Antibody response to seasonal influenza vaccination in patients with multiple sclerosis receiving immunomodulatory therapy.

BACKGROUND AND PURPOSE: We have previously shown that patients with multiple sclerosis receiving immunomodulatory treatment have reduced seroprotection rates after influenza immunization. The aim of this study was to further investigate the influence of immunomodulatory therapies on the antibody response and seroprotection rates in patients immunized with seasonal influenza vaccine in 2012/2013 compared with healthy controls. METHODS: Ninety patients receiving fingolimod, glatiramer acetate, interferon beta-1a/1b, natalizumab or no therapy were compared with 62 healthy controls. All subjects received the inactivated split virus vaccine in 2012 and serum samples were collected pre-vaccination and 3, 6 and 12 months post-vaccination. The vaccine responses were evaluated by the hemagglutination inhibition assay and adjusted for age and gender. RESULTS: No significant differences in rates of protection against H1N1 for interferon beta-1a/1b and glatiramer acetate were observed as compared with controls at 3, 6 and 12 months. Fingolimod provided reduced protection at all time points post-vaccination, whereas natalizumab displayed reduced protection at 3 and 6 months. Patients without immunomodulation did not display protection rates that were significantly different from the controls at 3 and 12 months. CONCLUSION: These findings suggest that patients with multiple sclerosis receiving fingolimod or natalizumab should be considered for a second dose of the vaccine in cases of insufficient protection. Our results further indicate that new immunomodulatory treatment regimens should be systematically evaluated for their influence on influenza-specific vaccine responses.

A 60-year follow-up of the incidence and prevalence of multiple sclerosis in Hordaland County, Western Norway.

OBJECTIVE: Investigate the incidence of multiple sclerosis during 1953-2013 and estimate the prevalence rate of MS on 1 January 2003 and 2013 in Hordaland County, Western Norway. METHODS: All patients with onset of disease in Hordaland 1953-2013 were identified in files from previous studies until 2003 and from patient records at the departments of Neurology, Haukeland University Hospital and Haugesund Hospital during 2003-2013. 1558 patients were assessed and 1402 of these were included, of whom 1035 were alive and living in Hordaland at prevalence day 1 January 2013. Annual incidence rates were calculated for 1953-2013. RESULTS: On 1 January 2003, the crude prevalence rate was 191/100 000 population and on 1 January 2013, the crude prevalence rate was 211.4 (95% CI 198.3 to 224.2) per 100 000; 270.9 (95% CI 250.6 to 292.3) for women and 151.8 (95% CI 136.8 to 167.9) for men. Prevalence peaked at ages 55-59 years for women and 60-64 years for men. The annual incidence rate increased from 1.9 (95% CI 1.2 to 2.6) per 100 000 during 1953-1957 to 7.2 (95% CI 6.0 to 8.5) during 1978-1982 and to 8.5 (95% CI 7.3 to 9.7) during 2003-2007, thus indicating a stabilising incidence over the past 35 years. The female/male ratio ranged from 1.2:1 to 1.8:1 (p=0.381) during the period. CONCLUSIONS: Stabilising rather than increasing incidence combined with the stable female/male ratio are indicative of non-fluctuating environmental factors in a geographical area otherwise characterised by lack of vitamin D effective sun exposure. The rising prevalence of MS could result from improved survival and follow-up methodology.

Disease-modifying treatments for multiple sclerosis - a review of approved medications.

BACKGROUND AND PURPOSE: There is still no curative treatment for multiple sclerosis (MS), but during the last 20 years eight different disease-modifying compounds have been approved for relapsing-remitting MS (RRMS). METHODS: A literature search was conducted on published randomized controlled phase III trials indexed in PubMed on the approved medications until 21 May 2015. RESULTS: In this review the mode of action, documented treatment effects and side effects of the approved MS therapies are briefly discussed. CONCLUSIONS: Based on current knowledge of risk-benefit of the approved MS medications, including factors influencing adherence, it is suggested that oral treatment with dimethyl fumarate or teriflunomide should be preferred as a starting therapy amongst the first-line preparations for de novo RRMS. In the case of breakthrough disease on first-line therapy, or rapidly evolving severe RRMS, second-line therapy with natalizumab, fingolimod or alemtuzumab should be chosen based on careful risk-benefit stratification.

