Is neutrophilic dermatosis a manifestation of familial Mediterranean fever?

Objectives: Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disease. It is associated with MEFV mutations. Its main features are recurrent episodes of fever and serositis. Patients can display dermatological manifestations such as erysipelas-like erythema, generally considered as a neutrophilic dermatosis (ND). It has been suggested that FMF can be associated with other types of ND. Our aim was to perform a systematic review of the literature to assess the link between ND and FMF.Method: A systematic review of the literature was performed using MEDLINE from 1946 to 2018. Three independent investigators identified reports of non-erysipelas-like erythema neutrophilic dermatosis (NEND) associated with FMF, selected the criteria to establish the diagnosis of FMF and ND, and evaluated the link between the two conditions. FMF-associated NEND was supported by confirmation of both diagnoses and exclusion of other causes of ND.Results: Eighteen articles were selected. Nine articles reported FMF patients with the following NEND: neutrophilic panniculitis (n = 4), Sweet syndrome (n = 6), and pyoderma gangrenosum (n = 1). None of these cases was supported by histological confirmation, fulfilled diagnostic criteria for definitive or probable FMF, or confirmed the exclusion of all the most frequent diseases associated with NEND. As a result, there is insufficient evidence to support a potential relationship between NEND and FMF.Conclusions: The association between FMF and NEND remains unclear. In FMF patients with NEND, every differential diagnosis and alternative cause of NEND should be excluded before drawing any conclusions about a potential causal relationship.

Schnitzler syndrome: validation and applicability of diagnostic criteria in real-life patients.

BACKGROUND: Schnitzler syndrome is characterized by an urticarial rash, a monoclonal gammopathy, and clinical, histological, and biological signs of neutrophil-mediated inflammation. The aim of this study was to assess the applicability and validity of the existing diagnostic criteria in real-life patients. METHODS: This multicentric study was conducted between 2009 and 2014 in 14 hospitals in which patients with Schnitzler syndrome or controls with related disorders were followed up. We compared the sensitivities and specificities and calculated the positive and negative predictive values of the Lipsker and of the Strasbourg criteria for the patients with Schnitzler syndrome and for the controls. We included 42 patients with Schnitzler syndrome, 12 with adult-onset Still's disease, 7 with cryopyrin-associated periodic disease, 9 with Waldenström disease, and 10 with chronic spontaneous urticaria. RESULTS: All patients with Schnitzler syndrome met the Lipsker criteria. According to the Strasbourg criteria, 34 patients had definite Schnitzler syndrome, five had probable Schnitzler syndrome, and three did not meet the criteria. One control met the Lipsker criteria and had probable Schnitzler syndrome according to the Strasbourg criteria. Sensitivity and specificity of the Lipsker criteria were 100% and 97%, respectively. For the Strasbourg criteria, sensitivity for definite and probable diagnosis was 81% and 93%, respectively, with a corresponding specificity of 100% and 97%. CONCLUSION: Diagnostic criteria currently in use to diagnose Schnitzler syndrome are reliable. More investigations must be done to attest their efficiency in patients with recent-onset manifestations.

Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group.

Hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS; MIM 260920) is a rare, apparently monogenic, autosomal recessive disorder characterized by recurrent episodes of fever accompanied with lymphadenopathy, abdominal distress, joint involvement and skin lesions. All patients have high serum IgD values (>100 U/ml) and HIDS 'attacks' are associated with an intense acute phase reaction whose exact pathophysiology remains obscure. Two other hereditary febrile disorders have been described. Familial Mediterranean fever (MIM 249100) is an autosomal recessive disorder affecting mostly populations from the Mediterranean basin and is caused by mutations in the gene MEFV (refs 5,6). Familial Hibernian fever (MIM 142680), also known as autosomal dominant familial recurrent fever, is caused by missense mutations in the gene encoding type I tumour necrosis factor receptor. Here we perform a genome-wide search to map the HIDS gene. Haplotype analysis placed the gene at 12q24 between D12S330 and D12S79. We identified the gene MVK, encoding mevalonate kinase (MK, ATP:mevalonate 5-phosphotransferase; EC 2.7.1.36), as a candidate gene. We characterized 3 missense mutations, a 92-bp loss stemming from a deletion or from exon skipping, and the absence of expression of one allele. Functional analysis demonstrated diminished MK activity in fibroblasts from HIDS patients. Our data establish MVK as the gene responsible for HIDS.

French protocol for the diagnosis and management of familial Mediterranean fever.

