Safety and Discontinuation Rate of Dimethyl Fumarate (Zadiva®) in Patients with Multiple Sclerosis: An Observational Retrospective Study.

BACKGROUND: This study evaluates the real-world safety and discontinuation rate of Zadiva® (generic product of dimethyl fumarate (DMF)) in Iranian patients with relapsing-remitting multiple sclerosis (RRMS), supplementing existing clinical evidence from randomized controlled trials. METHODS: This retrospective observational study evaluated the real-world safety and discontinuation rate of DMF in RRMS patients from Amir A'lam referral hospital's neurology clinic. Data on safety, discontinuation rate, and clinical disease activity were collected retrospectively. The study aimed to assess the discontinuation rate, safety, and reasons for discontinuation, as well as the number of patients experiencing a relapse, MRI activity, and EDSS scores. RESULTS: In total, 142 RRMS patients receiving DMF were included in the study, with 15 discontinuing treatment due to adverse events, lack of efficacy, or pregnancy. Notably, a significant reduction in relapse rates was observed, with 90.8% of patients remaining relapse-free throughout the study period. After 1 year of treatment with Zadiva®, only 17.6% of patients experienced MRI activity, whereas the EDSS score remained stable. CONCLUSIONS: This study provides important real-world data on the safety and tolerability of Zadiva® in RRMS patients. The results indicate that Zadiva® is generally well tolerated and safe, with a low discontinuation rate due to adverse events or lack of efficacy. These findings suggest that Zadiva® is an effective and safe treatment option for RRMS patients in real-world practice.

Prevalence of Sexual Dysfunction and Related Risk Factors in Men with Multiple Sclerosis in Iran: A Multicenter Study.

INTRODUCTION: Sexual dysfunction (SD) is a common complaint in patients with multiple sclerosis (MS). The aim of this study was to assess the prevalence of SD and its related risk factors in men with MS in Iran. METHODS: In this cross-sectional study, 320 men who had been diagnosed with MS according to the McDonald revised criteria were recruited from January to June 2019, from the north, south, east, west, and central parts of Iran. Patients were assessed using the Male Sexual Health Questionnaire (MSHQ), International Index of Erectile Function (IIEF), The Multiple Sclerosis Intimacy and Sexuality Questionnaire-(MSISQ 19), Sexual Quality of Life-Men (SQOL-M), and Standard General Health Questionnaire (GHQ). RESULTS: Sexual dysfunction, defined as total IIEF score ≤ 45 was present in 114 patients (35.6%). The results of univariate logistic regression showed that there were significant direct relations between age (OR 1.050, 95% CI 1.02-1.08), Expanded Disability Status Scale (EDSS) (OR 1.45, 95% CI 1.24-1.7), duration of MS (OR 1.005, 95% CI 1.002-1.009), MSISQ-19 (OR 1.103, 95% CI 1.078-1.128), GHQ (OR 1.04, 95% CI 1.03-1.06), SQOL-M (OR 0.930, 95% CI 0.914-0.947), smoking (OR 1.941, 95% CI 1.181-3.188), non-MS chronic disease (OR 1.91, 95% CI 1.20-3.04), having a main sexual partner (OR 2.56, 95% CI 1.32-4.94), and significant inverse relations between exercise (OR 0.584, 95% CI 0.364-0.936) and regular sexual activity (OR 0.241, 95% CI 0.15-0.40), with the prevalence of SD. The results of multiple logistic regression indicated that the age, MSISQ-19, and SQOL-M were the only independent predictive factors for SD in these patients. CONCLUSION: The prevalence of SD in men with MS in Iran is relatively high. These patients should be screened, diagnosed, and treated for SD and influencing factors.

Increased Level of Caspase-1 in the Serum of Relapsing-remitting Multiple Sclerosis (RRMS) Patients.

