Systemic Immune-mediated Diseases Research Articles

Genetic Landscape of Patients With Dilated Cardiomyopathy and a Systemic Immune-Mediated Disease.

Systemic immune-mediated diseases (SIDs) are a well-known cause of dilated cardiomyopathy (DCM), a cardiac phenotype influenced by genetic predispositions and environmental factors. This study sought to examine if an underlying genetic predisposition is present in patients with DCM and SID. Genotyped DCM-SID patients (n=183) were enrolled at 3 European centers. Genetic variants were compared with healthy control subjects (n=20,917), DCM patients without SID (n=560), and individuals with a suspicion of an SID (n=1,333). Clinical outcomes included all-cause mortality, heart failure hospitalization, and life-threatening arrhythmias. The SID diagnosis preceded the DCM diagnosis by 4.8months (Q1-Q3:-68.4 to+2.4months). The prevalence of pathogenic/likely pathogenic (P/LP) variants in DCM patients with an SID from the Maastricht cohort was 17.1%, compared with 1.9% in healthy control subjects (P< 0.001). In the Madrid/Trieste cohort, the prevalence was 20.5% (P< 0.001). Truncating variants showed the strongest enrichment (10.7% [OR: 24.5] (Maastricht) and 16% [OR: 116.6 (Madrid/Trieste); both P< 0.001), with truncating TTN (titin) variant (TTNtv) being the most prevalent. Left ventricular ejection fraction at presentation was reduced in TTNtv-SID patients compared with DCM patients with SID without a P/LP (P = 0.016). The presence of a P/LP variant in DCM-SID had no impact on clinical outcomes over a median follow-up of 8.4 years (Q1-Q3: 4.9-12.1 years). One in 6 DCM patients with an SID has an underlying P/LP variant in a DCM-associated gene. This highlights the role of genetic testing in those patients with immune-mediated DCM, and supports the concept that autoimmunity may play a role in unveiling a DCM phenotype in genotype-positive individuals.

Duration of Postvaccination Neutralizing Antibodies to SARS-CoV-2 and Medication Effects: Results from the Safety and Immunogenicity of COVID-19 Vaccination in Systemic Immune-Mediated Inflammatory Diseases Cohort Study.

In the face of the ongoing circulation of SARS-CoV-2, the durability of neutralization post-COVID-19 vaccination in immune-mediated inflammatory disease (IMID) is a key issue, as are the effects of medications. Adults (n = 112) with inflammatory bowel disease, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log-transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild-type and Omicron strains BA.1 and BA.5. Compared with 30 to 120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild-type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron-specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID-19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti-tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses. Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron-specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID-19 immunity.

Long-term efficacy and safety of tailored immunosuppressive therapy in immune-mediated biopsy-proven myocarditis: A propensity-weighted study.

Standardized immunosuppressive therapy (IS) had been previously investigated in biopsy-proven (BP) lymphocytic myocarditis with heart failure (HF). This study evaluated efficacy and safety of tailored IS in BP immune-mediated myocarditis, irrespective of histology and clinical presentation. Consecutive BP myocarditis patients treated with long-term tailored IS on top of optimal medical therapy (OMT), were compared with OMT non-IS controls using propensity-score weighting. The primary outcome was a composite of death or heart transplant, the secondary outcome was a composite of biventricular function, New York Heart Association (NYHA) class variation, and relapse. IS was managed by a multidisciplinary Cardioimmunology Team, involved a safety checklist and active patients' education. Ninety-one IS patients were compared with 267 non-IS patients. IS patients more frequently had systemic immune-mediated diseases (35% vs. 9.7%), lower baseline echocardiographic left ventricular ejection fraction (35% vs. 43%), lower right ventricular fractional area change (34% vs. 41%) and higher frequency of active lymphocytic, eosinophilic and giant cell myocarditis (71% vs. 58%, 12% vs. 1.1%, and 6.6% vs. 1.5%, respectively). At 5-year follow up, no difference was observed in the primary outcome (survival rate 93% in IS vs. 87% in non-IS), but IS patients had a higher relapse rate. Thus, IS patients, with a lower biventricular function and a higher risk profile at baseline, presented similar biventricular function and NYHA class to non-IS patients at follow-up. Minor adverse drug reactions occurred in 13% of patients, all resolved with therapy switch. Prolonged tailored IS is effective and safe in BP immune-mediated myocarditis irrespective of histology and clinical presentation.

