Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties.

BACKGROUND: Flu-like symptoms (FLS) are common side effects of interferon beta (IFN-ß) treatment in patients with Multiple Sclerosis (PwMS) and are associated with post-injection cytokine surge. We hypothesized that vitamin D3 supplementation would ameliorate FLS by decreasing related serum cytokines' levels. METHODS: In a randomized, double blind study of 45 IFNß-treated PwMS, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 24 patients received 4,370 IU per day (high dose) for one year. FLS were assessed monthly by telephonic interviews. Serum levels of 25-hydroxy-D (25-OH-D), calcium, PTH, IL-17, IL-10 and IFN-γ were measured periodically. EDSS, relapses, adverse events and quality of life (QoL) were documented. RESULTS: 25-OH-D levels increased to a significantly higher levels and PTH levels decreased in the high dose group. There was no significant change in FLS. IL-17 levels were significantly increased in the low dose group, while patients receiving high dose vitamin D had a heterogeneous IL-17 response. No significant differences in relapse rate, EDSS, QoL, serum IL-10 and IFNγ were found. Hypercalcemia or other potential major adverse events were not observed. CONCLUSION: Vitamin D supplementation to IFN-ß treated PwMS, at the doses used, seems safe and associated with dose-dependent changes in IL-17 serum levels, while not affecting IFN-ß related FLS. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01005095.

The influence of vitamin D supplementation on melatonin status in patients with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) incidence is higher in geographic regions with less sunlight exposure. Both vitamin D and melatonin are essential mediators of the effect of sunlight in health, and as such are candidates to play a key role in MS. We hypothesized that vitamin D and melatonin may have related influences in patients with MS. METHODS: In a randomized, double blind study of 40 IFN-ß treated MS patients, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 19 patients received 4,370 IU vitamin D3 per day (high dose) for one year. Serum 25-hydroxy-vitamin-D (25-OH-D) and nighttime urine melatonin metabolite, 6-sulphatoxy-melatonin (6-SMT), were measured at baseline, 3 months and 1 year from enrolment. RESULTS: After 3 months supplementation, 25-OH-D levels increased and nighttime melatonin secretion decreased significantly in the high dose group, but not in the low dose group. After 1 year, a decrease in 25-OH-D levels, accompanied by an increase of urine nighttime 6-SMT were observed in the high dose group. Percent change in serum 25-OH-D was significantly and negatively correlated with percent change in urine 6-SMT after 3 months and between 3 months to 1 year. 25-OH-D levels by the end of the study were significantly and negatively correlated to BMI. CONCLUSIONS: Melatonin secretion is negatively correlated with alterations in serum 25-OH-D in IFN-ß treated patients with MS. The finding suggests that melatonin should be considered as a potential mediator of vitamin D neuro-immunomodulatory effects in patients with MS.

Multiple sclerosis in diverse populations: characteristics in distinct Arab ethnicities in Israel.

BACKGROUND: Multiple sclerosis (MS) prevalence and genetic susceptibility varies among the different ethnic groups of Jews and Arabs in Israel. OBJECTIVE: Characterization of MS disease course in Christian, Muslim and Druze Arabs in Israel. METHODS: Historical cohort and three-year follow-up cohort analyses based on interviews and clinical charts of 149 Arab MS patients (78 Muslims, 49 Christians and 22 Druze) from three MS centers in Israel. Significant findings were adjusted for use of disease modifying therapy. RESULTS: Age of onset (means between 30 and 31 years) and incomplete recovery rates after the first relapse (~50%) were similar for Christian, Muslim and Druze patients. Low rates of primary progressive MS (≤1%) were observed. Differences between the ethnicities in the time from onset to the second neurological episode were observed among females, but not males. Druze and Muslim women were more likely to have a second event within two years from the first event compared with Christians (odds ratios =8.8, p= 0.02; odds ratio=6.6, p=0.007 respectively). Trends for higher annual relapse rates, annual disability progression rates and MS Severity Scores were observed among the Druze. CONCLUSIONS: Among the Israeli Arab female MS patients, Druze and Muslims exhibit a more rapid disease course in comparison with Christians. Further elucidation of population-specific MS phenotypes may contribute to improved disease management.

High risk of colorectal and endometrial cancer in Ashkenazi families with the MSH2 A636P founder mutation.

