Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients.

BACKGROUND: A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome'). OBJECTIVES: To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome. METHODS: One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded. RESULTS: The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis. CONCLUSIONS: VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.

Is gene panel sequencing more efficient than clinical-based gene sequencing to diagnose autoinflammatory diseases? A randomized study.

The aim of this study was to compare the effectiveness of the gene-panel next-generation sequencing (NGS) strategy versus the clinical-based gene Sanger sequencing for the genetic diagnosis of autoinflammatory diseases (AIDs). Secondary goals were to describe the gene and mutation distribution in AID patients and to evaluate the impact of the genetic report on the patient's medical care and treatment. Patients with AID symptoms were enrolled prospectively and randomized to two arms, NGS (n = 99) (32-55 genes) and Sanger sequencing (n = 197) (one to four genes). Genotypes were classified as 'consistent/confirmatory', 'uncertain significance' or 'non-contributory'. The proportion of patients with pathogenic genotypes concordant with the AID phenotype (consistent/confirmatory) was significantly higher with NGS than Sanger sequencing [10 of 99 (10·1%) versus eight of 197 (4·1%)]. MEFV, ADA2 and MVK were the most represented genes with a consistent/confirmed genotype, whereas MEFV, NLRP3, NOD2 and TNFRSF1A were found in the 'uncertain significance' genotypes. Six months after the genetic report was sent, 54 of 128 (42·2%) patients had received effective treatment for their symptoms; 13 of 128 (10·2%) had started treatment after the genetic study. For 59 of 128 (46%) patients, the results had an impact on their overall care, independent of sequencing group and diagnostic conclusion. Targeted NGS improved the diagnosis and global care of patients with AIDs.

Early-onset granulomatous arthritis, uveitis and skin rash: characterization of skin involvement in Blau syndrome.

BACKGROUND: Blau syndrome (BS) is a rare monogenic autoinflammatory disease caused by NOD2 mutations. BS classically presents in early childhood as a triad of granulomatous polyarthritis, uveitis and skin involvement. Joint and ocular involvement have been characterized by several cohort studies but only very little data are available on skin lesions. OBJECTIVES: We aimed to provide a detailed clinical and microscopic analysis of skin manifestations and to study whether they may contribute to an early diagnosis. METHODS: We conducted a retrospective multicentre study in a French cohort of 21 patients diagnosed with genetically confirmed BS. RESULTS: Skin involvement was the first clinical manifestation of BS in 15/16 patients with dermatological manifestations. The presence of skin lesions was associated with significant shorter age at diagnosis (P = 0.03) and diagnostic delay (P = 0.04). Dermatological assessment allowed an earlier diagnosis (P = 0.001) and reduces the diagnostic delay (P = 0.007). Early skin lesions had a homogeneous, stereotypical clinical presentation, namely non-confluent erythematous or pigmented millimetric papules in 13/14(93%) patients. In contrast, skin lesions occurring during later disease stages had a more heterogeneous clinical presentation, including ichthyosiform dermatosis, panniculitis, livedoid lesions and vasculitis. Whatever their time of occurrence and the clinical aspect, all biopsied showed histologically presence of granuloma. CONCLUSION: Skin involvement in BS is the earliest clinical manifestation of the BS in the large majority of patients. The recognition of dermatological manifestations as granulomatous skin lesions and early dermatological expertise are the key to an early diagnosis of BS. In view of our results, it seems reasonable to propose a simplified view of skin lesions of BS in which the granuloma is the key structure.

[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.

[Clinical overview of auto-inflammatory diseases]. / Panorama des maladies auto-inflammatoires.

