Safety Of Disease-modifying Therapies Research Articles

Practical Considerations for Managing Pregnancy in Patients With Multiple Sclerosis: Dispelling the Myths.

Lack of consistent data and guidance have led to variations between clinicians in the management of pregnancy in women with multiple sclerosis (MS). Pregnant and/or lactating women are often excluded from clinical trials conducted in MS, and thus, the labeling for most disease-modifying therapies (DMTs) excludes use during pregnancy. This has led to heterogeneity in interpretation and labeling regarding the safety of DMTs during pregnancy and lactation and the required preconception washout periods. This review identifies key themes where there is conflicting information surrounding family planning and pregnancy in MS, focusing on the most common discussion points between physicians and patients during preconception planning, pregnancy, postpartum, and lactation. The goal was to inform the patient-physician conversation and provide best practice recommendations based on expert clinical expertise and experience. We outline the latest evidence-based data for DMT use during pregnancy and lactation, the effect of MS on fertility and fertility treatments, the risk of adverse pregnancy and delivery outcomes, the risk of postpartum relapse, and immunization and clinical imaging safety during pregnancy and breastfeeding. Management of family planning and pregnancy in patients with MS requires the most current information. Health care providers should discuss family planning early and frequently with patients with MS, and partners where practicable. Because management of pregnant people with MS will often require a risk/benefit analysis of their needs, shared decision-making in family planning discussions is emphasized. Additional data are needed for specific and underrepresented populations with MS (e.g., single parents or those from the LGBTQ+ community) and those at risk of racial and socioeconomic disparities in care. Pregnancy registries and the design and conduct of clinical trials focused on pregnant and lactating patients should provide additional data to guide the ongoing management of patients with MS.

Precision Medicine in Diabetic Kidney Disease: A Narrative Review Framed by Lived Experience

Purpose of review: Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease (CKD) for which many treatments exist that have been shown to prevent CKD progression and kidney failure. However, DKD is a complex and heterogeneous etiology of CKD with a spectrum of phenotypes and disease trajectories. In this narrative review, we discuss precision medicine approaches to DKD, including genomics, metabolomics, proteomics, and their potential role in the management of diabetes mellitus and DKD. A patient and caregivers of patients with lived experience with CKD were involved in this review. Sources of information: Original research articles were identified from MEDLINE and Google Scholar using the search terms “diabetes,” “diabetic kidney disease,” “diabetic nephropathy,” “chronic kidney disease,” “kidney failure,” “dialysis,” “nephrology,” “genomics,” “metabolomics,” and “proteomics.” Methods: A focused review and critical appraisal of existing literature regarding the precision medicine approaches to the diagnosis, prognosis, and treatment of diabetes and DKD framed by a patient partner’s/caregiver’s lived experience. Key findings: Distinguishing diabetic nephropathy from CKD due to other types of DKD and non-DKD is challenging and typically requires a kidney biopsy for a diagnosis. Biomarkers have been identified to assist with the prediction of the onset and progression of DKD, but they have yet to be incorporated and evaluated relative to clinical standard of care CKD and kidney failure risk prediction tools. Genomics has identified multiple causal genetic variants for neonatal diabetes mellitus and monogenic diabetes of the young that can be used for diagnostic purposes and to specify antiglycemic therapy. Genome-wide-associated studies have identified genes implicated in DKD pathophysiology in the setting of type 1 and 2 diabetes but their translational benefits are lagging beyond polygenetic risk scores. Metabolomics and proteomics have been shown to improve diagnostic accuracy in DKD, have been used to identify novel pathways involved in DKD pathogenesis, and can be used to improve the prediction of CKD progression and kidney failure as well as predict response to DKD therapy. Limitations: There are a limited number of large, high-quality prospective observational studies and no randomized controlled trials that support the use of precision medicine based approaches to improve clinical outcomes in adults with or at risk of diabetes and DKD. It is unclear which patients may benefit from the clinical use of genomics, metabolomics and proteomics along the spectrum of DKD trajectory. Implications: Additional research is needed to evaluate the role of the use of precision medicine for DKD management, including diagnosis, differentiation of diabetic nephropathy from other etiologies of DKD and CKD, short-term and long-term risk prognostication kidney outcomes, and the prediction of response to and safety of disease-modifying therapies.

Cost associated with a relapse-free patient in multiple sclerosis: A real-world health indicator.

