Disease-modifying Drug Exposure Research Articles

Adverse Events Associated With Disease-Modifying Drugs for Multiple Sclerosis: A Multiregional Population-Based Study

It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study. We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised β-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models. We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87). Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS. This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.

Ten-year follow-up after mitoxantrone induction for early highly active relapsing-remitting multiple sclerosis: An observational study of 100 consecutive patients

BackgroundSix monthly courses of mitoxantrone were approved in France in 2003 for patients with highly active multiple sclerosis (MS). ObjectiveTo report the 10-year clinical follow-up and safety of mitoxantrone as an induction drug followed by maintenance therapy in patients with early highly active relapsing–remitting MS (RRMS) and an Expanded Disability Status Scale (EDSS) score<4, 12months prior to mitoxantrone initiation. MethodsIn total, 100 consecutive patients with highly active RRMS from the Rennes EDMUS database received monthly mitoxantrone 20mg combined with methylprednisolone 1g for 3 (n=75) or 6months (n=25) followed by first-line disease-modifying drug (DMD). The 10-year clinical impact was studied through clinical activity, DMD exposure, and adverse events. ResultsTwenty-four percent were relapse-free over 10years and the mean annual number of relapses was 0.2 at 10years. The mean EDSS score remained significantly improved for up to 10years, changing from 3.5 at mitoxantrone initiation to 2.7 at 10years. The probability of disability worsening and improvement from mitoxantrone initiation to 10years were respectively 27% and 58%, and 13% converted to secondary progressive MS. Patients only remained untreated or treated with a first-line maintenance DMD for 6.5years in average. In our cohort, mitoxantrone was generally safe. No leukemia was observed and six patients developed neoplasms, including 4 solid cancers. ConclusionMonthly mitoxantrone for 3 or 6months, followed by maintenance first-line treatment, may be an attractive therapeutic option for patients with early highly active RRMS, particularly in low-income countries.

Metagenomic Analysis of the Pediatric-Onset Multiple Sclerosis Gut Microbiome.

Little is known of the functional potential of the gut microbiome in pediatric-onset multiple sclerosis (MS). We performed metagenomic analyses using stool samples from individuals with pediatric-onset MS and unaffected controls. Persons ≤21 years old enrolled in the Canadian Pediatric Demyelinating Disease Network providing a stool sample were eligible. Twenty patients with MS (McDonald criteria) with symptom onset <18 years were matched to 20 controls by sex, age (±3 years), stool consistency, and race. Microbial taxonomy and functional potentials were estimated from stool sample-derived metagenomic reads and compared by disease status (MS vs controls) and disease-modifying drug (DMD) exposure using alpha diversity, relative abundance, and prevalence using Wilcoxon rank sum, ALDEx2, and Fisher exact tests, respectively. Individuals with MS were aged 13.6 years (mean) at symptom onset and 8 were DMD-naive. Mean ages at stool sample were 16.1 and 15.4 years for MS and control participants, respectively; 80% were girls. Alpha diversity of enzymes and proteins did not differ by disease or DMD status (p > 0.20), but metabolic pathways, gene annotations, and microbial taxonomy did. Individuals with MS (vs controls) exhibited higher methanogenesis prevalence (odds ratio 10, p = 0.044) and Methanobrevibacter abundance (log2 fold change [LFC] 1.7, p = 0.0014), but lower homolactic fermentation abundance (LFC -0.48, p = 0.039). Differences by DMD status included lower phosphate butyryl transferase for DMD-naive vs exposed patients with MS (LFC -1.0, p = 0.033). The gut microbiome's functional potential and taxonomy differed between individuals with pediatric-onset MS vs controls, including higher prevalence of a methane-producing pathway from Archaea and depletion of the lactate fermentation pathway. DMD exposure was associated with butyrate-producing enzyme enrichment. Together these findings indicate that the gut microbiome of individuals with MS may have a disturbed functional potential.

Socioeconomic status and disability progression in multiple sclerosis: A multinational study.

