Systemic Autoinflammatory Diseases Research Articles

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.

Systematic search for the UBA1 mutation in men after a first episode of venous thromboembolism: A monocentric study

Systematic search for the UBA1 mutation in men after a first episode of venous thromboembolism: A monocentric study

Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases.

Systemic autoimmune diseases are characterized by the failure of the immune system to differentiate self from non-self. These conditions are associated with significant morbidity and mortality, and they can affect many organs and systems, having significant clinical heterogeneity. Recent discoveries have highlighted that neutrophils, and in particular the neutrophil extracellular traps that they can release upon activation, can have central roles in the initiation and perpetuation of systemic autoimmune disorders and orchestrate complex inflammatory responses that lead to organ damage. Dysregulation of neutrophil cell death can lead to the modification of autoantigens and their presentation to the adaptive immune system. Furthermore, subsets of neutrophils that seem to be more prevalent in patients with systemic autoimmune disorders can promote vascular damage and increased oxidative stress. With the emergence of new technologies allowing for improved assessments of neutrophils, the complexity of neutrophil biology and its dysregulation is now starting to be understood. In this Review, we provide an overview of the roles of neutrophils in systemic autoimmune and autoinflammatory diseases and address putative therapeutic targets that may be explored based on this new knowledge.

Genotype and Phenotype of Adenosine Deaminase 2 Deficiency: a Report from Saudi Arabia.

Adenosine deaminase 2 deficiency (DADA2), a rare and potentially fatal systemic autoinflammatory disease, is characterized by low or lack of ADA2 activity due to ADA2 mutations. DADA2 symptoms are variable and include vasculitis, immunodeficiency, and cytopenia. Minimal data are available from Saudi Arabia. This retrospective study conducted at seven major tertiary medical centers examined the phenotypic and genotypic variabilities, clinical and diagnostic findings, and treatment outcomes among 20 Saudi patients with DADA2 from 14 families. The median age of the study cohort was 9.5years (4-26years). The clinical presentation was before the age of 5months in 25% of patients. Homozygous c.1447-1451del mutation was the most frequent ADA2 alteration (40%), followed by c.882-2A:G (30%). All tested patients exhibited absent or near-absent ADA2 activity. Phenotypic manifestations included stroke (40%), hematological abnormalities (95%), lymphoproliferation (65%), and recurrent infection (45%). Five and three patients had extracranial vasculitis features and Hodgkin lymphoma, respectively. Atypical manifestations included growth retardation (30%) and transverse myelitis. Anti-tumor necrosis factor (anti-TNF) therapy was the main treatment. Some patients underwent blood transfusion, splenectomy, cyclosporine and colony-stimulating factor therapies, and hematopoietic stem cell transplantation due to anti-TNF therapy failure. Fulminant hepatitis and septic multiorgan failure caused mortality in three patients. Thus, this study revealed the variability in the molecular and clinical characteristics of DADA2 in the study cohort with predominant aberrant hematological and immunological characteristics. Consensus diagnostic criteria will facilitate early diagnosis and treatment. Additionally, disease registries or large prospective studies are needed for evaluating rare disease complications, such as cancer.

Autoimmune Pericarditis: Multimodality Imaging.

The purpose of this review is to understand the underlying mechanism that leads to pericarditis in systemic autoimmune and autoinflammatory diseases. The underlying mechanism plays a vital role in the appropriate management of patients. In addition, we will review the current landscape of available cardiac imaging modalities with emphasis on pericardial conditions as well as proposed treatment and management tailored toward pericardial autoimmune and autoinflammatory processes. Approximately 22% of all cases of pericarditis with a known etiology are caused by systemic autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and vasculitis. In recent years, there have been advancements of imaging modalities including cardiac MRI, cardiac CT scan, and PET scan and their respective nuances in regard to contrast use, technique, and views which clinicians may utilize to better understand the extent of a patient's pericardial pathology and the trajectory of his or her disease process. In this review, we will discuss systemic autoimmune and autoinflammatory diseases that involve the pericardium. We will also review different imaging modalities that are currently used to further characterize such conditions. Having a deeper understanding of such techniques will improve patient outcomes by helping clinicians tailor treatment plans according to the unique underlying condition.

