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The steady increase in the number of autoimmune diseases and immune-mediated autoinflammatory processes causes an increased interest of doctors of all specialties in this topic and makes the issue of early detection of autoimmune disorders / autoimmune syndrome (AS) extremely urgent. These disorders often develop against the backdrop of an atypical stream of chronic active viral infections caused by persistent viruses, in particular those of the Herpesviridae family, and remain undiagnosed due to polysymptomatic disease, and various “clinical masks” of the disorders caused by them. The semi-quantitative method developed by us for screening assessment of the content of autoantibodies in the blood serum of patients suffering from ACAI caused by herpes viruses using the ELISA method (Immunodot) is a highly specific screening method that can allow for an objective assessment of the dynamics of the autoimmune process, as well as control the effectiveness of the ongoing complex antiviral and immunomodulatory therapy. The detection of autoantibodies of various specificity in the blood serum of patients suffering from an atypical chronic active infection caused by herpes viruses (ACAI) is an early diagnostic marker, necessary, first of all, to identify autoimmune pathology of the nervous system, which is associated with a long course of the active mixed herpes-viral process.

The innate immunity works as a defence bullwark that safeguards healthy tissues with the power of detecting infectious agents in the human body: errors in the context of innate immunity identify autoinflammatory disorders (AIDs), which arise as bouts of aberrant inflammation with little or no involvement of T and B cells and neither recognized infections, nor associated autoimmune phenomena. Hereditary AIDs tend to have a pediatric-onset heralded by stereotyped inflammatory symptoms and fever, while AIDs without an ascertained cause, such as systemic juvenile idiopathic arthritis, derive from the interaction of genetic factors with environmental noxae and are unevenly defined. A dysregulated inflammasome activation promotes the best-known family of AIDs, as well as several degenerative and metabolic disorders, but also nuclear factor κB- and interferon-mediated conditions have been framed as AIDs: the zenith of inflammatory flares marks different phenotypes, but diagnosis may go unnoticed until adulthood due to downplayed symptoms and complex kaleidoscopic presentations. This review summarizes the main AIDs encountered in childhood with special emphasis on the clinical stigmata that may help establish a correct framework and blueprints to empower young scientists in the recognition of AIDs. The description focuses inflammasomopathies as paradigms of interleukinopathies, nuclear factor-κB -related disorders and interferonopathies. The challenges in the management of AIDs during childhood have been recently boosted by numerous therapeutic options derived from genomically-based approaches, which have led to identify targeted biologic agents as rationalized treatments and achieve more tangible perspectives of disease control. Supplementary Information The online version contains supplementary material available at 10.1007/s11739-021-02751-7.

Autoinflammatory diseases are conditions in which pathogenic inflammation arises primarily through antigen-independent hyperactivation of immune pathways. First recognized just over 2 decades ago, the autoinflammatory disease spectrum has expanded rapidly to include more than 40 distinct monogenic conditions. Related mechanisms contribute to common conditions such as gout and cardiovascular disease. Here, we review the basic concepts underlying the "autoinflammatory revolution" in the understanding of immune-mediated disease and introduce major categories of monogenic autoinflammatory disorders recognized to date, including inflammasomopathies and other IL-1-related conditions, interferonopathies, and disorders of nuclear factor kappa B and/or aberrant TNF activity. We highlight phenotypic presentation as a reflection of pathogenesis and outline a practical approach to the evaluation of patients with suspected autoinflammation.

ObjectivesThe prevalence and clinical outcomes of COVID-19 in patients with autoimmune diseases who are frequently treated with disease modifying therapies remains poorly understood. This meta-analysis aims to assess the prevalence and clinical outcomes of COVID-19 in autoimmune diseases.MethodsElectronic databases were searched for observational and case–controlled studies. We sorted medications into glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic or targeted synthetic DMARDs (b/tsDMARDs), which was also divided into monotherapy and b/tsDMARDs–csDMARDs combination therapy.ResultsWe analysed 62 observational studies with a total of 319 025 patients with autoimmune diseases. The prevalence of COVID-19 was 0.011 (95% CI: 0.005 to 0.025). Meta-analysis of seven case–controlled studies demonstrated that the risk of COVID-19 in autoimmune diseases was significantly higher than in control patients (OR: 2.19, 95% CI: 1.05 to 4.58, p=0.038). Meta-regression analysis showed glucocorticoids were significantly associated with the risk of COVID-19. For clinical outcomes, we assessed 65 studies with 2766 patients with autoimmune diseases diagnosed with COVID-19. The rates of hospitalisation and mortality were 0.35 (95% CI: 0.23 to 0.50) and 0.066 (95% CI: 0.036 to 0.12), respectively. Glucocorticoids, csDMARDs and b/tsDMARDs–csDMARDs combination therapy increased the risk of these outcomes, whereas b/tsDMARDs monotherapy, particularly antitumour necrosis factor agents, were associated with a lower risk of hospitalisation and death.ConclusionsOur meta-analysis demonstrated that patients with autoimmune diseases had an increased risk of COVID-19, primarily attributed to glucocorticoid use. b/tsDMARDs monotherapy was associated with a lower risk of severe COVID-19 suggesting its safety in the COVID-19 pandemic.

