study reported at the 2019 ECTRIMS meeting involved using molecular sequencing of stool samples to study the gut microbiota – or composition of bacterial species – of 16 people with RRMS and 15 healthy controls. The investigators then followed the people with MS over 24 months. They found that levels of Lactobacillaceae family of bacteria, and particularly two types of bacteria within that family known as Lactobacillus and Lachnoclostridium were associated with an increased risk of relapses and new lesions appearing on MRI. While this was a small study whose findings need to be explored on a larger scale, it points to the many ways researchers are homing in on factors that help chart the likely course of disease – and that eventually will help patients and their clinicians formulate treatment plans accordingly.
People with MS have elevated risk for other conditions even before their MS diagnosis
Even before they are diagnosed with multiple sclerosis, people with MS are more likely than others to have bladder problems, eye issues, and other conditions, according to a Swedish study involving more than 6,600 people with MS and almost 62,000 healthy controls.21
The people ultimately identified as having MS had a higher pre-diagnosis incidence of epilepsy (1.5% vs. 0.8%), autoimmune disease (1.3% vs 0.7%), bladder dysfunction (1.2% vs 0.2%), and retinal disorders (2.4% vs 1.2%) compared with controls. After MS diagnosis, the patients continued to have considerably higher rates of epilepsy, autoimmune diseases, and bladder dysfunction, as well as of toxic liver disease. The research team concluded, “Before a diagnosis of MS, patients already displayed an increased rate of comorbidity compared with MS-free controls. After diagnosis, patients with MS continued to display increased risk of several comorbidities, some of which may be explained by surveillance bias due to more frequent contact with healthcare.”
Measuring the toll of MS on women’s physical, mental function
Multiple sclerosis accelerates age-related physiologic decline in physical and mental function by 10-20 years in women with MS compared to their same-age counterparts. 22
That is the unwelcome but important conclusion of researchers who drew on data from the large-scale Nurses Health Study and Nurses Health Study II and compared participants’ physical function and cognitive function scores with those of 582 women with confirmed MS.
They found that women with MS who were ages 36 to 41 years had, on average, physical function comparable to that of unaffected women aged 58 to 62 years. Middle-aged women with MS were about three-times more likely than their age peers to report a slower walking pace and more than twice as likely to report almost daily urine leaks. At higher ages, women with MS were five-times more likely than unaffected peers to report problems with balance. Among women over age 75 years, women with MS were less likely to report good cognitive function than women without MS.
The results, while not encouraging, are not entirely surprising either, and underscore the importance of pursuing overall good health through clinician-approved diet and exercise programs in order to optimize well-being.
Recurrent demyelinating events in children: Identifying frequency and risk factors
Two-thirds of children who have a first demyelinating event (FDE) will go on to have at least one more such event, with older age at FDE, presence of more than five lesions on magnetic resonance imaging (MRI), and symptoms suggestive of a brainstem syndrome being among several risk factors for further events.23
Those were the key findings to emerge from an observational cohort study involving 75 children who had an FDE between 1999 and 2018. The children included 46 girls and 29 boys; their median age was 12 years. In 80% of cases, the FDE involved a single neurological symptom. Thirty-six had optic neuritis, while 15 had transverse myelitis, and 14 had symptoms indicative of a brainstem syndrome. Final diagnoses included multiple sclerosis (32 children), relapsing optic neuritis (7), and syndromes including polyphasic acute disseminated encephalomyelitis and neuromyelitis optica.
Fifty-six percent of the children experienced a relapse within 60 months of their FDE, and the overall risk of relapse was calculated at 65%. A clinical presentation indicating a brainstem syndrome was associated with a 10-fold higher risk for a second demyelinating event compared with other clinical presentations, while being age 11 years or older at the time of the FDE more than doubled the risk of recurrence compared to younger children. MRI findings of periventricular, subcortical, brainstem, and lateral spinal lesions also were associated with increased risk.
As investigators better understand the risks of – and risk factors for – recurrent demyelinating events in young people, clinicians can formulate their counseling approaches, diagnostic strategies, and treatment decisions accordingly to enhance care and help children and their families know what to anticipate.
For general information or to speak with a trained Client Services Specialist, please call MSAA’s Helpline at (800) 532-7667, extension 154. Questions to MSAA’s Client Services department may also be emailed to MSquestions@mymsaa.org.