004 Systemic autoinflammatory diseases: a multicenter cohort study

BackgroundSystemic autoinflammatory diseases (SAIDs) are a group of hereditary diseases characterized by inflammatory attacks accompanied by clinical findings such as fever, skin rash, abdominal pain, and musculoskeletal symptoms and with high acute phase response.ObjectivesThis study sought to define the characteristics, to report 24-month follow-up of children with SAIDs and to compare the performances of both the previously validated classification criteria Federici and new Eurofever/PRINTO classification criteria in a multicentre cohort under real-life conditions.MethodThe medical charts of 60 children diagnosed with SAIDs (CAPS, TRAPS and HIDS) who were followed up regularly every 1–3 months between 2010 and 2021 in 6 pediatric rheumatology centers in Turkey were retrospectively analyzed. Demographic data, clinical findings, laboratory results and treatments were recorded. All patients were analyzed by NGS panel containing 16 genes.ResultsA total of 60 patients with SAID were evaluated. Among them 30 (50%) were male and 30 (50%) were female. The median age at disease onset and diagnosis were 22 (0–193) months and 72 (2–213) months, respectively. The current age was median 10.3 (1.7–20.4) years. All patients were follow-up with a median 31 (6–97) months. Among 60 patients, 22 were diagnosed with CAPS, 8 with TRAPS and 30 with HIDS. The frequency of clinical symptoms was 95%, arthralgia 63.3%, gastrointestinal complaints 58.3%, urticarial rash 56.7%, myalgia 48.3%, lymphadenopathy 33.3%, respectively.Urticarial rash (86.4%), cold induced rash (45.5%) and arthritis (50%) were significantly higher in CAPS patients compared with other two groups (p< 0.05). Lymphadenopathy (46.7%) was more common in HIDS patients (p = 0.03).When we applied the diagnostic/classification criteria to our cohort, 71.7% met the Federici criteria, 53.3% fulfilled the Eurofever/PRINTO classification criteria. When performance of two diagnostic criteria (Federici and Eurofever/PRINTO criteria) was compared, the proportion of patients fulfilling the Eurofever/PRINTO criteria higher in TRAPS patients compared with other groups (p = 0.008).Statistically significant decreases were found in AIDAI scores, CRP, ESR levels from the 1st month and in the leucocyte counts from the 6th month of the treatment in CAPS patients (p = <0.001, p = 0.035, p = 0.03 and p = 0.006, respectively). In addition, AIDAI scores were correlated with CRP values (p = 0.047).In HIDS patients, there was a statistically significant decrease in AIDAI scores and ESR levels from the 1st month, CRP levels from the 3rd month, and leucocyte counts from the 12th month of treatment (p = <0.001, p = 0.003, p = <0.001 and p = 0.034, respectively). In addition, ESR values were correlated with CRP (p = 0.006). In TRAPS patients, on the other hand, there was a statistically significant decrease in AIDAI scores from the 1st month of treatment (p = 0.018).At the last visit, 93.3% of the patients were receiving anti-IL-1, 5% anti-IL-6, and 1.7% were receiving colchicine. Ninety percent of the patients were in complete remission.ConclusionWe showed that the diagnostic/classification criteria may not always be sufficient to make the diagnosis, and there is still low agreement between clinical diagnoses and molecular analyzes. Anti-IL-1 treatments have been found to be quite effective in the treatment from the early period.

Break down the barriers of auto-inflammation: How to deal with a monogenic auto-inflammatory disease and immuno-haematological features in 2022?

In the past few years, the spectrum of monogenic systemic auto-inflammatory diseases (MSAID) has widely expanded beyond the typical recurrent fever. Immuno-haematological features, as cytopenias, hypogammaglobulinemia, hypereosinophilia, lymphoproliferation and immunodeficiency, have been described in association of several MSAID. The objective of this review was to describe these particular MSAID. MSAID must be suspected in front of immuno-haematological features associated with non-infectious recurrent fever, chronic systemic inflammation, inflammatory cutaneous manifestations, arthritis or inflammatory bowel disease. Genes and cellular mechanisms involved are various but some of them are of special interest. Defects in actine regulation pathway are notably associated with cytopenia and immune deficiency. Because of their frequency, ADA2 deficiency and Vacuoles, E1-Enzyme, X-linked, auto-inflammatory, Somatic (VEXAS) syndrome deserve to be noticed. ADA2 deficiency results in polyarteritis nodosa-like presentation with a wide panel of manifestations including cytopenia(s), lymphoproliferation and immune deficiency. Neutrophilic dermatosis or chondritis associated with macrocytic anaemia or myelodysplasia should lead to screen for VEXAS. Of note, most of MSAID are associated with inflammatory anaemia. We proposed here a clinical and pragmatic approach of MSAID associated with immuno-haematological features.

