Successful treatment with tofacitinib for anti-melanoma differentiation-associated gene 5 antibody-positive juvenile dermatomyositis: case reports and review of the literature.

Although the clinical efficacy of tofacitinib has been reported in adult patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive (Ab+) dermatomyositis, data on its use in refractory juvenile dermatomyositis (JDM) are scarce. We describe two female Japanese patients with anti-MDA5 Ab + JDM and rapidly progressive interstitial lung disease who achieved remission by adding tofacitinib to existing immunosuppressive drugs and present a literature review. While both patients received various immunosuppressive or anti-inflammatory treatments for induction therapy, remission could not be achieved. Subsequently, tofacitinib was administered to reduce the Krebs von den Lungen-6 level 5 months after diagnosis in one patient; the other patient received tofacitinib 4 months after diagnosis to reduce ferritin levels and skin manifestations. Subsequently, both patients achieved remission, and prednisolone was withdrawn. Tofacitinib reduced the interferon signature associated with dermatomyositis/JDM disease progression and exerted a therapeutic effect on dermatomyositis/JDM. We found six published cases from five articles of tofacitinib for refractory anti-MDA5 Ab + JDM. Except for one case of herpes simplex meningitis, the other cases, including ours, had improved disease activity without severe adverse events, and steroids and immunosuppressive medicines could be tapered. Tofacitinib could be considered an available therapy for refractory anti-MDA5 Ab + JDM.

A retrospective study of SARS-CoV-2 antibodies in children with allergies.

BACKGROUND: The dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children are continually changing. We conducted a survey of pediatric allergy patients attending our department to determine the prevalence of antibodies against SARS-CoV-2 in children. METHODS: A retrospective study was performed among children aged <11 years, referred to a pediatric allergy department between February 2020 and January 2022 with a chief complaint of allergy. The data of children with blood examination findings were retrospectively studied. Qualitative testing for anti-SARS-CoV-2 IgG and IgM antibodies was performed using a SARS-CoV-2 rapid antibody test. Participants were retested 1 year later to evaluate changes in antibody levels. RESULTS: In total, 310 patients with a median age of 26 months (interquartile range: 11.6-58.4 months) and male/female ratio of 1.31 were included. A total of 32 patients tested positive for anti-SARS-CoV-2 IgG or IgM antibodies. No differences were observed in the severity of allergic disease. The prevalence of antibodies was higher among children enrolled in preschool or school (odds ratio: 13.19, 95% confidence interval; 2.30-249.7). A total of 66.7% of patients underwent follow-up testing. The antibody positivity rate increased between the first and second testing, but this was not related to the number of medical visits or the severity of allergic disease. CONCLUSION: Antibody prevalence in children was low but increased during the study period. The majority of children who tested positive for SARS-CoV-2 antibodies did not have a history of coronavirus disease 2019, suggesting that most infections were subclinical.

Evidence of off-label inhalation therapy on pediatric asthma practice in Japan.

BACKGROUND: In Japan, many asthma inhalers do not have formal approval for use in the pediatric population because of the lack of domestic data. In real-world settings, however, numerous off-label medications are prescribed. Currently, the nature of off-label prescriptions of asthma inhalers on pediatric patients in Japan remains unclear. METHODS: Using public open-source national medical claims data, we investigated the real-world descriptive epidemiology of off-label prescriptions for asthma inhalers for pediatric patients. We obtained the number of off-label prescriptions of formulations for patients aged 0-14 years from anonymously summarized prescription data for a 7-year period starting from April 2014. The actual prescription numbers and their chronology over time were then analyzed. RESULTS: In 2019, 143,439 asthma inhalers were used off label in children and adolescents. Overall, 96.1% were inhaled corticosteroids (ICSs) or long-acting beta stimulants (LABAs), and 3.9% were high-dose ICS. Of ICSs and LABAs, 18.8% were off-label prescriptions. The total number of off-label ICS/LABA prescriptions and their percentage relative to the overall formulations gradually decreased but a notable disparity was observed among inhaler types. CONCLUSIONS: There was a surprisingly large number of off-label prescriptions of asthma inhalers in the pediatric population in Japan. The proper use of ICSs/LABAs and expansion of insurance coverage should be advocated to reduce off-label use.