When Should I Get My Next COVID-19 Vaccine? Data From the Surveillance of Responses to COVID-19 Vaccines in Systemic Immune-Mediated Inflammatory Diseases (SUCCEED) Study.

To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.

Psoriasis dermatitis, a common phenotype of early forms of both psoriasis and atopic dermatitis in children: A prospective multicenter study.

Psoriasis (Ps) and atopic dermatitis (AD) are chronic systemic immune-mediated diseases that can coexist in an overlapping condition called psoriasis dermatitis (PD). PD patients have intermediate lesions with characteristics of both Ps and AD. PD is very rare in adults but much more frequent in children. Little is known, however,about the course of PD in the pediatric population. The aim of this study was to evaluate the percentage of PD cases in children that evolved to a definite form of Ps or AD and to identify any clinical or epidemiological variables that could predict the course of the disease. We performed a prospective multicenter cohort study of children diagnosed with PD between January 2018 and December 2020. We collected participants' clinical and epidemiological characteristics, and pediatric dermatologists determined the percentage of participants who developed Ps or AD. The study included 24 children with PD, with a median age of 7.0 years. After a median follow-up period of 31 months, 83.3% of cases had evolved to a definite form of Ps or AD (44.4% to Ps and 38.9% to AD). Younger age and family history of Ps were associated with progression to AD. Participants who progressed to AD or Ps had a longer follow-up than those with an unchanged PD diagnosis. Given sufficient time, a large percentage of PD cases in children will evolve into Ps or AD. Long-term clinical follow-up is necessary for a correct diagnosis.

Autophagy differentially regulates tissue tolerance of distinct target organs in graft-versus-host disease models.

Tissue-intrinsic mechanisms that regulate severity of systemic pathogenic immune-mediated diseases, such as acute graft-versus-host disease (GVHD), remain poorly understood. Following allogeneic hematopoietic stem cell transplantation, autophagy, a cellular stress protective response, is induced in host nonhematopoietic cells. To systematically address the role of autophagy in various host nonhematopoietic tissues, both specific classical target organs of acute GVHD (intestines, liver, and skin) and organs conventionally not known to be targets of GVHD (kidneys and heart), we generated mice with organ-specific knockout of autophagy related 5 (ATG5) to specifically and exclusively inhibit autophagy in the specific organs. When compared with wild-type recipients, animals that lacked ATG5 in the gastrointestinal tract or liver showed significantly greater tissue injury and mortality, while autophagy deficiency in the skin, kidneys, or heart did not affect mortality. Treatment with the systemic autophagy inducer sirolimus only partially mitigated GVHD mortality in intestine-specific autophagy-deficient hosts. Deficiency of autophagy increased MHC class I on the target intestinal epithelial cells, resulting in greater susceptibility to damage by alloreactive T cells. Thus, autophagy is a critical cell-intrinsic protective response that promotes tissue tolerance and regulates GVHD severity.

Alterations in intestinal Archaea composition in pediatric patients with Crohn’s disease based on next-generation sequencing – a pilot study

