Patients' Preferences for Sphingosine-1-Phosphate Receptor Modulators in Multiple Sclerosis Based on Clinical Management Considerations: A Choice Experiment.

BACKGROUND: Several sphingosine-1-phosphate receptor (S1PR) modulators are available in the US for treating relapsing forms of multiple sclerosis (RMS). Given that these S1PR modulators have similar efficacy and safety, patients may consider the clinical management characteristics of the S1PR modulators when deciding among treatments. However, none of the S1PR modulators is clearly superior in every aspect of clinical management, and for some treatments, clinical management varies based on a patient's comorbid health conditions (e.g., heart conditions [HC]). OBJECTIVES: This study aimed to determine which S1PR modulator patients with relapsing-remitting multiple sclerosis (RRMS) would prefer based on clinical management considerations, and to estimate how different clinical management considerations might drive these preferences. Preferences were explored separately for patients with and without comorbid HC. METHODS: A multicriteria decision analysis was conducted on S1PR modulators approved to treat RMS: fingolimod, ozanimod, siponimod, and ponesimod. Clinical management preferences of patients with RRMS were elicited in a discrete choice experiment (DCE) in which participants repeatedly chose between hypothetical S1PR modulator profiles based on their clinical management attributes. Attributes included first-dose observations, genotyping, liver function tests, eye examinations, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Preferences were estimated separately for patients with HC and without HC (noHC). Marginal utilities were calculated from the DCE data for each attribute and level using a mixed logit model. In the multicriteria decision analysis, partial value scores were created by applying the marginal utilities for each attribute and level to the real-world profiles of S1PR modulators. Partial value scores were summed to determine an overall clinical management value score for each S1PR modulator. RESULTS: Four hundred patients with RRMS completed the DCE. Ponesimod had the highest overall value score for patients both without (n = 341) and with (n = 59) HC (noHC: 5.1; HC: 4.0), followed by siponimod (noHC: 4.9; HC: 3.3), fingolimod (noHC: 3.4; HC: 2.8), and ozanimod (noHC: 0.9; HC: 0.8). Overall, immune system recovery time contributed the highest partial value scores (noHC: up to 1.9 points; HC: up to 1.2 points), followed by the number of drug-drug interactions (noHC: up to 1.2 points; HC: up to 1.7 points). CONCLUSIONS: When considering the clinical management of S1PR modulators, the average patient with RRMS is expected to choose a treatment with shorter immune system recovery time and fewer interactions with other drugs. Patients both with and without heart conditions are likely to prefer the clinical management profile of ponesimod over those of siponimod, fingolimod, and ozanimod. This information can help inform recommendations for treating RRMS and facilitate shared decision making between patients and their doctors.

Tolerability of subcutaneous ofatumumab with long-term exposure in relapsing multiple sclerosis.

Background: Ofatumumab is approved for treating relapsing multiple sclerosis (RMS). Examining tolerability will enable understanding of its risk-benefit profile. Objective: Report the tolerability profile of ofatumumab in RMS during treatment of up to 4 years and the effect of pre-medication. Methods: Cumulative data from the overall safety population included patients taking continuous ofatumumab or being newly switched from teriflunomide. Injection-related reactions (IRRs) by incidence and severity, and post-marketing surveillance data, with an exposure of 18,530 patient-years, were analyzed. Results: Systemic IRRs affected 24.7% of patients (487/1969) in the overall safety population; most (99.2% [483/487]) were mild (333/487) to moderate (150/487) in Common Terminology Criteria for Adverse Events severity; most systemic IRRs occurred after first injection. Local-site IRRs affected 11.8% (233/1969) and most (99.6% [232/233]) were mild/moderate. Incidence and severity of systemic and localized IRRs were similar between continuous and newly switched patients across repeated injections. Systemic IRR incidence and severity were not substantially affected by steroidal or non-steroidal pre-medication. Post-marketing surveillance identified no new tolerability issues. Conclusion: Ofatumumab is well tolerated, displays a consistent safety profile during continuous use or after switching from teriflunomide and does not require pre-medication. This enables home management of RMS with a high-efficacy treatment.

Analysis of Pregnancy Outcomes Following Exposure to Intramuscular Interferon Beta-1a: The AVONEX® Pregnancy Exposure Registry.

