Risk of Autoimmune Disease: Challenges for Immunotoxicity Testing

BackgroundStudies have demonstrated elevated risk for autoimmune disease associated with perinatal mental illness, but the extent to which this risk is specific to mental illness arising perinatally, and not mental illness generally, is unknown. Our objective was to compare the risk of autoimmune disease in women with mental illness arising within the perinatal period to (1) women with mental illness arising outside the perinatal period and (2) women who did not develop mental illness.MethodsWe conducted a population-based matched cohort study of women aged 15–49 years with no history of mental illness or autoimmune disease in Ontario, Canada, 1998–2018. The exposed, 60,701 women with mental illness arising between conception and 365 days postpartum were propensity score-matched to (1) 264,864 women with mental illness arising non-perinatally and (2) 469,164 women who did not develop mental illness. Hazard ratios (HR) for autoimmune disease were generated using Cox proportional hazards models.ResultsThe incidence of autoimmune disease was similar among women with mental illness arising perinatally compared to those with mental illness arising non-perinatally (138.4 vs 140.7 per 100,000 person-years; HR 0.98, 95% CI 0.92–1.05), and elevated among women with mental illness arising perinatally compared to those who did not develop mental illness (138.4 vs 88.9 per 100,000 person-years; HR 1.54, 95% CI 1.44–1.64). The HR for the latter comparison was more pronounced for autoimmune disease with brain-reactive antibodies than other autoimmune disease.ConclusionPerinatal mental illness is associated with increased risk of autoimmune disease that is no different than that of mental illness arising non-perinatally. Women with mental illness, regardless of the timing of onset, could benefit from early detection of autoimmune disease.

ObjectiveTo evaluate the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and risk of autoimmune rheumatic diseases in adults with type 2 diabetes.DesignRetrospective cohort study.SettingNationwide healthcare database in South Korea, 2012-22.Participants2 032 157 adults aged ≥18 years with type 2 diabetes: 552 065 initiated SGLT-2 inhibitors and 1 480 092 initiated sulfonylureas.Main outcome measuresThe primary outcome was autoimmune rheumatic disease, defined using a validated algorithm incorporating diagnostic codes and registration in a disease specific nationwide programme. Secondary outcomes were individual types of autoimmune rheumatic diseases, including inflammatory arthritis and connective tissue diseases. Genital infections and herpes zoster were used as positive and negative control outcomes, respectively, to evaluate residual confounding. Hazard ratios and rate differences per 100 000 person years were estimated after normalised inverse probability treatment weighting based on propensity score.ResultsAfter propensity score weighting, 1 030 088 initiators of SGLT-2 inhibitors (mean age 58.5 years; 59.9% men) and 1 002 069 initiators of sulfonylurea (mean age 58.5 years; 60.1% men) were included in the analysis. The weighted incidence rate per 100 000 person years was 51.90 and 58.41 in individuals initiating SGLT-2 inhibitors and sulfonylureas, respectively. Over a median of nine months’ follow-up, SGLT-2 inhibitors were associated with an 11% lower risk of incident autoimmune rheumatic diseases compared with sulfonylureas (hazard ratio 0.89 (95% confidence interval (CI) 0.81 to 0.98); rate difference −6.50 (95% CI −11.86 to −1.14) per 100 000 person years). Findings were overall consistent among subgroups stratified by age, sex, type of SGLT-2 inhibitor, baseline cardiovascular disease, and obesity status. The hazard ratios for the control outcomes were 2.78 (2.72 to 2.83) for genital infections and 1.03 (1.01 to 1.05) for herpes zoster.ConclusionsIn this large cohort of adults with type 2 diabetes, SGLT-2 inhibitors were associated with an 11% lower risk of autoimmune rheumatic diseases compared with sulfonylureas. These results suggest that SGLT-2 inhibitors may contribute to reducing the risk of autoimmune diseases. This potential benefit, however, should be carefully weighed against known adverse events and concerns about tolerability. Replication in other populations and settings, as well as studies in patients with existing autoimmune rheumatic diseases, are warranted to confirm and extend these observations.