ABSTRACT Intestinal dysbiosis can lead to the induction of systemic immune-mediated inflammatory diseases, such as Crohn’s disease Although archaea are part of the commensal microbiota, they are still one of the least studied microorganisms. The aim of our study was the standardization of the optimal conditions and primers for sequencing of the gut archaeome using Next Generation Sequencing, and evaluation of the differences between the composition of archaea in patients and healthy volunteers, as well as analysis of the changes that occur in the archaeome of patients depending on disease activity. Newly diagnosed patients were characterized by similar archeal profiles at every taxonomic level as in healthy individuals (the dominance of Methanobacteria at the class level, and Methanobrevibacter at the genus level). In turn, in patients previously diagnosed with Crohn’s disease (both in active and remission phase), an increased prevalence of Thermoplasmata, Thermoprotei, Halobacteria (at the class level), and Halococcus, Methanospaera or Picrophilus (at the genus level) were observed. Furthermore, we have found a significant correlation between the patient’s parameters and the individual class or species of Archaea. Our study confirms changes in archaeal composition in pediatric patients with Crohn’s disease, however, only in long-standing disease. At the beginning of the disease, the archeal profile is similar to that of healthy people. However, in the chronic form of the disease, significant differences in the composition of archaeome begin to appear. It seems that some archaea may be a good indicator of the chronicity and activity of Crohn’s disease.

Genetic testing in inflammatory cardiomyopathy/myocarditis: a red flag for cardiomyopathy-like histologic findings

Abstract Background Myocarditis/inflammatory cardiomyopathy is characterized by the presence of an inflammatory infiltrate in the myocardium. Its etiology is heterogeneous, predominantly mediated by viral infection, as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Outcome could vary from a complete recovery to a residual myocardial injury with the subsequent development of dilated cardiomyopathy (DCM). The factors that play a role in the disease progression are not clear, but it has been shown that inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. Purpose To characterize the genetic background of inflammatory cardiomyopathy affected patients to determine the prevalence of pathogenic/likely pathogenic (P/LP) variants in cardiomyopathy-related genes and correlate to histopathologic findings in endomyocardial biopsies (EMB). Methods Eighty-nine myocarditis-affected patients (mean age 43±14, 55 males) underwent genetic screening of 200 genes related to inherited cardiomyopathies. Definite/moderate gene association with DCM and Arrhythmogenic Cardiomyopathy was based on the ClinGen framework. Variant prioritization was carried out using American College of Medical Genetics and Genomics rules. Correlation with histopathologic findings of the endomyocardial biopsy and family history was appraised. Results Twenty of the 89 suspected myocarditis patients (22%) carried a P/LP variant in cardiac-related genes: 8 in Titin, 3 in Myosin Heavy Chain 7, 2 in Desmoplakin, 2 in Lamin A/C; and Troponin T2, Filamin-C, Myosing Binding Protein C3, Desmin and Sodium Voltage-Gated Channel Alpha Subunit 5 carried one variant each. A re-analysis of the EMBs revealed that 82% of patients showed cardiomyopathy-like features at first histologic findings, with fibrosis in the myocardium and DCM-like phenotype at the second EMB. Further, 13 of the genotype-positive patients referred positive family history for cardiomyopathy and/or sudden cardiac death, whereas only 7 genotype-negative patients declared family history, showing a significant difference among both groups (p-value&amp;lt;0,0001). Conclusion The prevalence of P/LP variants in inflammatory cardiomyopathy/myocarditis patients is 22%, most of them associated with DCM. Cardiomyopathy-like features were already observed at the first EMB during the histologic re-evaluation in the majority of genotype-positive patients, and among them, high frequency of positive family history was observed. These findings suggest that genotype-positive inflammatory cardiomyopathy/myocarditis affected patients should be deeply clinically evaluated in order to guarantee an appropriate management for them and their families.

Speckle-tracking global longitudinal strain as a predictor of clinical outcomes in patients with idiopathic inflammatory myopathies