Monogenic auto-inflammatory diseases are characterized by genetic abnormalities coding for proteins involved in innate immunity. They were initially described in mirror with auto-immune diseases because of the absence of circulating autoantibodies. Their main feature is the presence of peripheral blood inflammation in crisis without infection. The best-known auto-inflammatory diseases are mediated by interleukines that consisted in the 4 following diseases familial Mediterranean fever, cryopyrinopathies, TNFRSF1A-related intermittent fever, and mevalonate kinase deficiency. Since 10 years, many other diseases have been discovered, especially thanks to the progress in genetics. In this review, we propose the actual panorama of the main known auto-inflammatory diseases. Some of them are recurrent fevers with crisis and remission; some others evaluate more chronically; some are associated with immunodeficiency. From a physiopathological point of view, we can separate diseases mediated by interleukine-1 and diseases mediated by interferon. Then some polygenic inflammatory diseases will be shortly described: Still disease, Schnitzler syndrome, aseptic abscesses syndrome. The diagnosis of auto-inflammatory disease is largely based on anamnesis, the presence of peripheral inflammation during attacks and genetic analysis, which are more and more performant.

[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.

[Mevalonate kinase deficiency in 2016]. / Le déficit en mévalonate kinase en 2016.

Mevalonate kinase deficiency is a rare, autosomal recessive, auto-inflammatory disease. This results from mutations in the gene MVK coding for the enzyme mevalonate kinase. This enzyme is involved in cholesterol and isoprenoids synthesis. Depending partially of the residual activity of the mevalonate kinase, the clinical spectrum realizes a continuum which extends from the mild phenotype of the hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) to a lethal form of mevalonic aciduria. The HIDS is characterized by recurrent episodes of fever with an intense inflammatory syndrome, accompanied with lymphadenopathy, abdominal pain, diarrhea, arthralgia, hepatomegaly, splenomegaly and skin rash. The first attack more frequently takes place in the first year of life, even during the neonatal period, where it can be confused with a maternofetal infection. There is furthermore in mevalonate aciduria a psychomotor retardation, a failure to thrive, a cerebellar ataxia, a dysmorphic syndrome and a reduction of the visual acuity. The diagnosis is based on the mevalonic aciduria during febrile attack. Genetics confirm the diagnosis in more than 80 % of the cases. The dosage of IgD, low sensitive and specific, has no interest. There is no reference treatment. The less severe forms can be treated by non-steroidal anti-inflammatory drugs or steroids during febrile attacks. The most severe patients can be treated by biotherapy: antagonists of IL-1, TNF-α and IL-6.

[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.

ADA2 deficiency: case report of a new phenotype and novel mutation in two sisters.

The objective of this paper is to: describe the phenotype compound heterozygote for mutations in CECR1 in two children. We describe the clinical and immunological phenotype, including the assessment of ADA2 activity, cytokine expression, interferon-stimulated and neutrophil-stimulated gene signatures, and the results of CECR1 sequencing. The first patient presented with intermittent fever, cutaneous vasculitis, myalgia and muscle inflammation on MRI leading to a provisional diagnosis of periarteritis nodosa. Subsequently, two cerebral lacunar lesions were identified following a brain stroke. Clinical features improved on anti-tumour necrosis factor therapy. The first patient's sister demonstrated early-onset, long-lasting anaemia with mild biological inflammation; at the ages of 3 and 5 years, she had presented 2 acute, transient neurological events with lacunar lesions on MRI. CECR1 sequencing identified both sisters to be compound heterozygous for a p.Tyr453Cys mutation and a previously undescribed deletion of exon 7. ADA2 activity was reduced by 50%. Neutrophil-stimulated genes were not overexpressed, but interferon-stimulated genes were. The expression of a panel of other cytokine transcripts was not significantly altered. In conclusion, searching for CECR1 mutation or assessing ADA2 activity should be considered in patients with an atypical presentation of inflammatory disease.

The autoinflammatory diseases: a fashion with blurred boundaries!

Monogenic autoinflammatory diseases are defined as a group of conditions with a clinical and biological inflammatory syndrome but little or no evidence of autoimmunity. Over 17 years have passed since the discovery of the first autoinflammatory gene, MEFV, responsible for familial Mediterranean fever. Substantive progress has been made since then, highlighting the key role of the inflammasome in the maintenance of the cell homeostasis but also unravelling new pathophysiological pathways involved in these diseases. The history of autoinflammatory gene discovery demonstrates the powerfulness of next-generation sequencing approaches in linking inflammatory disorders with various overlapping phenotypes. It can be easily anticipated that new genes will be exponentially identified in the coming years. Integrating these new concepts should help to promote personalized patient care through novel therapeutic opportunities.