Multiple sclerosis (MS) is an inflammatory autoimmune disease of the central nervous system, in which proinflammatory cytokines play a critical role in the pathogenic formation of lesions. Caspase-1 is a cysteine protease that proteolytically cleaves precursors of interleukin (IL)-18 and IL-1ß and turns them into their active forms. These inflammatory cytokines play an important role in the development of MS. The aim of the present study was the investigation of caspase-1 and its downstream products, IL-18 and IL-1ß, in relapsing-remitting MS (RRMS) patients. In this study, we used an ELISA assay to measure serum and cellular caspase-1 and serum levels of IL-18 and IL-1ß in RRMS patients in the relapse phase (n=23) and healthy age-and gender-matched controls (n=19). We observed that the caspase-1 level was significantly increased in the serum of MS patients compared to the healthy controls (p=0.03). Although caspase-1 concentration in the lysate of peripheral blood mononuclear cells (PBMCs) was higher than serum among patients and controls (p<0.001), no significant difference was found in cellular levels of caspase-1 between the two groups. There was no significant difference in serum levels of IL-18 and IL-1ß between patients and controls. In this study, we found an elevation of extracellular caspase-1, as a reflection of its intracellular level, in the serum of RRMS patients during the relapse phase. Therefore, it suggests being a suitable peripheral biomarker of disease activity in multiple sclerosis.

A Comparison Study of Efficacy and Safety of a Biosimilar Form of Intramuscular Βeta-interferon I-a Versus the Reference Product: A Randomized Controlled Clinical Trial in Iran.

We compared the efficacy and safety of a biosimilar form of beta-interferon-1a (Actovex) versus the reference product in the treatment of relapsing remitting multiple sclerosis (RRMS). In a double blind, randomized phase 3 clinical trial, we evaluated 138 patients with RRMS that were allocated to receive the biosimilar medication and the reference treatment (30 µg intramuscular, weekly for one year). We investigated changes in EDSS, relapse rate and MRI changes within one year. In sixty-nine patients who were allocated to each arm and analyzed mean age and its standard deviation was 32.4 ± 8.8 and 31.5 ± 8 for the biosimilar medication and the reference arm respectively. One-year follow-up revealed a mean difference of 0.084 in EDSS (95% CI: 0.069-0.237) between the two groups in favor of the biosimilar medication. This value did not exceed the predefined non-inferiority margin of 0.1. There were no statistically significant differences in relapse rate and systemic and local adverse events of the two groups. The results show that the biosimilar interferon 1-a is non-inferior to the reference product in terms of efficacy while it demonstrates comparable safety. In conclusion the biosimilar interferon 1-a can be considered as an effective and safe alternative to the reference product due to lower cost and more availability.

Tolerability and Safety Profile of a New Brand-Generic Product of Glatiramer Acetate in Iranian Patients with Relapsing-Remitting Multiple Sclerosis: An Observational Cohort Study.

BACKGROUND: The aim of this study was to evaluate the safety, tolerability, and efficacy of a brand-generic glatiramer acetate product in patients with relapsing-remitting multiple sclerosis over a 12-month period. A noninterventional cohort study was conducted on 185 patients. The patients had a confirmed and documented diagnosis of relapsing-remitting multiple sclerosis as defined by the Revised McDonald Criteria (2010), were ambulatory with a Kurtzke Expanded Disability Status Scale score of 0 to 5.5, and their treatment by glatiramer acetate 40 mg/mL was just started. METHODS: Adverse drug reactions, relapse rate, magnetic resonance imaging parameters, and Expanded Disability Status Scale score were evaluated over 1 year. RESULTS: Of 185 enrolled patients from 21 different cities, 170 completed the study. The mean (SD) Expanded Disability Status Scale score was 1.97 (0.75) at the time of screening. The mean age was 33 years with an average of 4-year multiple sclerosis history, and 83% were women. Hepatic disorder and depression were the most frequent medical history. The most common adverse drug reactions were local pain (45.4%) and erythema (38.9%). The immediate postinjection reactions included dyspnea (10.3%), anxiety (9.7%), palpitation (8.1%), urticaria (5.4%), flushing (3.24%), chest pain (2.16%), and throat constriction (0.54%). The percentage of relapse-free patients at Month 12 was 87%, and the annual relapse rate was 0.134. An increase in the Expanded Disability Status Scale score was observed in 20% of patients, and new T2 and gadolinium-enhancing lesions were found in 34.7% and 9.4%, respectively. The rate of treatment failure was 1.6% and 4.3% according to the Modified Rio and Rio scores, respectively. CONCLUSIONS: The 40 mg brand-generic glatiramer acetate product was well tolerated in this selected group of Iranian patients with relapsing-remitting multiple sclerosis, and patient adherence was favorable over 1 year. (Curr Ther Res Clin Exp. 2018; 79:XXX-XXX).