Familial Mediterranean fever is the most common monogenic auto-inflammatory disease in the world. It mainly affects people originating from the Mediterranean region. The mutated gene is MEFV, which codes for pyrin. Transmission is autosomal recessive. Patients present with recurrent attacks of fever since childhood associated with abdominal and/or thoracic pain lasting an average of 2-3days and a biological inflammatory syndrome. Other symptoms include arthralgia or arthritis in large joints such as the knees and ankles, myalgia in the lower limbs and pseudo-erysipelas in the ankles. The most serious complication is inflammatory amyloidosis, which can lead to kidney failure. Treatment is based on colchicine, which helps to prevent flares and the onset of renal amyloidosis. This paper proposes national guidelines for the diagnosis, management and follow-up of familial Mediterranean fever in France, where we estimate there are between 5000 and 10,000 patients with the disease at all stages of life. The diagnosis is suspected on the basis of clinical and anamnestic factors and confirmed by genetic analysis. These guidelines also suggest a "treat-to-target" approach to disease management, particularly in case of suspected colchicine resistance - a very rare situation that should remain a diagnosis of elimination, especially after colchicine compliance has been verified. Two special situations are also addressed in these guidelines: kidney failure and pregnancy.

French practical guidelines for the diagnosis and management of AA amyloidosis.

AA amyloidosis is secondary to the deposit of excess insoluble Serum Amyloid A (SAA) protein fibrils. AA amyloidosis complicates chronic inflammatory diseases, especially chronic inflammatory rheumatisms such as rheumatoid arthritis and spondyloarthritis; chronic infections such as tuberculosis, bronchectasia, chronic inflammatory bowel diseases such as Crohn's disease; and auto-inflammatory diseases including familial Mediterranean fever. This work consists of the French guidelines for the diagnosis workup and treatment of AA amyloidosis. We estimate in France between 500 and 700 cases in the whole French population, affecting both men and women. The most frequent organ impaired is kidney which usually manifests by oedemas of the lower extremities, proteinuria, and/or renal failure. Patients are usually tired and can display digestive features anf thyroid goiter. The diagnosis of AA amyloidosis is based on detection of amyloid deposits on a biopsy using Congo Red staining with a characteristic green birefringence in polarized light. Immunohistochemical analysis with an antibody directed against Serum Amyloid A protein is essential to confirm the diagnosis of AA amyloidosis. Peripheral inflammatory biomarkers can be measured such as C Reactive protein and SAA. We propose an algorithm to guide the etiological diagnosis of AA amyloidosis. The treatement relies on the etiologic treatment of the undelying chronic inflammatory disease to decrease and/or normalize Serum Amyloid A protein concentration in order to stabilize amyloidosis. In case of renal failure, dialysis or even a kidney transplant can be porposed. Nowadays, there is currently no specific treatment for AA amyloidosis deposits which constitutes a therapeutic challenge for the future.

Poor performance of albumin or protein-adjusted plasma calcium to diagnose dyscalcemia in hospitalized patients: A confirmatory study in a general internal medicine department.

INTRODUCTION: Hypo- and hypercalcemia are common and some causes require urgent diagnosis and treatment. Measurement of ionized calcium is the reference test to diagnose calcium disorders but total calcium adjusted for protein or albumin concentration is more often used. METHODS: Patients hospitalised in a general internal medicine department from September 2013 to December 2015 who had a total plasma calcium concentration and a serum albumin or protein concentration measured within 24h of a ionized calcium blood measurement were included. Total calcium was adjusted for protein or albumin concentration using widely used formulas and compared to ionized calcium as the gold standard. RESULTS: Among 210 included patients, 46 (22%) had hypocalcemia, 124 (59%) normocalcemia and 40 (19%) hypercalcemia according to ionized calcium concentration. Total calcium had 50% sensitivity and 95% specificity to diagnose hypocalcemia and a 93% sensitivity and 89% specificity to diagnose hypercalcemia. Adjusting total calcium for protein or albumin concentrations did not increase and sometimes decreased diagnostic accuracy. CONCLUSION: Total calcium, with or without albumin/protein adjustment, is poorly sensitive to screen for hypocalcemia. Unadjusted total calcium is as sensitive as protein- or albumin-adjusted total calcium to screen for hypercalcemia. These data argue against the use of albumin- or protein-adjusted calcium. Ionized calcium measurement should be performed to confirm dyscalcemia in patients with abnormal total calcium concentration and to rule out hypocalcemia in patients with total calcium concentration in the lower range of normal values.

Is procalcitonin a marker of invasive bacterial infection in acute sickle-cell vaso-occlusive crisis?

