Concomitant autoimmunity and risk of multiple sclerosis disability worsening.

BACKGROUND: Few studies have examined the effect of concomitant autoimmune diseases on multiple sclerosis (MS) disability worsening. We set out to examine whether concomitant Crohn's Disease (CD), Ulcerative Colitis (UC), or Type 1 Diabetes (T1D) affect MS disability worsening in a nationwide cohort of MS patients as defined by reaching expanded disability scale status (EDSS) scores 3.0, 4.0 and 6.0. METHODS: Patients with MS onset between January 2004 and January 2019 were identified from the Swedish MS registry and the Swedish National Patient Register. Kaplan-Meier analysis was used to estimate the median time to reach sustained disability milestones. Adjusted Cox proportional hazard regression models were used to calculate the risk of reaching disability milestones among persons with and without CD, UC, or T1D. RESULTS: Out of 8972 persons with MS, 88 (1.0 %) had T1D, 47 (0.8 %) had UC, and 78 (0.9 %) had CD. There was a significantly higher risk of disability progression, for persons with MS and T1D for reaching EDSS 6.0, hazard ratio (HR) = 2.21 (95 % confidence interval (CI) = 1.48 -3.31) and persons with MS and comorbid CD for reaching EDSS 3.0, HR = 2.30 (95 %CI = 1.74-3.04) and 4.0, HR = 1.59 (95 %CI = 1.09-2.32), and persons with MS and comorbid UC for reaching EDSS 3.0 HR = 1.57 (95 %CI = 1.15-2.14). As defined by Charlson's comorbidity index, the co-existence of other co-morbidities conferred a significant increase in the risk of reaching all endpoints, with HR ranging from 1.23 to 1.62. CONCLUSION: Comorbidity is associated with a significantly increased risk of reaching disability end-points, and T1D, CD, and UC increase the risk further. Thus, there appears to be a need for increased vigilance of comorbidites in persons with MS in order to optimise the long-term outcome of MS.

The CLARION study: first report on safety findings in patients newly initiating treatment with cladribine tablets or fingolimod for multiple sclerosis.

OBJECTIVES: As part of the CLARION study: (1) characterize the incidence of severe infections, herpes zoster, and malignancies in patients newly initiating cladribine or fingolimod for relapsing multiple sclerosis (MS); (2) estimate the incidence of severe lymphopenia among cladribine users; and (3) describe prior/subsequent disease-modifying therapy (DMT) in both cohorts. METHODS: Patients were identified from seven participating MS registries/data sources. The incidence rate (IR) of each outcome per 1000 patient-years and its 95% confidence interval (95%CI) were estimated for cohorts using Poisson regression. RESULTS: By cut-off date (01-April-2020), 742 cladribine and 867 fingolimod users were included. Mean follow-up was ∼1 year. The IR for severe infections from all contributing sources (except Denmark) was: cladribine, 7.37 (2.76,19.6); fingolimod, 6.55 (2.46,17.4). The corresponding IR for herpes zoster was 5.51 (1.78,17.1) and 3.27 (0.82,13.1), respectively, while values for opportunistic infections were 0 (0,6.76) and 1.63 (0.23,11.6), respectively. There were no events of progressive multifocal leukoencephalopathy in either cohort. The IR of severe lymphopenia was 63.9 (40.7,100.1) in 349 cladribine users from contributing sources. The IR of malignancies (cut-off date 01-April-2022) was 3.55 (1.59,7.90) for the cladribine cohort (n = 1035) and 3.55 (1.48,8.52) for the fingolimod cohort (n = 843) from three MS registries/data sources. In the combined data sources, 36.8% of cladribine and 27.4% of fingolimod users were DMT-naïve; after initiation of study treatment, 2.5% and 20.2% switched to another DMT, respectively. CONCLUSION: No new safety signal was observed in patients treated with cladribine tablets, although results are limited by a relatively short duration of follow-up.

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.

Smoking Attributable Risk in Multiple Sclerosis.

