Clinical analysis of 50 children with juvenile dermatomyositis.

OBJECTIVE: We performed a retrospective review of medical records to assess the clinical characteristics of 50 Japanese children with juvenile dermatomyositis (JDM). METHODS: Fourteen boys and 36 girls who visited Yokohama City University Hospital between 1983 and 2008 were enrolled. Gender, age at disease onset and diagnosis, presenting clinical features, laboratory data at onset, complications, treatment, and outcome were reviewed. RESULTS: Mean age at disease onset was 6.9 years. Clinical manifestations at the first visit were muscle pain and/or weakness (90 %), malar rash (90 %), Gottron's papules (86 %), and heliotrope rash (80.0 %). Elevated serum levels of creatine kinase were found in 57.0 % of patients and aldolase in 95 %. T2-weighted magnetic resonance (MR) images with fat suppression demonstrated positive findings in 89.5 % of patients. Initial treatment was prednisolone (PSL) orally or pulsed methylprednisolone (mPSL) i.v. Pulsed mPSL therapy showed efficacy superior to PSL [flare in 8 of 19 (42 %) vs. 18 of 25 (72 %)]. Children refractory to initial treatment were given additional pulsed mPSL and/or cyclophosphamide (IVCY; n = 19) i.v.. Four patients with interstitial pneumonia responded well to IVCY. CONCLUSIONS: Our findings support the notion that JDM might be considered as both a systemic inflammatory and noninflammatory vasculopathy best treated by IVCY, as shown in previous literature.

Interleukin-6 inhibits early differentiation of ATDC5 chondrogenic progenitor cells.

Interleukin (IL)-6 is a causative agent of systemic juvenile idiopathic arthritis (sJIA), a chronic inflammatory disease complicated with severe growth impairment. Recent trials of anti-IL-6 receptor monoclonal antibody, tocilizumab, indicated that tocilizumab blocks IL-6/IL-6 receptor-mediated inflammation, and induces catch-up growth in children with sJIA. This study evaluates the effects of IL-6 on chondrogenesis by ATDC5 cells, a clonal murine chondrogenic cell line that provides an excellent model for studying endochondral ossification at growth plate. ATDC5 cells were examined for the expression of IL-6 receptor and gp130 by fluorescence-activated cell sorting analysis. Recombinant murine IL-6 was added to ATDC5 cultures to observe cell differentiation, using a quantitative RT-PCR for the chondrogenic differentiation markers type II collagen, aggrecan, and type X collagen. To block IL-6, the anti-mouse IL-6 receptor monoclonal antibody MR16-1 was added. As a result, the cells expressed IL-6 receptor and gp130. The expression of chondrogenic differentiation marker gene was reduced by IL-6, but this was abrogated by MR16-1. We conclude that IL-6 inhibits early chondrogenesis of ATDC5 cells suggesting that IL-6 may affect committed stem cells at a cellular level during chondrogenic differentiation of growth plate chondrocytes, and that IL-6 may be a cellular-level factor in growth impairment in sJIA.

Survey of psychological support for bereaved families in Japan.

BACKGROUND: The aim of the present study was to investigate the current conditions of psychological support for the families of children who died suddenly of disease or accident. METHODS: A questionnaire survey was conducted in 2415 medical facilities across the country that have at least 100 beds and are staffed by pediatricians. Of these, 981 facilities (40.6%) responded to the questionnaire. RESULTS: There were 653 infant deaths soon after admission in 254 facilities (25.9%). For pronouncement of death, approximately 43% of the pediatricians made no attempt to provide psychological support for the family members affected. In contrast, some 53% of the pediatricians did offer psychological support. In self-assessments, approximately 53% of the pediatricians stated that the support was 'not very satisfactory' or 'unsatisfactory', while only 28% considered that they were 'fully satisfied with the help being given'. Reasons for this response were appropriate specialized knowledge, and enough time for such tasks. The proportion of institutions that employed staff specializing in psychological support for families was only 7%. Approximately 83% of institutions without such specialist staff, however, acknowledged the need for them. The number of medical facilities that gave information regarding family support associations to bereaved families was very low (11%). CONCLUSION: Psychological support for families of children who died shortly after entering hospital cannot be characterized as satisfactory. The provision of grief care by family associations is desirable, and the cooperation of the institutions and family associations is important.

