Decisional Conflict Regarding Disease-Modifying Treatment Choices Among Patients with Mid-Stage Relapsing-Remitting Multiple Sclerosis.

Purpose: Shared decision-making is critical in multiple sclerosis (MS) due to the uncertainty of the disease trajectory over time and the large number of treatment options with differing efficacy, safety and administration characteristics. The aim of this study was to assess patients' decisional conflict regarding the choice of a disease-modifying therapy and its associated factors in patients with mid-stage relapsing-remitting multiple sclerosis (RRMS). Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS (2017 revised McDonald criteria) and disease duration of 3 to 8 years were included. The level of uncertainty experienced by a patient when faced with making a treatment choice was assessed using the 4-item Decisional Conflict Scale. A battery of patient-reported and clinician-rated measures was administered to obtain information on symptom severity, illness perception, illness-related uncertainty, regret, MS knowledge, risk taking behavior, preferred role in the decision-making process, cognition, and self-management. Patients were recruited during routine follow-up visits and completed all questionnaires online using electronic tablets at the hospital. A multivariate logistic regression analysis was conducted. Results: A total of 201 patients were studied. Mean age (Standard deviation) was 38.7 (8.4) years and 74.1% were female. Median disease duration (Interquartile range) was 6.0 (4.0-7.0) years. Median EDSS score was 1.0 (0-2.0). Sixty-seven (33.3%) patients reported a decisional conflict. These patients had lower MS knowledge and more illness uncertainty, anxiety, depressive symptoms, fatigue, subjective symptom severity, a threatening illness perception, and poorer quality of life than their counterparts. Lack of decisional conflict was associated with MS knowledge (Odds ratio [OR]=1.195, 95% CI 1.045, 1.383, p=0.013), self-management (OR=1.049, 95% CI 1.013, 1.093, p=0.018), and regret after a healthcare decision (OR=0.860, 95% CI 0.756, 0.973, p=0.018) in the multivariate analysis. Conclusion: Decisional conflict regarding the selection of a disease-modifying therapy was a common phenomenon in patients with mid-stage RRMS. Identifying factors associated with decisional conflict may be useful to implement preventive strategies that help patients better understand their condition and strengthen their self-management resources.

Pharmacogenetics of siponimod: A systematic review.

Multiple sclerosis is a chronic inflammatory neurological disease, and siponimod (Mayzent) is the first oral treatment option for adult patients with secondary progressive multiple sclerosis. We performed a systematic review of the pharmacogenetics of Siponimod, and we found that (430 C>T; rs1799853) and CYP2C9 * 3 (1075 A>C; rs1057910), both translated no-function alleles, have been related to a lower metabolism of siponimod by CYP2C9 enzyme. The FDA-approved drug label and EMA risk management plan for siponimod require testing patients for CYP2C9 genotype before treatment starts. The FDA drug label states that siponimod is contraindicated in patients carrying a CYP2C9 * 3/* 3 genotype, and a daily maintenance dose of 1 mg in patients with CYP2C9 * 1/* 3 and * 2/* 3 genotypes. The EMA reported the potential long-term safety implications in CYP2C9 poor metabolizer patients treated with this drug. Based on this systematic review we concluded that CYP2C9 SNPs influence on siponimod response might be stated by assessing not only CYP2C9 * 2 and CYP2C9 * 3 but other genetic variants resulting in CYP2C9 IM/PM status. CYP2C9 IM phenotype translated from the CYP2C9 * 2 genotype should be revised since it is contradictory compared to other CYP2C9 no-function alleles, and CYP2C9 * 2 might be excluded from PGx testing recommendation before treatment starts with siponimod since it is not translated into a therapeutic recommendation.

Progressive Multifocal Leukoencephalopathy and Immune Reconstitution Inflammatory Syndrome after Discontinuation of Fingolimod.

Progressive multifocal leukoencephalopathy (PML) is a rare complication of immunosuppressive treatment in MS patients. Immune reconstitution inflammatory syndrome (IRIS) appears after the withdrawal of certain drugs such as natalizumab (NTZ) or fingolimod. The development of PML-IRIS after NTZ treatment has been described, and its diagnosis is made by clinical and radiological criteria and the determination of the John Cunningham virus in CSF. We present a clinical case of a patient with MS who, after the withdrawal of fingolimod, developed PML-IRIS despite sustained lymphopenia. This is important for pharmacovigilance purposes, not only for NTZ but also for alternative drugs used in MS treatment.

