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Background: In the trial of Minocycline in Clinically Isolated Syndrome (MinoCIS), minocycline significantly reduced the risk of conversion to clinically definite multiple sclerosis (CDMS). Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are emerging biomarkers in MS, and minocycline modulates matrix metalloproteinases (MMPs). Objective: To assess the value of blood NfL and GFAP as a biomarker of baseline and future disease activity and its utility to monitor treatment response in minocycline-treated patients with clinically isolated syndrome (CIS). Methods: We measured NfL, GFAP, and MMPs in blood samples from 96 patients with CIS from the MinoCIS study and compared biomarkers with clinical and radiologic characteristics and outcome. Results: At baseline, NfL levels correlated with T2 lesion load and number of gadolinium-enhancing lesions. Baseline NfL levels predicted conversion into CDMS at month 6. GFAP levels at baseline were correlated with T2 lesion volume. Minocycline treatment significantly increased NfL levels at 3 months but not at 6 months, and decreased GFAP levels at month 6. Minocycline decreased MMP-7 concentrations at month 1. Discussion: Blood NfL levels are associated with measures of disease activity in CIS and have prognostic value. Minocycline increased NfL levels at month 3, but reduced GFAP and MMP-7 levels.

Background and purpose While diffusely abnormal white matter (DAWM) is a nonlesional MRI abnormality identified in ∼25% of patients with multiple sclerosis (MS), it has yet to be investigated in patients at an earlier disease stage, namely clinically isolated syndrome (CIS). The goals of this study were to (1) determine the prevalence of DAWM in patients with a CIS suggestive of MS, (2) evaluate the association between DAWM and demographic, clinical, and MRI features, and (3) evaluate the prognostic significance of DAWM on conversion from CIS to MS. Methods One hundred and forty-two CIS participants were categorized into DAWM and non-DAWM groups at baseline and followed for up to 24 months or until MS diagnosis. The primary outcome was conversion to MS (2005 McDonald criteria) within 6 months. Results DAWM was present in 27.5% of participants, and was positively associated with brainstem symptom onset, receiving corticosteroids, dissemination in space, and T2 lesion volume. DAWM was associated with an increased risk of conversion to MS over 6 months after adjustment for age and disability (hazard ratio [HR] = 2.24, p = 0.004). This association remained at a trend-level after adjustment for high-risk imaging features (HR = 1.68, p = 0.10). Conclusions DAWM is present in a similar proportion of patients with CIS and clinically definite MS, and it is associated with increased risk of conversion to MS over 6 months.

Background Identification of therapies to prevent severe COVID-19 remains a priority. We sought to determine whether hydroxychloroquine treatment for outpatients with SARS-CoV-2 infection could prevent hospitalization, mechanical ventilation or death. Methods This randomized controlled trial was conducted in Alberta during the first wave of the COVID-19 pandemic without direct contact with participants. Community-dwelling individuals with confirmed SARS-CoV-2 infection (by reverse transcription polymerase chain reaction [RT-PCR] viral ribonucleic acid test) within the previous 4 days, and symptom onset within the previous 12 days, were randomly assigned to oral hydroxychloroquine or matching placebo for 5 days. Enrolment began Apr. 15, 2020. The primary outcome was the composite of hospitalization, invasive mechanical ventilation or death within 30 days. Secondary outcomes included symptom duration and disposition at 30 days. Safety outcomes, such as serious adverse events and mortality, were also ascertained. Outcomes were determined by telephone follow-up and administrative data. Results Among 4919 individuals with a positive RT-PCR test, 148 (10.2% of a planned 1446 patients) were randomly assigned, 111 to hydroxychloroquine and 37 to placebo. Of the 148 participants, 24 (16.2%) did not start the study drug. Four participants in the hydroxychloroquine group met the primary outcome (4 hospitalizations, 0 mechanical ventilation, 4 survived to 30 days) and none in the placebo group. Hydroxychloroquine did not reduce symptom duration (hazard ratio 0.77, 95% confidence interval 0.49-1.21). Recruitment was paused on May 22, 2020, when a since-retracted publication raised concerns about the safety of hydroxychloroquine for hospitalized patients with COVID-19. Although we had not identified concerns in a safety review, enrolment was slower than expected among those eligible for the study, and cases within the community were decreasing. Recruitment goals were deemed to be unattainable and the trial was not resumed, resulting in a study underpowered to assess the effect of treatment with hydroxychloroquine and safety. Interpretation There was no evidence that hydroxychloroquine reduced symptom duration or prevented severe outcomes among outpatients with proven COVID-19, but the early termination of our study meant that it was underpowered. Trial registration ClinicalTrials.gov, no. NCT04329611.

