A de novo dominant-negative variant is associated with OTULIN-related autoinflammatory syndrome.

OTULIN-related autoinflammatory syndrome (ORAS), a severe autoinflammatory disease, is caused by biallelic pathogenic variants of OTULIN, a linear ubiquitin-specific deubiquitinating enzyme. Loss of OTULIN attenuates linear ubiquitination by inhibiting the linear ubiquitin chain assembly complex (LUBAC). Here, we report a patient who harbors two rare heterozygous variants of OTULIN (p.P152L and p.R306Q). We demonstrated accumulation of linear ubiquitin chains upon TNF stimulation and augmented TNF-induced cell death in mesenchymal stem cells differentiated from patient-derived iPS cells, which confirms that the patient has ORAS. However, although the de novo p.R306Q variant exhibits attenuated deubiquitination activity without reducing the amount of OTULIN, the deubiquitination activity of the p.P152L variant inherited from the mother was equivalent to that of the wild-type. Patient-derived MSCs in which the p.P152L variant was replaced with wild-type also exhibited augmented TNF-induced cell death and accumulation of linear chains. The finding that ORAS can be caused by a dominant-negative p.R306Q variant of OTULIN furthers our understanding of disease pathogenesis.

Safety and efficacy of elapegademase in patients with adenosine deaminase deficiency: A multicenter, open-label, single-arm, phase 3, and postmarketing clinical study.

INTRODUCTION: Adenosine deaminase (ADA) deficiency is an ultrarare inherited purine metabolism disorder characterized by severe combined immunodeficiency. Elapegademase-lvlr is a new pegylated recombinant bovine ADA used in enzyme-replacement therapy (ERT) for ADA deficiency. Therefore, replacement with the new drug may eliminate the infectious risks associated with the currently used bovine intestinal-derived product, pegademase. METHODS: We conducted a multicenter, single-arm, open-label, phase 3, and postmarketing clinical study of elapegademase for patients with ADA deficiency. The following biochemical markers were monitored to determine an appropriate dose of elapegademase: the trough deoxyadenosine nucleotide (dAXP) level ≤0.02 µmol/mL in erythrocytes or whole blood and the trough serum ADA activity ≥1100 U/L (equivalent to plasma levels ≥15 µmol/h/mL) indicated sufficient enzyme activity and detoxification as efficacy endpoints and monitored adverse events during the study as safety endpoints. RESULTS: A total of four patients (aged 0-25 years) were enrolled. One infant patient died of pneumonia caused by cytomegalovirus infection whereas the other three completed the study and have been observed in the study period over 3 years. The infant patient had received elapegademase at 0.4 mg/kg/week until decease and the others received elapegademase at maximum doses of 0.3 mg/kg/week for 164-169 weeks. As a result, all four patients achieved undetectable levels of dAXPs together with sufficient enzyme activity, increased T and B cell numbers, and slightly elevated and maintained IgM and IgA immunoglobulin levels. Serious adverse events occurred in three patients, all of which were assessed as unrelated to elapegademase. CONCLUSIONS: This study showed that elapegademase had comparable safety and efficacy to pegademase as ERT for ADA deficiency by demonstrating stable maintenance of sufficient ADA activity and lowering dAXP to undetectable levels, while no drug-related adverse events were reported (Trial registration: JapicCTI-163204).

Therapeutic Drug Monitoring of Oral Voriconazole in an Infant Less than Six Months of Age and Pharmacokinetics Changes Induced by Development of CYP2C19 in the Growth Process: A Novel Case Report.

Therapeutic drug monitoring (TDM) is recommended for voriconazole (VRCZ) to avoid adverse events and maximize antifungal efficacy. Currently, the appropriate dose for patients under the age of 2 years is unknown. Here, we report the case of a 1.5-month-old infant with inborn errors of immunity who was orally administered VRCZ. This patient's plasma concentration decreased significantly from 3.8 µg/mL (day 6) to 0.09 µg/mL (day 21), leading to repeated dose escalations to achieve the target concentration (1.38 µg/mL, day 58). The signal intensity ratio of VRCZ to its main metabolite, N-oxide VRCZ, in LC/MS/MS also decreased from 5.30 (day 6) to 0.57 (day 64). Consequently, we suspected that VRCZ metabolism may be enhanced during infant growth. To our knowledge, this is the first report of remarkable changes in VRCZ pharmacokinetics with metabolic activity enhanced by the growth process. In conclusion, we propose that frequent TDM helped to maintain adequate VRCZ plasma concentration in a infants less than 6 months of age.