Low billing rates for pediatric sedation fee on magnetic resonance imaging.

BACKGROUND: The 2018 revision of social insurance in Japan allows additional fees to be calculated for pediatric magnetic resonance imaging (MRI) that must be performed under sedation. The number and trend of actual claims since this revision was established is unknown. The aim of this study to investigate the use of the additional fees and any regional differences in the use. METHODS: To analyze the claims of additional fees for pediatric sedated MRI after the fiscal year (FY) 2018, the actual claims in inpatient and outpatient practice was analyzed using publicly-available data from the Ministry of Health, Labour and Welfare (MHLW). We analyzed the calculation rate for all MRI scans. Annual changes in the actual number and calculation rate were analyzed. The ratio of the number of additional fees to the overall number of pediatric radiological procedures was used to examine the geographic disparity. RESULTS: The number of calculations from FY 2018 to FY 2020 was available. In FY 2020, only 1347 additional fees were calculated, corresponding to 0.35% of the total number of MRI scans. The number of fees showed a decreasing trend. Most cases were in the 0-4 year age group; however, there were a few cases in the 10-14 year age group without such a decrease. The relative number of calculations by prefecture showed an up to 14-fold disparity. CONCLUSIONS: The requirements for sedation for pediatric MRI are strict, but they are not fully utilized. Measures such as relaxing the requirements for the fee are needed to make MRI-related sedation safer.

Evaluation of the use of non-invasive hemoglobin measurement in early childhood.

BACKGROUND: Iron deficiency anemia in children affects psychomotor development. We compared the accuracy and trend of a non-invasive transcutaneous spectrophotometric estimation of arterial hemoglobin (Hb) concentration (SpHb) by rainbow pulse CO-oximetry technology to the invasive blood Hb concentration measured by an automated clinical analyzer (Hb-Lab). METHODS: We measured the SpHb and Hb-Lab in 109 patients aged 1-5 years. Regression analysis was used to evaluate differences between the two methods. The bias, accuracy, precision, and limits of agreement of SpHb compared with Hb-Lab were calculated using the Bland-Altman method. RESULTS: Of the 109 enrolled subjects, 102 pairs of the SpHb and Hb-Lab datasets were collected. The average value of measured Hb was 12.9 ± 1.03 (standard deviation [SD]) g/dL for Hb-Lab. A significant correlation was observed between SpHb and Hb-Lab measurements (SpHb = 7.002 + 0.4722 Hb-Lab, correlation coefficient r = 0.548, 95% confidence interval = 0.329-0.615). Bland-Altman analysis showed good visual agreement, with a mean bias between SpHb and Hb-Lab of 0.188 ± 0.919 g/dL (mean ± SD). CONCLUSIONS: We concluded that non-invasive Hb measurement is useful for Hb estimation in children and provides new insights as a screening tool for anemia. IMPACT: Our results indicated a good correlation between non-invasive transcutaneous spectrophotometric estimation of arterial hemoglobin (Hb) concentration using a finger probe sensor by rainbow pulse CO-oximetry technology and invasive blood Hb concentration. Although previous studies have indicated that in patients with a worse condition, the bias between the two methods was large, this study, which was conducted on children with stable disease, showed a relatively small bias. Further studies using this non-invasive device might help to understand the current status of anemia in Japan and promote iron intake and nutritional management in children.

Gender disparities in the pediatric allergy-related guidelines in Japan.