Introduction: Proteinuria is recognized as an independent risk factor for cardiovascular disease in kidney transplant recipients, but previous studies have not considered the impact of changes in urine protein over time. Research Question and Design: We used time-dependent, multivariable Cox proportional hazards models in this observational cohort study of adult kidney transplant recipients to evaluate whether proteinuria measured by dipstick on random spot urine samples starting from 1-month post-transplant was associated with the risk of major adverse cardiac events and graft loss. Results: A total of 144 major adverse cardiac events, defined as acute myocardial infarction, cerebrovascular accident, revascularization, or all-cause mortality, were observed in 1106 patients over 5728.7 person-years. Any level of proteinuria greater or equal to trace resulted in a two-fold increase in the risk of major adverse cardiac events (hazard ratio 2.00 [95% confidence interval 1.41, 2.84]). This relationship was not found to be dose-dependent (hazard ratios of 2.98, 1.76, 1.63, and 1.54 for trace, 1+, 2+, and 3+ urine protein, respectively). There was an increased risk of graft failure with greater urine protein concentration (hazard ratios 2.22, 2.85, 6.41, and 19.71 for trace, 1+, 2+, and 3+, respectively). Conclusion: Urine protein is associated with major adverse cardiac events and graft loss in kidney transplant recipients. The role of interventions to reduce proteinuria on decreasing the risk of adverse cardiovascular and graft outcomes in kidney transplant recipients requires further study.

Background: Recent evidence suggests a role for the gut–brain axis in the pathophysiology of multiple sclerosis (MS). Materials and methods: We studied biomarkers of intestinal permeability in 126 people with MS (57 relapsing-remitting multiple sclerosis (RRMS) and 69 progressive MS) and in a group of healthy controls for comparison. Serum/plasma concentrations of zonulin (a regulator of enterocyte tight junctions), tight junction proteins (ZO-1 and occludin), intestinal fatty acid binding protein (IFABP)/ileal bile acid binding protein (IBABP), D-lactate, and lipopolysaccharide (LPS) binding protein were measured. Results: Zonulin concentrations were significantly higher when a concurrent magnetic resonance imaging (MRI) confirmed the presence of blood–brain barrier (BBB) disruption (Gad+ RRMS) and were correlated with tight junction proteins. IBABP and D-lactate were elevated in people with RRMS compared to controls, but did not discriminate between Gad+ and Gad– subgroups. Baseline zonulin concentrations were associated with 1-year disease progression in progressive MS. Conclusions: People with MS have altered biomarkers of intestinal barrier integrity. Zonulin concentrations are associated with 1-year disease progression in progressive MS and closely mirror BBB breakdown in RRMS. Zonulin may mediate breakdown of both the intestinal barrier and the BBB in gut dysbiosis through the regulation of tight junctions. This could explain how the gut–brain axis modulates neuroinflammation in MS.

Background Increasing evidence suggests that various inflammatory, immunological and metabolic pathways are altered in the clinically isolated syndrome (CIS) of multiple sclerosis (MS). Moreover, recent diagnostic criteria have made possible the very early diagnosis of MS. We evaluated multiple fluid biomarkers in people with early MS and CIS. Methods We measured blood levels of cytokines, matrix metalloproteinases (MMPs), serum metabolomics and immune cell immunophenotyping in participants in the Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis. Results When compared with healthy controls, people with early MS/CIS had higher levels of eotaxin, MCP-3, IL-1 receptor antagonist, IL-1β, IL-9 and IP-10, as well as MMPs 1, 8 and 9. In metabolomics analysis, the alanine, aspartate and glutamate metabolism and the synthesis and degradation of ketone bodies pathways were altered compared to healthy controls. There were no differences in lymphocyte subpopulation numbers. Out of all these biomarkers, only MMP-1 was able to differentiate between early MS and CIS, and was found to correlate with lesion volume and gadolinium enhancing lesions on MRI. Conclusion The immunological and metabolic profile of CIS and early MS is remarkably similar, supporting that these are a continuum of a common underlying pathophysiological process.