Actin-binding domain of Rng2 sparsely bound on F-actin strongly inhibits actin movement on myosin II.

We report a case in which sub-stoichiometric binding of an actin-binding protein has profound structural and functional consequences, providing an insight into the fundamental properties of actin regulation. Rng2 is an IQGAP contained in contractile rings in the fission yeast Schizosaccharomyces pombe Here, we used high-speed atomic force microscopy and electron microscopy and found that sub-stoichiometric binding of the calponin-homology actin-binding domain of Rng2 (Rng2CHD) induces global structural changes in skeletal muscle actin filaments, including shortening of the filament helical pitch. Sub-stoichiometric binding of Rng2CHD also reduced the affinity between actin filaments and muscle myosin II carrying ADP and strongly inhibited the motility of actin filaments on myosin II in vitro. On skeletal muscle myosin II-coated surfaces, Rng2CHD stopped the actin movements at a binding ratio of 11%. Rng2CHD also inhibited actin movements on myosin II of the amoeba Dictyostelium, but in this case, by detaching actin filaments from myosin II-coated surfaces. Thus, sparsely bound Rng2CHD induces apparently cooperative structural changes in actin filaments and inhibits force generation by actomyosin II.

Rheumatologic manifestations with elevated levels of IL-6, IL-17A, and IL-23 in a patient with scurvy.

Symptomatic vitamin C deficiency, scurvy, is a relatively rare disease in developed countries, but it has been reported in patients with autism spectrum disorder or developmental delay who tend to have selective diets. Patients with scurvy often demonstrate musculoskeletal manifestations with unknown pathophysiology. Herein, we report a case of scurvy in an 11-year-old boy who presented with iron-deficiency anaemia, systemic osteomyelitis, myositis predominantly in the lower extremities, and right ventricular volume overload with mild pulmonary hypertension and was diagnosed with scurvy. He had a mild developmental disorder and a selective diet, which resulted in severe vitamin C deficiency. He received intravenous and oral vitamin C supplementation, which relieved his arthralgia and muscle pain in a week. Following 4 months of vitamin C supplementation, he demonstrated no abnormal manifestations on laboratory or imaging examination and recovered without sequelae. Inflammatory cytokine and chemokine evaluations demonstrated elevated levels of interleukin (IL)-6, IL-17A, and IL-23, which are associated with T-helper (Th) 17 cell activation. This study is the first to suggest the association between the inflammation seen in scurvy, rheumatic manifestations in the patient, and Th17 cell activation. Further analysis of the association between the inflammation and vitamin C supplementation may contribute to new insights for the comprehension and treatment of other inflammatory diseases, such as rheumatic diseases.

Educational Approaches That Enhance Online Clinical Clerkship during the COVID-19 Pandemic.

Objective This cross-sectional national study determined which educational approaches are associated with the effectiveness of online clerkship for medical students. Method A survey was conducted for medical students at 78 medical schools in Japan from May 29 to June 14, 2020. It comprised the following aspects: (a) participants' profiles, (b) number of opportunities to learn from each educational approach (lecture, medical quiz, assignment, oral presentation, observation of a physician's practice, clinical skill practice, participation in interprofessional meetings, and interactive discussions with physicians) in online clerkship, (c) frequency of technical problems, and (d) educational outcome measurement (satisfaction, motivation, knowledge acquisition, skill acquisition, change in self-study time, and understanding of the importance of medical care team). Results Of the 2,640 respondents, 2,594 (98.3%) agreed to cooperate. Ultimately, 1,711 matched our inclusion criteria. All educational approaches but assignments were positively associated with satisfaction and motivation. All educational approaches excluding assignment submission and interprofessional meeting were positively associated with knowledge acquisition. Observation, practice, and interprofessional meeting were positively associated with skill acquisition. Only assignment submission was positively associated with the change in self-study time. Educational approaches excluding medical quizzes were positively associated with understanding the importance of the medical care team. Technical problems were negatively associated with motivation, knowledge acquisition, and skill acquisition. Conclusions Educators should implement various educational approaches, especially observation and practice, even in online clinical clerkship. They also need to minimize the technical problems associated with the Internet, as they reduce the effectiveness of online clerkship.

Case Report: Rotavirus Vaccination and Severe Combined Immunodeficiency in Japan.

Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.

Identification of Germline Non-coding Deletions in XIAP Gene Causing XIAP Deficiency Reveals a Key Promoter Sequence.