BACKGROUND: Inclusion of female authors has been noted as potentially beneficial in the development of medical guidelines. Japanese professional committees representing allergic subspecialties develop practical guidelines with recommendations to caregivers, but these committees may be influenced by their gender composition. The objective of our study was to examine the influence of gender in developing pediatric allergic disease guidelines in Japan from 1999 to 2020. METHODS: We examined the gender parities among the guideline committee members in allergic rhinitis, atopic dermatitis, bronchial asthma, and food allergy guidelines in Japan. We examined the gender composition of the committees, annual trends, and differences in guideline content. RESULTS: The median proportion of women members among the 22 guidelines committees was 6.6% (range: 0%-27.3%). The analysis of the quadrant period did not show a significant increase in the proportion of female members. The food allergy group had a significantly higher proportion of female members than other guidelines (P < 0.01), but the proportion decreased from 25% to 14.3% during the observation period. For the pediatric asthma guidelines, the proportion of female committee members decreased from 5.3% in the 2000 version to 0% in the most recent revision in 2017. CONCLUSIONS: The proportion of women on the committees that develop pediatric guidelines continues to be low and has not improved over the past 20 years.

Novel pediatric granulomatosis with polyangiitis with a marked bloody pericardial effusion and bloody stool: a case report.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is a syndrome of refractory vasculitis involving the upper respiratory tract, lungs, kidneys, and systemic small and medium-sized arteries that affects all age groups. No pediatric case with a bloody pericardial effusion resulting in cardiac tamponade and co-existing hematochezia has been reported. CASE PRESENTATION: A 14-year-old boy was referred for evaluation of prolonged fever, chest pain, and intermittent hematochezia. Diagnostic imaging showed a prominent pericardial effusion. Immediately after admission, his systolic blood pressure decreased. Emergent pericardiocentesis resulted in aspiration of a massive amount of bloody pericardial fluid. This was diagnosed as cardiac tamponade because his blood pressure recovered immediately after the drainage. The patient had an elevated serine proteinase 3-anti-neutrophil cytoplasmic antibody (PR3-ANCA) level on serological examination. Head MRI showed thickening of nasal and sinusoidal mucosa and a cystic mass in the left sphenoid sinus. After ruling out malignancy based on the cytology of the effusion, chest MRI, and gallium scintigraphy, total colonoscopy showed multiple irregular-shaped aphthae from the right transverse colon to the cecum on the contralateral side of the mesenteric attachments. Biopsy specimens of aphthous lesions confirmed necrotizing granulomatous inflammation. A diagnosis of GPA was made based on these findings, and oral prednisolone (PSL) and azathioprine were started. The hematochezia disappeared rapidly, and no recurrence of pericardial effusion was seen after PSL tapering was completed. The PR3-ANCA level decreased into the normal range immediately after the initial therapy. CONCLUSIONS: Pericarditis is a common cardiac complication of GPA, but there have been no reports of resultant cardiac tamponade. This is the first case of pediatric GPA with cardiac and gastrointestinal complications preceding the common symptoms such as respiratory or renal symptoms. A case of pediatric GPA with hematochezia is also extremely rare. In conclusion, serial measurement of ANCA levels is important in patients with persistent fever and bloody stool, such as in inflammatory bowel disease, to make the diagnosis of a vasculitic syndrome.

Epithelial Claudin Proteins and Their Role in Gastrointestinal Diseases.

Our bodies are protected from the external environment by mucosal barriers that are lined by epithelial cells. The epithelium plays a critical role as a highly dynamic, selective semipermeable barrier that separates luminal contents and pathogens from the rest of the body and controlling the absorption of nutrients, fluid and solutes. A series of protein complexes including the adherens junction, desmosomes, and tight junctions function as the principal barrier in paracellular diffusion and regulators of intracellular solute, protein, and lipid transport. Tight junctions are composed of a series of proteins called occludins, junctional adhesion molecules, and claudins that reside primarily as the most apical intercellular junction. Here we will review one of these protein families, claudins, and their relevance to gastrointestinal and liver diseases.

Eosinophilic esophagitis: pathophysiology and its clinical implications.