To examine the association between socioeconomic status (SES) and disability outcomes and progression in multiple sclerosis (MS). Health administrative and MS clinical data were linked for 2 cohorts of patients with MS in British Columbia (Canada) and South East Wales (UK). SES was measured at MS symptom onset (±3 years) based on neighborhood-level average income. The association between SES at MS onset and sustained and confirmed Expanded Disability Status Scale (EDSS) 6.0 and 4.0 and onset of secondary progression of MS (SPMS) were assessed using Cox proportional hazards models. EDSS scores were also examined via linear regression, using generalized estimating equations (GEE) with an exchangeable working correlation. Models were adjusted for onset age, sex, initial disease course, and disease-modifying drug exposure. Random effect models (meta-analysis) were used to combine results from the 2 cohorts. A total of 3,113 patients with MS were included (2,069 from Canada; 1,044 from Wales). A higher SES was associated with a lower hazard of reaching EDSS 6.0 (adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI] 0.89-0.91), EDSS 4.0 (aHR 0.93, 0.88-0.98), and SPMS (aHR 0.94, 0.88-0.99). The direction of findings was similar when all EDSS scores were included (GEE: β = -0.13, -0.18 to -0.08). Lower neighborhood-level SES was associated with a higher risk of disability progression. Reasons for this association are likely to be complex but could include factors amenable to modification, such as lifestyle or comorbidity. Our findings are relevant for planning and development of MS services.

Prognostic indicators in pediatric clinically isolated syndrome.

To assess prognostic factors for a second clinical attack and a first disability-worsening event in pediatric clinically isolated syndrome (pCIS) suggestive of multiple sclerosis (MS) patients. A cohort of 770 pCIS patients was followed up for at least 10 years. Cox proportional hazard models and Recursive Partitioning and Amalgamation (RECPAM) tree-regression were used to analyze data. In pCIS, female sex and a multifocal onset were risk factors for a second clinical attack (hazard ratio [HR], 95% confidence interval [CI] = 1.28, 1.06-1.55; 1.42, 1.10-1.84, respectively), whereas disease-modifying drug (DMD) exposure reduced this risk (HR, 95% CI = 0.75, 0.60-0.95). After pediatric onset MS (POMS) diagnosis, age at onset younger than 15 years and DMD exposure decreased the risk of a first Expanded Disability Status Scale (EDSS)-worsening event (HR, 95% CI = 0.59, 0.42-0.83; 0.75, 0.71-0.80, respectively), whereas the occurrence of relapse increased this risk (HR, 95% CI = 5.08, 3.46-7.46). An exploratory RECPAM analysis highlighted a significantly higher incidence of a first EDSS-worsening event in patients with multifocal or isolated spinal cord or optic neuritis involvement at onset in comparison to those with an isolated supratentorial or brainstem syndrome. A Cox regression model including RECPAM classes confirmed DMD exposure as the most protective factor against EDSS-worsening events and relapses as the most important risk factor for attaining EDSS worsening. This work represents a step forward in identifying predictors of unfavorable course in pCIS and POMS and supports a protective effect of early DMD treatment in preventing MS development and disability accumulation in this population. Ann Neurol 2017;81:729-739.

Paternal therapy with disease modifying drugs in multiple sclerosis and pregnancy outcomes: a prospective observational multicentric study

BackgroundMost of Multiple Sclerosis (MS) patients undergo disease modifying drug (DMD) therapy at childbearing age. The objective of this prospective, collaborative study, was to assess outcomes of pregnancies fathered by MS patients undergoing DMD.MethodsStructured interviews on pregnancies fathered by MS patients gathered in the Italian Pregnancy Dataset were collected; pregnancies were divided according to father exposure or unexposure to DMD at time of procreation. Treatment were compared with multivariable logistic and linear models.ResultsSeventy-eight pregnancies fathered by MS patients were tracked. Forty-five patients were taking DMD at time of conception (39 beta-interferons, 6 glatiramer acetate), while 33 pregnancies were unexposed to DMD. Seventy-five pregnancies ended in live-births, 44 in the exposed and 31 in the unexposed group. No significant differences between the two groups were found in the risk of spontaneous abortion or malformations (p > 0.454), mean gestational age (p = 0.513), frequency of cesarean delivery (p = 0.644), birth weight (p = 0.821) and birth length (p = 0.649). In comparison with data of the Italian general population, the proportion of spontaneous abortion and caesarean delivery in exposed pregnancies fell within the estimates, while the proportion of pre-term delivery in the exposed group was higher than expected.ConclusionsOur data indicate no association between paternal DMD exposure at time of conception and risk of spontaneous abortion, adverse fetal outcomes and congenital malformations. Further studies clarifying the role of DMD fathers intake prior and during pregnancy are desirable, to supply guidelines for clinical practice.

