Multiple sclerosis (MS) is an inflammatory and neurodegenerative demyelinating disease of the central nervous system (CNS), most likely autoimmune in origin, usually beginning in early adulthood. The ...aetiology of the disease is not well understood; it is viewed currently as a multifactorial disease which results from complex interactions between genetic predisposition and environmental factors, of which a few are potentially modifiable. Improving our understanding of these factors can lead to new and more effective approaches to patient counselling and, possibly, prevention and management of the disease. The 2016 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) addressed the topic of environmental, modifiable risk factors for MS, gathering experts from around the world, to collate experimental and clinical research into environmental factors that have been associated with the disease onset and, in a few cases, disease activity and progression. A number of factors, including infections, vitamin D deficiency, diet and lifestyle factors, stress and comorbidities, were discussed. The meeting provided a forum to analyse available evidence, to identify inconsistencies and gaps in current knowledge and to suggest avenues for future research.
Abstract
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.
Abstract
Background
Our study aims to investigate an intrinsic link underlying sex hormone-binding globulin (SHBG) and rheumatoid arthritis (RA), which remains inconclusive in observational settings.
...Methods
Summary statistics were collected from the largest GWAS(s) on SHBG adjusted for BMI (SHBG
adj
BMI;
N
overall
= 368,929;
N
men
= 180,094;
N
women
= 188,908), crude SHBG (
N
overall
= 370,125;
N
men
= 180,726;
N
women
= 189,473), and RA (
N
case
= 22,350;
N
control
= 74,823). A genome-wide cross-trait design was performed to quantify global and local genetic correlation, identify pleiotropic loci, and infer a causal relationship.
Results
Among the overall population, a significant global genetic correlation was observed for SHBG
adj
BMI and RA (
$$r_{{\text{g}}}$$
r
g
= 0.11,
P
= 1.0 × 10
−4
) which was further supported by local signal (1q25.2). A total of 18 independent pleiotropic SNPs were identified, of which three were highly likely causal variants and four were found to have effects on both traits through gene expression mediation. A putative causal association of SHBG
adj
BMI on RA was demonstrated (OR = 1.20, 95% CI = 1.01–1.43) without evidence of reverse causality (OR = 0.999, 95% CI = 0.997–1.000). Sex-specific analyses revealed distinct shared genetic regions (men: 1q32.1-q32.2 and 5p13.1; women: 1q25.2 and 22q11.21-q11.22) and diverse pleiotropic SNPs (16 in men and 18 in women, nearly half were sex-specific) underlying SHBG
adj
BMI and RA, demonstrating biological disparities between sexes. Replacing SHBG
adj
BMI with crude SHBG, a largely similar yet less significant pattern of results was observed.
Conclusion
Our cross-trait analysis suggests an intrinsic, as well as a sex-specific, link underlying SHBG and RA, providing novel insights into disease etiology.
Elevated levels of anti-EBNA-1 antibodies and infectious mononucleosis (IM) history have consistently been associated with multiple sclerosis (MS) risk. We aimed to study whether these aspects of ...Epstein-Barr virus (EBV) infection represent separate risk factors for MS and whether they both interact with MS-associated HLA genes in disease development.
Two Swedish-population-based case-control studies were used, comprising 5,316 cases and 5,431 matched controls. Subjects with different HLA alleles, EBNA-1, and IM status were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Causal mediation analysis was used to assess to what extent the relationship between IM history and MS risk was mediated by high anti-EBNA-1 antibody levels and vice versa.
The causal mediation analysis revealed that both aspects of EBV infection mainly act directly on MS risk. The direct effect of elevated anti-EBNA-1 antibody levels on MS risk, expressed on the OR scale, was 2.8 (95% CI 2.5-3.1), and the direct effect of IM history on MS risk was 1.7 (95% CI 1.5-2.0). A significant interaction between the two aspects of EBV infection was observed (RERI 1.2, 95% CI 0.3-2.0), accounting for about 50% of the total effect. Further, both aspects of EBV infection interacted with DRB1
15:01 and absence of A
02:01.
Elevated anti-EBNA-1 antibody levels and IM history are different risk factors for MS. The two aspects of EBV infection act synergistically to increase MS risk, indicating that they partly are involved in the same biological pathways.
Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune ...response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
Objective
To investigate potential associations between dietary intake of polyunsaturated fatty acids (FAs) and pain patterns in early rheumatoid arthritis (RA) patients after 3 months of ...methotrexate (MTX) treatment.
Methods
We included 591 early RA patients with MTX monotherapy from a population‐based prospective case–control study, the Epidemiological Investigation of Rheumatoid Arthritis. Dietary data on polyunsaturated FAs (food frequency questionnaires) were linked with data on unacceptable pain (visual analog scale VAS >40 mm), noninflammatory/refractory pain (VAS >40 mm and C‐reactive protein CRP level <10 mg/liter), and inflammatory pain (VAS >40 mm and CRP level >10 mg/liter) after 3 months. Statistical analysis included logistic regression.
Results
After 3 months of MTX treatment, 125 patients (21.2%) had unacceptable pain, of which 92 patients had refractory pain, and 33 patients had inflammatory pain. Omega‐3 FA intake was inversely associated with unacceptable pain and refractory pain (odds ratio OR 0.57 95% confidence interval (95% CI) 0.35–0.95 and OR 0.47 95% CI 0.26–0.84, respectively). The omega‐6:omega‐3 FA ratio, but not omega‐6 FA alone, was directly associated with unacceptable pain and refractory pain (OR 1.70 95% CI 1.03–2.82 and OR 2.33 95% CI 1.28–4.24, respectively). Furthermore, polyunsaturated FAs were not associated with either inflammatory pain or CRP level and erythrocyte sedimentation rate at followup. Omega‐3 FA supplementation was not associated with any pain patterns.
Conclusion
Omega‐3 FA was inversely associated with, and the omega‐6:omega‐3 FA ratio was directly associated with, unacceptable and refractory pain, but not with inflammatory pain or systemic inflammation. The inverse association between omega‐3 FA and refractory pain may have a role in pain suppression in RA.
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.
Cigarette smoking is an established environmental risk factor for Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease, although a mechanistic basis remains largely unknown. ...We aimed at investigating how smoking affects blood DNA methylation in MS patients, by assaying genome-wide DNA methylation and comparing smokers, former smokers and never smokers in two Swedish cohorts, differing for known MS risk factors. Smoking affects DNA methylation genome-wide significantly, an exposure-response relationship exists and the time since smoking cessation affects methylation levels. The results also show that the changes were larger in the cohort bearing the major genetic risk factors for MS (female sex and HLA risk haplotypes). Furthermore, CpG sites mapping to genes with known genetic or functional role in the disease are differentially methylated by smoking. Modeling of the methylation levels for a CpG site in the AHRR gene indicates that MS modifies the effect of smoking on methylation changes, by significantly interacting with the effect of smoking load. Alongside, we report that the gene expression of AHRR increased in MS patients after smoking. Our results suggest that epigenetic modifications may reveal the link between a modifiable risk factor and the pathogenetic mechanisms.
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disorder of the brain and spinal cord in which focal lymphocytic infiltration leads to the damage of myelin and axons. As a ...multi-factorial complex trait, both genetic background and environmental factors are involved in MS etiology. The disease is more prevalent among women, and an overall female-to-male sex ratio of around 3 is usually reported. The fact that the female preponderance is only apparent among patients with disease onset after age 12 points toward a role of puberty in MS. A key marker of female pubertal development is menarche, however, evidence from previous epidemiological investigations has been sparse and conflicting: although some studies have linked earlier age at menarche (AAM) to an increased risk of MS, others have found no association or an inverse association. Understanding the effect of AAM in MS could increase our knowledge to the disease etiology, as well as deliver meaningful implication to patients' care by aiding clinical diagnosis. Therefore, we reviewed all the currently available epidemiological studies conducted for AAM and
in
. We found evidence supporting a possible favorable role of late AAM on MS risk, but this should be further confirmed by well-designed large-scale epidemiological studies and meta-analysis. Future work may be focused on Mendelian randomization analysis incorporating genetic markers to provide additional evidence of a putative causal relationship between AAM and MS. More work should be conducted for non-European populations to increase generalizability, and among the males to complementary with results from females. Future work may also be conducted focusing on hormonal reproductive factors other than menarche, and their effects in MS prognosis, severity, and drug response.
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