BACKGROUND AND OBJECTIVES: There is a lack of well-controlled US studies of intramuscular (IM) interferon beta (IFNß)-1a use in pregnant women with multiple sclerosis; however, in the European Medicines Agency region, IFNß formulations may be considered during pregnancy if clinically needed based on data from European Union cohort registries. The AVONEX Pregnancy Exposure Registry was established to prospectively study the effects of IM IFNß-1a on the risk of birth defects and spontaneous pregnancy loss in a US population. METHODS: Pregnant women with multiple sclerosis exposed to IM IFNß-1a within ~ 1 week of conception or during the first trimester were included. Participants were followed until there was a pregnancy outcome, live-born infants were followed until age 8-12 weeks. Data were collected on IM IFNß-1a exposure, demographics, patient characteristics, medical history, and pregnancy outcomes, including live births (with or without birth defect), spontaneous abortions/miscarriages and fetal death/stillbirth, elective abortions (with and without birth defect), and ectopic pregnancies. A population-based birth defect surveillance program, the Metropolitan Atlanta Congenital Defects Program (MACDP), served as the primary external control group for evaluating the risk of birth defects. RESULTS: Three-hundred and two patients with a median (range) age of 31.0 (16-48) years and a median (range) gestational age at the time of enrollment of 10.1 (4-39) weeks were evaluable. Most patients (n = 278/302; 92%) reported IM IFNß-1a exposure in the week before conception and most (n = 293/302; 97%) discontinued treatment before the end of the first trimester. Of 306 pregnancy outcomes, there were 272 live births, 28 spontaneous abortions of 266 pregnancies enrolled before 22 weeks' gestation (rate 10.5%; 95% confidence interval 7.2-15.0), five elective abortions, and one stillbirth. There were 17 adjudicator-confirmed major birth defects of 272 live births (rate 6.3%; 95% confidence interval 3.8-10.0); the pattern of birth defects observed was not suggestive of a relationship to prenatal IM IFNß-1a exposure. CONCLUSIONS: This large US registry study suggests IM IFNß-1a exposure during early pregnancy was not clinically associated with adverse pregnancy outcomes in women with multiple sclerosis. These findings help inform clinicians and patients in weighing the risks and benefits of IM IFNß-1a use during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT00168714, 15 September, 2005.

Factors Associated With Disease-Modifying Therapy Adherence and Persistence in Multiple Sclerosis: A Scoping Literature Review.

BACKGROUND: Patients with multiple sclerosis (MS) receiving disease-modifying therapies (DMT) show published adherence rates of 27.0% to 93.8% and published persistence rates of 49.7% to 96.5%. Improvements in DMT adherence and persistence are key to optimizing MS care, and enhanced understanding could improve MS disease management and identify research gaps. This scoping literature review aims to examine the nature and findings of the literature evaluating factors associated with DMT adherence and persistence in patients with MS. METHODS: Eligible articles included in the literature review were quantitative clinical studies written in English, included adherence or persistence as primary outcomes, and accounted for covariates/confounders. The articles were assessed to identify factors associated with adherence/persistence and analyzed according to DMT type (self-injectable, oral, infusion). RESULTS: Fifty-eight studies (103,450 patients) were included. Study distribution by DMT type was self-injectable only (n = 41), oral only (n = 2), infusion only (n = 1), and more than 1 type (n = 14). Older age and previous DMT use were associated with increased adherence and/or persistence. Increased alcohol consumption, DMT adverse events, higher education, and higher body mass index were negatively associated with adherence and/or persistence. Greater number and severity of relapses was associated with increased adherence but decreased persistence. CONCLUSIONS: Most studies examined factors associated with adherence and persistence to self-injectable DMTs. These factors should be evaluated further for oral and infusion DMTs. Insights into the modifiable factors associated with adherence and persistence could guide treatment decisions and help improve adherence and clinical outcomes.

Patient and nurse preference for Sensoready autoinjector pen versus other autoinjectors in multiple sclerosis: results from a pilot multicenter survey.

BACKGROUND: Sensoready® autoinjector pen facilitates self-administration of subcutaneous ofatumumab injections at home. We aim to investigate patient and nurse preference for using Sensoready® versus comparator autoinjectors in multiple sclerosis (MS). METHODS: A pilot survey was conducted in Germany followed by in-field interviews across United States, Germany, France, and Italy. The survey recruited 80 MS patients and 50 MS nurses. Respondents were interviewed for 45-min on qualitative open-ended and quantitative close-ended survey consisting of 31 questions for patients and 41 for nurses. Ratings were measured on Likert scale from 1 (not at all important) to 10 (extremely important). RESULTS: "Easy to perform self-injection with the pen" and "Patient able to use independently" (both, mean overall score 9.4) were the most important attributes for both patients and nurses. Sensoready® scored high across most important attributes for both patients and nurses (p < 0.05). Sensoready® was preferred over comparator devices across majority of the important attributes (84%; p < 0.05), especially ease of use of the pen (mean overall score 9.4). Sensoready® was preferred over their current device by 9/10 nurses and 8/10 patients if they had to choose a treatment based on the device alone. CONCLUSION: Both MS patients and nurses preferred the Sensoready® (ofatumumab) over comparator autoinjectors for their treatment, mostly driven by ease of administration.

