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Autoinflammatory disease (AID) is a vast spectrum of disorders characterized by recurrent attacks of sterile inflammation. Since the first cloning of the familial Mediterranean fever gene in 1997, there has been a rapid rate of discovery of new AIDs. As of 2022, there have been 485 inborn errors of immunity documented by the International Union of Immunological Societies, for which many display aspects of autoinflammation. The pathophysiology of AIDs is complex. Although many are caused by rare mutations in genes that govern innate immunity, others are polygenic, where disease expression is thought to be triggered by environmental factors in genetically predisposed hosts. AIDs range in prevalence from common entities like gout to ultrarare monogenic diseases. Whereas AIDs were initially studied in pediatric populations, it is now apparent that they can present in adulthood and even in the elderly. AIDs can be clinically challenging given their rarity, as well as the heterogeneity in presentation and underlying etiology. Although the care of AIDs can span medical disciplines, the rheumatologist often plays a central role given the inflammatory nature of these illnesses. In this review, we explore the current understanding of the pathophysiology of these complex conditions and propose a classification system for AIDs. We place an emphasis on AIDs that present to the adult rheumatologist and discuss important AIDs that can mimic more classic rheumatic diseases such as systemic lupus erythematosus and inflammatory arthritis. Finally, we offer an approach to the clinical assessment, diagnosis, and management of AIDs. [ABSTRACT FROM AUTHOR]

Systemic autoinflammatory diseases (SAID) are a growing family of disorders of the innate immune system. Over the years, there have been changes in the definition, classification and nomenclature of SAID as new syndromes and pathophysiologic mechanisms continue to be described. Recognizing the clinical manifestations of SAID is important for their early diagnosis and management. The field continues to advance with potential new therapies underway. [ABSTRACT FROM AUTHOR]

Equine common variable immunodeficiency (CVID) is a rare, late-onset, nonfamilial humoral deficiency characterized by B-cell depletion and/or dysfunction resulting in inadequate antibody production and predisposition to recurrent infections. Serum immunoglobulin concentration and peripheral blood lymphocyte immunophenotyping are required to diagnose and characterize CVID in horses. Early recognition of the disease by the equine practitioner is paramount to managing the quality of life for these patients, for whom specific treatment is not yet available and long-term prognosis remains poor. An approach to the diagnosis, identification of complicating factors, and management of horses with CVID are discussed., Competing Interests: Disclosure Dr M.J.B. Felippe is the head of the Equine Immunology Laboratory, a not-for-profit research laboratory that provides immunologic testing for horses with suspected immunodeficiencies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Monogenic autoinflammatory diseases (AIDs, formerly known as hereditary periodic fever syndromes) cover a spectrum of diseases which lead to chronic or recurrent inflammation caused by activation of the innate immune system. The most common monogenic AID is familial Mediterranean fever. Monogenic autoinflammatory diseases are generally considered intracellular signalling defects. Some stereotypical knowledge may be misleading; e.g. monogenic AIDs are not exclusively found in children, family history is often negative, fever frequently is not a leading manifestation and frequency of attacks in adults is usually variable. Lack of genetic confirmation should not stop anti-inflammatory ex juvantibus therapy. The pattern of tissue injury in AIDs is basically different from that observed in autoimmunity. There is no autoaggression against organ-specific antigens, but substantial damage (amyloidosis, cachexia, premature cardiovascular disease) is secondary to long-lasting inflammation. The Polish national programme of anti-interleukin 1 treatment opens new possibilities for the treatment. However, monogenic AIDs are frequently misdiagnosed and more awareness is needed.

