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Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs., STING炎症シグナルの終結分子機構 --新規細胞内分解システムの発見--. 京都大学プレスリリース. 2023-03-14.

Advances in next-generation sequencing technology have identified many genes responsible for inborn errors of immunity (IEI). However, there is still room for improvement in the efficiency of genetic diagnosis. Recently, RNA sequencing and proteomics using peripheral blood mononuclear cells (PBMCs) have gained attention, but only some studies have integrated these analyses in IEI. Moreover, previous proteomic studies for PBMCs have achieved limited coverage (approximately 3000 proteins). More comprehensive data are needed to gain valuable insights into the molecular mechanisms underlying IEI. Here, we propose a state-of-the-art method for diagnosing IEI using PBMCs proteomics integrated with targeted RNA sequencing (T-RNA-seq), providing unique insights into the pathogenesis of IEI. This study analyzed 70 IEI patients whose genetic etiology had not been identified by genetic analysis. In-depth proteomics identified 6498 proteins, which covered 63% of 527 genes identified in T-RNA-seq, allowing us to examine the molecular cause of IEI and immune cell defects. This integrated analysis identified the disease-causing genes in four cases undiagnosed in previous genetic studies. Three of them could be diagnosed by T-RNA-seq, while the other could only be diagnosed by proteomics. Moreover, this integrated analysis showed high protein–mRNA correlations in B- and T-cell-specific genes, and their expression profiles identified patients with immune cell dysfunction. These results indicate that integrated analysis improves the efficiency of genetic diagnosis and provides a deep understanding of the immune cell dysfunction underlying the etiology of IEI. Our novel approach demonstrates the complementary role of proteogenomic analysis in the genetic diagnosis and characterization of IEI.

OBJECTIVE Coatomer subunit alpha (COPA) syndrome, also known as autoinflammatory interstitial lung, joint, and kidney disease, is caused by heterozygous mutations in COPA. We identified a novel COPA variant in 4 patients in one family. We undertook this study to elucidate whether and how the variant causes manifestations of COPA syndrome by studying these 4 patients and by analyzing results from a gene-targeted mouse model. METHODS We performed whole-exome sequencing in 7 family members and measured the type I interferon (IFN) signature of the peripheral blood cells. We analyzed the effects of COPA variants in in vitro experiments and in Copa mutant mice that were generated. RESULTS We identified a heterozygous variant of COPA (c.725T>G, p.Val242Gly) in the 4 affected members of the family. The IFN score was high in the members carrying the variant. In vitro analysis revealed that COPA V242G, as well as the previously reported disease-causing variants, augmented stimulator of interferon genes (STING)-induced type I IFN promoter activities. CopaV242G/+ mice manifested interstitial lung disease and STING-dependent elevation of IFN-stimulated gene expression. In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production. CONCLUSION V242G, a novel COPA variant, was found in 4 patients from one family. In gene-targeted mice with the V242G variant, interstitial lung disease was recapitulated and augmented responses of the STING pathway, leading to an increase in type I IFN production, were demonstrated.

Background Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive inflammatory disease caused by loss-of-function mutations in both alleles of the ADA2 gene. Most patients with DADA2 exhibit systemic vasculopathy consistent with polyarteritis nodosa, but large phenotypic variability has been reported, and the pathogenesis of DADA2 remains unclear. Objectives This study sought to assess the clinical and genetic characteristics of Japanese patients with DADA2 and to gain insight into the pathogenesis of DADA2 by multi-omics analysis. Methods Clinical and genetic data were collected from 8 Japanese patients with DADA2 diagnosed between 2016 and 2019. ADA2 variants in this cohort were functionally analyzed by in vitro overexpression analysis. PBMCs from 4 patients with DADA2 were subjected to transcriptome and proteome analyses. Patient samples were collected before and after introduction of anti- TNF-α therapies. Transcriptome data were compared with those of normal controls and patients with other autoinflammatory diseases. Results Five novel ADA2 variants were identified in these 8 patients and were confirmed pathogenic by in vitro analysis. Anti-TNF-α therapy controlled inflammation in all 8 patients. Transcriptome and proteome analyses showed that upregulation of type II interferon signaling was characteristic of DADA2. Network analysis identified STAT1 as a key regulator and a hub molecule in DADA2 pathogenesis, a finding supported by the hyperactivation of STAT1 in patients’ monocytes and B cells after IFN-γ stimulation. Conclusions Type II interferon signaling and STAT1 are associated with the pathogenesis of DADA2.

PurposeUpregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulated IFN signature has been suggested as a potential biomarker to identify IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type Ⅰ IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type Ⅰ IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature. Methods A type Ⅰ IFN signature was measured in patients’ whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature.ResultsA total of 113 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with ten exhibiting clinical features commonly found in type Ⅰ interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance, in genes linked to type Ⅰ IFN signaling, in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling.ConclusionsHalf of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type Ⅰ IFN signature.