Does low socioeconomic status in early life protect against multiple sclerosis? A multinational, case-control study.

BACKGROUND AND PURPOSE: The findings from existing research on the association between socioeconomic status (SES) and multiple sclerosis (MS) are inconsistent. Most previous studies are limited to one country and do not adequately adjust for other risk factors for the disease. METHODS: The association between SES and MS was examined using data from the multinational Environmental Risk Factors in Multiple Sclerosis (EnvIMS) case-control study, comprising 2144 cases and 3859 controls from Norway, Canada and Italy. Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals for the association between early life SES, measured by parental educational level, and MS. Analyses were adjusted for age, sex, sunlight exposure, history of infectious mononucleosis, smoking, obesity and family size. RESULTS: Relative to those whose parents had primary school education or below, the adjusted odds ratio (95% confidence interval) for MS amongst individuals with university-educated parents, and the P value for trend across education levels, were 1.45 (1.03-2.05) in Canada (P for trend 0.030), 1.09 (0.85-1.39) in Norway (P for trend 0.395) and 0.65 (0.39-1.07) in Italy (P for trend 0.158). CONCLUSION: There is no consistent association between parental SES and MS risk in Norway, Canada and Italy, with a protective effect of low SES only found in Canada.

Vitamin D, HLA-DRB1 and Epstein-Barr virus antibody levels in a prospective cohort of multiple sclerosis patients.

BACKGROUND AND PURPOSE: Our objective was to study the association between serum levels of anti Epstein-Barr virus nuclear antigen 1 (EBNA-1) antibody and 25-hydroxyvitamin D (25(OH)D) in a prospective cohort of patients with relapsing-remitting multiple sclerosis. METHOD: The study comprised 90 patients with relapsing-remitting multiple sclerosis, all participants in a randomized clinical trial of ω-3 fatty acids (the OFAMS study). Repeated, paired measurements of serum 25(OH)D and serum EBNA-1 immunoglobulin G (IgG) levels were obtained at baseline and every 6 months for 24 months. The association between serum EBNA-1 IgG and serum 25(OH)D levels was analysed using generalized linear models for hierarchical data. RESULTS: There was a significant variation in EBNA-1 IgG antibody level between sampling months (Fdf 11 = 1.8, P = 0.043, one-way anova). There was a negative association between EBNA-1 IgG and 25(OH)D [B = -0.230, 95% confidence interval (CI) (-0.440, -0.023), P = 0.030] and a positive association between EBNA-1 IgG and HLA-DRB1*15 positive status [B = 94.7, 95% CI (2.423, 186.9), P = 0.044]. The association between 25(OH)D and EBNA-1 IgG remained significant after adjusting for the patient's age, gender, HLA-DRB1*15, retinol levels and interferon ß-1a treatment. CONCLUSION: Our study demonstrates monthly differences in EBNA-1 IgG levels and an association between EBNA-1 IgG, 25(OH)D levels and HLA-DRB1*15. These results indicate that EBNA-1 IgG serum levels are affected by genetic and environmental factors that also modulate multiple sclerosis risk.

WT1 and interferon-ß-vitamin D association in MS: a longitudinal study.

BACKGROUND: It has been suggested that polymorphisms in the WT1 gene modulate the effect of IFN-ß treatment in multiple sclerosis (MS) through regulation of the relationship between IFN-ß and vitamin D. OBJECTIVE: To examine whether WT1 modulates the relationship between IFN-ß and vitamin D in a longitudinal study with repeated assessment of vitamin D before and after initiation of IFN-ß. METHODS: In a prospective study of 85 patients with relapsing remitting MS, 25-hydroxyvitamin D was measured at month 0, 1, 3, 6, 7, 9, 12, 18 and 24. None of the patients used any immunomodulatory treatment at inclusion, and all started IFN-ß treatment at month 6. RESULTS: The mean concentrations of seasonally adjusted 25-hydroxyvitamin increased slightly (3.1 ± 1.2 nmol/l, P = 0.008) after initiation of IFN-ß. The association between IFN-ß treatment and 25-hydroxyvitamin D was similar in patients carrying any of the two alleles in the WT1 SNPs (rs10767935 and rs5030244) recently reported to modulate this relationship. CONCLUSIONS: In this prospective study with repeated measurements of 25-hydroxyvitamin D before and during treatment with IFN-ß, we did not find that genetic variation in WT1 plays any role in regulating the relationship between IFN-ß and serum 25-hydroxyvitamin D.

