Symptomatic COVID-19 course and outcomes after three mRNA vaccine doses in multiple sclerosis patients treated with high-efficacy DMTs.

BACKGROUND: Little is known about COVID-19 course and outcomes after a third booster dose of mRNA vaccine against SARS-CoV-2 (mRNA-Vax) in patients with multiple sclerosis (pwMS) treated with ocrelizumab (OCR) and fingolimod (FNG), which showed a weakened immune response to mRNA-vax. OBJECTIVES: The aim of this study was to evaluate COVID-19 course and outcomes in pwMS on OCR and FNG after receiving the third dose of mRNA-Vax and to compare it with pwMS on natalizumab (NTZ). METHODS: Inclusion criteria: >18 years of age, being treated with OCR/FNG/NTZ since the first mRNA-Vax dose; COVID-19 after a third booster dose of mRNA-Vax; no steroids use. RESULTS: Overall, 290 pwMS (79 NTZ, 126 OCR, and 85 FNG) from 17 Italian MS centers were included. Age, Expanded Disability Status Scale (EDSS) score, MS phenotype, disease, and treatment duration were significantly different across groups. PwMS who had COVID-19 on OCR and FNG compared with those on NTZ were slightly more symptomatic with higher hospitalization rates (11.1% vs 7.1% vs 1.3%, respectively). Regression models showed that the majority of the differences observed were not related to the disease-modifying treatments (DMTs) used. No fatal cases were observed. CONCLUSION: Our results support the effectiveness of the third booster dose of mRNA-Vax against severe forms of COVID-19 in pwMS treated with OCR and FNG.

The Role of BDNF in Multiple Sclerosis Neuroinflammation.

Multiple sclerosis (MS) is a chronic, inflammatory, and degenerative disease of the central nervous system (CNS). Inflammation is observed in all stages of MS, both within and around the lesions, and can have beneficial and detrimental effects on MS pathogenesis. A possible mechanism for the neuroprotective effect in MS involves the release of brain-derived neurotrophic factor (BDNF) by immune cells in peripheral blood and inflammatory lesions, as well as by microglia and astrocytes within the CNS. BDNF is a neurotrophic factor that plays a key role in neuroplasticity and neuronal survival. This review aims to analyze the current understanding of the role that inflammation plays in MS, including the factors that contribute to both beneficial and detrimental effects. Additionally, it explores the potential role of BDNF in MS, as it may modulate neuroinflammation and provide neuroprotection. By obtaining a deeper understanding of the intricate relationship between inflammation and BDNF, new therapeutic strategies for MS may be developed.

Exposure to natalizumab throughout pregnancy: effectiveness and safety in an Italian cohort of women with multiple sclerosis.

OBJECTIVE: Assessing the risk of clinical and radiological reactivation during pregnancy and post partum in women with multiple sclerosis (MS) treated with natalizumab (NTZ) throughout pregnancy (LONG_EXP) compared with women interrupting treatment before (NO_EXP) and within >-30 days and ≤90 days from conception (SHORT_EXP), and describing newborns' outcomes. METHODS: Maternal clinical and radiological outcomes and obstetric and fetal outcomes were retrospectively collected and compared among groups (NO_EXP, SHORT_EXP, LONG_EXP). Predictors of clinical and radiological reactivation were investigated through univariable and multivariable analysis. RESULTS: 170 eligible pregnancies from 163 women referring to 29 Italian MS centres were included. Annualised relapse rate (ARR) was significantly lower in LONG_EXP (n=66, 0.02 (0.001-0.09)) compared with NO_EXP (n=31, 0.43 (0.21-0.75), p=0.002) and SHORT_EXP (n=73, 0.46 (0.30-0.66), p=0.0004) during pregnancy, and in LONG_EXP (0.12 (0.05-0.24)) compared with SHORT_EXP (0.30 (0.17-0.50), p=0.008) during post partum. Gadolinium-enhancing (Gd+) lesions were less frequent in LONG_EXP (n=6/50, 2.00%) compared with NO_EXP (n=9/21, 42.86%) and SHORT_EXP after delivery (n=17/49, 34.69%, p=0.010).Delaying NTZ resumption after delivery significantly increased the risk of relapses (OR=1.29 (95% CI 1.07 to 1.57), p=0.009) and Gd+ lesions (OR=1.49 (95% CI 1.17 to 1.89, p=0.001). Newborns' weight, length, head circumference and gestational age did not differ among groups after adjusting for confounders. Anaemia was tracked in 4/69 LONG_EXP newborns. Congenital anomaly rate was within the expected range for the untreated MS population. CONCLUSIONS: Our findings indicate that in women with MS treated with NTZ before conception, continuation of NTZ throughout pregnancy and its early resumption after delivery mitigate the risk of clinical and radiological reactivation. This approach has no major impact on newborns' outcomes.