Written by Tom Garry, Medical Writer
Reviewed by Dr. Barry Hendin, MSAA Chief Medical Officer
Edited by Susan Wells Courtney, MSAA Senior Writer
1 Novartis. Novartis ofatumumab demonstrates superiority versus Aubagio® in two head-to-head Phase III multiple sclerosis studies. August 30, 2019. Accessed November 16, 2019.
2 Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017; 376:221-234.
3 Novartis. Novartis Phase III ASCLEPIOS trials demonstrate robust efficacy of ofatumumab in patients with relapsing multiple sclerosis. September 13, 2019. Accessed November 16, 2019.
4 Novartis. Novartis receives FDA approval for Mayzent® (siponimod), the first oral drug to treat secondary progressive MS with active disease. March 26, 2019. Accessed November 14, 2019.
5 Vermersch P, Gold R, Kappos L, et al. Siponimod delays the time to wheelchair in patients with SPMS: results from the EXPAND study. ECTRIMS 2019 [P158].
6 Butzkueven H, Kappos L, Spelman T, et al. Natalizumab extended interval dosing or remaining on standard interval dosing: propensity score comparative effectiveness analysis of patients in the TYSABRI observational program
ECTRIMS 2019 [P1033].
7 Gunduz T, Ismailov R, Kürtüncü M. Rebound disease activity after cessation of fingolimod treatment. ECTRIMS 2019 [P1036].
8 Moss B, Parrotta E, Baldassari L. Real-world experience with ocrelizumab. ECTRIMS 2019 [P1409].
9 Hauser SL, Bar-Or A, Cohen J, et al. Efficacy and safety of ofatumumab versus teriflunomide in relapsing multiple sclerosis: results of the phase 3 ASCLEPIOS I and II trials. ECTRIMS 2019. [P336]
10 Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med. 2017; 376:209-220.
11 Biogen Inc and Alkermes PLC. Biogen and Alkermes announce FDA approval of Vumerity™ (diroximel fumarate) for multiple sclerosis. October 30, 2019. Accessed November 16, 2019.
12 Tecfidera® (dimethyl fumarate) delayed-release capsules. [Prescribing information]. Biogen Inc. Cambridge, Massachusetts. July 2019.
13 Naismith R, Robinson J, Schobel V. Trending perceptions and usage share of first-line multiple sclerosis therapies among US neurologists. ECTRIMS 2019 [P973].
14 Kalincik T, Malpa C, Sharmin S, et al. Modifiers of the effectiveness of MS immunotherapies. ECTRIMS 2019 [P1421].
15 Silberman E, Orban A, Senders A, et al. Use and perceived benefit of complementary and alternative therapies for multiple sclerosis in the Western United States: a 17-year update. ECTRIMS 2029 [P1425].
16 Zhukovsky C, Tolf A, Cherif H, Carlson K, Burman J. Efficacy of autologous hematopoietic stem cell transplantation for MS. A single-centre report of 81 patients. ECTRIMS 2019 [P1622].
17 Uccelli A, Laroni A, Brundin L, et al. MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a multi-center, randomized, double blind, cross-over phase 2 clinical trial with autologous mesenchymal stem cells (MSC). ECTRIMS 2019 [P1378].
18 Blechinger S, Ehler J, Santer A, et al. Therapeutic plasma exchange in steroid refractory MS relapses. A retrospective multicenter cohort study. ECTRIMS 2019 [P1429].
19 Abdoli M, Thebault S, Freedman MS, et al. Long term MS clinical outcomes predicted by baseline serum neurofilament light levels. ECTRIMS 2019 [P965].
20 Mendez Miralles MA. Gut microbiota as a new predictive factor of prognosis in relapsing-remitting multiple sclerosis. ECTRIMS 2019 [P1231].
21 Piehl F, Castelo-Branco A, Chiesa F, et al. Risk of comorbidity in patients with multiple sclerosis: a nationwide cohort study in Sweden. ECTRIMS 2019 [A272].
22 Cortese M, Chitnis T, Ascherio A, Munger KL. Aging with MS – physical and mental function in women with MS compared to non-affected peers in two US cohorts. ECTRIMS 2019 P1121].
23 Nevmerzhitskaya K, Volkova L, Sergeev A. Clinical predictors of relapse in children with the first demyelinating event. ECTRIMS 2019 [P1111].