Epidemiological, pathological and radiological studies suggest that inflammatory demyelination in MS is an age-dependent process, and that the formation of focal inflammatory demyelinating lesions decreases with age. Gadolinium-enhancing lesions are a biomarker of inflammatory disease activity in MS, but little is known about the relation of age and gadolinium enhancement on cranial MRI scans in people with MS. In this study, we investigated the association of age and other risk factors with gadolinium enhancement on cranial MRI in a retrospective cross-sectional clinical MS cohort. In a cohort including 1543 people with CIS and MS, we investigated the association of the risk factors age, sex, disease course, immunomodulatory drug (IMD) treatment, and disability with gadolinium enhancement on cranial MRI scans using a binary logistic regression model. Age was the most important factor associated with gadolinium enhancement, with the odds of gadolinium enhancement decreasing with advancing age. Participants with CIS had lower odds of gadolinium enhancement (odds ratio of 0.42, 95% confidence interval of 0.24–0.72 compared to RRMS). Sex, disease course and IMD treatment were not significantly associated with gadolinium enhancement in our cohort. Our investigation shows that gadolinium enhancement is strongly associated with age. Since gadolinium enhancement is a marker of inflammatory disease activity, our findings suggest that inflammatory disease activity declines with age, and that IMD treatment may be more beneficial in younger and less useful in older people with MS.

Background Though many people with multiple sclerosis (MS) have comorbidities, the use of generic and disease-specific health related quality of life (HRQOL) scales to discriminate the effects of comorbidity has not been established. The utility of these scales to discriminate differences between persons with varying levels of disability is also unknown. Methods Using online questionnaires, a convenience sample of Albertans with MS was recruited between July 2011 and March 2013. Participants completed demographic questions, a validated comorbidity questionnaire, a self-reported disability scale, and the following HRQOL scales: the Short Form (SF)-36, SF-6D, Health Utilities Index-Mark III (HUI-III), and Multiple Sclerosis Quality of Life-54 (MSQOL-54). The ability of each HRQOL scale to distinguish between comorbidity groups was assessed using a one-way analysis of covariance, adjusting for age, sex, disease course, and disability level. Results Five hundred sixty three participants completed all relevant questionnaires. All HRQOL measures distinguished between persons with or without depression, while none were able to distinguish between participants with or without hypertension, thyroid disease, irritable bowel syndrome, or osteoporosis. The SF-36 physical scale, SF-6D, HUI-III, and MSQOL-54 physical scales were able to distinguish between all disability groups, though the HUI-III was better able to distinguish between individuals with moderate versus severe disability. Conclusions Disease-specific measures would discriminate better between those with and without comorbidities than generic-specific measures and the HUI-III would discriminate best between persons with differing severities of disability. Generic or disease-specific measures may be useful in future studies examining the effects of comorbidity in MS and the effects of treatment of comorbidities in MS. Electronic supplementary material The online version of this article (10.1186/s12955-017-0828-0) contains supplementary material, which is available to authorized users.

