Switching from injectable to other Disease Modifying Therapies may improve sexual dysfunction in people with Multiple Sclerosis.

BACKGROUND: Multiple Sclerosis (MS) a central nervous system autoimmune disorder, mainly affecting young adults and more prevalent among women, can lead to sexual dysfunction (SD) among both males and females with MS. Female sexual dysfunction can be defined as dyspareunia, a lack of sexual desire, disorders in the arousal and orgasm phases, and sexual pain disorders. The purpose of this study is to investigate the changes in sexual function among females with MS whose treatment was switched from first-line injectable medications to other agents after a six-month duration. And assess the changes in all three domains of SD. METHODS: In this longitudinal study females diagnosed with MS, aged between 18 and 50 years old, and were candidates for switching their treatment from interferon beta-1a (intra-muscular and subcutaneous), and Glatiramer Acetate (GA), to Fingolimod, Dimethyl Fumarate (DMF), or Natalizumab (NTZ) due to patients' convenience and tolerability and adverse events were included. "Multiple Sclerosis Intimacy and Sexuality Questionnaire-19" was used to evaluate the SD changes before and six months after the new treatment initiation. Statistical analysis was conducted using SPSS V.24 software. Histograms and the Shapiro-Wilk test were used to assess the normality of the variables; due to the non-normal distribution of quantitative variables (except for age), the Wilcoxon signed-rank test was used to compare the scores, before and six months after the medication change. The level of significance was considered less than 0.05. RESULTS: Out of 107 female participants (average age: 35.09 ± 5.61), The mean of overall MSISQ-19 scores, before and six months after the medication change were not significant (p-value = 0.091). However, considering the subdomains, the medication changes only affected the tertiary subdomain of MSISQ-19 (p-value = 0.017). Still, the scores of other subdomains did not change significantly (p-value = 0.761 for primary SD and 0.479 for secondary SD). Also, there wasn't any significant difference between EDSS before and after the medication change (p-value = 0.461). CONCLUSIONS: To our knowledge, this was the first study, assessing the effect of MS medication change on the improvement of SD among patients. According to the results of the presented cross-sectional study, we found that during a six-month period, the tertiary subdomain of MSISQ-19 symptoms improved significantly, while the changes in other SD domains were not significant.

Intravenous Interferon-ß1a for the Treatment of Ischemia-Reperfusion Injury in Acute Myocardial Infarct in Pigs.

BACKGROUND: To investigate the potential of intravenously administered porcine recombinant interferon-ß1a (IFN-ß1a) for myocardial protection during acute ischemia-reperfusion (IR) injury in an experimental animal model. METHODS: Twenty-two piglets (mean ± standard deviation, 26.7 ± 1.65 kg) were assigned to either the IFN group (n = 12) or the control group (n = 10). IR injury was induced by occluding the distal left descending coronary artery for 30 minutes, with a reperfusion period of 6 h. In the IFN group, the animals received 12.5 µg IFN-ß1a intravenously repeatedly; the control group received saline solution. The levels of interleukin-6 (IL-6) and cardiac troponin I (TnI) were measured, and the amount of myocardial damage was quantified by analyzing myocardial apoptosis and the mean fluorescence intensity (MFI) of methylene blue-stained cardiac tissue. RESULTS: In the IFN group, significantly more premature deaths occurred compared with the control group (25% versus 17%, P = .013). Between the groups, the mean heart rate was higher in the IFN group (102 ± 22 versus 80 ± 20 beats per minute, P = .02). IL-6 and TnI levels were comparable between the groups, with no significant difference, and there was no difference between the study groups in myocardial apoptosis in the infarcted myocardium. The percentage of MFI differed significantly between the IFN and control groups (90.75% ± 4.90% versus 96.02% ± 2.73%, P = .01). CONCLUSION: In this acute IR injury animal model, IFN-ß1a did not protect the myocardium from IR injury, but rather increased some of the unfavorable outcomes studied.