The systemic autoinflammatory disorders (SAIDs) or periodic fever syndromes are disorders of innate immunity, which can be inherited or acquired. They are almost all very rare and easily overlooked; typically, patients will have seen multiple specialities prior to diagnosis, so a high level of clinical suspicion is key. It is important to note that these are 'high-value' diagnoses as the majority of these syndromes can be very effectively controlled, dramatically improving quality of life and providing protection against the development of irreversible complications such as AA amyloidosis. In this article, we take an overview of SAIDs and look at the common features; in Part 2, we take a more in-depth look at the better recognized or more dermatologically relevant conditions.

Disruption of innate immunity leading to systemic inflammation and multi-organ dysfunction is the basilar footprint of autoinflammatory disorders (AIDs), ranging from rare hereditary monogenic diseases to a large number of common chronic inflammatory conditions in which there is a simultaneous participation of multiple genetic components and environmental factors, sometimes combined with autoimmune phenomena and immunodeficiency. Whatever their molecular mechanism, hereditary AIDs are caused by mutations in regulatory molecules or sensors proteins leading to dysregulated production of proinflammatory cytokines or cytokine-inducing transcription factors, fever, elevation of acute phase reactants, and a portfolio of manifold inflammatory signs which might occur in a stereotyped manner, mostly with overactivity or misactivation of different inflammasomes. Symptoms might overlap in the pediatric patient, obscuring the final diagnosis of AIDs and delaying the most appropriate treatment. Actually, the fast-paced evolution of scientific knowledge has led to recognize or reclassify an overgrowing number of multifactorial diseases, which share the basic pathogenetic mechanisms with AIDs. The wide framework of classic hereditary periodic fevers, AIDs with prominent skin involvement, disorders of the ubiquitin-proteasome system, defects of actin cytoskeleton dynamics, and also idiopathic nonhereditary febrile syndromes occurring in children is herein presented. Interleukin-1 dependence of these diseases or involvement of other predominating molecules is also discussed.

ObjectivesTo evaluate the long-term efficacy and safety of canakinumab to treat patients with colchicine-resistant familial Mediterranean fever (crFMF) during Epoch 4 (weeks 41 to 113) of the CLUSTER study.MethodsPatients received open-label canakinumab 150 or 300 mg, every 4 or 8 weeks during a 72-week period. We evaluated disease activity every 8 weeks using the physician global assessment (PGA) of disease activity, counting the number of flares, and measuring concentrations of C reactive protein (CRP) and serum amyloid A (SAA). Safety was studied by determination and classification of observed adverse events (AEs). We analysed safety and efficacy separately in two subgroups of patients receiving a cumulative dose of less than 2700 mg, or equal or more than 2700 mg.ResultsOf the 61 patients that started the CLUSTER study, 60 entered Epoch 4 and 57 completed it. During the 72-week period, 35/60 (58.3%) patients experienced no flares, and 23/60 (38.3%) had one flare, as compared with a median of 17.5 flares per year reported at baseline. PGA scores indicated no disease activity for the majority of patients throughout the study. Median CRP concentrations were always lower than 10 mg/L, while median SAA concentrations remained over the limit of normal (10 mg/L) but under the 30 mg/L threshold. No new or unexpected AEs were reported.ConclusioncrFMF patients treated with canakinumab during 72 weeks experienced a minimal incidence of flares and good control of clinical disease activity, with no new safety concerns reported.

Since 2013, the International Union of Immunological Societies (IUIS) expert committee (EC) on Inborn Errors of Immunity (IEI) has published an updated phenotypic classification of IEI, which accompanies and complements their genotypic classification into ten tables. This phenotypic classification is user-friendly and serves as a resource for clinicians at the bedside. There are now 430 single-gene IEI underlying phenotypes as diverse as infection, malignancy, allergy, autoimmunity, and autoinflammation. We herein report the 2019 phenotypic classification, including the 65 new conditions. The diagnostic algorithms are based on clinical and laboratory phenotypes for each of the ten broad categories of IEI.

The past two decades have seen an exponential increase in the number of monogenic autoinflammatory disorders described, coinciding with improved genetic sequencing techniques. This group of disorders has evolved to be heterogeneous and certainly more complex than the original four 'periodic fever syndromes' caused by innate immune over-activation. This review aims to provide an update on the classic periodic fever syndromes as well as introducing the broadening spectrum of clinical features seen in more recently described conditions.

Autoinflammatory diseases comprise a group of chronic disabling entities characterized by inflammation without the presence of infectious agents, auto-antibodies or antigen-specific T-cells. Many autoinflammatory diseases are caused by monogenic defects, which lead to disturbed immune signalling with release of proinflammatory mediators. In addition to interleukin-1β and interleukin-18, interferons play a key role in the pathophysiology of these disorders. Patients with autoinflammatory diseases show a broad variety of clinical symptoms, including skin involvement. Wheals, pustules and ulcerative lesions are the most common cutaneous findings observed. Knowledge of the clinical presentation of autoinflammatory diseases is crucial for establishing the diagnosis and guiding appropriate treatment. This review focuses on the dermatological findings in selected autoinflammatory disorders based on their distinct pathomechanisms.

Spondyloarthropathies (SpA) refer to a multifactorial disease affecting the axial and peripheral skeleton, mainly in the larger joints of the lower limbs. The exact mechanism that causes most SpAs is still vague; however, it is clear that both genetics and environmental factors are involved in the pathogenesis of the disease. Environmental factors directly implicate innate immunity, which is a vital compartment in triggering autoinflammatory disorders. To date, only a few studies specifically focused on the potential role of these factors, including mechanical, psychological, and oxidative stresses, smoking, diet, and infections. Here we discuss the contribution of named stresses and related molecular mechanisms on SpA diseases, apart from the diet and infection, which were the concept of previous chapters.