PURPOSE: X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants in XIAP including missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of XIAP was identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression. METHODS: Targeted next-generation sequencing (NGS) of the entire locus of XIAP was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells. RESULTS: NGS of XIAP identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839 bp that encompassed the first non-coding exon of XIAP and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839 bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression. CONCLUSIONS: These results identify a key promoter sequence contained in the first non-coding exon of XIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.

Hematopoietic Cell Transplantation for Inborn Errors of Immunity Other than Severe Combined Immunodeficiency in Japan: Retrospective Analysis for 1985-2016.

PURPOSE: Hematopoietic cell transplantation (HCT) is a curative therapy for most patients with inborn errors of immunity (IEI). We conducted a nationwide study on HCT for patients with IEI other than severe combined immunodeficiency (non-SCID) in Japan. METHODS: Data from the Japanese national database (Transplant Registry Unified Management Program, TRUMP) for 566 patients with non-SCID IEI, who underwent their first HCT between 1985 and 2016, were retrospectively analyzed. RESULTS: The 10-year overall survival (OS) and event-free survival (EFS) were 74% and 64%, respectively. The 10-year OS for HCT from unrelated bone marrow (URBM), accounting for 39% of HCTs, was comparable to that for HCT from matched sibling donor (MSD), 79% and 81%, respectively. HCT from unrelated cord blood (URCB), accounting for 28% of HCTs, was also common, with a 10-year OS of 69% but less robust engraftment. The intensity of conditioning was not associated with OS or neutrophil recovery; however, myeloablative conditioning was more frequently associated with infection-related death. Patients who received myeloablative irradiation showed poor OS. Multivariate analyses revealed that HCT in 1985-1995 (hazard ratio [HR], 2.0; P = 0.03), URCB (HR, 2.0; P = 0.01), and related donor other than MSD (ORD) (HR, 2.9; P < 0.001) were associated with poor OS, and URCB (HR, 3.6; P < 0.001) and ORD (HR, 2.7; P = 0.02) showed a higher incidence of retransplantation. CONCLUSIONS: We present the 1985-2016 status of HCT for non-SCID IEI in Japan with sufficient statistical power, highlighting the potential of URBM as an alternative donor and the feasibility of reduced intensity conditioning.

Predicting the effectiveness of the online clinical clerkship curriculum: Development of a multivariate prediction model and validation study.

Given scientific and technological advancements, expectations of online medical education are increasing. However, there is no way to predict the effectiveness of online clinical clerkship curricula. To develop a prediction model, we conducted cross-sectional national surveys in Japan. Social media surveys were conducted among medical students in Japan during the periods May-June 2020 and February-March 2021. We used the former for the derivation dataset and the latter for the validation dataset. We asked students questions in three areas: 1) opportunities to learn from each educational approach (lectures, medical quizzes, assignments, oral presentations, observation of physicians' practice, clinical skills practice, participation in interprofessional meetings, and interactive discussions with physicians) in online clinical clerkships compared to face-to-face, 2) frequency of technical problems on online platforms, and 3) satisfaction and motivation as outcome measurements. We developed a scoring system based on a multivariate prediction model for satisfaction and motivation in a cross-sectional study of 1,671 medical students during the period May-June 2020. We externally validated this scoring with a cross-sectional study of 106 medical students during February-March 2021 and assessed its predictive performance. The final prediction models in the derivation dataset included eight variables (frequency of lectures, medical quizzes, oral presentations, observation of physicians' practice, clinical skills practice, participation in interprofessional meetings, interactive discussions with physicians, and technical problems). We applied the prediction models created using the derivation dataset to a validation dataset. The prediction performance values, based on the area under the receiver operating characteristic curve, were 0.69 for satisfaction (sensitivity, 0.50; specificity, 0.89) and 0.75 for motivation (sensitivity, 0.71; specificity, 0.85). We developed a prediction model for the effectiveness of the online clinical clerkship curriculum, based on students' satisfaction and motivation. Our model will accurately predict and improve the online clinical clerkship curriculum effectiveness.

Development of Graves' disease during drug-free remission of juvenile dermatomyositis.