Immune thrombocytopenia in alemtuzumab-treated MS patients: Incidence, detection, and management.

BACKGROUND: Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. OBJECTIVE: To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials. METHODS: CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion. RESULTS: Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials. CONCLUSION: Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.

Effect of Intravenous Interferon ß-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Importance: Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) ß-1a may prevent the underlying event of vascular leakage. Objective: To determine the efficacy and adverse events of IFN-ß-1a in patients with moderate to severe ARDS. Design, Setting, and Participants: Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018. Interventions: Patients were randomized to receive an intravenous injection of 10 µg of IFN-ß-1a (144 patients) or placebo (152 patients) once daily for 6 days. Main Outcomes and Measures: The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error. Results: Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-ß-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-ß-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-ß-1a group and 33 [21.7%] in the placebo group). Conclusions and Relevance: Among adults with moderate or severe ARDS, intravenous IFN-ß-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-ß-1a in the management of ARDS. Trial Registration: ClinicalTrials.gov Identifier: NCT02622724.

Infection risk with alemtuzumab decreases over time: pooled analysis of 6-year data from the CAMMS223, CARE-MS I, and CARE-MS II studies and the CAMMS03409 extension study.

BACKGROUND: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. OBJECTIVE: To evaluate infections over 6 years in alemtuzumab-treated patients. METHODS: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 µg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. RESULTS: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%-1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. CONCLUSION: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study.

BACKGROUND: On-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon ß-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial. METHODS: Exploratory analyses assessed whether active T2 and T1 Gd + lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS. RESULTS: Mean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN ß-1a SC) 44 µg and 22 µg 3×/week (tiw) than with placebo (p < 0.0001). The presence of ≥4 versus 0 active T2 lesions predicted disability progression at Years 3-4 in the IFN ß-1a SC 22 µg group only (p < 0.05), whereas the presence of ≥2 versus 0-1 active T2 lesions predicted disability progression in the placebo/delayed treatment (DTx) (Years 2-4; p < 0.05) and IFN ß-1a SC 22 µg groups (Years 3-4; p < 0.05). Greater active T2 lesion number at 6 months predicted relapses in the placebo/DTx group only (≥4 vs. 0, Years 1-4; ≥2 vs. 0-1, Years 2-4; p < 0.05), and the presence of T1 Gd + lesions at 6 months predicted disability progression in the IFN ß-1a SC 44 µg group only (Year 1; p < 0.05). The presence of ≥2 versus 0-1 active T2 lesions at 12 months predicted disability progression over 3 and 4 years in the IFN ß-1a SC 44 µg group. CONCLUSION: Active T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN ß-1a SC 22 µg, but not in those receiving IFN ß-1a SC 44 µg. Active T2 lesions at 12 months may predict outcomes in those receiving IFN ß-1a SC 44 µg and are possibly more suggestive of poor response to therapy than T2 results at 6 months.

CD40-Mediated NF-κB Activation in B Cells Is Increased in Multiple Sclerosis and Modulated by Therapeutics.

CD40 interacts with CD40L and plays an essential role in immune regulation and homeostasis. Recent research findings, however, support a pathogenic role of CD40 in a number of autoimmune diseases. We previously showed that memory B cells from relapsing-remitting multiple sclerosis (RRMS) patients exhibited enhanced proliferation with CD40 stimulation compared with healthy donors. In this study, we used a multiparameter phosflow approach to analyze the phosphorylation status of NF-κB and three major MAPKs (P38, ERK, and JNK), the essential components of signaling pathways downstream of CD40 engagement in B cells from MS patients. We found that memory and naive B cells from RRMS and secondary progressive MS patients exhibited a significantly elevated level of phosphorylated NF-κB (p-P65) following CD40 stimulation compared with healthy donor controls. Combination therapy with IFN-ß-1a (Avonex) and mycophenolate mofetil (Cellcept) modulated the hyperphosphorylation of P65 in B cells of RRMS patients at levels similar to healthy donor controls. Lower disease activity after the combination therapy correlated with the reduced phosphorylation of P65 following CD40 stimulation in treated patients. Additionally, glatiramer acetate treatment also significantly reduced CD40-mediated P65 phosphorylation in RRMS patients, suggesting that reducing CD40-mediated p-P65 induction may be a general mechanism by which some current therapies modulate MS disease.