Tobacco smoke is an important modifiable environmental risk factor for multiple sclerosis (MS) risk. The population attributable fraction (AF) of MS due to smoking can be used to assess the contribution of smoking to the risk of MS development. We conducted a matched case-control study, including individuals with MS and population-based controls. Overall, sex- and genetic risk score-stratified AF due to smoking were calculated by fitting logistic regression models. We included 9,419 individuals with MS and 9,419 population-based matched controls. At the time of MS onset 44.1% of persons with MS and 35.9% of controls ever regularly smoked of which 38.1% and 29.2% were still smoking. The overall AF was 13.1% (95%CI: 10.7 to 15.4). The AF was 10.6% (95%CI: 7.4 to 13.7) in females and 19.1% (95%CI: 13.1 to 25.1) in males. The AF was 0.6% (95%CI: 0.0 to 2) in ex-smokers. In those having human leucocyte antigen (HLA) and non-HLA risk scores above the median levels of controls, the AF was 11.4% (95%CI: 6.8 to 15.9) and 12% (95%CI: 7.7 to 16.3), respectively. The AF was 17.6% (95%CI: 10.2 to 24.9) and 18.6% (95%CI: 5.5 to 31.6) in those with HLA and non-HLA risk scores below the median levels in controls, respectively. We noticed a decline in AF in recent birth cohorts. This study indicates that at least 13% of cases of MS could be prevented through the avoidance of tobacco smoking. Considering the prevalence of MS, this represents a very large group of people in absolute number.

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.

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.

Bariatric and metabolic surgery in patients with morbid obesity and multiple sclerosis - a nationwide, matched cohort study.

BACKGROUND: Despite an association between obesity and multiple sclerosis (MS), very little is known regarding the safety and efficacy outcomes for patients with MS and severe obesity undergoing metabolic surgery. OBJECTIVES: The aim of the present study was to evaluate early complications and efficacy outcomes of metabolic surgery in patients with severe obesity and MS. SETTING: Nationwide, Sweden. METHODS: In this, matched cohort study, 196 patients with an MS diagnosis in the Swedish MS register who were undergoing metabolic surgery (gastric bypass or sleeve gastrectomy) with a registration in the Scandinavian Obesity Surgery Registry (SOReg) were matched 1:10 with a control group without MS diagnosis from the SOReg. A 2-stage matching procedure was used (exact match by surgical method, followed by propensity Score matching, including age, sex, preoperative BMI, surgical center, surgical access, year of surgery, hypertension, diabetes, sleep apnea, and dyslipidemia). RESULTS: Weight loss at 2 years after surgery was similar for patients with MS and controls (total weight loss 31.6 ± 9.1 versus 31.8 ± 9.2, P = .735). No significant differences were seen in either the overall postoperative complication rate (7.9% versus 7.2%, P = .778), or serious postoperative complications (3.7% versus 2.8%, P = .430). All aspects of health-related quality of life (HRQoL) improved in both groups but less so for the physical aspects of HRQoL in patients with MS. CONCLUSION: Metabolic surgery is a safe and efficient treatment for severe obesity in patients with MS, and it leads to subsequent improvements in HRQoL. Further studies addressing the effects of metabolic surgery on MS-related symptoms are needed.

Cost-of-illness trajectories among people with multiple sclerosis by comorbidity: A register-based prospective study in Sweden.

BACKGROUND: Comorbidities are common among people with multiple sclerosis (PwMS); yet, their impact on the cost-of-illness (COI) in MS is unknown. OBJECTIVE: Explore the heterogeneity in COI trajectories among newly diagnosed PwMS in relation to type of comorbidity. METHODS: A nationwide longitudinal cohort study, using prospectively collected Swedish register data for seven years. The COI/year of 639 PwMS diagnosed in 2006, when aged 25-60, was estimated until 2013. Using healthcare data, PwMS were categorised into six comorbidity groups: ocular; cardiovascular, genitourinary or cancer disease; musculoskeletal; mental; neurological other than MS; and injuries. One group of PwMS without comorbidity was also created. Group-based trajectory modelling was applied, examining different COI trajectories within each comorbidity group. RESULTS: Across the seven follow-up years, PwMS with mental comorbidities had the highest COI overall (€36,482). Four COI trajectories were identified within each comorbidity group; the largest trajectory had high healthcare costs and productivity losses (36.3%-59.6% of PwMS, across all comorbidity groups). 59.6% of PwMS with mental comorbidity had high healthcare costs and productivity losses. CONCLUSION: High COI and heterogeneity in COI trajectories could be partly explained by the presence of chronic comorbidities in the year around MS diagnosis, including the presence of mental comorbidity.

