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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 MEFVP257L variant, for comparison of IL-1β secretion using a cell-based assay and a novel THP-1-based assay. Disease-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 MEFVP257L variants, the results were consistent between the cell-based assay and the THP-1-based assay. Our assay facilitates a rapid and comprehensive assessment of the pathogenicity of MEFV variants and contributes to a refined definition of PAAD subtypes.

A 55-year-old-man presented with low-grade fever, general fatigue, appetite loss and body weight loss. An electrocardiogram (ECG) showed the presence of long QT syndrome (LQTS), and laboratory test...

Background Pulmonary artery involvement (PAI) in Takayasu arteritis (TAK) can lead to severe complications, but the relationship between the two has not been fully clarified. Methods We retrospectively investigated 166 consecutive patients with TAK who attended Kyoto University Hospital from 1997 to 2018. The demographic data, clinical symptoms and signs, comorbidities, treatments, and imaging findings were compared between patients with and without PAI. TAK was diagnosed based on the American College of Rheumatology Classification Criteria (1990) or the Japanese Clinical Diagnostic Criteria (2008). PAI was identified using enhanced computed tomography, magnetic resonance imaging, or lung scintigraphy. Results PAI was detected in 14.6% (n = 24) of total TAK patients. Dyspnea (25.0% vs. 8.6%; p = 0.043), pulmonary arterial hypertension (PAH) (16.7% vs. 0.0%; p < 0.001), ischemic heart disease (IHD) (29% vs. 9.3%; p = 0.018), respiratory infection (25.0% vs. 6.0%; p = 0.009), and nontuberculous mycobacteria (NTM) infection (20.8% vs. 0.8%; p < 0.001) were significantly more frequent, and renal artery stenosis (0% vs. 17%; p = 0.007) was significantly less frequent in TAK patients with PAI than in those without PAI. PAI and biologics were risk factors for NTM. Conclusions TAK patients with PAI more frequently have dyspnea, PAH, IHD, and respiratory infection, including NTM, than TAK patients without PAI.

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.

Supplemental Digital Content is available in the text, Recent large observational studies of antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) show that severe infection is a major cause of death and that the majority of infections occur during the early phase of initiating remission-induction therapy. Many risk factors for severe infection have been suggested, but these have been inconsistent. Nevertheless, infectious risk factors in elderly patients with AAV have not been adequately investigated in previous studies. In this retrospective observational study, we examined potential predictors of severe infection within 90 days (early severe infections) after remission-induction therapy in patients with AAV aged 65 years or older. We included 167 consecutive elderly patients with AAV admitted to our hospital. Data from medical history and remission-induction therapy were analyzed for predictive risk factors associated with early severe infections. The relationship between initial doses of corticosteroids and cumulative incidence of severe infections was also analyzed. A multivariate analysis of risk factors for early severe infections was performed using logistic regression analysis. The Kaplan–Meier method was used to estimate the overall survival, and the log-rank test was used to evaluate the differences between patients with and without early severe infections. Gray method was used to compare the cumulative incidence of severe infections in patients who did and did not receive initial high-dose corticosteroids. Logistic regression analysis showed that initial high-dose corticosteroid administration (prednisolone ≥0.8 mg/kg/d) (odds ratio [OR] 3.86, P = .030) and serum creatinine levels at diagnosis ≥1.5 mg/dL (OR 5.13, P = .003) were independent predictors of early severe infection although administration of cyclophosphamide or rituximab was not. The cumulative incidence of severe infections was also significantly higher in patients who received initial high-dose corticosteroids (P = .042), and patients with early severe infections exhibited a high mortality rate within 6 months (P