BACKGROUND & AIMS: The MSH2 A636P mutation is a founder mutation in Ashkenazi Jews that causes Lynch syndrome, with a prevalence of 0.4%-0.7%. Estimates of age-specific cumulative risk and lifetime risk for colorectal cancer (CRC) and endometrial cancer (EC) specific to carriers of this mutation are not available. METHODS: We studied 27 families with MSH2 A636P gene mutations identified in Israel; 13 were identified via a population-based, case-control study and 14 were identified from a clinical genetics service. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general Ashkenazi population using modified segregation analysis. An ascertainment-corrected likelihood that combined population-based and clinic-based sampling provided a powerful analysis for estimating penetrance. We analyzed 74 cases of CRC (40 in the clinic series and 34 in the population-based series), diagnosed at median ages of 50 years (men) and 49 years (women) in the combined sample. RESULTS: The cumulative risk of CRC at age 70 was 61.62% for men (95% confidence interval [CI], 37.49%-76.45%) and 61.08% for women (95% CI, 39.39%-75.14%), with overall HRs of 31.8 (19.9-51.0) and 41.8 (27.4-64.0), respectively. There were 28 cases of EC, diagnosed at a median age of 53.0 years. The cumulative risk of EC was 55.64% (95% CI, 33.07%-70.58%) with an overall HR of 66.7 (41.7-106.7). CONCLUSIONS: Lifetime risks of CRC and EC in MSH2 A636P carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer screening is necessary for carriers of this mutation.

The evolving role of the multiple sclerosis nurse: an international perspective.

A greater understanding of the pathogenesis of multiple sclerosis (MS) and the need for treatments with increased efficacy, safety, and tolerability have led to the ongoing development of new treatments. The evolution of treatments for MS is expected to have a dramatic impact on the entire health-care team, especially MS nurses, who build strong collaborative partnerships with their patients. MS nurses help patients better understand their disease and treatment options, facilitate the initiation and management of treatment, and encourage adherence. With new oral therapies entering the market, the potential for increased efficacy, tolerability, adherence, and convenience for patients is evident. However, the resulting change in the treatment paradigm means that the skill set required of an MS nurse will inevitably expand. There will be a growing need for professional training and development to ensure that nurses are familiar with the wider range of treatments and their specific modes of action, dosing schedules, and benefit/risk profiles. In addition, the MS nurse's role will expand to include management of the complex monitoring needs specific to each therapy. This article explores how the role of the MS nurse is evolving with the development of new MS therapies, including novel oral therapies.

Patients with multiple sclerosis in a war zone: coping strategies associated with reduced risk for relapse.

The objective of this article is to examine the role of coping strategies in multiple sclerosis outcomes among civilians under a military attack during the 2006 war between Hezbollah and Israel. Participants were 156 patients with relapsing-remitting multiple sclerosis. We analysed the relationships between coping and emotional distress and between coping and multiple sclerosis exacerbation. We also assessed a model of the relationship between perceived stress, event-related stress, and coping with increased risk of multiple sclerosis exacerbations using multivariate logistic regression. Ways of coping and subjective stress were evaluated by means of structured interviews using questionnaires previously validated. The more distressed our respondents were during the war, the more likely they were to employ a variety of ways of coping. Correlation coefficients between coping scores and perceived war stress ranged from 0.2 to 0.44 (p < 0.001-0.01). Correlation coefficients between the various coping scores and broader indices of distress ranged from 0.28 to 0.5 (p < 0.001). Of the remitting patients during and following the war, 47.1% reported the use of 'direct coping and planning', compared to 16.7% of patients who relapsed during the same period (p = 0.014). 'Direct coping and planning' was negatively related to exacerbation of multiple sclerosis symptoms (OR = 0.1, 95% CI = 0.02-0.5). The Nagelkerke R(2) was 0.26. Our findings point to an association between 'direct coping and planning' and reduced multiple sclerosis relapse rate during wartime. Further research should explore whether the employment of specific ways of coping can reduce the risk for relapse among patients with multiple sclerosis during periods of distress.

Internet usage by patients with multiple sclerosis: implications to participatory medicine and personalized healthcare.

