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Objective: FMF is the most common monogenic autoinflammatory disease associated with MEFV mutations. Disease phenotype and response to treatment vary from one patient to another, despite similar genotype, suggesting the role of environmental factors. The objective of this study was to analyse the gut microbiota of a large cohort of FMF patients in relation to disease characteristics., Methods: The gut microbiotas of 119 FMF patients and 61 healthy controls were analysed using 16 s rRNA gene sequencing. Associations between bacterial taxa, clinical characteristics, and genotypes were evaluated using multivariable association with linear models (MaAslin2), adjusting on age, sex, genotype, presence of AA amyloidosis (n = 17), hepatopathy (n = 5), colchicine intake, colchicine resistance (n = 27), use of biotherapy (n = 10), CRP levels, and number of daily faeces. Bacterial network structures were also analysed., Results: The gut microbiotas of FMF patients differ from those of controls in having increased pro-inflammatory bacteria, such as the Enterobacter, Klebsiella and Ruminococcus gnavus group. Disease characteristics and resistance to colchicine correlated with homozygous mutations and were associated with specific microbiota alteration. Colchicine treatment was associated with the expansion of anti-inflammatory taxa such as Faecalibacterium and Roseburia, while FMF severity was associated with expansion of the Ruminococcus gnavus group and Paracoccus. Colchicine-resistant patients exhibited an alteration of the bacterial network structure, with decreased intertaxa connectivity., Conclusion: The gut microbiota of FMF patients correlates with disease characteristics and severity, with an increase in pro-inflammatory taxa in the most severe patients. This suggests a specific role for the gut microbiota in shaping FMF outcomes and response to treatment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Autoinflammatory diseases (AIDs) are defined as disorders of innate immunity. They were initially defined in contrast to autoimmune diseases because of the lack of involvement of the adaptive immune system and circulating autoantibodies. The four monogenic AIDs first described are called the 'historical' AIDs and include FMF (associated with MEFV mutations), cryopyrinopathies (associated with NLRP3 mutations), TNF receptor-associated periodic syndrome (associated with TNFRSF1A mutations) and mevalonate kinase deficiency (MKD; associated with MVK mutations). In the last 10 years, >50 new monogenic AIDs have been discovered due to genetic advances. The most important discovery for adult patients is VEXAS syndrome associated with somatic UBA1 mutations leading to an AID affecting mostly elderly men. Diagnosis of monogenic AIDs is based on personal and family history and detailed analysis of symptoms associated with febrile attacks in the context of elevated peripheral inflammatory markers. This review proposes a practical approach for the diagnosis of the main monogenic AIDs among adult patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To identify the molecular basis of a systemic autoinflammatory disorder (SAID) evocative of TNF receptor-associated periodic syndrome (TRAPS)., Methods: (i) Deep next generation sequencing (NGS) through a SAID gene panel; (ii) variant allele distribution in peripheral blood subpopulations; (iii) in silico analyses of mosaic variants using TNF receptor superfamily 1A (TNFRSF1A) crystal structure; (iv) review of the very rare TNFRSF1A mosaic variants reported previously., Results: In a 36-year-old man suffering from recurrent fever for 12 years, high-depth NGS revealed a TNFRSF1A mosaic variant, c.176G>A p.(Cys59Tyr), which Sanger sequencing failed to detect. This mosaic variant displayed a variant allele fraction of 14% in whole blood; it affects both myeloid and lymphoid lineages. p.(Cys59Tyr), a recurrent germline pathogenic variant, affects a crucial cysteine located in the first cysteine-rich domain (CRD1) and involved in a disulphide bridge. Introduction of a tyrosine at this position is expected to disrupt the CRD1 structure. Review of the three previously reported TNFRSF1A mosaic variants revealed that they are all located in a small region of CRD2 and that germinal cells can be affected., Conclusion: This study expands the localization of TNFRSF1A mosaic variants to the CRD1 domain. Noticeably, residues involved in germline TNFRSF1A mutational hot spots can also be involved in post-zygotic mutational events. Including our study, only four patients have been thus far reported with TNFRSF1A mosaicism, highlighting the need