Systemic Autoinflammatory Diseases Research Articles

Attempts to identify the molecular cause of autoinflammatory recurrent fever

Systemic autoinflammatory diseases caused by dysregulation of the innate immunity are a known cause of recurrent fevers. We present the molecular diagnosis results of 12 children with recurrent fever, analyzing the correlation between molecular findings and clinical symptoms. No pathogenic variants confirming autoinflammatory disease were found. One child was diagnosed with SRP54 deficiency, linked to congenital neutropenia with a cyclic pattern. Variants of uncertain significance were found in 6 patients in genes associated with autoinflammatory disorders, though two lacked clinical correlation. Variants of uncertain significance in the NLRC4 gene were detected in 2 patients with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, in the PLSG2 gene in 1 child with systemic juvenile idiopathic arthritis, and in the MEFV gene in 1 patient with syndrome of uncertain recurrent fever. COVID-19 was identified as a triggering factor in 54.5% of cases. Further research is needed to clarify the role of genetic variants and environmental factors in recurrent fevers.

Adult-onset Still’s disease masquerading as acute coronary syndrome: a case report and review of the literature

IntroductionAdult-onset Still’s disease is a rare systemic autoinflammatory disease. We present a case of a young man with a constellation of symptoms and myopericarditis as a complication of this disease.CaseA 36-year-old Hispanic man with no significant past medical history developed a quotidian fever pattern following an upper respiratory tract infection. He initially presented with chest pain concerning for myocardial infarction and underwent cardiac catheterization, which revealed non-obstructive coronary artery disease. He was found to have myopericarditis, significant neutrophilic leukocytosis, and hyperferritinemia. He improved on high-dose corticosteroids but developed steroid-induced psychosis, and 4 months from symptom onset, he finally received tocilizumab, which eventually induced remission without adverse reactions.DiscussionAdult-onset Still’s disease should be considered in a patient with fevers of undetermined origin. Due to its multisystemic involvement, adult-onset Still’s disease is often a diagnosis arrived at after an extensive cardiac, hematologic, malignant, and infectious workup. Imaging, laboratory testing, and bone marrow biopsy were necessary to rule out alternative etiologies of this patient’s presentation. Steroids are the mainstay of treatment because they are easily affordable, although the high risk of adverse effects makes them less desirable. Interleukin-1 inhibitors (anakinra or canakinumab) and interleukin-6 inhibitor tocilizumab are the steroid-sparing biologic agents of choice but are cost-prohibitive.ConclusionAdult-onset Still’s disease should be considered in the differential diagnoses of fever of undetermined origin. Early identification and initiation of treatment are critical to faster recovery and prevention of progression to severe complications. Steroids remain the standard first-line therapy and should be followed by disease-modifying steroid sparing drugs. The social determinants of health may preclude their timely initiation and should alert providers of proactive ways to avoid further delays.

Follicular Skin Disorders, Inflammatory Bowel Disease, and the Microbiome: A Systematic Review.

Follicular skin disorders, including hidradenitis suppurativa (HS), frequently coexist with systemic autoinflammatory diseases, such as inflammatory bowel disease (IBD) and its subtypes, Crohn's disease and ulcerative colitis. Previous studies suggest that dysbiosis of the human gut microbiome may serve as a pathogenic link between HS and IBD. However, the role of the microbiome (gut, skin, and blood) in the context of IBD and various follicular disorders remains underexplored. Here, we performed a systematic review to investigate the relationship between follicular skin disorders, IBD, and the microbiome. Of the sixteen included studies, four evaluated the impact of diet on the microbiome in HS patients, highlighting a possible link between gut dysbiosis and yeast-exclusion diets. Ten studies explored bacterial colonization and HS severity with specific gut and skin microbiota, including Enterococcus and Veillonella. Two studies reported on immunological or serological biomarkers in HS patients with autoinflammatory disease, including IBD, and identified common markers including elevated cytokines and T-lymphocytes. Six studies investigated HS and IBD patients concurrently. Our systematic literature review highlights the complex interplay between the human microbiome, IBD, and follicular disorders with a particular focus on HS. The results indicate that dietary modifications hold promise as a therapeutic intervention to mitigate the burden of HS and IBD. Microbiota analyses and the identification of key serological biomarkers are crucial for a deeper understanding of the impact of dysbiosis in these conditions. Future research is needed to more thoroughly delineate the causal versus associative roles of dysbiosis in patients with both follicular disorders and IBD.