Abstract Background Idiopathic inflammatory myopathies (IIM) are systemic immune-mediated diseases that involve the skeletal muscle and several other organ systems, including the heart. Nonetheless, cardiac involvement in IIM is frequent and initially subclinical. Previous studies have demonstrated how speckle-tracking-derived global longitudinal strain (GLS), as a measurement of the subclinical systolic ventricular dysfunction, is significantly lower in IIM compared to healthy controls. Purpose To assess the progression of myocardial deformation in patients with IIM and test GLS as a prognostic marker of death and cardiovascular events. Methods We enrolled all consecutive patients with a diagnosis of IIM sent to our Cardiology Clinic. The diagnosis of definite idiopathic polymyositis or idiopathic dermatomyositis as made according to the Bohan and Peter criteria and confirmed by muscle biopsy. Patients with inclusion body myositis, necrotizing autoimmune myositis, overlap myositis, and juvenile myositis were excluded from our study. All patients underwent full evaluation, including clinical, ecg and echocardiographic assessment as well as GLS calculation both at baseline and follow up appointments. Primary endpoint was a composite of death and cardiovascular events. Results 41 consecutive patients (28 females, 58±15 years) with IIM were consecutively enrolled and followed up for a median of 8 years (4-11 years). During follow-up, a progressive worsening of LVEF (-4%; p=.03) and left GLS (LGLS: +3%; p=.04) was shown, along with an increase in atrial volumes (iLAV: +8 cm2/m2; p=.02; iRAV: +10 cm2/m2; p=0.01) and estimated filling pressures (E/e': +2; p=.01). A left GLS (LGLS) &amp;gt; -16% predicted the composite endpoint with a sensitivity of 80% and a specificity of 67% (AUC 0.74). Estimated survival from the composite endpoint was 85% for the normal LGLS group and 35% for the impaired LGLS group (Figure 1). Right GLS was not significantly associated with the primary endpoint. Conclusions Heart involvement is becoming a major cause of death in patients with myositis. Data reported that subclinical heart involvement, characterized by biochemical and instrumental modifications, is estimated to affect around 70% of patients with myositis. Cardiac involvement in IIM is often subclinical in the early stages of the disease. GLS has been proven to be an effective tool to predict heart disease. Our results show that GLS worsens over time and can be used as a possible predictor of death and cardiovascular events in this population.Figure 1

Rubella virus-associated uveitis at a tertiary care hospital in Germany between 2013 and 2019

Uveitis is a process of intraocular inflammation that may involve different sections of the uveal tract. Apart from systemic or localized immune-mediated diseases, infections are key players in the etiology of uveitis and entail different treatment strategies. Rubella virus (RuV) is a recognized causative agent for the development of Fuchs uveitis, representing a major cause of virus-associated intraocular inflammation. A cohort of 159 patients diagnosed with different forms of uveitis between 2013 and 2019 was subjected to diagnostic antibody testing of the aqueous or vitreous humor. The diagnostic panel included RuV, cytomegalovirus, herpes simplex virus, varicella-zoster virus, and toxoplasmosis. Within this cohort, 38 RuV-associated uveitis (RAU) patients were identified based on a pathologic Goldman-Witmer coefficient indicative of an underlying RuV infection. With a mean age of 45.9 years, the RAU patients were younger than the non-RAU patients (56.3, p < 0.001). The evaluation of clinical parameters revealed a predominance of anterior uveitis and late sequalae such as cataract and glaucoma among the RAU patients. In 15 of the patients a history of prior RuV infections could be confirmed. The study underlines the importance of long-term surveillance of RuV associated diseases that originate from infections before the introduction of RuV vaccination programs.

Novel potential pharmacological applications of dimethyl fumarate-an overview and update.

Dimethyl fumarate (DMF) is an FDA-approved drug for the treatment of psoriasis and multiple sclerosis. DMF is known to stabilize the transcription factor Nrf2, which in turn induces the expression of antioxidant response element genes. It has also been shown that DMF influences autophagy and participates in the transcriptional control of inflammatory factors by inhibiting NF-κB and its downstream targets. DMF is receiving increasing attention for its potential to be repurposed for several diseases. This versatile molecule is indeed able to exert beneficial effects on different medical conditions through a pleiotropic mechanism, in virtue of its antioxidant, immunomodulatory, neuroprotective, anti-inflammatory, and anti-proliferative effects. A growing number of preclinical and clinical studies show that DMF may have important therapeutic implications for chronic diseases, such as cardiovascular and respiratory pathologies, cancer, eye disorders, neurodegenerative conditions, and systemic or organ specific inflammatory and immune-mediated diseases. This comprehensive review summarizes and highlights the plethora of DMF's beneficial effects and underlines its repurposing opportunities in a variety of clinical conditions.