Classically, eosinophilic esophagitis is an antigen-mediated chronic disease distinct from gastroesophageal reflux disease. Eosinophilic esophagitis is an emerging clinical problem that is growing in recognition. It is characterized clinically by feeding dysfunction, dysphagia, and reflux-like symptoms. Histologically, eosinophilic esophagitis is identifiable by a dense epithelial eosinophilic infiltrate. Experimental modeling and clinical studies over the last decade have greatly improved mechanistic insights and led to improvements in clinical understanding and the assessment of therapeutic options for patients and their clinicians who manage this disease. Here, we review the clinicopathologic diagnostic criteria and our understanding of eosinophilic esophagitis as an allergic disease with genetic and immunological components. We present studies defining the importance of the epithelial barrier and the concept of barrier dysfunction as an initiating or perpetuating factor for this disease. We discuss the relationship between the symptoms of dysphagia and feeding dysfunction, our current knowledge of the underlying pathophysiologic mechanisms, and advances in clinical assessment of esophageal distensibility and narrowing in eosinophilic esophagitis patients. Finally, therapeutic implications relating to the advances that have led to our current understanding of the pathophysiology of eosinophilic esophagitis are explored.

Eosinophilic gastroenteritis in a patient with Bruton's tyrosine kinase deficiency.

Eosinophilic gastrointestinal diseases (EGID) are relatively rare diseases characterized by eosinophilic infiltration of the gastrointestinal tract resulting in various gastrointestinal symptoms. EGID are often caused by allergic reactions or systemic eosinophilic disorders, but their comorbidity with Bruton's tyrosine kinase (BTK) deficiency has not been previously documented. Here, we report a case of eosinophilic gastroenteritis (EG) in a patient with BTK deficiency. Despite adequate replacement immunoglobulin (Ig) therapy, trough serum IgG was not maintained. To identify the underlying cause of the low trough level and chronic diarrhea, the intestine was investigated on endoscopy. We also screened for the variable number of tandem repeat polymorphism in FCGRT. Genetic analysis could not explain the low trough IgG, but endoscopy indicated eosinophilic enterocolitis. EG may be an important differential diagnosis when primary immunodeficiency patients have chronic diarrhea or continued low serum IgG.

Outcome of infants presenting rectal bleeding: a retrospective study in a single institution.

BACKGROUND: Although rectal bleeding in infancy (RBI) is not a rare phenomenon, the clinical course of RBI is not fully understood. METHODS: To investigate the outcome and pathogenesis of RBI, especially when concomitant with food-protein-induced proctocolitis (FPIP) and neonatal transient eosinophilic colitis (NTEC), 22 neonates with rectal bleeding with FPIP and NTEC from January 2008 to June 2012 were enrolled and their clinical course and mechanisms of inflammation were examined. RESULTS: Thirteen infants showed rectal bleeding after feeding and were diagnosed with FPIP, and nine infants showed rectal bleeding before feeding and were diagnosed with NTEC. Elevated peripheral white blood cell (12,685 ± 3754/µl and 30,978 ± 16,166/µl) and eosinophil (1084 ± 816/µl and 4456 ± 3341/µl) were confirmed in FPIP and NTEC, respectively. Colonoscopy revealed nodular lymphoid hyperplasia, a pale mucosal surface and oozing with diffuse infiltration of neutrophils, lymphocytes, and eosinophils in both groups. Reverse transcription polymerase chain reaction analysis revealed enhanced expression of the interleukin-6, CCL11, and CXCL13 genes, where CXCL13 expression was more prominent in FPIP. Mucosal infiltration by CD3- and immunoglobulin-A- but not immunoglobulin-E-positive cells was confirmed. Among them, only one infant with FPIP developed milk allergy, whereas none with NTEC had developed milk allergy at the age of 1 year. CONCLUSIONS: FPIP in infancy and NTEC are similar diseases and interleukin-6, CCL11, and CXCL13 may play a major role in the pathogenesis of rectal bleeding. Although the involvement of allergic reaction is possible, milk allergy was not a common outcome after 1 year of follow up.

Critical Roles for PU.1, GATA1, and GATA2 in the expression of human FcεRI on mast cells: PU.1 and GATA1 transactivate FCER1A, and GATA2 transactivates FCER1A and MS4A2.