Non-Skewed X-inactivation Results in NF-κB Essential Modulator (NEMO) Δ-exon 5-autoinflammatory Syndrome (NEMO-NDAS) in a Female with Incontinentia Pigmenti

PurposeGenetic hypomorphic defects in X chromosomal IKBKG coding for the NF-κB essential modulator (NEMO) lead to ectodermal dysplasia and immunodeficiency in males and the skin disorder incontinentia pigmenti (IP) in females, respectively. NF-κB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NEMO-NDAS) is a systemic autoinflammatory disease caused by alternative splicing and increased proportion of NEMO-Δex5. We investigated a female carrier presenting with IP and NEMO-NDAS due to non-skewed X-inactivation.MethodsIKBKG transcripts were quantified in peripheral blood mononuclear cells isolated from the patient, her mother, and healthy controls using RT-PCR and nanopore sequencing. Corresponding proteins were analyzed by western blotting and flow cytometry. Besides toll-like receptor (TLR) and tumor necrosis factor (TNF) signaling, the interferon signature, cytokine production and X-inactivation status were investigated.ResultsIP and autoinflammation with recurrent fever, oral ulcers, hepatitis, and neutropenia, but no immunodeficiency was observed in a female patient. Besides moderately reduced NEMO signaling function, type I interferonopathy, and elevated IL-18 and CXCL10 were found. She and her mother both carried the heterozygous variant c.613 C > T p.(Gln205*) in exon 5 of IKBKG previously reported in NEMO-deficient patients. However, X-inactivation was skewed in the mother, but not in the patient. Alternative splicing led to increased ratios of NEMO-Dex5 over full-length protein in peripheral blood cell subsets causing autoinflammation. Clinical symptoms partially resolved under treatment with TNF inhibitors.ConclusionNon-skewed X-inactivation can lead to NEMO-NDAS in females with IP carrying hypomorphic IKBKG variants due to alternative splicing and increased proportions of NEMO-∆ex5.

Expanding clinical characteristics and genotypic profiling of Yao syndrome in Chinese patients.

Yao syndrome (YAOS, OMIM# 617321) is a kind of systemic autoinflammatory diseases (SAIDs) linked to the nucleotide-binding oligomerization domain containing 2 (NOD2). Clinical reports of YAOS in China are sparse. Herein, we reported the largest YAOS cohort of Chinese patients to expand the understanding of its phenotype, genotype, and therapeutic responses. This study enrolled 15 adult patients diagnosed with YAOS at Peking Union Medical College Hospital from April 2015 to May 2024. Whole-exome sequencing was performed on all patients. Clinical data, genetic variations, and treatment responses were documented and compared with a Caucasian cohort. The mean age of disease onset was 35 ± 17 years old. The most common clinical manifestations included recurrent high-grade fever (100%), gastrointestinal symptoms (73.3%), arthralgia/arthritis, fatigue, myalgia, and lower extremity swelling (46.7%). All patients exhibited elevated acute-phase reactants during episodes. 12 heterozygous NOD2 variants were identified, with Q902K in 4 patients, R471C in 3, and variants c.-14C>T, A110T, S127L, R311W, A432V, Y514H, R541P, A661P, K818Q, A886V each found in individual patients. 90% of the patients responded well to glucocorticoids, and 55.6% to sulfasalazine. 66.7% of patients who received TNF inhibitors achieved complete resolution of symptoms. Additionally, one patient each responded favorably to canakinumab and tocilizumab. Compared to the Caucasian cohort, our cohort exhibited a more balanced gender ratio and a higher proportion of recurrent fever, proteinuria/hematuria as well as more frequent leukocytosis, elevated acute phase reactants, and anemia. Lower proportions of arthralgia/arthritis, skin rashes, headaches, and sicca-like symptoms were noted in our cohort. Moreover, a higher proportion of patients in our cohort showed a good response to TNF inhibitors. Chinese patients with YAOS had more pronounced inflammatory manifestations compared to the Caucasian cohort. Variants c.-14C>T, A110T, S127L, A661P, K818Q, A886V, R471C, and A432V were identified as novel NOD2 variants in YAOS. TNF, IL-6, and IL-1 inhibitors are the promising treatment options. These findings expand the clinical spectrum, genetic profile, and treatment efficacy of YAOS, underscoring the need for heightened awareness of this disease in diverse populations.

