A case of planned pregnancy with an interruption in infliximab administration in a 27-year-old female patient with rheumatoid-factor-positive polyarthritis juvenile idiopathic arthritis which improved after restarting infliximab and methotrexate.

We report a 27-year-old case of juvenile idiopathic arthritis (JIA) having been stopped infliximab during pregnancy. She was safely treated by infliximab therapy with premedications for preventing infusin reactions after her delivery, and then improved in the same manner as when she had been treated with infliximab therapy before pregnancy. As a result, it remains unclear whether or not we can use infliximab to control disease activities during pregnancy. In addition, it is also important to clarify whether or not premedications should be used when resuming infliximab treatment in such patients after pregnancy. These problems still remain controversial. More definitive data are needed in order to allow rheumatologists to better select the optimal TNF-alpha inhibitor therapy when treating pregnant JIA patients.

Multifocal osteomyelitis due to Bartonella henselae in a child without focal pain.

We describe a case of an 11-year-old girl who presented with osteomyelitis of the vertebrae and right femur due to Bartonella henselae. Her only symptom was prolonged fever without focal pain. Magnetic resonance imaging (MRI) and nested polymerase chain reaction (PCR) were useful for the diagnosis. Osteomyelitis due to B. henselae should be considered in cases of prolonged fever of unknown origin.

A promoter haplotype of the interleukin-18 gene is associated with juvenile idiopathic arthritis in the Japanese population.

Recently, we reported that genetic polymorphisms within the human IL18 gene were associated with disease susceptibility to adult-onset Still's disease (AOSD), which is characterized by extraordinarily high serum levels of IL-18. Because high serum IL-18 induction has also been observed in the systemic type of juvenile idiopathic arthritis (JIA), we investigated whether similar genetic skewing is present in this disease. Three haplotypes, S01, S02, and S03, composed of 13 genetic polymorphisms covering two distinct promoter regions, were determined for 33 JIA patients, including 17 with systemic JIA, 10 with polyarthritis, and 6 with oligoarthritis. Haplotypes were also analyzed for 28 AOSD patients, 164 rheumatoid arthritis (RA) patients, 102 patients with collagen diseases, and 173 healthy control subjects. The frequency of individuals carrying a diplotype configuration (a combination of two haplotypes) of S01/S01 was significantly higher in the JIA patients, including all subgroups, than in the healthy controls (P = 0.0045, Fischer exact probability test; odds ratio (OR) = 3.55, 95% confidence interval (CI) = 1.55-8.14). In patients with systemic JIA, its frequency did not differ statistically from that of normal controls. Nevertheless, it is possible that haplotype S01 is associated with the phenotype of high IL-18 production in systemic JIA because the patients carrying S01/S01 showed significantly higher serum IL-18 levels compared with patients with other diplotype configurations (P = 0.017, Mann-Whitney U test). We confirmed that the frequency of the diplotype configuration of S01/S01 was significantly higher in AOSD patients than in healthy control subjects (P = 0.011, OR = 3.45, 95% CI = 1.42-8.36). Furthermore, the RA patients were also more predisposed to have S01/S01 (P = 0.018, OR = 2.00, 95% CI = 1.14-3.50) than the healthy control subjects, whereas the patients with collagen diseases did not. In summary, the diplotype configuration of S01/S01 was associated with susceptibility to JIA as well as AOSD and RA, and linked to significantly higher IL-18 production in systemic JIA. Possession of the diplotype configuration of S01/S01 would be one of the genetic risk factors for susceptibility to arthritis in the Japanese population.

Immune response to a laminin-binding protein (Lmb) in group A streptococcal infection.

BACKGROUND: A laminin-binding protein (Lmb) similar to that of group B streptococcus is conserved in group A streptococcus (GAS) and has a role in adhesion of GAS to epithelial cells. The role of this protein is yet to be clarified in disease process and thus, it is important to know its role in binding of GAS to laminin and the immunogenic response against it in patients related with GAS infection. METHODS: A recombinant protein (rGAS-Lmb) was purified using the lmb gene from M1 GAS and tested for its role in binding of GAS with laminin. The antibody response against rGAS-Lmb in patient sera related with GAS infection was measured by ELISA. RESULTS: The rGAS-Lmb bound with laminin directly and inhibited the binding of GAS to laminin. The antibody response against rGAS-Lmb in patients with uncomplicated streptococcal infection (U. Strep) and those with rheumatic fever (RF) were significantly higher than those in the control group (P < 0.0001 and P < 0.001, respectively). No difference of anti-rGAS-Lmb antibody titer could be found between these two disease groups. CONCLUSION: The higher antibody response in patients with GAS infection implies that the protein is well expressed during the period of infection and may be related with the colonization and infection of GAS in pharyngeal mucosa.