Systemic autoinflammatory disorders (SAIDs) encompass a heterogeneous group of monogenic disorders characterized by recurrent episodes of systemic and organ-specific inflammation. Genetic studies have facilitated the identification of Mendelian forms of SAIDs but many patients still remain without a diagnosis. Recent studies have uncovered that somatic (acquired) mutations can cause later-onset SAIDs. In this review, we will discuss the current knowledge surrounding the genetics of these acquired auto-inflammatory disorders (AAIDs), with a focus on VEXAS, NLRP3-associated AAIDs and Schnitzler's syndrome and provide suggestions for future research in this field.

We conducted a nationwide survey of inborn errors of immunity (IEI) in Japan for the second time in 10 years, focusing on protective measures for IEI patients against infectious diseases. Questionnaires were sent to various medical departments nationwide, and a total of 1307 patients were reported. The prevalence of IEI was 2.2 patients per 100,000 population, which was comparable with the previous nationwide study. The most common disease category was autoinflammatory disorders (25%), followed by antibody deficiencies (24%) and congenital defects of phagocyte number or function (16%). We found that a significant number of patients received contraindicated vaccines, principally because the patients were not diagnosed with IEI by the time of the vaccination. Regarding diseases for which BCG vaccination is contraindicated, 43% of patients had actually received BCG, of which 14% developed BCG-related infections. BCG-related infections were mainly observed among patients with CGD and MSMD. In order to prevent IEI patients from receiving inadequate vaccines, continuous education to parents and physicians is needed, along with the expansion of newborn screening, but efforts to screen IEI at the site of vaccination also remain important.

Background: We investigated the pattern of reported immune diseases in the international ASIA syndrome registry. Methods: Data from 500 subjects exposed to adjuvants from the ASIA syndrome international registry were analysed. Results: The patient mean age was 43 ± 17 years and 89% were female. Within the reported immune diseases, 69% were well-defined immune diseases (autoimmune, autoinflammation, and mixed pattern diseases). Among the well-defined immune diseases following the exposure to adjuvants, polygenic autoimmune diseases were significantly higher than autoinflammatory disorders (92.7% vs 5.8%, respectively, p < 0.001). Polygenic autoimmune diseases such as connective tissue diseases were significantly linked to the exposure to HBV vaccine (OR 3.15 [95%CI 1.08–9.23], p = 0.036). Polygenic autoinflammatory diseases were significantly associated with the exposure to influenza vaccination (OR 10.98 [95%CI 3.81–31.67], p < 0.0001). Conclusions: Immune conditions following vaccination are rare, and among these, polygenic autoimmune diseases represent the vast majority of the well-defined immune diseases reported under the umbrella ASIA syndrome. However, vaccines benefit outweighs their autoimmune side effects.

The purpose of regenerative medicine is to restore or enhance the normal function of human cells, tissues, and organs. From a clinical point of view, the use of stem cells is more advantageous than differentiated cells because they can be collected more easily and in larger quantities, their proliferation capacity is more pronounced, they are more resistant in cell culture, their aging is delayed, they are able to form a number of cell lines, and they are able to promote vascularization of tissue carriers. The therapeutic use of stem cells for disease modification, immunomodulation, or regenerative purposes are undoubtedly encouraging, but most studies are still in their early stages, and the clinical results reported are not clear with regard to therapeutic efficacy and potential side effects. Uniform regulation of the clinical application of stem cells is also indispensable for this highly customizable, minimally invasive, individualized therapeutic method to become a successful and safe treatment alternative in many different autoimmune and autoinflammatory disorders.

The autoinflammatory diseases encompass approximately 30 monogenic disorders in which inborn errors in the innate immune system lead to episodic systemic inflammation. Largely mediated by dysregulation of myeloid cells, interleukin (IL)-1β, type I interferon, and NF-κB, these disorders have rapidly expanded over the past several years, and increasing numbers of patients identified. Crossover disorders, bridging autoinflammation and immunodeficiency, have recently been described. This article focuses on the clinical presentation of IL-1 and interferon-driven autoinflammatory disorders, and discusses novel diseases with features of immunodeficiency. Approaches to the clinical diagnosis, genetic testing, and treatment of these disorders are addressed.

Primary antibodydeficiencies (PAD) constitute the majority of all primary immunodeficiency diseases (PID) also termed in born errors of immunity (IEI). This category (PAD) representsaround 52% of all IEI and the proportion overall is still greater given that antibody deficiency is a component of other groups including combined and severe combined immunodeficiencies (SCID), autoinflammatory disorders, diseases of immune dysregulation and other well defined PIDs(1,2). Secondary antibody deficiencies (SAD) represent a larger and expanding number of individuals resulting from the use of a wide range of immunosuppressive therapies, in particular those targeting B cells, and may also result from renal orgastrointestinal immunoglobulin losses, infections, for example HIVormalaria,malnutritionorothers(3).

Background Adult onset Still’s disease (AOSD) is a rare inflammatory disorder that classically presents with high spiking fevers, evanescent rash, and arthritis. The diagnosis is one of exclusion and can be further complicated by atypical presentations, particularly in elderly patients in whom AOSD is very rare. Case presentation A case of AOSD in a 73-year-old woman with a non-classic presentation, leading to delayed diagnosis and management, is presented along with a review of the English literature for AOSD cases in elderly people over 70 years of age. Thirty nine case reports and series were identified and the current case was added, totaling 42 individual cases. Significant findings included a four-times higher prevalence in females, a higher prevalence of macrophage activation syndrome despite lower mortality, the presence of pruritic rash in almost one fifth of the cases, and high prevalence of delayed diagnosis. Conclusions AOSD in the elderly may vary from the classic criteria described in the medical literature and may lead to delayed diagnosis and management. Further evaluation and better characterization of AOSD in the elderly remains an area of interest.

