Julia Pakpoor

The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis

Background: Epstein-Barr virus (EBV) infection is widely considered to be a risk factor for multiple sclerosis (MS). A previous meta-analysis estimated an odds ratio (OR) for MS in individuals seronegative for EBV of 0.06. Given the potential importance of this finding, we aimed to establish a more precise OR for adult and paediatric onset MS in EBV seronegative individuals. Methods: PubMed and EMBASE searches were undertaken to identify studies investigating the association between MS and EBV. Twenty-two adult and three paediatric studies were included. ORs were calculated using a fixed effects model. A sub-group analysis based on the method of EBV detection was performed. Results: The OR for developing adult MS in EBV seronegatives was 0.18 (95% confidence interval (CI) 0.13–0.26)) and for paediatric MS was 0.18 (95% CI 0.11–0.30). Sub-group analysis on EBV detection method showed that studies which used immunofluoresence generated an OR=0.07 (95% CI 0.03–0.16); for those that used enzyme-linked immunosorbent assay (ELISA) OR=0.33 (95% CI 0.22–0.50) and for studies which used ELISA and immunofluoresence OR=0.00 (95% CI 0–0.43). Conclusion: The sensitivity and specificity of the assay used to measure EBV antibody titres have an influence on the association between MS and EBV. Looking at studies where two independent methods are used and therefore are likely to be the most robust, EBV appears to be present in 100% of MS patients. This has implications for future studies of EBV in MS. MS patients without EBV infection, if they truly exist, should be studied in more detail.

Breastfeeding and multiple sclerosis relapses: a meta-analysis

An increased relapse rate immediately post-partum in multiple sclerosis (MS) patients is well established [1]; however, no consensus has been reached regarding the impact of breastfeeding on post-partum relapse risk. Women with MS make a difficult choice between not restarting disease-modifying drugs and breastfeeding, or restarting therapy and not breastfeeding, or curtailing the duration of breastfeeding. In this study we aimed to metaanalyse all available data to give a more accurate estimate of the impact of breastfeeding on the risk of post-partum relapse. A comprehensive search of the PubMed database was undertaken using the search terms ‘‘breastfeeding’’ and ‘‘multiple sclerosis’’. There was no time period restriction. Abstracts of the identified studies were hand-searched to select studies comparing post-partum relapse occurrence in a breastfeeding (BF) versus not breastfeeding group (not BF). Studies were excluded if they were not available in English, an interventional drug trial where drug effect was the primary aim, or if they did not compare relapse occurrence in breastfeeding versus not breastfeeding mothers. Where a study was considered suitable for inclusion but raw data were not available, authors were contacted. In total 12 studies were selected for inclusion [2–11] (details found in Online Resource 1), of which for two unpublished data were obtained from KH, yielding a total of 869 MS patients who breast-fed versus 689 MS patients who did not. The inverse variance with the random effects model in Review Manager 5.1 was used to calculate the overall odds ratio (OR) of having at least one post-partum relapse in MS patients who breastfeed versus those who do not, 95 % confidence interval (CI) and test statistic for heterogeneity. The Egger p value was calculated to assess publication bias. Women who did not breastfeed were almost twice as likely to have at least one post-partum relapse [OR 0.53 (95% CI 0.34–0.82), Fig. 1]; however, significant heterogeneity was present (P = 0.002; I = 63 %). A funnel plot showed no evidence of bias (Egger p value 0.67), Fig. 2. Sensitivity analysis showed that inclusion of only the eight prospective studies [3, 5–9, 11] had an OR = 0.46 (0.30–0.70) with no significant heterogeneity (P = 0.18, I = 32%). Four studies [2, 6, 8, 9] reported the prepregnancy relapse rate; this was not significantly lower in women who breastfed as compared to women who did not [mean relapse rate (MRR) 0.61 vs. 0.82; P = 0.57]. Three studies [6, 8, 9] reported data on the relapse rate during Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6553-z) contains supplementary material, which is available to authorized users.