Pregnancy Outcomes from the Branded Glatiramer Acetate Pregnancy Database.

BACKGROUND: Appropriate counseling and treatment for women with multiple sclerosis (MS) who may become pregnant requires an understanding of the effects of exposure to disease-modifying therapies (DMTs) during pregnancy. Current reports and studies are limited in their usefulness, mostly by small sample size. Branded glatiramer acetate (GA) is a DMT approved for the treatment of relapsing forms of MS. For more than 2 decades, it has been shown to be efficacious and to have a favorable safety profile. The Teva Pharmaceutical Industries Ltd global pharmacovigilance database comprises data from more than 7000 pregnancies, during which women with MS were exposed to treatment with branded GA. METHODS: We analyzed data from Teva's global pharmacovigilance database. Pregnancy outcomes for patients treated with branded GA were compared with reference rates of abnormal pregnancy outcomes reported in two large registries representing the general population. RESULTS: Pregnancies exposed to branded GA were not at higher risk for congenital anomalies than what is expected in the general population. CONCLUSIONS: These data provide evidence that branded GA exposure during pregnancy seems safe, without teratogenic effect.

Patient Satisfaction with the New Interferon Beta-1b Autoinjector (BETACONNECT™).

INTRODUCTION: Multiple sclerosis (MS) typically requires life-long management with disease-modifying therapies (DMTs). Many DMTs require regular self-injection, and can be associated with injection site reactions, pain, and needle/injection phobia-but these can be addressed by improvements in autoinjector design. The aim of this study was to investigate patient satisfaction and preference for BETACONNECT™ (Bayer Pharma AG), a novel interferon beta-1b autoinjector. METHODS: Patients in Germany performing self-injections using BETACONNECT took part in the study. Data were collected through an online 15-min structured survey. Participants rated their experience with BETACONNECT on a 6-point scale and those satisfied with BETACONNECT were asked to describe the reason using a free-text box. RESULTS: One-hundred and eighteen patients with MS completed the survey. Ninety percent preferred BETACONNECT to their previous injection method (only 4% previously used manual injections, so most had previously used other autoinjectors). Ninety-two percent were very confident/confident in their ability to perform an injection using BETACONNECT. The most common free-text responses to "Why are you satisfied with the BETACONNECT™ autoinjector?" were ease of use (46%), less irritation/pain at the injection site (33%), and smoother injections (24%). Features considered most useful were automated injections (98%), adjustable injection speed (98%), and adjustable injection depth (98%). Ninety-seven percent thought it was easy to know when an injection was complete and 95% agreed/strongly agreed it was easy to learn to use the autoinjector. Seventy-three percent agreed that the quietness and effortlessness of the BETACONNECT reduced their level of injection anxiety, 92% that its size and shape makes it easy to handle during injections, and 67% that it decreases injection site pain. Eighty percent of those using the reminder function thought they were less likely to miss an injection. CONCLUSION: Patients with MS self-injecting interferon beta-1b expressed a high level of satisfaction and preference for BETACONNECT. Thus, BETACONNECT represents a valid option to improve patients' overall injection experience. FUNDING: Bayer HealthCare Pharmaceuticals.

Adherence in multiple sclerosis (ADAMS): classification, relevance, and research needs. A meeting report.

BACKGROUND: Adherence to medical interventions is a global problem. With an increasing amount of partially effective but expensive drug treatments adherence is increasingly relevant in multiple sclerosis (MS). Perceived lack of efficacy and side effects as well as neuropsychiatric factors such as forgetfulness, fatigue and depression are major determinants. However, research on adherence to behavioural interventions as part of rehabilitative interventions has only rarely been studied. METHODS: In a one-day meeting health researchers as well as patient representatives and other stakeholders discussed adherence issues in MS and developed a general draft research agenda within a focus group session. RESULTS: The focus group addressed four major areas: (1) focussing patients and their informal team; (2) studying health care professionals; (3) comparing practice across cultures; and (4) studying new adherence interventions. CONCLUSIONS: A focus on patient preferences as well as a non-judgmental discussion on adherence issues with patients should be at the core of adherence work.

Development of a short form and scoring algorithm from the validated actionable bladder symptom screening tool.