Time trends in the incidence and prevalence of multiple sclerosis in Norway during eight decades.

Norway has been subjected to numerous epidemiological investigations on the prevalence and incidence of multiple sclerosis (MS), dating back to 1935. The objective of this study was to review the studies on the prevalence and incidence of MS in Norway, provide an update on the prevalence of MS in Norway, and describe the time trends in the prevalence and incidence of MS in relation to risk factors, case ascertainment, and data. We performed a systematic search on PubMed and MEDLINE up to November 2014 using the search string 'multiple sclerosis prevalence in Norway' or 'multiple sclerosis incidence in Norway'. In addition, we scrutinized the reference lists of the publications identified for relevant citations. We retrieved data on the distribution of MS in Norway on December 31, 2013 from the Norwegian Multiple Sclerosis Registry and Biobank and the Norwegian Patient Registry. We identified 29 articles. From 1961 to 2014, the reported prevalence of MS increased from 20 to 203 per 100,000 inhabitants, and the incidence increased from 1.9 to 8.0 per 100,000. The nationwide crude prevalence in Norway, based on the Norwegian Patient Registry, was 208 per 100,000 on December 31, 2013. The reported prevalence of MS in Norway has increased 10-fold, with several possible causes. During eight decades, neurological health services have generally become more accessible to the population, and transforming diagnostic criteria has made the diagnosis of MS more precise and valid. There have also been changes in lifestyle behavior and known risk factors, such as vitamin D and smoking, that might have contributed to the increased incidence of MS. A possible role of increased survival in MS needs to be examined further.

The Norwegian Multiple Sclerosis Registry and Biobank.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with unknown cause and various benefits from disease modifying therapies. Systematic recording of data into national MS registries is therefore needed to optimize treatment and define the pathogenesis of the disease. The Norwegian MS Registry and Biobank was established for systematic collection of clinical and epidemiological data, as well as biological samples. Data collection is based on informed consent from the individual patients and recordings by treating neurologists. All researchers have, by application, access to data and biological samples from the Norwegian Multiple Sclerosis Registry and Biobank. By this combined effort from both patients and healthcare personnel, the Registry and Biobank aims to facilitate research for improved understanding of disease mechanisms and improved health care in MS.

Health related quality of life in patients recently diagnosed with multiple sclerosis.

OBJECTIVE: To describe a representative population of patients recently diagnosed with MS in terms of both motor and non-motor disability. In particular we wanted to examine the HRQoL in this population to get a better understanding of what impact various clinical features have on the patients' experience of distress in the early phase of the disease. METHODS: Ninety three patients diagnosed with MS in Hordaland and Rogaland county in 1998-2000 and 96 healthy controls were examined through questionnaires on HRQoL (SF-36), depression (Beck's depression inventory), fatigue (fatigue severity scale) and apathy (Starkstein's apathy scale). The patients also underwent neurological examination including the expanded disability status scale and the Multiple Sclerosis Functional Composite, as well as the symbol digit memory test and the selective reminder test. RESULTS: Patients with MS reported a lower HRQoL than the controls with a mean physical health summary score of 57.3 compared to 84.5 (P < 0.001), and a mental health summary score of 66.4 vs 79.2 (P < 0.001). The controls scored significantly higher on all SF-36 sub scores except for bodily pain. The incidence of fatigue was 71% in patients compared to 27% in controls (P < 0.001), whereas 46% of patients vs 18% of controls reported depression (P < 0.001). The mean score for apathy was significantly higher among patients. CONCLUSIONS: Patients with recently diagnosed MS reported significantly lower on both physical and mental aspects of HRQoL compared with controls. Depression, fatigue and apathy were more common and more severe in MS. We found no correlation between cognitive decline and HRQoL scores.

Increasing age of multiple sclerosis onset from 1920 to 2022: a population-based study.