Objectives The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. Methods We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. Results Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0–6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. Conclusion Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine. [ABSTRACT FROM AUTHOR]

Monogenic autoinflammatory diseases (AIDs, formerly known as hereditary periodic fever syndromes) cover a spectrum of diseases which lead to chronic or recurrent inflammation caused by activation of the innate immune system. The most common monogenic AID is familial Mediterranean fever. Monogenic autoinflammatory diseases are generally considered intracellular signalling defects. Some stereotypical knowledge may be misleading; e.g. monogenic AIDs are not exclusively found in children, family history is often negative, fever frequently is not a leading manifestation and frequency of attacks in adults is usually variable. Lack of genetic confirmation should not stop anti-inflammatory ex juvantibus therapy. The pattern of tissue injury in AIDs is basically different from that observed in autoimmunity. There is no autoaggression against organ-specific antigens, but substantial damage (amyloidosis, cachexia, premature cardiovascular disease) is secondary to long-lasting inflammation. The Polish national programme of anti-interleukin 1 treatment opens new possibilities for the treatment. However, monogenic AIDs are frequently misdiagnosed and more awareness is needed. [ABSTRACT FROM AUTHOR]

Auto-inflammatory diseases are characterized by unexplained and recurrent attacks of systemic inflammation often involving the skin, joints, or serosal membranes. They are due to a dysfunction or dysregulation of the innate immunity, which is the first line of defense against pathogens. Early recognition of these diseases by the clinician, especially by pediatricians encountering such pathologies in pediatric patients, is primordial to avoid complications. Skin manifestations, common in most auto-inflammatory diseases, are helpful for prompt diagnosis. After a brief physiopathological review, we will describe auto-inflammatory recurrent fevers by their main dermatological presentations: urticarial lesions, neutrophilic dermatoses, panniculitis, other maculopapular eruptions, dyskeratosis, skin vasculitis, and oral aphthous. We finally suggest a decision tree to help clinicians better target genetic exams in patients with recurrent fevers and dermatological manifestations. [ABSTRACT FROM AUTHOR]

Recurrent fevers make up a significant yet underappreciated proportion (18-42%) of fevers of unknown origin. A group of recurrent fevers, known as autoinflammatory diseases or hereditary periodic fever syndromes occur due to a deregulated response of innate immunity, whereby an autoinflammatory reaction occurs resulting in tissue damage. Unlike autoimmune diseases, the autoinflammatory diseases are not associated to specific autoantibodies or major histocompatibility complexes (MHCs), but rather result from an aberrant activation of innate immune cells such as macrophages and neutrophils. Although the majority of cases begin during childhood, several are often diagnosed years after their debut or begin during adult life, justifying the need for internists to be familiar with these diseases. In this review we discuss the epidemiology, pathophysiology, clinical presentation, diagnosis and management of the main autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

Background: The Mediterranean fever (MEFV) gene codes for protein pyrin, one of the regulators of inflammasome activity in innate immune cells. Mutations in this gene are considered the primary cause of Familial Mediterranean fever, but are also found in other monogenic and multifactorial autoinflammatory diseases. The aim of the study was to determine if healthy carriers of MEFV gene mutations and R202Q polymorphism have clinical manifestations of inflammation and impaired oxidative stress parameters. Methods: One hundred DNA samples from healthy volunteers (13.3 ± 8.87 years of age (mean ± SD); range 2-35) were sequenced by ABI PRISM 310 automated sequencer (PE Applied Biosystems, Norwalk, USA). The Eurofever questionnaire was used to collect retrospectively medical history data. Oxidative stress was determined by measuring spectrophotometrically thiobarbituric acid reactive substances (TBARS) in plasma and erythrocytes, as well as advanced oxidation protein products in plasma. Superoxide dismutase (SOD) activity was determined by McCord and Fridovich method in plasma and erythrocytes, while the catalase erythrocyte activity was assessed using a catalase ELISA kit. Results: We found heterozygous carriers of K695R/N mutations in 5 %, E148Q/N mutations in 6 %, R202Q homozygous polymorphism in 10 % and heterozygous R202Q alterations in 45 % of healthy volunteers. The MEFV mutation carriers and R202Q polymorphism homozygotes reported significantly more often recurrent febrile episodes (p = 0.009), diffuse abdominal pain (p = 0.025), and malaise (p = 0.012) compared to non-carriers. Erythrocyte TBARS levels and plasma SOD activity were higher in persons with MEFV mutations and R202Q/R202Q (p = 0.03 and p = 0.049, respectively). Conclusions: Healthy individuals may bear E148Q and K695R MEFV gene mutations, as well as R202Q polymorphism in homozygous state. The determined gene alterations contribute to a subtle oxidative stress and may be associated with more frequent episodes of fever and unspecific inflammatory manifestations. An incomplete penetrance or variable expressivity of R202Q in populations of different ethnicity could influence the expression of autoinflammatory diseases phenotype. [ABSTRACT FROM AUTHOR]