The high-affinity IgE receptor, FcεRI, which is composed of α-, ß-, and γ-chains, plays an important role in IgE-mediated allergic responses. In the current study, involvement of the transcription factors, PU.1, GATA1, and GATA2, in the expression of FcεRI on human mast cells was investigated. Transfection of small interfering RNAs (siRNAs) against PU.1, GATA1, and GATA2 into the human mast cell line, LAD2, caused significant downregulation of cell surface expression of FcεRI. Quantification of the mRNA levels revealed that PU.1, GATA1, and GATA2 siRNAs suppressed the α transcript, whereas the amount of ß mRNA was reduced in only GATA2 siRNA transfectants. In contrast, γ mRNA levels were not affected by any of the knockdowns. Chromatin immunoprecipitation assay showed that significant amounts of PU.1, GATA1, and GATA2 bind to the promoter region of FCER1A (encoding FcεRIα) and that GATA2 binds to the promoter of MS4A2 (encoding FcεRIß). Luciferase assay and EMSA showed that GATA2 transactivates the MS4A2 promoter via direct binding. These knockdowns of transcription factors also suppressed the IgE-mediated degranulation activity of LAD2. Similarly, all three knockdowns suppressed FcεRI expression in primary mast cells, especially PU.1 siRNA and GATA2 siRNA, which target FcεRIα and FcεRIß, respectively. From these results, we conclude that PU.1 and GATA1 are involved in FcεRIα transcription through recruitment to its promoter, whereas GATA2 positively regulates FcεRIß transcription. Suppression of these transcription factors leads to downregulation of FcεRI expression and IgE-mediated degranulation activity. Our findings will contribute to the development of new therapeutic approaches for FcεRI-mediated allergic diseases.

GATA2 is a critical transactivator for the human IL1RL1/ST2 promoter in mast cells/basophils: opposing roles for GATA2 and GATA1 in human IL1RL1/ST2 gene expression.

The IL1RL1/ST2 gene encodes a receptor for IL-33. Signaling from IL1RL1/ST2 induced by IL-33 binding was recently identified as a modulator of the Th2 response. The target cells for IL-33 are restricted in some hematopoietic lineages, including mast cells, basophils, eosinophils, Th2 cells, natural killer cells, and dendritic cells. To clarify the molecular mechanisms of cell type-specific IL1RL1/ST2 expression in mast cells and basophils, transcriptional regulation of the human IL1RL1/ST2 promoter was investigated using the mast cell line LAD2 and the basophilic cell line KU812. Reporter assays suggested that two GATA motifs just upstream of the transcription start site in the ST2 promoter are critical for transcriptional activity. These two GATA motifs possess the capacity to bind GATA1 and GATA2 in EMSA. ChIP assay showed that GATA2, but not GATA1, bound to the ST2 promoter in LAD2 cells and that histone H3 at the ST2 promoter was acetylated in LAD2 cells, whereas binding of GATA1 and GATA2 to the ST2 promoter was detected in KU812 cells. Knockdown of GATA2 mRNA by siRNA reduced ST2 mRNA levels in KU812 and LAD2 cells and ST2 protein levels in LAD2 cells; in contrast, GATA1 siRNA transfection up-regulated ST2 mRNA levels in KU812 cells. The ST2 promoter was transactivated by GATA2 and repressed by GATA1 in coexpression analysis. When these siRNAs were introduced into human peripheral blood basophils, GATA2 siRNA reduced ST2 mRNA, whereas GATA1 siRNA up-regulated ST2 mRNA. These results indicate that GATA2 and GATA1 positively and negatively control human ST2 gene transcription, respectively.

Involvement of PU.1 in mast cell/basophil-specific function of the human IL1RL1/ST2 promoter.