Pharmacokinetics, efficacy, and safety of short-term (12 weeks) etanercept for methotrexate-refractory polyarticular juvenile idiopathic arthritis in Japan.

We examined and evaluated the pharmacokinetics, efficacy, and safety of etanercept in patients with methotrexate (MTX)-refractory polyarticular juvenile idiopathic arthritis (JIA) in Japan. All MTX-refractory polyarticular JIA patients 4-17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to 3 months in the open-label, prospective, and multicenter trial. A response was defined as an improvement of 30%, 50%, 70%, or more from baseline in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30% from baseline (30%, 50%, or 70% definition of improvement, respectively), and disease activity score (DAS28) by EULAR (European League Against Rheumatism) response criteria. At the end of the 12-week study, 20 of the 22 patients (90.9%) had responses with both 30% and 50% definition of improvement after etanercept treatment. To our surprise, 15 of 22 patients (68.2%) had a response with 70% definition of improvement. Moreover, in DAS28, eight patients were evaluated as having a good response and there were no patients with a poor response to etanercept. Treatment had to be stopped in one patient who developed joint contracture during the study period, but there were no significant adverse events in the other patients. In conclusion, treatment with etanercept leads to significant improvement in patients with active polyarticular JIA in Japan. Etanercept is well tolerated by pediatric patients as well as adults.

Serum levels of interleukin-18 are elevated in the subacute phase of kawasaki syndrome.

BACKGROUND: Elevations of various cytokines, including Th1 and Th2 cytokines, have been reported in the acute phase of Kawasaki syndrome (KS). As interleukin (IL)-18 plays an important role in the Th1 cell response, investigating the relevance of IL-18 in KS should be helpful in determining the pathophysiology of KS. Therefore, we examined the IL-18 values in KS. METHODS: Serum IL-18 values were measured by an enzyme-linked immunosorbent assay. Samples were obtained from 41 patients in the acute and subacute phase of KS, 35 age-matched febrile controls and 13 afebrile controls. RESULTS: No difference was observed in the values of white blood cell counts or C-reactive protein between acute-phase KS patients and febrile controls. On the contrary, acute-phase KS patients showed a significantly lower mean IL-18 value (398 +/- 206 pg/ml) than that of febrile controls (584 +/- 307 pg/ml) (p = 0.006). Subacute-phase KS patients showed a significantly elevated level of IL-18 (517 +/- 276 pg/ml) compared to acute-phase patients (p = 0.0008). The IL-18 values in the subacute-phase patients showed a significant positive correlation with the duration of fever (r = 0.427, p = 0.0055) and also with the presence of coronary artery abnormalities (r = 0.332, p = 0.0340). The incidence of elevated IL-18 values in the subacute-phase patients was significantly higher than that in the afebrile controls (p = 0.048). CONCLUSIONS: Patients with KS showed normal IL-18 values in the acute phase and elevated values in the subacute phase. IL-18 pathways were activated in the subacute phase of KS, and subacute IL-18 values might be reflected in the severity of KS.

Efficacy of mizoribine in the treatment of systemic lupus erythematosus in children.

BACKGROUND: Mizoribine (MZR) is a novel immunosuppressant developed in Japan. As MZR is reported to be less toxic than other cytotoxic drugs, it is frequently used in Japan in the treatment of adult patients with rheumatoid arthritis or lupus nephritis. The objective of this study was to evaluate the efficacy of MZR in children with SLE. Nine female children with lupus nephritis who had undergone renal biopsy before starting MZR, were involved in this study. Their mean disease duration was 4.8 years at the time MZR treatment was initiated. Patients who had received intensive medications, such as methyl-prednisolone pulse therapy, intravenous cyclophosphamide pulse therapy, and/or other immunosuppressants, within the 4 months prior to the start of the study, were excluded. METHODS: Patients treated with 3 mg/kg per day of MZR were monitored every month for up to 1 year. The efficacy of MZR was evaluated by the changes from baseline values of serum C3, serum C4, anti-dsDNA antibody titer, erythrocyte sedimentation rate (ESR), urinary protein, dosage of prednisolone (PSL), and the sum of the scores defined by these parameters. RESULTS: Favorable changes were observed in C3 and ESR after 2 months and 3 months of MZR therapy, respectively. At 3 months of MZR therapy, the sum of scores defined by the parameters for disease activity indicated that MZR was more effective in non-class IV nephritis patients (n = 5) than in class IV nephritis patients (n = 4) (P = 0.0197). All nine children involved in the study tolerated the MZR therapy well during the study. CONCLUSION: MZR was safe in lupus children, but its efficacy was limited in patients with non-class IV nephritis. Further study is necessary, in which higher dosages and/or earlier use of MZR is provided to a larger number of children.