Diagnosis and management of Neuromyelitis Optica Spectrum Disorder (NMOSD) in Iran: A consensus guideline and recommendations.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is a relapsing neuro inflammatory disease of the central nervous system that typically presents with optic neuritis or myelitis and may cause severe disability. The diagnostic criteria have been updated and several immunosuppressive agents have been demonstrated to prevent acute exacerbations. As the disease rarely develops in a progressive course, management of acute attacks and proper prevention of exacerbations may change the long term out-come and prevent future disability. Consensus recommendations and guidelines will help the physicians to improve their practice and unify the treatment approaches in different communities. In order to develop a national consensus and recommendations for the diagnosis and management of NMOSD in Iran, a group of neurologists with long term experience in management of NMOSD were gathered to develop this consensus based on available national and international data. The primary draft was prepared and discussed to suggest the most appropriate treatment for these patients. We propose strategies for early diagnosis and treatment for prevention of relapses and minimizing consequences of attacks as a primary therapeutic goal. Attacks are currently treated with intravenous corticosteroids and, in refractory cases, with plasma exchange. All participants agreed on preventive treatment with currently available immunosuppressive agents such as azothioprin, rituximab and mycofenolate mofetil based on previous positive data in NMOSD in order to reduce attack frequency. The current consensus reviews the previous data and provides the clinicians with practical recommendations and advices for the diagnosis and management of NMOSD based on scientific data and clinical experience.

Trends of quality of life changes in amyotrophic lateral sclerosis patients.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is an incurable progressive neurodegenerative disease and thus the assessment of quality of life (QOL) changes and factors that may influence its course is valuable in the meantime. OBJECTIVES: The present study aimed to assess the deterioration rate of QOL and influencing factors in different subgroups of Iranian ALS patients. METHODS: 132 patients were evaluated in this prospective multicenter observational study. QOL was measured using ALS Assessment Questionnaire (ALSAQ-40) during 1year follow up and its progression rate was assessed in different subgroups of patients according to age, sex, stage of disease, riluzole consumption, onset type. Also physical disability and functional disability were measured using MMT and ALSFRS-R scores respectively and their progression rates were compared with ALSAQ-40 changes. RESULTS: Significant deterioration of the scores of ALSAQ-40 during study was consistent in all of its domains (p=0.000). There was a significant negative correlation between ALSFRS-R and MMT changes and ALSAQ-40 change (p=0.000) and this was consistently observed in all domains of ALSAQ-40 (p=0.00). ALSAQ-40 deterioration rate was shown to be significantly lower in severe/terminal stages compared to mild/moderate stages (p=0.00). Significantly higher deterioration rate was observed in bulbar onset versus limb onset patients [F (1,130)=4.52, p=0.04] but no significant difference was observed among other subgroups according to age, sex and riluzole consumption. CONCLUSION: All domains of QOL significantly deteriorate during ALS course and there is a significant correlation between their changes and progression of physical and functional disabilities. Rate of degradation of QOL may be different at different stages of the disease. QOL worsens independent of factors such as sex, age and consumption of riluzole; but onset type (bulbar versus limb) is an imperative factor in quality of life changes during the disease course.

Amyotrophic lateral sclerosis progression: Iran-ALS clinical registry, a multicentre study.