Serum lipid profile changes predict neurodegeneration in interferon-ß1a-treated multiple sclerosis patients.

The purpose of this work was to determine whether changes in cholesterol profiles after interferon-ß (IFN-ß)1a treatment initiation following the first demyelinating event suggestive of multiple sclerosis are associated with clinical and MRI outcomes over 4 years. A group of 131 patients (age: 27.9 ± 7.8 years, 63% female) with serial 3-monthly clinical and 12-monthly MRI follow-ups over 4 years were investigated. Serum cholesterol profiles, including total cholesterol (TC), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were obtained at baseline, 1 month, 3 months, and every 6 months thereafter. IFN-ß1a initiation caused rapid decreases in serum HDL-C, LDL-C, and TC within 1 month of IFN-ß1a initiation (all P < 0.001) that returned slowly toward baseline. In predictive mixed model analyses, greater percent decreases in HDL-C after 3 months of IFN-ß1a treatment initiation were associated with less brain atrophy over the 4 year time course, as assessed by percent brain volume change (P < 0.001), percent gray matter volume change (P < 0.001), and percent lateral ventricle volume change (P = 0.005). Decreases in cholesterol biomarkers following IFN-ß1a treatment are associated with brain atrophy outcomes over 4 years. Pharmacological interventions targeting lipid homeostasis may be clinically beneficial for disrupting neurodegenerative processes.

Subcutaneous interferon ß-1a in the treatment of clinically isolated syndromes: 3-year and 5-year results of the phase III dosing frequency-blind multicentre REFLEXION study.

OBJECTIVE: Early treatment following a first clinical demyelinating event (FCDE) delays further disease activity in patients with multiple sclerosis (MS). This study determined the effects of early versus delayed treatment (DT) with subcutaneous interferon (sc IFN) ß-1a 44 µg in patients with an FCDE up to 60 months postrandomisation. METHODS: Patients who completed the 24-month double-blind REFLEX (REbif FLEXible dosing in early MS) study entered an extension (REFLEXION, REbif FLEXible dosing in early MS extensION): patients initially randomised to sc IFN ß-1a and not reaching clinically definite MS (clinically definite MS, CDMS (second attack or sustained Expanded Disability Status Scale (EDSS) score increase)) continued original treatment (three times weekly (tiw) or once weekly (qw)); placebo patients switched to tiw (DT); patients with CDMS switched to tiw. Clinical, MRI and adverse event data up to month 60 are reported. RESULTS: 402/517 (77.8%) REFLEX patients entered REFLEXION (DT, n=133; tiw, n=127; qw, n=142). At month 60, cumulative probability of CDMS was: DT 44.6%; qw 40.7% (nominal p=0.084 vs DT); tiw 39.2% (nominal p=0.032 vs DT). Cumulative probability of McDonald MS conversion (CDMS or new MRI activity) at month 60 was also reduced for tiw versus DT (nominal p<0.001). At month 60, mean cumulative numbers of new T2, gadolinium-enhancing and T1 hypointense lesions were lower with sc IFN ß-1a qw (nominal p<0.05) and tiw versus DT (nominal p<0.001); T2 and T1 hypointense lesion volume change was lower for sc IFN ß-1a tiw versus DT (nominal p<0.01). Treatment was well tolerated; fewer patients receiving tiw versus qw were positive for neutralising or binding antibodies. CONCLUSIONS: Over 5 years in patients presenting with an FCDE, early sc IFN ß-1a tiw administration versus DT prolonged time to CDMS and McDonald MS, and reduced overall MRI activity. TRIAL REGISTRATION NUMBER: NCT00813709; Results.