NON-NECROTIZING DIFFUSE ANTERIOR SCLERITIS AS AN ISOLATED OCULAR MANIFESTATION OF SYSTEMIC LUPUS ERYTHEMATOSUS: A CASE REPORT

Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical manifestation in numerous organ systems, including the eye. Ocular involvements have been reported in up to one-third of patients with SLE, although scleritis is considered a less common manifestation of the disease found in only about 1% of cases Case Report: A 46-year-old female patient presented with a painful right eye for 1 week. She reported having the same symptom last year which resolved without treatment. There was no known history of systemic immune-mediated diseases and no prior ocular trauma. Ophthalmological examination revealed dilatation of deep scleral vessels on the right eye. The patient tested positive for the antinuclear antibody and anti-double-stranded deoxyribonucleic acid tests. She was diagnosed with non-necrotizing diffuse anterior scleritis caused by SLE and was treated with topical prednisolone acetate and systemic methylprednisolone. After 1 week of treatment, the patient showed an improvement in ocular signs and symptoms. Discussion: Scleritis is a rare inflammatory disease usually associated with systemic immune-mediated diseases such as SLE. It can cause significant visual loss and may be life-threatening. We reported a non-necrotizing diffuse anterior subtype of scleritis presented as an isolated manifestation in SLE, which benefited from early diagnosis and treatment of corticosteroids. Conclusion: Scleritis may present as an early or isolated manifestation of systemic immune-mediated disease. Therefore, a comprehensive examination is of the essence to exclude multisystem disease and treat the underlying cause even when there is no systemic manifestation.

Clinical outcomes for Clostridioides difficile associated diarrhea in inflammatory bowel disease patients versus non-IBD population: A retrospective cohort study.

Patients with inflammatory bowel disease (IBD) have a higher incidence of Clostridioides difficile infection (CDI). Previous studies have demonstrated negative clinical outcomes in IBD patients with CDI compared to patients without CDI. The clinical presentation of CDI is indistinguishable from IBD exacerbation, thus posing a frequent clinical dilemma on the role of Clostridioides infection in the testing, diagnosis, and treatment of these patients. To compare clinical outcomes of CDI in patients with IBD to those without IBD. Retrospective cohort of adult patients admitted to Rabin Medical Center Israel between the years 2014 and 2020 with a concurrent diagnosis of IBD and CDI. Matching 1:2 was performed between the IBD patients and the non-IBD population with respect to age and sex. Sixty-seven patients with IBD and 134 patients without IBD were included in the study. The groups' median age was 40.6 (interquartile range [IQR] of 29.8-68.9), with 45.8% male and 54.2% female. The non-IBD group had a higher Charlson score with 2 (IQR 0; 5) versus 0 (IQR 0; 4) in the IBD group (P value <.01). Patients with IBD had more exposure to systemic antibiotics, 71.1% versus 26.3% (P value <.01). In a multivariable analysis we found no difference in 90-day mortality and rate of relapse between the 2 study groups with an odds ratio of 1.709 (95% confidence interval 0.321-9.905) and odds ratio of 0.209 (95% confidence interval 0.055-1.513) respectively. In our cohort patients with IBD who present with diarrhea and concomitant CDI have similar rates of relapse and mortality compared with patients without IBD.

Current view on the pathogenesis of immune-mediated inflammatory diseases associated with ocular manifestations

This literature review discusses the new concept of pathogenesis of systemic immune-mediated inflammatory diseases (IMIDs), presents their classification and analyzes their association with ocular manifestations.