Prevalence of hypothyroidism in patients with hyponatremia: A retrospective cross-sectional study.

OBJECTIVE: Hypothyroidism has been suggested to be an uncommon cause of hyponatremia. However, little is known about the prevalence of hypothyroidism in patients with different levels of hyponatremia. The objective of this study was to investigate the prevalence of hypothyroidism among patients with hyponatremia of varying severity while taking into consideration potential confounders associated with thyroid function. METHODS: All data on thyrotropin (TSH), free thyroxine (T4), and serum sodium (Na) levels were retrospectively collected from medical records at two Japanese tertiary hospitals. The main outcome measure was overt hypothyroidism, defined as TSH > 10.0 µIU/mL and free T4 < 1.01 ng/dL. RESULTS: Of 71,817 patients, 964 patients (1.3%) had overt hypothyroidism. The prevalence of overt hypothyroidism in each category of hyponatremia (Na ≥136, 130-135, and ≤129 mEq/L) was 1.2% (787/65,051), 2.4% (124/5,254) and 3.5% (53/1,512), respectively. A significant increase in prevalence was observed as the severity of hyponatremia increased (P < 0.001 for trend). Multivariate logistic regression with adjustment for age, sex, kidney function, and serum albumin level showed that the odds ratios for overt hypothyroidism increased with increasing severity of hyponatremia when compared with Na ≥ 136 mEq/L (130-135 mEq/L: 1.43, 95% confidence interval [CI], 1.15 to 1.78, P = 0.001; ≤129 mEq/L: 1.87, 95% CI, 1.32 to 2.63, P < 0.001; P< 0.001 for trend). CONCLUSION: The prevalence of overt hypothyroidism was significantly higher as the severity of hyponatremia progressed, even after adjusting for potential confounders. Hypothyroidism should be differentiated in patients with hyponatremia.

[Three cases of childhood-onset male systemic lupus erythematosus (SLE) successfully treated with a combination of pulse methylprednisolone and pulse cyclophosphamide].

We reported three cases of childhood-onset male systemic lupus erythematosus (SLE), all of whom successfully treated with a combination of pulse methylprednisolone (mPSL) and pulse cyclophosphamide (IVCY). All of them had severe lupus nephritis and were complicated with other collagen diseases. Two cases were complicated with Sjögren syndrome (SS) and the other was complicated with both SS and anti-phospholipid syndrome (APS). After a combination of pulse mPSL and IVCY for a year, followed by oral predonisolone (PSL) and azathioprine (AZA), following up renal biopsy were performed in all cases, which showed histological improvement in glomerulonephritis. One case had flares a year later, but no flares were observed either in clinical symptoms or in laboratory examinations in the others. Their autoantibodies except anti-nuclear antibody (ANA) were eliminated. We suggest a combination of pulse mPSL and IVCY is effective for the patients who are suffering with severe lupus nephritis complicated with the other collagen diseases.

[A case of autoimmune hepatitis needed to be differentiated from EBV hepatitis, in that the histology of liver biopsy specimen was useful for diagnosis].