Fever is often present during painful vaso-occlusive crisis (VOC) in sickle-cell disease (SCD), but does not always indicate infection. The aim of our study was to test procalcitonin as a marker of invasive bacterial infection in VOC. Consecutive SCD adults hospitalized for VOC were included. Data were collected at admission and within 24 h after the onset of fever. We distinguished patients with clinically defined and microbiologically documented invasive bacterial infection from patients with no evidence of invasive bacterial infection and who fared well without antibiotics. One hundred and twelve patients were enrolled (61% females, median age 23 years, 88% homozygous SCD). All patients with procalcitonin (PCT) level ≥1 µg/L had an invasive bacterial infection, but two patients (33%) with an invasive bacterial infection had a PCT level <1 µg/L. High levels of PCT indicate invasive bacterial infection. However, a single low PCT level without follow-up measurement cannot rule out an invasive bacterial infection and should not withhold the prescription of antibiotics.

Mutations in NALP12 cause hereditary periodic fever syndromes.

NALP proteins, also known as NLRPs, belong to the CATERPILLER protein family involved, like Toll-like receptors, in the recognition of microbial molecules and the subsequent activation of inflammatory and immune responses. Current advances in the function of NALPs support the recently proposed model of a disease continuum bridging autoimmune and autoinflammatory disorders. Among these diseases, hereditary periodic fevers (HPFs) are Mendelian disorders associated with sequence variations in very few genes; these variations are mostly missense mutations whose deleterious effect, which is particularly difficult to assess, is often questionable. The growing number of identified sporadic cases of periodic fever syndrome, together with the lack of discriminatory clinical criteria, has greatly hampered the identification of new disease-causing genes, a step that is, however, essential for appropriate management of these disorders. Using a candidate gene approach, we identified nonambiguous mutations in NALP12 (i.e., nonsense and splice site) in two families with periodic fever syndromes. As shown by means of functional studies, these two NALP12 mutations have a deleterious effect on NF-kappaB signaling. Overall, these data identify a group of HPFs defined by molecular defects in NALP12, opening up new ways to manage these disorders. The identification of these first NALP12 mutations in patients with autoinflammatory disorder also clearly demonstrates the crucial role of NALP12 in inflammatory signaling pathways, thereby assigning a precise function to this particular member of an emerging family of proteins whose putative biological properties are currently inferred essentially through in vitro means.

[Periodic fever syndrome associated with mutations in the TNF type 1 receptor gene: A differential diagnosis of familial Mediterranean fever that should not be overlooked in patients of Mediterranean origin]. / Le syndrome de fièvre prolongée associée aux mutations du gène du récepteur au TNF de type 1 : un diagnostic différentiel de la fièvre méditerranéenne familiale à ne pas méconnaître chez les patients d'origine méditerranéenne.

INTRODUCTION: Tumor Necrosis Factor Type 1 Receptor Associated Periodic Syndrome (TRAPS) is a rare autosomal dominant autosomal autoinflammatory disease associated with mutations in the TNF type 1 receptor gene (TNFRSF1A). It is characterized by relatively long recurrent febrile seizures with an average duration of 7 days accompanied by arthralgia, myalgia, and usually a rash. In a patient of Mediterranean origin with recurrent fever, familial Mediterranean fever is the first diagnosis to be suspected by argument of frequency. METHODS: A retrospective observational study was conducted on patients from Mediterranean origin followed for TRAPS and included in the "Juvenile Inflammatory Rheumatism" (JIR) observational cohort in the national French autoinflammatory center. The age of onset of symptoms, age of diagnosis, number of years of wandering and treatments received were collected for each index case. RESULTS: Nine patients from 6 families of Mediterranean origin were included. A molecular diagnosis confirmed TRAPS in all patients. The median age at diagnosis was 26 years, the mean number of years of wandering was 17 years. The diagnosis of FMF was made first in all patients. AA amyloidosis revealed TRAPS in 2 patients. Colchicine was started without any efficacy in all cases. Five patients were treated with interleukin-1 inhibitory biotherapy with 100% efficacy. CONCLUSION: In a patient of Mediterranean origin presenting with recurrent febrile abdominal pain of AA amyloidosis, the first diagnosis to be suspected is FMF. Long relapses, dominant transmission, a non-Mediterranean relative, and the ineffectiveness of colchicine should evoke TRAPS.

AA amyloidosis secondary to adult onset Still's disease: About 19 cases.