No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine

Objective: To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS). Methods: Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test. Results: Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% (p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) (p = 0.6546). Conclusions: Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.

Epstein–Barr virus and multiple sclerosis: association or causation?

Multiple sclerosis (MS) is a multifactorial disease in which both genetic and environmental factors and their interactions underlie causation. The current evidence base supports a strong association between Epstein–Barr virus (EBV) and MS, but potential causality remains strongly debated. It is not possible to exclude the possibility that an abnormal response to EBV infection is a consequence, rather than a cause, of the underlying pathophysiology of MS, or indeed that the association may be a reflection of a similar underlying disease mechanism. Substantial experimental progress is necessary to achieve consistency of molecular findings to complement the strong epidemiological association between EBV and MS, which cannot alone show causation. Collectively, the strength of the association between EBV and MS warrants careful development and trial of anti-EBV drugs to observe any effect on MS disease course.

High reprint orders in medical journals and pharmaceutical industry funding: case-control study

Objectives To assess the extent to which funding and study design are associated with high reprint orders. Design Case-control study. Setting Top articles by size of reprint orders in seven journals, 2002-09. Participants Lancet, Lancet Neurology, Lancet Oncology (Lancet Group), BMJ, Gut, Heart, and Journal of Neurology, Neurosurgery & Psychiatry (BMJ Group) matched to contemporaneous articles not in the list of high reprint orders. Main outcome measures Funding and design of randomised controlled trials or other study designs. Results Median reprint orders for the seven journals ranged from 3000 to 126 350. Papers with high reprint orders were more likely to be funded by the pharmaceutical industry than were control papers (industry funding versus other or none: odds ratio 8.64, 95% confidence interval 5.09 to 14.68, and mixed funding versus other or none: 3.72, 2.43 to 5.70). Conclusions Funding by the pharmaceutical industry is associated with high numbers of reprint orders.

Testicular hypofunction and multiple sclerosis risk: A record‐linkage study

The influence of gonadal hormones on multiple sclerosis (MS) is not well characterized and has thus far been investigated primarily in animal models or as a proposed therapeutic approach. We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and MS risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. We report a strong positive association between testicular hypofunction and subsequent MS (rate ratio = 4.62, 95% confidence interval = 2.3–8.24, p < 0.0001). Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females. Ann Neurol 2014;76:625–628The influence of gonadal hormones on multiple sclerosis (MS) is not well characterized and has thus far been investigated primarily in animal models or as a proposed therapeutic approach. We investigated a potential association between testicular hypofunction, as a proxy for low testosterone levels, and MS risk through analysis of linked English national Hospital Episode Statistics from 1999 to 2011. We report a strong positive association between testicular hypofunction and subsequent MS (rate ratio = 4.62, 95% confidence interval = 2.3–8.24, p < 0.0001). Future work should aim more directly to elucidate the relationship between testosterone levels and MS in both males and females. Ann Neurol 2014;76:625–628

Epstein–Barr virus, latitude and multiple sclerosis

Several lines of evidence support a role for Epstein–Barr virus (EBV) in the aetiology of multiple sclerosis (MS). This includes the observation that nearly all MS patients show serological markers of past EBV infection. Given the well-known association between MS prevalence and latitude, we investigated whether EBV seropositivity also increases with distance from the equator. We found that the proportion of EBV positive individuals is positively associated with latitude independently of MS status (odds ratio = 1.06, 95% CI = 1.02–1.09, p = 0.002). Latitude-related factors may be implicated in the immune response to EBV and its role in MS aetiology.

