Autoimmunity can be triggered by many environmental factors, among which infectious agents are pivotal. Here, we summarize current knowledge of the relationship between infection and autoimmunity. An ...autoimmune disease can be induced or triggered by infectious agents, which can also determine its clinical manifestations. Most infectious agents, such as viruses, bacteria and parasites, can induce autoimmunity via different mechanisms. In many cases, it is not a single infection but rather the ‘burden of infections’ from childhood that is responsible for the induction of autoimmunity. The development of an autoimmune disease after infection tends to occur in genetically susceptible individuals. By contrast, some infections can protect individuals from specific autoimmune diseases (i.e. the hygiene hypothesis).
Objective
Familial Mediterranean fever (FMF) is refractory to colchicine prophylaxis in 10–20% of patients. In a number of patient series, treatment with anakinra, an interleukin‐1–blocking agent, ...prevented FMF attacks in those with colchicine‐resistant FMF. This study was undertaken to evaluate the efficacy and safety of anakinra in the treatment of colchicine‐resistant FMF, using a randomized controlled trial.
Methods
Patients with colchicine‐resistant FMF receiving colchicine (dosage ≥1.5 to ≤3 mg/day) were recruited and randomly assigned to receive anakinra or placebo (vehicle). The treatment duration was 4 months. Primary efficacy outcomes were the number of attacks per month, and the number of patients with a mean of <1 attack per month. Quality of life was assessed using a 0–10‐grade visual analog scale (VAS), and safety was assessed according to the number and severity of adverse events.
Results
Twenty‐five patients with colchicine‐resistant FMF (14 women) were enrolled, of whom 12 were randomized to receive anakinra and 13 to receive placebo. The mean ± SD number of attacks per patient per month was 1.7 ± 1.7 in those receiving anakinra and 3.5 ± 1.9 in those receiving placebo (P = 0.037). Six patients in the anakinra group, compared to none in the placebo group, had <1 attack per month (P = 0.005). A beneficial effect of anakinra was noted in the number of attacks in the joints per month in patients receiving anakinra (mean ± SD 0.8 ± 1.6 versus 2.1 ± 1.1 in the placebo group; P = 0.019) and in quality of life (mean ± SD VAS score 7.7 ± 2.3 in the anakinra group versus 4.2 ± 2.9 in the placebo group; P = 0.045). The number of adverse events per patient per month was comparable between the anakinra group and the placebo group (mean ± SD 2.03 ± 1.75 versus 3.34 ± 2.5; P = 0.22). There were no severe adverse events.
Conclusion
In this randomized controlled trial, anakinra appears to be an effective and safe treatment for colchicine‐resistant FMF.
Background Diabetes mellitus and impaired glucose metabolism are associated with increased risk for cardiovascular disease (CVD). However, it is still not clear whether glucose levels can predict CVD ...risk among patients without diabetes. The primary aim of this study is to assess whether normoglycemic fasting plasma glucose (FPG) is associated with increased risk of CVD outcomes in healthy patients. Methods We obtained blood measurements, data from physical examination, and medical and lifestyle information from 10,913 men and women who were evaluated in the Institute for Preventive Medicine of Sheba Medical Center. Enrolled were participants with FPG < 100 mg/dL as well as 100 to 125 mg/dL, who were free of diagnosis of CVD. The participants were actively screened for coronary disease using a stress test. Primary end points were coronary heart disease or self-reported cerebral vascular disease. Results A total of 1,119 incident cases of CVD occurred during a mean follow-up of 4.3 years. Subjects with fasting glucose levels in the high normal range (95-99 mg/dL) had an increased CVD risk when compared with levels < 80 mg/dL, (HR 1.53;CI 95% 1.22-1.91, P < .001). A multivariate model, adjusted for age, sex, family history of CVD, blood pressure, body mass index, smoking status, pharmacologic treatment, serum triglycerides, and high-density lipoprotein and low-density lipoprotein cholesterol levels, revealed an independent increased risk of CVD with rising FPG levels in the normal range. Conclusion Elevated CVD risk is strongly and independently associated with glucose levels within the normoglycemic range. Fasting plasma glucose may help in identifying apparently healthy persons with early metabolic abnormalities who are at increased risk for CVD before progression to prediabetes and overt diabetes mellitus.
Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an ...association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, defined as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 ± 1.1 mg/dl for men (n = 6,580) and 4.4 ± 1.1 mg/dl for women (n = 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence interval 1.00 to 1.13) for men (p for interaction = 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations.
Clinical and experimental data support a critical role for inflammation in cardiovascular disease. The purpose of the current study was to examine the relation between an inflammatory marker, ...neutrophil-to-lymphocyte ratio (NLR), and incident atrial fibrillation (AF) in asymptomatic adults. We investigated 21,118 self-referred men and women who were annually screened in a tertiary medical center. All subjects were free of AF at baseline and had their serum NLR calculated at the first annual visit. Subjects were divided into 2 groups based on their baseline NLR: Low (<2.83; n = 17,524) and high (≥2.83; n = 3,594; Upper Sextile). The primary endpoint was new onset AF during follow-up. Mean age of study population was 48 ± 10 years and 72% were men. A total of 563 (2.7%) incident events occurred during an average follow-up of 7.5 ± 5 years. Unadjusted Cox regression analysis demonstrated that each 1 unit increase in NLR was associated with a significant 14% increase in risk of occurrence of a first AF event (95% confidence interval 1.06 to 1.23, p < 0.001) and 20% increased risk of death. Kaplan-Meier's survival analysis showed that the cumulative probability of incident AF was significantly higher among subjects with high NLR compared with low NLR group (p = 0.006). Interaction analysis with adjustment to clinical parameters showed that NLR-related risk was age-dependent, such that in the younger age-group (< =50 years) high NLR group had two folds increased risk for AF event compared with low NLR group (95% confidence interval 1.08 to 3.51; p = 0.027) whereas among older subjects the rate of events was similar between both NLR groups (p = NS; p for interaction = 0.024). In conclusion, our findings suggest that high NLR is associated with increased risk of new onset AF. This finding is more pronounced among young adults.
Abstract Sjögren's syndrome (SS) is an autoimmune disease characterized primarily by lymphocytic infiltration of the exocrine glands, and autoantibody production. Multiple environmental factors ...affecting an individual with a genetic susceptibility may trigger the development of SS. Herein, we aimed to evaluate links between the different pebbles in the mosaic of SS. Demographic, clinical data and blood samples were gathered from 82 consecutive patients with SS, and 139 healthy controls. Samples were analyzed for infectious serology and auto-antibodies as well as for relevant genetic mutations (TAP genes) and cytokines levels. An immune response (IgG) against Epstein–Barr virus (EBV) early antigen (EA) was positively associated with SS (OR 4; 95% CI: 1.82–8.83, p = 0.001) while a protective effect of IgG anti-cytomegalovirus (CMV) was observed (OR 0.3; 95%CI: 0.16–0.74, p = 0.009). Anti-Ro/SSA, anti-LA/SSB, anti-nuclear, anti-gliadin, anti-TTG-IgG and anti-RNP antibodies were statistically more prevalent among SS patients than controls. Notably, the presence of anti-Ro/SSA and anti La/SSB correlated with anti-EBVEA IgG (OR 3.1; 95%CI: 1.08–8.74) and (OR 3.9; 95%CI: 1.37–10.96) respectively. Autoantibodies, cytokines and several genetic markers correlated with clinical manifestation of SS. Our data suggest that infectious agents may play both a causative and protective role in the pathogenesis of SS. Moreover certain autoantibodies, cytokines and specific TAP alleles correlate with clinical manifestations of SS, and may enable better prediction and/or directed therapy once confirmed in future studies.