BACKGROUND: The majority of multiple sclerosis (MS) patients develop some form of lower urinary tract dysfunction, usually as a result of neurogenic detrusor overactivity (NDO). Patients identify urinary incontinence as one of the worst aspects of this disease. Despite the high prevalence of NDO, urological evaluation and treatment are significantly under-accessed in this population. The objectives of this study were: 1) to adapt the previously validated Actionable Bladder Symptom Screening Tool (ABSST) to a short form for ease and brevity of application in a clinical setting that is clinically meaningful; and 2) to develop a scoring algorithm that would be interpretable in terms of referring/considering precise diagnosis and treatment. METHODS: A US-based, non-randomized, multi-center, stand-alone observational study was conducted to assess the psychometric properties of the ABSST among patients who have MS with and without NDO. Mixed psychometric methods (e.g., classical statistics (Psychometric theory (3rd ed.). New York: McGraw-Hill; 1994) and item response methods (Applying the Rasch Model: Fundamental Measurement in the Human Sciences. New Jersey: Lawrence Earlbaum Associates; 2001)) were used to evaluate the predictive and clinical validity of the shortened form. The latter included clinicians flagging clinically meaningful items and associated response options which would indicate the need for further evaluation or treatment. RESULTS: A total of 151 patients, all with MS and with and without NDO, were recruited by 28 clinicians in various US geographical locations. Approximately 41% of patients reported a history of or currently having urinary incontinence and/or urinary urgency. The prediction model across the entire range of classification thresholds was evaluated, plotting the true positive identification rate against the false positive rate (1-Specificity) for various cut scores. In this study, the cut-point or total score of greater than or equal to 6 had a sensitivity of approximately 85%, and specificity of approximately 93% (i.e., 85% patients would warrant being referred to a urologist and 93% of the patients whose symptoms would not warrant urologist referral). CONCLUSIONS: Overall the short form ABSST demonstrated sensitivity and specificity as it maintained the integrity of the longer form tool. Concurrent validity for each subscale as well as predictive and concurrent validity of the total shortened instrument was demonstrated. This instrument provides a new method for assessing bladder problems among MS patients, and may facilitate earlier and more precise diagnosis, treatment, and/or referral to a specialist.

Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropic hormone.

Relapses in multiple sclerosis (MS) are disruptive and frequently disabling for patients, and their treatment is often a challenge to clinicians. Despite progress in the understanding of the pathophysiology of MS and development of new treatments for long-term management of MS, options for treating relapses have not changed substantially over the past few decades. Corticosteroids, a component of the hypothalamic-pituitary-adrenal axis that modulate immune responses and reduce inflammation, are currently the mainstay of relapse treatment. Adrenocorticotropic hormone (ACTH) gel is another treatment option. Although it has long been assumed that the efficacy of ACTH in treating relapses depends on the peptide's ability to increase endogenous corticosteroid production, evidence from research on the melanocortin system suggests that steroidogenesis may only partly account for ACTH influences. Indeed, the melanocortin peptides [ACTH and α-, ß-, γ-melanocyte-stimulating hormones (MSH)] and their receptors (Melanocortin receptors, MCRs) exert multiple actions, including modulation of inflammatory and immune mediator production. MCRs are widely distributed within the central nervous system and in peripheral tissues including immune cells (e.g., macrophages). This suggests that the mechanism of action of ACTH includes not only steroid-mediated indirect effects, but also direct anti-inflammatory and immune-modulating actions via the melanocortin system. An increased understanding of the role of the melanocortin system, particularly ACTH, in the immune and inflammatory processes underlying relapses may help to improve relapse management.

Development and validation of the actionable bladder symptom screening tool for multiple sclerosis patients.

Bladder symptoms such as urinary urgency, frequency, and incontinence are common in people with multiple sclerosis (MS). These symptoms, which often result from neurogenic detrusor overactivity (NDO), can have a major impact on patients' day-to-day lives. However, in many cases they are over-looked in the clinical management of MS. The objective of this study was to develop and validate a reliable, sensitive, and specific screening tool for patients with bladder problems related to MS. We performed a literature review and then conducted a content validation study followed by a multisite observational study of a new screening tool, the Actionable Bladder Symptom Screening Tool (ABSST). All ABSST domains as well as the total score met the threshold for good internal consistency (Cronbach α ≥ 0.70), with a Cronbach α value of 0.95 for the total score and values ranging from 0.85 to 0.90 for the three domains. The validity of the ABSST was demonstrated by high correlation of the domains and total score with the Overactive Bladder Questionnaire Short Form (OAB-q SF) Symptom Severity and Total Health-Related Quality of Life (HRQOL) scores (Spearman correlation coefficient ≥ 0.782). The predictive validity of the ABSST total score to identify patients who might receive a recommendation to see a urologist was strong. This new instrument, which was developed with input from clinicians as well as MS patients, meets the current content validity and psychometric testing thresholds established by the US Food and Drug Administration, with high sensitivity and specificity.