OBJECTIVE: To study the age at onset of relapsing-remitting multiple sclerosis (RRMS) during the past century. METHODS: This is a population-based cohort study of persons diagnosed with RRMS in Hordaland, Møre, and Romsdal counties, Western Norway, from 1920 to 2022. Individual patient data were available and assessed from previously conducted prevalence and incidence studies in addition to hospital records up until October 31, 2022. Participants were categorized according to onset period and analyzed for temporal trends in age at onset, time from onset to diagnosis, and distribution of onset over time. RESULTS: We identified 3364 persons with confirmed RRMS. The mean age at onset significantly increased (p < 0.001) throughout the study period, despite a decrease in time from symptom onset to diagnosis (p < 0.001). The proportion of persons with MS onset after 50 years of age increased from 2.6% before 1970 to 11.9% after 2010. We also found a trend toward a bimodal distribution of age at onset that peaked at around 30 years and 40-45 years of age in the latest period. CONCLUSION: Age at onset of MS significantly increased throughout the study period. This was mainly due to an increasing number of persons with MS, predominantly female, experiencing onset after 40-45 years of age. This bimodal distribution could indicate different susceptibility periods of MS or changes in exposure to risk factors during the observation period.

Modelling and prediction of 25-hydroxyvitamin D levels in Norwegian relapsing-remitting multiple sclerosis patients.

BACKGROUND/AIM: 25-Hydroxyvitamin D (25(OH)D) levels are suggested to influence the susceptibility and risk of disease progression in multiple sclerosis (MS). Seasonal fluctuation of 25(OH)D levels may differ in magnitude between individuals. The purpose of this paper was to model the seasonal fluctuation of vitamin D in Norwegian MS patients and to examine to which extent one single 25(OH)D measurement predicts the level at other time points throughout the year. METHODS: During December 2004 and July 2008, 762 serum samples were collected from 92 Norwegian relapsing-remitting MS patients. Time series analysis and multivariate modelling techniques were used to model seasonal fluctuations and intra- and inter-individual variations in 25(OH)D values. RESULTS: Most patients reached their lowest 25(OH)D level in March/April and the highest in July/August. There were substantial intra-individual variations in the extent of seasonal fluctuation, with 36.6% of explainable variation in seasonally adjusted 25(OH)D levels (on a logarithmic scale) attributable to the patient level. The remaining 63.4% could be accounted for by sources of inter-individual variation. Both the total and inter-individual variabilities were lowest in February, and the prediction interval in this month was up to 26% narrower compared to other months. The prediction intervals would be at least 21% wider with only one observation available per patient. CONCLUSIONS: The seasonal fluctuations of 25(OH)D levels in Norwegian relapsing-remitting MS patients are subject to pronounced intra- and inter-individual variation. The most representative measurements of 25(OH)D levels are taken in February.

Exploring the CLEC16A gene reveals a MS-associated variant with correlation to the relative expression of CLEC16A isoforms in thymus.

Genomewide association studies have implicated the CLEC16A gene in several autoimmune diseases, including multiple sclerosis (MS) and type 1 diabetes. However, the most associated single-nucleotide polymorphism (SNP) varies, and causal variants are still to be defined. In MS, two SNPs in partial linkage disequilibrium with each other, rs6498169 and rs12708716, have been validated at genomewide significance level. To explore the CLEC16A association in MS in more detail, we genotyped 57 SNPs in 807 Norwegian MS patients and 1027 Norwegian controls. Six highly associated SNPs emerged and were then replicated in two large independent sample sets (Norwegian and British), together including 1153 MS trios, 2308 MS patients and 4044 healthy controls. In combined analyses, SNP rs12708716 gave the strongest association signal in MS (P=5.3 x 10⁻8, odds ratio 1.18, 95% confidence interval=1.11-1.25), and was found to be superior to the other SNP associations in conditional logistic regression analyses. Expression analysis revealed that rs12708716 genotype was significantly associated with the relative expression levels of two different CLEC16A transcripts in thymus (P=0.004), but not in blood, possibly implying a thymus- or cell-specific splice regulation.

Fatigue in multiple sclerosis: associations with health-related quality of life and physical performance.

