Background Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. Methods Using case–control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus–specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. Results A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion–deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. Conclusions A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.)

We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS.

We investigated the paraclinical profile of monosymptomatic optic neuritis (ON) and its prognosis for multiple sclerosis (MS). The correct identification of patients with very early MS carrying a high risk for conversion to clinically definite MS is important when new treatments are emerging that hopefully will prevent or at least delay future MS. We conducted a prospective single observer and population-based study of 147 consecutive patients (118 women, 80%) with acute monosymptomatic ON referred from a catchment area of 1.6 million inhabitants between January 1, 1990 and December 31, 1995. Of 116 patients examined with brain MRI, 64 (55%) had three or more high signal lesions, 11 (9%) had one to two high signal lesions, and 41 (35%) had a normal brain MRI. Among 143 patients examined, oligoclonal IgG (OB) bands in CSF only were demonstrated in 103 patients (72%). Of 146 patients analyzed, 68 (47%) carried the DR15,DQ6,Dw2 haplotype. During the study period, 53 patients (36%) developed clinically definite MS. The presence of three or more MS-like MRI lesions as well as the presence of OB were strongly associated with the development of MS (p < 0.001). Also, Dw2 phenotype was related to the development of MS (p = 0.046). MRI and CSF studies in patients with ON give clinically important information regarding the risk for future MS.

Objectives: To describe variations in fatigue over the course of 2 years in a sample of persons with multiple sclerosis (MS), and to investigate the predictive value of the following variables on variations in fatigue: sex, age, sense of coherence, living with a partner, living with children, work status, immunomodulatory treatment, mood, disease severity, disease course, time since diagnosis and time. Methods: Every 6 months, 219 outpatients at an MS specialist clinic were assessed using the Fatigue Severity Scale (FSS). Predictive values were explored with Generalised Estimating Equation employing proportional odds models; FSS scores were categorised as nonfatigue, borderline fatigue or fatigue. Results: FSS scores varied significantly (p = 0.02); 54% changed FSS category one or several times, 27% were persistently fatigued and 19% persistently non-fatigued. Independent predictors of increased fatigue were depressive symptoms, weak/moderate sense of coherence, living with a partner and not working. Furthermore, moderate disease severity predicted increase when combined with .10 years since diagnosis or a progressive course. Independent predictors of decreased fatigue were no depressive symptoms, strong sense of coherence, living alone and working. Moreover, mild and severe disease predicted a decrease when combined with .10 years since diagnosis, and mild severity combined with a progressive course. Conclusion: Mood, sense of coherence and living with a partner were independent predictors of fatigue in persons with MS. In addition to monitoring disease related variables, health related services should apply a broad range of approaches and repeatedly assess fatigue in persons with MS, to provide preventive care and appropriate interventions.