Background IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition characterized by tumefactive lesions and, often but not always, elevated serum IgG4 levels [1]. Glucocorticoids (GC) are usually used as induction therapy for IgG4-RD. However, relapse often occurs following GC tapering, and predictors of relapse remain unclear. Objectives To identify predictors of relapse of IgG4-RD after induction therapy. Methods We retrospectively reviewed 57 patients diagnosed with IgG4-RD and treated with GC in our hospital between January 2004 and November 2018. Clinical features at baseline, including organ involvement and blood markers (total hemolytic complement [CH50], its fractions [C3 and C4], IgG4, IgG, IgE, anti-nuclear antibody, rheumatoid factor, C-reactive protein, soluble interleukin-2 receptor, eosinophils), were collected. We divided patients into 2 groups on the basis of clinical features and examined whether they relapsed. In this study, hypocomplementemia was defined as decreased serum C3, C4, or CH50 less than the lower limit of normal. A relapse was defined as any new or worsened state of disease activity that required an escalation in treatment (immunosuppressants and/or GC). The follow-up period was defined as 182 days. Results Forty-three men and 14 women (mean age 68.1 ± 10.9 years) were included. Both serum IgG4 and IgG were measured at baseline in all patients (mean IgG4 798.8 ± 873.1 mg/dL and mean IgG 2874.0 ± 1934.1 mg/dL, respectively). All of the serum C3, C4, and CH50 were measured at baseline in 34/57 patients (mean C3 75.7 ± 33.3 mg/dL; mean C4 14.8 ± 11.5 mg/dL; and mean CH50 37.0 ± 23.1 U/mL). Fifteen patients had at least one episode of hypocomplementemia, and 19 patients did not. Most patients had multiple organ lesions. The details of dominant lesions were as follows: Dacryoadenitis and/or sialadenitis (Mikulicz disease), 36/57 patients (63.2%); biliary or pancreatic lesion, 29/57 (50.1%); retroperitoneal fibrosis, 22/57 (38.6%); and renal lesion 16/57 (28.1%). All patients were given prednisolone and gradually reduced (mean induction dose 31.7 ± 9.8 mg/day). No patients received immunosuppressant as induction therapy. During the follow-up period, 6 patients relapsed, and the dose of prednisolone was increased immediately. Relapsed lesions were as follows: Mikulicz disease, 3/6 patients (50.0%); biliary or pancreatic lesion, 1/6 (16.7%); retroperitoneal fibrosis 1/6 (16.7%); and pulmonary lesion 1/6 (16.7%). Patients with hypocomplementemia had significantly shorter relapse-free survival than those without (p=0.039, Figure 1). Patients with decreased serum C4 or CH50 (less than the lower limit of normal) also had significantly shorter relapse-free survival than those without, but those with decreased serum C3 did not. Such a tendency was not seen in other blood markers (IgG4, IgG, IgE, anti-nuclear antibody, rheumatoid factor, C-reactive protein, soluble interleukin-2 receptor, eosinophils). Conclusion Hypocomplementemia at baseline in patients with decreased serum C4 or CH50 may predict relapse of IgG4-RD after prednisolone therapy. References [1] Stone JH, et al. N Engl J Med2012; 366: 539-51. Disclosure of Interests None declared

Rationale: Thrombocytepenia, anasarca, fever, renal insufficiency, and organomegaly (TAFRO) syndrome is a novel disease entity characterized by a constellation of symptoms (thrombocytopenia, anasarca, fever, renal insufficiency, and organomegaly). Here, we describe the development of TAFRO syndrome-like features during the treatment of rheumatoid arthritis with a Janus kinase (JAK) inhibitor. Patient concerns: In this report, a 74-year-old woman treated with a JAK inhibitor (tofacitinib) for rheumatoid arthritis was admitted because of fever and thrombocytopenia. Diagnoses: On laboratory examination, marked thrombocytopenia and elevated creatinine and C-reactive protein levels were present. A computed tomography scan revealed lymphadenopathy, hepato-splenomegaly, and anasarca. A left axillary lymph node biopsy revealed Castleman's disease-like features. These clinical features satisfied the proposed diagnostic criteria for TAFRO syndrome. Since autoimmune disorders should be excluded when diagnosing TAFRO syndrome, it is not strictly correct to diagnose her as TAFRO syndrome. Therefore, we diagnosed her as rheumatoid arthritis complicated by TAFRO syndrome-like features. Interventions: The patient was treated with high-dose glucocorticoid, tacrolimus, eltrombopag, intravenous immunoglobulin, and rituximab. Outcomes: Her condition was refractory to the above-mentioned treatment, and she eventually died because of multi-organ failure 6 months after the first admission. Lessons: TAFRO syndrome-like features can develop during treatment with a JAK inhibitor for rheumatoid arthritis. Patients with autoimmune diseases complicated by TAFRO syndrome-like features can follow a fatal clinical course, and thus, an intensive combined treatment is warranted for such patients, especially in cases refractory to glucocorticoid.

We aimed to investigate the efficacy of plasma exchange on severe anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Of 182 patients with AAV in our hospital, 12 patients with life-threatening organ damage (rapidly progressive glomerulonephritis and/or diffuse alveolar hemorrhage) underwent centrifuge-based therapeutic plasma exchange and immunosuppressive therapy. Twenty-four patients matched for age, serum creatinine, and severity of vasculitis, who received high-dose glucocorticoids with or without immunosuppressants, were included in the nonplasma exchange group. Renal survival rate at 2 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.524). Mortality rate at 5 years from induction treatment was not significantly different between the plasma and nonplasma exchange groups (P = 0.631). In this retrospective study, we could not show the significant differences in the renal survival rate and survival rate between the two groups.