BackgroundThe efficacy and safety of disease-modifying therapies (DMTs) in multiple sclerosis (MS) are well known; however, owing to their high costs, determining real-world outcomes is essential to evaluate the cost-effectiveness of different therapeutic strategies. This study aimed to investigate the variability in the annual cost of DMTs associated with a relapse-free patient in a representative population cohort of relapsing-remitting MS (RRMS), and whether this could serve as an appropriate health indicator.MethodsWe analyzed the patients followed up in our MS clinic during the years 2016 and 2019, and selected patients belonging to our health district diagnosed with RRMS. The treatment cost associated with a relapse-free patient was the ratio between the total cost of DMTs and the number of relapse-free patients, treated and not treated, during the year of the study.ResultsA total of 158 patients with RRMS in 2016 and 183 in 2019 were included in our study. In 2016, 101 patients with RRMS (63.9%) received treatment with DMTs and 120 patients (75.9%) remained relapse-free. The mean cost of DMTs per patient in 2016 was €7414.3 (95% confidence interval [CI]: 6325.2–8503.4) considering all the patients (treated and not treated). In 2019, 126 patients (68.9%) received DMTs and 151 patients (82.5%) remained relapse-free. The mean cost of DMTs per patient in 2019 was €6985.4 (95% CI: 5986.9–7983.9) considering all the patients. The cost per year of DMTs to achieve a relapse-free patient was €9762.2 in 2016 and €8465.8 in 2019.ConclusionsThe treatment cost per year to achieve a relapse-free patient was stable during successive measurements in the same population. Therefore, it may be considered a good real-world health indicator for patients with RRMS treated with DMTs.

Disease-Modifying Drugs and Breastfeeding in Multiple Sclerosis: A Narrative Literature Review.

Pregnancy-related issues in women with multiple sclerosis (MS) have been receiving increasing attention, with particular interest for the use of disease-modifying therapies (DMTs) before conception, during pregnancy, and postpartum, including breastfeeding. The risk of relapse is higher in the early postpartum period, especially in cases of significant disease activity prior to pregnancy, and thus treatment resumption and/or switching strategies might be necessary. Moreover, breastfeeding provides unmatched health benefits for babies and mothers, and is recommended as the best source of nutrition for infants. Furthermore, a protective role of breastfeeding on MS disease course has not been fully demonstrated and it remains debatable. At the same time, a source of concern is the potential transfer of DMTs into breastmilk and the resulting infant exposure. The use of most DMTs is unlicensed during breastfeeding mainly due to the limited data available on the excretion in human milk and on the effects on infants' exposure. Consequently, women have to face the difficult challenge of choosing between breastfeeding and DMT resumption. The present narrative review summarizes and discusses the available evidence on the safety of DMTs during breastfeeding and the relative approved labels. At the time of diagnosis of MS, specific counseling should be offered to women of childbearing age, making them aware of the possible therapeutic options and their impact on pregnancy and breastfeeding. Women can be encouraged to breastfeed, if clinically feasible, following a review of their medications and clinical status, with a personalized approach.

Treatment Updates in Paediatric-onset Multiple Sclerosis

A number of new disease-modifying therapies have recently been developed and approved for use in adult-onset multiple sclerosis. However, few treatment options are approved for patients with paediatric-onset multiple sclerosis. There are an increasing number of clinical trials evaluating the efficacy and safety of disease-modifying therapies in children and teens living with multiple sclerosis. Clinical trials are difficult to complete in rare diseases like paediatric-onset multiple sclerosis; however, it is critical to assess safety and monitoring in this vulnerable population by applying robust research methodology to randomized controlled clinical trials. Longer-term extension analyses are also needed to better evaluate the efficacy, dosing and long-term safety of adult disease-modifying therapy for use in paediatric-onset multiple sclerosis. Future research should focus on defining optimal first-line disease-modifying therapy in paediatric-onset multiple sclerosis as related to both efficacy and safety, improving recruitment and completion rates of clinical trials, identifying relevant biomarkers of disease activity, analysing outcome measures related to treatment response and assessing long-term safety for this unique population living with a chronic disease.

Treatment of Women with Multiple Sclerosis Planning Pregnancy.

Purpose of ReviewWe review data available for treatment of multiple sclerosis (MS) before, during, and after pregnancy. We present recent data on disease-modifying therapies (DMT) before/during pregnancy and while breastfeeding, with treatment recommendations.Recent FindingsObservational data support the safety of injectable DMTs (glatiramer acetate, interferon-beta) for use in pregnancy, while some oral DMTs might be associated with fetal risk. Monoclonal antibodies (mAbs) before pregnancy such as rituximab or natalizumab likely do not pose significant fetal risks, but can cross the placenta with neonatal hematological abnormalities if given in the second trimester or later. Breastfeeding is associated with decreased risk of postpartum relapses. Finally, injectables and mAbs likely have low transfer into breastmilk.SummaryMany women with MS do not require DMTs during pregnancy, although injectables could be continued. For women with highly active MS, cell-depleting therapies could be given before conception, or natalizumab could be continued through pregnancy, with monitoring of the fetus. Women should be encouraged to breastfeed, and those with higher relapse risk could consider injectables or mAbs while breastfeeding. Further data on safety of DMTs around pregnancy are needed. Maximizing function through non-pharmacologic approaches is complementary to DMTs. Special considerations for pregnancy and DMTs during the COVID-19 pandemic are needed.