No evidence of disease activity in patients receiving daclizumab versus intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis in the DECIDE study.

BACKGROUND: No evidence of disease activity (NEDA) is a composite endpoint being increasingly applied as an outcome measure in clinical trials as well as proposed for individual therapeutic decisions in multiple sclerosis (MS). OBJECTIVE: Assess the proportion of patients with relapsing-remitting MS achieving NEDA in the DECIDE study of daclizumab 150 mg subcutaneous versus intramuscular interferon beta-1a 30 µg for 96-144 weeks. METHODS: NEDA was defined as no relapses, no onset of 12-week confirmed disability progression (CDP), no new/newly enlarging T2 hyperintense lesions (NET2), and no gadolinium-enhancing (Gd+) lesions. Logistic regression models adjusted for baseline covariates compared treatment groups for baseline to week 96, weeks 0-24, and weeks 24-96. RESULTS: From baseline to week 96, more daclizumab versus intramuscular interferon beta-1a patients achieved NEDA (24.6% vs 14.2%; odds ratio (OR; 95% confidence interval): 2.059 (1.592-2.661); p < 0.0001). ORs for clinical NEDA (no relapses, no CDP) and magnetic resonance imaging (MRI) NEDA (no NET2, no Gd+ lesions) were 1.651 (1.357-2.007; p < 0.0001) and 2.051 (1.628-2.582; p < 0.0001), respectively. ORs in favor of daclizumab for weeks 24-96 were consistently higher than for weeks 0-24. CONCLUSION: More daclizumab versus intramuscular interferon beta-1a patients achieved NEDA early in DECIDE, with effects increasing over time.

Reasons for discontinuation of subcutaneous interferon ß-1a three times a week among patients with multiple sclerosis: a real-world cohort study.

BACKGROUND: Continuation of interferon (IFN) ß-based therapies is important for maximum treatment effectiveness in patients with multiple sclerosis (MS); however, few real-world data are available on discontinuation from IFN ß. The aim of this cohort analysis was to estimate real-world discontinuation rates up to 3 years among MS patients in the United States taking subcutaneous (sc) IFN ß-1a three times a week (tiw) and to identify whether the factors associated with discontinuation change over time. METHODS: Patient data were pooled from the MarketScan© Commercial and Medicare Supplemental healthcare claims databases. Patients with ≥1 multiple sclerosis diagnosis who were sc IFN ß-1a tiw naïve, had ≥1 year of continuous eligibility before treatment, and ≥1 prescription were followed from first prescription (index date) until date of discontinuation, switch, or end of observation. Treatment status was analysed at exactly 1, 2 or 3 years after index. Multivariable models were used to identify drivers of discontinuation. RESULTS: Data from 5956 patients were included; 2862 patients (48.1%) discontinued therapy. Discontinuation rates were 36.9% (1 year), 49.5% (2 years) and 55.8% (3 years). A greater proportion of discontinuing patients had poor adherence (<80% [94.0%] versus ≥80% [51.7%]) or were taking additional medication at follow-up versus the overall population. Factors independently associated with discontinuation irrespective of time on therapy were increasing number of magnetic resonance imaging scans (1 year adjusted odds ratio 1.45, 95% confidence interval 1.26-1.67; 2 years 1.18, 1.06-1.32; 3 years 1.20, 1.07-1.34) and adherence <80% versus ≥80% (1 year 180.95, 135.84-241.03; 2 years 135.80, 100.10-184.23; 3 years 174.89, 115.27-265.38). Factors associated only with early discontinuation (at 1 year) were ≥3 sets of laboratory investigations versus none (2.54, 1.20-5.38), and anxiolytic use at follow-up (1.40, 1.06-1.82). Factors associated only with later discontinuation (at 2 years and/or at 3 years) were antidepressant use at follow-up (2 years 1.46, 1.10-1.94) and greater number of relapses (2 years 1.60, 1.11-2.30; 3 years 2.31, 1.27-4.22). CONCLUSIONS: Potential drivers of discontinuation change over time. Improved awareness of the drivers of discontinuation could lead to targeted interventions to improve adherence.