for a high-depth NGS-based approach to avoid the misdiagnosis of TRAPS. Genetic counselling has to consider the potential occurrence of TNFRSF1A mosaic variants in germinal cells., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Cryopyrin-associated periodic syndrome (CAPS) is a rare but treatable inherited autoinflammatory condition including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurologic cutaneous articular syndrome (CINCA). Our objective was to describe the main features of CAPS AA amyloidosis (AA-CAPS) associated and the efficacy of IL-1 inhibitors in this indication., Methods: Retrospective study in France associated with a systematic literature review., Results: Eighty-six patients were identified: 23 new French cases and 63 from the literature, with a median age at amyloidosis diagnosis of 39 years old. CAPS subtypes were MWS (n = 62), FCAS (n = 9), frontier forms between MWS and FCAS (n = 12) and between CINCA and MWS (n = 3). NLRP3 had been sequenced in 60 patients (70%) and the most frequent mutation was R260W (60%). Three AA-CAPS patients displayed somatic NLRP3 mutations. Death occurred in 35 patients (41%), none of whom having ever received IL-1 inhibitors. Twenty-eight patients (33%) received IL-1 inhibitors, with a >50% decrease in proteinuria in 89% of cases., Conclusion: AA amyloidosis can occur in nearly all CAPS subtypes. IL-1 inhibitors are effective, underlining the necessity of an early diagnosis of CAPS in order to start this treatment as soon as possible among AA-CAPS patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: TNF receptor-1-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder associated with mutations in the TNF receptor super family 1 A (TNFRSF1A) gene. AA amyloidosis (AA) is the most severe complication of TRAPS. To study the occurrence and prognosis of AA in TRAPS, we conducted a retrospective study of all French cases and a systematic literature review., Methods: This case series includes TRAPS patients followed by our centre from 2000 to 2020 presenting with histologically confirmed AA. We conducted a systematic literature review on the PubMed and EMBASE databases for articles published up to February 2021 following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines and using the keywords: amyloidoisis, amyloid, TNF receptor-associated periodic syndrome, TNF receptor-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome, TRAPS, TNFRSF1A, familial hibernian fever and hibernian familial fever., Results: A total of 41 TRAPS with AA were studied: three new patients and 38 cases from the literature. AA diagnosis preceded that of TRAPS in 96% of cases, and 17/36 (47%) required renal replacement therapy. Death occurred in 5/36 (14%) with a median follow-up of 23 months. Effect of biologics on AA were available for 21 regimens in 19 patients: 10 improved renal function, seven stabilized and four worsened. Four patients (36% of transplanted patients) relapse AA on kidney graft (only one under etanercept)., Conclusion: TRAPS is revealed by AA in most cases. Therefore, clinical features of TRAPS should be screened for in AA patients. IL-1 antagonist can help to normalize inflammation and to preserve renal function., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder, for which systemic AA amyloidosis is the major complication revealed most of the time by renal abnormalities. Current treatment is daily colchicine that prevents both recurrent inflammatory attacks and amyloidosis deposition in most patients. However, some patients still develop amyloidosis and renal failure. Functional studies suggest that interleukin (IL)-1 is implicated in the inflammatory reaction in FMF and therefore, IL-1 inhibitors could be a new approach to treat FMF. The aim of this series study was to evaluate anakinra in patients with FMF complicated with amyloidosis and renal failure., Methods: We studied a series of adult patients with FMF complicated with amyloidosis and treated with anakinra in one reference centre were reviewed. A search for published patients with FMF associated amyloidosis treated with anakinra was performed by screening PubMed., Results: We report four cases of patients with FMF-associated amyloidosis treated with anakinra and discuss the clinical pertinence of its use in these particular clinical settings., Conclusions: Anakinra has a strong effect on both inflammatory attacks and general status in patients with FMF-associated amyloidosis. It may contribute to changing the prognosis of these patients. Long-term studies are needed to appreciate the effect of anakinra or other IL-1 inhibitors on the natural history of amyloidosis in these patients.