The DQB1*03:02 Genotype and Treatment for Pain in People With and Without Multiple Sclerosis.

Murine models have demonstrated that the major histocompatibility complex (MHC) is associated with pain-like behavior in peripheral nerve injury, however, the same association has not been shown when considering injury to the central nervous system (CNS), which more closely mimics the damage to the CNS experienced by MS patients. Previous research has indicated the DQB1*03:02 allele of the class II HLA genes as being associated with development of neuropathic pain in persons undergoing inguinal hernia surgery or with lumbar spinal disk herniation. Whether this HLA allele plays a part in susceptibility to pain, has not, as far as we are aware, been previously investigated. This study utilizes information on DQB1*03:02 alleles as part of the EIMS, GEMS, and IMSE studies in Sweden. It also uses register data for 3,877 MS patients, and 4,548 matched comparators without MS, to assess whether the DQB1*03:02 allele is associated with prescribed pain medication use, and whether associations with this genotype differ depending on MS status. Our results showed no association between the DQB1*03:02 genotype and pain medication in MS patients, with an adjusted odds ratio (OR) of 1.02 (95% CI 0.85-1.24). In contrast, there was a statistically significant association of low magnitude in individuals without MS [adjusted OR 1.18 (95% CI 1.03-1.35)], which provides support for HLA influence on susceptibility to pain in the general population. Additionally, the effect of zygosity was evident for the non-MS cohort, but not among MS patients, suggesting the DQB1*03:02 allele effect is modified by the presence of MS.

Cigarette smoking patterns preceding primary Sjögren's syndrome.

BACKGROUND: Cigarette smoking is a well-established risk factor for several autoimmune diseases, but its role in primary Sjögren's syndrome (pSS) remains unclear. Here, we investigated the association between cigarette smoking and subsequent development of pSS. METHODS: Information on smoking habits was collected from lifestyle habit questionnaires of patients with pSS (n=815) and a matched control group (n=4425) for a case-control study. Differences in smoking exposure were analysed by conditional logistic regression. Potential interactions between smoking and risk-associated human leucocyte antigens (HLA) were assessed by multivariate regression. RESULTS: The fraction of patients with pSS having ever smoked prior to diagnosis was lower than in controls (OR 0.67, 95% CI 0.55 to 0.81). Current smoking at diagnosis was also less prevalent in cases (OR 0.37, 95% CI 0.26 to 0.53). However, period prevalence of smoking during early adulthood was not statistically different from controls (OR 0.89, 95% CI 0.66 to 1.22) but markedly decreased over time. This was partly due to patients being more prone to stop smoking, starting already 30 years prior to diagnosis (OR 2.01, 95% CI 1.22 to 3.30). Smoking patterns were also stratified by autoantibody status, yielding similar estimates. No interaction effects between HLA-DRB1 haplotypes and smoking were observed. CONCLUSION: The observed smoking patterns indicate that individuals who develop pSS smoke equally much as the general population during early life but are then more prone to stop. The data can be interpreted as smoking conferring protective effects, or reflecting early symptoms of pSS that affect smoking habits, emphasising the slow, progressive development of the disease.

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.

Cancer Risk for Fingolimod, Natalizumab, and Rituximab in Multiple Sclerosis Patients.

OBJECTIVE: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking. METHODS: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer. RESULTS: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84). INTERPRETATION: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. ANN NEUROL 2020;87:688-699.

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.

Molecular mimicry between Anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk.

