Alexandre Belot

EULAR/PRINTO/PRES criteria for Henoch–Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria

Objectives To validate the previously proposed classification criteria for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). Methods Step 1: retrospective/prospective web-data collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a representative sample of 280 cases. Step 3: statistical (sensitivity, specificity, area under the curve and κ-agreement) and nominal group technique consensus evaluations. Results 827 patients with HSP, 150 with c-PAN, 60 with c-WG, 87 with c-TA and 52 with c-other were compared with each other. A patient was classified as HSP in the presence of purpura or petechiae (mandatory) with lower limb predominance plus one of four criteria: (1) abdominal pain; (2) histopathology (IgA); (3) arthritis or arthralgia; (4) renal involvement. Classification of c-PAN required a systemic inflammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of five criteria: (1) skin involvement; (2) myalgia/muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classification of c-WG required three of six criteria: (1) histopathological evidence of granulomatous inflammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classification of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of five criteria: (1) pulse deficit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) elevated acute phase reactant. Conclusion European League Against Rheumatism/Paediatric Rheumatology International Trials Organisation/Paediatric Rheumatology European Society propose validated classification criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specificity.

Protein kinase Cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation

OBJECTIVE Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that is assumed to occur via a complex interplay of environmental and genetic factors. Rare causes of monogenic SLE have been described, providing unique insights into fundamental mechanisms of immune tolerance. The aim of this study was to identify the cause of an autosomal-recessive form of SLE. METHODS We studied 3 siblings with juvenile-onset SLE from 1 consanguineous kindred and used next-generation sequencing to identify mutations in the disease-associated gene. We performed extensive biochemical, immunologic, and functional assays to assess the impact of the identified mutations on B cell biology. RESULTS We identified a homozygous missense mutation in PRKCD, encoding protein kinase δ (PKCδ), in all 3 affected siblings. Mutation of PRKCD resulted in reduced expression and activity of the encoded protein PKCδ (involved in the deletion of autoreactive B cells), leading to resistance to B cell receptor- and calcium-dependent apoptosis and increased B cell proliferation. Thus, as for mice deficient in PKCδ, which exhibit an SLE phenotype and B cell expansion, we observed an increased number of immature B cells in the affected family members and a developmental shift toward naive B cells with an immature phenotype. CONCLUSION Our findings indicate that PKCδ is crucial in regulating B cell tolerance and preventing self-reactivity in humans, and that PKCδ deficiency represents a novel genetic defect of apoptosis leading to SLE.

Efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in the treatment of vasculopathy associated with TMEM173-activating mutations in 3 children

Marie-Louise Frémond, MD, Mathieu Paul Rodero, PhD, Nadia Jeremiah, PhD, Alexandre Belot, MD, PhD, Eric Jeziorski, MD, Darragh Duffy, PhD, Didier Bessis, MD, Guilhem Cros, MD, Gillian I. Rice, PhD, Bruno Charbit, MSc, Anne Hulin, PharmD, PhD, Nihel Khoudour, MD, Consuelo Modesto Caballero, MD, Christine Bodemer, MD, PhD, Monique Fabre, MD, Laureline Berteloot, MD, Muriel Le Bourgeois, MD, Philippe Reix, MD, Thierry Walzer, PhD, Despina Moshous, MD, PhD, Stéphane Blanche, MD, PhD, Alain Fischer, MD, PhD, Brigitte Bader-Meunier, MD, Fréderic Rieux-Laucat, PhD, Yanick Joseph Crow, MD, PhD, Bénédicte Neven, MD, PhD