Fetal microchimerism is the study of persisting fetal cells in the mother years after pregnancy and the purported implications for her health and longevity. Due to the association between pregnancy and autoimmune disease (AID), and the preponderance of these diseases in women, laboratory studies have for years attempted to link microchimeric fetal cells with the onset of AID after pregnancy. This new study gave us the opportunity to examine for the first time if this theory could be proven clinically in a large cohort of women. By examining whether different types of delivery affected the onset of AID, we also aimed to indirectly relate this finding to fetal microchimerism. The results did suggest an association between pregnancy and the risk of subsequent maternal AID, with increased risks noted after caesarean section (CS) and decreased risks after abortion. This is the first epidemiological study on the risk of AID following pregnancy.

An immunologic component to schizophrenia and depression has been increasingly recognized, which has led to extensive research into the associations with infections and autoimmune diseases. Large-scale nationwide epidemiological studies have displayed an increased prevalence of both autoimmune diseases and infections among persons with schizophrenia and depression. Autoimmune diseases, and especially the number of infections requiring hospitalization, increase the risk of schizophrenia and depression in a dose–response relationship. Infections are a common exposure and a broad spectrum of infections are associated with schizophrenia and depression. Particularly the autoimmune diseases with a potential presence of brain-reactive antibodies were associated with psychiatric disorders. However, the associations seem to be bidirectional, since the risk of autoimmune diseases and infections is also increased after diagnosis with schizophrenia and depression. The risk of autoimmune diseases was particularly increased in individuals with prior hospital contacts for infections.It has been suggested that inflammation and autoimmunity could be involved in the etiology and pathogenesis of some patients with symptoms of schizophrenia and depression. The psychiatric symptoms can be directly triggered by immune components, such as brain-reactive antibodies and cytokines, or infections reaching the central nervous system (CNS), or be secondary to systemic inflammation indirectly affecting the brain. However, the associations could also be caused by shared genetic factors, other environmental factors, or common etiological components. Nonetheless, autoimmune diseases and infections should be considered by clinicians in the treatment of individuals with psychiatric symptoms, since treatment would probably improve the psychiatric symptoms, quality of life, and the survival of the individuals.

Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study

Fetal microchimerism is the study of persisting fetal cells in the mother years after pregnancy and the purported implications for her health and longevity. Due to the association between pregnancy and autoimmune disease (AID), and the preponderance of these diseases in women, laboratory studies have for years attempted to link microchimeric fetal cells with the onset of AID after pregnancy. This new study gave us the opportunity to examine for the first time if this theory could be proven clinically in a large cohort of women. By examining whether different types of delivery affected the onset of AID, we also aimed to indirectly relate this finding to fetal microchimerism. The results did suggest an association between pregnancy and the risk of subsequent maternal AID, with increased risks noted after caesarean section (CS) and decreased risks after abortion. This is the first epidemiological study on the risk of AID following pregnancy.

A small number of cancer patients respond exceptionally well to therapies and survive significantly longer than patients with similar diagnoses. Profiling the germline genetic backgrounds of exceptional responder (ER) patients, with extreme survival times, can yield insights into the germline polymorphisms that influence response to therapy. As ERs showed a high incidence in autoimmune diseases, we hypothesized the differences in autoimmune disease risk could reflect the immune background of ERs and contribute to better cancer treatment responses. We analyzed the germline variants of 51 ERs using polygenic risk score (PRS) analysis. Compared to typical cancer patients, the ERs had significantly elevated PRSs for several autoimmune-related diseases: type 1 diabetes, hypothyroidism, and psoriasis. This indicates that an increased genetic predisposition towards these autoimmune diseases is more prevalent among the ERs. In contrast, ERs had significantly lower PRSs for developing inflammatory bowel disease. The left-skew of type 1 diabetes score was significant for exceptional responders. Variants on genes involved in the T1D PRS model associated with cancer drug response are more likely to co-occur with other variants among ERs. In conclusion, ERs exhibited different risks for autoimmune diseases compared to typical cancer patients, which suggests that changes in a patient’s immune set point or immune surveillance specificity could be a potential mechanistic link to their exceptional response. These findings expand upon previous research on immune checkpoint inhibitor-treated patients to include those who received chemotherapy or radiotherapy.