Idiopathic inflammatory myopathies (IIM) are a rare group of disorders that feature progressive immune-mediated skeletal muscle destruction along with skin, lung, and joint involvement. Management of ...IIMs necessitates glucocorticoid therapy followed by conventional steroid-sparing agents to control disease activity. In the settings of refractory myositis or life-threatening manifestations, e.g. lung involvement or oropharyngeal dysphagia, second-line therapies are needed to minimize disease burden, avoid end-organ damage and steroid toxicity, and decrease mortality. These therapies may include biological disease-modifying antirheumatic drugs (bDMARDs), and to a lesser extent, targeted synthetic disease-modifying antirheumatic drugs (TSD). This article reviews the current use of bDMARDs, e.g. intravenous immunoglobulin and rituximab, and a TSD-Janus kinase inhibitors (JAKI)-along with their indications, efficacy, and safety in managing IIM.
Prolonged steroid treatment has a suppressive effect on the immune system, however, its effect on the cellular response to mRNA vaccine is unknown. Here we assessed the impact of prolonged steroid ...treatment on the T-cell and humoral response to the SARS-CoV-2 spike (S) peptide following the third dose of the BNT162b2 vaccine in systemic autoimmune rheumatic disease patients. We found that CD4 T-cell response to the S peptide in patients on high-dose long-term steroid treatment showed significantly less S-peptide specific response, compare to low-dose or untreated patients. Remarkably, these results were not reflected in their humoral response, since almost all patients in the cohort had sufficient antibody levels. Moreover, S-peptide activation failed to induce significant mRNA levels of IFNγ and TNFα in patients receiving high-dose steroids. RNA-sequencing datasets analysis implies that steroid treatments' inhibitory effect of nuclear factor kappa-B signaling may interfere with the activation of S-specific CD4 T-cells. This reveals that high-dose steroid treatment inhibits T-cell response to the mRNA vaccine, despite having sufficient antibody levels. Since T-cell immunity is a crucial factor in the immune response to viruses, our findings highlight the need for enhancing the efficiency of vaccines in immune-suppressive patients, by modulation of the T-cell response.
Background Increased body mass index (BMI) and obesity are associated with increased risk of new-onset atrial fibrillation (AF) among middle-aged adults. Objectives The objective of the study is to ...investigate the association between BMI and the risk for new-onset AF among middle-aged adults. Methods We investigated 18,290 men and women who were annually screened in a tertiary medical center. Participants were divided at baseline into 3 groups: normal weight (BMI ≥18 and <25 kg/m2 , n = 7,692), overweight (BMI ≥25 and <30 kg/m2 , n = 8,032), and obese (BMI ≥30 kg/m2 , n = 2,566). The primary end point was new-onset AF during follow-up. Results Mean age of study population was 49 ± 11 years, and 73% were men. A total of 288 incident events (1.6%) occurred during 6 ± 4 years. Kaplan-Meier survival analysis showed that the cumulative probability of AF at 6 years was highest among obese participants, intermediate among overweight participants, and lowest among participants with normal weight (2.1%, 1.7%, and 0.8% respectively, P < .001). Multivariable Cox regression analysis showed that overweight and obesity were independently associated with increased AF risk (hazard ratio 1.54 P = .004 and 2.41 P < .001, respectively). Assessment of BMI change as a time-dependent covariate in the multivariable model showed that each 1 kg/m2 reduction in BMI during follow-up was associated with a significant 7% reduction in the risk for the occurrence of a first AF event (hazard ratio 0.93, 95% CI 0.88-0.99, P = .019). Consistently, similar analysis showed that each 5-kg weight loss during follow-up was independently associated with a significant 12% reduced risk of new-onset AF (95% CI 0.81-0.98, P = .02). Conclusions Our findings suggest that overweight and obesity are associated with increased AF risk, whereas weight reduction is independently associated with reduced risk of de novo AF.
Abstract
A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (
...MEFV
) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in
MEFV
as shown by genetic testing performed between 2001 and 2017. We introduced the term ‘origin score’ to capture the dose and different combinations of the grandparents’ origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common
MEFV
variant types and a geographical region. A strong geographic association could arise from positive selection of a specific
MEFV
variant conferring resistance to endemic infectious agents.
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