The most recent updated classification of inborn errors of immunity/primary immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee, was published in January 2020. Within days of completing this report, it was already out of date, evidenced by the frequent publication of genetic variants proposed to cause novel inborn errors of immunity. As the next formal report from the IUIS Expert Committee will not be published until 2022, we felt it important to provide the community with a brief update of recent contributions to the field of inborn errors of immunity. Herein, we highlight studies that have identified 26 additional monogenic gene defects that reach the threshold to represent novel causes of immune defects. ispartof: JOURNAL OF CLINICAL IMMUNOLOGY vol:41 issue:3 pages:666-679 ispartof: location:Netherlands status: published

Childhood is a period where most vaccines are administered in order to build-up immunological memory, and immunization against vaccine-preventable diseases is an essential part of child care and health. The administration of vaccines to children with inflammatory diseases is a frequent point of concern for parents and physicians. Published information on the relation between vaccines and autoinflammatory diseases of the central nervous system (CNS) consists of case and cohort studies and reviews, in great majority on adult patients. Vaccines do not have any established causative or triggering effects on these diseases. Another issue is the immunization schedule of patients with autoinflammatory CNS diseases, specifically the interactions between the disorder, the clinical status, the treatment and the vaccine. In this review, we summarize the existing information between autoinflammatory disorders of the CNS and vaccines in childhood and underline the points to be considered under various treatment regimens.

Systemic autoinflammatory disorders comprise an expanding group of rare conditions. They are mediated by dysfunction of the innate immune system and share a core of phenotypic manifestations including recurrent attacks of fever, cutaneous signs, chest or abdominal pain, lymphadenopathy, vasculopathy, and musculoskeletal symptoms. Diagnosis is often established in childhood, but a growing number of adult patients are being recognized with systemic autoinflammatory disorders, including adult-onset disease. In this review, we provide a concise update on the pathophysiology, clinical presentation, and diagnostic approach of systemic autoinflammatory disorders with an emphasis on the adult patient population. Despite the recent advances in genetic testing, the diagnosis of autoinflammatory disease in adult patients is often based on a thorough knowledge of the clinical phenotype. Becoming acquainted with the clinical features of these rare disorders may assist in developing a high index of suspicion for autoinflammatory disease in patients presenting with unexplained episodes of fever or inflammation. ispartof: AUTOIMMUNITY REVIEWS vol:20 issue:4 ispartof: location:Netherlands status: published

Pemphigus has been associated with other autoimmune and autoinflammatory disorders. Specifically, some case reports in the literature document coexistence of pemphigus with psoriasis, but this association is lacking larger scale investigation. With this in mind, we conducted a systematic review and meta-analysis to evaluate the association between pemphigus and psoriasis. In doing so, we found an association between the two conditions. Pemphigus was more common in patients with psoriasis than in controls (OR 2.64, 95% CI 1.24-5.59, P=0.01), with heterogeneity (I2=94%). We go on to propose pathophysiologic mechanisms and its relevance for diagnostic and management considerations.

Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively). Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.

Sarcoidosis is a complex disease that belongs to the vast group of autoinflammatory disorders, but the etiological mechanisms of which are not known. At the crosstalk of environmental, infectious, and genetic factors, sarcoidosis is a multifactorial disease that requires a multidisciplinary approach for which genetic research, in particular, next generation sequencing (NGS) tools, has made it possible to identify new pathways and propose mechanistic hypotheses. Codified treatments for the disease cannot always respond to the most progressive forms and the identification of new genetic and metabolic tracks is a challenge for the future management of the most severe patients. Here, we review the current knowledge regarding the genes identified by both genome wide association studies (GWAS) and whole exome sequencing (WES), as well the connection of these pathways with the current research on sarcoidosis immune-related disorders.

This article provides an overview of the main drugs to treat autoinflammatory disorders focusing on the four emblematic diseases within this group which represent, to date, the vast majority of patients with monogenic SAID; i.e. familial Mediterranean fever, mevalonate kinase deficiency, TNF receptor 1 deficiency and cryopyrin-associated periodic syndrome. We will therefore resume the evolutionary risks of the four main IL-1 dependent SAID, there treatments and monitoring tools. After having exposed the general principles, we will detail specific guidelines for the management in everyday clinical practice of patients according to the four main pathologies based on both our expertise and international recommendations. We aim herein to guide practitioners in charge of patients with common SAID towards optimal follow-up with appropriate monitoring of anti-inflammatory drugs.

ObjectivesIncreasing data about COVID-19 have been acquired from the general population. We aim to further evaluate the clinical characteristics of COVID-19 in patients with systemic autoimmune diseases (AIDs).MethodsWe included all confirmed inpatients with COVID-19 and systemic AIDs in Wuhan Tongji Hospital from 29 January to 8 March 2020. We retrospectively collected and analysed information on epidemiology of 1255 inpatients and additional clinical characteristics of patients with systemic AIDs. Outcomes were followed up until 16 April 2020.ResultsOf the 1255 patients with COVID-19, the median age was 64.0 years and 53.1% were male. More than half (63.0%) had chronic comorbidities. The proportions of elderly, male and patients with comorbidities were significantly higher in intensive care unit (ICU) than in the general ward (pConclusionsOlder males with chronic comorbidities are more vulnerable to severe COVID-19. The lower proportion of COVID-19 in patients with systemic AIDs needs more high-quality human clinical trials and in-depth mechanism researches. Of note, the withdrawal of anti-AIDs treatments during hospitalisation can lead to flares of diseases.