Background Research on the health benefits of cannabis has been limited because use remains restricted or illegal in most countries. Medical cannabis has been legal in Canada since 2001 and recreational use became legal in October 2018. While there are data that support a biological mechanism by which cannabinoids can impact various other symptoms of MS, the evidence of effectiveness of cannabis as a treatment for bladder symptoms remains unsettled. We conducted an exploratory study to describe the current trends of cannabis product consumption among people with MS (PwMS) and their association with perceived benefits on MS symptoms. Methods A cross-sectional survey study of PwMS, recruited from the MS Clinic in Calgary, Alberta, Canada was undertaken. Logistic regression analyses were performed to assess the associations between cannabis consumption and improvement in bladder function symptoms. Results There were 775 respondents out of 2899 PwMS contacted by email. Among respondents, 734 reported cannabis use in the past 3 months. There were 275 (37.5%) respondents who reported cannabis use in the prior 3 months, and 73.8% of these reported at least weekly use of cannabis. Among all users, 78.1% reported a primary medical or therapeutic indication for consumption. The most common modes of cannabis consumption were oral-edible (69.0%) and smoked (57.1%), while 59.3% used more than one mode of consumption and 2.6% used five different modes. The most common reasons for cannabis use were for sleep (58.3%), pain (51.5%), relaxation (44.4%), muscle spasms (40.2%), anxiety (33.8%) and depression (22.9%). Among the 19 participants who reported bladder symptoms as a main reason for cannabis use, 89.5% reported “better” bladder symptoms when using cannabis. Cannabis consumption in the past 3 months was associated with a two-fold increased odds of reporting improvement in urinary frequency, urinary urgency, bladder leakage and wetness, pad use and bladder emptying. Conclusions Cannabis is commonly used in this survey study of personal cannabis use among PwMS. Patterns of use, dosing, frequency and mode of delivery are diverse among survey respondents. This pilot study provides some initial glimpses into real world therapeutic use of cannabinoids among PwMS for bladder symptoms.

On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on TA total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

The nine hole peg test (9HPT) is an emerging outcome measure in clinical trials in multiple sclerosis (MS). In this study we investigated how performance on the 9HPT at baseline is related to annualized direct MS related cost.We enrolled patients with a definite diagnosis of MS from two Canadian MS centers. 9HPT and demographic information were recorded at baseline, and patients prospectively recorded all MS related costs for 6months. Costs were compared among five groups according to the baseline 9HPT, and we built a multiple linear regression model including cost (dependent variable) and 9HPT at baseline, age, disease duration, sex and disease course (independent predictor variables).We analyzed data from 298 patients. Cost significantly increased with increasing 9HPT scores (p0.0001), with the costs for health care providers, changes to the home or car and long-term care dominating in the most disabled patient groups. The 9HPT score was a significant predictor of cost in the regression model (p=0.006).Performance on the 9HPT is closely related to cost. Our data add another aspect of patient relevance to using the 9HPT as an outcome measure in clinical trials.

Background: Depression is a common comorbidity in multiple sclerosis (MS), but little is known about its long-term prognosis. Depression in the general population is usually episodic with relatively short-lasting depressive episodes. In this study we investigate the long-term prognosis of depression in MS. Methods: Using data from a large longitudinal observational study and from the Calgary MS clinic database, we investigated changes in Center for Epidemiological Studies Depression Scale (CESD) scores in MS patients over four years of follow-up. We used logistic regression to investigate the association of the factors sex, age, disease duration, Expanded Disability Status Scale (EDSS), depression at baseline, and antidepressant use with depression at each year of follow-up. Results: CESD scores remained largely stable, or decreased slightly over four years of follow-up, whereas EDSS scores steadily increased. Depression at baseline was the strongest predictor of depression at follow-up; the other factors were not or not consistently associated with depression at follow-up. As expected, antidepressant use was associated with a greater risk of depression at follow-up. Starting and stopping antidepressant treatment during follow-up was not associated with the risk of depression at follow-up or with significant change in CESD scores. Conclusion: In contrast to depression in the general population, depression in MS is largely chronic, which suggests a different pathophysiology.

Background Risk factors for psychiatric comorbidity in multiple sclerosis (MS) are poorly understood. Objective We evaluated the association between physical comorbidity and incident depression, anxiety disorder, and bipolar disorder in a MS population relative to a matched general population cohort. Methods Using population-based administrative data from Alberta, Canada we identified 9624 persons with MS, and 41,194 matches. Using validated case definitions, we estimated the incidence of depression, anxiety disorder, and bipolar disorder, and their association with physical comorbidities using Cox regression, adjusting for age, sex, socioeconomic status, and index year. Results In both populations, men had a lower risk of depression and anxiety disorders than women, as did individuals who were ≥45 years versus