New and future perspectives in familial Mediterranean fever and other autoinflammatory diseases.

Systemic autoinflammatory diseases are a group of disorders characterized by sterile episodes of inflammation resulting from defects in the innate immune system. In contrast to classical autoimmune diseases, where circulating autoantibodies and the adaptive immune system are involved, these conditions involve excessive presence of proinflammatory cytokines leading to inflammatory attacks. Excessive cytokine production, functional mutations in regulatory pathways, excessive interferon production, defects in the nuclear factor-kappa B signaling pathway, abnorARCHmal protein folding, and complement activation are the mechanisms leading to autoinflammatory diseases. A defect in the mTOR pathway and trained immunity are newly discovered possible causes in pathogenesis. Early onset and severe forms of classical rheumatological diseases have been more frequently associated with autoinflammatory diseases in the last decade. Therefore, monogenic autoinflammatory diseases should be considered in rheumatic diseases with family history, consanguinity, early onset, and severe disease. The combination of functional and genotyping research will help to identify unclassified patients. The optimal treatment strategy remains uncertain, functional studies such as interferon signature and cytokine profiling, may prove valuable in guiding the treatment process. Stem cell transplantation strategies in autoinflammatory diseases with partial response to biological therapies can be considered. Autoinflammatory diseases are becoming increasingly complex and are bringing new perspectives to already known rheumatic diseases. Although we have effective treatments, we are still far from personalized recommendations.

Yao syndrome: a novel systemic autoinflammatory disease with cutaneous manifestations.

Yao syndrome (YAOS) is a novel systemic autoinflammatory disease linked to the nucleotide-binding oligomerization domain (NOD2) gene. It is characterized by periodic fevers, gastrointestinal (GI) symptoms, arthritis, and dermatitis, among other symptoms. A sparse literature exists on this disease, and little is known about its dermatological manifestations. A review of available literature was performed to characterize the cutaneous manifestations of Yao syndrome. Cutaneous manifestations were documented in 85.7% of patients, with common characteristic descriptions of erythematous patches and plaques involving the face, trunk, abdomen, and extremities. Based on our review of treatment modalities employed for Yao syndrome, prednisone is an appropriate initial approach, with oral sulfasalazine and other disease-modifying antirheumatic drugs serving as appropriate secondary options. YAOS should be considered in the differential diagnosis of patients presenting with a dermatitic rash, especially in the context of concurrent articular symptoms, periodic fever, and GI symptoms.

TNFRSF11A variants contribute to systemic autoinflammatory diseases: A case series of 12 patients