Outcome measures for disease-modifying therapies in relapsing multiple sclerosis randomized clinical trials: a scoping review protocol.

The objective of the review is to explore randomized controlled trials on disease-modifying therapies for relapsing multiple sclerosis to identify and quantify the different outcome measures, instruments and definitions of efficacy, safety outcomes, health-related quality of life instruments and population subgroups. A wide range of therapies are available for relapsing multiple sclerosis, as well as a wide range of outcome measures and definitions, which can be explained by the absence of a core outcome set for this disease. Establishing a core outcome set is fundamental for guiding future studies as they improve the consistency and relevance of new findings and enable the results of trials to be compared and combined. These features are especially important for relapsing multiple sclerosis due to the limited number of head-to-head studies on this disease. Although many systematic reviews and meta-analyses have focused on the efficacy and safety of disease-modifying therapies in relapsing multiple sclerosis, none have had the specific objective of mapping outcome measures. This review will consider randomized controlled trials that explore populational subgroups, efficacy, safety outcomes, health-related quality of life instruments and their definitions in the context of disease-modifying therapies for adults with relapsing multiple sclerosis. Electronic searches will be performed in PubMed, Scopus, the Cochrane Library, ClinicalTrials.gov, and JBI Evidence Synthesis with no time limit. Two researchers will independently select registries (screening and eligibility steps) and extract data on study characteristics, outcome measures, definitions and population subgroups. Data will be presented in graphical or tabular form, accompanied by a narrative summary.

The effect of cardiovascular diseases on the course of multiple sclerosis (review of literature)

Comorbidity is one of the factors determining the course of multiple sclerosis. Cardiovascular pathology is one of the most common in the population as a whole, especially in age groups over 50. Several studies showed that arterial hypotension and dyslipidemia affected the course, progression rate, and neuroimaging characteristics of patients with multiple sclerosis. An important issue is the effect of disease modifying therapy on the course of concomitant diseases in patients with multiple sclerosis and the effect of concomitant diseases on the effectiveness and safety of disease modifying therapy. The question of the use of statins in multiple sclerosis remains controversial. This review presents data on vascular comorbidity in multiple sclerosis, including the prevalence of risk factors for cardiovascular pathology and concomitant vascular diseases in the population of patients with multiple sclerosis. Data on the effect of cardiovascular pathology on the course and treatment of multiple sclerosis were also analyzed.

Harnessing real-world data to inform treatment decisions in multiple sclerosis

Consensus is lacking regarding the initiation and sequencing of disease-modifying therapies (DMTs) for management of multiple sclerosis (MS), resulting in variable use in clinical practice. As novel DMTs with different efficacy and safety profiles emerge based on clinical trials, it is increasingly important to compare the effectiveness and safety of DMTs in clinical practice. Comparing individual therapies in a pairwise fashion in a robust randomized clinical trial (RCT) is costly, rarely occurs, and may not generalize well to the clinical setting, given that clinical trial populations often exclude individuals with comorbidities and of extreme ages.1

Long-term follow-up of multiple sclerosis studies and outcomes from early treatment of clinically isolated syndrome in the BENEFIT 11 study.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) with a diverse disease course involving inflammation and degeneration of neurons and axons. Multiple sclerosis results from a complex interaction of genetic and environmental factors and clinically several disease subtypes with marked variation in symptoms can be discerned. Disease-modifying therapies (DMTs) impact disease activity and outcome. Long-term follow-up studies of DMTs in MS have generally shown that the short-term effects in clinical trials are maintained for up to 21 years, e.g. in the case of interferon beta-1b. However, attainment can be a problem in these studies. On the one hand, so-called real-world studies can augment clinical trials by providing data on the long-term effectiveness and safety of DMTs but lack, on the other hand, randomization and may, in addition, also yield biased findings as a result of compliance issues. Long-term data from clinical trials in clinically isolated syndrome (CIS) patients have been limited but in the case of interferon beta-1b this aspect has been addressed over 11years in the BENEFIT 11 trial. The results suggest that early treatment results in persistent long-term benefits including conversion to clinically definite MS (CDMS) as well as time to and risk of a first relapse. Here we primarily review the findings of the BENEFIT 11 trial in the context of long-term studies.

Editorial.