This study was designed to evaluate ALS progression among different subgroups of Iranian patients. Three hundred and fifty-eight patients from centres around the country were registered and their progression rate was evaluated using several scores including Manual Muscle Test scoring (MMT) and the revised ALS Functional Rating Scale (ALSFRS-R). Progression rate was analysed separately in subgroups regarding gender, onset site, stage of disease and riluzole consumption. A significant difference in MMT deterioration rate (p = 0.01) was noted between those who used riluzole and those who did not. No significant difference was observed in progression rates between male/female and bulbar-onset/limb-onset groups using riluzole. In conclusion, riluzole has a significant effect on muscle force deterioration rate but not functional scale. Progression rate was not influenced by site of onset or gender.

HLA-DRB1 does not have a role in clinical response to interferon-beta among Iranian multiple sclerosis patients.

BACKGROUND & OBJECTIVES: The role of human leukocyte antigen (HLA) in clinical response to immunotherapy is not completely known. In this study we evaluated the relationship between HLA-DRB1 genotype, which has been proved to be more common in Iranian MS patients, and clinical response to interferon-beta (IFNß), which is the most common immunotherapy for relapsing-remitting MS. DESIGN AND SETTING: In this study 68 Iranian patients with confirmed diagnosis of RRMS who had been referred to and admitted in Neurology Department of Amiralam and Khatam Hospitals in Tehran were selected. Patients were followed prospectively for 2 years since initiation of therapy and clinical data, including EDSS scores were recorded every 3 months. MRI was performed at the time of diagnosis and each year. METHODS: HLA-DRB1 typing was performed by polymerase chain reaction (PCR) for all patients and data was analyzed by STATA 12th edition. RESULTS: There were 47 (69.1%) responders and 21 (30.9%) non-responders. These two groups were demographically and clinically comparable. Fisher's exact test did not show any difference between HLA-DRB1 allele frequencies in responders and non-responders. CONCLUSIONS: Our findings confirmed the lack of association between HLA-DRB1 and clinical response to IFNß among MS patients as previous studies had done.

Interaural difference values of vestibular evoked myogenic.

Migraine is a neurologic disease, which often is associated with a unilateral headache. Vestibular abnormalities are common in migraine. Vestibular evoked myogenic potentials (VEMPs) assess otolith function in particular functional integrity of the saccule and the inferior vestibular nerve. We used VEMP to evaluate if the migraine headache can affect VEMP asymmetry parameters. A total of 25 patients with migraine (22 females and 3 males) who were diagnosed according to the criteria of IHS-1988 were enrolled in this cross-sectional study. Control group consisted of 26 healthy participants (18 female and 8 male), without neurotological symptoms and history of migraine. The short tone burst (95 dB nHL, 500 Hz) was presented to ears. VEMP was recorded with surface electromyography over the contracted ipsilateral sternocleidomastoid (SCM) muscle. Although current results showed that the amplitude ratio is greater in migraine patients than normal group, there was no statistical difference between two groups in mean asymmetry parameters of VEMP. Asymmetry measurements in vestibular evoked myogenic potentials probably are not indicators of unilateral deficient in saccular pathways of migraine patients.

Knowledge and attitude assessment of Iranian multiple sclerosis patients receiving interferon beta.

BACKGROUND: Multiple sclerosis (MS) patients permanently confronted with serious challenges from treatment regimen. Developing a new questionnaire in MS management, through evaluation of patients' perspectives and knowledge regarding treatment will help to identify the sources of tension, and to build a therapeutic alliance. We purposed to describe MS patients' understanding of their treatments. METHODS: About 425 completed and returned questionnaire were assessed of a total of 500 recruited MS patients. The knowledge of correct using interferon-beta (IFN-ß) and attitude toward medical care were assessed using self-reported questionnaires consisted of 25 items with validity of multidisciplinary panel and pre-testing on 20 patients. RESULTS: Knowledge about IFN-ß therapy was very low; however, attitude was at a high level. Female patients, self-injection ability, higher educational level, normal functional status, delay from the start of diagnostic workup to definite diagnosis, and being younger were related to a higher level of knowledge. Attitude was associated with functional status, family history of disease and the summary of knowledge variable. CONCLUSION: Developing educational interventions are needed for MS patients regarding to their low levels of knowledge.