Online health information and services for patients were suggested to improve symptom management and treatment adherence, thereby contributing to healthcare optimization. This paper aimed to characterize multiple sclerosis (MS) patients Internet usage. Information regarding browsing habits, Internet reliability, and the medical team's attitude to information collected online was obtained by questionnaires from MS patients. Data was compared between nonbrowsers, browsers on MS topics, and browsers on non-MS topics only. From the 96 patients recruited, 61 (63.5%) performed MS-related searches. The most viewed topics were "understanding the disease" and "treatments". Patients reported that the information helped coping with MS and assured them of the appropriateness of their therapy. Shorter disease duration was correlated with higher Internet activity. Disabled patients were more interested in online interaction with specialists and support groups. This paper suggests that MS patients benefit from online information, and it emphasizes the importance of resources tailored to patients needs.

BRCA1 breast cancer risk is modified by CYP19 polymorphisms in Ashkenazi Jews.

Exposure to sex hormones is a major risk factor for breast cancer and current treatments include hormone modifying drugs, among them aromatase inhibitors. We studied the association of CYP19 (Val(80) and [TTTA](n)) polymorphisms, the gene translated to aromatase, and the risk of breast cancer in BRCA carriers and noncarriers. The study consisted of 958 cancer cases and 931 healthy controls, including 474 carriers and 1,415 noncarriers. Cases and controls came from a population-based study of breast cancer in Israel, enriched with BRCA carriers from a clinical familial cancer service. Val(80) G/G genotype was associated with significantly increased risk of breast cancer compared with the Val(80) A/A genotype in BRCA1 carriers ages <50 years (odds ratio, 2.81; 95% confidence interval, 1.09-7.22; P = 0.032) but not in BRCA2 carriers or noncarriers of any age. A similar magnitude suggestive association, although nonstatistically significant, was found between Val(80) polymorphism and estrogen receptor-negative status of the breast tumors. A common haplotype composed of the Val(80) G allele and three haplotype-tagging single nucleotide polymorphisms (rs727479, rs10046, and rs4646) in the CYP19 coding region showed a trend to association with breast cancer risk in BRCA1 carriers ages <50 years. Published expression data show higher estrogen levels with higher repeats in [TTTA](n) found in linkage disequilibrium with Val(80). The present study suggests that the CYP19 Val(80) polymorphism and a haplotype that includes this polymorphism are associated with increased breast cancer risk in young women with BRCA1 mutations.

Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation.

OBJECTIVE: A founder mutation A636P in the MSH2 gene was found to be related to hereditary nonpolyposis colorectal cancer in Ashkenazi Jews. Although the incidence of colorectal cancer in carriers is relatively well established, the frequency of other tumors is less clear. STUDY DESIGN: We studied a consecutive series of 19 carrier families that were cared for by the Clalit Health Studies National Familial Cancer Consultation Service, most of whom were identified through a population-based case-control study of colorectal cancer in northern Israel. RESULTS: Gynecologic cancers, 88% of which (28 cases) were endometrial cancers, were diagnosed in 78.9% of the carrier families and in 26.2% of the women who were at risk, with a mean age at diagnosis of 51.2 years. Forty-six percent of the women with endometrial cancer reported at least 1 other primary tumor. CONCLUSION: Genetic counseling and testing for the MSH2 A636P mutation is indicated for Ashkenazi Jewish women with an endometrial cancer, especially if the cancer is detected before the age of 70 years in women with a personal or family history of colorectal cancer.

Impact of exposure to war stress on exacerbations of multiple sclerosis.

OBJECTIVE: To assess the relation between stress caused by the perils of rocket attack on civilian centers in northern Israel during the 2006 war between Hezbollah and Israel and multiple sclerosis (MS) exacerbations. METHODS: Participants were 156 patients with relapsing-remitting MS. We compared the number of relapses during and after the war with similar time periods at the preceding year. Exposure to war events and resulting subjective stress were evaluated by means of structured interviews using questionnaires previously validated. RESULTS: During the 33 days of the war, there were 18 relapses among our patients, compared with 1 to 6 relapses in similar time periods over the 12 months before the war (p < 0.001-0.02). There was no increase in relapse rate during the 3 months that followed the war (p = 0.58). The percentage of patients reporting the experience of intense subjective stress during the hostilities was significantly greater among patients with wartime relapse compared with the rest of the patients (44 vs 20%). The proportion of patients reporting high levels of distress associated with exposure to rocket attacks, displacement from home, and perceived life threat was greater in relapsing patients compared with those in remission (67 vs 42%, p = 0.05; 33 vs 11%, p = 0.02; and 33 vs 15%, p = 0.08, respectively). INTERPRETATION: Our data suggest that civilian exposure to war stress is associated with increased risk for MS relapse. These findings provide insight to stress-related risk factors associated with relapses of MS.