Rheuminations

I’ll be honest…it has been 35+ years since I started Medical School [MBBS]. And in the realm of Medicine at large, and Immunology/Rheumatology in specific, we are still struggling to find a ‘cure’ for chronic systemic inflammatory immune-mediated diseases also known as ‘autoimmune rheumatic diseases (ARD)’. Rheumatology is still in its cradle having gotten the recognition as a subspecialty of Medicine only in 1972. I have seen the field evolve in terms of understanding the orchestrated ‘play’ of the immune cells along with cytokines etc. over the past 3 decades, all of which has led to the concept and birth of ‘biologic’ disease modifying anti-rheumatic drugs [b-DMARDs]. The first b-DMARD to get approved by the Food and Drugs Administration [FDA] was etanercept, a TNF-alpha receptor fusion protein in 1998. Infliximab, a chimeric monoclonal antibody against TNF soon followed in 1999. Ever since then, there has been a flurry of b-DMARDs including 3 more in the same family of TNF-antagonists, 2 in the Interleukin [IL]-6 antagonist class, 1 blocker of the second co-stimulatory T-cell signaling: CTLA-4Ig, 3 IL-1 antagonists, B-cell depleting chimeric monoclonal antibody directed against CD-20 etc. Also, 3 oral Janus-kinase inhibitors have joined the ‘gang’ and are called targeted synthetic DMARDs. I still remember the pre-b-DMARD era when rip roaring rheumatoid arthritis was still around, and with my Ustaad Saheb (Mentor), all what we had to offer pharmaceutically were the conventional synthetic [cs] DMARDs including methotrexate, hydroxychloroquine, sulfasalazine, leflunomide and [the younger generation can hold their breath] cyclosporine, d-penicillamine, chlorambucil…GOLD injections and even cyclophosphamide! Corticosteroids have been around since 1950! The 1st and “so far” […well, I/You might be next one!] the only Nobel Prize winning revelation in the realm of Rheumatology......................................

Аутоиммунитет, аутовоспаление и почки

Systemic autoimmune and autoinflammatory disease are associated with all types of diffuse kidney disease, that is, glomerulonephritis (including rapidly progressive), thrombotic microangiopathy, tubulointerstitial nephritis, and AA-amyloidosis. However, the occurrence and types of nephropathies differ significantly in patients with various systemic immunemediated inflammatory diseases. For example, glomerulonephritis is one of the leading manifestation of systemic lupus erythematosus and small-vessels vasculitis, thrombotic angiopathy occurs frequently in patients with both primary and secondary antiphosholipid syndrome, tubulointerstitial nephritis is frequently found in patients with Sjogren syndrome and IgG4-associated disease, whereas AA-amyloidosis can complicate rheumatoid arthritis, ankylosing spondilytis, psoriatic arthritis, familial Meditarranean fever, and certain other monogenic autoinflammatory diseases. Over last decades, renal survival in patients with autoimmune and autoinflammatory diseases improved significantly due to earlier diagnosis and development of effective immunosuppressive and anti-inflammatory treatments. However, a proportion of patients still present with progressive impairment of kidney function that can be unrelated to activity of underlying diseases.

Immune-mediated diseases are associated with a higher incidence of dementia: a prospective cohort study of 375,894 individuals

