OBJECTIVES: To study the expression levels of CD4⁺NKG2D⁺ T cells and NKG2D soluble ligands, the soluble MHC class I chain-related molecules A and B (sMICA/sMICB) in the active stage and stable stage of juvenile idiopathic arthritis (JIA) and their role in the disease activity of JIA. METHODS: Nineteen children with systemic JIA and 20 children with articular JIA who were diagnosed in Children's Hospital of Chongqing Medical University from November 2019 to December 2021 were enrolled in this prospective study. Six healthy children were enrolled as the control group. After peripheral blood samples were collected, ELISA was used to measure the levels of sMICA and sMICB, and flow cytometry was used to measure the percentage of CD4⁺NKG2D⁺ T cells. Systemic Juvenile Arthritis Disease Activity Score-27 (sJADAS-27)/Juvenile Arthritis Disease Activity Score-27 (JADAS-27) was used to evaluate the disease activity in children with JIA. The Pearson correlation analysis and the receiver operating characteristic (ROC) curve were used to assess the role of CD4⁺NKG2D⁺ T cells, sMICA and sMICB in the disease activity of JIA. RESULTS: The active systemic JIA and active articular JIA groups had a significant increase in the percentage of CD4⁺NKG2D⁺ T cells compared with the control group and their corresponding inactive JIA group (P<0.05). The JIA groups had significantly higher levels of sMICA and sMICB than the control group (P<0.05), and the active articular JIA group had a significantly higher level of sMICB than the stable articular JIA group (P<0.05). In the children with JIA, the percentage of CD4⁺NKG2D⁺ T cells and the levels of sMICA and sMICB were positively correlated with sJADAS-27/JADAS-27 disease activity scores (P<0.05). The ROC curve analysis showed that sMICB had an area under the curve of 0.755 in evaluating the disease activity of JIA, with a specificity of 0.90 and a sensitivity of 0.64. CONCLUSIONS The percentage of CD4⁺NKG2D⁺ T cells and the levels of sMICA and sMICB increase in children with JIA compared with healthy children and are positively correlated with the disease activity of JIA, suggesting that CD4⁺NKG2D⁺ T cells and NKG2D ligands can be used as potential biomarkers for evaluating the disease activity of JIA.
Child ; Humans ; Arthritis, Juvenile/pathology* ; Ligands ; NK Cell Lectin-Like Receptor Subfamily K ; Prospective Studies ; T-Lymphocytes/pathology*

OBJECTIVES: To study the expression of V-domain Ig suppressor of T cell activation (VISTA) in peripheral blood of children with juvenile idiopathic arthritis (JIA) and its role in the pathogenesis of JIA. METHODS: In this prospective study, peripheral blood was collected from 47 children with different subtypes of JIA and 10 healthy children. Flow cytometry was used to measure the expression levels of VISTA, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on CD14⁺ mononuclear cells, CD4⁺ T lymphocytes, and CD8⁺ T lymphocytes. RESULTS: The children with JIA had a significantly lower expression level of VISTA than the healthy children (P<0.05). There was a significant difference in the expression of VISTA between the children with different subtypes of JIA, with the lowest expression level in those with systemic JIA (P<0.05). There was also a significant difference in the expression of VISTA between different immune cells, with a significantly higher expression level on the surface of monocytes (P<0.05). Correlation analysis showed that VISTA was negatively correlated with the expression of IFN-γ and TNF-α on CD4⁺ T cells (r=-0.436 and -0.382 respectively, P<0.05), CD8⁺ T cells (r=-0.348 and -0.487 respectively, P<0.05), and CD14⁺ mononuclear cells (r=-0.582 and -0.603 respectively, P<0.05). CONCLUSIONS The insufficient expression of VISTA may be associated with the pathogenesis of JIA, and enhancing the immunomodulatory effect of VISTA might be one option for the treatment of JIA in the future.
Child ; Humans ; Arthritis, Juvenile/pathology* ; Tumor Necrosis Factor-alpha/metabolism* ; CD8-Positive T-Lymphocytes ; Prospective Studies ; Interferon-gamma/metabolism*

OBJECTIVETo study the clinical manifestations of rheumatic disorders with macrophage activation syndrome (MAS) in children.