A 10-year-old girl with autoimmune hepatitis (AIH) was reported. She was admitted to our hospital because of cholestasis and elevation of liver enzymes for 2 months. Laboratory examination revealed that EBV-DNA copy number in the PBMNC (peripheral mononuclear cells) was 1.2 x 10(3) copies/microg of DNA, hypergammaglobulinemia, and positive antinuclear antibody, positive anti-smooth muscle antibody. The histology of her liver biopsy specimen revealed interface hepatitis, dense mononuclear cell infiltrates, mild fibrosis, and negative for EBV in situ hybridization assay indicating AIH and not EBV-associated hepatitis. She was treated firstly with methylprednisolone pulses, then will prednisolone p.o.+azathioprine p.o.. Intravenous cyclophosphamide pulse therapy was introduced because of her abnormal immune pathology. All abnormal laboratory parameters improved to normal levels within 2 months, and EBV-DNA copy number in the PBMNC became negative after 4 months. The histology of liver biopsy specimen was useful for the diagnosis of AIH in such a difficult case needed to be differentiated from EBV hepatitis.

The role of heme oxygenase-1 in systemic-onset juvenile idiopathic arthritis.

We have determined the serum levels of heme oxygenase-1 (HO-1) in 56 patients with systemic-onset juvenile idiopathic arthritis (s-JIA) and compared these with serum HO-1 levels in healthy controls and patients with other pediatric rheumatic diseases. Serum HO-1 levels were measured by the sandwich enzyme-linked immunosorbent assay. The mean serum HO-1 level in s-JIA patients during the active phase was 123.6 +/- 13.83 ng/ml, which was significantly higher than that in patients with polyarticular juvenile idiopathic arthritis (p-JIA), Kawasaki disease, systemic lupus erythematosus or mixed connective tissue disease (P < 0.0005). The serum levels of HO-1, cytokines and cytokine receptors in patients with s-JIA were also assessed at both the active and inactive phases. The serum HO-1 level in patients with s-JIA in the active phase was found to be significantly greater than that in patients with the disease in the inactive phase (P < 0.0001). An assessment of the relationships between serum HO-1 levels and other laboratory parameters or cytokines in patients with s-JIA did not reveal any strong correlations. These results suggest that the serum level of HO-1 may be a useful marker for the differential diagnosis of s-JIA. Further study will be necessary to elucidate the mechanism of HO-1 production and to clarify the role of HO-1 in the disease process.

Improvement of reduced serum cartilage oligomeric matrix protein levels in systemic juvenile idiopathic arthritis patients treated with the anti-interleukin-6 receptor monoclonal antibody tocilizumab.

In this study, we determined serum cartilage oligomeric matrix protein (COMP) levels in systemic juvenile idiopathic arthritis (sJIA) patients during both the active and the remission phases to investigate how the growth cartilage turnover changed under tocilizumab treatment. Specimens were collected from 201 healthy children under 16 years of age with no growth impairment, and paired sera were collected from 11 sJIA patients treated with tocilizumab. Disease activity was assessed from white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and ferritin, and the COMP concentration was determined by sandwich enzyme-linked immunosorbent assay. Serum COMP concentrations were found independent of age, and the mean value in healthy children was 17.74+/-5.6 U/L. The mean serum COMP in sJIA patients during the active phase was 10.75+/-3.9 U/L, lower than that of healthy children. The mean serum COMP in the remission phase (14.89+/-3.9 U/L) was significantly higher than that in the active period (P<0.05). These results suggested that in sJIA patients, a reduced serum COMP concentration is a useful marker of active disease and growth impairment, and that the growth cartilage turnover suppressed during the active phase is improved in the remission phase under tocilizumab treatment.

[Clinical features and laboratory findings in children with both anti-dsDNA and anti-U1-RNP antibody].