Patients with refractory graft-versus-host disease (GVHD) have a dismal prognosis. Therefore, novel therapeutic targets are still needed to be identified. Runt-related transcriptional factor (RUNX) family transcription factors are essential transcription factors that mediate the essential roles in effector T cells. However, whether RUNX targeting can suppress, and GVHD is yet unknown. Here, we showed that RUNX family members have a redundant role in directly transactivating NFATC2 expression in T cells. We also found that our novel RUNX inhibitor, Chb-M’, which is the inhibitor that switches off the entire RUNX family by alkylating agent–conjugated pyrrole-imidazole (PI) polyamides, inhibited T-cell receptor mediated T cell proliferation and allogenic T cell response. These were designed to specifically bind to consensus RUNX-binding sequences (TGTGGT). Chb-M’ also suppressed the expression of NFATC2 and pro-inflammatory cytokine genes in vitro. Using xenogeneic GVHD model, mice injected by Chb-M’ showed almost no sign of GVHD. Especially, the CD4 T cell was decreased and GVHD-associated cytokines including tissue necrosis factor-α and granulocyte-macrophage colony-stimulating factor were reduced in the peripheral blood of Chb-M’ injected mice. Taken together, our data demonstrates that RUNX family transcriptionally upregulates NFATC2 in T cells, and RUNX-NFATC2 axis can be a novel therapeutic target against GVHD.

Familial hemophagocytic lymphohistiocytosis type 3 is a fatal inborn error of immunity due to abnormal cytotoxic activity of T and NK cells and is caused by variants in UNC13D, which encodes Munc13-4. One published case was reported to carry a tandem duplication of UNC13D exons 7-12, and we here present another case with the exact same duplication breakpoints. The patient carried the tandem duplication from maternal origin, and a c.2346_2349 variant on the paternal allele. Single nucleotide polymorphism analysis around UNC13D revealed that the allele with tandem duplication was most likely a founder allele. Transposable element analysis showed that the breakpoints occurred within Alu elements in introns 12 and 6. Multiple sequence alignment revealed that Alu elements containing the truncated points are highly homologous. Sequence homology was thought to be a factor predisposing to the tandem duplication variant.

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.

STXBP2, encoding syntaxin-binding protein 2, is involved in intracellular organelle trafficking and is associated with familial hemophagocytic lymphohistiocytosis type 5. Although STXBP2 mutations reportedly cause monogenic inflammatory bowel disease, the clinical course and underlying pathogenic mechanisms remain unclear. We identified a novel mutation in STXBP2 [c.1197delC, p.Ala400fs] in a boy with congenital intractable diarrhea and hemophagocytic lymphohistiocytosis (HLH). HLH was treated with intravenous prednisolone, cyclosporine, and dexamethasone palmitate. Hematopoietic stem cell transplantation (HSCT) along with prophylaxis for graft-versus-host-disease was performed at 5 months of age. Additionally, colonoscopies done before and after HSCT showed mild colitis with cryptitis. The patient showed elevated fecal calprotectin levels and persistent diarrhea even after HSCT and required partial parenteral nutrition. While anti-inflammatory treatment reduced diarrhea, it was not completely normalized even after HSCT, suggesting that the pathogenesis of inflammatory bowel disease associated with STXBP2 mutations involves both hyperinflammation and functional epithelial barrier defects.

The concept of autoinflammation, first proposed in 1999, refers to a seemingly unprovoked episode of sterile inflammation manifesting as unexplained fever, skin rashes, and arthralgia. Autoinflammatory diseases are caused mainly by hereditary abnormalities of innate immunity, without the production of autoantibodies or autoreactive T cells. The revolutionary discovery of induced pluripotent stem cells (iPSCs), whereby a patient’s somatic cells can be reprogrammed into an embryonic pluripotent state by forced expression of a defined set of transcription factors, has the transformative potential to enable in vitro disease modeling and drug candidate screening, as well as to provide a resource for cell replacement therapy. Recent reports demonstrate that recapitulating a disease phenotype in vitro is feasible for numerous monogenic diseases, including autoinflammatory diseases. In this review, we provide a comprehensive overview of current advances in research into autoinflammatory diseases involving iPSC-derived monocytes/macrophages. This review may aid in the planning of new studies of autoinflammatory diseases.

To evaluate the efficacy and safety of tocilizumab (TCZ), an interleukin 6 receptor monoclonal antibody, in a subset of Japanese patients with familial Mediterranean fever (FMF).We performed a double-blind, randomised, parallel-group trial, followed by an open-label extension trial, in patients with colchicine-resistant or -intolerant FMF (crFMF) (UMIN000028010). Patients were randomly assigned (1:1) to receive TCZ (162 mg every week) or placebo, administered subcutaneously, for 24 weeks. Rescue treatment was allowed if the rescue criteria were met. The primary endpoint was the number of fever attacks over the 24 weeks of treatment. Secondary endpoints included the frequency of accompanying symptoms during attacks, serum CRP and SAA values, and adverse events (AEs). The open-label extension study evaluated the long-term safety and efficacy of TCZ in patients who had completed the preceding study (UMIN000032557).We randomly assigned 23 patients to either TCZ (n=1) or placebo (n=12). The TCZ-placebo rate ratios were 0.691 (95% confidence intervals (CI), 0.189-2.531; p=0.577) for the fever attacks, based on the group rates per week. The recurrence of attacks was significantly lower in the TCZ group (hazard ratio = 0.457; 95% CI, 0.240-0.869). Fever attacks, accompanying symptoms, serum CRP and SAA values were controlled in most of the patients who received long-term TCZ. In these trials, the numbers and severity of AEs did not differ between groups.Although a primary endpoint was not met in the preceding trial, long-term administration of TCZ showed stable efficacy and safety for patients with crFMF.