Improving Diagnosis and Clinical Management of Acquired Systemic Autoinflammatory Diseases.

Systemic autoinflammatory diseases (SAID) are conditions caused by dysregulation or disturbance of the innate immune system, with neutrophils and macrophages the main effector cells. Although there are now more than 40 distinct, genetically defined SAIDs, the genetic/molecular diagnosis remains unknown for a significant proportion of patients with the disease onset in adulthood. This review focuses on new developments related to acquired/late onset SAID, including phenocopies of monogenic disorders, Schnitzler’s syndrome, Adult onset Still’s disease, VEXAS syndrome, and autoinflammatory complications associated with myelodysplastic syndrome.

High Respiratory Tract Infection Rate in Patients With Familial Mediterranean Fever.

Background Familial Mediterranean fever (FMF) is a systemic autoinflammatory disease genetically transmitted with the autosomal recessive trait. Although the pathogenesis is not certain, it is known that there is a deficiency in the regulation of the natural immune system. In this study, we aimed to search whether patients with FMF are predisposed to respiratory tract infections and whether mannose-binding lectin (MBL), as a natural immune system member, contributes to it. Methods Fifty FMF patients and 20 control groups were enrolled in the study. First, the frequencies of upper respiratory tract infection (URTI) within the previous year of both patient and control groups were evaluated retrospectively. Then, both groups were followed up for URTI for one year after starting the study. The patient's immunoglobulin A (IgA), IgM, IgG, C-reactive protein (CRP), hemogram parameters, and mannose-binding lectin were evaluated. Results The median frequency of annual URTI with a retrospective evaluation of patients was higher than that of the control group. Also, the median frequency of URTI with the prospective evaluation of patients with FMF was higher than the control group.The rate of patients with low serum IgG levels was higher in the patient group than in the control group. However, serum IgG levels of FMF patients with frequent URTI were not different from those without. The median MBL levels of both groups were similar (1312 vs. 1534 ng/mlfor the patient and control group, respectively). The rate of patients having low serum MBL levels was also similar between the groups. Conclusions In the present study, we found that patients with FMF had more URTI than healthy controls. However, the underlying cause is not fully explained. There is a need for further studies with a higher number of patients evaluating URTI in patients with FMF.

Rare, rarer, lung involvement in adult-onset Still's disease: A mini-review

Adult-onset Still's disease (AOSD) is a polygenic systemic autoinflammatory disease which is associated with increased morbidity and mortality. Pulmonary involvement is a rare, but serious complication of AOSD. As in AOSD, IL-1b, IL-18, and IL-6 dominate the molecular pathogenesis, which mediate a type 1 and type 3 inflammatory signature of the adaptive immune system. This is evidenced by the success of IL-1- and IL-6 inhibition in the management of AOSD. However, anaphylactic reactions to treatment with IL-1- or IL-6-inhibitors is currently being discussed as a potential trigger for lung involvement inf AOSD, while genetic risk factors have also been identified. Clinically, pulmonary involvement in AOSD can manifest in many different forms. Parenchymal inflammation with peripheral consolidations is the most frequent form while PAH is less common, but often very difficult to manage. This mini-review provides an overview of the pathophysiology as well as the clinical presentation and the diagnostic features of pulmonary involvement in AOSD.

Multidisciplinarity as the key to success : Cooperation between dermatology and rheumatology to optimize patient care