Health-related quality of life in multiple sclerosis: The impact of disability, gender and employment status.

OBJECTIVES: (1) Evaluate the impact of the patient characteristics of disability, gender and employment status on health-related quality of life (HRQOL) in multiple sclerosis (MS) and (2) Characterize the functional relationship between HRQOL and disability overall, and by gender and employment status. METHODS: We assessed the HRQOL of 215 MS outpatients in our clinic using the MSQOL-54 and Fatigue Severity Scale (FSS), and that of 172 healthy controls, using the SF-36 (a subset of MSQOL-54). We compared QOL between MS subgroups defined by disability, gender and employment, and computed the linear and non-linear relationships between disability level measured by the Expanded Disability Status Scale (EDSS) and MSQOL-54 dimensions. RESULTS: QOL of MS patients measured by SF-36 is lower than controls, varying by QOL dimension with the greatest difference emerging for physical aspects of the disease. The relationship of physical disability, measured by EDSS, and all 14 MSQOL-54 dimensions and FSS is negative; for 12 of the 14 dimensions and FSS it is also non-linear. Non-linearity is most pronounced among women, who show a weak EDSS/QOL relationship at higher levels of physical disability, suggesting women better able to "psychologically buffer" the debilitating aspects of MS. While employed have higher QOL than unemployed, the former are more affected by physical disability. CONCLUSIONS: Multiple attributes, including disability, gender and employment status, affect QOL. QOL's relationship with disability is complex, displaying non-linearity and interacting with patient characteristics. This has implication for QOL research methodology and provides insight into factors affecting patients' perceptions of well-being.

Health-related quality of life in multiple sclerosis: psychometric analysis of inventories.

OBJECTIVE: Measuring health-related quality of life (HRQoL) enables attainment of a comprehensive picture of chronic patients' conditions. The aim was to gain insight into HRQoL as viewed by Israeli multiple sclerosis (MS) patients, with an eye to its cross-cultural applicability, using psychometric analysis and a regression-based procedure. METHODS: The reliability and validity of the MSQoL-54 was assessed in 215 Israeli MS patients. Subsequently a novel method in QoL research for assessing the relative importance to patients of different aspects of the construct, comparing these between males and females, was applied. Using factor analysis, the degree to which the MSQoL-54 dimensions are applicable in our population and the existence of a separate dimension of Fatigue were tested. Finally, structural equation modelling (SEM) was used to examine relationships between QoL dimensions. RESULTS: The MSQoL-54 showed reliabilities and validities comparable to those found in other populations. Females attach importance to emotional aspects of QoL, while males are more concerned with physical aspects. The distinction between Emotional and Physical dimensions emerged from SEM, as did a distinction between Fatigue and Energy, the former being primarily Physical, and the latter Emotional. SEM indicated a reciprocal causality between Physical and Emotional dimensions. CONCLUSIONS: Based on internal structure, reliability and validity, the MSQoL-54 is applicable to Israeli MS patients. However, the scale's Social Function dimension is indecisively defined, which requires further study. QoL research in MS should distinguish between emotional and physical Fatigue. Assessing importance of QoL dimensions should inform clinicians in tailoring treatment to the individual patient.

BRCA1/2 mutation carriers: living with susceptibility.

OBJECTIVES: To examine whether being a BRCA1/2 mutation carrier affects a wide array of aspects of life, and if so, how. METHODS: Participants were grouped according to their carrier status (carrier and noncarrier status), health status (affected or unaffected by cancer), and their enrollment at the counseling service (probands and other family members). One hundred and sixty-five women completed a self-administered questionnaire following their genetic consultation session. RESULTS: Probands/nonprobands and carriers/noncarriers did not differ with regard to demographic characteristics, health behaviors including medical checkups, the distress they experience or their resources (sense of coherence, social integration, religiosity). Individuals affected by cancer did differ on some of these aspects from participants without cancer. CONCLUSIONS: From the results of this study, being a carrier could not be considered a psychosocial risk factor, nor does it seem to have an effect on carriers' resources and lifestyle.