BACKGROUND AND PURPOSE: fatigue is a common, but still one of the least understood symptoms in multiple sclerosis (MS). We aimed to investigate whether fatigue was associated with demographic-, clinical-, health-related quality of life (HRQoL)- and physical performance variables, and whether change in fatigue after treatment was associated with changes in HRQoL and physical performance. METHODS: sixty patients were included for inpatient physiotherapy. Fifty-six patients completed the study and were available for analysis. Fatigue (Fatigue Severity Scale; FSS), HRQoL (Multiple Sclerosis Impact Scale; MSIS-29) and physical performance (walking ability and balance) were assessed at screening, baseline, after treatment and at follow-up after 3 and 6 months. We analysed possible associations between fatigue and other variables at baseline by regression models, and between change in fatigue versus changes in both HRQoL and physical performance variables after physiotherapy by correlation analysis. RESULTS: fatigue at baseline was associated with HRQoL (explained 21.9% of variance), but not with the physical performance tests. Change in fatigue was correlated with change in HRQoL, but not with changes in physical performance. All measures were improved after treatment (P ≤ 0.001). While improvements in fatigue and HRQoL were lost at follow-up, improvements in physical performance tests were maintained for at least 6 months (P ≤ 0.05). CONCLUSIONS: fatigue was associated with HRQoL at baseline. Improvement in fatigue seemed to be related to other factors than improvement in physical performance. A broader strategy including both physical and psychological dimensions seems to be needed to improve fatigue over the long-term.

The influence of warm versus cold climate on the effect of physiotherapy in multiple sclerosis.

OBJECTIVE: To compare the effect of inpatient physiotherapy in a warm versus cold climate in short- and long-term perspectives. METHODS: Sixty multiple sclerosis (MS) patients with gait problems, without heat intolerance, were included in a randomized cross-over study of 4-week inpatient physiotherapy in warm (Spain) and cold (Norway) climate. The primary outcome, 6-min walk test (6MWT), and secondary physical performance and self-reported measures were scored at screening, baseline, after treatment and at 3 and 6 months of follow-up. Treatment effects were analysed by mixed models. RESULTS: After treatment, the mean walking distance had increased by 70 m in Spain and 49 m in Norway (P = 0.060). Improvement in favour of warm climate was demonstrated at 6 months of follow-up, 43 m (Spain) compared to 20 m (Norway) (P = 0.048). The patients reported less exertion after walking (6MWT) in favour of treatment in Spain at all time points (P < 0.05). No significant differences in change were detected for the other physical performance measures. Most self-reported measures showed more improvement after treatment in Spain, but these improvements were not sustained at follow-up. CONCLUSION: The results indicate that MS patients without heat intolerance have additional benefits from physiotherapy in a warm climate.

Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Glatiramer acetate, approved for the treatment of relapsing-remitting multiple sclerosis, reduces relapses and disease activity and burden monitored by MRI. We assessed the efficacy of early treatment with glatiramer acetate in delaying onset of clinically definite multiple sclerosis. METHODS: In this randomised, double-blind trial, undertaken in 80 sites in 16 countries, 481 patients presenting with a clinically isolated syndrome with unifocal manifestation, and two or more T2-weighted brain lesions measuring 6 mm or more, were randomly assigned to receive either subcutaneous glatiramer acetate 20 mg per day (n=243) or placebo (n=238) for up to 36 months, unless they converted to clinically definite multiple sclerosis. The randomisation scheme used SAS-based blocks stratified by centre, and patients and all personnel were masked to treatment assignment. The primary endpoint was time to clinically definite multiple sclerosis, based on a second clinical attack. Analysis was by intention to treat. A preplanned interim analysis was done for data accumulated from 81% of the 3-year study exposure. This study was registered with ClinicalTrials.gov, number NCT00666224. FINDINGS: All randomly assigned participants were analysed for the primary outcome. Glatiramer acetate reduced the risk of developing clinically definite multiple sclerosis by 45% compared with placebo (hazard ratio 0.55, 95% CI 0.40-0.77; p=0.0005). The time for 25% of patients to convert to clinically definite disease was prolonged by 115%, from 336 days for placebo to 722 days for glatiramer acetate. The most common adverse events in the glatiramer acetate group were injection-site reactions (135 [56%] glatiramer acetate vs 56 [24%] placebo) and immediate post-injection reactions (47 [19%] vs 12 [5%]). INTERPRETATION: Early treatment with glatiramer acetate is efficacious in delaying conversion to clinically definite multiple sclerosis in patients presenting with clinically isolated syndrome and brain lesions detected by MRI. FUNDING: Teva Pharmaceutical Industries, Israel.

