Revisiting TNF Receptor-Associated Periodic Syndrome (TRAPS): Current Perspectives.

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.

Adult-onset systemic autoinflammatory disorders: a clinical approach.

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.

Chronic Recurrent Multifocal Osteomyelitis and Related Diseases-Update on Pathogenesis.

PURPOSE OF REVIEW: We focus on recent advances in the understanding of the genetic, molecular, immunologic, and environmental factors implicated in the pathogenesis of autoinflammatory bone diseases including the syndromic and non-syndromic forms of chronic recurrent multifocal osteomyelitis (CRMO). RECENT FINDINGS: Evidence implicating the IL-1 pathway in the pathogenesis of the Mendelian forms of CRMO is growing. LIPIN2 can regulate the NLRP3 inflammasome by affecting P2X7 receptor activation, and intracellular cholesterol can modulate P2X7R currents. Work in a mouse model of CRMO demonstrates that dietary manipulation can alter the microbiome and protect these mice from the development of sterile osteomyelitis in vivo. Although the genetic and immunologic basis of non-syndromic CRMO remains only partially understood, the IL-1 pathway is central to the pathogenesis in the syndromic autoinflammatory bone disorders. Recent work implicates lipids and the microbiome in sterile osteomyelitis.

[Pathogenesis and Clinical Examination of Autoinflammatory Syndrome].

Autoinflammatory syndrome is characterized by: 1) episodes of seemingly unprovoked inflammation, 2) the absence of a high titer of autoantibodies or auto-reactive T cells, and 3) an inborn error of innate immunity. In this decade, many autoinflammatory syndromes have been reported in Japan, and so many Japanese physicians have become aware of this syndrome. Monogenic autoinflammatory syndromes present with excessive systemic inflammation including fever, rashes, arthritis, and organ-specific inflammation and are caused by defects in single genes encoding proteins that regulate innate inflammatory pathways. The main monogenic autoinflammatory syndromes are familial Mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndrome (CAPS), Blau syndrome, and syndrome of pyogenic arthritis with pyoderma gangrenosum and acne (PAPA). We diagnosed these syndromes as clinical manifestations and performed genetic screening. Many serum cytokines are elevated in patients with autoinflammatory syndrome, but this is not disease-specific. The pathogeneses of many autoinflammatory syndromes are known to be related to inflammasomes, which are multiprotein complexes that serve as a platform for caspase 1 activation and interleukin-1ß(IL-1ß) and IL-18 maturation. Especially, NLRP3 inflammasomes may play a crucial role in the initiation and progression of FMF and CAPS. Recently, it was reported that NETs (neutrophil extracellular traps) derived from neutrophils may also play an important role in the pathogenesis of FMF. In the future, we hope to discover new clinical examinations which can provide evidence of inflammasome activation independent of genetic screening. In this issue, I introduce autoinflammatory syndromes and discuss the pathogenesis and clinical examination of these syndromes.

Approach to Diagnosing Inborn Errors of Immunity.

Inborn errors of immunity are now understood to encompass manifold features including but not limited to immunodeficiency, autoimmunity, autoinflammation, atopy, bone marrow defects, and/or increased malignancy risk. As such, it is essential to maintain a high index of suspicion, as these disorders are not limited to specific demographics such as children or those with recurrent infections. Clinical presentations and standard immunophenotyping are informative for suggesting potential underlying etiologies, but integration of data from multimodal approaches including genomics is often required to achieve diagnosis.

Proteostasis Perturbations and Their Roles in Causing Sterile Inflammation and Autoinflammatory Diseases.

Proteostasis, a portmanteau of the words protein and homeostasis, refers to the ability of eukaryotic cells to maintain a stable proteome by acting on protein synthesis, quality control and/or degradation. Over the last two decades, an increasing number of disorders caused by proteostasis perturbations have been identified. Depending on their molecular etiology, such diseases may be classified into ribosomopathies, proteinopathies and proteasomopathies. Strikingly, most-if not all-of these syndromes exhibit an autoinflammatory component, implying a direct cause-and-effect relationship between proteostasis disruption and the initiation of innate immune responses. In this review, we provide a comprehensive overview of the molecular pathogenesis of these disorders and summarize current knowledge of the various mechanisms by which impaired proteostasis promotes autoinflammation. We particularly focus our discussion on the notion of how cells sense and integrate proteostasis perturbations as danger signals in the context of autoinflammatory diseases to provide insights into the complex and multiple facets of sterile inflammation.