Antiagalactosyl IgG antibodies in juvenile idiopathic arthritis, juvenile onset Sjögren's syndrome, and healthy children.

OBJECTIVE: To determine the normal range of antiagalactosyl IgG antibodies in healthy children, and to investigate the utility of determination of antiagalactosyl IgG antibodies in patients with juvenile idiopathic arthritis (JIA) and juvenile onset Sjögren's syndrome (SS). METHODS: Serum concentrations of antiagalactosyl IgG antibodies were measured in 225 healthy children, 68 patients with JIA (systemic arthritis in 21, polyarthritis in 29, oligoarthritis in 18), and 15 patients with juvenile onset SS, using a lectin-enzyme immunoassay employing prepared human agalactosyl IgG as antigen. A comparison was made between the prevalence and utility of antiagalactosyl IgG antibodies in patients and those of conventional rheumatoid factors (RF) determined by laser nephelometry. RESULTS: The average serum concentration of antiagalactosyl IgG antibodies for healthy controls was 2.41 +/- 0.93 arbitrary units (AU)/ml, and the cutoff value of the normal range was set at 4.3 AU/ml (mean + 2 SD). As a result, antiagalactosyl IgG antibodies were positive in 25 (37%) of 68 patients with JIA, and 14 (93%) of 15 patients with juvenile onset SS, in whom values were much higher than the frequencies of RF positivity. The serum concentrations of antiagalactosyl IgG antibodies in patients were closely correlated with those of RF. Thirteen patients with JIA and 6 patients with juvenile onset SS were positive for antiagalactosyl IgG antibodies despite being negative for RF. With regard to prognosis during followup periods of at least 5 years, JIA patients positive for antiagalactosyl IgG antibodies, even if negative for RF, were resistant to treatment. However, positivity for antiagalactosyl IgG antibodies had no relation to joint destruction. CONCLUSION: Our data suggest that antiagalactosyl IgG antibodies, compared with RF, show higher sensitivity to detect immunological disorders in JIA and juvenile onset SS.

Health-related quality of life in juvenile-onset systemic lupus erythematosus and its relationship to disease activity and damage.

OBJECTIVE: To assess the health-related quality of life (HRQL) of patients with juvenile-onset systemic lupus erythematosus (JSLE) and its relationship with disease activity and accumulated damage. METHODS: In this cross-sectional study, HRQL was assessed using the Child Health Questionnaire (CHQ), disease activity using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and accumulated damage using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). RESULTS: A total of 297 patients were included. The mean +/- SD physical and psychosocial summary scores of the CHQ were 40.2 +/- 15.0 and 44.8 +/- 10.7, respectively. The most impaired CHQ subscales were global health, general health perceptions, and parent impact-emotional. The SLEDAI score was significantly correlated with both the physical summary score (r = -0.29, P < 0.0001) and psychosocial summary score (r = -0.25, P < 0.0001), whereas the SDI score was significantly correlated only with the physical summary score (r = -0.23, P = 0.0001). CONCLUSION: We found that patients with JSLE have significant impairment of their HRQL, particularly in the physical domain. HRQL may be affected by both disease activity and accumulated damage, particularly in the renal, central nervous, and musculoskeletal systems.

Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage-activation syndrome.

The aberrant induction of proinflammatory cytokines is considered to be crucial in the pathogenesis of systemic juvenile idiopathic arthritis and adult-onset Still's disease. Interleukin-18 (IL-18) in particular has been reported to be a candidate for the key cytokine in both diseases; however, the origin of IL-18 is unclear. To clarify the origin, we investigated specimens from various organs obtained during autopsy of a child with systemic JIA and macrophage activation syndrome, using immunohistochemical staining. Our results showed a high number of cells expressing IL-18 in the bone marrow but not in the other organs. This finding suggests that bone marrow is the origin of increased serum IL-18 and raises the possibility that other proinflammatory cytokines are also induced by IL-18 in bone marrow in this disease. Bone marrow may be an essential organ in the pathogenesis of systemic JIA.