BackgroundImmune system dysregulation plays a vital role in the pathogenesis of neurodegenerative diseases, even considered to be as important as classical pathological protein aggregation assumption. However, the associations of immune-mediated diseases with incident dementia are unclear and need to be clarified in prospective studies with a large population and long follow-up time.MethodsWe investigated the relationship between any or individual immune-mediated diseases and incident dementia based on a prospective cohort UK Biobank. The risk for dementia was assessed with multivariable hazard ratio (HR) and 95% confidence interval (CI) after adjusting for various potential confounders using time-varying Cox proportional hazards regression. We also performed the subgroup Cox analysis stratified by time since immune-mediated diseases and gender. Causal mediation analyses with 1000 bootstrapped iterations were conducted to explore the mediation effects of peripheral immune cells on the associations of immune-mediated diseases with dementia.ResultsA total of 375,894 participants were included in the study, among which 5291 developed dementia during a median follow-up of 9.08 years. Immune-mediated diseases were associated with an increased risk of dementia (HR, 1.10; 95% CI, 1.00–1.21), and the risk was highest between 1 and 2 years after immune-mediated diseases onset (HR, 2.74; 95% CI, 1.86–4.04). Females who suffered from immune-mediated diseases were more prone to AD, while males were more susceptible to VD. Four of the individual immune-mediated diseases including type I diabetes mellitus (HR, 2.49; 95% CI, 1.97–3.15), rheumatic fever or rheumatic heart diseases (HR, 1.36; 95% CI, 1.05–1.77), multiple sclerosis (HR, 2.87; 95% CI, 1.92–4.30), and necrotizing vasculopathies (HR, 1.71; 95%CI, 1.03–2.85) were significantly related to higher dementia incidence. The relationship between immune-mediated diseases and dementia was partially mediated by peripheral immune cells including neutrophils and lymphocytes.ConclusionsIn this large cohort study, immune-mediated diseases were proven to be significantly associated with an increased risk of incident dementia, especially for type I diabetes mellitus which was observed to be related to the higher incidence of all types of dementia. Our findings could provide new sights on dementia pathogenesis and intervention from the perspective of systemic immunology and immune-mediated diseases.

The gut microbiome and the immune system

The human body contains trillions of microbes which generally live in symbiosis with the host. The interaction of the gut microbiome with elements of the host immune system has far-reaching effects in the development of normal gut and systemic immune responses. Disturbances to this intricate relationship may be responsible for a multitude of gastrointestinal and systemic immune mediated diseases. This review describes the development of the gut microbiome and its interaction with host immune cells in both health and disease states.

Pathogénie des vascularites associées aux ANCA en 2021 : mise au point

Anticytoplasmic neutrophil antibodies (ANCA)-associated vasculitis (AAV) are rare systemic immune-mediated diseases characterized by small vessel necrotizing vasculitis and/or respiratory tract inflammation. Over the last 2 decades, anti-MPO vasculitis mouse model has enlightened the role of ANCA, neutrophils, complement activation, T helper cells (Th1, Th17) and microbial agents. In humans, CD4T cells have been extensively studied, while the dramatic efficacy of rituximab demonstrated the key role of B cells. Many areas of uncertainty remain, such as the driving force of GPA extra-vascular granulomatous inflammation and the relapse risk of anti-PR3 AAV pathogenesis. Animal models eventually led to identify complement activation as a promising therapeutic target. New investigation tools, which permit in depth immune profiling of human blood and tissues, may open a new era for the studying of AAV pathogenesis.

Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach.

The four Janus kinase (JAK) proteins and seven signal transducer and activator of transcription (STAT) transcription factors mediate intracellular signal transduction downstream of cytokine receptors, which are implicated in the pathology of autoimmune, allergic and inflammatory diseases. Development of targeted small-molecule therapies such as JAK inhibitors, which have varied selective inhibitory profiles, has enabled a paradigm shift in the treatment of diverse disorders. JAK inhibitors suppress intracellular signalling mediated by multiple cytokines involved in the pathological processes of rheumatoid arthritis and many other immune and inflammatory diseases, and therefore have the capacity to target multiple aspects of those diseases. In addition to rheumatoid arthritis, JAK inhibition has potential for treatment of autoimmune diseases including systemic lupus erythematosus, spondyloarthritis, inflammatory bowel disease and alopecia areata, in which stimulation of innate immunity activates adaptive immunity, leading to generation of autoreactive T cells and activation and differentiation of B cells. JAK inhibitors are also effective in the treatment of allergic disorders, such as atopic dermatitis, and can even be used for the COVID-19-related cytokine storm. Mechanism-based treatments targeting JAK–STAT pathways have the potential to provide positive outcomes by minimizing the use of glucocorticoids and/or non-specific immunosuppressants in the treatment of systemic immune-mediated inflammatory diseases.