Pharmacogenetic Predictors of Response to Interferon Beta Therapy in Multiple Sclerosis.

First-line therapy with interferon beta (IFN-ß), involved in gene expression modulation in immune response, is widely used for multiple sclerosis. However, 30-50% of patients do not respond optimally. Variants in CBLB, CTSS, GRIA3, OAS1 and TNFRSF10A genes have been proposed to contribute to the variation in the individual response. The purpose of this study was to evaluate the influence of gene polymorphisms on the IFN-ß response in relapsing-remitting multiple sclerosis (RRMS) patients. CBLB (rs12487066), GRIA3 (rs12557782), CTSS (rs1136774), OAS1 (rs10774671) and TNFRSF10A (rs20576) polymorphisms were analysed by Taqman in 137 RRMS patients. Response to IFN-ß and change in the Expanded Disability Status Scale (EDSS) after 24 months were evaluated using multivariable logistic regression analysis. Carriers of at least one copy of the C allele of CTSS-rs1136774 had a better response to IFN-ß (p = 0.0423; OR = 2.94; CI95% = 1.03, 8.40). Carriers of TT genotype of TNFRSF10A-rs20576 had a higher probability of maintaining their EDSS stable after 24 months of IFN-ß treatment (p = 0.0251; OR = 5.71; CI95% = 1.39, 31.75). No influence of CBLB (rs12487066), OAS1 (rs10774671) and GRIA3 (rs12557782) gene polymorphisms in the variation of the individual response to IFN-ß was shown. Our results suggest that the TNFRSF10A-rs20576 and CTSS-rs1136774 gene polymorphisms influence the response to IFN-ß after 24 months, while the CBLB (rs12487066), OAS1 (rs10774671) or GRIA3 (rs12557782) gene polymorphisms had no effect on the variation of the individual response to IFN-ß.

Effectiveness of a Functional Rehabilitation Program for Upper Limb Apraxia in Poststroke Patients: A Randomized Controlled Trial.

OBJECTIVE: To analyze the effectiveness of a home-based restorative and compensatory upper limb apraxia (ULA) rehabilitation program. DESIGN: Randomized controlled trial. SETTING: Neurology Unit of San Cecilio Hospital and 2 private and specialized health care centers. PARTICIPANTS: Community dwelling participants (N=38) between the ages of 25 and 95 years old (sex ratio, 1:1) with unilateral mild-to-moderate poststroke lesions (time of evolution since stroke, 12.03±8.98mo) and secondary ULA. INTERVENTIONS: Participants were randomly assigned to an 8-week combined ULA functional rehabilitation group (n=19) 3 days per week for 30 minutes or to a traditional health care education protocol group (n=19) once a month for 8 weeks. Both interventions were conducted at home. MAIN OUTCOME MEASURES: Sociodemographic and clinical data, Barthel Index (primary outcome), Lawton and Brody Scale, observation and scoring activities of daily living, the De Renzi tests for ideational and ideomotor apraxia and imitating gestures test, recognition of gestures, test for upper limb apraxia , and stroke-specific quality of life scale were assessed at 3 time points: baseline, posttreatment (8wk), and follow-up (8wk). RESULTS: There were statistically significant differences among the groups regarding ideomotor apraxia, imitating gestures, global recognition of gestures, intransitive gestures, and comprehension of gesture production (P<.05) in favor of the experimental group. However, no statistically significant differences were found between the groups regarding functionality or quality of life (P>.05). Regarding the within-group effect, statistically significant differences were found in all neuropsychological outcomes at posttreatment and follow-up (P<.05). CONCLUSION: A functional rehabilitation program was found to be superior to a traditional health care education program and resulted in improvements in neuropsychological functioning in ULA poststroke. Conventional education showed an insufficient effect on apraxia recovery. Further studies with larger sample sizes are needed to determine the effect of rehabilitation strategies on functionality and quality of life of poststroke ULA patients.