Subjective patient-reported versus objective adherence to subcutaneous interferon ß-1a in multiple sclerosis using RebiSmart®: the CORE study.

BACKGROUND: Patient adherence to treatment is key to preventing the worsening of neurological disability in multiple sclerosis (MS). The RebiSmart® autoinjector facilitates self-administration of subcutaneous interferon ß-1a (sc IFN ß-1a) and records objective adherence data. The CORE study was undertaken to evaluate the relationship between subjectively reported and objective adherence of MS patients using RebiSmart® in Switzerland and explore variables associated with objective adherence. METHODS: Patients with relapsing-remitting MS who were treated with sc IFN ß-1a 44 or 22 µg three times weekly using RebiSmart® for at least 9 months participated in this phase IV non-interventional study. Neurologist questionnaires were used at month 0 to collect patient demographics, medical history and estimates of patients' adherence. Patient questionnaires were used to record subjective patient-reported adherence at month 0 and estimates of variables influencing adherence. Objective adherence data were obtained from the RebiSmart® log-files at months 0 and 6. RESULTS: Of 56 patients who completed the observation period, 53 had evaluable data. Objective adherence differed significantly between self-reported compliant (n = 33) and non-compliant groups (n = 20) (p = 0.00001). Older age, greater disability, patient's perception of the importance of ease of use and storage, being well informed about RebiSmart® features and neurologists' estimations of adherence were all positively associated with treatment adherence. CONCLUSIONS: We showed for the first time that subjective patient-reported adherence in MS was well in line with objective adherence, suggesting that the frequency of administration is reported accurately by patients to their neurologist. This observation may have implications for future treatment monitoring strategies and strategic medical decisions. Patients, particularly those who are younger and with lower levels of disability, may benefit from being better informed of the importance of being adherent to their treatments and receiving information about their medication and the device they are using.

Alemtuzumab versus interferon beta 1a for relapsing-remitting multiple sclerosis.