METHODSThe authors characterized MAS by carrying out a retrospective study on patients who were identified during the past 12 years in Tianjin Children's Hospital.

RESULTSSix cases (4 females, 2 males) were studied. Four had typical systemic onset juvenile idiopathic arthritis (SOJIA), two had systemic lupus erythematosus (SLE) with lupus nephritis. Clinical manifestations at diagnosis, which occurred in the lower activity state of these primary diseases, included high spiking fever (in 5 cases) or high fever (in 1), hepatosplenomegaly (in 6), lymphadenopathy (in 6), profound decrease of all 3 blood cell lines (in 6), significant injury of liver (in 6), diseminated intravascular coagulation (DIC)-like picture (in 2), and central nervous system dysfunction (in 3). Hypofibrinogenemia, elevated liver enzymes and hypertriglyceridemia were found consistently. The phagocytic histiocytes with plasmacytosis were found in 3 bone marrow smears (not done in others). MAS was presumed to have been precipitated by viral infections in 3 patients, two had evidences for herpes simplex virus infection and one for hepatitis A virus infection. The treatment regimen was tailored to each patient, as the clinical course was variable.

CONCLUSIONSMAS may not only be most frequently seen in children with SOJIA, but also in those with other rheumatic diseases, and may be a syndrome that is more common than previously thought. Infection may be main trigger factor for MAS. The immunoapheresis combined with immunochemotherapy may be optimal for severe injury of the liver in patients with MAS.

Adolescent ; Arthritis, Juvenile ; complications ; pathology ; Child ; Child, Preschool ; Female ; Humans ; Lupus Erythematosus, Systemic ; complications ; pathology ; Macrophage Activation Syndrome ; etiology ; pathology ; Male ; Retrospective Studies

OBJECTIVEMacrophage activation syndrome (MAS) is a rare but life-threatening complication in children with rheumatic diseases, particularly systemic-onset juvenile idiopathic arthritis (SOJIA). Because of the potential fatality of this condition, prompt recognition and immediate therapeutic intervention are important. This study reviewed the data of MAS in 13 cases with SOJIA.

METHODSRetrospective review was performed on the precipitating events, clinical manifestations, laboratory data, treatment, and outcome of macrophage activation syndrome in 13 children with SOJIA seen from 1996 to 2005.

RESULTSOver the past 10 years the unit has had 90 new patients with SOJIA. Thirteen of those patients (14.4%) developed MAS during the course of their primary SOJIA, of whom ten were male. All patients were noted to have active SOJIA prior to developing MAS; 3 patients had medications, which were considered as trigger factors; 8 had infections prior to MAS, in two of them the infections were possible triggers. All the patients had high grade fever; 12 cases (92.3%) had hepatomegaly; 10 patients (76.9%) had coagulopathy, and eight patients (61.5%) had central nervous system dysfunction. The counts of platelet, white blood cells and the mean erythrocyte sedimentation rate fell dramatically in all patients; hyperferritinemia was identified in 8 patients, in 5 of whom serum ferritin (SF) was >or= 10,000 microg/L; in 8 (72.7%) of 11 cases fibrinogen was or= 2.5 mmol/L in 9 (69.2%) of 13 cases.

CONCLUSIONMAS is a rare and potentially fatal complication of children with SOJIA. Primary disease activity, medications and infections preceding MAS were all important triggers. The strongest clinical discriminators were hepatomegaly, hemorrhages and central nervous system dysfunction. The strongest laboratory tests were decreased counts of platelet and white blood cells, decreased ESR and fibrinogen, dramatically increased SF and TG. It calls for the immediate treatments, particularly with cyclosporin A, which are often effective.