OBJECTIVE: Adult onset Still's disease (AOSD) is an inflammatory disorder characterized by high spiking fever, evanescent rash, polyarthritis, and many other systemic manifestations. Recurrent or persistent disease can lead to AA amyloidosis (AAA). Our objectives were to present 3 French cases and perform a systematic review of the literature, in order to determine the prevalence, characteristics, predisposing factors, and therapeutic response of AOSD-related AAA. METHODS: A systematic literature review was performed by searching MEDLINE from 1971 to 2018. Two independent investigators selected reports of AAA complicating AOSD. New French cases were identified with the help of the Reference Center for rare Auto-Inflammatory Diseases and Amyloidosis (CEREMAIA). Patients with juvenile idiopathic arthritis were excluded. RESULTS: The prevalence of AAA in AOSD was 0.88% (95%CI [0.49-1.28]) based on 45 articles. In addition to 3 new cases from the CEREMAIA, 16 patients were assessed for clinical presentation, risk factors, and therapeutic response of AOSD-related AAA. Mean age at AOSD onset was 29.6 ±â€¯12.6 years, with a mean delay before AAA diagnosis of 16.75±5.8 years. Renal involvement was the most common manifestation of AAA. The majority of patients presented active AOSD at AAA diagnosis. Various treatments of AOSD-related AAA were attempted including corticosteroids and biotherapies. CONCLUSION: AAA is a rare and severe complication that may occur during the course of uncontrolled active AOSD. It could be prevented by early diagnosis and better control of AOSD, with more frequent use of biotherapies.

Diagnostic value of procalcitonin in acutely hospitalized elderly patients.

The aim of this study was to evaluate procalcitonin as an adjunct to diagnose bacterial infections in older patients. One hundred seventy-two patients admitted to an acute-care geriatric unit during a 6-month period were prospectively included, 39 of them with an invasive bacterial infection. The best cut-off value to rule in a bacterial infection was 0.51 microg/l with sensitivity 64% and specificity 94%. The best cut-off value to rule out a bacterial infection was 0.08 microg/l with sensitivity 97% and specificity 20%. Procalcitonin was inconclusive (between 0.08 and 0.51 microg/l) for 112 admissions. Procalcitonin over 0.51 microg/l was useless 22 times out of 33 (infection already ruled in on clinical grounds) and misleading in eight of the 11 remaining cases (no infection). Procalcitonin below 0.08 microg/l was useless 23 times out of 27 (infection already ruled out on clinical grounds) and misleading in one of the four remaining cases (infection). Despite a good overall diagnostic accuracy, the clinical usefulness of PCT to diagnose invasive bacterial infections in elderly patients hospitalized in an acute geriatric ward appears to be very limited.

New CIAS1 mutation and anakinra efficacy in overlapping of Muckle-Wells and familial cold autoinflammatory syndromes.

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.

[Multiple sclerosis and familial Mediterranean fever: a case report]. / Sclérose en plaques et fièvre méditerranéenne familiale : un cas et revue de la littérature.

INTRODUCTION: Few cases of patients with both Familial Mediterranean Fever (FMF) and Multiple Sclerosis (MS) have been reported, mainly from Turkey. Central nervous system manifestations are rare in FMF. CASE REPORT: We report the case of a 37-year-old right-handed man with FMF diagnosed at 17 the age of years and successfully treated with colchicine. The patient was born in Algeria and lived in France since he was four years old. He had a brother who had multiple sclerosis. When the patient was 23 years old, he experienced diplopia and leg numbness that resolved spontaneously without treatment. Ten years later, new neurological events appeared every six months and were treated with corticoid-steroids. The diagnosis of MS was made. In 2006, he was hospitalized for new explorations in order to search for neuro-Behçet's disease, because of the development of a canker sore. There was no argument for neuro-Behçet's disease. DISCUSSION: Neurological complications of FMF are rare. It is important to rule out a neuro-Behçet disease in a FMF patient with neurological disorders. Previous studies and case reports on the association between FMF and MS have failed to draw a clear conclusion as to whether this is a true association or a simple coincidence. In our patient's clinical situation, we found no argument for changing the treatment of MS and FMF.

[What's new in autoinflammatory diseases?]. / Quoi de neuf dans les maladies auto-inflammatoires ?

PURPOSE: The concept of auto-inflammation was initially coined to define the group of mendelian disorders characterized by recurrent inflammatory symptoms. The core of this group mainly consists of hereditary recurrent fevers, which has been lately enlarged to other inflammatory mendelian disorders as well as to some sporadic diseases with a genetic component relevant to innate immunity. CURRENT KNOWLEDGE AND KEY POINTS: Cryopyrin, the product of the CIAS1/PYPPAF1/NALP3/NLRP gene, whose mutations underline some mendelian syndromes (Mückle-Wells and chronic infantile neurological cutaneous and articular (CINCA), familial cold urticaria) can now be considered as a major factor of the regulation of interleukin-1 production within the multiprotein complex called inflammasome. This discovery has lit up our view of innate immunity. FUTURE PROSPECTS AND PROJECTS: The contribution of the innate immunity mechanisms in inflammatory disorders have led to a new look to the current nosology of this vast group of diseases and to suggest a classification with two poles. The first would be defined by the predominance of auto-inflammation, whereas in the second one auto-immunity predominates.