BACKGROUND: Alemtuzumab is a humanised monoclonal antibody that alters the circulating lymphocyte pool, causing prolonged lymphopenia, thus remoulding the immune repertoire that accompanies homeostatic lymphocyte reconstitution. It has been proved more effective than interferon (IFN) 1a for the treatment of relapsing-remitting multiple sclerosis (RRMS). OBJECTIVES: To compare the efficacy, tolerability and safety of alemtuzumab versus interferon beta 1a in the treatment of people with RRMS to prevent disease activity. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register (1 February 2017) which, among other sources, contains records from CENTRAL, MEDLINE, Embase, CINAHL, LILACS, PEDRO and the trial registry databases Clinical Trials.gov and WHO International Clinical Trials Registry Platform for all prospectively registered and ongoing trials. SELECTION CRITERIA: All double-blind, randomised, controlled trials comparing intravenous alemtuzumab (12 mg per day or 24 mg per day on five consecutive days during the first month and on three consecutive days at months 12 and 24) versus subcutaneous IFN beta 1a (22 µg or 44 µg three times per week (Rebif) or intramuscular injection 30 µg once a week (Avonex)) in people of any gender and age with RRMS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included three trials involving 1694 participants. All trials compared alemtuzumab 12 mg per day or 24 mg per day versus IFN beta 1a for treating RRMS. In CAMMS223, participants received either subcutaneous IFN beta 1a 44 µg three times per week or annual intravenous cycles of alemtuzumab (at a dose of 12 mg per day or 24 mg per day) for 36 months. In CARE-MS I and CARE-MS II, participants received subcutaneous IFN beta 1a 44 µg three times per week or annual intravenous cycles of alemtuzumab 12 mg per day for 24 months. The methodological quality was good for all three studies.In the alemtuzumab 12 mg per day group, the results showed statistically significant difference in reducing relapses (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.52 to 0.70), preventing disease progression (RR 0.60, 95% CI 0.45 to 0.79) and developing new T2 lesions on magnetic resonance imaging (RR 0.75, 95% CI 0.61 to 0.93) after 24 and 36 months' follow-up, but found no statistically significant difference in the changes of Expanded Disability Status Scale (EDSS) score (mean difference (MD) -0.35, 95% CI -0.73 to 0.03). In the alemtuzumab 24 mg per day group, the results showed statistically significant differences in reducing relapses (RR 0.38, 95% CI 0.23 to 0.62), preventing disease progression (RR 0.42, 95% CI 0.21 to 0.84) and the changes of EDSS score (MD -0.83, 95% CI -1.17 to -0.49) after 36 months' follow-up.All three trials reported adverse events and serious adverse events. There was no statistically significant difference in the number of participants with at least one adverse event (RR 1.03, 95% CI 0.97 to 1.08) and the number of participants who experienced serious adverse events (RR 1.03, 95% CI 0.83 to 4.54). AUTHORS' CONCLUSIONS: There is low- to moderate-quality evidence that annual intravenous cycles of alemtuzumab at a dose of 12 mg per day or 24 mg per day reduces the proportion of participants with relapses, disease progression, change of EDSS score and developing new T2 lesions on MRI over 24 to 36 months in comparison with subcutaneous IFN beta-1a 44 µg three times per week.Alemtuzumab appeared to be relatively well tolerated. The most frequently reported adverse events were infusion-associated reactions, infections and autoimmune events. The use of alemtuzumab requires careful monitoring so that potentially serious adverse effects can be treated early and effectively.

A multicenter, observational, prospective study of self- and parent-reported quality of life in adolescent multiple sclerosis patients self-administering interferon-ß1a using RebiSmart™-the FUTURE study.

Besides the impact of disease per se, the use of immunomodulatory therapies in adolescents with relapsing-remitting multiple sclerosis (RRMS) may have an effect on quality of life (QL). The FUTURE (Quality of liFe in adolescent sUbjecTs affected by mUltiple sclerosis treated with immunomodulatoRy agEnt using self-injecting device) study was designed to evaluate the changes in QL of Italian adolescents with RRMS receiving treatment with IFN-ß1a (Rebif; 22 µg), administered subcutaneously three times weekly using the RebiSmart™ electronic autoinjection device over a 52-week period. Fifty adolescents with RRMS were enrolled and 40 completed the study. Changes from baseline to end of treatment (EoT) in adolescent self-reported and parent-reported QL were assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL), which has been validated for use in pediatric MS and for which an Italian version is available. The adolescent self-reported total PedsQL4.0 score and all of its subscales tended to increase from baseline to EoT, the only exception being "Emotional functioning." In parent-reported measures, the total PedsQL4.0 score increased significantly from baseline to EoT (+ 5.27 points, p = 0.041). Significant increases were also evident for parent-reported "Psychosocial health summary score" (+ 5.90 points; p = 0.015) and "School functioning" (+ 7.84 points; p = 0.029). Our results indicate that adolescents with RRMS using the electronic injection device RebiSmart™ for self-administration of Rebif® can experience long-term improvements in QL.

Cognitive dysfunction in patients with multiple sclerosis treated with first-line disease-modifying therapy: a multi-center, controlled study using the BICAMS battery.