ObjectivesThere is little known about the impact of SARS-CoV-2 on patients with inflammatory rheumatic and musculoskeletal diseases (iRMD). We examined epidemiological characteristics associated with severe disease, then with death. We also compared mortality between patients hospitalised for COVID-19 with and without iRMD.MethodsIndividuals with suspected iRMD-COVID-19 were included in this French cohort. Logistic regression models adjusted for age and sex were used to estimate adjusted ORs and 95% CIs of severe COVID-19. The most significant clinically relevant factors were analysed by multivariable penalised logistic regression models, using a forward selection method. The death rate of hospitalised patients with iRMD-COVID-19 (moderate–severe) was compared with a subset of patients with non-iRMD-COVID-19 from a French hospital matched for age, sex, and comorbidities.ResultsOf 694 adults, 438 (63%) developed mild (not hospitalised), 169 (24%) moderate (hospitalised out of the intensive care unit (ICU) and 87 (13%) severe (patients in ICU/deceased) disease. In multivariable imputed analyses, the variables associated with severe infection were age (OR=1.08, 95% CI: 1.05–1.10), female gender (OR=0.45, 95% CI: 0.25–0.80), body mass index (OR=1.07, 95% CI: 1.02–1.12), hypertension (OR=1.86, 95% CI: 1.01–3.42), and use of corticosteroids (OR=1.97, 95% CI: 1.09–3.54), mycophenolate mofetil (OR=6.6, 95% CI: 1.47–29.62) and rituximab (OR=4.21, 95% CI: 1.61–10.98). Fifty-eight patients died (8% (total) and 23% (hospitalised)). Compared with 175 matched hospitalised patients with non-iRMD-COVID-19, the OR of mortality associated with hospitalised patients with iRMD-COVID-19 was 1.45 (95% CI: 0.87–2.42) (n=175 each group).ConclusionsIn the French RMD COVID-19 cohort, as already identified in the general population, older age, male gender, obesity, and hypertension were found to be associated with severe COVID-19. Patients with iRMD on corticosteroids, but not methotrexate, or tumour necrosis factor alpha and interleukin-6 inhibitors, should be considered as more likely to develop severe COVID-19. Unlike common comorbidities such as obesity, and cardiovascular or lung diseases, the risk of death is not significantly increased in patients with iRMD.Trial registration numberClinicalTrials.gov Registry (NCT04353609).

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant autoinflammatory syndrome characterized by prolonged and recurrent episodes of fever, abdominal and/or chest pain, arthralgia, myalgia, and erythematous rash. TRAPS is associated with heterozygous variants in the TNFRSF1A gene, which encodes the TNFR1 (tumor necrosis factor receptor 1) receptor. Disease-causing variants are found exclusively in the extracellular domain of TNFR1 and affect receptor structure and binding to the TNF ligand. The precise mechanism of the disease is still unclear, but it is thought that intracellular accumulation of misfolded mutant protein leads to endoplasmic reticulum stress and enhanced inflammatory responses through constitutive activation of various immune pathways. Other possible mechanisms contributing to the disease pathogenesis include defective receptor shedding, TNF-induced cell death, production of reactive oxygen species, and autophagy impairment. Patients’ leucocytes are hyperresponsive to stimulation and produce elevated levels of proinflammatory cytokines. Systemic autoimmune (AA) amyloidosis is an important cause of morbidity and mortality in TRAPS. Over the last two decades, new therapies have changed the progression and outcome of the disease. In this review, we summarize clinical data from 209 patients with validated pathogenic variants reported in the literature and discuss TRAPS diagnosis, pathogenesis, and treatment options.

Summary The systemic autoinflammatory disorders (SAIDS) or periodic fever syndromes are disorders of innate immunity, which can be inherited or acquired. They are almost all very rare and easily overlooked; typically, patients will have seen multiple specialities prior to diagnosis, so a high level of clinical suspicion is key. It is important to note that these are ‘high-value’ diagnoses as the majority of these syndromes can be very effectively controlled, dramatically improving quality of life and providing protection against the development of irreversible complications such as AA amyloidosis. In Part 1 of this review, we took an overview of SAIDS and described the common features; in this article, we take a more in-depth look at the better recognized or more dermatologically relevant conditions.

Autoinflammatory disorders are rare genetic defects that result in inflammation in the absence of an infectious or autoimmune disease. Although very rare, these disorders can occur in the perinatal period, and recognizing their presentation is important because there are often long-term complications and effective targeted therapies for these disorders. Most of these disorders present with rash, fevers, and laboratory evidence of inflammation. Importantly, these disorders can now be separated into their pathophysiologic mechanisms of action, which can also guide therapies. The article reviews the different mechanisms of autoinflammatory disorders and highlights those disorders that can present in the newborn period.

Autoinflammatory disorders are inherited diseases of innate immunity leading to uncontrolled activation of the interleukin-1 pathway. The disorders are characterized by unprovoked recurrent inflammation affecting primarily the skin, as well as the serosal and synovial membranes. As innate immunity is the culprit, there are no autoantibodies or autoreactive T-cells to aid in the diagnosis and reactive amyloidosis is a potential severe long-term complication [1, 2].