Switch from sequestering to anti-CD20 depleting treatment: disease activity outcomes during wash-out and in the first 6 months of ocrelizumab therapy.

OBJECTIVES: Switching between treatments is an opportunity for patients with multiple sclerosis (MS) to ameliorate disease control or safety. The aim of this study was to investigate the impact of switching from fingolimod (FTY) or natalizumab (NTZ) to ocrelizumab (OCR) on disease activity. METHODS: We retrospectively enrolled 165 patients treated with OCR from 11 MS centres. We assessed the association of demographic and clinical characteristics on relapse rate (RR) and activity on magnetic resonance imaging (MRI) during wash-out and after 6 months of treatment with OCR through univariable and multivariable negative binomial regression models. RESULTS: We registered a total of 35 relapses during the wash-out period. Previous treatment with FTY, relapses in the previous year, and relapsing-remitting course were associated with higher RR. In the first 6 months of OCR, 12 patients had clinical or MRI disease activity. Higher Expanded Disability Status Scale (EDSS) and higher lymphocyte count at OCR start were associated with a reduced probability of relapse. DISCUSSION AND CONCLUSION: This study confirms that withdrawal from sequestering agents as FTY increases the risk of relapses in the wash-out period. Nevertheless, starting OCR before achieving complete immune reconstitution could limit its effectiveness in the first 6 months probably because trapped lymphocytes escape the CD20-mediated depletion.

Defining the course of tumefactive multiple sclerosis: A large retrospective multicentre study.

BACKGROUND AND PURPOSE: Tumefactive multiple sclerosis (TuMS) (i.e., MS onset presenting with tumefactive demyelinating lesions [TDLs]) is a diagnostic and therapeutic challenge. We performed a multicentre retrospective study to describe the clinical characteristics and the prognostic factors of TuMS. METHODS: One hundred two TuMS patients were included in this retrospective study. Demographic, clinical, magnetic resonance imaging (MRI), laboratory data and treatment choices were collected. RESULTS: TuMS was found to affect women more than men (female:male: 2.4), with a young adulthood onset (median age: 29.5 years, range: 11-68 years, interquartile range [IQR]: 38 years). At onset, 52% of TuMS patients presented with the involvement of more than one functional system and 24.5% of them with multiple TDLs. TDLs most frequently presented with an infiltrative MRI pattern (38.7%). Cerebrospinal fluid immunoglobulin G oligoclonal bands were often demonstrated (76.6%). In 25.3% of the cases, more than one acute-phase treatment was administered, and almost one-half of the patients (46.6%) were treated with high-efficacy treatments. After a median follow-up of 2.3 years (range: 0.1-10.7 years, IQR: 3.4 years), the median Expanded Disability Status Scale (EDSS) score was 1.5 (range: 0-7, IQR: 2). Independent risk factors for reaching an EDSS score ≥3 were a higher age at onset (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03-1.14, p < 0.01), a higher number of TDLs (OR: 1.67, 95% CI: 1.02-2.74, p < 0.05) and the presence of infiltrative TDLs (OR: 3.34, 95% CI: 1.18-9.5, p < 0.001) at baseline. CONCLUSIONS: The management of TuMS might be challenging because of its peculiar characteristics. Large prospective studies could help to define the clinical characteristics and the best treatment algorithms for people with TuMS.