Multiple sclerosis (MS) can impair cognitive functions even in the early stages. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery is very short and highly sensitive and can be used to evaluate cognitive status in the disease. Several clinical trials have shown beneficial effects of disease-modifying drugs (DMDs) on long-term cognitive measures which may even reduce cognitive deficits in MS patients. Relapsing remitting MS patients using DMDs were enrolled in the study and monitored for 12 months. BICAMS and the Expanded Disability Status Scale were applied to the study group. We evaluated and monitored 161 newly diagnosed cases of definite MS by the end of the trial. 110 patients (68.2%) were female. One hundred and two healthy subjects (female to male ratio 68:34) were enrolled into the study. MS patients were categorized into three DMT groups: IFNB1-a SC, IFNB1-b, and GA. Mean scores of all three cognitive tests (SDMT, BVMT-R, and CVLT-II) were significantly higher in the control group than in the MS patients. The number of cognitively impaired patients decreased from 31.7 to 21.7% on the basis of CVLT (p = 0.024), and 42 (26.1%) to 30 (18.6%) on the basis of BVMT-R at month 12. A significant difference was determined in terms of cognitive status between MS patients using both IFNB and GA and the healthy control group. Ours is the first study to compare IFNB and GA in terms of evaluating cognitive involvement and to use the BICAMS battery in monitoring treatment.

Health-related quality of life in patients with relapsing-remitting multiple sclerosis treated with subcutaneous interferon ß-1a in Iran.

PURPOSE: Multiple sclerosis (MS) requires long-term therapy and can affect many aspects of a patient's life, including quality of life. MS patients score lower on health-related quality of life (HRQoL) measures. The efficacy of subcutaneous interferon (IFN) ß-1a has been extensively evaluated by using objective measures but its impact on HRQoL is currently unclear. In this observational study, we evaluated HRQoL of Iranian patients with relapsing-remitting MS (RRMS) treated with IFN ß-1a by using short-form 36 (SF-36) and multiple sclerosis international quality of life (MusiQoL) questionnaires. METHODS: Four hundred recruited RRMS patients were treated with human serum album free IFN ß-1a for 1 year. Patients were required to fill in SF-36 and MusiQoL questionnaires at the first visit and at each follow-up visit. Expanded disability status scale (EDSS) evaluation was performed at baseline and at each visit. Comparisons in HRQoL between visits were calculated using Cohen's d effect size. The relationship between change in EDSS score and the score of each questionnaire was calculated using Pearson correlation coefficients. RESULTS: Three-hundred and eighty three completed the study. Two-hundred and thirty nine were female. Mean (SD) age was 28.75 (±5.49). After 1 year, overall MusiQoL Index score effect size was -0.16 and SF-36 physical component and mental component showed overall effect sizes of -0.28 and -0.53, respectively. Mean (range) EDSS change was 1 (1-4). Three-hundred and seventy four were clinically stable with mean (range) EDSS change of 0.1 (-2-0.5). Increase in EDSS was linked to a decrease in both MusiQoL and SF-36. CONCLUSION: We found that, HRQoL did not change significantly over the first year of therapy. Furthermore, decreases in HRQoL were inversely correlated with increases in EDSS score.

Effect of intramuscular interferon beta-1a on gray matter atrophy in relapsing-remitting multiple sclerosis: A retrospective analysis.

BACKGROUND: Changes in gray matter (GM) volume may be a useful measure of tissue loss in multiple sclerosis (MS). OBJECTIVES: To investigate the rate, patterns, and disability correlates of GM volume change in an MS treatment clinical trial. METHODS: Patients (n=140) with relapsing-remitting MS were randomized to intramuscular (IM) interferon (IFN) beta-1a or placebo. Treatment effects on GM fraction (GMF) and white matter (WM) fraction (WMF) changes, differences in rates of GMF and WMF change in year one and two on treatment, and differences in atrophy rates by disease progression status were assessed retrospectively. RESULTS: Significantly less GM atrophy (during year two), but not WM atrophy (at any point), was observed with IM IFN beta-1a compared with placebo. Pseudoatrophy effects were more apparent in WM than in GM; in year one, greater WM volume loss was observed with IM IFN beta-1a than with placebo, whereas GM volume loss was similar between groups. Risk of sustained disability progression was significantly associated with GM, but not WM, atrophy. CONCLUSIONS: These results suggest that GMF change is more meaningful than WMF as a marker of tissue loss and may be useful to augment whole brain atrophy measurements in MS clinical trials.