Mutations in CECR1 associated with a neutrophil signature in peripheral blood

BackgroundA reduction of ADA2 activity due to autosomal recessive loss of function mutations in CECR1 results in a newly described vasculopathic phenotype reminiscent of polyarteritis nodosa, with manifestations ranging from fatal systemic vasculitis with multiple strokes in children to limited cutaneous disease in middle-aged individuals. Evidence indicates that ADA2 is essential for the endothelial integrity of small vessels. However, CECR1 is not expressed, nor is the ADA2 protein detectable, in cultured human endothelial cells, thus implicating additional cell types or circulating factors in disease pathogenesis.MethodsConsidering the phenotypic overlap of ADA2 deficiency with the type I interferonopathy Aicardi-Goutières syndrome due to mutations in SAMHD1, we looked for the presence of an interferon signature in the peripheral blood of two newly ascertained ADA2-deficient patients.ResultsWe identified biallelic CECR1 mutations in two patients consistent with ADA2 deficiency. Both patients demonstrated an upregulation of interferon stimulated gene transcripts in peripheral blood. More strikingly however, genome-wide analysis revealed a marked overexpression of neutrophil-derived genes, suggesting that the vasculitis seen in ADA2 deficiency may be an indirect effect resulting from chronic and marked activity of neutrophils.ConclusionsWe hypothesise that ADA2 may act as a regulator of neutrophil activation, and that a reduction of ADA2 activity results in significant endothelial damage via a neutrophil-driven process.

Pathogenesis of adult-onset Still's disease: new insights from the juvenile counterpart.

Abstract Adult-onset Still’s disease (AOSD) is a rare inflammatory disease characterized by the classical triad of daily fever, arthritis, and typical salmon-colored rash. Recent accumulation of knowledge, mostly arising from hereditary autoinflammatory diseases and from the systemic-onset juvenile idiopathic arthritis (sJIA), has given raise to new hypotheses on the pathophysiology of AOSD. In this review, we first discuss on the continuum between AOSD and sJIA. Then, we summarize current hypotheses on the underlying pathogenesis: (1) an infectious hypothesis; (2) an autoinflammatory hypothesis; (3) a lymphohistiocytic hypothesis; and (4) a hyperferritinemic hypothesis. Finally, we present the recent data suggesting that patients with AOSD fall into two distinct subgroups with different courses, one with prominent systemic features and one with chronic arthritis.

Pseudohypoaldosteronisms, report on a 10-patient series

BACKGROUND Type 1 pseudohypoaldosteronism (PHA1) is a salt-wasting syndrome caused by mineralocorticoid resistance. Autosomal recessive and dominant hereditary forms are caused by Epithelial Na Channel and Mineralocorticoid Receptor mutation respectively, while secondary PHA1 is usually associated with urological problems. METHODS Ten patients were studied in four French pediatric units in order to characterize PHA1 spectrum in infants. Patients were selected by chart review. Genetic, clinical and biochemistry data were collected and analyzed. RESULTS Autosomal recessive PHA1 (n = 3) was diagnosed at 6 and 7 days of life in three patients presenting with severe hyperkalaemia and weight loss. After 8 months, 3 and 5 years on follow-up, neurological development and longitudinal growth was normal with high sodium supplementation. Autosomal dominant PHA1 (n = 4) was revealed at 15, 19, 22 and 30 days of life because of failure to thrive. At 8 months, 3 and 21 years of age, longitudinal growth was normal in three patients who were given salt supplementation; no significant catch-up growth was obtained in the last patient at 20 months of age. Secondary PHA1 (n = 3) was diagnosed at 11, 26 days and 5 months of life concomitantly with acute pyelonephritis in three children with either renal hypoplasia, urinary duplication or bilateral megaureter. The outcome was favourable and salt supplementation was discontinued after 3, 11 and 13 months. CONCLUSIONS PHA1 should be suspected in case of severe hyperkalemia and weight loss in infants and need careful management. Pathogenesis of secondary PHA1 is still challenging and further studies are mandatory to highlight the link between infection, developing urinary tract and pseudohypoaldosteronism.

Recommendations for using TNFα antagonists and French Clinical Practice Guidelines endorsed by the French National Authority for Health.

