Objectives To validate the previously proposed classifi cation criteria for Henoch-Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA). MethodsStep 1: retrospective/prospective webdata collection for children with HSP, c-PAN, c-WG and c-TA with age at diagnosis ≤18 years.Step 2: blinded classifi cation by consensus panel of a representative sample of 280 cases.Step 3: statistical (sensitivity, specifi city, 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 classifi ed 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. Classifi cation of c-PAN required a systemic infl ammatory disease with evidence of necrotising vasculitis OR angiographic abnormalities of medium-/small-sized arteries (mandatory criterion) plus one of fi ve criteria: (1) skin involvement; (2) myalgia/ muscle tenderness; (3) hypertension; (4) peripheral neuropathy; (5) renal involvement. Classifi cation of c-WG required three of six criteria: (1) histopathological evidence of granulomatous infl ammation; (2) upper airway involvement; (3) laryngo-tracheo-bronchial involvement; (4) pulmonary involvement (x-ray/CT); (5) antineutrophilic cytoplasmic antibody positivity; (6) renal involvement. Classifi cation of c-TA required typical angiographic abnormalities of the aorta or its main branches and pulmonary arteries (mandatory criterion) plus one of fi ve criteria: (1) pulse defi cit or claudication; (2) blood pressure discrepancy in any limb; (3) bruits; (4) hypertension; (5) Paediatric Rheumatology European Society propose validated classifi cation criteria for HSP, c-PAN, c-WG and c-TA with high sensitivity/specifi city. INTRODUCTIONIn 1990 the American College of Rheumatology (ACR) proposed classifi cation criteria for patients with vasculitides 1-5 by analysing 807 adults patients with different form of vasculitis: 85 with Henoch-Schönlein purpura (HSP), 118 with polyarteritis nodosa (PAN), 85 with Wegener granulomatosis (WG), 63 with Takayasu arteritis (TA) and 456 with other vasculitides (Churg-Strauss, hypersensitivity, giant cell arteritis and other unspecifi ed forms). 6 Patients with each specifi c vasculitis were compared with all the remaining diseases grouped into a single control category.The ACR criteria for HSP (sensitivity 87.1%, specifi city 87.7%) require the presence of at least two of the following: (1) age ≤20 years at disease onset; (2) palpable purpura; (3) acute abdominal pain; (4) biopsy showing granulocytes in the walls of small arterioles/venules. 1 The ACR criteria for PAN (sensitivity 82.2%, specifi city 86.6%) require at least three of the 10 following criteria: (1) granulocyte or mixed leucocyte infi ...

Recessive loss-of-function mutations of ADA2, a growth factor that is the major extracellular adenosine deaminase, can cause polyarteritis nodosa vasculopathy with highly varied clinical expression. (Funded by the Shaare Zedek Medical Center and others.).

BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595.FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

BackgroundAlopecia areata (AA) is an autoimmune disease resulting in hair loss with devastating psychosocial consequences. Despite its high prevalence, there are no FDA-approved treatments for AA. Prior studies have identified a prominent interferon signature in AA, which signals through JAK molecules.MethodsA patient with AA was enrolled in a clinical trial to examine the efficacy of baricitinib, a JAK1/2 inhibitor, to treat concomitant CANDLE syndrome. In vivo, preclinical studies were conducted using the C3H/HeJ AA mouse model to assess the mechanism of clinical improvement by baricitinib.FindingsThe patient exhibited a striking improvement of his AA on baricitinib over several months. In vivo studies using the C3H/HeJ mouse model demonstrated a strong correlation between resolution of the interferon signature and clinical improvement during baricitinib treatment.InterpretationBaricitinib may be an effective treatment for AA and warrants further investigation in clinical trials.

The deubiquitinase OTULIN removes methionine‐1 (M1)‐linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF‐driven inflammation in OTULIN‐related autoinflammatory syndrome (ORAS). Five ORAS patients have been reported, but how dysregulated M1‐linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN‐Gly281Arg mutation leads to reduced activity and stability in vitro and in cells. In contrast to OTULIN‐deficient monocytes, in which TNF signalling and NF‐κB activation are increased, loss of OTULIN in patient‐derived fibroblasts leads to a reduction in LUBAC levels and an impaired response to TNF. Interestingly, both patient‐derived fibroblasts and OTULIN‐deficient monocytes are sensitised to certain types of TNF‐induced death, and apoptotic cells are evident in ORAS patient skin lesions. Remarkably, haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea. Therefore, haematopoietic cells are necessary for clinical manifestation of ORAS. Together, our data suggest that ORAS pathogenesis involves hyper‐inflammatory immune cells and TNF‐induced death of both leukocytes and non‐haematopoietic cells.

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Key Points VPS45 is a new gene associated with severe infections and bone marrow failure in infancy that can be treated by bone marrow transplantation. The mutation affects intracellular storage and transport and results in increased programmed cell death in neutrophils and bone marrow.

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