Neonatal causes of fever are a major source of concern for clinicians. If fever is combined with organ-specific sterile inflammatory manifestations the suspicion of autoinflammatory disorders should be considered, and the list of such conditions starting in the neonatal period includes chronic infantile neurological cutaneous articular syndrome, mevalonate kinase deficiency, deficiency of the interleukin-1 receptor antagonist, otulipenia, STING-associated vasculopathy with onset in infancy and Blau syndrome. Other causes of noninfectious fever that can rarely occur in newborns are Kawasaki disease, Behcet's disease, and hemophagocytic lymphohistiocytosis. Diagnosis of these exceptionally rare disorders is challenging for neonatologists. An early recognition of these complex diseases might lead to use more specific or rational drugs preventing permanent consequences. This review focuses on the rarest causes of fever occurring in the neonatal age with the aim of portraying many protean clinical pictures associated with fever and reviewing the potential available treatments.

Neutrophilc dermatoses (ND) comprises a group of autoinflammatory disorders characterized by a neutrophilic-rich infiltrate in the skin. Based on their frequent overlapping features ND have been classified into three major groups: (1) superficial ND; (2) dermal ND, and (3) deep ND.1,2 ND are often associated with haematological malignancies and chronic inflammatory diseases.1,2 We report a striking localized form of relapsing ND.

The gasdermins, family of pore‐forming proteins, are emerging key regulators of infection, autoinflammation and antitumor immunity. Multiple studies have recently characterised their crucial roles in driving pyroptosis, a lytic pro‐inflammatory type of cell death. Additionally, gasdermins also act as key effectors of NETosis, secondary necrosis and apoptosis. In this review, we will address current understanding of the mechanisms of gasdermin activation and further describe the protective and detrimental roles of gasdermins in host defence and autoinflammatory diseases. These data suggest that gasdermins play a prominent role in innate immunity and autoinflammatory disorders, thereby providing potential new therapeutic avenues for the treatment of infection and autoimmune disease., This review summarises the latest advances in several aspects of mode of activation of gasdermins, which finally drives pyroptosis, NETosis, secondary necrotic death and apoptosis. Here, we also highlight the current understanding of gasdermin involvement in infections and autoimmunity disorders, providing a promising translational approach to the treatment of infectious and autoinflammatory diseases.

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

Advances in genetic techniques have led to the discovery of new autoinflammatory syndromes in the last three years. The purpose of this review is to discuss novel autoinflammatory syndromes including disease mechanisms, characteristics, and treatments. We will also discuss recent findings regarding the pathophysiology of well-known autoinflammatory disorders. Several recently described autoinflammatory disorders will be discussed including NLRC4-MAS, NAIAD, CANDLE, SAVI, ORAS, HA20, DADA2, and APLAID. There is now a better understanding of the pathophysiology of autoinflammatory disorders that has allowed for categorization of these disorders into interferonopathies, inflammasome mediated, or NF-κB dysregulated. With a better understanding of these disorders, targeted treatments based on their mechanism are now possible. Some of these disorders have an unknown mechanism of action, and novel disorders are likely. Further research on autoinflammatory disorders is necessary to improve the outcomes of these patients.

ObjectiveTo report the long-term safety and effectiveness of canakinumab, a fully human anti-interleukin 1β monoclonal antibody, in patients with cryopyrin-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), in a real-world setting.MethodsFrom December 2009 to December 2015, the β-Confident Registry prospectively enrolled patients with CAPS and non-CAPS conditions who received canakinumab per routine care and were prospectively followed for up to 6 years. The registry protocol did not mandate specific visits or procedures; however, all observed adverse events (AEs) and serious adverse events (SAEs) had to be recorded. Canakinumab effectiveness was evaluated by Physician’s Global Assessment (PGA).ResultsOf 288 patients enrolled, 3 were excluded due to missing informed consent. Among the remaining 285 patients, 243 (85.3%) were patients with CAPS and 42 (14.7%) had atypical CAPS (6.3%) or other conditions (8.4%). The median age was 26.6 years. Based on PGA, 58 of 123 (47.2%) patients with CAPS had no disease activity at 48 months, and 65 of 123 (52.8%) experienced mild/moderate disease activity at 48 months. Among CAPS phenotypes, AE incidence rates per 100 patient-years were lowest for FCAS (73.1; 95% CI 60.3 to 87.8) compared with those with MWS (105.0; 95% CI 97.2 to 113.2) or NOMID (104.6; 95% CI 86.6 to 125.2). One hundred twenty-eight SAEs were reported in 68 patients with CAPS (incidence rate/100 patient-years, 14.0; 95% CI 11.6 to 16.6). One death (metastatic rectal adenocarcinoma in a patient with MWS) was reported.ConclusionsThe response to canakinumab was sustained for up to 6 years. Canakinumab demonstrated a favourable safety profile over long-term treatment in patients with CAPS.Trial registration numberNCT01213641.