Birth Outcomes in Newborns Fathered by Men with Multiple Sclerosis Exposed to Disease-Modifying Drugs

The aim of this study was to determine the incidence of births fathered by men with multiple sclerosis (MS) exposed to a disease-modifying drug (DMD) around the time of conception, and investigate the association between DMD exposure and birth outcomes in newborns of exposed and unexposed MS fathers. Population-based databases in British Columbia (BC), Canada, (the BCMS database, Vital Statistics Birth Registry, Population Data BC Consolidation File/Census GeoData, BC PharmaNet and the BC Perinatal Database Registry) were linked in this retrospective cohort study (1996 to 2010). Multivariate models were used to examine the association between interferon-beta (IFNβ) or glatiramer acetate (GA) exposure (within 64 days prior to or at conception; i.e., the duration of spermatogenesis) with birth weight and gestational age of newborns. Of 195 births fathered by men with relapsing-onset MS, 80 births (41%) were to fathers treated with a DMD before their child was born, with 53/195 (27%) exposed within 64 days prior to or at the time of conception. Of the 53 exposed births, 37 were to IFNβ and 16 to GA. Mean birth weight of IFNβ-exposed and GA-exposed newborns was similar to that of unexposed newborns (adjusted difference: -107 g for both, p>0.3). IFNβ-exposed and GA-exposed newborns also had comparable mean gestational ages relative to unexposed newborns (adjusted difference: -0.5 and -0.3 weeks, respectively, p>0.2). About one in three would-be fathers with MS were exposed to IFNβ or GA around the time of conception; there was no compelling evidence to suggest that exposure was associated with either lower birth weight or gestational age.

Disease-modifying drugs for multiple sclerosis in pregnancy

To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS). A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. Fifteen studies identified 761 interferon β-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon β exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes. Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.

Perinatal outcomes in women with multiple sclerosis exposed to disease-modifying drugs

Background: The incidence of disease-modifying drug (DMD) exposure during pregnancy in multiple sclerosis (MS) is unknown and limited data exists regarding the potential harm of DMD exposure during pregnancy. Objective: To investigate the incidence and effect of in utero DMD exposure on perinatal outcomes. Methods: We conducted a retrospective analysis by linking two provincial, population-based databases, the British Columbia (BC) MS database with the BC Perinatal Database Registry. Delivery (duration of the second stage of labor, assisted vaginal delivery and Cesarean section) and neonatal (birth weight, gestational age, 5-minute Apgar score and congenital anomalies) outcomes were compared between women exposed and unexposed to a DMD within 1 month prior to conception and/or during pregnancy. Findings were reported as odds ratios (ORs) with 95% confidence intervals (CIs). Results: In all, 311 women with relapsing–remitting MS delivered 418 singleton babies between April 1998 and March 2009. 21/101 (21%) of births to MS women treated with DMD prior to pregnancy were exposed to a DMD. In all cases, exposure was documented as unintentional and DMD treatment was stopped within 2 months of gestation. The overall incidence of exposure was 21/418 (5%). DMD exposure was associated with a trend towards a greater risk of assisted vaginal delivery compared to the DMD naïve groups (OR = 3.0; 95% CI: 1.0–9.2). All other comparisons of perinatal outcomes were unremarkable. Conclusion: The incidence of DMD exposure was relatively low and no cases were intentional. Further studies are needed to ascertain the safety of DMD exposure during pregnancy in MS.