Safety and efficacy of fecal microbiota transplantation for autoimmune diseases and autoinflammatory diseases: A systematic review and meta-analysis.

Objective: To evaluate the safety and efficacy of fecal microbiota transplantation for autoimmune diseases and autoinflammatory diseases. Methods: Relevant literature was retrieved from the PubMed database, Embase database, Cochrane Library database, etc. The search period is from the establishment of the database to January 2022. The outcomes include clinical symptoms, improvement in biochemistry, improvement in intestinal microbiota, improvement in the immune system, and adverse events. Literature screening and data extraction were independently carried out by two researchers according to the inclusion and exclusion criteria, and RevMan 5.3 software was used for statistics and analysis. Results: Overall, a total of 14 randomized controlled trials (RCTs) involving six types of autoimmune diseases were included. The results showed the following. 1) Type 1 diabetes mellitus (T1DM): compared with the autologous fecal microbiota transplantation (FMT) group (control group), the fasting plasma C peptide in the allogenic FMT group at 12 months was lower. 2) Systemic sclerosis: at week 4, compared with one of two placebo controls, three patients in the experimental group reported a major improvement in fecal incontinence. 3) Ulcerative colitis, pediatric ulcerative colitis, and Crohn's disease: FMT may increase clinical remission, clinical response, and endoscopic remission for patients with ulcerative colitis and increase clinical remission for patients with Crohn's disease. 4) Psoriatic arthritis: there was no difference in the ratio of ACR20 between the two groups. Conclusion: Based on current evidence, the application of FMT in the treatment of autoimmune diseases is effective and relatively safe, and it is expected to be used as a method to induce remission of active autoimmune diseases. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021235055, identifier CRD42021235055.

Clinical care of children with sterile bone inflammation.

PURPOSE OF REVIEW: To review the current literature of sterile bone inflammation in childhood and to evaluate the evidence for clinical care including diagnostic methods and treatment. RECENT FINDINGS: Chronic noninfectious osteomyelitis includes several different entities marked by sterile bone inflammation associated with histologic evidence of a predominant neutrophil infiltration in the absence of autoantibodies and autoreactive T cells, some of which are associated with a genetic mutation. Whole body MRI is helpful in detecting asymptomatic lesions. Initial treatment with NSAIDs is usually sufficient to control symptoms as the bone heals. However, if the lesions persist and do not respond to first-line treatment, or involve the spine or hip, treatment with bisphosphonate will usually lead to a resolution of symptoms. Rarely, treatment with anti-TNF agents is required. SUMMARY: This review summarizes recent information on diagnosis, treatment and prognosis of disorders involving sterile bone inflammation in childhood. It also addresses the evolving differential diagnosis for autoinflammatory disorders that include sterile bone inflammation and presents a treatment algorithm for management.

Inflammasome activation: from inflammatory disease to infection.

The recognition of pathogen-derived molecules by the innate immune system is mediated by a number of receptors, including members of the TLR (Toll-like receptor), RLH [RIG (retinoic acid-inducible gene)-like helicase] and the NLR (NOD-like receptor) families. NLRs in particular are also involved in the recognition of host-derived 'danger'-associated molecules which are produced under conditions of cellular stress or injury. Activation of these receptors leads to the assembly of high-molecular-mass complexes called inflammasomes which in turn leads to the generation of active caspase 1 and to the production of mature IL-1ß (interleukin 1ß). The discovery that NLRP3 (NLR-related protein 3) can recognize host-derived particulate matter such as uric acid and cholesterol crystals has led to this inflammasome being implicated in a number of inflammatory diseases, including gout, atherosclerosis and Type 2 diabetes. In addition, aberrant NLRP3 activation has also been observed in a number of heritable disorders now referred to as cryopyrinopathies. On the other hand, a number of studies have reported that recognition of both viral and bacterial products by NLRs is required for effective pathogen clearance. The present review discusses both aspects of NLR activation and will highlight the role of additional inflammasome complexes in sensing infection.

Mutation screening of the IL-1 receptor antagonist gene in chronic non-bacterial osteomyelitis of childhood and adolescence.