HintergrundPatienten mit systemischen Autoimmun- und/oder autoinflammatorischen Erkrankungen (AI/AInf) bedürfen in der Regel einer multidisziplinären Zusammenarbeit durch verschiedene Fachrichtungen.Ziel der Arbeit (Fragestellung)Wir evaluierten, ob die Etablierung eines multidisziplinären Boards (sog. Rheumaboard [RB]) zur Optimierung der Versorgung von Patienten mit Psoriasisarthritis (PsA) oder anderen AI/AInf führt.Material und MethodenEs wurden n = 272 Patienten mit AI/AInf eingeschlossen, die in 3 Gruppen eingeteilt wurden; Gruppe 1: 41 Patienten mit oder mit Verdacht auf (V. a.) PsA, von der Dermatologie in der Rheumatologie konsiliarisch avisiert; Gruppe 2: 166 Patienten mit oder mit V. a. PsA, vorstellig in der Dermatologie und im RB; Gruppe 3: 65 Patienten mit anderen AI/AInf, vorstellig in der Dermatologie und im RB. Evaluiert wurde die durchschnittliche Zeit von der initialen Vorstellung bis zur Therapieeinleitung nach erfolgter Beurteilung und Diagnostik durch beide Fachrichtungen. Darüber hinaus wurden die Diagnosesicherung/-bestätigung und die Therapieweiterführung/-optimierung bei allen 3 Gruppen analysiert.ErgebnisseDie durchschnittliche Zeitspanne von der initialen Vorstellung bis zur Therapieeinleitung betrug in Gruppe 1 85 ± 42,24 (5 bis 173) Tage, in Gruppe 2 15 ± 13,09 (0 bis 78) Tage und in Gruppe 3 20 ± 16,71 (1 bis 75) Tage. In Gruppe 2 und 3 konnte die Diagnose schneller gesichert oder bestätigt sowie die Wartezeit auf Diagnostik und Therapie deutlich reduziert werden.DiskussionDurch die Etablierung eines RB zeigt sich eine signifikante Verkürzung der Zeitspanne zwischen Erstvorstellung und Therapieeinleitung und damit eine deutliche Verbesserung des Versorgungsmanagements bei Patienten mit AI/AInf inklusive Diagnosesicherung und Therapieoptimierung.Graphic abstract

Features predicting colchicine efficacy in treatment of children with undefined systemic autoinflammatory disease: A retrospective cohort study

Patients with undefined systemic autoinflammatory diseases (uSAIDs) are challenging to manage, as there are no guidelines or recommendations for targeted therapy. We aimed to evaluate the efficacy of empiric treatment with colchicine in our single-center uSAID population in the United States, as well as the patient characteristics associated with the most robust colchicine response. Children with uSAID 18 years old at initial evaluation during 2000-2019 were included if they received 3 months of colchicine therapy. Data on demographics, clinical features, laboratory/ genetic studies, and treatment responses were collected. Most statistics were based on chi-square analyses for categorical data. Complete response to colchicine was defined as resolution of episodes or the presence of minor residual symptoms that did not require any further therapy. A partial response was defined as a decrease in the frequency, severity, or length of episodes but still necessitating additional therapy. Patients were considered nonresponders if they did not experience any improvement with colchicine at target therapeutic dosing. We identified 133 children diagnosed with uSAID who met our inclusion criteria. The median time to starting empiric colchicine was 5 months from the diagnosis of autoinflammatory disease. 92.5% (n = 123) of patients had a beneficial response to colchicine, including 46.6% (n = 62) partial responders and 45.9% (n = 61) complete responders. The presence of a nonurticarial rash was associated with an incomplete colchicine response (29.2% (n = 21) vs 13.1% (n = 8), P = .025). The presence of a heterozygous MEFV mutation in patients who did not fit Familial Mediterranean Fever diagnostic criteria (n = 25) appeared to be associated with a greater likelihood of complete colchicine response, although this was not statistically significant (62.5% (n = 14) vs 42.6% (n =11), P = .08). In MEFV mutation-negative patients, a nonurticarial rash was even more strongly associated with incomplete colchicine response, with an OR of 27.53 (CI [1.59-477], P = .023). The presence of oral ulcers also corresponded to incomplete colchicine response, although this did not reach clinical significance (38.9% (n = 28) vs 24.6% (n = 15), P = .08). There was no significant association between episode duration or frequency and colchicine response. Colchicine leads to clinical benefits in most children with uSAID. We, thus, recommend an early trial of colchicine in newly diagnosed patients with uSAID.

GSDMD drives canonical inflammasome-induced neutrophil pyroptosis and is dispensable for NETosis.