Lower urinary tract disorders in multiple sclerosis patients: prevalence, clinical features, and response to treatments.

AIMS: Lower urinary tract symptoms are common in multiple sclerosis (MS) and have a great impact on quality of life. We evaluated prevalence and characteristics of urological symptoms in a cohort of patients with MS. METHODS: This is a cross-sectional study conducted on consecutive patients with MS attending our Center in 2018. We evaluated prevalence, clinical features, and response to symptomatic treatments of lower urinary tract disorders; we investigated the relationship between them and clinical and demographic features. Data of urodynamic studies were also collected. RESULTS: In our cohort of 806 patients, the overall prevalence of urological symptoms was 52.9% and urgency was the most frequent symptom (59.4%). Symptomatic patients had a higher disability, a longer disease duration, a later age at onset, and a greater mean age at the time of evaluation. Urinary disorders were more frequent in patients with progressive disease and in women. About 41.8% of patients were under treatment for the urological disorder and 81.5% of them reported an improvement of symptoms. CONCLUSION: Urinary disorders in patients with MS have a high prevalence. An early and correct characterization of types of symptoms and an early and targeted therapeutic strategy are essential to improve the patient's quality of life and avoid future complications.

Abortion induces reactivation of inflammation in relapsing-remitting multiple sclerosis.

OBJECTIVE: To investigate clinical and radiological outcomes of women with relapsing-remitting multiple sclerosis (RRMS) undergoing abortion. METHODS: An independent, multicentre retrospective study was conducted collecting data from eight Italian MS centres. We compared the preconception and postabortion annualised relapse rate (ARR) and number of Gadolinium enhancing (Gd+) lesions, by analyses of covariance. Variables associated with postabortion clinical and MRI activity were investigated using Poisson regression models; each abortion was considered as a statistical unit. RESULTS: From 1995 to 2017, we observed 188 abortions (17 elective) in 153 women with RRMS. Abortions occurred after a mean time of 9.5 (4.4) weeks from estimated conception date. In 86 events out of 188, conception happened during treatment with disease modifying drugs. The mean postabortion ARR (0.63±0.74) was significantly increased (p=0.037) compared with the preconception year (0.50±0.71) as well as the postabortion mean number of new Gd+ lesions (0.77±1.40 vs 0.39±1.04; p=0.004). Higher likelihood of relapses was predicted by higher preconception ARR, discontinuation of preconception treatment and elective abortion; the occurrence of new Gd+ lesions was associated with higher preconception number of active lesions, discontinuation of preconception treatment, shorter length of pregnancy maintenance and elective abortion. CONCLUSIONS: Abortion was associated with clinical and radiological inflammatory rebound remarkably in the first 12 months postevent. Deregulated proinflammatory processes arising at the early stages of pregnancy might play a role both in MS reactivation and abortion. Women with MS should be counselled about these risks of abortion and followed up accordingly.

Systematic assessment and characterization of chronic pain in multiple sclerosis patients.