Autoimmune diseases have been little studied in gay men and lesbians. We followed 4.4 million Danes, including 9,615 same-sex married (SSM) persons, for 47 autoimmune diseases in the National Patient Registry between 1989 and 2008. Poisson regression analyses provided first hospitalization rate ratios (RRs) comparing rates between SSM individuals and persons in other marital status categories. SSM individuals experienced no unusual overall risk of autoimmune diseases. However, the risk of autoimmune thyroid dysfunction was increased, notably Hashimoto's thyroiditis (women(SSM), RR = 2.92; 95% confidence interval (CI) 1.74-4.55) and Graves' disease (men(SSM), RR = 1.88; 95% CI 1.08-3.01). There was also an excess of primary biliary cirrhosis (women(SSM), RR = 4.09; 95% CI 1.01-10.7), and of psoriasis (men(SSM), RR = 2.48; 95% CI 1.77-3.36), rheumatic fever (men(SSM), RR = 7.55; 95% CI 1.87-19.8), myasthenia gravis (men(SSM), RR = 5.51; 95% CI 1.36-14.4), localized scleroderma (men(SSM), RR = 7.16; 95% CI 1.18-22.6) and pemphigoid (men(SSM), RR = 6.56; 95% CI 1.08-20.6), while Dupuytren's contracture was reduced (men(SSM), RR = 0.64; 95% CI 0.39-0.99). The excess of psoriasis was restricted to same-sex married men with HIV/AIDS (men(SSM), RR = 10.5; 95% CI 6.44-15.9), whereas Graves' disease occurred in excess only among same-sex married men without HIV/AIDS (men(SSM), RR = 1.99; 95% CI 1.12-3.22). Lesbians and immunologically competent gay men in same-sex marriage face no unusual overall risk of autoimmune diseases. However, the observed increased risk of thyroid dysfunction in these lesbians and gay men deserves further study.

IntroductionMyasthenia gravis (MG) is clinically heterogeneous and can be life-threatening if bulbar or respiratory muscles are involved. However, relative contributions of genetic, shared, and nonshared environmental factors to MG susceptibility remain unclear. The aim of this study was to examine the familial aggregation and heritability of MG and the relative risks (RRs) of other autoimmune diseases in the relatives of patients with MG.MethodsA population-based family study using the Taiwan National Health Insurance (NHI) Database was conducted. Participants included all individuals (N=23,422,955) who were actively registered in the NHI Database in 2013, 15,066 of whom had at least one first-degree relative with MG. We identified 8,638 parent–child relationships, 3,279 with an affected offspring, 3,134 with affected siblings, and 26 with affected twins. Prevalence and RRs of MG and other autoimmune diseases in the relatives of patients as well as the relative contributions of heritability, shared, and nonshared environmental factors to MG susceptibility were measured.ResultsRRs (95% confidence intervals [CIs]) for MG were 17.85 (8.71–36.56) for patients’ siblings, 5.33 (2.79–10.18) for parents, 5.82 (3.03–11.16) for offspring, and 1.42 (0.20–10.10) for spouses without genetic similarities. RRs (95% CIs) in individuals with a first-degree relative with MG were 2.18 (1.53–3.12) for systemic lupus erythematosus, 1.73 (1.09–2.74) for primary Sjögren’s syndrome, 1.90 (1.66–2.18) for autoimmune thyroid disease, and 1.68 (1.22–2.30) for rheumatoid arthritis. Accountability for the phenotypic variance of MG was 82.1% for familial transmission and 17.9% for nonshared environmental factors.ConclusionIndividual risks of MG and other autoimmune diseases are increased in the relatives of patients with MG. Familial transmission of MG was estimated to be 82.1%.

Human papillomavirus vaccination and risk of autoimmune diseases: A large cohort study of over 2million young girls in France.