Subcutaneous immunoglobulin is one of the standard treatments for hypogammaglobulinemia in primary immunodeficiencies (PID) worldwide. In Japan, IgPro20 (HizentraThis multicenter, open label post-marketing surveillance study was conducted between January 2014 and March 2019. Patients who received IgPro20 due to PID or SID were included after informed consent. Physicians completed a case report form for each patient. Safety was determined from reported adverse events (AEs), adverse drug reactions, and serious AEs (SAEs); effectiveness was assessed by infection rates after the first IgPro20 dose.Of 85 patients receiving IgPro20 in the safety analysis, 39 developed AEs (45.9%; PID n = 28, SID n = 11). At least one adverse drug reaction was observed in 27 patients (31.8%; PID n = 21, SID n = 6), and the most common were injection site reactions (n = 17, 20.0%). Four patients (PID n = 3, SID n = 1) reported SAEs but two were unrelated to IgPro20 administration. The infection rate decreased from 0.54 per patient during the 6 months before IgPro20 to 0.39 per patient during IgPro20 treatment. Serious bacterial infections occurred in six patients before IgPro20 (7.9%; PID n = 2; SID n = 4) but in only one patient with SID during IgPro20 treatment (1.2%).In Japan, IgPro20 was considered safe and effective among patients with agammaglobulinemia or hypogammaglobulinemia due to PID or SID.

X-linked agammaglobulinemia (XLA) is characterized by severe or recurrent infections, hypogammaglobulinemia, and circulating B cell deficiency. The frequent pathogens seen in patients with XLA include Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and enterovirus as well as Campylobacter and Helicobacter species. Here, we describe two patients with XLA who developed cellulitis and bacteremia caused by Helicobacter cinaedi even when administered an appropriate immunoglobulin replacement therapy. H. cinaedi may be difficult to isolate using a conventional blood culture system and could be identified by sequence analysis and mass spectrometry. H. cinaedi infection causes recurrent symptoms frequently, and patients require a long course of antibiotic treatment. Recently, the case of non-H. pylori Helicobacter (NHPH) infection such as H. cinaedi and H. bilis infection is increasing in number in patients with XLA. Systemic NHPH infection should be suspected, and extensive microbiological analysis should be performed to appropriately treat patients with XLA who present with fever and skin lesions.

We report a case of a 27-year old woman with persistent fever and pancytopenia who had multiple episodes of a hemophagocytic lymphohistiocytosis (HLH) like condition. The criterion for HLH was satisfied; primary cytomegalovirus (CMV) infection was identified as the cause. Further examination revealed a GATA binding protein 2 mutation. Reports of GATAs deficiency presenting with HLH after primary CMV infection is very limited. As early recognition and diagnosis will improve patients' outcomes, internists and infectious disease specialists should be aware of this disease.

Objective To evaluate the efficacy and safety of tocilizumab (TCZ), an interleukin 6 receptor monoclonal antibody, in patients with familial Mediterranean fever (FMF). Methods We performed a double-blind, randomized, parallel-group trial, followed by an open-label extension trial, in patients with colchicine-resistant or -intolerant FMF (crFMF). Patients were randomly assigned (1:1) to receive TCZ (162 mg every week) or placebo, administered subcutaneously, for 24 weeks. Rescue treatment was allowed if the rescue criteria were met. The primary endpoint was the number of fever attacks over the 24 weeks of treatment. Secondary endpoints included the frequency of accompanying symptoms during attacks, serum CRP and SAA values, and adverse events (AEs). The open-label extension study evaluated the long-term safety and efficacy of TCZ in patients who had completed the preceding study. Results We randomly assigned 23 patients to either TCZ (n = 11) or placebo (n = 12). The TCZ–placebo rate ratios were 0.691 (95% confidence intervals (CI), 0.189–2.531; P = 0.577) for the fever attacks, based on the group rates per week. The recurrence of attacks was significantly lower in the TCZ group (hazard ratio = 0.457; 95% CI, 0.240–0.869). Fever attacks, accompanying symptoms, serum CRP and SAA values were controlled in most of the patients who received long-term TCZ. In these trials, the numbers and severity of AEs did not differ between groups. Conclusion Although a primary endpoint was not met in the preceding trial, long-term administration of TCZ showed stable efficacy and safety for patients with crFMF.

Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Effectiveness of IL-1β–blocking therapy indicates that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42[R186C], we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42[R186C] protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42[*192C*24] that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but not that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave the way for elucidating the mechanism of pyrin inflammasome formation., CDC42-C末端異常症に於ける炎症病態を解明 --ゴルジ体への異常蓄積がパイリンインフラマソーム形成を過剰促進--. 京都大学プレスリリース. 2022-05-02.