Meta-Analysis of the Relationship between Multiple Sclerosis and Migraine

Background Studies investigating a proposed association between multiple sclerosis (MS) and migraine have produced conflicting results and a great range in the prevalence rate of migraine in MS patients. By meta-analysing all available data we aimed to establish an overall estimate of any association in order to more accurately inform clinicians and care-givers about a potential association between MS and migraine. Methods Pubmed and EMBASE were searched to identify suitable studies. Studies were included if they were a case-control study or cohort study in which controls were not reported to have another neurological condition, were available in English, and specified migraine as a headache sub-type. The odds ratio (OR) of migraine in MS patients vs. controls was calculated using the inverse variance with random effects model in Review Manager 5.1. Results Eight studies were selected for inclusion, yielding a total of 1864 MS patients and 261563 control subjects. We found a significant association between migraine and MS (OR = 2.60, 95% CI 1.12–6.04), although there was significant heterogeneity. Sensitivity analysis showed that migraine without aura was associated with MS OR = 2.29 (95% CI 1.14–4.58), with no significant heterogeneity. Conclusions MS patients are more than twice as likely to report migraine as controls. Care providers should be alerted to ask MS patients about migraine in order to treat it and potentially improve quality of life. Future work should further investigate the temporal relationship of this association and relationship to the clinical characteristics of MS.

DNase hypersensitive sites and association with multiple sclerosis

Genome-wide association studies (GWASs) have shown that approximately 60 genetic variants influence the risk of developing multiple sclerosis (MS). Our aim was to identify the cell types in which these variants are active. We used available data on MS-associated single nucleotide polymorphisms (SNPs) and deoxyribonuclease I hypersensitive sites (DHSs) from 112 different cell types. Genomic intervals were tested for overlap using the Genomic Hyperbrowser. The expression profile of the genes located nearby MS-associated SNPs was assessed using the software GRAIL (Gene Relationships Across Implicated Loci). Genomic regions associated with MS were significantly enriched for a number of immune DHSs and in particular T helper (Th) 1, Th17, CD8+ cytotoxic T cells, CD19+ B cells and CD56+ natural killer (NK) cells (enrichment = 2.34, 2.19, 2.27, 2.05 and 1.95, respectively; P < 0.0001 for all of them). Similar results were obtained when genomic regions with suggestive association with MS and additional immune-mediated traits were investigated. Several new candidate MS-associated genes located within regions of suggestive association were identified by GRAIL (CARD11, FCRL2, CHST12, SYK, TCF7, SOCS1, NFKBIZ and NPAS1). Genetic data indicate that Th1, Th17, cytotoxic T, B and NK cells play a prominent role in the etiology of MS. Regions with confirmed and suggestive association have a similar immunological profile, indicating that many SNPs truly influencing the risk of MS actually fail to reach genome-wide significance. Finally, similar cell types are involved in the etiology of other immune-mediated diseases.

Evidence for an Association Between Vitamin D and Multiple Sclerosis

The cause of MS remains unknown, but a number of genetic and environmental risk factors, and their interactions, are thought to contribute to disease risk. A substantial evidence base now exists supporting an association between vitamin D and MS, primarily illustrated by a latitudinal gradient of MS prevalence, a month of birth effect, an interaction of vitamin D with MS-associated genes and the fact that high vitamin D levels have been associated with a reduced MS risk in longitudinal prospective work. The association is primarily based on epidemiological studies which renders the more elusive question of whether this association truly represents causation, or indeed reverse causality in the light of a potentially uncharacterised pro-dromal phase of the disease. The prospect of vitamin D supplementation preventing MS is a very attractive notion, but a number of areas of inconsistencies and unanswered questions exist. Most notably, future work will need to establish appropriate dosing, timing and method of vitamin D supplementation in optimising any potential clinical benefit. In this chapter, we discuss the strong epidemiological and growing mechanistic evidence supporting an association between vitamin D and MS, and aim to highlight areas of current debate and where future efforts would be well worth targeting. Given that MS is currently the most common, and a rising, cause of neurological disability in young adults in the Western world, elucidating the relationship between vitamin D and MS is a necessary priority in aiming to further develop therapeutic and preventative strategies against this disease.