Assessing relapses and response to relapse treatment in patients with multiple sclerosis: a nursing perspective.

There are currently no assessment tools that focus on evaluating patients with multiple sclerosis (MS) who are experiencing a relapse or that evaluate patients' response to acute relapse treatment. In practice, assessments are often subjective, potentially resulting in overlooked symptoms, unaddressed patient concerns, unnoticed or underrecognized side effects of therapies (both disease modifying and symptomatic), and suboptimal therapeutic response. Systematic evaluation of specific symptoms and potential side effects can minimize the likelihood of overlooking important information. However, given the number of potential symptoms and adverse events that patients may experience, an exhaustive evaluation can be time-consuming. Clinicians are thus challenged to balance thoroughness with brevity. A need exists for a brief but comprehensive objective assessment tool that can be used in practice to 1) help clinicians assess patients when they present with symptoms of a relapse, and 2) evaluate outcomes of acute management. A working group of expert nurses convened to discuss recognition and management of relapses. In this article, we review data related to recognition and management of relapses, discuss practical challenges, and describe the development of an assessment questionnaire that evaluates relapse symptoms, the impact of symptoms on the patient, and the effectiveness and tolerability of acute treatment. The questionnaire is designed to be appropriate for use in MS specialty clinics, general neurology practices, or other practice settings and can be administered by nurses, physicians, other clinicians, or patients (self-evaluation). The relapse assessment questionnaire is currently being piloted in a number of practice settings.

Recent developments in the early diagnosis and management of multiple sclerosis.

The management paradigm for multiple sclerosis (MS) is moving toward earlier diagnosis (on the basis of clinical, paraclinical, and laboratory findings), differentiation of patients with varying prognoses, and earlier implementation of treatment in selected individuals. On the basis of a survey conducted at the American Association of Neuroscience Nurses Annual Conference in 2009, several topics were identified for which nurses indicated a need for new and updated information, including current diagnostic methods for MS, optimal time to initiate treatment of MS, and emerging therapies for MS. This article was designed to address these issues.

Tolerability, adherence, and patient outcomes.

Providing optimal patient care in multiple sclerosis (MS) is dependent on both the patient and the healthcare system. One of the greatest challenges to optimal patient care is ensuring patient adherence to treatment. The two reasons given most often for treatment discontinuation are adverse effects and lack of efficacy. Adverse effects can be anticipated and managed, in part through well-established protocols, but also through industry-sponsored nursing support programs. These strategies can reduce needless discontinuations when patients experience common adverse effects. Lack of efficacy can be addressed for many patients by providing them with enough education to develop reasonable expectations for treatment and long-term prognosis. As important as early and continuous treatment are, these strategies are essential for providing optimal patient care in MS.

Effective multiple sclerosis management through improved patient assessment.

Multiple sclerosis (MS) is a complex disease with a wide range of clinical manifestations. Current disease-modifying drugs (DMDs) are effective, but they are associated with effects that may negatively influence treatment compliance. A recent nursing advisory board of MS nurse experts from the Midwest discussed management approaches that can enhance DMD compliance and improve patient satisfaction and quality of life. One such approach is the use of patient questionnaires as tools to assess signs and symptoms of MS and treatment-related adverse effects. Information gained in this manner is beneficial to MS healthcare professionals as well as patients and has the potential to improve treatment compliance and outcomes and disease management.

Rethinking cognitive function in multiple sclerosis: a nursing perspective.

Cognitive impairment is a common problem in multiple sclerosis (MS); up to 65% of patients exhibit some neuropsychological dysfunction during the course of their disease. It is a major contributing factor to unemployment, accidents, impairment of daily functioning, and loss of social activity in those affected by MS. The areas of cognition typically impaired are memory, attention, information processing, executive functions, and visuospatial skills. Cognitive dysfunction is independent of disease duration and level of disability; cognitive decline may begin in the earliest stages of MS before patients become even mildly disabled. Structural brain imaging studies show a positive correlation between the extent of brain atrophy and cognitive dysfunction. Despite its prevalence in MS, cognitive dysfunction often goes undiagnosed or is misdiagnosed as depression, stress, stubbornness, lack of intelligence, or psychosis. Because nurses play such an important role in the care of patients with MS, they are in a position to identify patients with cognitive dysfunction, educate patients and their families on ways to cope with cognitive deficits, and counsel patients on available treatment options. Practical guidelines help nurses identify and care for cognitively impaired MS patients.