Mutations in the C-terminal region of the CDC42 gene cause severe neonatal-onset autoinflammation. Elevated levels of serum IL-18 in patients and effectiveness of IL-1β-blocking therapy indicate that the pathology involves abnormal inflammasome activation; however, the mechanism underlying autoinflammation remains to be elucidated. Using induced-pluripotent stem cells established from patients carrying CDC42R186C, we found that patient-derived cells secreted larger amounts of IL-1β in response to pyrin-activating stimuli. Aberrant palmitoylation and localization of CDC42R186C protein to the Golgi apparatus promoted pyrin inflammasome assembly downstream of pyrin dephosphorylation. Aberrant subcellular localization was the common pathological feature shared by CDC42 C-terminal variants with inflammatory phenotypes, including CDC42*192C*24 that also localizes to the Golgi apparatus. Furthermore, the level of pyrin inflammasome overactivation paralleled that of mutant protein accumulation in the Golgi apparatus, but no that of the mutant GTPase activity. These results reveal an unexpected association between CDC42 subcellular localization and pyrin inflammasome activation that could pave way for elucidating the mechanism of pyrin inflammasome formation.

Issues related to transitioning from paediatric to adult healthcare are currently receiving international attention. In Japan, 1000 patients with childhood-onset chronic rheumatological diseases reach adulthood every year and require transition from care by paediatric to care by adult rheumatologists. Here, we propose a guide for the latter, wherein the adult caregiver poses the clinical questions about transitional support that they need to have answered, and the paediatric caregiver mainly compiles the plans for the transition. To formulate the guide, we sought comments from both the Japan College of Rheumatology and the Pediatric Rheumatology Association of Japan and obtained their approval. Here, we present the outcome of this consultation in the form of a Guide for Supporting Transitional Care, aiming to provide essential knowledge to physicians in the fields of adult internal medicine and orthopaedics who may be involved in treating patients with rheumatic disease during the transition from paediatric to adult care. The features of transitional support that are common for patients with various different rheumatic diseases are presented in this guide, with the aim of informing policy and strategies to deliver optimal outcomes in transitional care by non-paediatric rheumatologists.

Patients with refractory graft-versus-host disease (GVHD) have a dismal prognosis. Therefore, novel therapeutic targets are still needed to be identified. Runt-related transcriptional factor (RUNX) family transcription factors are essential transcription factors that mediate the essential roles in effector T cells. However, whether RUNX targeting can suppress, and GVHD is yet unknown. Here, we showed that RUNX family members have a redundant role in directly transactivating

X-linked dominant incontinentia pigmenti (IP) and X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) are caused by loss-of-function and hypomorphic IKBKG (also known as NEMO) mutations, respectively. We describe a European mother with mild IP and a Japanese mother without IP, whose 3 boys with EDA-ID died from ID. We identify the same private variant in an intron of IKBKG, IVS4+866 C>T, which was inherited from and occurred de novo in the European mother and Japanese mother, respectively. This mutation creates a new splicing donor site, giving rise to a 44-nucleotide pseudoexon (PE) generating a frameshift. Its leakiness accounts for NF-κB activation being impaired but not abolished in the boys’ cells. However, aberrant splicing rates differ between cell types, with WT NEMO mRNA and protein levels ranging from barely detectable in leukocytes to residual amounts in induced pluripotent stem cell–derived (iPSC-derived) macrophages, and higher levels in fibroblasts and iPSC-derived neuronal precursor cells. Finally, SRSF6 binds to the PE, facilitating its inclusion. Moreover, SRSF6 knockdown or CLK inhibition restores WT NEMO expression and function in mutant cells. A recurrent deep intronic splicing mutation in IKBKG underlies a purely quantitative NEMO defect in males that is most severe in leukocytes and can be rescued by the inhibition of SRSF6 or CLK.

Asymptomatic carriers (ACs) of pathogenic biallelic mutations in causative genes for primary hemophagocytic lymphohistiocytosis (HLH) are at high risk of developing life-threatening HLH, which requires allogeneic hematopoietic stem cell transplantation (HSCT) to be cured. There are no guidelines on the management of these asymptomatic patients. We analyzed the outcomes of pairs of index cases (ICs) and subsequently diagnosed asymptomatic family members carrying the same genetic defect. We collected data from 22 HSCT centers worldwide. Sixty-four children were evaluable. ICs presented with HLH at a median age of 16 months. Seven of 32 ICs died during first-line therapy, and 2 are alive after chemotherapy only. In all, 23/32 underwent HSCT, and 16 of them are alive. At a median follow-up of 36 months from diagnosis, 18/32 ICs are alive. Median age of ACs at diagnosis was 5 months. Ten of 32 ACs activated HLH while being observed, and all underwent HSCT: 6/10 are alive and in complete remission (CR). 22/32 ACs remained asymptomatic, and 6/22 have received no treatment and are in CR at a median follow-up of 39 months. Sixteen of 22 underwent preemptive HSCT: 15/16 are alive and in CR. Eight-year probability of overall survival (pOS) in ACs who did not have activated HLH was significantly higher than that in ICs (95% vs 45%; P = .02), and pOS in ACs receiving HSCT before disease activation was significantly higher than in ACs receiving HSCT after HLH activation (93% vs 64%; P = .03). Preemptive HSCT in ACs proved to be safe and should be considered.