Multiple sclerosis (MS) is a chronic inflammatory, likely autoimmune disease of the central nervous system with a combination of genetic and environmental risk factors, among which Epstein-Barr virus (EBV) infection is a strong suspect. We have previously identified increased autoantibody levels toward the chloride-channel protein Anoctamin 2 (ANO2) in MS. Here, IgG antibody reactivity toward ANO2 and EBV nuclear antigen 1 (EBNA1) was measured using bead-based multiplex serology in plasma samples from 8,746 MS cases and 7,228 controls. We detected increased anti-ANO2 antibody levels in MS (P = 3.5 × 10-36) with 14.6% of cases and 7.8% of controls being ANO2 seropositive (odds ratio [OR] = 1.6; 95% confidence intervals [95%CI]: 1.5 to 1.8). The MS risk increase in ANO2-seropositive individuals was dramatic when also exposed to 3 known risk factors for MS: HLA-DRB1*15:01 carriage, absence of HLA-A*02:01, and high anti-EBNA1 antibody levels (OR = 24.9; 95%CI: 17.9 to 34.8). Reciprocal blocking experiments with ANO2 and EBNA1 peptides demonstrated antibody cross-reactivity, mapping to ANO2 [aa 140 to 149] and EBNA1 [aa 431 to 440]. HLA gene region was associated with anti-ANO2 antibody levels and HLA-DRB1*04:01 haplotype was negatively associated with ANO2 seropositivity (OR = 0.6; 95%CI: 0.5 to 0.7). Anti-ANO2 antibody levels were not increased in patients from 3 other inflammatory disease cohorts. The HLA influence and the fact that specific IgG production usually needs T cell help provides indirect evidence for a T cell ANO2 autoreactivity in MS. We propose a hypothesis where immune reactivity toward EBNA1 through molecular mimicry with ANO2 contributes to the etiopathogenesis of MS.

Increased Serological Response Against Human Herpesvirus 6A Is Associated With Risk for Multiple Sclerosis.

Human herpesvirus (HHV)-6A or HHV-6B involvement in multiple sclerosis (MS) etiology has remained controversial mainly due to the lack of serological methods that can distinguish the two viruses. A novel multiplex serological assay measuring IgG reactivity against the immediate-early protein 1 from HHV-6A (IE1A) and HHV-6B (IE1B) was used in a MS cohort (8,742 persons with MS and 7,215 matched controls), and a pre-MS cohort (478 individuals and 476 matched controls) to investigate this further. The IgG response against IE1A was positively associated with MS (OR = 1.55, p = 9 × 10-22), and increased risk of future MS (OR = 2.22, p = 2 × 10-5). An interaction was observed between IE1A and Epstein-Barr virus (EBV) antibody responses for MS risk (attributable proportion = 0.24, p = 6 × 10-6). In contrast, the IgG response against IE1B was negatively associated with MS (OR = 0.74, p = 6 × 10-11). The association did not differ between MS subtypes or vary with severity of disease. The genetic control of HHV-6A/B antibody responses were located to the Human Leukocyte Antigen (HLA) region and the strongest association for IE1A was the DRB1*13:01-DQA1*01:03-DQB1*06:03 haplotype while the main association for IE1B was DRB1*13:02-DQA1*01:02-DQB1*06:04. In conclusion a role for HHV-6A in MS etiology is supported by an increased serological response against HHV-6A IE1 protein, an interaction with EBV, and an association to HLA genes.

Association of Pre-Disease Body Mass Index With Multiple Sclerosis Prognosis.

Both high body mass index (BMI) and smoking tobacco are known risk factors for developing multiple sclerosis (MS). However, it is unclear whether BMI, like smoking, is a risk factor for the secondary progressive (SP) course. We, therefore, sought to determine if high/low BMI at age 20 is associated to risk of SP development, in the context of smoking status. Using data from MS patients with BMI and smoking information available, we examined relapsing onset patients with MS onset after 20 years of age. Cox regressions were conducted on smokers and non-smokers, with BMI as the main exposure. In total, 5,598 relapsing onset MS patients were included. The models demonstrated that BMI > 30 was associated to increased risk of SPMS in smokers (hazard ratio 1.50, p = 0.036). This association of obesity at age 20 with increased risk of SP was not observed in non-smokers (hazard rate 0.97, p = 0.900). Since the risk is confined to smokers, the interaction observed may give insight to disease driving mechanisms.

The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement.

Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.