BACKGROUND: The human IL1RL1/ST2 gene encodes IL33 receptor. Recently, IL33 has been recognized as a key molecule for the development of Th2 response. Although mast cells and basophils are major targets of IL33 and play important roles in IL33-mediated Th2-type immune responses, the expression mechanism of ST2 in mast cells and basophils is largely unknown. In the present study, we analyzed regulation mechanism of the human ST2 promoter in the human mast cell line LAD2 and basophilic cell line KU812. METHODS: Promoter activity was determined by reporter assay with plasmids carrying the wild-type ST2 promoter obtained from human genomic DNA and its mutant. The transcription factor binding to the identified cis-element was identified by an electrophoretic mobility shift assay (EMSA). The effect of candidate transcription factor on ST2 expression was confirmed by analyzing ST2 mRNA level in siRNA-introduced cells. RESULTS: Reporter assay demonstrated that a cis-element of typical Ets-family binding sequence was critical for promoter activity in LAD2 and KU812. An Ets-family transcription factor PU.1 bound to this element in an EMSA. When PU.1 expression was suppressed by siRNA, ST2 mRNA level was significantly reduced in KU812. CONCLUSIONS: These observations indicated that PU.1 positively regulates the ST2 promoter as a transcription factor that directly transactivates the ST2 promoter via Ets-family-related cis-element in mast cells and basophils.

Prophylaxis for ribavirin-related anemia using eicosapentaenoic acid in chronic hepatitis C patients.

BACKGROUND: Ribavirin-related anemia is a serious side-effect of the pegylated interferon and ribavirin therapy used for hepatitis C, and may be cause for a reduction in ribavirin dose or even cessation of treatment. The aim of this study was to evaluate the prophylactic effects of oral eicosapentaenoic acid (EPA) supplementation on ribavirin-induced hemolytic anemia in pediatric and young adult patients. METHODS: Twelve chronic hepatitis C patients ranging in age from 3 to 21 years (mean, 13.9 ± 5.1 years) who received pegylated interferon α-2b and ribavirin combination therapy were randomized to either the control group (n = 6) or EPA group (n = 6). Blood samples were collected before, and at 4, 8, and 16 weeks after treatment to measure clinical laboratory parameters. RESULTS: The reduction in hemoglobin levels of the EPA group was significantly ameliorated at 8 and 16 weeks when compared to the control group (P < 0.05). There was no significant difference in plasma ribavirin concentrations between the two groups during the treatment. However, one patient in the control group had a reduction in ribavirin dose. CONCLUSION: EPA supplementation prevented ribavirin-induced hemolytic anemia during combination therapy with pegylated interferon α-2b and ribavirin in pediatric and young adult patients.

ω-3 fatty acids attenuate mucosal inflammation in premature rat pups.

BACKGROUND: Necrotizing enterocolitis (NEC) is a devastating intestinal disease of premature infants. Although ω-3 fatty acids are known to have antiinflammatory effects, their effect against NEC remains unclear. METHODS: Mother rats fed a soybean-based, docosahexaenoic acid (DHA)- or eicosapentaenoic acid (EPA)-enriched diet from days 7 to 20 of gestation were examined. On day 20, the rat pups were delivered by abdominal incision, their intestines were removed, and messenger RNA was extracted. A rat NEC model was used to confirm the effects of ω-3 fatty acids on the inflamed intestine (n = 20-28). The expression of inflammatory molecules was analyzed by real-time polymerase chain reaction (n = 11-14). RESULTS: The concentrations of DHA and EPA in the intestine were significantly increased in the DHA and EPA groups (P < .01). The expression of the antiinflammatory prostaglandin E2 receptor EP3 was increased in the DHA (P < .05) and EPA groups (P < .01). In the NEC model, the reduced incidence of colitis was confirmed in the DHA and EPA groups. The expression of peroxisome proliferator-activated receptor γ was increased (P < .05), and the inhibitor of nuclear factor-κB α/ß decreased in both the DHA (P < .01) and EPA groups (P < .05). CONCLUSION: Our findings indicate that ω-3 fatty acids are beneficial for protecting the premature intestine from inflammation by regulating eicosanoid- and nuclear factor-κB-related metabolite expression.