Patients with CTLA4 mutations present with autoimmune diseases, lymphoproliferation, and hypogammaglobulinemia, and a subset of patients developed Epstein-Barr virus (EBV)-associated malignancies, suggesting an impaired immune function against EBV. Here we investigated EBV infection in individuals with CTLA4 mutations. We measured EBV viral DNA in healthy individuals, individuals with autoimmune diseases, and individuals with CTLA4 mutations. In addition, we evaluated the numbers and function of EBV-specific T cells, invariant NKT cells, and NK cells. More than half of individuals with CTLA4 mutations including asymptomatic ones had detectable EBV DNA, which is a significantly higher frequency with higher viral loads compared with healthy and disease controls. However, individuals with CTLA4 mutations had almost normal immunity against EBV. Individuals with CTLA4 mutations have an increased susceptibility to Epstein-Barr virus infections. Asymptomatic viremia occurs at high frequencies, which can be persistent and can occur in unaffected individuals.

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.

Dried blood spots (DBS) are widely used for screening biomolecular profiles, including enzymatic activities. However, detection of minor proteins in DBS by liquid chromatography-mass spectrometry (LC-MS/MS) without pre-enrichment remains challenging because of the coexistence of large quantities of hydrophilic proteins. In this study, we address this problem by developing a simple method using sodium carbonate precipitation (SCP). SCP enriches hydrophobic proteins from DBS, allowing substantial removal of soluble proteins. In combination with SCP, we used quantitative LC-MS/MS proteome analysis in a data-independent acquisition mode (DIA) to enhance the sensitivity and quantification limits of proteome analysis. As a result, identification of 1977 proteins in DBS is possible, including 585 disease-related proteins listed in the Online Mendelian Inheritance in Man.

Background This study aimed to determine the influence of tocilizumab (TCZ) in modifying the clinical and laboratory features of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (s-JIA). Furthermore, we assessed the performance of the 2016 MAS classification criteria for patients with s-JIA-associated MAS while treated with TCZ. Methods A panel of 15 pediatric rheumatologists conducted a combination of expert consensus and analysis of real patient data. Clinical and laboratory features of s-JIA-associated MAS in 12 TCZ-treated patients and 18 untreated patients were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented full-blown MAS. Results Clinically, the TCZ-treated patients with s-JIA-associated MAS were less likely febrile and had significantly lower ferritin, triglyceride, and CRP levels than the untreated patients with s-JIA-associated MAS. Other laboratory features of MAS including lower platelet counts and lower fibrinogen were more pronounced in TCZ-treated patients. The TCZ-treated patients with s-JIA-associated MAS were less likely to be classified as MAS based on the MAS classification criteria (25% vs 83.3%, p Conclusion TCZ could modify the clinical and laboratory features of s-JIA-associated MAS. When evaluating the s-JIA patients while treated with TCZ, it is not applicable to use MAS classification criteria. Care must be taken to not underdiagnose MAS based on the MAS classification criteria.

Objective To validate whether the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA) is practical in the real world. Methods A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. A total of 65 profiles comprised 18 patients with systemic JIA-associated MAS and 47 patients with active systemic JIA without evidence of MAS. From these profiles, 10 patient data points for full-blown MAS, 11 patient data points for MAS onset, and 47 patient data points for acute systemic JIA without MAS were evaluated. Results Evaluation of the classification criteria to discriminate full-blown MAS from acute systemic JIA without MAS showed a sensitivity of 1.000 and specificity of 1.000 at the time of full-blown MAS. Sensitivity was 0.636 and specificity was 1.000 at the time of MAS onset. The number of measurement items that fulfilled the criteria increased in full-blown MAS compared to that at MAS onset. At MAS onset, the positive rates of patients who met the criteria for platelet counts and triglycerides were low, whereas those for aspartate aminotransferase were relatively high. At full-blown MAS, the number of patients who met the criteria for each measurement item increased. Conclusion The classification criteria for MAS complicating systemic JIA had a very high diagnostic performance. However, the diagnostic sensitivity for MAS onset was relatively low. For the early diagnosis of MAS in systemic JIA, the dynamics of laboratory values during the course of MAS should be further investigated.

Familial hemophagocytic lymphohistiocytosis (FHL) is the major form of hereditary hemophagocytic lymphohistiocytosis (HLH); as such, it requires prompt and accurate diagnosis. We previously reported that FHL type 3 (FHL3) can be rapidly screened by detecting munc13-4 expression in platelets using flow cytometry; however, the reliability of the munc13-4 expression assay for FHL3 diagnosis is unclear. Regardless of the type of UNC13D mutation, all reported FHL3 cases examined for the munc13-4 protein showed significantly reduced expression. However, the translated munc13-4 protein of some reportedly disease-causing UNC13D missense variants has not been assessed in terms of expression or function; therefore, their clinical significance remains unclear. The aim of this study was to determine the reliability of a munc13-4 expression assay for screening FHL3. Between 2011 and 2016, 108 HLH patients were screened by this method in our laboratory, and all 15 FHL3 patients were diagnosed accurately. To further elucidate whether munc13-4 expression analysis can reliably identify FHL3 patients harboring missense mutations in UNC13D, we developed an alloantigen-specific cytotoxic T lymphocyte (CTL) line and a CTL line immortalized by Herpesvirus saimiri derived from FHL3 patients. We then performed a comprehensive functional analysis of UNC13D variants. Transient expression of UNC13D complementary DNA constructs in these cell lines enabled us to determine the pathogenicity of the reported UNC13D missense variants according to expression levels of their translated munc13-4 proteins. Taken together with previous findings, the results presented herein show that the munc13-4 protein expression assay is a reliable tool for FHL3 screening.