Neutrophils are the most prevalent immune cells in circulation, but the repertoire of canonical inflammasomes in neutrophils and their respective involvement in neutrophil IL-1β secretion and neutrophil cell death remain unclear. Here, we show that neutrophil-targeted expression of the disease-associated gain-of-function Nlrp3A350V mutant suffices for systemic autoinflammatory disease and tissue pathology in vivo. We confirm the activity of the canonical NLRP3 and NLRC4 inflammasomes in neutrophils, and further show that the NLRP1b, Pyrin and AIM2 inflammasomes also promote maturation and secretion of interleukin (IL)-1β in cultured bone marrow neutrophils. Notably, all tested canonical inflammasomes promote GSDMD cleavage in neutrophils, and canonical inflammasome-induced pyroptosis and secretion of mature IL-1β are blunted in GSDMD-knockout neutrophils. In contrast, GSDMD is dispensable for PMA-induced NETosis. We also show that Salmonella Typhimurium-induced pyroptosis is markedly increased in Nox2/Gp91Phox -deficient neutrophils that lack NADPH oxidase activity and are defective in PMA-induced NETosis. In conclusion, we establish the canonical inflammasome repertoire in neutrophils and identify differential roles for GSDMD and the NADPH complex in canonical inflammasome-induced neutrophil pyroptosis and mitogen-induced NETosis, respectively.

Efficacy of anakinra treatment in pediatric rheumatic diseases: Our single-center experience.

This study aims to present our experience on anakinra, a recombinant interleukin-1 (IL-1) receptor antagonist, and efficacy results in pediatric rheumatic diseases in our clinic. Between July 1st, 2016 and July 1st, 2020, a total of 33 pediatric patients (18 males, 15 females; mean age: 6±3.4 years; range 4 to 13 years) with pediatric rheumatic diseases who were treated with anakinra were retrospectively analyzed. The patients with over one-month treatment period and followed for at least one year were included. Demographic and clinical findings, outcomes, adverse events, prior and/or additional treatments were collected at baseline, at 3 and 12 months of therapy. There were 33 patients with different pediatric rheumatic diseases (11 with systemic juvenile idiopathic arthritis [sJIA] complicated by macrophage activation syndrome [MAS], six with hyperimmunoglobulin-D syndrome, five with cryopyrin-associated periodic syndrome, five with familial Mediterranean fever, four with idiopathic recurrent pericarditis, one with NLRP12-associated periodic fever syndrome and one with unclassified systemic autoinflammatory disease), in the study group. The complete response was observed 69.7% of patients, partial response in 24.2%, and no response in 6.1% at three months of treatment. Inactive disease status was achieved in 45.5% of the patients with remission-on medication and 18.2% of the patients with remission-off medication at the end of a year. Anakinra was switched to other biological treatments in 51.5% of patients (n=17). Biological switch to canakinumab and tocilizumab were observed in 70.6% and 29.4% of these patients. Except for local reactions (n=2), no adverse events were observed in any of the patients. Anakinra appears to be a promising treatment alternative owing to its rapid effect as a result of its short half-life in autoinflammatory conditions. While short-term therapy seems to be sufficient for the sJIA complicated by MAS, the patients with systemic autoinflammatory diseases maintenance a more anakinra-dependent course.

Rare mutations in NLRP3 and NLRP12 associated with familial cold autoinflammatory syndrome: two Chinese pedigrees.

Familial cold autoinflammatory syndrome (FCAS) is the mildest subtype of cryopyrin-associated periodic syndrome (CAPS) and is a rare inherited systemic autoinflammatory disease (SAID). CAPS is the consequence of a rare group of genetic disorders that are mostly reported in European and American populations, but scarcely reported in Chinese populations. NLRP3, NLRP12, PLCG2, and NLRC4 are known pathogenic genes associated with FCAS, and the aim of this study was to identify pathogenic mutations in two intact pedigrees of Chinese FCAS. We performed Sanger sequencing of genomic DNA samples from 25 affected and 32 unaffected members of the two intact pedigrees and analyzed the pathogenic mutations for their conservativeness using multiple sequence alignment tools. In addition, we reviewed previously reported pathogenic genes of FCAS and their pathogenicity classification and summarized the characteristics of different genotypes and phenotypes of FCAS. This study reported two intact FCAS pedigrees with different genotypes and phenotypes, the heterozygous mutation (p.V72M) in NLRP3 in pedigree 1 and the heterozygous mutation (p.R754H) in NLRP12 in pedigree 2. There are no reports targeting p.V72M in NLRP3 in FCAS1, and there are relatively few relevant phenotypic data on the clinical manifestations identified in previous pedigrees. Multiple sequence comparisons of NLRP3 indicate that the p.V72M mutation is highly conserved during evolution. Our study has enriched the understanding of the pathogenesis of FCAS, a rare disease especially in Asian populations. KEY POINTS: •The NLRP3 (p.V72M) variant was first discovered in the Chinese pedigree of FCAS1 •NLRP12 (p.R754H) variants are not conserved in multiple sequence alignments, but they are still co-segregated and expressed in the big Chinese diseased pedigree.

