Extra-osseous manifestations in chronic recurrent multifocal osteomyelitis: a retrospective study.

OBJECTIVES: Extra-osseous (EO) manifestations are poorly characterized in chronic recurrent multifocal osteomyelitis (CRMO). This study aimed to further define the frequency, characteristics and treatment of EO events in CRMO and whether different phenotypes can be distinguished and benefit from special management. METHODS: This multicentre retrospective study included CRMO patients followed in several paediatric rheumatology departments in France, between 2015 and 2022. EO manifestations were defined as skin lesions, gastrointestinal manifestations, arthritis, enthesitis, sacroiliitis, uveitis, vasculitis, and fever. At the last visit, the physician defined CRMO as active in the presence of clinical manifestations including both osseous and EO symptoms. RESULTS: We included 133 patients; 87 (65.4%) were girls; the median age at first symptoms was 9.0 years (interquartile range 7.0-10.0). EO manifestations were described in 90 (67.7%) patients, with a predominance of skin lesions (n = 51/90; 56.7%), followed by sacroiliitis (n = 38/90; 42.2%), enthesitis (n = 21/90; 23.3%), arthritis (n = 14/90, 15.6%) and gastrointestinal manifestations (n = 6/90, 6.7%). The use of non-steroidal anti-inflammatory drugs and bisphosphonates did not differ by presence or not of EO manifestations. Biologics were taken more frequently by patients with than without EO manifestations (p< 0.001); tumour necrosis factor inhibitors were used in 33 (36.7%) EO+ patients. Under this treatment, 18 (54.5%) patients achieved complete remission of osseous and EO manifestations. At the last visit, more EO-positive than EO-negative patients were on treatment (p= 0.009), with active disease in 58 (64.4%) patients. CONCLUSION: The analysis of EO manifestations in CRMO delineates 2 groups of patients in terms of severity and treatments used. Our study opens up new pathophysiological leads that may underlie the wide range of CRMO phenotypes.

Case Report: Comorbid Hyper-IgD Syndrome and Hidradenitis Suppurativa - A New Syndromic Form of HS? A Report of Two Cases.

Hidradenitis Suppurativa (HS) is a chronic suppurative disease of the pilosebaceous unit. The current model of HS pathophysiology describes the condition as the product of hyperkeratinisation and inflammation at the hair follicular unit. Environmental factors (such as smoking and obesity), gender, genetic predisposition, and skin dysbiosis are considered the main pathogenic drivers of the disease. Autoinflammatory syndromes associated with HS are rare but may help to highlight the potential roles of autoinflammation and dysregulated innate immune system in HS. Therefore, it is of major relevance to increase the awareness about these diseases in order to improve the understanding of the disease and to optimize the management of the patients. Herein, we report for the first time, to our knowledge, two clinical cases of Hyper-IgD syndrome-associated HS. Hyper-IgD is an autoinflammatory syndrome caused by a mevalonate kinase deficiency (MKD), a key kinase in the sterol and isoprenoid production pathway. We describe the potentially shared pathophysiological mechanisms underpinning comorbid MKD-HS and propose therapeutic options for the management of these patients.

LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages.

Juvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages.

Fast diagnostic test for familial Mediterranean fever based on a kinase inhibitor.

BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) is the most frequent hereditary autoinflammatory disease. Its diagnosis relies on a set of clinical criteria and a genetic confirmation on identification of biallelic pathogenic MEFV variants. MEFV encodes pyrin, an inflammasome sensor. Using a kinase inhibitor, UCN-01, we recently identified that dephosphorylation of FMF-associated pyrin mutants leads to inflammasome activation. The aim of this study was to assess whether quantifying UCN-01-mediated inflammasome activation could discriminate FMF patients from healthy donors (HD) and from patients with other inflammatory disorders (OID). METHODS: Real-time pyroptosis and IL-1ß secretion were monitored in response to UCN-01 in monocytes from FMF patients (n=67), HD (n=71) and OID patients (n=40). Sensitivity and specificity of the resulting diagnostic tests were determined by receiver operating characteristic curve analyses. RESULTS: Inflammasome monitoring in response to UCN-01 discriminates FMF patients from other individuals. Pyroptosis assessment leads to a fast FMF diagnosis while combining pyroptosis and IL-1ß dosage renders UCN-01-based assays highly sensitive and specific. UCN-01-triggered monocytes responses were influenced by MEFV gene dosage and MEFV mutations in a similar way as clinical phenotypes are. CONCLUSIONS: UCN-01-based inflammasome assays could be used to rapidly diagnose FMF, with high sensitivity and specificity.

Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome.

Objectives: FMF is the most frequent autoinflammatory disease and is associated in most patients with bi-allelic MEFV mutations. MEFV encodes Pyrin, an inflammasome sensor activated following RhoGTPase inhibition. The functional consequences of MEFV mutations on the ability of Pyrin variants to act as inflammasome sensors are largely unknown. The aim of this study was to assess whether MEFV mutations affect the ability of Pyrin to detect RhoGTPase inhibition and other inflammasome stimuli. Methods: IL-1ß and IL-18 released by monocytes from healthy donors (HDs) and FMF patients were measured upon specific engagement of the Pyrin, NLRP3 and NLRC4 inflammasomes. Cell death kinetics following Pyrin activation was monitored in real time. Results: Monocytes from FMF patients secreted significantly more IL-1ß and IL-18 and died significantly faster than HD monocytes in response to low concentrations of Clostridium difficile toxin B (TcdB), a Pyrin-activating stimulus. Monocytes from patients bearing two MEFV exon 10 pathogenic variants displayed an increased Pyrin inflammasome response compared with monocytes from patients with a single exon 10 pathogenic variant indicating a gene-dosage effect. Using a short priming step, the response of monocytes from FMF patients to NLRP3- and NLRC4-activating stimuli was normal indicating that MEFV mutations trigger a specific hypersensitivity of monocytes to low doses of a Pyrin-engaging stimulus. Conclusion: Contrary to the NLRP3 mutations described in cryopyrin-associated periodic syndrome, FMF-associated MEFV mutations do not lead to a constitutive activation of Pyrin. Rather, FMF-associated mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome without affecting other canonical inflammasomes.

Musculoskeletal symptoms in patients with cryopyrin-associated periodic syndromes: a large database study.

OBJECTIVE: To determine the type and frequency of musculoskeletal symptoms at onset and during followup of cryopyrin-associated periodic syndromes (CAPS). METHODS: We retrospectively recorded the articular and muscular symptoms of patients with CAPS followed up in French hospitals. Data were presented as frequencies or the median (range), and patient groups were compared using chi-square test, Fisher's exact test, and Mann-Whitney test. RESULTS: The study included 133 patients (33 children), 20 with familial cold autoinflammatory syndrome, 88 with Muckle-Wells syndrome, 22 with chronic infantile neurologic, cutaneous, articular syndrome, and 3 with unclassified CAPS. The median age was 35 years (range 0-78 years) at the time of the study, 1 year (range 0-41 years) at symptom onset, and 23 years (range 0-58 years) at diagnosis. The disease was sporadic in 17% of the patients. Cutaneous symptoms predominated at onset (77%), followed by articular symptoms (30%). The p.Thr348Met and p.Arg260Trp NLRP3 mutations were significantly associated with the presence and absence of articular symptoms at onset, respectively. During followup, 86% of the patients had musculoskeletal symptoms, 88% had arthralgia, and 58% had arthritis, but only 9% had joint destruction. Tendinopathies occurred in 21.5% of the patients, tender points in 16.5%, and myalgia in 33%. Only 3 patients had typical knee deformities. Radiographs were rarely obtained. Except for bone deformities, osteoarticular symptoms occurred at similar frequencies in the different CAPS phenotypes. CONCLUSION: Joint manifestations were frequent in all CAPS phenotypes. Bone deformities were rare. Musculoskeletal manifestations varied within given families but tended to worsen over time.