Pain is one of the most disabling clinical symptoms in patients with multiple sclerosis (MS). Several studies have already assessed the prevalence of pain in MS patients, reporting variable results, probably due to methodological differences. The aim of this single-centre cross-sectional study was to define the prevalence and characteristics of chronic pain in a population of MS patients using validated tools, and to analyse these data in relation to demographic and clinical features, including disease duration and disability (EDSS and its single functional system scores). Of 397 enrolled patients, 23 were excluded due to a Beck's Depression Inventory Score > 19. In the remaining 374 patients, the overall prevalence of chronic pain was 52.1%, most frequently affecting the lower limbs (36.9%). Neuropathic pain was the most frequent type of chronic pain (89 patients, overall prevalence of 23.7%) and was associated with a sensory functional system involvement. Pain intensity was significantly higher in patients with neuropathic pain as opposed to patients with non-neuropathic pain. Patients with chronic pain and, in particular, patients with neuropathic pain had significantly higher EDSS scores than those without pain. Only 24% of patients with chronic pain and 33% of patients with neuropathic pain were on a specific long-lasting treatment for pain. The present study supports the routine assessment of neuropathic pain in MS patients, especially in those with a sensory functional system involvement, in order to avoid underdiagnosing and undertreating a potentially disabling condition.

Identifying Relapses in Multiple Sclerosis Patients through Administrative Data: A Validation Study in the Lazio Region, Italy.

BACKGROUND: Relapse is frequently considered an outcome measure of disease activity in relapsing-remitting multiple sclerosis (MS). The objectives of this study were to identify relapse episodes in patients with MS in the Lazio region using health administrative databases and to evaluate the validity of the algorithm using patients enrolled at MS treatment centers. METHODS: MS cases were identified in the period between January 1, 2006 and December 31, 2009 using data from regional Health Information Systems (HIS). An algorithm based on HIS was used to identify relapse episodes, and patients recruited at MS centers were used to validate the algorithm. Positive and negative predictive values (PPV, NPV) and the Cohen's kappa coefficient were calculated. RESULTS: The overall MS population identified through HIS consisted of 6,094 patients, of whom 67.1% were female and the mean age was 41.5. Among the MS patients identified by the algorithm, 2,242 attended the centers and 3,852 did not. The PPV was 58.9%, the NPV was 76.3%, and the kappa was 0.36. CONCLUSIONS: The proposed algorithm based on health administrative databases does not seem to be able to reliably detect relapses; however, it may be a helpful tool to detect healthcare utilization, and therefore to identify the worsening condition of a patient's health.

Serum lactate as a novel potential biomarker in multiple sclerosis.

Multiple sclerosis (MS) is a primary inflammatory demyelinating disease associated with a probably secondary progressive neurodegenerative component. Impaired mitochondrial functioning has been hypothesized to drive neurodegeneration and to cause increased anaerobic metabolism in MS. The aim of our multicentre study was to determine whether MS patients had values of circulating lactate different from those of controls. Patients (n=613) were recruited, assessed for disability and clinically classified (relapsing-remitting, secondary progressive, primary progressive) at the Catholic University of Rome, Italy (n=281), at the MS Centre Amsterdam, The Netherlands (n=158) and at the S. Camillo Forlanini Hospital, Rome, Italy (n=174). Serum lactate levels were quantified spectrophotometrically with the analyst being blinded to all clinical information. In patients with MS serum lactate was three times higher (3.04±1.26mmol/l) than that of healthy controls (1.09±0.25mmol/l, p<0.0001) and increased across clinical groups, with higher levels in cases with a progressive than with a relapsing-remitting disease course. In addition, there was a linear correlation between serum lactate levels and the expanded disability scale (EDSS) (R(2)=0.419; p<0.001). These data support the hypothesis that mitochondrial dysfunction is an important feature in MS and of particular relevance to the neurodegenerative phase of the disease. Measurement of serum lactate in MS might be a relative inexpensive test for longitudinal monitoring of "virtual hypoxia" in MS and also a secondary outcome for treatment trials aimed to improve mitochondrial function in patients with MS.

Second-line therapy with fingolimod for relapsing-remitting multiple sclerosis in clinical practice: the effect of previous exposure to natalizumab.