Treatment withdrawal in relapsing-remitting multiple sclerosis: a retrospective cohort study.

BACKGROUND: To investigate the effect of drug withdrawal on the course of relapsing-remitting multiple sclerosis (RR-MS). METHODS: An observational cohort retrospective study was performed to compare the time to relapse of patients who discontinued disease-modifying therapy (1a or 1b beta-interferons or glatiramer acetate) with the patients who did not. One hundred and twenty-eight RR-MS patients were investigated using a time-dependent approach. RESULTS: Over a median follow-up of 108 months, 60 patients discontinued treatment and 89 relapses were observed. The time to relapse was shorter in patients who discontinued treatment compared with those who did not (P < 0.001), median times being 31.1 months (95% confidence interval 10.4-50.8) and 85.8 months (95% confidence interval 58.6-106.3), respectively, whilst the baseline covariates (gender, Expanded Disability Status Scale at diagnosis) did not significantly affect the prognosis. CONCLUSIONS: It was found that stopping treatment strongly reduces the time to relapse and this information may be useful in patient management.

COMPARE: Pharmacokinetic profiles of subcutaneous peginterferon beta-1a and subcutaneous interferon beta-1a over 2 weeks in healthy subjects.

AIM: Subcutaneous (s.c.) peginterferon beta-1a injected once every 2 weeks and s.c. interferon beta-1a injected three times per week (Rebif®) have demonstrated efficacy in relapsing-remitting multiple sclerosis, but direct comparisons of pharmacological activity and tolerability between the two products are lacking. COMPARE was an open label, crossover, pharmacokinetic (PK) study evaluating drug exposure and the safety and tolerability of s.c. peginterferon beta-1a and s.c. interferon beta-1a, over 2 weeks in healthy subjects. METHODS: Thirty healthy subjects received one dose of peginterferon beta-1a (125 µg s.c.) or six doses of interferon beta-1a (44 µg s.c.) over 2 weeks, followed by the alternate treatment after a 2 week washout period. Drug concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and PK parameters including cumulative area under the concentration-time curve (AUC0-336h ) over 2 weeks and maximum observed serum concentrations (Cmax ) were estimated using a non-compartmental analysis. RESULTS: The PK analysis population comprised 26 subjects for each treatment. Drug exposure (AUC0-336h ) was 60% higher with s.c. peginterferon than with s.c. interferon beta-1a (117.4 ng ml(-1) h, 95% confidence interval 95.6, 144.3 vs. 73.1 ng ml(-1) h, 95% confidence interval 61.2, 87.3, respectively; P < 0.0001). Injection-site reactions (ISRs) were the most common adverse events (AEs) observed with both treatments. Numerically lower frequencies and incidence rates of ISRs, headache, myalgia and chills were observed with s.c. peginterferon beta-1a. CONCLUSIONS: One dose of s.c. peginterferon delivered significantly greater drug exposure than s.c. interferon beta-1a three times a week over 2 weeks, and a lower frequency of AEs.

Severe Respiratory Failure Due to Interferon Beta-Related Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is an uncommon but devastating disease. There is increasing evidence of a correlation between interferon (IFN) use and PAH. Very few cases of PAH in patients treated with IFN are reported in literature. We report a case of a 47-year-old woman with previous diagnosis of multiple sclerosis treated with IFN ß-1a for 6 years, presenting severe respiratory failure (paO2/FiO2 228) because of pulmonary hypertension. The suspension of the drug along with the treatment of PAH improved the clinical picture allowing cessation of oxygen administration. Pathophysiological effects of IFN on endothelial vascular cells are discussed.