OBJECTIVES: Chronic non-bacterial osteomyelitis CNO is an inflammatory disorder of the musculoskeletal system with unknown etiology. In addition to bone inflammation, patients may present with inflammatory involvement of other tissues including, e.g., skin. Recently, a novel syndrome due to deficiency of interleukin-1 receptor antagonist (IL1RN), DIRA has been identified. Clinically the syndrome is characterized by neonatal onset of pustular dermatosis, periostitis and chronic sterile multifocal osteomyelitis, strongly resembling CNO. Homozygous mutations of IL1RN have been identified and resulted in a truncated protein that is not secreted, hence leaving the action of interleukin-1 unopposed. METHODS: Because of similar clinical, radiological and histological features of CNO and DIRA, we hypothesized that both disorders might share a common autoinflammatory process. Thus, we searched for the presence of mutations in the interleukin-1 receptor antagonist gene in 60 patients diagnosed with CNO. RESULTS: In one patient with chronic multifocal osteomyelitis a heterozygous missense variant: c.281G>T (p.Cys94Phe) was detected. In the other patients only frequent polymorphisms were found. CONCLUSIONS: Our findings were not able to confirm mutations in IL1RN being an important contributing factor to the pathogenesis of CNO.

Ankylosing spondylitis: an autoimmune or autoinflammatory disease?

Ankylosing spondylitis (AS) is a chronic inflammatory disorder of unknown aetiology. Unlike other systemic autoimmune diseases, in AS, the innate immune system has a dominant role characterized by aberrant activity of innate and innate-like immune cells, including γδ T cells, group 3 innate lymphoid cells, neutrophils, mucosal-associated invariant T cells and mast cells, at sites predisposed to the disease. The intestine is involved in disease manifestations, as it is at the forefront of the interaction between the mucosal-associated immune cells and the intestinal microbiota. Similarly, biomechanical factors, such as entheseal micro-trauma, might also be involved in the pathogenesis of the articular manifestation of AS, and sentinel immune cells located in the entheses could provide links between local damage, genetic predisposition and the development of chronic inflammation. Although these elements might support the autoinflammatory nature of AS, studies demonstrating the presence of autoantibodies (such as anti-CD74, anti-sclerostin and anti-noggin antibodies) and evidence of activation and clonal expansion of T cell populations support an autoimmune component to the disease. This Review presents the evidence for autoinflammation and the evidence for autoimmunity in AS and, by discussing the pathophysiological factors associated with each, aims to reconcile the two hypotheses.

Phenotypic Associations of PSTPIP1 Sequence Variants in PSTPIP1-Associated Autoinflammatory Diseases.

Pathogenic variants in the PSTPIP1 gene cause pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome. They were also identified in a broad spectrum of phenotypes. As their interpretation is sometimes challenging, we discuss the genotype-phenotype association in PSTPIP1-associated autoinflammatory diseases (PAIDs) in light of a recent consensus classification of variant pathogenicity. Only 7 of 39 (18%) of the PSTPIP1 variants found in all reported cases and our national reference center (161 patients [114 probands]) were pathogenic. They were clearly associated with PAPA and PSTPIP1-associated myeloid-related proteinemia inflammatory syndrome (PAMI), reflecting a variable clinical expression of PAIDs.

Somatic Mutations and the Risk of Undifferentiated Autoinflammatory Disease in MDS: An Under-Recognized but Prognostically Important Complication.

Objectives: We theorized that myelodysplastic syndrome (MDS) with somatic mutations and karyotype abnormalities are associated with autoinflammation, and that the presence of autoinflammatory disease affected prognosis in MDS. Methods: One hundred thirty-four MDS patients were assessed for the prevalence of autoinflammatory complications and its link with karyotypes and somatic mutation status. Autoinflammatory complications were described either as well-defined autoinflammatory diseases (AD) or undifferentiated "autoinflammatory disease" (UAD) (defined as CRP over 10.0 mg/L on five consecutive occasions, taken at separate times and not explained by infection). Several patient characteristics including demographic, clinical, laboratory, cytogenetics charts, and outcomes, were compared between different groups. Results: Sixty-two (46.3%) patients had an autoinflammatory complication manifesting as arthralgia (43.5% vs. 23.6%, p = 0.0146), arthritis (30.6% vs. 15.3%, p = 0.0340), skin rash (27.4% vs. 12.5%, p = 0.0301), pleuritis (14.5% vs. 4.2%, p = 0.0371) and unexplained fever (27.4% vs. 0%, p < 0.0001). AD were found in 7.4% of MDS patients (with polymyalgia rheumatic being the most frequently one). Classical autoimmune diseases were found only in 4 MDS patients (3.0%). Transcription factor pathway mutations (RUNX1, BCOR, WTI, TP53) (OR 2.20 [95%CI 1.02-4.75], p = 0.0451) and abnormal karyotypes (OR 2.76 [95%CI 1.22-6.26], p = 0.0153) were associated with autoinflammatory complications. Acute leukaemic transformation was more frequent in MDS patients with autoinflammatory features than those without (27.4% vs. 9.7%, p = 0.0080). Conclusions: Autoinflammatory complications are common in MDS. Somatic mutations of transcription factor pathways and abnormal karyotypes are associated with greater risk of autoinflammatory complications, which are themselves linked to malignant transformation and a worse prognosis.