BACKGROUND: To evaluate efficacy and safety of fingolimod for relapsing-remitting multiple sclerosis, particularly in patients previously exposed to natalizumab. METHOD: Prospective observational single-centre second-line cohort study. RESULTS: Among 71 patients treated with fingolimod 0.5 mg/day for a mean duration of 21.75 ± 12.60 months, the annualized relapse rate was 0.66 (C.I. 95% 0.27-1.05) with a significant difference between 26 patients with prior natalizumab exposure (1.15; C.I. 95% 0.12-2.17) and 45 not exposed (0.38; C.I. 95% 0.18-0.57; p = 0.002). In a multivariate negative regression model, only previous exposure to natalizumab (p = 0.049) and duration of fingolimod treatment (p < 0.001) significantly correlated with the annualized relapse rate. Previous exposure to natalizumab (p = 0.028) and duration of treatment with fingolimod (p < 0.001) were confirmed by restricting the analysis to the first 12 months of treatment with fingolimod, but were no longer statistically significant by analysing only patients (n = 51) with at least 12 months of treatment with fingolimod (0.32; C.I. 95% 0.08-0.55 vs. 0.22; C.I. 95% 0.11-0.32; p = NS). No differences were observed in neuroradiological outcomes and disability progression in patients exposed to natalizumab and not exposed. The rate of discontinuation due to adverse events was 11.3%, with no differences between the two groups. CONCLUSIONS: Our study confirms efficacy and side effects of fingolimod in a second-line clinical practice cohort. Prior natalizumab exposure and duration of treatment with fingolimod are independent predictors of annualized relapse rate during the first 12 months of treatment with fingolimod, but not in the long-term, and may be influenced by the 3 months washout period between the two drugs.

Thyroid autoimmunity and dysfunction in multiple sclerosis patients during long-term treatment with interferon beta or glatiramer acetate: an Italian multicenter study.

Few long-term follow-up data are available on thyroid dysfunction (TD) in multiple sclerosis (MS) patients treated with glatiramer acetate (GA) or with interferon-beta (IFNb). In a cohort of 787 relapsing-remitting MS (RRMS) patients whom were followed up for 8 years, we observed an increased prevalence of TD and thyroid autoimmunity (TA) within the first year of IFNb treatment, regardless of the dose or frequency of administration, while no change was observed with GA treatment. The increased prevalence of TD and TA within the first year of IFNb treatment suggested the need for close monitoring of thyroid function and autoimmunity, though only during the first year of IFNb treatment.

Challenges in Diagnosis and Therapeutic Strategies in Late-Onset Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory and degenerative demyelinating disease of the central nervous system of unknown etiology, which affects individuals in their early adulthood. However, nearly 5-10% of people with MS can be diagnosed at ages above 50 years old, referred to as late-onset multiple sclerosis (LOMS). Some studies have reported a distinctive presentation, clinical course, and prognosis for LOMS, implicating a different diagnostic and therapeutic approach for this population. Furthermore, similar manifestations between LOMS and other age-related conditions may lead to potential misdiagnosis and diagnostic delays, and a higher burden of multimorbidity associated with aging can further complicate the clinical picture. This review aims to explore the clinical characteristics, the disease course, and the differential diagnosis of LOMS and addresses therapeutic considerations for this population.

Optical Coherence Tomography Advanced Parameters in Patients With Multiple Sclerosis: Ophthalmological and Neurological Assessments.