Disease modifying therapies (DMTs) reduce the frequency of relapses and accumulation of disability in multiple sclerosis (MS). Long-term persistence with treatment is important to optimize treatment benefit. This long-term, cohort study was conducted at the Calgary MS Clinic. All consenting adults with relapsing-remitting MS who started either glatiramer acetate (GA) or interferon-β 1a/1b (IFN-β) between January 1st, 1996 and July 1st, 2011 were included. Follow-up continued to February 1st, 2014. Time-to-discontinuation of the initial and subsequently-prescribed DMTs (switches) was analysed using Kaplan-Meier survival analyses. Group differences were compared using log-rank tests and multivariable Cox regression models. Analysis included 1471 participants; 906 were initially prescribed GA and 565 were initially prescribed IFN-β. Follow-up information was available for 87%; 29 (2%) were lost to follow-up and 160 (11%) moved from Southern Alberta while still using DMT. Median time-to-discontinuation of all injectable DMTs was 11.1 years. Participants with greater disability at treatment initiation, those who started treatment before age 30, and those who started between 2006 and 2011 were more likely to discontinue use of all injectable DMTs. Median time-to-discontinuation of the initial DMT was 8.6 years. Those initially prescribed GA remained on treatment longer. Of 610 participants who discontinued injectable DMT, 331 (54%) started an oral DMT, or a second-line DMT, or resumed injectable DMT after 90 days. Persistence with injectable DMTs was high in this long-term population-based study. Most participants who discontinued injectable DMT did not remain untreated. Further research is required to understand treatment outcomes and outcomes after stopping DMT.

Background Primary progressive multiple sclerosis (PPMS) is the least common MS disease course and carries the worst prognosis. In relapsing–remitting multiple sclerosis (RRMS) disability accumulation occurs in two distinct phases, but it is unclear whether this is also true for PPMS. Here we investigate factors associated with early and late disability accumulation in PPMS. Methods We used Kaplan–Meier survival analyses and Cox regression to investigate the influence of sex, age at disease onset and onset symptoms on time to, and age at, Expanded Disability Status Scale (EDSS) 4 and 6, as well as the time from EDSS 4 to 6 in patients with PPMS. Results We identified 500 patients with PPMS. The analyses on time to EDSS 4 included 358 patients, and those on time to EDSS 6 included 392 patients. The median times to EDSS 4 and EDSS 6 were 5 and 9 years. The analyses on age at EDSS 4 included 360 patients, and those on age at EDSS 6 included 402 patients. The median ages at EDSS 4 and EDSS 6 were 51 and 55 years. Older age at onset and bilateral motor onset symptoms were independently associated with a shorter time to both EDSS 4 and EDSS 6. Sex and other onset symptoms were not associated with time to, or age at, landmark disability. Only age at onset was significantly associated with the time from EDSS 4 to EDSS 6. Conclusions Age at disease onset is the most important predictor of disability accumulation in PPMS. Bilateral motor onset symptoms were associated with quicker disease progression. In contrast to RRMS, we found no evidence for distinct phases of disability accumulation in PPMS. Disability accumulation in PPMS appears to be affected by the same factors throughout its course.

Background: Dimethyl fumerate (DF) is a first line therapy for relapsing remitting multiple sclerosis (RRMS). This retrospective cohort study aims to determine adverse events (AEs) after initiation of DF in a real world clinical setting. Methods: Data from patients at the Calgary MS Clinic with RRMS who initiated DF between July 1, 2013 and December 31, 2014 were analyzed. Demographic, clinical and lab information were collected from patient electronic medical records and the clinic database. Results: This analysis included 170 patients. At treatment initiation mean age was 42.1 years, 75% were women, mean disease duration was 12.5 years, median EDSS was 2.0, and 24% were treatment naïve. Median follow-up was 6.4 months (range: 1.5-17.7). AEs occurred in 101 (59%); the most common were flushing (31%), gastrointestinal (GI) side effects (24%), and elevated liver enzymes (18%). Other less frequent AEs included lymphopenia (lymphocyte count < 0.5) (4%) and proteinuria (4%). DF was discontinued by 17 (10%); median time to discontinuation was 3.1 months. Fifteen (9%) discontinued due to AE. Conclusions: AE associated with DF in a real world clinical setting is comparable to the Canadian monograph for flushing, GI side effects, and lymphopenia but lower for elevated liver enzymes and proteinuria.