International audience; The knowledge on systemic autoinflammatory disorders (SAID) is expanding rapidly and new signalling pathways are being decrypted. The concept of autoinflammation has been proposed since 1999, to define a group of diseases with abnormal innate immunity activation. Since then, more than 30 monogenic SAID have been described. In this review, we first describe inflammasomopathies and SAID related to the interleukin-1 pathway. Recent insights into the pathogenesis of familial Mediterranean fever and the function of Pyrin are detailed. In addition, complex or polygenic SAID, such as Still’s disease or PFAPA syndrome, are also discussed. Then, major players driving autoinflammation, such as type-1 interferonopathies (including the recently described haploinsuffiency in A20 and otulipenia), TNF-associated periodic syndromes, defects in ubiquitination, and SAID with overlapping features of autoimmunity or immunodeficiency. Discoveries of the pathogenic role of mosaicism, intronic defects coupled to the likelihood to identify digenic or polygenic diseases are providing new challenges for physicians and geneticists. This comprehensive review depicts the various SAID, presenting them according to their predominant pathophysiological mechanism, with a particular emphasis on recent findings. Epidemiologic data are also presented. Finally, we propose a practical diagnostic approach to the most common monogenic SAID, based on the most characteristic clinical presentation of these disorders.

Autoinflammatory disorders are disorders characterized by rash, arthritis, fever, and systemic inflammation. These disorders are caused by mutations in genes important in innate immune system sensors. This review highlights the workup of an individual with recurrent episodes of inflammation, features of these disorders, the genetic defects that cause these disorders, and the specific treatments available.

Monogenic IFN-mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes-associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.Eighteen patients were treated for a mean duration of 3.0 years (1.5-4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93-1.78) to 0.25 (IQR, 0.1-0.63) (P0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31-1.09) to 0.11 mg/kg/day (IQR, 0.02-0.24) (P0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients' quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.ClinicalTrials.gov NCT01724580 and NCT02974595.This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Autoinflammatory disorders were first recognized nearly two decades ago as unique historical and physical features caused by dysregulation in the innate immune system. Since then, the application of the next-generation sequencing techniques have led to the identification of new monogenic disorders and help to understand the molecular link between disease-causing mutations and inflammation. Most of the newly identified syndromes are characterized by fever episodes and systemic inflammation. Specifically, pediatric rheumatologists are likely to be asked to evaluate patients with periodic or nonperiodic fever syndromes. It is important that they should be aware of the clinical, laboratory characteristics and treatment modalities of these rare autoinflammatory disorders. In this chapter, we review some of these monogenic autoinflammatory diseases, including Behcet-like autoinflammatory syndrome (AISBL), otulipenia, DIRA (deficiency of interleukin 1 receptor antagonist), and DITRA (deficiency of interleukin-36 receptor antagonist). We describe clinical features of these syndromes and further examine their molecular mechanisms and therapeutic options.

International audience; Monogenic autoinflammatory disorders (AIDs) are rare diseases caused by variants in genes regulating the innate immune system. The identification of the first four genes responsible for the prototype group of hereditary recurrent fevers prompted the development of genetic diagnosis, followed by external quality assessment and guidelines for the interpretation of sequence variants in these diseases. Recent changes in the diagnosis of genetic diseases, namely the implementation of next-generation sequencing (NGS), lead to discovery of the new genes associated with at least 40 novel AIDs, which revolutionized patient care and prognosis. However, these rapid advances resulted in nonstandardized molecular strategies that can influence genetic diagnosis and reporting of results. In order to assess factors, which may have an impact on performance and quality of results in the NGS era, we carried out an online survey among member laboratories of the European Molecular Genetics Quality Network, which highlighted different strategies being used and identified pitfalls that deserve discussion and improvement.

Familial mediterranean fever (FMF) is an inherited autoinflammatory disorder characterized by recurrent episodes of fever and painful inflammation involving the intra-abdominal organs, the lungs and the joints, which is highly prevalent in specific ethnic groups including the Iranians. We report a 12-year-old boy from Iran, with a clinical history of recurrent fever. Based on the suggestive clinical data, mutational analysis revealed the presence of the novel c.1945C>T heterozygous variant in exon 10, which leads to a leucine to phenylalanine change at position 649 of the protein. The mutation was inherited from the mother. This novel mutation lies in exon 10 of the MEFV gene, which encodes for a domain called B30.2-SPRY, located in the C-terminal region of the pyrin protein and contains the most frequent mutations associated with FMF. The present report expands the spectrum of MEFV gene mutations associated with FMF. The uniqueness of this study, compared with other published case reports, consists in the new mutation found in the MEFV gene. In fact, new mutations in this gene are of high interest, in order to better understand the role of this gene in autoinflammation.

Background Many autoinflammatory diseases are associated with mutations in myeloid lineage cells including neutrophils and macrophages. Myelodysplastic syndrome (MDS) is clinically linked to autoinflammatory diseases e.g. Sweets syndrome and NLRP3 inflammasome activation, is an intrinsic feature of some MDS cases. Objectives We tested the hypothesis that autoinflammatory disease is common in MDS cohorts and we further theorised that MDS with somatic mutations and karyotypic abnormalities were associated with autoinflammation. Methods 140 MDS patients referred to St. James’s University Hospital in Leeds during the period 2012-2018 were systematically and retrospectively recruited with karyotypes and somatic mutations status being performed. Patients with autoinflammation were classified as well-defined autoinflammatory disease or poorly defined “autoinflammatory state” (non-infection related elevated CRP over 10.0 mg/L in 5 consecutive times, taken at separate occasions) based on their final diagnosis and compared in terms of demographic, clinical, laboratory, cytogenetics charts, and outcomes. Results The average age was 77.08±11 years (median 79 years), with (n=91, 65.0%) male. 72 (51%) patients had an autoinflammatory state and were younger (75.15±11.23 versus 79.15±11.92, p Conclusion Both well-defined and poorly defined autoinflammatory diseases are common in MDS. Transcription factors pathway somatic mutations and abnormal karyotype are associated with the risk of autoinflammation. Autoinflammation is linked to a worse prognosis which may be linked to the higher risk of malignant transformation. Disclosure of Interests Abdulla Watad: None declared, Mark Kacar: None declared, Nicola Luigi Bragazzi: None declared, Qiao Zhou: None declared, Catherine Cargo: None declared, Jan Taylor: None declared, Eve Roman: None declared, Alexandra Smith: None declared, Richard A. Jones: None declared, Howard Amital Grant/research support from: Pfizer, AbbVie, Janssen, Grant/research support from: Pfizer, AbbVie, Janssen, Consultant for: Pfizer, Merck Sharp & Dohme, Consultant for: Pfizer, Merck Sharp & Dohme, Speakers bureau: Pfizer, Merck Sharp & Dohme, Janssen, Sanofi, Bristol-Myers Squibb, Abbvie, Neopharm, Speakers bureau: Pfizer, Merck Sharp & Dohme, Janssen, Sanofi, Bristol-Myers Squibb, Abbvie, Neopharm, Sinisa Savic Grant/research support from: Novartis and Sobi, Dennis McGonagle Consultant for: Lilly, Novartis UCB, Speakers bureau: Lilly, Novartis UCB