A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference.

BACKGROUND: The systemic autoinflammatory disorders (SAID) share many clinical manifestations, albeit with variable patterns, intensity and frequency. A common definition of disease activity would be rational and useful in the management of these lifelong diseases. Moreover, standardised disease activity scores are required for the assessment of new therapies in constant development. The aim of this study was to develop preliminary activity scores for familial Mediterranean fever, mevalonate kinase deficiency, tumour necrosis factor receptor-1-associated periodic syndrome and cryopyrin-associated periodic syndromes (CAPS). METHODS: The study was conducted using two well-recognised consensus formation methods: the Delphi technique and the nominal group technique. The results from a two-step survey and data from parent/patient interviews were used as preliminary data to develop the agenda for a consensus conference to build a provisional scoring system. RESULTS: 24 of 65 experts in SAID from 20 countries answered the web questionnaire and 16 attended the consensus conference. There was consensus agreement to develop separate activity scores for each disease but with a common format based on patient diaries. Fever and disease-specific clinical variables were scored according to their severity. A final score was generated by summing the score of all the variables divided by the number of days over which the diary was completed. Scores varied from 0 to 16 (0-13 in CAPS). These scores were developed for the purpose of clinical studies but could be used in clinical practice. CONCLUSION: Using widely recognised consensus formation techniques, preliminary scores were obtained to measure disease activity in four main SAID. Further prospective validation study of this instrument will follow.

Occurrence of inflammatory bowel disease during treatment of juvenile idiopathic arthritis with etanercept: a French retrospective study.

OBJECTIVES: To identify juvenile idiopathic arthritis (JIA) patients who developed IBD during treatment with anti-TNF-alpha agents and better characterize the IBD clinical and pathological presentation. METHODS: A retrospective French multicentre study included patients with a diagnosis of JIA according to the ILAR criteria who developed IBD while under anti-TNF-alpha therapy before 18 years of age. Intestinal biopsies were collected and reviewed by the same pathologist. RESULTS: Eight patients were included. They had been treated with etanercept from 11 to 78 months before IBD onset. Gastro-intestinal symptoms included abdominal pain (six patients), diarrhoea (four patients), anorexia (four patients), anal abscess (three patients) and oral ulcers (one patient). Five patients presented with Crohn's disease (CD) and three with indeterminate IBD, of whom four had severe pancolitis. Clinical remission of IBD was obtained in all patients after discontinuation of etanercept and initiation of IBD-specific therapy, including infliximab in six patients. CONCLUSION: IBD must be suspected in JIA patients treated with etanercept who develop intestinal symptoms, including anal abscess. This series raises the possibility of a relationship between etanercept therapy and the occurrence of IBD in a subset of patients with JIA.

Autoimmune hypoparathyroidism in a 12-year-old girl with McKusick cartilage hair hypoplasia.

McKusick type metaphyseal chondrodysplasia, or cartilage hair hypoplasia (CHH), is a rare autosomal recessive osteochondrodysplasia secondary to a mutation in the RMRP gene. In addition to the metaphyseal chondrodysplasia and the short-limb dwarfism, patients may present with a multisystemic disease, associating immune deficiency with recurrent infantile or childhood infections, hematological abnormalities, and gastrointestinal dysfunction. The probability of malignancy is increased in these patients, as are disimmune manifestations. We report on a 12-year-old girl with a new mutation of the RMRP gene and a severe multisystemic CHH (hematological and pulmonary lesions, severe immune deficiency, arthritis, pancreatic insufficiency, malabsorption, chronic diarrhea) receiving parenteral nutrition who presented with acute symptomatic hypocalcemia and hypercalciuria associated with the presence of autoantibodies directed against the calcium-sensor receptor. At the same time, there was an important escalation of diarrhea. Corticosteroids led to a progressive improvement of biological signs (hypocalcemia, hypoparathyroidism). By contrast, gastrointestinal symptoms and malabsorption did not improve. To our knowledge, this is the first report of autoimmune hypoparathyroidism in CHH.