Vitamin D deficiency as a risk factor for PFAPA syndrome.

OBJECTIVE: The periodic fever, aphthous stomatitis, pharangytis and cervical adenitis (PFAPA) syndrome, is an idiopathic chronic disease of non-hereditary origin, primarily affecting pre-school children and is the most common periodic fever disorder in children. Rapid response to corticosteroid treatment suggest an immune dysregulation. Recently, emerging evidence suggest that vitamin D plays an important role in immunity regulation. The aim of our study was to assess the vitamin D levels in children with PFAPA syndrome. METHODS: This study was conducted prospectively. We have consecutively evaluated 50 patients after having excluded other causes of recurrent fever between May 2017 and May 2018 in addition to age-matched 50 patients as control group. All patients has complete physical examination and laboratory tests. Laboratory tests included complete blood count, C-reactive protein (CRP), and vitamin D levels. Serum 25 (OH) vitamin D levels were measured in all patients twice yearly. RESULTS: Vitamin D levels was 18 ±â€¯10 ng/ml in the patient group and 35 ±â€¯13 ng/ml in the control group. There was statistically significant difference between the groups (p < 0.001). 38 patients from the PFAPA group and 20 patients from the control group had low vitamin D levels. Multivariate logistic regression analysis showed that CRP (odd ratio (OR) = 2.7, 95% confidence interval (CI) = 2.4-4.1) and serum 25 (OH) vitamin D levels <30 ng/ml OR = 2.1, 95% CI = 1.8-2.5) were associated with PFAPA occurrence. CONCLUSION: We found strong correlation between PFAPA and vitamin D insufficiency. Hypovitaminosis D can be a significant risk factor for PFAPA episode recurrence.

Hereditary Autoinflammatory Disorders: Recognition and Treatment.

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)-1ß, 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.

Autoinflammatory Disorders: A Review and Update on Pathogenesis and Treatment.

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.

Dynamics of Inflammatory Response in Autoinflammatory Disorders: Autonomous and Hyperinflammatory States.

Autoinflammatory diseases were originally defined as a group of monogenic disorders associated with seemingly unprovoked inflammatory episodes mediated mainly by the innate immune system and without direct involvement of adaptive immunity. The renewed concept encompasses a larger group of disorders including multifactorial diseases, which share the same inflammatory and clinical features with the monogenic disorders. Coining of the "auto" prefix to these inflammatory diseases suggests a constitutively active and self-augmenting innate immune response, but only a subgroup of them including cryopyrin-associated periodic syndrome (CAPS), associated with dominantly inherited gain-of-function NLRP3 variants, fits well with the definition of the "autonomous" inflammatory conditions. However, the "autoinflammation" concept also includes another group of disorders characterized by episodes of exaggerated inflammatory response only when challenged by certain triggers. The dynamics of this latter group can be better defined as a "hyperinflammatory" state, which shares similar characteristics with the innate memory or trained immunity. Differentiation of "autonomous" and "hyperinflammatory" states of autoinflammatory disorders can provide additional insights to understand their pathogenesis and develop better management strategies since both conditions may have different inflammatory dynamics affecting the severity and frequency of clinical findings and treatment responses.

Update on the epidemiology and disease outcome of Familial Mediterranean fever.

Autoinflammatory diseases (AIDs) are diseases of the innate immune system, with clinical and laboratory evidence of attacks of inflammation. The more common AIDs are those associated with periodic fevers: Familial Mediterranean fever (FMF); Mevalonate Kinase Deficiency (MKD)/Hyperimmunoglobulin D Syndrome (HIDS); Cryopyrin-associated Autoinflammatory Syndrome (CAPS); and Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS). Classification criteria have been developed for all these types. FMF is the most common AID worldwide with a particularly high prevalence in the Eastern Mediterranean region. Environmental factors are thought to affect the course of the disease. Outcome measures are being developed for AIDs.