Arthritis, Juvenile ; complications ; drug therapy ; pathology ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Macrophage Activation Syndrome ; drug therapy ; etiology ; pathology ; Male ; Retrospective Studies

OBJECTIVETo review and analyze the clinical features, treatment, and outcome of macrophage activation syndrome (MAS) in children with systemic onset juvennil rheumatoid arthritis (SOJRA).

METHODRetrospective review and analysis were performed on cases with MAS from a prospectively collected database of children with SOJRA from the year of 2003 to 2006 in the Hospital.

RESULTSTwenty four patients (21 boys, 3 girls) were diagnosed as having MAS with SOJRA. Mean age of the patients with MAS at diagnosis was 7 years, and the duration prior to diagnosis of MAS was 12 months. No trigger factors were found except in one case whose MAS was triggered by use of methotrexate and in another by parvovirus B19 infection. High grade fever, new onset hepatosplenomegaly and lymphadenopathy, pancytopenia, liver dysfunction were common clinical features in all the 24 cases (100%). Bleeding from skin, mucous membrane and gastrointestinal tract were noted in 9 cases (38%). Twelve (50%) cases had CNS dysfunction (high intracranial pressure, seizure and coma). Six cases (25%) developed ARDS. One patient suffered from renal damage. The laboratory test revealed elevated live enzymes and ferritin, decreased value of ESR, albumin, complete blood count and fibrinogen in all the 24 cases. Bone marrow examination supported the diagnosis of definite hemophagocytosis in the 24 cases. Lymph node biopsy was done for one case and histopathological examination showed that the node was full of activated macrophage. As to treatment, five cases only received high dose steroids (three of them died), 14 cases were treated with high dose steroids plus cyclosporine (one died), two were treated with steroids plus cyclosporine and etoposide (none died). The causes of deaths were ARDS and CNS involvement. In three of the cases who died, treatment was given up by their parents.

CONCLUSIONSMAS is a rare and potentially fatal complication of SOJRA. Most of our patients were male. Bone marrow studies support the diagnosis. CNS involvement and ARDS were poor prognostic signs. Early diagnosis and aggressive therapy are essential.

Adolescent ; Arthritis, Juvenile ; complications ; drug therapy ; pathology ; Child ; Child, Preschool ; Female ; Humans ; Infant ; Macrophage Activation Syndrome ; drug therapy ; etiology ; pathology ; Male ; Retrospective Studies

Adolescent ; Arthritis, Juvenile ; blood ; immunology ; pathology ; Child ; Child, Preschool ; Female ; Humans ; Immunoglobulin A ; blood ; Immunoglobulin G ; blood ; Immunoglobulin M ; blood ; Interferon-gamma ; blood ; Interleukin-4 ; blood ; Male

Arthritis, Juvenile ; diagnosis ; pathology ; Biomarkers, Tumor ; blood ; Biopsy ; Bone Neoplasms ; diagnosis ; pathology ; Child, Preschool ; Diagnostic Errors ; Female ; Hip Joint ; diagnostic imaging ; pathology ; Humans ; Ilium ; diagnostic imaging ; pathology ; Magnetic Resonance Imaging ; Radiography ; Sarcoma, Ewing ; diagnosis ; pathology

OBJECTIVETo examine the expression of FLICE-inhibitory protein (FLIP) in juvenile idiopathic arthritis (JIA) and analyze its correlation with synovial inflammation.

METHODSThe expression of FLIP was assessed in 11 JIA and 3 normal synovial tissue samples by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. The cell types expressing FLIP were further characterized, and the correlation of FLIP expression with the degree of synovial inflammation, as well as the activity of caspase 8 was then analyzed.