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost., This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and the Ministry of Health, Labour, and Welfare of Japan., Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.alit.2017.06.003

Background Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by mutations in the adenosine deaminase 2 (ADA2) gene. Loss of functional ADA2 activity results in vasculitis syndrome, immunodeficiency, and hematopoietic disorders. Early diagnosis is required for effective treatment. Methods We developed a dried blood spot (DBS)-based ADA2 activity colorimetric assay. Heparin-affinity purification was used during sample preparation to improve the assay more efficiently. The stability of ADA2 during DBS storage and ADA2 activity of DADA2 patients and healthy controls were examined. Results Active ADA2 was extracted from the DBS of healthy controls. ADA2 activity in DBS, stored either frozen or refrigerated, remained stable for at least 90 days. A significant difference in ADA2 activity was observed between healthy controls and patients. No ADA2 activity was detected in DBS from patients. Conclusions Our new DBS ADA2 activity assay is experimentally simple, highly adaptable, and requires no special equipment except for a microplate reader. A low background was achieved with heparin-affinity purification. The method differentiates clearly between healthy controls and patients. ADA2 activity can be reliably measured in DBS, providing an opportunity to diagnose DADA2 at an early stage.

Colchicine is an anti-inflammatory drug. The combination of colchicine and NSAIDs is the first-line therapy for acute pericarditis in adults. However, in children, colchicine is recommended only for recurrent pericarditis, and its efficacy against acute pericarditis is unknown. This study describes a 6-year-old boy who suffered from acute idiopathic pericarditis that was refractory to aspirin and ibuprofen. Colchicine led to a marked improvement in his symptoms (fever and pericardial effusion) and inflammatory data. It also prevented disease recurrence. An ascending dose regimen also prevented gastrointestinal side effects. Thus, colchicine should be useful for refractory cases of acute idiopathic pericarditis in children.

Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a genetic disorder that results in immune dysregulation. It requires prompt and accurate diagnosis. A natural killer (NK) cell degranulation assay is often used to screen for FHL3 patients. However, we recently encountered two cases of late-onset FHL3 carrying novel UNC13D missense mutations: in these cases, the degranulation assays using freshly isolated and interleukin (IL)-2-activated NK cells yielded contradictory results. Since the defective degranulation of CD57+ cytotoxic T lymphocytes (CTLs) in these cases was helpful for making the diagnosis, we assessed whether the CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell assays. Forty additional patients with hemophagocytic lymphohistiocytosis were prospectively screened for FHL3 by measuring the perforin expression in NK cells and the expression of Munc13-4, syntaxin-11, and Munc18-2 in platelets and by performing NK cell and CTL degranulation assays. The results were confirmed by genetic analysis. The freshly isolated NK cell degranulation assay detected FHL3 patients with high sensitivity (100%) but low specificity (71%). The IL-2-stimulated NK cell assay had improved specificity, but 3 out of the 31 non-FHL3 patients still showed degranulation below the threshold level. The CD57+ CTL degranulation assay identified FHL3 patients with high sensitivity and specificity (both 100%). The CD57+ CTL degranulation assay more effectively identified FHL3 patients than the NK cell-based assays.

Summary Objectives Patients with primary immunodeficiency diseases (PID) are highly susceptible to various microorganisms. However, no population-based studies have been performed among common viral pathogens, such as respiratory syncytial virus (RSV), rotavirus (RV), varicella-zoster virus (VZV) and influenza virus (IV). The objective of this study was to reveal the clinical burden of these four infections among PID patients in Japan. Methods We conducted a nationwide survey by sending questionnaires to 898 hospitals with pediatric departments throughout Japan. Results Nine hundred ten PID patients from 621 hospitals were registered (response rate: 69.2%). Fifty-four of the patients were hospitalized due to these viral infections. The durations of hospitalization due to RSV and RV infections differed significantly in the PID patients with and without cellular immunodeficiency (12.0 vs 6.5 days, p = 0.041 ; and 14.0 vs 6.0 days, p = 0.031 , respectively). There was no significant difference in the duration of hospitalization in PID patients with and without cellular immunodeficiency who were hospitalized with IV infections (7.3 vs 6.1 days, p = 0.53). Conclusions Special attention should be paid to PID patients with compromised cellular immunity who present with RSV and RV infection due to their high risk for severe disease.