Mixed connective tissue disease (MCTD) includes clinical features of systemic lupus erythematosus (SLE), dermatomyositis/polymyositis (DM/PM), and systemic sclerosis (SSc) occurring in conjunction with a high anti-U1-RNP antibody titer. Childhood MCTD rarely manifests the symptoms and signs of DM/PM and SSc, and mostly does those of SLE. Thus, the diagnosis of childhood MCTD is inevitably based on the two major findings, Raynaud's phenomenon and a high titer of anti-U1-RNP antibody. However, in clinical setting there exist patients who have both anti-dsDNA antibody, a SLE disease-marker, and anti-U1-RNP antibody, a MCTD disease-marker, and thus it is hard to differentiate MCTD patients from SLE. Eighty children were enrolled in this study, and divided into 3 groups ; group A, those who are positive for anti-dsDNA antibody/negative for anti-U1-RNP antibody (48 cases, 60.0%), group B : those who are positive for both anti-dsDNA and anti-U1-RNP antibody (22 cases, 27.5%), group C; those who are negative for anti-dsDNA antibody/positive for anti-U1-RNP antibody (10 cases, 12.5%), and each of the clinical characteristics among these 3 groups was mutually examined. The results indicated that the frequency of hypocomplementemia in group B was close to group A rather than group C, and the frequencies of both hyper-gamma-globulinemia and Raynaud's phenomenon were very close to group C, but not to group A. On the contrary, the findings which seemed to be specific to MCTD, high titers of speckled type anti-nuclear antibody and rheumatoid factor, located at the middle between group A and group C. Thus, children in group B essentially carried characteristic symptoms and signs of both SLE and MCTD, and it will be difficult to differentiate these two diseases at the onset of the disease. Taken together, children with high titers of both anti-dsDNA antibody and anti-U1-RNP antibody as well as clinical symptoms and signs such as hyper-gamma-globulinemia, Raynaud's phenomenon, membranous nephritis, positive speckled type anti-nuclear antibody and rheumatoid factor should be followed and treated as children with MCTD along with SLE.

HLA-DRB1*15021 is the predominant allele in Japanese patients with juvenile dermatomyositis.

OBJECTIVE: To investigate HLA molecules and genes in Japanese patients with juvenile dermatomyositis (JDM). METHODS: Twelve patients (8 girls and 4 boys) with ages of onset between 3 and 15 years were included. HLA class I antigen phenotypes were serologically typed by the Terasaki-NIH standard method. DNA was extracted from peripheral blood leukocytes using the phenol-chloroform extraction procedure, and stored at -70 degrees C until use. Genomic DNA for HLA-DRB1, HLA-DQA1, and HLA-DQB1 alleles in JDM patients and controls was determined by the direct sequence method. RESULTS: HLA-A24 and B52 were each detected in 7 cases (OR = 0.86, 5.02, p = 0.930, 0.006, respectively). HLA-DRB1*15021 was observed in 7 patients. This was significantly more frequent than occurred in the controls (OR = 5.72, p = 0.002). Seven patients out of 12 (58%) had the combination HLA-B52, DRB1*15021, DQA1*0103, and DQB1*0601. CONCLUSION: Our results suggest that the susceptibility gene for JDM either is HLA-DRB1*15021 or is present near the HLA-DRB1 locus. This differs from previous reports that describe the association with HLA-DQA1*0501 in Caucasian patients with JDM. The combination HLA-B52, DRB1*15021, DQA1*0103, and DQB1*0601 may contribute to the pathogenesis of JDM in Japanese patients.

[Effects of therapies on childhood systemic lupus erythematosus].

We analyzed the effects of three therapies on 30 patients with childhood systemic lupus erythematosus, and classified the patients into three groups. The therapies were as follows; Group A (8 cases), methylpredni-solone (mPSL) pulses plus oral prednisolone (PSL) alone, Group B (10 cases), mPSL pulses plus oral PSL and mizoribine (MZB) or azathioprine (AZP), Group C (12 cases), mPSL pulses and intravenous cyclophosphamide (IVCY) pulse therapy plus oral PSL and MZB or AZP. Three years after treatment, we compared the laboratory data (C3, C4, CH50 and anti-DNA antibody), the SLEDAI scores and numbers of relapses in these three groups. We demonstrated that group C had the best data, and this data indicated that the median C3, C4 and CH50 increased and that the median anti-DNA antibody and the mean of the numbers of relapses decreased. In conclusion, the combination of immunosuppressants and IVCY appeared to offer great benefits in childhood systemic lupus erythematosus.