Increased risk of autoimmune diseases in dengue patients: A population-based cohort study

Free AccessObstructive Sleep ApneaObstructive Sleep Apnea and Autoimmune Disease: A Two-Way Process Aibek E. Mirrakhimov, M.D., Erkin M. Mirrakhimov, M.D., Ph.D. Aibek E. Mirrakhimov, M.D. Address correspondence to: Aibek E. Mirrakhimov, Saint Joseph Hospital, Department of Internal Medicine, 2900 N. Lake Shore, Chicago, IL 60657(773) 665-3022(773) 665-3384 E-mail Address: [email protected] Saint Joseph Hospital, Department of Internal Medicine, Chicago, IL Search for more papers by this author , Erkin M. Mirrakhimov, M.D., Ph.D. Kyrgyz State Medical Academy, Bishkek, Kyrgyzstan Search for more papers by this author Published Online:April 15, 2013https://doi.org/10.5664/jcsm.2604SectionsPDF ShareShare onFacebookTwitterLinkedInRedditEmail ToolsAdd to favoritesDownload CitationsTrack Citations AboutINTRODUCTIONWe read with a keen interest the article published by Walsh et al.1 These researchers analyzed 63 subjects with ankylosing spondylitis (SpA) and found that patients using TNF-inhibitors were less likely to have obstructive sleep apnea (OSA). Moreover, a non-statistically significant trend toward an improvement of OSA severity was found. The authors speculated regarding potential mechanisms responsible for this clinical observation such as more frequent corticosteroid use, cervical spine abnormalities and systemic inflammation. We are grateful to authors for studying this important problem. Nevertheless, we believe that some aspects merit attention.Loubaki et al. showed that upper airways (UA) of patients with OSA have a greater expression of TNF-α, which may lead to UA inflammation and greater collapsibility.2 Walsh et al.1 discussed that both OSA and SpA share systemic inflammation as a pathophysiologic feature. On the other hand, a research group from Taiwan showed that OSA increases the risk for the incidence of autoimmune diseases in a prospective epidemiological studies.3,4 It is interesting to speculate that OSA related increase in TNF-α may initiate the disease in susceptible individuals. Therefore, OSA may be not only the consequence of autoimmune rheumatic disease, but also as a risk factor for their occurrence. Future studies should address whether OSA treatment would have an impact on reduction of rheumatic disease incidenceDISCLOSURE STATEMENTThe authors have indicated no financial conflicts of interest.CITATIONMirrakhimov AE; Mirrakhimov EM. Obstructive sleep apnea and autoimmune disease: a two-way process. J Clin Sleep Med 2013;9(4):409.REFERENCES1 Walsh JA, Duffi n KC, Crim Jet al.Lower frequency of obstructive sleep apnea in spondyloarthritis patients taking TNF-inhibitors. J Clin Sleep Med; 2012;8:643-8, 23243397. LinkGoogle Scholar2 Loubaki L, Jacques E, Semlali Aet al.Tumor necrosis factor-alpha expression in uvular tissues differs between snorers and apneic patients. Chest; 2008;134:911-8, 18689593. CrossrefGoogle Scholar3 Kang JH, Lin HCObstructive sleep apnea and the risk of autoimmune diseases: a longitudinal population-based study. Sleep Med; 2012;13:583-8, 22521311. CrossrefGoogle Scholar4 Yang YW, Kang JH, Lin HCIncreased risk of psoriasis following obstructive sleep apnea: a longitudinal population-based study. Sleep Med; 2012;13:285-9, 22285106. CrossrefGoogle Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 09 • Issue 04 • April 15, 2013ISSN (print): 1550-9389ISSN (online): 1550-9397Frequency: Monthly Metrics History Submitted for publicationJanuary 1, 2013Accepted for publicationJanuary 1, 2013Published onlineApril 15, 2013 Information© 2013 American Academy of Sleep MedicinePDF download