BackgroundLimited evidence suggests that variants in TNFRSF11A gene, encoding RANK, may contribute to systemic autoinflammatory disease (SAID). Aim/MethodsTo estimate the prevalence of TNFRSF11A variants in a cohort of patients with SAIDs screened for 26 related genes and describe the disease phenotypic expression. ResultsA total of 12 out of 167 patients, 7 males, aged (median) 38 years at disease onset, yielded at least one TNFRSF11A rare variant. All patients carried a coexisting variant in at least one other SAID-related gene, most frequently MEFV (6 patients), but also TNFRSF1A, NOD2, NLRP3, NLRP7, MVK, IL36RN, RBCK1, PLCG2 and PSMB8. SAID episodes lasting (median) 9 days manifested with high grade fever (91%), myalgias (75%), malaise (67%), serositis (58%), arthralgias/arthritis (58%), gastrointestinal involvement (33%), and rash (25%), and responded to corticosteroids. The most common initial clinical diagnosis was TNF-associated periodic fever syndrome (TRAPS), which was, however, confirmed, in only one patient. The emergence of MEFV variations supported the diagnosis of atypical Familial Mediterranean Fever in two cases, whereas the diagnosis of Yao syndrome was speculated in two patients with NOD2 variants. The presence of atypical disease and the inability of defining diagnosis in the remaining 7 patients, supported the possible involvement of TNFRSF11A variants in the phenotypic expression of SAIDs. ConclusionTNFRSF11A variants, occurring in 7% of SAID patients always in combination with other SAID-related gene variants, contribute to the development of an autoinflammatory syndrome resembling to TRAPS. Additional studies to confirm novel pathogenic SAID pathways are clearly warranted.

Inflammation in Fabry disease: stages, molecular pathways, and therapeutic implications.

Fabry disease, a multisystem X-linked disorder caused by mutations in the alpha-galactosidase gene. This leads to the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), culminating in various clinical signs and symptoms that significantly impact quality of life. Although treatments such as enzyme replacement, oral chaperone, and emerging therapies like gene therapy exist; delayed diagnosis often curtails their effectiveness. Our review highlights the importance of delineating the stages of inflammation in Fabry disease to enhance the timing and efficacy of diagnosis and interventions, particularly before the progression to fibrosis, where treatment options are less effective. Inflammation is emerging as an important aspect of the pathogenesis of Fabry disease. This is thought to be predominantly mediated by the innate immune response, with growing evidence pointing towards the potential involvement of adaptive immune mechanisms that remain poorly understood. Highlighted by the fact that Fabry disease shares immune profiles with systemic autoinflammatory diseases, blurring the distinctions between these disorders and highlighting the need for a nuanced understanding of immune dynamics. This insight is crucial for developing targeted therapies and improving the administration of current treatments like enzyme replacement. Moreover, our review discusses the complex interplay between these inflammatory processes and current treatments, such as the challenges posed by anti-drug antibodies. These antibodies can attenuate the effectiveness of therapies, necessitating more refined approaches to mitigate their impact. By advancing our understanding of the molecular changes, inflammatory mediators and causative factors that drive inflammation in Fabry disease, we aim to clarify their role in the disease's progression. This improved understanding will help us see how these processes fit into the current landscape of Fabry disease. Additionally, it will guide the development of more effective diagnostic and therapeutic approaches, ultimately improving patient care.

Innovations in the care of childhood interstitial lung disease associated with connective tissue disease and immune-mediated disorders.

Childhood interstitial lung disease (chILD) associated with connective tissue and immune mediated disorders is the second most common chILD diagnostic category. As knowledge of the molecular and genetic underpinnings of these rare disorders advances, the recognized clinical spectrum of associated pulmonary manifestations continues to expand. Pulmonary complications of these diseases, including ILD, confer increased risk for morbidity and mortality and contribute to increased complexity for providers tasked with managing the multiple organ systems that can be impacted in these systemic disorders. While pulmonologists play an important role in diagnosis and management of these conditions, thankfully they do not have to work alone. In collaboration with a multidisciplinary team of subspecialists, the pulmonary and other systemic manifestations of these conditions can be managed effectively together. The goal of this review is to familiarize the reader with the classic patterns of chILD and other pulmonary complications associated with primary immune-mediated disorders (monogenic inborn errors of immunity) and acquired systemic autoimmune and autoinflammatory diseases. In addition, this review will highlight current, emerging, and innovative therapeutic strategies and will underscore the important role of multidisciplinary management to improving outcomes for these patients.