The role of interleukin 1 in the development of human diseases: focus on Anakinra (IL-1 receptor antagonist)

According to modern concepts, human immune-mediated inflammatory diseases (IMIDs), depending on the prevailing mechanisms of immunopathogenesis, are divided into two main categories – autoimmune and autoinflammatory.At the same time, both autoimmune and autoinflammatory mechanisms are involved in the pathogenesis of most IMIDs, the complex interaction of which is reflected in the polymorphism of clinical manifestations, course variants, outcomes, and therapy efficacy. It is assumed that hyperproduction of cytokines of the interleukin (IL) 1 family, which is one of the key regulators of innate immunity, determines the “crossover” between the mechanisms of autoinflammation and autoimmunity in IMIDs. Anakinra is currently used in clinical practice to suppress the pathological effects of IL-1. An analysis of the results of the clinical use of Anakinra indicates that treatment with this drug should be considered as a promising direction in the pharmacotherapy of systemic autoinflammatory diseases (SAIDs) and critical conditions in children and adults associated with the development of hyperinflammation. The main directions of the Anakinra clinical research program are presented, including: determining the place of the drug in the implementation of the "Treat to Target" strategy and personalization of therapy, primarily in patients with “resistant” (difficult-to-treat) subtype of rheumatoid arthritis and comorbid pathology, as well as with severe forms of microcrystalline arthritis; the possibility of using Anakinra to improve the early diagnosis of SAIDs in children and adults; creation of the Russian register of patients with SAIDs, who are potentially indicated for treatment with Anakinra.

RNF213-associated urticarial lesions with hypercytokinemia

Urticarial lesions are observed in both cutaneous and systemic disorders. Familial forms of urticarial syndromes are rare and can be encountered in systemic autoinflammatory diseases. We sought to investigate a large family with dominantly inherited chronic urticarial lesions associated with hypercytokinemia. We performed a genetic linkage analysis in 14 patients from a 5-generation family, as well as whole-exome sequencing, cytokine profiling, and transcriptomic analyses on samples from 2 patients. The identified candidate protein was studied after invitro expression of the corresponding normal and mutated recombinant proteins. An unsupervised proteomic approach was used to unveil the associated protein network. The disease phenotype of the most affected family members is characterized by chronic urticarial flares associated with extremely high plasma levels of proinflammatory (IL-1β, IL-6, and TNF-α) and anti-inflammatory (IL-10 and IL-1 receptor antagonist [IL-1RA]) cytokines, with no secondary organ dysfunction, no susceptibility to infections, no fever, and normal C-reactive protein levels. Monocyte transcriptomic analyses identified an immunotolerant profile in the most affected patient. The affected family members carried a loss-of-function mutation in RNF213 that encodes mysterin, a protein with a poorly known physiologic role. We identified the deubiquitinase CYLD, a major regulator of inflammation, as an RNF213 partner and showed that CYLD expression is inhibited by wild-type but not mutant RNF213. We identified a new entity characterized by chronic urticarial lesions associated with a clinically blunted hypercytokinemia. This disease, which is due to loss of function of RNF213, reveals mysterin's key role in the complex molecular network of innate immunity.

Autoinflammatory syndromes with coexisting variants in Mediterranean FeVer and other genes: Utility of multiple gene screening and the possible impact of gene dosage