Objectives: Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS) are rare periodic fevers associated with CIAS1 mutations. A third entity, the chronic infantile neurological, cutaneous, articular (CINCA) syndrome was also recently associated with mutation in the same gene. A phenotypic and genotypic continuum seems to exist from the most benign (FCAS) to the most severe forms (CINCA). Although a CIAS1 mutation can be associated with two different phenotypes., Methods: We report a family of three patients exhibiting the MWS and FCAS phenotypes. These phenotypes were associated with a novel missense mutation in CIAS1., Results: Anakinra controlled inflammatory flares in the three patients., Conclusions: FCAS, MWS and CINCA could be different phenotype expressions of the same disease.

Objective: The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was originally defined by the presence of a high serum level of immunoglobulin D associated with recurrent fever. Since the discovery of the mevalonate kinase gene (MVK) gene encoding the mevalonate kinase enzyme, most patients with a clinical diagnostic of HIDS are now found to have a mevalonate kinase deficiency based on metabolic and genetic data. We aimed to asses the value of a high IgD serum level for the diagnosis of HIDS in a cohort of patients with a phenotype of recurrent fever, and to characterize patients with a high IgD serum level without mevalonate kinase mutation., Methods: Main clinical and biological data of 50 patients who presented with clinical signs compatible with HIDS have been prospectively registered on a standard form. Clinical data have been analysed according the IgD serum level and the presence of MVK mutation., Results: The metabolic and genetic data establishing the diagnosis of HIDS correlated in all cases. In this series of 50 patients, the sensitivity of a high IgD value for the diagnosis of HIDS is 0.79. In five patients with MVK mutation, IgD levels were found to be in the normal range. Likelihood ratios indicate that IgD measurement is not relevant for the diagnostic of HIDS. Most patients with a high serum IgD level and no MVK mutation have no definite diagnosis., Conclusion: The clinical relevance of the IgD measurement for the diagnosis of MKD in our population appears as poor, as reflected by likelihood ratios which are both close to 1.

Hereditary periodic fever syndromes are a group of diseases characterized by intermittent bouts of clinical inflammation with focal organ involvement, mainly of the abdomen, musculoskeletal system and skin. The most frequent is familial Mediterranean fever, which affects patients of Mediterranean descent all over the world. Three other types have recently been characterized clinically and genetically. A thorough diagnosis is warranted, as clinical and therapeutic management is specific for each of these diseases. The underlying mechanisms of these inflammatory diseases appear to be specific for each type, involving so far unknown proteins, and have already opened new avenues in our understanding of the inflammatory response.

Background: Among hereditary fevers characterized by recurrent attacks of fever and organ localized inflammation, familial Mediterranean fever (FMF), and tumour necrosis factor receptor superfamily 1A (TNFRSF1A) receptor associated periodic syndrome (TRAPS) are diseases with identified genes that can be associated with renal amyloidosis of the AA type. In this study we have characterized FMF and TRAPS genotypes in 38 unrelated patients suffering from amyloidosis AA and recurrent inflammatory attacks., Methods: Mutations of the MEFV and TNFRSF1A genes, responsible respectively for FMF and TRAPS, were searched for by amplifying, using polymerase chain reaction (PCR), genomic DNA, and direct sequencing., Results: Twenty-seven patients (71%) carried mutations in MEFV (22 patients with two mutations, two patients with a single mutation) or TNFRSF1A genes (three patients). Patients with MEFV mutations belonged to the classical at-risk ethnic group for FMF: Sephardic Jews, Turks, Armenians, and Arabs from the Maghreb. The main genotype encountered was M694V/M694V (19/22), one Turkish patient was M680I/M680I, and two Arab patients from the Maghreb were M694I/M694I. We found three Caucasian patients with the C55S, C70Y, R92Q mutations in the TNFRSF1A gene., Conclusions: In this series we observed that FMF is the main cause of AA amyloidosis in Sephardic Jews and Turks. MEFV and TNFRSF1A mutations were found in only 6 of 14 Arab patients from the Maghreb. We found three families (one Caucasian and two from Maghreb) with AA amyloidosis without MEFV or TNFRSF1A mutations, suggesting that other genetic cause(s) exist(s). The characterization of mutations in MEFV and TNFRSF1A is important for the therapeutic behaviour of AA amyloidosis associated with inherited recurrent fever.

Six cases of chronic renal failure related to granulomatous renal sarcoidosis are reported and compared with data in the literature. The particular features of sarcoidosis granulomatous interstitial nephritis should be emphasised because presentation may be misleading. Renal failure usually presents with a rapidly progressive course, either isolated or associated with mild proteinuria and sterile leukocyturia, while extrarenal localisations may be absent. Diagnosis should be suspected on the basis of elevated or paradoxically normal serum calcium concentrations, due to increased plasma concentrations of calcitriol, while immunoreactive circulating parathormone concentrations are depressed. Calcitriol as well as angiotensin-converting enzyme could represent unregulated secretion products from granulomatous tissue and their plasma concentrations may roughly reflect activity of the disease. Early corticosteroid treatment dramatically improves renal function but long-term renal prognosis may be oblitered due to progressive chronic renal failure related to fibrosis scarring.

Primary hyperoxaluria leading to calcium oxalate urinary stones and renal deposits occurs rarely in adults. We report three cases in whom end-stage renal failure was precipitated by urological surgery. In contrast, in one case renal stones were destroyed by extracorporeal shock-wave lithotripsy and renal function was not significantly altered. This emphasises the need for early diagnosis. This may not be easy in adult patients: urolithiasis may not be severe, radiological nephrocalcinosis may be lacking, and renal failure may develop late in life.