Risk of death, thrombotic and hemorrhagic events in patients with atrial fibrillation and systemic autoimmune diseases

Abstract Background Growing evidence showing that systemic autoimmune diseases (SAD) are associated with a high risk of incident atrial fibrillation (AF). However, the impact of SAD on the clinical course of AF patients is largely unknown. Purpose To assess the risk of all-cause death, thrombotic events, and bleeding in AF patients with SAD. Methods Retrospective cohort study within a global health care network (TriNetx). Using ICD codes, AF patients were categorized into two groups: 1) AF patients with SAD (M32: Systemic Lupus Erythematosus; M33: Dermato-polymyositis; M34: Systemic Sclerosis; M35: Sjogren syndrome), and 2) AF controls (without systemic autoimmune, autoinflammatory, or rheumatic diseases). The primary outcomes were the 5-year risks of 1) all-cause death, 2) thrombotic events (ischemic stroke, transient ischemic attack, peripheral arterial thromboembolism, acute myocardial infarction, deep vein thrombosis, and pulmonary embolism), and 3) hemorrhagic outcome (intracranial hemorrhage and gastrointestinal bleeding). Secondary outcomes were each component of the composite primary outcomes. Cox regression analysis before and after propensity-score-matching (PSM) was used to estimate HR and 95% confidence interval (95%CI). Sensitivity analyses were done to investigate the risk of primary outcomes associated with each systemic autoimmune disease and with different types of oral anticoagulant (OAC). Results We identified 22,371 AF patients with SAD (67.7±13.7 years, 72.2% females), and 1,478,693 AF controls (69.7±14.0, 42.6% females). Before PSM, AF patients with SAD were younger, more often females, and with a higher prevalence of cardiovascular risk factors; no differences were found after PSM. After PSM, AF patients with SAD showed a higher risk of all-cause death (HR 1.21, 95% 1.17-1.25), thrombotic events (HR 1.55, 95%CI 1.49-1.61), and hemorrhagic events (HR 1.39, 95%CI 1.32-1.46) compared to AF controls (Table 1). On sensitivity analyses, we found that the risk of primary outcomes in AF patients with SAD was independent from the OAC type, but NOAC was more effective than warfarin in reducing the risk of thrombotic events. The highest risk of all-cause death was associated with Systemic Sclerosis, while the highest risk of composite thrombotic events was associated with Systemic Lupus Erythematosus, and Dermato-polymyositis. The highest risk of stroke was associated with Sjogren syndrome; and myocardial infarction and deep vein thrombosis with Dermato-polymyositis, Systemic Lupus Erythematosus was associated with the highest risk of Intracranial hemorrhage, while Systemic Sclerosis to the highest risk of gastrointestinal bleeding (Table 2). Conclusion In AF patients the coexistence of SAD is associated with a high risk of all-cause death, thrombotic events, and bleeding. A personalized approach aimed to minimize the impact of SAD on the clinical course of AF patients is needed.Figure 1Figure 2

Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.

Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.

3D clustering of gene expression data from systemic autoinflammatory diseases using self-organizing maps (Clust3D)

Background and objectiveSystemic autoinflammatory diseases (SAIDs) are characterized by widespread inflammation, but for most of them there is a lack of specific biomarkers for accurate diagnosis. Although a number of machine learning algorithms have been used to analyze SAID datasets, aiding in the discovery of novel biomarkers, there is a growing recognition of the importance of SAID timeseries clustering, as it can capture the temporal dynamics of gene expression patterns. MethodologyThis paper proposes a novel clustering methodology to efficiently associate three-dimensional data. The algorithm utilizes competitive learning to create a self-organizing neural network and adjust neuron positions in time-dependent and high dimensional feature space in order to assign them as clustering centers. The quantitative evaluation of the clustering was based on well-known clustering indices. Furthermore, a differential expression analysis and classification pipeline was employed to assess the capability of the proposed methodology to extract more accurate pathway-specific genes from its clusters. For that, a comparative analysis was also conducted against a heuristic timeseries clustering method. ResultsThe proposed methodology achieved better overall clustering indices scores and classification metrics using genes derived from its clusters. Notable cases include a threefold increase in the Calinski-Harabasz clustering index, a twofold improvement in the Davies–Bouldin clustering index and a ∼60% increase in the classification specificity score. ConclusionA novel clustering methodology was developed and applied on several gene expression timeseries datasets from systemic autoinflammatory diseases, and its ability to efficiently produce well separated clusters compared to existing heuristic methods was demonstrated.

C-reactive protein is more suitable than Serum Amyloid A to monitor crises and attack-free periods in Systemic Auto-Inflammatory Diseases.

BackgroundWith their broad presentations and no global biomarker to discriminate crises and attack-free periods, Systemic Auto-Inflammatory Diseases (SAID) are difficult to manage. This study assessed Serum Amyloid A (SAA), C-reactive protein (CRP) and serum calprotectin as potential biomarkers to monitor patients with SAID. MethodSAA (already studied in Familial Mediterranean Fever (FMF)), CRP and serum calprotectin were measured on SAID adult patients from Juvenile Inflammatory Rheumatism (JIR) cohort during their follow-up visits between 2020 and 2022. Crises and attack-free periods were clinically determined. Results96 measures, mainly from FMF (43 %) and Unclassified SAID (USAID) (37 %) patients were included. Using ROC curves, a threshold with sensitivity and specificity of/over 75 % was determined for SAA (9 mg/L) and CRP (9 mg/L) but not for serum calprotectin, not investigated further. With this threshold, the results were similar in FMF and USAID patients’ subgroups. SAA and CRP showed a positive correlation with crises and attack-free periods in SAID patients (r = 0.4796, p < 0.001 and r = 0.5525, p < 0.001, respectively) as in FMF and USAID patients, with no significant difference between both markers in diagnosis value and ROC curves Area Under Curve (AUC) (p = 0.32). Only the CRP results were not influenced by obesity. ConclusionSAA and CRP can discriminate crisis and attack-free periods in our cohort of SAID patients mainly composed of FMF and USAID patients. However, only CRP can be used regardless of body mass index. It is the first report of common biomarkers for all SAID, including USAID patients, with CRP widely accessible in routine worldwide.

Time for a new approach to drug development for rare systemic autoinflammatory diseases.

Time for a new approach to drug development for rare systemic autoinflammatory diseases.

Anti-LAMP-2 Antibody Seropositivity in Children with Primary Systemic Vasculitis Affecting Medium- and Large-Sized Vessels.

Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.

Genetic and epigenetic dysregulation of innate immune mechanisms in autoinflammatory diseases.

Dysregulation and hyperactivation of innate immune responses can lead to the onset of systemic autoinflammatory diseases. Monogenic autoinflammatory diseases are caused by inborn genetic errors and based on molecular mechanisms at play, can be divided into inflammasomopathies, interferonopathies, relopathies, protein misfolding, and endogenous antagonist deficiencies. On the other hand, more common autoinflammatory diseases are multifactorial, with both genetic and non-genetic factors playing an important role. During the last decade, long-term memory characteristics of innate immune responses have been described (also called trained immunity) that in physiological conditions provide enhanced host protection from pathogenic re-infection. However, if dysregulated, induction of trained immunity can become maladaptive, perpetuating chronic inflammatory activation. Here, we describe the mechanisms of genetic and epigenetic dysregulation of the innate immune system and maladaptive trained immunity that leads to the onset and perpetuation of the most common and recently described systemic autoinflammatory diseases.

VEXAS-Defining UBA1 Somatic Variants in 245,368 Diverse Individuals in the NIH All Of Us Cohort.