Norwegian Sami differs significantly from other Norwegians according to their HLA profile.

This study reports extensive genomic data for both human leukocyte antigen (HLA) class I and II loci in Norwegian Sami, a native population living in the northwest of Europe. The Sami have a distinct culture and their own languages, which belong to the Uralic linguistic family. Norwegian Sami (n = 200) were typed at the DNA level for the HLA-A, -C, -B, -DRB1 and -DQB1 loci, and compared with a non-Sami Norwegian population (n = 576). The two populations exhibited some common genetic features but also differed significantly at all HLA loci. The most significantly deviating allele frequencies were an increase of HLA-A*03, -B*27, -DRB1*08 and -DQB1*04 and a decrease of HLA-A*01, C*01, -DRB1*04 and -DQB1*02 among Sami compared with non-Sami Norwegians. The Sami showed no deviation from Hardy-Weinberg equilibrium. The hypothesis of selective neutrality was rejected at all loci except for the A- and C- loci for the Sami. HLA haplotype frequencies also differed between the two populations. The most common extended HLA haplotypes were A*02-B*27-C*01-DR*08-DQB1*04 in the Sami and A*01-B*08-C*07-DR*03-DQB1*02 in the other Norwegians. Genetic distance analyses indicated that the Norwegian Sami were highly differentiated from other Europeans and were most closely related to Finns whose language also belongs to the Uralic linguistic family. In conclusion, the Norwegian Sami and the non-Sami Norwegians were significantly different at all HLA loci. Our results can be explained by the fact that the two populations have different origins and that the Sami population has remained smaller and more isolated than its neighbors.

Coping with multiple sclerosis: a 5-year follow-up study.

OBJECTIVES: To examine how coping styles among patients with multiple sclerosis (MS) change over time and how patients' coping styles after 5 years are associated with disability pension. MATERIALS AND METHODS: Seventy-six MS patients and 94 healthy controls were included in this study. The patients were examined at baseline and 5 years later. This included a neurological examination and information on disability pension and a questionnaire assessing coping (the COPE scale). Controls were registered at baseline only. RESULTS: Compared to healthy controls, MS patients were more passive in coping with disease related distress. This was even more pronounced 5 years later. Disability pensioned patients employed more social support, venting of emotions and behavioural disengagement at follow-up. CONCLUSION: This study shows that patients with MS employ coping styles that may be inadequate and this is not improved by adaption over time. Although patients also use strategies to enhance their lives, these findings suggest that there may be a potential for improving the lives of patients with MS through interventions that may enhance adequate coping with the disease.

Psychometric properties of a Norwegian version of Multiple Sclerosis Impact Scale (MSIS-29).

OBJECTIVES: To examine psychometric properties of Multiple Sclerosis Impact Scale (MSIS-29) for use in Norwegian patients with multiple sclerosis. METHODS: Translation was performed according to international guidelines. The questionnaire was answered by 64 patients prior to and at a screening session, and re-answered by 59 patients before and after 4 weeks of physiotherapy. RESULTS: Internal consistency (α) was 0.92 for the physical and 0.85 for the psychological subscales. Reliability by intraclass correlation coefficients were 0.86 for the physical and 0.81 for the psychological subscales, smallest detectable change being 18.4 and 21.1, respectively. The physical but not the psychological subscale demonstrated mostly satisfactory associations with other physical measures. Responsiveness by area under the receiver operating characteristics curve was 0.83 and 0.76, respectively. As hypothesized, effect size was larger for the physical (1.01) than for the psychological (0.76) subscale after treatment. CONCLUSIONS: MSIS-29, Norwegian Version demonstrated satisfactory psychometric properties.

A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes.

Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six different autoimmune diseases, that is autoimmune Addison's disease (n=333), type 1 diabetes (n=1086), multiple sclerosis (n=502), rheumatoid arthritis (n=945), systemic lupus erythematosus (n=156) and juvenile idiopathic arthritis (n=505), against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the coding SNP rs12150220 revealed significant association with autoimmune Addison's disease compared with controls (OR=1.25, 95% CI: 1.06-1.49, P=0.007), and with type 1 diabetes (OR=1.15, 95% CI: 1.04-1.27, P=0.005). Trends toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious, multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases.