Medically unexplained symptoms are common in women in tertiary neurological healthcare center: A survey cohort study of persons investigated for suspected multiple sclerosis.

BACKGROUND: A significant proportion of individuals with suspicious onset of multiple sclerosis (MS) does not fulfill the diagnostic criteria. Although some receive other diagnoses, many remain undiagnosed and lack healthcare follow-up. This study aimed to characterize persons with undetermined diagnosis (PwUD) through a questionnaire. METHODS: Incident cases with suspected MS were consecutively admitted to a tertiary neurological healthcare center in a prospective cohort study. Those who remained undiagnosed after 40 months (mean, range 31-52) were considered PwUD. They completed a modified questionnaire, previously used in a population-based case-control study of incident MS cases. Their responses were compared with two control cohorts, persons with MS (PwMS) and healthy controls, randomly selected from national registries, matched by age, gender, and area of residence. RESULTS: Out of 271 patients with suspected MS onset, 72 (20.3%) were PwUD with a female majority (79%). The response rate was 83% and 39% reported persisting MS-like symptoms. Compared to controls (n = 548) and PwMS (n = 277), fewer PwUD were currently smoking (p = .4 and p = .03), consumed less alcohol (p = .04 and p = .01), and had children (p = .02 and p = .002). PwUD reported occurrence of other autoimmune disease in 29%, higher compared to PwMS and controls (p < .001 and p < .001). CONCLUSIONS: UD is common among persons investigated for suspected MS, in particular among female parents. Our data suggest that PwUD can be characterized as nonsmokers with low alcohol consumption and a higher prevalence of autoimmune disease, in particular thyroid disease.

Risk factors for multiple sclerosis in the context of Epstein-Barr virus infection.

Compelling evidence indicates that Epstein Barr virus (EBV) infection is a prerequisite for multiple sclerosis (MS). The disease may arise from a complex interplay between latent EBV infection, genetic predisposition, and various environmental and lifestyle factors that negatively affect immune control of the infection. Evidence of gene-environment interactions and epigenetic modifications triggered by environmental factors in genetically susceptible individuals supports this view. This review gives a short introduction to EBV and host immunity and discusses evidence indicating EBV as a prerequisite for MS. The role of genetic and environmental risk factors, and their interactions, in MS pathogenesis is reviewed and put in the context of EBV infection. Finally, possible preventive measures are discussed based on the findings presented.

Treatment Options for Epstein-Barr Virus-Related Disorders of the Central Nervous System.

Epstein-Barr virus (EBV), a causative agent for several types of lymphomas and mucosal cancers, is a human lymphotropic herpesvirus with the capacity to establish lifelong latent infection. More than 90% of the human population worldwide is infected. The primary infection is usually asymptomatic in childhood, whereas infectious mononucleosis (IM) is common when the infection occurs in adolescence. Primary EBV infection, with or without IM, or reactivation of latent infection in immunocompromised individuals have been associated with a wide range of neurologic conditions, such as encephalitis, meningitis, acute disseminated encephalomyelitis, and cerebellitis. EBV is also involved in malignant lymphomas in the brain. An increasing number of reports on EBV-related disorders of the central nervous system (CNS) including the convincing association with multiple sclerosis (MS) have put in focus EBV-related conditions beyond its established link to malignancies. In this review, we present the clinical manifestations of EBV-related CNS-disorders, put them in the context of known EBV biology and focus on available treatment options and future therapeutic approaches.

Inverse association between Mediterranean diet and risk of multiple sclerosis.

OBJECTIVE: There is some evidence implicating diet in the development of inflammatory diseases. We aimed to study the influence of dietary habits on the risk of developing multiple sclerosis (MS). METHODS: We used a population-based case-control study recruiting incident cases of MS (1953 cases, 3557 controls). Subjects with different dietary habits 5 years prior to MS diagnosis were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Adjustment was made for a large number of environmental and lifestyle habits, including ancestry, smoking, alcohol consumption, body mass index, physical activity, and sun exposure habits. RESULTS: Mediterranean diet was associated with lower risk of developing MS (adjusted OR = 0.54, 95% CI: 0.34-0.86, p = 0.009), compared with Western-style diet. There was no significant association between vegetarian/vegan diet and MS risk (adjusted OR = 0.96, 95% CI: 0.75-1.24, p = 0.976), nor between diet with low glycemic index and MS risk (adjusted OR = 0.93, 95% CI: 0.60-1.42, p = 0.518). CONCLUSIONS: Mediterranean diet may exert a protective influence regarding the risk of subsequently developing MS compared with Western-style diet.

Influence of oral tobacco versus smoking on multiple sclerosis disease activity and progression.

We aimed to study the influence of smoking habits, exposure to passive smoking and snuff use on disease progression, cognitive performance and quality of life in patients with multiple sclerosis (MS). METHOD: Patients from two population-based case-control studies were categorised based on tobacco exposure at diagnosis and were followed up to 15 years post diagnosis through the Swedish MS registry (n=9089) regarding changes in Expanded Disability Status Scale (EDSS), Multiple Sclerosis Impact Scale 29 and Symbol Digit Modalities Test. We used linear mixed models to analyse long-term changes, and Cox regression models with 95% CI using 24-week confirmed disability worsening, reaching EDSS 3 and EDSS 4, respectively, physical and psychological worsening and cognitive disability worsening as end points. The influence of smoking cessation post diagnosis was also investigated. RESULTS: Compared with non-smokers, current smokers had a faster EDSS progression (ßcurrent smoking×time=0.03, 95% CI 0.02 to 0.04). A faster EDSS progression was also associated with passive smoking (ßcurrent passive smoking×time=0.04, 95% CI 0.03 to 0.06). Smoke exposure negatively impacted all secondary outcomes. Those who continued smoking had worse outcomes than those who stopped smoking post diagnosis. Snuff users had a more favourable EDSS progression, compared with never users. CONCLUSIONS: Our findings indicate that both smoking and passive smoking have a negative influence on MS and that smoking cessation post diagnosis may be an important secondary preventive measure. Snuff use was associated with slower disease progression, suggesting that nicotine replacement therapy could be an attractive way to increase the chance of quitting smoking among patients with MS.

Observed associations between indicators of socioeconomic status and risk of multiple sclerosis in Sweden are explained by a few lifestyle-related factors.

BACKGROUND AND PURPOSE: The association between socioeconomic status (SES) and the risk of multiple sclerosis (MS) is unclear. The aim was to study whether a potential association between indicators of SES and MS risk in Sweden is explained by lifestyle/environmental factors. METHODS: Using the Swedish MS registry and the Swedish patient registries, a register study was performed comprising all cases diagnosed with MS in Sweden between 1990 and 2018 (N = 24,729) and five randomly selected controls per case, matched by year and age at disease onset, sex and residential area at disease onset. Data from two matched case-control studies combined comprising data on environment/lifestyle factors (7193 cases, 9609 controls, inclusion period 2005-2018) were also utilized. For all participants, information regarding ancestry, formal education (available 1990-2018) and family income (available 1998-2018) was retrieved from the National Board of Health and Welfare. RESULTS: The registry study revealed no association between education and MS risk, whereas an income exceeding the upper quartile was associated with lower MS risk compared to having an income in the lowest quartile (odds ratio 0.86, 95% confidence interval 0.82-0.90). These findings were replicated in the crude analyses of the case-control study. However, after adjustment for confounding, no association was observed between income and risk of MS. CONCLUSIONS: Education and income were not associated with occurrence of MS after adjustment for a few lifestyle-related factors (smoking, alcohol consumption, body mass index and sun exposure habits), indicating that SES has no influence on MS risk besides its association with these lifestyle factors in the Swedish context.

Association between exposure to combustion-related air pollution and multiple sclerosis risk.

BACKGROUND: Smoking and occupational pulmonary irritants contribute to multiple sclerosis (MS) development. We aimed to study the association between ambient air pollution and MS risk and potential interaction with the human leukocyte antigen (HLA)-DRB1*15:01 allele. METHODS: Exposure to combustion-related air pollution was estimated as outdoor levels of nitrogen oxides (NOx) at the participants' residence locations, by spatially resolved dispersion modelling for the years 1990-18. Using two population-based case-control studies (6635 cases, 8880 controls), NOx levels were associated with MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) using logistic regression models. Interaction between high NOx levels and the HLA-DRB1*15:01 allele regarding MS risk was calculated by the attributable proportion due to interaction (AP). In addition, a register study was performed comprising all MS cases in Sweden who had received their diagnosis between 1993 and 2018 (n = 22 173), with 10 controls per case randomly selected from the National Population register. RESULTS: Residential air pollution was associated with MS risk. NOx levels (3-year average) exceeding the 90th percentile (24.6 µg/m3) were associated with an OR of 1.37 (95% CI 1.10-1.76) compared with levels below the 25th percentile (5.9 µg/m3), with a trend of increasing risk of MS with increasing levels of NOx (P <0.0001). A synergistic effect was observed between high NOx levels (exceeding the lower quartile among controls) and the HLA-DRB1*15:01 allele regarding MS risk (AP 0.26, 95% CI 0.13-0.29). CONCLUSIONS: Our findings indicate that moderate levels of combustion-related ambient air pollution may play a role in MS development.

Influence of Smoking on Disease Activity and Quality of Life in Patients With Rheumatoid Arthritis: Results From a Swedish Case-Control Study With Longitudinal Follow-Up.

OBJECTIVE: Inconclusive findings have been reported regarding the influence of smoking on disease outcomes in established rheumatoid arthritis (RA). This study was undertaken to investigate the influence of smoking habits on disease activity and health-related quality of life (HRQoL) in RA patients. METHODS: Patients with newly diagnosed RA (n = 1,531) from the population-based case-control Epidemiological Investigation of Rheumatoid Arthritis study were followed up for up to 3 years after recruitment. Using logistic regression models, the risks of unfavorable outcomes in patients with different smoking habits were compared using self-reported swollen and tender joint counts, the Short Form 36 health survey, the Health Assessment Questionnaire, and the Hospital Anxiety and Depression Scale by calculating odds ratios with 95% confidence intervals. RESULTS: At 1-year and 3-year follow-up, current smokers reported higher disease activity and lower HRQoL life compared to non-smokers, regarding both physical and mental aspects. Patients who stopped smoking within 1-year post-baseline had less disease activity measured as swollen joint counts at 1-year follow-up compared to those who continued smoking. Patients who stopped smoking after the 1-year follow-up had higher disease activity and lower HRQoL at baseline than smokers who did not quit, and late smoking cessation was not associated with more favorable outcomes compared to continued smoking. CONCLUSION: Current smoking is associated with increased disease activity and lower HRQoL among RA patients. Smoking cessation within the first year after baseline appears to have a favorable effect on disease activity.

Neither low social support nor low decision latitude at work is associated with disease remission among patients with rheumatoid arthritis: results from the Swedish EIRA study.

OBJECTIVES: To investigate the association between psychosocial vulnerability, defined as either low social support or low decision latitude at work, and disease remission at 3, 12, and 60 months in patients with rheumatoid arthritis (RA). METHODS: This cohort study included all patients enrolled in both the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA) 1996-2015 and the Swedish Rheumatology Quality Register (SRQ, n = 2820). Information on social support and decision latitude at work at RA diagnosis were identified from the EIRA questionnaire. Indexes for levels of social support and decision latitude at work, respectively, were calculated based on the questionnaire. Low social support and low decision latitude at work, respectively, were identified by a score in the lowest quartile and compared with the three other quartiles (not low). Disease-activity parameters were retrieved from SRQ at 3, 12, and 60 months. The associations between social support or decision latitude at work, respectively, and Disease Activity Score 28 joint count with C-reactive protein (DAS28-CRP) remission were analysed using logistic regression models adjusted for age, sex, smoking habits, alcohol habits, symptom duration, and educational level. RESULTS: Having low social support (n = 591) was not associated with DAS28-CRP remission at 3 (OR 0.93, 95% CI 0.74-1.16), 12 (OR 0.96, 95%CI 0.75-1.23), or 60 (OR 0.89, 95%CI 0.72-1.10) months compared to not low social support (n = 2209). No association was observed for low (n = 212) versus not low (n = 635) decision latitude at work and DAS28-CRP remission at 3 (OR 0.84, 95%CI 0.54-1.31), 12 (OR 0.81, 95%CI 0.56-1.16), or 60 (OR 1.37, 95%CI 0.94-2.01) months. CONCLUSION: In a country with general access to healthcare, psychosocial vulnerability does not influence the likelihood of achieving remission in early RA.

High antibody levels against human herpesvirus-6A interact with lifestyle factors in multiple sclerosis development.

BACKGROUND: Infection with human herpesvirus 6A (HHV-6A) has been suggested to increase multiple sclerosis (MS) risk. However, potential interactions between HHV-6A and environmental/lifestyle risk factors for MS have not previously been studied. METHODS: We used two Swedish population-based case-control studies comprising 5993 cases and 5995 controls. Using logistic regression models, subjects with different HHV-6A antibody levels, environmental exposures, and lifestyle habits were compared regarding MS risk, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). Potential interactions between high HHV-6A antibody levels and common environmental exposures and lifestyle factors were evaluated on the additive scale. RESULTS: High HHV-6A antibody levels were associated with increased risk of developing MS (OR = 1.5, 95% CI = 1.4-1.6). Regarding MS risk, significant interactions were observed between high HHV-6A antibody levels and both smoking (attributable proportion (AP) = 0.2, 95% CI = 0.1-0.3), low ultraviolet radiation (UVR) exposure (AP = 0.3, 95% CI = 0.1-0.4), and low vitamin D levels (AP = 0.3, 95% CI = 0.0-0.6). CONCLUSION: High HHV-6A antibody levels are associated with increased MS risk and act synergistically with common environmental/lifestyle risk factors for MS. Further research is needed to investigate potential mechanisms underlying the interactions presented in this study.

The increased risk of multiple sclerosis associated with HLA-DRB1*15:01 and smoking is modified by alcohol consumption.

Previous studies have observed an inverse association between alcohol consumption and multiple sclerosis (MS) risk. We aimed to investigate possible interactions between alcohol consumption, MS-associated human leukocyte antigen (HLA) genes and smoking regarding MS risk. We used a Swedish population-based case-control study (2059 incident cases, 2887 controls) matched by age, sex, and residential area. Subjects with different genotypes and alcohol consumption habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals using logistic regression models. Interaction on the additive scale between non-drinking and both genotype and smoking were assessed by calculating the attributable proportion due to interaction (AP). There was a dose-dependent inverse association between alcohol consumption and MS risk (p for trend < 0.0001). A potentiating effect was observed between non-drinking and presence of DRB1*15:01 (AP 0.3, 95% CI 0.2-0.5) which was of similar magnitude irrespective of smoking habits. Non-drinking also interacted with smoking to increase MS risk (AP 0.2, 95% CI 0.06-0.4). Non-drinking interacts with DRB1*15:01 and smoking to increase the risk of MS. Better understanding of the mechanisms behind our findings may help to define ways to achieve protection against MS by other means than alcohol consumption.

Low sun exposure acts synergistically with high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels in multiple sclerosis etiology.

BACKGROUND: Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA-1 antibody levels regarding MS risk. METHODS: We used a population-based case-control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA-1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). RESULTS: Low sun exposure acted synergistically with high EBNA-1 antibody levels (AP 0.2, 95% CI 0.03-0.3) in its association to increased MS risk. The interaction was present regardless of HLA-DRB1*15:01 status. CONCLUSIONS: Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.

Factors affecting the risk of relapsing-onset and progressive-onset multiple sclerosis.

OBJECTIVE: It has been debated whether the different clinical disease courses in multiple sclerosis (MS) are the consequence of different pathogenic mechanisms, with distinct risk factors, or if all MS clinical phenotypes are variations of similar underlying disease mechanisms. We aimed to study environmental risk factors and their interactions with human leucocyte antigen DRB1*15:01 with regards to relapsing-onset and progressive-onset MS. METHODS: We used two Swedish population-based case-control studies, including 7520 relapsing-onset cases, 540 progressive-onset cases and 11 386 controls matched by age, sex and residential area. Logistic regression was used to estimate ORs with 95% CIs for associations between the different MS phenotypes and a number of environmental and lifestyle factors. Interaction between the DRB1*15:01 allele and environmental risk factors was evaluated on the additive scale. RESULTS: All environmental and lifestyle factors associated with risk of developing MS apply to both relapsing-onset and progressive-onset disease. Smoking, obesity and Epstein-Barr virus nuclear antigen-1 (EBNA-1) antibody levels were associated with increased risk of both MS phenotypes, whereas snuff use, alcohol consumption and sun exposure were associated with reduced risk. Additive interactions between DRB1*15:01 and smoking, obesity, EBNA-1 antibody levels and sun exposure, respectively, occurred to increase MS risk regardless of the clinical phenotype. INTERPRETATION: Our finding that the same environmental and lifestyle factors affect both relapsing-onset and progressive-onset MS supports the notion that the different clinical phenotypes share common underlying disease mechanisms.

DRB1-environment interactions in multiple sclerosis etiology: results from two Swedish case-control studies.

OBJECTIVE: We aimed to investigate the influence of environmental risk factors for multiple sclerosis (MS) in different genetic contexts, and study if interactions between environmental factors and human leucocyte antigen (HLA) genes differ in magnitude according to heterozygocity and homozygocity for HLA-DRB1*15:01. METHODS: Using population-based case-control studies (6985 cases, 6569 controls), subjects with different genotypes and smoking, EBNA-1 status and adolescent Body Mass status, were compared regarding MS risk, by calculating OR with 95% CI employing logistic regression. The interaction between different genotypes and each environmental factor was evaluated on the additive scale. RESULTS: The effect of each DRB1*15:01 allele on MS risk was additive on the log-odds scale for each additional allele. Interaction between DRB1*15:01 and each assessed environmental factor was of similar magnitude regardless of the number of DRB1*15:01 alleles, although ORs were affected. When any of the environmental factors were present in DRB1*15:01 carriers without the protective A*02:01 allele, a three-way interaction occurred and rendered high ORs, especially among DRB1*15:01 homozygotes (OR 20.0, 95% CI 13.1 to 30.5 among smokers, OR 21.9, 95% CI 15.0 to 31.8 among those with elevated EBNA-1 antibody levels, and OR 44.3, 95% CI 13.5 to 145 among those who reported adolescent overweight/obesity). CONCLUSIONS: The strikingly increased MS risk among DRB*15:01 homozygotes exposed to any of the environmental factors is a further argument in favour of these factors acting on immune-related mechanisms. The data further reinforce the importance of preventive measures, in particular for those with a genetic susceptibility to MS.

Effects of alcohol consumption and smoking on risk for RA: results from a Swedish prospective cohort study.

OBJECTIVE: Several, but not all studies, have shown a dose-dependent inverse association with alcohol consumption and rheumatoid arthritis (RA), whereas smoking is an established risk factor for RA. We aimed to study the association between alcohol consumption and RA incidence and investigate a potential interaction between alcohol and smoking habits, regarding RA incidence. METHODS: We used a prospective cohort study, based on 41 068 participants with detailed assessment of alcohol intake, smoking and potential confounders at baseline in 1997. We ascertained a total of 577 incident cases of RA during a mean of 17.7 years of follow-up through linkage to nationwide and essentially complete databases. Multivariate Cox proportional hazards models were used to estimate HR with 95% CI. Interaction on the additive scale between alcohol and smoking was estimated by calculating the attributable proportion due to interaction (AP). RESULTS: Overall, alcohol consumption was associated with a 30% reduced incidence of RA (HR 0.69, 95% CI 0.55 to 0.86) with a dose-response relationship (p value for trend <0.001) which remained significant after stratification by age and smoking habits. The positive association between smoking and RA incidence was reduced with increasing alcohol consumption (p value for trend <0.001). A synergistic effect was observed between alcohol and smoking (AP 0.40, 95% CI 0.15 to 0.64), indicating that 40% of the cases among the double exposed are due to the interaction per se. CONCLUSIONS: Our findings suggest an inverse association between alcohol consumption and RA incidence, and a synergistic effect between alcohol and smoking.

Cotinine as a measure of smoking in observational studies of multiple sclerosis.

Studies using cotinine levels to define smokers have generally failed to detect an association between smoking and multiple sclerosis (MS). Using a Swedish population-based case-control study, we show that associations in relation to MS risk and progression differ considerably depending on how smoking is measured. The risk of conversion into secondary progressive disease was increased among smokers when self-reported smoking history, but not presumed cotinine levels, was used to define smokers. Defining smoking by cotinine levels without distinguishing between different sources of nicotine may lead to severely biased estimates of the association between smoking and both MS risk and progression.

Presence of autoantibodies in "seronegative" rheumatoid arthritis associates with classical risk factors and high disease activity.

BACKGROUND: Rheumatoid arthritis (RA) is classified as seropositive or seronegative, depending on the presence/absence of rheumatoid factor (RF), primarily IgM RF, and/or anti-citrullinated protein antibodies (ACPA), commonly detected using anti-cyclic citrullinated peptide (CCP) assays. Known risk factors associate with the more severe seropositive form of RA; less is known about seronegative RA. Here, we examine risk factors and clinical phenotypes in relation to presence of autoantibodies in the RA subset that is traditionally defined as seronegative. METHODS: Anti-CCP2 IgG, 19 ACPA fine-specificities, IgM/IgG/IgA RF, anti-carbamylated-protein (CarP) antibodies, and 17 other autoantibodies, were analysed in 2755 RA patients and 370 controls. Antibody prevalence, levels, and co-occurrence were examined, and associations with risk factors and disease activity during 5 years were investigated for different antibody-defined RA subsets. RESULTS: Autoantibodies were detected in a substantial proportion of the traditionally defined seronegative RA subset, with ACPA fine-specificities found in 30%, IgA/IgG RF in 9.4%, and anti-CarP antibodies in 16%, with a 9.6% co-occurrence of at least two types of RA-associated autoantibodies. HLA-DRB1 shared epitope (SE) associated with the presence of ACPA in anti-CCP2-negative RA; in anti-CCP2-positive RA, the SE association was defined by six ACPA fine-specificities with high co-occurrence. Smoking associated with RF, but not with ACPA, in anti-CCP2-negative RA. Presence of ACPA and RF, but not anti-CarP antibodies, in conventionally defined "seronegative" RA, associated with worse clinical outcome. CONCLUSIONS: "Seronegative" RA is not truly a seronegative disease subset. Additional screening for ACPA fine-specificities and IgA/IgG RF defines a group of patients that resembles seropositive patients with respect to risk factors and clinical picture and may contribute to earlier diagnosis for a subset of anti-CCP2-/IgM RF- patients with a high need for active treatment.

Smoking and Epstein-Barr virus infection in multiple sclerosis development.

It is unclear whether smoking interacts with different aspects of Epstein-Barr virus (EBV) infection with regard to multiple sclerosis (MS) risk. We aimed to investigate whether smoking acts synergistically with elevated EBNA-1 antibody levels or infectious mononucleosis (IM) history regarding MS risk. Two Swedish population-based case-control studies were used (6,340 cases and 6,219 matched controls). Subjects with different smoking, EBNA-1 and IM status were compared regarding MS risk, by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Current and past smokers had higher EBNA-1 antibody levels than never smokers (p < 0.0001). There was an additive interaction between current smoking and high EBNA-1 antibody levels (AP 0.3, 95% CI 0.2-0.4), but not between past smoking and high EBNA-1 antibody levels (AP 0.01, 95% CI - 0.1 to 0.1), with regard to MS risk. An interaction also occurred between current smoking and IM history (AP 0.2, 95% CI 0.004-0.4), but not between past smoking and IM history (AP - 0.06, 95% CI - 0.4 to 0.3). Current smoking increases EBNA-1 antibody levels and acts synergistically with both aspects of EBV infection to increase MS risk, indicating that there is at least one pathway to disease in which both risk factors are involved.

The influence of human leukocyte antigen-DRB1*15:01 and its interaction with smoking in MS development is dependent on DQA1*01:01 status.

BACKGROUND: HLA-DRB1*15:01, absence of HLA-A*02:01, and smoking interact to increase multiple sclerosis (MS) risk. OBJECTIVE: To analyze whether MS-associated human leukocyte antigen (HLA) alleles, apart from DRB1*15:01 and absence of A*02:01, interact with smoking in MS development, and to explore whether the established HLA-smoking interaction is affected by the DQA1*01:01 allele, which confers a protective effect only in the presence of DRB1*15:01. METHODS: In two Swedish population-based case-control studies (5838 cases, 5412 controls), subjects with different genotypes and smoking habits were compared regarding MS risk, by calculating odds ratios with 95% confidence intervals employing logistic regression. Interaction on the additive scale between different genotypes and smoking was evaluated. RESULTS: The DRB1*08:01 allele interacted with smoking to increase MS risk. The interaction between DRB1*15:01 and both the absence of A*02:01 and smoking was confined to DQA1*01:01 negative subjects, whereas no interactions occurred among DQA1*01:01 positive subjects. CONCLUSION: Multifaceted interactions take place between different class II alleles and smoking in MS development. The influence of DRB1*15:01 and its interaction with the absence of A*02:01 and smoking is dependent on DQA1*01:01 status which may be due to differences in the responding T-cell repertoires.