We report a Japanese boy with Graves' disease (GD) which developed during drug-free remission of juvenile dermatomyositis (JDM). He had been diagnosed with JDM at the age of 6 years by typical skin rashes, muscle weakness, elevated serum transaminase levels, and typical findings of both magnetic resonance imaging and muscle biopsy. Although anti-melanoma differentiation antigen 5 autoantibody was positive, there was no complication of interstitial lung disease. He showed good response to methylprednisolone pulse therapy followed by oral prednisolone in combination with weekly methotrexate (MTX) and achieved drug-free remission after 3.5 years of treatment. Nevertheless, serum levels of soluble interleukin-2 receptor (sIL-2R) gradually elevated to 3185 U/ml despite no signs of relapse or malignancy. Hyperactivity and attention deficit was also noted. One year and 3 months after the cessation of MTX, he presented with abdominal pain, tachycardia, and apparent goitre. Laboratory tests showed elevated free triiodothyronine, undetectable thyroid stimulating hormone (TSH), and positive anti-TSH receptor antibodies. 99mTc scintigraphy showed high levels of thyroid uptake. He was diagnosed with GD and treated with 15 mg/day of thiamazole. Although transient drug eruption was observed, his thyroid functions are currently well-controlled on 5 mg/day of thiamazole. In conclusion, to our knowledge, this is the first report in English literature describing complication of GD with JDM. Unexpected elevation of sIL-2R could be a clue to the diagnosis of GD during the follow-up of JDM.

Absent X-linked inhibitor of apoptosis protein expression in T cell blasts and causal mutations including non-coding deletion.

BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease. METHODS: Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel. RESULTS: These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon. CONCLUSIONS: X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions.

Nonconditioned ADA-SCID gene therapy reveals ADA requirement in the hematopoietic system and clonal dominance of vector-marked clones.

Two patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency (ADA-SCID) received stem cell-based gene therapy (SCGT) using GCsapM-ADA retroviral vectors without preconditioning in 2003 and 2004. The first patient (Pt1) was treated at 4.7 years old, and the second patient (Pt2), who had previously received T cell gene therapy (TCGT), was treated at 13 years old. More than 10 years after SCGT, T cells showed a higher vector copy number (VCN) than other lineages. Moreover, the VCN increased with differentiation toward memory T and B cells. The distribution of vector-marked cells reflected variable levels of ADA requirements in hematopoietic subpopulations. Although neither patient developed leukemia, clonal expansion of SCGT-derived clones was observed in both patients. The use of retroviral vectors yielded clonal dominance of vector-marked clones, irrespective of the lack of leukemic changes. Vector integration sites common to all hematopoietic lineages suggested the engraftment of gene-marked progenitors in Pt1, who showed severe osteoblast (OB) insufficiency compared to Pt2, which might cause a reduction in the stem/progenitor cells in the bone marrow (BM). The impaired BM microenvironment due to metabolic abnormalities may create space for the engraftment of vector-marked cells in ADA-SCID, despite the lack of preconditioning.

Progressive multifocal leukoencephalopathy with mild clinical conditions and detection of archetype-like JC virus in cerebrospinal fluid.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system with a poor prognosis and is primarily caused by JC virus (JCV) with a mutation called prototype. We encountered a case of PML with moderate progression and analyzed the mutational patterns of JCV in the cerebrospinal fluid (CSF). A 19-year-old Japanese woman with mild neurological symptoms was diagnosed with combined immunodeficiency following pneumocystis pneumonia. Brain magnetic resonance imaging scan showed multiple brain lesions, and real-time polymerase chain reaction testing detected JCV in the CSF, leading to the diagnosis of PML. The disease course of PML was stable after administration of mefloquine and mirtazapine with immunoglobulin replacement therapy. In the JCV genome cloned from the patient CSF, DNA sequences of the gene encoding the capsid protein (VP1) and the non-coding control region exhibited small mutations. However, they were quite similar to those of the archetype JCV, which persists asymptomatically in healthy individuals. These findings provide insight into the mutational characteristics of JCV in PML with mild symptoms and progression.

Coexistence of acute poststreptococcal glomerulonephritis and acute rheumatic fever in a Japanese girl with primary Sjögren's syndrome.

Although acute poststreptococcal glomerulonephritis (APSGN) and acute rheumatic fever (ARF) are well-known complications of group A streptococcus infection, concomitant occurrence of both diseases is rare. We report an 11-year-old Japanese girl with primary Sjögren's syndrome complicated by acute renal failure about 2 weeks after the onset of pharyngitis. Although histopathological findings of the kidney were not confirmative, APSGN was suggested by the spontaneous recovery of her renal function, typical latent period with high levels of antistreptolysin O and low serum levels of C3 but not of C4. In addition, cardiac hypomotility and regurgitation of the 4 valves progressed in the convalescent phase of APSGN, which was accompanied by elevation of serum C-reactive protein and plasma brain natriuretic peptide (BNP) levels. Myocarditis was suggested by delayed gadolinium-enhancement of cardiac walls on cardiac magnetic resonance imaging. She was diagnosed with APSGN and ARF and was treated with a combination of short course prednisolone and prophylactic penicillin G. There is no relapse of renal or cardiac symptoms during 6 years follow-up. Unexpected elevation of plasma BNP in a convalescent stage of APSGN suggests the development of ARF. Underlying Sjögren's syndrome (SS) may modify the histopathological findings and make it difficult to differentiate APSGN from CTD-associated nephritis such as lupus nephritis (LN) even by renal biopsy.