Type 1 diabetes mellitus (T1D) results from autoimmune destruction of pancreatic β cells. T1D individuals face increased risk of autoimmune thyroid disease (AITD) and celiac disease (CD). While most patients present with β-cell autoantibodies, 5-10 % do not and are classified as antibody-negative T1D (AB- T1D). Whether autoimmune disease risk differs between AB- and antibody-positive T1D (AB+ T1D) remains uncertain. Children aged 6months to 18years diagnosed with T1D between January 2010 and June 2023 were reviewed and categorized as AB+ or AB- based on islet cell antigen, insulin, and GAD-65 autoantibodies at diagnosis. Each AB- patient was matched with two age- and sex-matched AB+ controls within the diagnosis date. Chi-square testing compared CD and AITD prevalence between groups, with significance set p<0.05. The study included 149 AB- and 298 AB+ subjects. CD prevalence was 5.0 % in the AB+ group and 3.4 % in the AB- group. AITD prevalence was 4.4 % in the AB+ group and 2.7 % in the AB- group. No significant differences were identified. A combined diagnosis of CD and AITD occurred only in the AB+ group (2.2 %, p=0.024). At diagnosis, AB+ patients had higher glucose and beta-hydroxybutyrate levels and lower C-peptide, while venous pHwas similar. AITD and CD prevalence did not differ significantly between AB- and AB+ children with T1D, though coexistence of both conditions occurred only in AB+ patients. These findings suggest that AB- T1D may still involve autoimmunity and support similar surveillance strategies for autoimmune diseases in both groups.

Treatment with biologic pharmaceuticals may be associated with an increased risk of immune-mediated disease. Palivizumab is a humanized monoclonal antibody designed to provide passive immunity against respiratory syncytial virus infection. Palivizumab is primarily used in preterm children known to be immunologically immature. The long-term effect of palivizumab in terms of autoimmune diseases has not yet been investigated. Our objective was to investigate whether exposure to palivizumab was associated with the development of autoimmune diseases in children. This was a population-based cohort study including data from 769,523 Danish children born between 1 January 1999 and 31 December 2010 and data from 581,742 Swedish children born between 1 July 2005 and 31 December 2010. Of the 1,351,265 children included, 1192 (0.09 %) were exposed to palivizumab. Nine cases of autoimmune disease were diagnosed among palivizumab-exposed children during the period of observation. Among the children exposed to palivizumab, one child in Denmark developed inflammatory bowel disease; in Sweden, children developed juvenile arthritis (one child), diabetes mellitus (two children), celiac disease (four children), and inflammatory bowel disease (one child). The risk of autoimmune disease was not significantly increased after palivizumab exposure (hazard ratio adjusted for age and country: 1.54; 95 % confidence interval 0.80-2.95). The risk of autoimmune disease was not increased after palivizumab exposure. Given the small number of incident cases of autoimmune disease observed, this finding should be interpreted with caution.

Constitutional structural chromosomal rearrangements (CSCRs) have facilitated the identification of genes associated with early-onset monogenic disorders and, more recently, genes associated with common and late-onset disorders. In an attempt to find genetic clues to their etiologies, we studied the risk of autoimmune diseases in a Danish cohort of CSCR carriers. We followed up 4,866 CSCR carriers over 71,230 person-years (1980 through 2004) for autoimmune diseases recorded in the Danish Hospital Discharge Register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95% CIs) served as measures of the relative risk. To identify possible candidate loci for autoimmune diseases, the reported chromosomal breakpoints and deletions in CSCR carriers who developed autoimmune diseases were compared with previously suggested loci for these diseases. The overall risk of any autoimmune disease among CSCR carriers was inconspicuous (SIR 1.2 [95% CI 0.95-1.5]; n = 74 cases observed versus 61.3 expected), but carriers of rearrangements involving chromosomes 2, 19, and 21 were at significantly increased risk. For the specific autoimmune diseases studied, cohort members were at significantly increased risk of Dupuytren's contracture, pernicious anemia, and juvenile rheumatoid arthritis (JRA). Sixteen carriers who developed an autoimmune disease had a chromosomal breakpoint or deletion coinciding with a previously suggested locus, including deletions 18p11, 18q22, and 22q11 associated with JRA. CSCR carriers do not have a generalized predisposition to autoimmune diseases. However, we confirmed a number of reported susceptibility loci for JRA, and we suggest new susceptibility loci on chromosomes 5 and 11 for Dupuytren's contracture, and 19p13 as a possible shared susceptibility locus for a range of autoimmune diseases.