[NLRC4 associated autoinflammatory diseases: A systematic review of the current literature]. / Les maladies auto-inflammatoires associées aux mutations de NLRC4 : revue systématique de la littérature.

The auto-inflammatory diseases linked to NLRC4 mutations are recently described entities. Transmission is autosomal dominant in 80 % of cases; cases of somatic mutation have already been reported. The disease may display two very different clinical phenotypes: the phenotype 1 (30 %), severe, is dominated by a multisystemic inflammation starting in the first year of life with symptoms of chronic inflammatory bowel disease (IBD), macrophagic actication syndrome (MAS), or even a presentation suggesting a cryopyrinopathy in its CINCA form; the mortality of this phenotype is high (25 %). The phenotype 2 (70 %), mild, usually starts after the age of 3 and is characterized by cold urticaria, arthralgia, ocular features and fever in 50 % of cases without visceral failure. Anti-interleukin-1 inhibitors are effective in most cases (83 %). Interleukin-18 (IL-18) levels are very high in both clinical forms. Interleukin-18 inhibitors and anti-interferon-gamma inhibitors were remarkably effective in two very severe phenotype 1 patients. Thus, NLRC4 mutations can induce various clinical manifestations with two distinct phenotypes. Although still rare, because very recently described, this group of diseases could be evoked by an internist in front of cold familial urticarial; probably more and more cases will be diagnosed thanks to the major progresses of genetic diagnostic tools such as next generation sequencing.

[Tumor necrosis receptor associated periodic syndrome (TRAPS): State of the art]. / La fièvre récurrente liée au récepteur 1 du TNF (TNF receptor associated periodic syndrome ­ TRAPS).

Tumour necrosis receptor associated periodic syndrome (TRAPS) is a rare cosmopolitan dominant autosomal disease that belongs to the group of recurrent autoinflammatory syndromes. TRAPS is characterized by recurrent bouts of fever lasting more than 7 days, with arthralgia, myalgia, abdominal pain, erythematous rash and sometimes ocular symptoms. During flares, raised inflammatory markers are constant. The age of onset may occur during childhood but also during adulthood. TRAPS is caused by mutations in the TNF receptor 1 (TNFRSF1A) gene that may occur in most of the populations over the world. In the majority of patients, history shows affected relatives, even if sporadic cases do exist. Management of TRAPS usually involves corticosteroid therapy during inflammatory flares. The most severe cases require a treatment with biological agents (mainly interleukin 1 inhibitors). The prognosis of TRAPS is overall good; the main risk is represented by the development of secondary inflammatory amyloidosis. This risk is greatest in patients with structural mutations leading to conformation abnormalities of the TNFRSF1A receptor. Regular clinical and biological monitoring is essential in the follow-up of TRAPS patients.

[Multiple facets of ADA2 deficiency: Vasculitis, auto-inflammatory disease and immunodeficiency: A literature review of 135 cases from literature]. / Les multiples facettes du déficit en ADA2, vascularite, maladie auto-inflammatoire et immunodéficit : mise au point à partir des 135 cas de la littérature.

Deficiency of adenosine deaminase 2 (DADA2) is a recently described auto-inflammatory disorder. It is an autosomal recessive inherited disease, caused by mutations in the ADA2 gene (formerly known as CECR1) encoding ADA2 enzyme. Besides its role in the purine metabolism, it has been postulated that ADA2 may act as a growth factor for endothelial cells and in the differenciation of monocytes. Thus, deficiency of ADA2 would lead to endothelial damage and a skewing of monocytes into M1 pro-inflammatory macrophage, causing DADA2 manifestations. Three core clinical features have been described: inflammatory-vascular signs, hematologic abnormalities and immunodeficiency. Clinically, patients display intermittent fever, cutaneous vascular manifestations, such as livedo, ischemic strokes, arthralgia and abdominal pain crisis. Corticosteroids and immunosuppressive agents (i.e. cyclophosphamide, azathioprine, ciclosporin, methotrexate) appear to be poorly effective. Although the mechanism has not been elucidated, anti-TNF agents have been proven efficient in DADA2 and should therefore be used as first line therapy for vasculitis. Role of anti-platelet and anticoagulant therapies in stroke-prophylaxis remains to be discussed, as those patients display a high risk of intracranial bleeding.