ObjectiveTo assess the possible impact conferred by co-existing variants in MEditerranean FeVer (MEFV) and other genes on systemic autoinflammatory disease (SAID) phenotype. MethodsConsecutive patients (n = 42) who underwent screening for SAIDs by next generation sequencing (NGS) targeting 26 genes, and carried at least one MEFV gene variant, were retrospectively studied. A total of 63 MEFV gene variants mainly located in exon 10 (n = 29) and exon 2 (n = 19) were identified in 21 patients with juvenile- and 21 with adult-onset disease. ResultsThe candidate clinical diagnosis was Familial Mediterranean Fever (FMF) in 11, polygenic SAIDs (PFAPA, Still's disease, atypical SAPHO and inflammatory bowel disease) in 9, whereas the disease could not be clinically defined in 22 patients. Notably, 33 out of the 42 patients (79%) had at least one co-existing variants in 19 genes other than MEFV. NGS confirmed all clinical diagnoses and helped defining diagnosis in 59% of the remaining cases. Patients with undefined SAIDs (n = 9) or atypical FMF phenotype (n = 12) carried significantly more disease-causing variants in genes other than MEFV compared to patients with typical FMF (n = 9). More than one variants in these genes were significantly associated with adult-onset disease, while disease–causing variants in the same genes were also associated with an overall more severe SAID phenotype. ConclusionCo-existing variants in SAID-related genes may explain the phenotypic variability of these diseases. Further studies should validate combined molecular and clinical data in order to better understand the cumulative gene dosage effect and improve the classification of these patients.

Development and Implementation of the AIDA International Registry for Patients With Undifferentiated Systemic AutoInflammatory Diseases

ObjectiveThis paper points out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients affected by Undifferentiated Systemic AutoInflammatory Diseases (USAIDs).MethodsThis is an electronic registry employed for real-world data collection about demographics, clinical, laboratory, instrumental and socioeconomic data of USAIDs patients. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is designed to obtain standardized information for real-life research. The instrument is endowed with flexibility, and it could change over time according to the scientific acquisitions and potentially communicate with other similar tools; this platform ensures security, data quality and data governance.ResultsThe focus of the AIDA project is connecting physicians and researchers from all over the world to shed a new light on heterogeneous rare diseases. Since its birth, 110 centers from 23 countries and 4 continents have joined the AIDA project. Fifty-four centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 179 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry is collecting baseline and follow-up data using 3,769 fields organized into 23 instruments, which include demographics, history, symptoms, trigger/risk factors, therapies, and healthcare information access for USAIDs patients.ConclusionsThe development of the AIDA International Registry for USAIDs patients will facilitate the online collection of real standardized data, connecting a worldwide group of researchers: the Registry constitutes an international multicentre observational groundwork aimed at increasing the patient cohort of USAIDs in order to improve our knowledge of this peculiar cluster of autoinflammatory diseases. NCT 05200715 available at https://clinicaltrials.gov/.

COVID-19: Clinical features and outcomes in unvaccinated 2-dose and 3-dose vaccinated against SARS-CoV-2 patients with systemic autoimmune and autoinflammatory rheumatic diseases

Clinical data on vaccinated patients with coronavirus disease 2019 (COVID-19) who have systemic autoimmune and autoinflammatory rheumatic diseases (SAARD) are limited. This observational study aimed to report the clinical features and outcomes of COVID-19 among cases with SAARD that were unvaccinated or were 2- and 3-dose vaccinated against SARS-CoV-2 and were consecutively recorded by the treating physician. Unvaccinated and 2- and 3-dose vaccinated patients were compared in terms of COVID-19 symptomatology, hospitalizations, oxygen supplementation requirements, and death rates. From the beginning of the pandemic to February 15, 2022, 134 vaccine-naïve COVID-19 cases were recorded among our study cohort. From March 1, 2021 to February 15, 2022, 89 2-dose vaccinated and 105 3-dose vaccinated patients who were infected with SARS-CoV-2 ≥14 days after the second dose were included. The hospitalization rate was higher in the unvaccinated (n = 36, 26.9%) than in the 2-dose (n = 13, 14.6%, p = 0.03) or 3-dose (n = 5, 4.8%, p < 0.001) vaccinated patients. Severe/critical COVID-19 cases requiring oxygen supplementation were the least among 3-dose vaccinated (n = 4, 3.8%) compared to both 2-dose vaccinated (n = 12, 13.5%, p = 0.018) and unvaccinated (n = 25, 18.7%, p < 0.001) patients. ICU admission and death rates were similar among unvaccinated (n = 5, 3.7% and n = 3, 2.2%, respectively) and 2-dose vaccinated patients (n = 4, 4.5%; and n = 2, 2.2%, respectively), while no 3-dose vaccinated patients died or required ICU admission. Logistic regression analysis revealed a significant inverse association between 3-dose vaccination and severe/critical COVID-19 (OR = 0.078, 95% CI: 0.022–0.273, p < 0.001). In conclusion, these findings argue in favor of booster vaccination against SARS-CoV-2 in patients with SAARD.