The International Journal of MS Care editorial team wishes all of our readers a Happy New Year. The year 2016 confirmed the continued growth of the journal, with our highest annual number of submissions ever! The IJMSC was accepted as a member of the Committee on Publication Ethics (COPE), a forum for editors and publishers of peer-reviewed journals with over 10,000 members worldwide. The membership in COPE highlights our dedication to the highest standards of publication ethics.In this issue, we are pleased to offer CME and CNE credits for the article from Newsome and colleagues, which reports on the outcome from a meeting of the Framework Taskforce, a multidisciplinary work group convened by the CMSC to evaluate the models of care in MS. This is a complement to the article published in our November/December 2016 issue, with a specific focus on symptom management and rehabilitation.Assessing the safety of disease-modifying therapies (DMTs) for MS is an ongoing process, as new concerns can emerge when more individuals are exposed to the medication for a longer time. Sørensen and colleagues report on pooled analyses of safety data from two phase 3 trials of laquinimod (ALLEGRO and BRAVO), which essentially confirm findings from the phase 2 study. In particular, there was no increased risk of malignancy over the 2-year period of observation, a concern raised in preclinical studies.While early initiation of DMTs is uniformly recommended, there is currently no consensus on the optimal timing for DMT discontinuation later in the course of the disease. Birnbaum presents experience from his clinical practice, suggesting that older individuals with no evidence of acute MS activity for at least 2 years have a low likelihood of developing recurrent disease activity after treatment discontinuation. Continued monitoring is warranted, however, as there are no identified predictors of who will develop new acute central nervous system inflammation after treatment discontinuation.Cognitive impairment is a known consequence of MS affecting a large number of individuals. Yet, screening for and monitoring cognitive deficits remains a challenge in the context of clinical practice. Based on the results of a study involving 100 MS patients, Kim and colleagues conclude that the Symbol Digit Modalities Test is the best predictor of cognitive impairment (assessed using a validated neuropsychological test battery). As previously reported, self-report measures of cognitive concerns were less accurate screening instruments. Exploratory analyses suggest that some self-report measures may be significant predictors of cognitive impairment, even after adjustment for depression.There is a strong interest among members of the MS community in therapies considered “alternative,” such as yoga, but clinicians have difficulty making recommendations because of a lack of evidence. Cohen and colleagues report positive preliminary findings on the feasibility and efficacy of an 8-week yoga program from an uncontrolled study, paving the way for future studies to gradually fill this evidence gap.It is important to remember that innovative clinical practice can be a great starting point for quality of care improvement, and to generate questions and hypotheses for clinical research. In their letter to the editor, Fjeldstad and Pardo report immediate improvement of gait speed with the use of a service dog in 44 MS patients without prior experience or training. Miletta and colleagues present a case report on the outcomes of multidisciplinary management of sexual dysfunction, perineal pain, and elimination dysfunction in a woman with MS, with an emphasis on the role of physical therapy.You will also find in this issue a list of abstracts from the Fifth Conference of the International Multiple Sclerosis Cognition Society (IMSCOGS), which took place at the New York Academy of Sciences in New York City on June 23–24, 2016. The full abstracts are available online at ijmsc.org.May this brand new year be filled with positive experiences, at the personal and professional levels.

[Current algorithms of diagnosis and treatment of multiple sclerosis based on the individual assessment of the patient].

This review presents the current knowledge on diagnosis, therapy of relapses of multiple Sclerosis (MS) and disease-modifying therapy (DMT) in MS. Algorithms of diagnosis and therapy of MS are presented. Special attention is paid to the analysis of efficacy, tolerability and safety of DMT in MS.

Examining the effects of comorbidities on disease-modifying therapy use in multiple sclerosis.

Objective:Comorbidities are common in multiple sclerosis (MS) and adversely affect health outcomes. However, the effect of comorbidity on treatment decisions in MS remains unknown. We aimed to examine the effects of comorbidity on initiation of injectable disease-modifying therapies (DMTs) and on the choice of the initial DMT in MS.Methods:We conducted a retrospective observational analysis using population-based health administrative and linked clinical databases in 3 Canadian provinces. MS cases were defined as any individual with ≥3 diagnostic codes for MS. Cohort entry (index date) was the first recorded demyelinating disease-related claim. The outcomes included choice of initial first-line DMTs and time to initiating a DMT. Logistic and Cox regression models were used to examine the association between comorbidity status and study outcomes, adjusting for sex, age, year of index date, and socioeconomic status. Meta-analysis was used to estimate overall effects across the 3 provinces.Results:We identified 10,698 persons with incident MS, half of whom had ≥1 comorbidities. As the total number of comorbidities increased, the likelihood of initiating a DMT decreased. Comorbid anxiety and ischemic heart disease were associated with reduced initiation of a DMT. However, patients with depression were 13% more likely to initiate a DMT compared to those without depression at the index date (adjusted hazard ratio 1.13; 95% confidence interval 1.00–1.27).Conclusions:Comorbidities are associated with treatment decisions regarding DMTs in MS. A better understanding of the effects of comorbidity on effectiveness and safety of DMTs is needed.