Background Colour doppler ultrasonography (CDU) in temporal arteries (TA) is useful for diagnosis and follow-up of giant cell arteritis (GCA).1 However, the usefulness of CDU in carotid arteries (CA) for follow-up of GCA is not fully understood. 2 Objectives We investigated retrospectively relationship between clinical features and vessel wall thickness of TA and CA on CDU at baseline and during follow-up. Methods We recruited patients with newly diagnosed GCA in our hospital from January in 2004 to July in 2017. Among 35 patients, both of TA and CA were evaluated by CDU before and after treatment in 14 patients (four male and 10 female). Trained ultrasonographers and rheumatologists evaluated the CDU findings. Vessel wall thickness was evaluated at thickest portion of parietal or frontal ramus of TA, where biopsy was often performed. Intima-media thickness (IMT) of CA was also evaluated at thickest portion in each carotid artery. Results Average age was 73.2±11.3 years old. Follow-up periods after starting treatment were 244±149 weeks. All patients were diagnosed as GCA according to ACR criteria (1990) or temporal artery biopsy. Twelve patients were complicated with polymyalgia rheumatica (PMR) meeting EULAR/.ACR classification criteria (2012). All patients were treated with oral glucocorticoids (0.2 to 1.0 mg/kg prednisolone, 0.886 mg/kg on average). Immunosuppressants were added in four patients (methotrexate; n=3, tacrolimus; n=1). Aspirin was prescribed in nine patients. Eleven patients (78.6%) had circumferential hypoechoic vessel wall thickness (halo sign) of TA at baseline, and halo signs dissapeared in eight patients during follow-up. Average of vessel wall thickness significantly decreased from 0.665 mm to 0.311 mm (p=0.0016). The vessel wall thickness apparently increased in two patients out of three on clinical relapse, but it didn’t increase in those who kept remission. Graphical changes consistent with vasculitis in CA were observed in six patients, who showed hypoechoic thick intima and media on ultrasound or integration of FDG on PET/CT. Average of IMT in CA decreased from 1.167 mm to 0.883 mm (p=0.090) during follow-up in patients with vasculitis on CA. IMT changed little in patients without vasculitis on CA. Improvement rate was significantly higher in CA-involved patients than in CA-non-involved patients (p=0.043). IMT increased during follow-up in two CA-non-involved patients. Difference in B/A between CA involved and non-involved: p=0.043 (Mann-Whitney U test) Conclusions CDU of temporal arteries is useful for follow-up of GCA. CDU of carotid arteries has limited usefulness only in CA-involved patients. References [1] Suelves AM, et al. Clin Ophthalmol. 2010; Nov 25;4:1383–4. [2] Hafner F, et al. Eur J Clin Invest2014; 44(3):249–256. Disclosure of Interest None declared

Background The introduction of treatment regimens comprising of cyclophosphamide or rituximab combined with corticosteroids has brought about dramatic improvements in the prognosis of ANCA-associated vasculitis. 1 Severe infectious events, especially in the early phase of treatment, associated with risk of death have been reported in the past several studies. 2,3 Objectives We retrospectively investigated the association between mortality and early severe infection in patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), and we also attempted to identify the potential predictors for early severe infection. Methods We recruited 182 consecutive hospitalised patients newly diagnosed with AAV at our hospital, from January 2000 to June 2017, in this retrospective cohort study. All cause mortality, relapse, and severe infections within six months after starting treatment (early severe infection) were analysed. Results The mean age was 70 years at diagnosis, and the classification according to the Chapel Hill Conference definition were microscopic polyangiitis (MPA) in 82 patients (45.1%), granulomatosis with polyangiitis (GPA) in 36 patients (19.8%), eosinophilic granulomatosis with polyangiitis (EGPA) in 24 patients (13.2%), and renal-limited vasculitis in 32 patients (17.6%). 4 Median follow up was 158 weeks (range 0–182 w). Using Cox regression analysis, elderly onset (age ≥75 years) AAV (p = 0.027) and early severe infection (p ≤ 0.001) were independent predictors of all cause mortality (table 1). Early severe infection tended to increase among patients who received immunosuppressive therapy of a corticosteroid combined with cyclophosphamide or rituximab (conventional treatment), and this trend was significant in non-severe (BVAS = 0.030) (table 2). Treatment response rate (p=0.058) and relapse rate (p = 0.137) were not significant between the different treatment groups. Conclusions Early severe infection is an independent predictor of death in patients with AAV, and conventional treatment has a potential risk of death due to severe infection. This study supports the current EULAR recommendation that several treatment strategies are recommended according to the disease severity of vasculitis. 5 AAV patients who receive conventional treatment should be carefully monitored to reduce the occurrence of severe infection, especially in early phase of treatment. References [1] Little MA, et al. Ann Rheum Dis2010;69:1036–43. [2] Lai QY, et al. J Rheumatol2014;41(9):1849–55. [3] Solans-Laque R, et al. Medicine2017;96(8):e6083. [4] Janette JC, et al. Arthritis Rheum2013;65:1–11. [5] Yates M et al. Ann Rheum Dis 2016;75(9):1583–94. Disclosure of Interest None declared