A deep intronic mutation of c.1166-285 T > G in SLC46A1 is shared by four unrelated Japanese patients with hereditary folate malabsorption (HFM).

Hereditary folate malabsorption (HFM) is an autosomal recessive disease caused by mutations in SLC46A1 encoding the proton-coupled folate transporter (PCFT). HFM patients present with various clinical features including megaloblastic anemia, thrombocytopenia, combined immunodeficiency and neurodevelopmental disorders. In this study, we report the same deep intronic mutation of c.1166-285 T > G shared by four unrelated Japanese patients with HFM. This mutation was shown to generate a cryptic splice donor site for a 168-bp insertion of intron 3 sequences, leading to premature termination in the middle of this insertion. This mutation could be a founder mutation in the Japanese population, but also could be a hot-spot and could be present in undiagnosed HFM patients worldwide because of the difficulty to detect this mutation.

Persistent systemic rotavirus vaccine infection in a child with X-linked severe combined immunodeficiency.

OBJECTIVE: The main aims of the present study were to elucidate the systemic group A rotavirus (RVA) infection and to clarify the genetic changes of persistent virus in the X-linked severe combined immunodeficiency (SCID) patient. METHODS: RotaTeq vaccine (RV5) genotype-specific real-time reverse transcription polymerase chain reaction was used to monitor viral RNA load in serially collected serum and stool samples. Next-generation sequence analysis was used to determine the genotype of the virus by sequencing 11 gene segments. Polyacrylamide gel electrophoresis (PAGE) analysis was used to identify rearrangement of viral genes. The gene rearrangement was examined in NSP5 gene by using Sanger sequence. RESULTS: A 7-month-old boy demonstrated chronic diarrhea following the third administration of RV5 and failure to thrive. He was diagnosed with X-linked SCID and successfully underwent cord blood transplantation. High copy numbers of RV5 genotype G1 RNA were detected in serially collected stool and serum samples and the kinetics of viral RNA loads were correlated with the degree of clinical disease. Next-generation sequence analysis revealed genetic reassortment at least between the strains WI79-9/G1P7[5] and WI79-4/G6P1A[8] in the VP7 gene and the VP4 gene among the vaccine-derived rotavirus strains. In addition, PAGE analysis suggested genetic rearrangements in several genes, and it was confirmed in the NSP5 gene by sequence analysis. CONCLUSIONS: The kinetics of RVA RNA load in serum and stool samples was consistent with the clinical course of the patient. Among five genotypes of RV5 vaccine, G1 genotype replicated well in this patient. Reassortment and rearrangements were demonstrated in persistently infected G1 genotype of RV5.

Evaluation of systemic activity of pediatric primary Sjögren's syndrome by EULAR Sjögren's syndrome disease activity index (ESSDAI).

OBJECTIVES: The purpose of this study is to evaluate systemic disease activity of pediatric Sjögren's syndrome (SS) using European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI). METHODS: We retrospectively reviewed medical records of patients with SS who have been diagnosed according to 1999 Japanese diagnostic criteria for SS before 16 years old at KKR Sapporo Medical Center, Hokkaido University Hospital, and affiliated hospitals. We analyzed clinical and laboratory data and calculated ESSDAI at both diagnosis and peak activity. RESULTS: Twenty-five patients (2 boys and 23 girls) were enrolled. Only 4 patients had sicca symptoms at diagnosis. Mean ESSDAI scores at diagnosis and peak activity were 12.68 (2-31) and 15.08 (2-38), respectively. Only 3 patients were inactive (ESSDAI score <5) at diagnosis. Frequently involved domains at diagnosis were the biological (96%) followed by the constitutional (68%), glandular (44%), articular (44%), cutaneous domains (28%), renal (16%), and central nervous system (12%). At peak activity, biological domain (96%) was followed by the constitutional (72%), glandular (60%), articular (44%), cutaneous (28%), central nervous system (20%), and renal domains (16%). CONCLUSION: Pediatric SS is suspected from active systemic manifestations. The items of ESSDAI are useful clues to the diagnosis of pediatric SS.