Safety and efficacy of helminth treatment in relapsing-remitting multiple sclerosis: Results of the HINT 2 clinical trial.

BACKGROUND: The hygiene hypothesis suggests that microbial replacement may be therapeutic in allergic and autoimmune diseases. Nevertheless, the results of helminth treatment, including in multiple sclerosis (MS), have been inconclusive. OBJECTIVE: To assess safety and brain magnetic resonance imaging (MRI) activity in subjects with relapsing-remitting multiple sclerosis (RRMS) during oral administration of ova from the porcine whipworm, Trichuris suis (TSO). METHODS: A total of 16 disease-modifying treatment (DMT) naive RRMS subjects were studied in a baseline versus treatment (BVT) controlled prospective study. MRI scans were performed during 5 months of screening-observation, 10 months of treatment, and 4 months of post-treatment surveillance. RESULTS: No serious symptoms or adverse events occurred during treatment. For the cohort, there was a trend consistent with a 35% diminution in active lesions when observation MRIs were compared to treatment MRIs ( p = 0.08), and at the level of individuals, 12 of 16 subjects improved during TSO treatment. T regulatory lymphocytes were increased during TSO treatment. CONCLUSION: TSO is safe in RRMS subjects. Potentially favorable MRI outcomes and immunoregulatory changes were observed during TSO treatment; however, the magnitude of these effects was modest, and there was considerable variation among the responses of individual subjects.

Phenome-wide association study maps new diseases to the human major histocompatibility complex region.

BACKGROUND: Over 160 disease phenotypes have been mapped to the major histocompatibility complex (MHC) region on chromosome 6 by genome-wide association study (GWAS), suggesting that the MHC region as a whole may be involved in the aetiology of many phenotypes, including unstudied diseases. The phenome-wide association study (PheWAS), a powerful and complementary approach to GWAS, has demonstrated its ability to discover and rediscover genetic associations. The objective of this study is to comprehensively investigate the MHC region by PheWAS to identify new phenotypes mapped to this genetically important region. METHODS: In the current study, we systematically explored the MHC region using PheWAS to associate 2692 MHC-linked variants (minor allele frequency ≥0.01) with 6221 phenotypes in a cohort of 7481 subjects from the Marshfield Clinic Personalized Medicine Research Project. RESULTS: Findings showed that expected associations previously identified by GWAS could be identified by PheWAS (eg, psoriasis, ankylosing spondylitis, type I diabetes and coeliac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with eight diseases not previously assessed by GWAS (eg, lichen planus) were also identified and replicated in an independent population. Many of these associated diseases appear to be immune-related disorders. Further assessment of these diseases in 16 484 Marshfield Clinic twins suggests that some of these diseases, including lichen planus, may have genetic aetiologies. CONCLUSIONS: These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP-disease associations, and is ideal when characterising cross-phenotype associations, and further emphasise the importance of the MHC region in human health and disease.

What is the risk of permanent disability from a multiple sclerosis relapse?

OBJECTIVE: To determine how often patients with relapsing-remitting multiple sclerosis (MS) develop severe (Expanded Disability Status Scale [EDSS] > or =6.0) sustained (greater than 6 months) disability due to an acute relapse. METHODS: We analyzed our database of all patients with MS followed up at the Marshfield Multiple Sclerosis Center. RESULTS: Among the 1,078 patients, there were 2,587 relapses (mean of 2.4 per patient, with a range of 1-11 attacks over 1-15 years). Only 7 patients had a relapse resulting in EDSS > or =6 that did not recover. Genetic analysis showed no difference in HLA-DR or NOS2A loci between these patients and other MS populations, nor were there any clinical factors that identified high risk. Two of these patients were on interferon treatment at the time of their disabling attack. CONCLUSIONS: The fear of a sudden irreversible disability should not influence therapeutic decisions because such attacks are very rare and can occur whether or not patients are treated with interferons.

The differential diagnosis of multiple sclerosis.

OBJECTIVE: This article will discuss the diagnosis of multiple sclerosis (MS), with particular attention to differentiating it from other diseases that can mimic it. METHODS: We reviewed our own data, as well as the published experience on the differential diagnosis of MS and the most common errors leading to misdiagnosis. RESULTS: Psychiatric diseases are mistaken for multiple sclerosis more often than any other conditions. Other multifocal illnesses or white-matter diseases are seldom confused with multiple sclerosis. CONCLUSION: Neurologists are most likely to misdiagnose multiple sclerosis in patients who have psychiatric problems or who have uncommon presentations of common diseases such as migraine, stroke, or neuropathies.

Thomas Jefferson's headaches: were they migraines?

Thomas Jefferson had severe headaches on a number of occasions during his adult life, as noted by most of his biographers. Some occurred during important historical events, including the period just before the writing of the Declaration of Independence. Historians generally have considered these headaches to be migraines, while some physician authors have considered the alternative diagnoses of tension-type headaches and cluster headaches. A review of the literature, including Jefferson's many letters, suggests that they probably were migraines, although not all of the current diagnostic criteria can be met.

IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.

BACKGROUND: The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed that IM interferon beta-1a (IFNbeta-1a) significantly slows the rate of development of clinically definite multiple sclerosis (CDMS) over 2 years in high-risk patients who experience a first clinical demyelinating event. This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]). OBJECTIVE: To determine if the benefits of IFNbeta-1a observed in CHAMPS are sustained for up to 5 years. METHODS: CHAMPS patients at participating CHAMPIONS sites were enrolled in the study. All patients were offered, but not required to take, IFNbeta-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization). Patients who received placebo in CHAMPS were considered the delayed treatment (DT) group, and patients who received IFNbeta-1a in CHAMPS were considered the immediate treatment (IT) group. The primary outcome measure was the rate of development of CDMS. Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years. RESULTS: Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS. The median time to initiation of IFNbeta-1a therapy in the DT group was 29 months. The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03). Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of neurologic symptoms. Few patients in either group developed major disability within 5 years. CONCLUSIONS: These results support the use of IM interferon beta-1a after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Disorders of flushing.

Disorders of flushing encompass a broad spectrum of diverse acquired and inherited conditions. Chemical mediators involved in the flushing response are incompletely understood. Flushing episodes rarely can be associated with significant morbidity and mortality. The goal of the physician is to separate benign from potentially life-threatening conditions. Accurate diagnosis requires a thorough history and physical examination emphasizing the age of the patient, temporal association of flushing with occupation, environmental, stress, food, or drug exposure, and the duration of the episode. In some cases, despite a thorough evaluation, the etiology for flushing remains unknown. Understanding the distinct mechanisms that lead to flushing helps provide a rational approach to treatment.