Background Previous studies including a systematic literature review revealed clinical manifestations and laboratory features of systemic juvenile idiopathic arthritis (s-JIA) associated macrophage activation syndrome (MAS) could be modified in patients treated with tocilizumab (TCZ) 1,2. Objectives To clarify whether TCZ modifies clinical manifestations and laboratory features of s-JIA associated MAS, and to assess performance of the 2016 MAS classification criteria for patients with s-JIA associated MAS while treated with TCZ in the real world. Methods A combination of expert consensus and analysis of real patient data was conducted by a panel of 15 pediatric rheumatologists. Clinical manifestations and laboratory features of s-JIA associated MAS at the MAS diagnosis in 12 patients while treated with TCZ and 18 patients not treated with TCZ were evaluated. Possible MAS was defined as having characteristic laboratory features but lack of clinical features of MAS, or atypical MAS, or early treatment that prevented fulminant MAS 3,4. Results Among 12 patients while treated with TCZ, only 2 patients were diagnosed with definite MAS, and other 10 patients were diagnosed with possible MAS. On the other hand, among 18 patients not treated with TCZ, 10 patients were diagnosed with definite MAS, and other 8 patients were diagnosed with possible MAS. MAS classification criteria could classify the patients diagnosed with definite MAS while treated with TCZ as having MAS as well as the patients not treated with TCZ (100% and 100%, respectively). However, this criteria were less likely to classify the patients diagnosed with possible MAS while treated with TCZ as well as the patients not treated with TCZ (60% and 75%, respectively). Furthermore, the patients with possible MAS while treated with TCZ were less likely febrile and significantly less often had rash, and had notably lower ferritin levels (587 versus 8518 ng/ml; P=0.0021), compared to the patients with possible MAS not treated with TCZ. Other laboratory features of MAS including lower platelet counts, lower fibrinogen were more pronounced in patients treated with TCZ. Conclusion These findings show TCZ could modify clinical manifestations and laboratory features of s-JIA associated MAS. When evaluating s-JIA patients while treated with TCZ, care must be taken to not underdiagnose MAS based on MAS classification criteria. References [1] Shimizu M, et al. Cytokine 2012;58:287-294. [2] Sculert GS, et al. Arthritis Care Res 2018;70:409-419 [3] Grom AA, et al. Arthritis Rheumatol 2016;68:218-228. [4] Yokota S, et al. J Rheumatol 2015;42:712-722. Disclosure of Interests Masaki Shimizu: None declared, Mao Mizuta: None declared, Takahiro Yasumi Shareholder of: Takeda, Speakers bureau: AbbVie, Novartis, CSL Behring, Naomi Iwata: None declared, Yuka Okura: None declared, Noriko Kinjo: None declared, Hiroaki Umebayashi Speakers bureau: AbbVie, Eisai, Novartis, Ono, Chugai, Tomohiro Kubota: None declared, Yasuo Nakagishi: None declared, Kenichi Nishimura: None declared, Masato Yashiro: None declared, Junko Yasumura: None declared, Hiroyuki Wakiguchi: None declared, Nami Okamoto: None declared, Masaaki Mori Grant/research support from: Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Towa Pharmaceutical Co., Ltd., UCB Japan Co. Ltd.

Background The transition from pediatric to adult healthcare systems has recently received worldwide attention, and it is “the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented healthcare systems.” In Japan, 1,000 patients with childhood-onset chronic disease reach adulthood every year, and many of them survive without serious sequelae or disabilities. The Japan Pediatric Society convened a committee of healthcare transition, summarized their statements, and the working group launched its activities in 2013. Objectives A clinical practice guidance for the transitional care of young people with childhood-onset rheumatic disorders has been established in Japan. Methods The guidance was designed to support pediatric and non-pediatric rheumatologic health care professionals make decisions about appropriate transitional health care for childhood-onset rheumatic disorders. It offered statements and recommendations addressing key clinical questions regarding transitional care proposed by leading pediatric and non-pediatric rheumatology medical experts and consisted of general core and disease-specific guidance. Results Category of clinical questions in the general core guidance involved the following: (1) initial statement of transitional care in rheumatology; (2) management of social life environment and public funded health care; (3) issues specific to adolescence; (4) risk management in childhood-onset rheumatic disorders; and (5) decision-making, privacy and consent, access to information, adherence to care, and preferred methods of communication, including attending to health literacy needs. In the disease-specific guidance, issues focused on each rheumatic disorder such as juvenile idiopathic arthritis, childhood-onset systemic lupus erythematosus, juvenile dermatomyositis, and Sjogren’s syndrome were brought up. Conclusion The guidance informs policy and strategies to reach optimal outcomes in transitional care for both pediatric and non-pediatric rheumatologists based on available evidence and expert opinion. References [1] Miyamae T, et al. Survey of attitudes of non-pediatric rheumatologists among councilors of the Japan College of Rheumatology regarding transitional care. Mod Rheumatol. 2017;27(6):1047-1050. [2] Matsui T, et al. Survey of the awareness of adult rheumatologists regarding transitional care for patients with juvenile idiopathic arthritis in Japan. Mod Rheumatol. 2018;28(6):981-985. Disclosure of Interests Takako Miyamae Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Ayumi, Taisyo-Toyama, Chugai, Shinji Akioka Grant/research support from: Eli Lily, Speakers bureau: Pfizer, Maruho, CSL Behring, Astellas, Chugai, Toru Igarashi: None declared, Yuzaburo Inoue Grant/research support from: MSD, Speakers bureau: Novartis, CSL Behring, MSD, Taishotoyama, Ono, Motomu Hashimoto Grant/research support from: Astellas, Brystol-Meyers, Eisai, Employee of: M. H. is affiliated with the department (Department of Advanced Medicine for Rheumatic Diseases, Kyoto University), which is financially supported by four pharmaceutical companies (Tanabe-Mitsubishi, Chugai, Ayumi, UCB Japan), Speakers bureau: Tanabe Mitsubishi, Brystol-Meyers, Toshihiro Matsui Speakers bureau: Takeda, Chugai, Eisai, Pfizer, Astellas, Eli Lilly, Ono, AbbVie, Mitsubishi Tanabe, AsahiKASEI, UCB, Teijin, Susumu Nishiyama Paid instructor for: Kissei Pharmaceutical Co., Ltd, Takeda Pharmaceutical Company, Mitsubishi Tanabe Pharma, Astellas Pharma, Eisai Pharmaceutical company, AbbVie Inc., TEIJIN Pharma, Asahi Kasei Corporation, Bristol- Myers Squibb Company, Chugai Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., AYUMI Pharmaceutical Corporation, Speakers bureau: Kissei Pharmaceutical Co., Ltd, DAIICHI SANKYO COMPANY, LIMITED, Shiro Ohshima Grant/research support from: AbbVie, Eisai, Asahikasei, Speakers bureau: AbbVie, Eisai, Bristol-Meyers, Novartis, Astellas, Nippon-Kayaku, Pfizer, UCB, Ayumi, Daiichi-Sankyo, Takeda, Tanabe-Matsubishi, Chugai, Hiroaki Umebayashi Speakers bureau: AbbVie, Eisai, Novartis, Ono, Chugai, Takahiro Yasumi Shareholder of: Takeda, Speakers bureau: AbbVie, Novartis, CSL Behring, Masaaki Mori Grant/research support from: Tokyo Medical and Dental University (TMDU) received unrestricted research grants for Department of Lifetime Clinical Immunology from AbbVie GK, Ayumi Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., CSL Behring K.K., Japan Blood Products Organization, Mitsubishi Tanabe Pharma Corporation, Nippon Kayaku Co., Ltd., Ono Pharmaceutical Co., Ltd., Towa Pharmaceutical Co., Ltd., UCB Japan Co. Ltd.

