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Pathogenic MEFV variants cause pyrin-associated autoinflammatory diseases (PAADs), which include familial Mediterranean fever (FMF), FMF-like disease, and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND). The diagnosis of PAADs is established by clinical phenotypic and genetic analyses. However, the pathogenicity of most MEFV variants remains controversial, as they have not been functionally evaluated. This study aimed to establish and validate a new functional assay to evaluate the pathogenicity of MEFV variants.We transfected THP-1 monocytes with 32 MEFV variants and analyzed their effects on cell death with or without stimulation with Clostridium difficile toxin A (TcdA) or UCN-01. These variants were classified using hierarchical cluster analysis. Macrophages were obtained from three healthy controls and two patients with a novel homozygous MEFVDisease-associated MEFV variants induced variable degrees of spontaneous or TcdA/UCN-01-induced cell death in THP-1. Cell death was caspase-1 dependent and was accompanied by ASC speck formation and IL-1β secretion, indicating that pathogenic MEFV variants induced abnormal pyrin inflammasome activation and subsequent pyroptotic cell deaths in this assay. The MEFV variants (n = 32) exhibiting distinct response signatures were classified into 6 clusters, which showed a good correlation with the clinical phenotypes. Regarding the pathogenicity of MEFVOur assay facilitates a rapid and comprehensive assessment of the pathogenicity of MEFV variants and contributes to a refined definition of PAAD subtypes.

An 8-year-old girl was presented to our clinic with fever, arthritis in her left knee, a necrotic right fifth toe, and multiple large deep-seated ulcerations. She was diagnosed with pyoderma gangrenosum. Treatment with corticosteroids alone was ineffective for her skin lesions, and therefore combination immunosuppressant therapy was administered. Her skin lesions rapidly improved, enabling discontinuation of the corticosteroid therapy and avoiding systemic infection through the ulcers. Combination immunosuppressant therapy may be a treatment option for patients with severe, rapidly progressive pyoderma gangrenosum.

The objective of this study is to identify risk factors for hypersensitivity reaction (HSR) to tocilizumab (TCZ) in systemic juvenile idiopathic arthritis (sJIA).Clinical records of 40 patients with sJIA administered TCZ at one center were retrospectively reviewed. Patients were divided into HSR or non-HSR groups depending on the presence of HSR between the first and third TCZ administrations; clinical and laboratory assessments, including serum cytokine profile, were compared.Five patients displayed HSR following the third TCZ administration. They were significantly younger, shorter, and lighter, with a higher peak body temperature than non-HSR patients following the third administration. Their serum C-reactive protein (CRP) level was undetectable following the first administration but detectable by the third administration. Before the third administration, the white blood cell counts and serum levels of CRP and sTNFRII were significantly higher in the HSR group than in the non-HSR group. The serum levels of interleukin-18 and -6 before the third TCZ administration were higher and lower than those before the first administration in the HSR and non-HSR groups, respectively.Patients with sJIA having a younger age, shorter stature, and lighter weight and those showing increased disease activity in the early period of TCZ administration may be at higher risk of TCZ-induced HSR.

Objectives To assess the performance of the EULAR/ACR idiopathic inflammatory myopathies (IIMs) classification criteria to classify juvenile IIMs (JIIMs) in an Asian paediatric population. Methods Sixty-eight JIIM patients and 49 non-JIIM patients diagnosed at seven major paediatric rheumatology centres in Japan between 2008 and 2015 were enrolled. Retrospective data were collected, and each patient’s data form was submitted. The expert group reviewed the forms and re-examined the diagnoses. The EULAR/ACR criteria were then applied and the probability of having JIIM was determined for each case. The sensitivity and specificity of the EULAR/ACR criteria were compared with those of other existing criteria. Results The sensitivity/specificity of the EULAR/ACR classification criteria were 92.1/100% with muscle biopsy data (n = 38); 86.7/100% without muscle biopsy data (n = 30) and 89.7/100% in our total cohort (n = 68). The sensitivity of Bohan and Peter’s criteria and Tanimoto’s criteria were 80.9 and 64.7% in our total cohort, respectively. Among 68 physician-diagnosed JIIM patients, seven cases (three JDM and four overlap myositis) were not classified as JIIM because the probability did not reach the cut-off point (55%). The three JDM patients all presented with only one of the three skin manifestations that are listed in the criteria: Gottron’s sign. Conclusion Our validation study with Japanese JIIM cases indicates that the EULAR/ACR classification criteria for IIM generally perform better than existing diagnostic criteria for myositis.

Objectives: This study investigated the association between myositis-specific autoantibodies (MSAs) and clinical subsets of juvenile dermatomyositis (JDM) in Japanese patients. Methods: Twenty-one patients at a single center who developed initial or relapsed JDM from 2011 to 2016 were analyzed. Serum concentrations of MSAs against TIF1-γ, MDA5, NXP2, Mi-2, ARS, and SAE were measured by enzyme-linked immunosorbent assays. Clinical symptoms and laboratory data were obtained from clinical records. Clinical characteristics were compared in patients with autoantibodies against TIF1-γ, MDA5, and NXP2. Results: Of the 21 patients, 20 (95.2%) were positive for one or more MSAs, including nine (42.9%), five (23.8%), six (28.6%), and one (4.8%) positive for anti-TIF1-γ, anti-MDA5, anti-NXP2, and anti-Mi-2 autoantibodies. No patient was positive for anti-ARS or anti-SAE autoantibodies. The frequency of diffuse cutaneous lesions was higher in patients with anti-TIF1-γ autoantibodies. Anti-MDA5 autoantibody-positive patients had features of interstitial lung disease on chest computed tomography. Severe muscle damage at disease onset was significantly associated with positivity for anti-NXP2 autoantibodies. Conclusion: Similar to findings in Western countries, the clinical characteristics of JDM in Japanese may differ for each type of MSAs.

Diffuse alveolar hemorrhage (DAH) is a rare disease characterized by dyspnea, cough, hemoptysis, and new alveolar infiltrates. Among the various underlying disorders, vasculitis is believed to play a significant role in the pathogenesis of DAH. Here we report the first case of a patient with Down syndrome who developed DAH secondary to anti-neutrophil cytoplasmic antibody-associated vasculitis. This case highlights the significance of vasculitis as well as pulmonary hypoplasia and vulnerability associated with Down syndrome in the development of DAH.