The use of TNFα antagonists must follow specific guidelines to ensure optimal effectiveness and safety. The French Society for Rheumatology (SFR) and Task Force on Inflammatory Joint Diseases (CRI), in partnership with several French learned societies, asked the French National Authority for Health (HAS) to develop and endorse good practice guidelines for the prescription and monitoring of TNFα antagonist therapy by physicians belonging to various specialties. These guidelines were developed, then, validated by two multidisciplinary panels of experts based on an exhaustive review of the recent literature and in compliance with the methodological rules set forth by the HAS. They pertain to the initial prescription of TNFα antagonists and to a variety of clinical situations that can arise during the follow-up of patients receiving TNFα antagonists (infections, malignancies, pregnancy, vaccination, paradoxical adverse events, surgery, use in older patients, and vasculitides).

Monogenic forms of systemic lupus erythematosus: new insights into SLE pathogenesis

The pathogenesis of Systemic Lupus Erythematosus (SLE) is complex and remains poorly understood. Infectious triggers, genetic background, immunological abnormalities and environmental factors are all supposed to interact for the disease development. Familial SLE as well as early-onset juvenile SLE studies make it possible to identify monogenic causes of SLE. Identification of these rare inherited conditions is of great interest to understand both SLE pathogenesis and molecular human tolerance mechanisms. Complement deficiencies, genetic overproduction of interferon-α and apoptosis defects are the main situations that can lead to monogenic SLE.Here, we review the different genes involved in monogenic SLE and highlight their importance in SLE pathogenesis.

Detection of interferon alpha protein reveals differential levels and cellular sources in disease

Type I interferons (IFNs) are essential mediators of antiviral responses. These cytokines have been implicated in the pathogenesis of autoimmunity, most notably systemic lupus erythematosus (SLE), diabetes mellitus, and dermatomyositis, as well as monogenic type I interferonopathies. Despite a fundamental role in health and disease, the direct quantification of type I IFNs has been challenging. Using single-molecule array (Simoa) digital ELISA technology, we recorded attomolar concentrations of IFN&agr; in healthy donors, viral infection, and complex and monogenic interferonopathies. IFN&agr; protein correlated well with functional activity and IFN-stimulated gene expression. High circulating IFN&agr; levels were associated with increased clinical severity in SLE patients, and a study of the cellular source of IFN&agr; protein indicated disease-specific mechanisms. Measurement of IFN&agr; attomolar concentrations by digital ELISA will enhance our understanding of IFN biology and potentially improve the diagnosis and stratification of pathologies associated with IFN dysregulation.

Pediatric-Onset Relapsing Polychondritis: Case Series and Systematic Review

OBJECTIVES To study the pediatric presentation and evolution of relapsing polychondritis (RP), a rare inflammatory disease characterized by recurrent inflammation of cartilage. STUDY DESIGN We retrospectively collected data from 10 patients observed in 3 French hospitals for relapsing polychondritis, with an age at onset <18 years. We also analyzed 37 cases of pediatric-onset RP from a systematic review. RESULTS The mean age at first symptoms was 8.6 years, and the sex ratio was 6 male patients and 4 female patients. Children came to medical attention with joint pain, ocular inflammation, and chondritis. Outcomes included severe visual impairment, chronic destructive chondritis, and 1 death caused by aortic dilatation. Treatment mainly consisted of non-steroidal-anti-inflammatory drugs, corticosteroids, and immunosuppressants. Growth was normal in 7 examined patients. Systematic literature review also suggested a high number of tracheostomy in pediatric cases, but this was not confirmed in our series. CONCLUSION RP in childhood shares the main clinical features of its adult counterpart, including destructive chondritis and systemic symptoms, but unlike adults, children frequently have a family history of autoimmunity and infrequently have other associated autoimmune diseases. RP can be fatal; close screening for complications is mandatory. Growth does not appear to be impaired by cartilage inflammation.