Relationship between HLA-DRB1* 11/15 genotype and susceptibility to multiple sclerosis in Iran.

BACKGROUND & OBJECTIVES: Analysis of the role of different alleles of human leukocyte antigen (HLA) in multiple sclerosis (MS) patients is necessary in many populations and geographical areas. The aim of the present study was to investigate the frequency of HLA-DRB1 genes and its influence on susceptibility to MS, comparing with that in control group. DESIGN AND SETTING: Two groups of case-control of multiple sclerosis patients referred to clinic at Khatam hospitals were studied. The first group consisted of 73 multiple sclerosis patients and the second group comprised 40 healthy volunteers with no known history of MS, living in Tehran. PATIENTS AND METHODS: The sample population consisted of 73 consecutive non-selected patients diagnosed with MS according to the McDonald criteria (2010) at the outpatient clinic for multiple sclerosis, 62 (85%) presented with RRMS and 11 (15%) with SPMS. The frequency of HLA-DRB1 alleles was determined in 73 MS patients (with age of 18-56) and 40 healthy subjects in Iran. These consisted of 57 females and 16 males. HLA-DRB1 allele types were identified by polymerase chain reaction products of 24 pair primers for low resolution SSP typing (PCR-SSP). RESULTS: The HLA-DRB1* 11/15 genotype was detected highest (6 times) in patients compare to normal control population (p-value 0.062), whereas the DRB1 4/11 genotype was detected highest (4 times) in controls compare to MS patients (p-value 0.033). The data showed that HLA-DRB1*03 is significantly more in patients compare to control normal people (p-value 0.0021) as well as DRB1 14 and 16 are significantly more in control normal people, compare to MS patients (p-values 0.0789 and 0.035). CONCLUSION: Allele frequency among patients with positive history of multiple sclerosis disease showed that DRB1 11 allele has a significantly low rate in MS patients with positive history compare to other patients. In contrast DRB1 15 allele has a significantly high rate in MS patients with positive history compare to other patients. The frequencies of other alleles were not significantly different between the MS patients and the control group. The frequency of the HLA-DRB1* 11/15 genotype detected in the present study showed that this genotype is partially significant factor for MS susceptibility and development in Iran.

Double-blind randomized parallel-group clinical trial of efficacy of the combination fluoxetine plus modafinil versus fluoxetine plus placebo in the treatment of major depression.

BACKGROUND: There is growing interest in the identification of novel therapeutic agents for the treatment of affective disorders, with modafinil being one promising substance. The purpose of the present investigation was to compare the efficacy of a combination of fluoxetine plus modafinil with that of fluoxetine plus placebo in the treatment of major depression in a 6-week double blind and placebo-controlled trial. METHODS: Forty-six adult outpatients who met the DSM-IV-TR criteria for major depression participated in the trial. Patients had a baseline Hamilton Rating Scale for depression score of at least 18. Patients were allocated in a random fashion, 23 to fluoxetine 40 mg/day plus modafinil 400 mg/day (200 mg bid) (morning and evening) and 23 to fluoxetine 40 mg/day plus placebo. Patients were assessed at baseline and after 1, 2, 4, and 6 weeks after start of medication. RESULTS: Forty-four patients completed the trial. Fluoxetine+modafinil and fluoxetine+placebo significantly decreased the Hamilton Rating Scale score for Depression over the trial period. However, the combination of fluoxetine and modafinil was significantly superior over fluoxetine alone in the treatment of symptoms of major depression. The difference between the two treatments was significant as indicated by the effect of group, the between-subjects factor (df = 1, F = 4.42, P = 0.046). There were no significant differences in the two groups in terms of observed side-effects. CONCLUSION: These findings suggest modafinil as a well-tolerated and potentially effective agent in combination with fluoxetine in the management of patients with major depression.