To describe a homogeneous group of patients with undifferentiated recurrent fevers followed-up in a tertiary referral center for systemic autoinflammatory diseases (SAIDs). Patients with undifferentiated recurrent fevers seen at our Center from 2008 to 2021 and followed-up for at least one year were included in a retrospective study. Monogenic recurrent fevers, patients carrying variants of unknown origin and PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis) syndrome were excluded. Fifty patients (34 male, 16 female) were included in the study. The median age at onset was 3 years, and the median follow-up was 3.3 years. At baseline, arthralgia (70%) and abdominal pain (65%) were the most frequent manifestations. NSAIDs or steroids on demand had a variable and transient effect. Tonsillectomy was ineffective in the 10 patients (20%) that underwent surgery. Forty-eight patients (96%) were treated with colchicine. A complete response (absence of fever) was achieved in 31 patients (64.6%). Nine patients (18%) showed a partial response, with a median reduction of fever episodes per year of 72%. Nine patients (16.7%) were considered resistant to colchicine. The presence of generalized lymphadenopathy and, to a lesser extent, exudative tonsillitis was associated with a lack of response to colchicine. We describe the largest series of patients with syndrome of undifferentiated recurrent fever (SURF) reported in the literature so far. SURF should be considered as a distinct clinical entity in the context of multifactorial autoinflammatory diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

New Eurofever/PRINTO classification criteria (EPCC) for Familial Mediterranean Fever (FMF) and other recurrent fevers have been recently developed, together with the classification of the pathogenicity of MEFV variants. To evaluate the impact in real life of both the EPCC and INSAID pathogenicity classification of MEFV variants in the large international Eurofever FMF cohort. Baseline demographic, genetic and clinical data of FMF patients included in the Eurofever registry were evaluated. The EPCC and the 2018 INSAID classification for MEFV variants were applied in all eligible FMF patients. Since November 2009, clinical information was available for 1012 FMF (532 males/480 females, 827 children/185 adults) from 119 centres. Complete data were available for 887 patients in whom 623 (70.2%) satisfied EPCC (EPCC+), while 264 (29.8%) did not (EPCC−). The majority of the EPCC− patients (172, 65.1%) displayed negative or non-informative genetics (monoallelic or biallelic benign variants, monoallelic variant of unknown significance). At baseline, colchicine was used in most of EPCC+ patients (88%) and in a lower percentage of EPCC− patients (69%, p < 0.0001), who were treated in a higher proportion with steroid or NSAID on demand (p = 0.003 and 0.008, respectively). Four percent of patients received Anti-IL-1 treatment. The combination of EPCC and the 2018 INSAID classification of MEFV variants is able to identify two distinct groups of patients, which differ in clinical characteristics, therapeutic approach and response to treatment. EPCC+ patients displayed the typical features of FMF, while EPCC− patients had a more variable phenotype with a lower percentage of response to colchicine. [Display omitted]. • The application of Eurofever/PRINTO classification criteria (EPCC) defines two distinct groups of patients, which differ in clinical characteristic, therapeutic approach and response to treatment. • Patients fulfilling the EPCC displayed higher rate of response to colchicine, in comparison to EPCC− patients. • The negativity of EPCC and the presence of non-informative genetic test should alert the physicians for the possibility of an alternative diagnosis and treatment in the context of an inflammatory phenotype. [ABSTRACT FROM AUTHOR]

We describe a 2-year old boy with consanguineous parents who recently emigrated from India and presented with oral ulcers and lymphadenopathy. He also had a history of recurrent fevers, polyarticular arthritis, chronic diarrhea, failure to thrive, and developmental delay. Infectious workup revealed herpes simplex virus 1 viremia and radiological evaluation revealed osteopenia and erosions involving multiple joints. We describe the immunologic and genetic evaluation of this patient and discuss the diagnostic and therapeutic approach to an infant with recurrent fevers. [ABSTRACT FROM AUTHOR]