The autoinflammatory diseases comprise a broad spectrum of disorders characterized by unchecked activation of the innate immune system. Whereas aberrations in adaptive immunity have long been identified in 'autoimmune' disorders, the concept of 'autoinflammation' emerged relatively recently, first describing a group of clinical disorders characterized by spontaneous episodes of systemic inflammation without manifestations typical of autoimmune disorders. Improved knowledge of innate immune mechanisms, coupled with remarkable progress in genomics and an expanding number of clinical cases, has since led to an increasing number of disorders classified as autoinflammatory or containing an autoinflammatory component. Biologic therapies targeting specific components of the innate immune system have provided immense clinical benefit, and have further elucidated the role of innate immunity in autoinflammatory disorders. This article reviews the basic mechanisms of autoinflammation, followed by an update on the pathophysiology and treatment of the monogenic and multifactorial autoinflammatory diseases, and the common dermatologic conditions in which autoinflammation plays a major role.

Over the past decade, major advances have been m`ade in understanding the molecular and cellular bases leading to autoinflammatory diseases, and a number of very rare entities have been described. Next-generation sequencing technologies led to the rapid identification of a number of additional genes responsible for syndromes observed in only a very small number of families or in sporadic cases. The identification of all these new genes and associated molecular pathways underlines that activation of interleukin (IL)-1β signaling is far from being the only pathogenic process involved in autoinflammatory disorders. Genetic defects found in patients with rare monogenic autoinflammatory diseases might also facilitate the study of common autoinflammatory diseases with a genetic component. Since these disorders affect multiple organs with potentially severe complications, management of patients is complex and warrants a multidisciplinary approach. Finally, it is necessary to translate discoveries of the pathophysiology of these conditions into more effective therapies, since the choice of therapeutic options often remains empirical.

Over the past 20 years, almost 30 new genes associated with autoinflammatory disorders have been identified. The genetic diagnosis is based on the identification of clearly pathogenic mutations, even in atypical cases (i.e. patients not meeting recognized clinical criteria). Therefore, genetic testing should be preferably ordered by healthcare providers who are familiar with the spectrum of clinical presentation of autoinflammatory diseases.

Autoinflammatory disorders (AIDs) are a subgroup of immune-mediated syndromes that result from a primary dysfunction of the innate immune system. AIDs can be either monogenic or polygenic diseases. Unlike organspecific AIDs, systemic AIDs are characterized by fever and/or elevation of acute-phase reactants. This review aims to describe the most common adult-onset systemic AIDs, focusing mostly on polygenic and mixed-pattern diseases which are expected to be more prevalent in adult patients than monogenic AIDs overall. The literature was searched in Medline database. Organ-specific or childhood-onset systemic AIDs were excluded. AIDs were divided in three distinct groups: mixed-pattern, polygenic and adult-onset monogenic AIDs. Most adult-onset AIDs are polygenic but late-onset disease is not rare among monogenic AIDs such as familial Mediterranean fever (FMF). The diagnosis of systemic AIDs in adults is often delayed due to several factors and sometimes it is only established when amyloidosis or other complications are present. Therefore, it probably makes sense to primarily exclude common AIDs in adult patients with fever of unknown origin (and probably different presentations such as polyserositis) since a high prevalence of adult-onset Still’s disease or FMF is usually expected. Colchicine, nonsteroidal anti-inflammatory drugs, steroids, immunosuppressive agents, interleukin-1 inhibitors and tumor necrosis factor antagonists constitute common therapeutic options for systemic AIDs.

Until the etiopathogenic factor(s) of autoimmune and autoinflammatory rheumatic disorders will be identified, their classification into entities will continue. However, their similar clinical manifestations, overlapping syndromes, evolution from one entity into another, as well as common autoantibody responses, suggest that autoimmune and autoinflammatory disorders may constitute distinct pathophysiologic processes on the basis of a different genetic background. Prognosis and effective therapeutic regimens are mostly based on the clinico-pathologic severity of the involved tissues or organs and not on the disease label., Highlights • Autoimmune rheumatic diseases (ARDs) can evolve from one into another disease. • Different ARDs can appear in the same individual. • Common humoral auto-reactivities appear in different ARDs. • Therapy is based on the severity of ARDs expression.