RESULTSRT-PCR revealed the expression of FLIP mRNA in all 11 JIA samples, but not in 3 normal synovial tissues. In JIA, FLIP expression could be found in both the lining and sublining layers, mainly in the macrophage-like cells. Moreover, the expression of FLIP in JIA synovial tissues was positively correlated with the degree of synovial inflammation (r = 0.563, P < 0.05).

CONCLUSIONThe expression of antiapoptotic FLIP in JIA synovial tissue and its correlation to accumulation of inflammatory cells in synovial tissue suggests that FLIP potentially extends the lifespan of synovial cells and thus contributes to the progression of joint destruction.

Adolescent ; Arthritis, Juvenile ; metabolism ; pathology ; CASP8 and FADD-Like Apoptosis Regulating Protein ; genetics ; metabolism ; Caspase 8 ; metabolism ; Child ; Female ; Humans ; Inflammation ; metabolism ; pathology ; Male ; Protein Isoforms ; genetics ; metabolism ; Synovial Membrane ; cytology ; metabolism ; pathology

Macrophage activation syndrome (MAS) is a rare and potentially fatal complication of rheumatic disorders in children. We describe a 13-month-old boy in whom MAS developed as a complication of systemic juvenile rheumatoid arthritis (S-JRA). He suffered from fever and generalized rash followed by multiple joints swelling for four months before admission. Physical examination revealed cervical lymphadenopathy and hepatosplenomegaly. Laboratory findings were: abnormal liver enzymes, increased triglyceride and ferritin levels, coagulopathies resembling disseminated intravascular coagulation, anemia and thrombocytopenia. Hyperplasia of hemophagocytic macrophages was remarkable in his bone marrow. Methylprednisolone and cyclosporin therapy resulted in clinical and laboratory improvements. This is the third case of MAS associated with S-JRA in Koreans, and the first one, in which hemophagocytic macrophages were proven in bone marrow.
Alanine Transaminase/metabolism ; Alkaline Phosphatase/metabolism ; Antigens, CD/blood ; Antigens, Differentiation, Myelomonocytic/blood ; Arthritis, Juvenile Rheumatoid/blood/*complications/pathology ; Aspartate Aminotransferases/metabolism ; Blood Cell Count ; Hepatomegaly/*etiology/pathology ; Humans ; Infant ; Liver/enzymology/pathology ; *Macrophage Activation ; Male ; Partial Thromboplastin Time ; Prothrombin Time ; Splenomegaly/*etiology/pathology ; Syndrome ; gamma-Glutamyltransferase/metabolism

Pseudomembranous colitis is mainly caused by antibiotics and Clostridium difficile infection. But conditions such as gastrointestinal surgery, antacid medication, anti-neoplastic agent or immunosuppressive agent which influences the normal flora of colon can induce colitis without the administration of any antibiotics. We experienced a 13 year-old male who was taking low-dose methotrexate for juvenile rheumatoid arthritis complained diarrhea and abdominal pain for 3 weeks. Sigmoidoscopic findings revealed diffuse patch yellowish pseudomembranes on the rectum. Histologic finding was compatible to pseudomembranous colitis. His symptom was improved after stop taking methotrexate and the administration of metronidazole. If a patient treated with immunosuppressive agents or antineoplastic agents complains diarrhea, fever or abdominal pain and has not improved with conservative care, pseudomembranous colitis should be taken into account as a differential diagnosis and prompt treatment is required for better prognosis.
Abdominal Pain/etiology ; Adolescent ; Anti-Infective Agents/therapeutic use ; Antirheumatic Agents/*adverse effects/therapeutic use ; Arthritis, Juvenile Rheumatoid/*drug therapy ; Diagnosis, Differential ; Diarrhea/etiology ; Enterocolitis, Pseudomembranous/*diagnosis/drug therapy/pathology ; Humans ; Male ; Methotrexate/*adverse effects/therapeutic use ; Metronidazole/therapeutic use ; Sigmoidoscopy ; Tomography, X-Ray Computed