Abstract: The title of this section, “New genetic interpretation of old diseases,” perfectly reflects the unique history of our understanding of autoinflammatory diseases (AIDs). Indeed, the main clinical feature of most AIDs is the recurrent fever, a symptom that has been extensively documented for centuries. However, the first clear description of a patient suffering from the AID prototype, familial Mediterranean fever (FMF), has only been reported in 1908, although dating studies have shown that ancestral mutations appeared in biblical times. FMF and 11 other AID genes were identified between 1997 and 2011. The patient''s care has dramatically benefited from the elucidation of the molecular defect underlying similar diseases of the innate immune system. However, accumulation of present and future sequence data let us anticipate that interpretation of genetic diagnosis will be increasingly difficult. [Copyright &y& Elsevier]

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Abel is the first Australopithecine known west of the East African Rift Valley. The fossil finds include a perisymphyseal fragment of an adult mandible with well-preserved crowns of the right I 2 -P 4 and the left C-P 4 . Abel's dentition displays many enamel defects, which are described in detail for each tooth. Pitting affected every tooth, while larger, shallow depressions were observed on the canines alone. From two to four pit bands occurred on the different teeth, each resulting from a separate hypoplastic episode. In modern humans, a large number of causes, both environmental and genetic, have been suggested for such enamel defects. It seems probable that Abel's pathology was systemic. However, the occurrence of a number of bands and the variable intensity of the attacks make it difficult to say whether there was a single, repetitive cause or different etiologies. Possible causes discussed here include recurrent fevers and seasonal nutritional deficiencies. [ABSTRACT FROM AUTHOR]

Abstract: The main common feature of autoinflammatory diseases is recurrent fever. Think of an autoinflammatory disease requires to make a link between previous acute episodes and to suspect a single disease. Indeed, physicians should look for clinical and biological features in order to suspect a define autoinflammatory disease. Acute phase reactants are constantly present. A discrepancy between high sedimentation rate or CRP levels and absence of infectious, tumoral disease, or autoimmunity features, is highly suggestive, in particular when spontaneous improvement and long-term duration are present. Family history and ethnicity, characteristics of fever and associated clinical symptoms and signs are key-points for diagnosis. Several diseases are monogenic and molecular genetic analysis is available, and others are only responding to sets of clinical criteria. [Copyright &y& Elsevier]

Auto-inflammatory diseases are characterized by unexplained and recurrent attacks of systemic inflammation often involving the skin, joints, or serosal membranes. They are due to a dysfunction or dysregulation of the innate immunity, which is the first line of defense against pathogens. Early recognition of these diseases by the clinician, especially by pediatricians encountering such pathologies in pediatric patients, is primordial to avoid complications. Skin manifestations, common in most auto-inflammatory diseases, are helpful for prompt diagnosis. After a brief physiopathological review, we will describe auto-inflammatory recurrent fevers by their main dermatological presentations: urticarial lesions, neutrophilic dermatoses, panniculitis, other maculopapular eruptions, dyskeratosis, skin vasculitis, and oral aphthous. We finally suggest a decision tree to help clinicians better target genetic exams in patients with recurrent fevers and dermatological manifestations., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Over the centuries the idea of recurrent fevers has mainly been associated with malaria, but many other fevers, such as typhoid and diphtheria were cause for concern. It is only in recent times, with the more severe forms of fever from infectious origin becoming less frequent or a cause for worry that we started noticing recurrent fevers without any clear infectious cause, being described as having a pathogenesis of autoinflammatory nature. The use of molecular examinations in many cases can allow a diagnosis where the cause is monogenic. In other cases, however the pathogenesis is likely to be multifactorial and the diagnostic-therapeutic approach is strictly clinical. The old fever tree paradigm developed to describe fevers caused by malaria has been revisited here to describe today's periodic fevers from the periodic fever adenitis pharyngitis aphthae syndrome to the more rare autoinflammatory diseases. This model may allow us to place cases that are yet to be identified which are likely to be of multifactorial origin.