Autoinflammatory disease is an ‘inborn error of immunity’, resulting in systemic inflammation. Cryopyrin-associated periodic syndrome (CAPS) is a prototypical autoinflammatory disease caused by gain-of-function mutations in the NLRP3 (NLR family pyrin domain containing 3) gene; these mutations activate the NLRP3 inflammasome, resulting in overproduction of IL-1β. The first case of CAPS caused by somatic NLRP3 mosaicism was reported in 2005 after identification of variant small peaks by Sanger sequencing. An international collaborative study revealed that the majority of mutation-negative CAPS cases are due to low-level NLRP3 mosaicism, suggesting that central nervous system involvement in somatic mosaicism patients is milder than in genotype-matched heterozygous patients. Recent advances in next-generation sequencing have expanded the number of NLRP3 somatic mosaicism cases and identified a new entity called ‘late-onset CAPS with myeloid-specific NLRP3 mosaicism’; however, no mosaic-specific clinical features have been identified/confirmed yet. With respect to NLRP3 mosaicism in CAPS, a prospective longitudinal study on the variant genotype, its allele frequency and its tissue distribution (along with a comprehensive clinical phenotype) would provide better understanding of NLRP3 mosaicism, resulting in more appropriate patient care and genetic counseling.

Background Infliximab (IFX), a mouse-human chimeric monoclonal antibody against human tumor necrosis factor alpha, is used in refractory cases of Takayasu arteritis. Several factors influence the pharmacokinetics of therapeutic antibodies including IFX. Monitoring plasma levels of IFX could be a useful approach in optimizing treatment via individual dose adjustment. Case presentation Here, we report the case of a 4-year-old Takayasu arteritis girl who was resistant to standard therapy. IFX was started at 5 mg/kg (day 0). C-reactive protein (CRP) levels decreased from 8.7 (day 0) to 1.6 mg/dL (day 10). CRP levels were thereafter elevated again on day 23 (9.0 mg/dL), and body fluid leakage at the inflammation site in the legs was observed. Trough IFX levels decreased from 23.6 (day 10) to 2.5 μg/mL (day 23). Based on the trough levels, IFX was given biweekly at 8 mg/kg. Plasma IFX levels gradually increased, and CRP levels decreased to around 2 mg/dL. A similar pattern -initial decreases followed by increases- was observed between clinical course of IFX and IgG levels. It was speculated that IgG and IFX losses were due to fluid leakage from the patient’s necrotizing legs. Conclusions Monitoring of plasma IFX levels can be a potential tool to optimize the treatment in Takayasu arteritis patients.

Background Although there are many reports on Juvenile Idiopathic arthritis-associated uveitis (JIA-U) from various countries, especially from Europe and North America, there are few reports from Asia. Our aim was to investigate the epidemiology, characteristics and predictors of JIA-U in Japan. Methods Data were retrospectively collected on 726 patients with JIA from medical records as of April 2016 at 15 medical centers specialized in pediatric rheumatic diseases. Of these, patients with uveitis were further investigated for the specific characteristics of this manifestation. Results The prevalence of uveitis was 6.1% in the 726 JIA patients examined. Incidence of uveitis was significantly higher in patients with an earlier arthritis onset (2.6-vs.-5.8 years, P

Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory syndrome characterised by recurrent episodes of urticarial rash and fever. Diagnosis is based on characteristic clinical...