PURPOSE: To evaluate ophthalmological, neurological, radiological, and laboratory data in patients with multiple sclerosis (MS) and to identify new ophthalmological factors that could be helpful as biomarkers of the disease, potentially leading to an earlier prediction of disease course and disability progression. DESIGN: Retrospective, cross-sectional-study. METHODS: Best-corrected visual acuity (BCVA), ophthalmological biomicroscopy of the anterior segment and fundus, structural optical coherence tomography (OCT) with retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), and OCT angiography (OCTA) with vascular density (VD) were performed. The following clinical and neuro-radiological features were assessed: MS phenotype, disease duration, clinical severity, type of treatment, and T2-weighted lesion and T1-weighted Gd+ enhancing lesion number on the brain and spinal cord MRI. RESULTS: One hundred and six patients (212 eyes) were analyzed. Sixty-six of them (62.2%) had MS and 40 (37.8%) were matched healthy controls (HCs). patients with MS showed lower RNFL, GCC, and VD in the radial peripapillary capillary plexus than controls in both eyes (P < .05). By Performing a logistic regression with a distinct MS outcome for both eyes, we were able to demonstrate that the value that was most predictive of MS was the average GCC thickness (P = .009). Regression analysis demonstrated that patients with a higher T2-weighted lesions showed a lower RNFL thickness value and reduced GCC and VD values than those with a low lesion load (P < .01 and P < .05, respectively). Similarly, relapsing MS patients showed lower RNFL values (P < .05). CONCLUSIONS: Several OCT and OCTA-optic nerve parameters could be useful prognostic biomarkers for the MS disease course in clinical practice. However, it is necessary to do additional research with larger sample sizes in order to validate these findings.

Treatment modifiers across different regimens of natalizumab treatment in MS: An Italian real-world experience.

Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 â€‹± â€‹1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.

SARS-CoV-2 vaccination and multiple sclerosis: a large multicentric study on relapse risk after the third booster dose.

BACKGROUND: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce. OBJECTIVE: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS. METHODS: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose. RESULTS: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%. CONCLUSIONS: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS.

Severe disability in patients with relapsing-remitting multiple sclerosis is associated with profound changes in the regulation of leptin secretion.

OBJECTIVES: Experimental evidences indicate that leptin is involved in the neuroinflammatory process sustaining multiple sclerosis (MS). However, the relationship between leptin and body fat, as assessed by body mass index (BMI), in MS was not previously evaluated. It was the aim of this study to compare serum leptin levels between patients with MS and healthy controls and to evaluate the possible relationship between circulating leptin levels and disease severity. PATIENTS AND METHODS: Eighty-four MS patients and 57 sex-matched healthy volunteers were enrolled. Serum leptin levels were measured in all patients and controls. MS patients were stratified in 3 groups according to their degree of disability as assessed by the Expanded Disability Status Scale (EDSS). Patients were classified as having low (33 patients with an EDSS score <1.5), intermediate (28 patients with an EDSS score from 2 to 3) and high disability (23 patients with an EDSS score ≥3.5). RESULTS: No significant differences in serum leptin levels and BMI were observed between patients and controls. In patients with MS, serum leptin levels were significantly correlated with BMI in those patients with low (R(2) = 0.363; p < 0.001) and intermediate disability (R(2) = 0.408; p < 0.001), but not in patients with a higher disability score (R(2) = 0.064; p = 0.256). CONCLUSION: BMI, the major determinant of leptin level in physiological conditions, has a minor role in determining the serum levels of leptin in MS patients with a high EDSS score. Future longitudinal studies will be required in order to provide further insights into the regulation of leptin secretion in patients with MS.

The Importance of Managing Modifiable Comorbidities in People with Multiple Sclerosis: A Narrative Review.

Multiple sclerosis (MS) is a chronic, inflammatory, degenerative demyelinating disease of the central nervous system (CNS) of unknown etiology that affects individuals in their early adulthood. In the last decade, life expectancy for people with MS (PwMS) has almost equaled that of the general population. This demographic shift necessitates a heightened awareness of comorbidities, especially the ones that can be prevented and modified, that can significantly impact disease progression and management. Vascular comorbidities are of particular interest as they are mostly modifiable health states, along with voluntary behaviors, such as smoking and alcohol consumption, commonly observed among individuals with MS. Vascular risk factors have also been implicated in the etiology of cerebral small vessel disease. Furthermore, differentiating between vascular and MS lesion load poses a significant challenge due to overlapping clinical and radiological features. This review describes the current evidence regarding the range of preventable and modifiable comorbidities and risk factors and their implications for PwMS.