Somatic variants in UBA1 cause VEXAS, a recently described, systemic autoinflammatory disease. Research on VEXAS has largely focused on highly symptomatic patients. We sought to determine the prevalence of canonical, VEXAS-associated somatic variants and their disease penetrance in a diverse, unselected population. We analyzed clinical-grade whole genome sequencing data from 245,368 participants in the All of Us Research Program. We compared persons carrying a canonical VEXAS-associated somatic variant to age, sex, and ancestry matched controls across the domains of diagnoses, medications, and laboratory values. 74 participants were identified who carry one VEXAS-defining somatic variant, UBA1 c.121A>C, p.Met41Leu. The variant allele fraction ranged from 4.5% to 33%. No other canonical VEXAS-associated variants were identified. Of the 74 carriers, 62 (84%) were women, 20 (27%) were African American, and 14 (19%) were American Admixed/Latino. There was no statistically significant association between case/control status and any VEXAS-associated diagnosis code, medication prescription, or laboratory value. We report the largest cohort to date of persons with the VEXAS-associated p.Met41Leu somatic variant. This cohort differed substantially from reported cohorts of patients with clinical VEXAS, having a higher proportion of persons who were young, female, and of diverse ancestry. Variant allele fractions were lower than reported in clinical VEXAS cohorts, and bioinformatic analysis detected no clinical manifestations of VEXAS. Thus, the UBA1 p.Met41Leu somatic variant displayed incomplete penetrance for VEXAS. Further study is needed to determine the natural history of VEXAS-associated somatic variants in the predisease phase.

Identifying functional dysregulation of NOD2 variant Q902K in patients with Yao syndrome

Background and objectivesThe study investigated the pathogenesis of Yao syndrome (YAOS), a rare systemic autoinflammatory disease associated with the nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants.MethodsRNA sequencing analyses were used to detect transcriptomic profile changes. Immunoblot and immunohistochemistry were used to examine the NOD2-mediated inflammatory signaling pathways and ELISA was used to detect cytokines.ResultsTranscriptome analysis of YAOS revealed NOD-like receptor signaling pathway enrichment. Compared with HCs, P-RIP2, p-p65, p-p38, p-ERK, and p-JNK notably increased in PBMCs of a patient with YAOS. P-RIP2, p-p65, and p-p38 elevated in small intestinal mucosa tissues. P-p65 and p-p38 in synovial tissues from YAOS were higher than those in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Serum interleukin (IL)-6 level along with tumor necrosis factor (TNF)-α and IL-6 secreted from PBMCs were markedly higher in patients with YAOS in comparison to healthy controls (HCs). The supernatants of synovial cells from a patient with YAOS showed substantially higher IL-1β and IL-6 levels than those of RA and OA. Canakinumab therapy of a Q902K heterozygous patient with YAOS resulted in notable clinical improvement.ConclusionOverproduction of pro-inflammatory cytokines and the hyperactivation of NOD2-mediated signaling pathways were found in the NOD2 variant Q902K patient with YAOS. NOD2-RIP2-MAPK pathway might play a pivotal role in the pathogenesis of YAOS. These results provide new perspectives for targeted therapies in YAOS.

Practical Approach to Diagnosis and Management of IL-1-Mediated Autoinflammatory Diseases (CAPS, TRAPS, MKD, and DIRA).

Systemic autoinflammatory diseases (SAIDs) are a group of rare genetic and nongenetic immune dysregulatory disorders associated with high morbidity and mortality if left untreated. Therefore, early diagnosis and initiation of targeted treatment is vital in SAID patients to control the disease activity and prevent long-term immune-mediated damage. A specific group of genetically defined SAIDs is associated with increased inflammasome-mediated production of active interleukin (IL)-1. Even though progress in immunobiology and genetics has brought forth diagnostic tools and novel treatments that have been described in the literature extensively, many challenges remain in the clinical setting. Some challenges that health care providers may face on a day-to-day basis include the requirement of a multidisciplinary approach due to the complexity of these diseases, limited evidence-based treatment options, and barriers to access available therapies. Primarily, IL-1 inhibitors anakinra, canakinumab, and rilonacept are used to control the inflammation in these patients, with the goal of achieving sustainable remission. Recently published provisional points to consider from the European Alliance of Associations for Rheumatology (EULAR) and American College of Rheumatology (ACR) provide diagnosis, management, and monitoring recommendations for four IL-1-mediated autoinflammatory diseases: cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), and deficiency of the IL-1 receptor antagonist (DIRA). The goal of this paper is to aid health care professionals by providing a practical approach to diagnosis and management of these four IL-1 mediated SAIDs on the basis of the recent EULAR/ACR recommendations.