The induction of intercellular adhesion molecule-1 on human umbilical vein endothelial cells by a heat-stable component of Porphyromonas gingivalis.

Live Porphyromonas gingivalis enhanced the expression of intercellular adhesion molecule-1 (ICAM-1) on the surface of human umbilical vein endothelial cells (HUVECs) in a bacterial dose-dependent manner. Inactivation of P. gingivalis by ultraviolet (UV), heat (56 degrees C, 30 min), or sonication did not alter its stimulatory activity. ICAM-1 expression began to increase at 4 h after stimulation, reached a maximum at 12 h, and remained at the maximum for at least the next 8 h. This time course was similar to that of expression by Escherichia coli LPS. Furthermore, the effect of UV-inactivated P. gingivalis was not inhibited by boiling or polymyxin B treatment. In addition, the effect of P. gingivalis strain W83 on ICAM-1 expression was stronger than that of strain ATCC 33277. Our results suggested that some unidentified, heat-stable proteins, polysaccharides, or lipids may be the stimulatory factor(s), although the participation of LPS could not be completely ruled out. The ability of P. gingivalis to stimulate ICAM-1 expression on endothelial cells may play an important role in the pathogenesis of periodontal disease.

Assessment of damage in juvenile-onset systemic lupus erythematosus: a multicenter cohort study.

OBJECTIVE: To investigate the prevalence of cumulative organ damage in patients with juvenile-onset systemic lupus erythematosus (SLE) and its association with demographic and clinical variables, medication use, and quality of life. METHODS: The occurrence of organ system damage, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), was determined for 387 patients consecutively enrolled in pediatric rheumatology centers from Europe, the US, Mexico, and Japan. Risk factors for damage included demographic variables; clinical manifestations at diagnosis; previous corticosteroid, immunosuppressive, and antimalarial therapies; disease activity; and quality of life. RESULTS: Overall, 195 (50.5%) patients had damage within a mean of 5.7 years after disease onset. Renal (21.8%) and neuropsychiatric (15.8%) system involvement were observed most frequently, followed by musculoskeletal (11.7%), ocular (10.9%) and skin (9.6%) system involvement, with a mean SDI score of 1.1. In multivariate models, the occurrence of neuropsychiatric manifestations at diagnosis, a longer disease duration, and a greater number of intravenous cyclophosphamide pulses showed the strongest association with the presence of damage. CONCLUSION: We found evidence of cumulative organ damage, as measured by the SDI, in half of the patients with juvenile-onset SLE. Damage was significantly more likely in patients who had experienced neuropsychiatric manifestations at diagnosis, had a longer disease duration, and had received more intravenous pulses of cyclophosphamide.

Diagnostic significance of increased serum hyaluronic acid in juvenile rheumatoid arthritis.

BACKGROUND: We have previously reported that serum levels of hyaluronic acid (HA) objectively reflect the severity of arthritis in juvenile rheumatoid arthritis (JRA). However, clear diagnostic standards do not exist for JRA; it is difficult to evaluate arthritis in children, particularly in small children and the diagnostic criteria for JRA requires an exclusion of several diseases. Therefore, if a specific test finding associated with JRA could be established, it would enable general pediatricians to make an objective diagnosis. METHODS: We measured the serum HA levels in children with joint symptoms as a chief complaint. The total number of subjects were 197 children; of these 89 had JRA, 39 had rheumatic diseases other than JRA, and 69 had non-rheumatic diseases (including systemic 31, polyarticular 40 and pauci-articular in 17), rheumatic diseases other than JRA in 39 subjects, and non-rheumatic diseases in 69 subjects. Sandwich enzyme-linked immunosorbent assay measured HA by using the HA binding protein. RESULTS: The serum level of HA was significantly higher in systemic and polyarticular JRA patients than in patients with pauci-articular JRA, with rheumatic diseases other than JRA, and non-rheumatic patients. With a cut-off value of 100 ng/mL, a diagnostic value of HA in all JRA patients was 48.3% sensitivity and 98.1% specificity. CONCLUSIONS: In children presenting with joint symptoms, serum HA measurement is useful for diagnosing systemic and polyarticular JRA.

Human lactiferous mammary gland cells produce vascular endothelial growth factor (VEGF) and express the VEGF receptors, Flt-1 AND KDR/Flk-1.

Human milk contains a variety of growth factors. Recently, it was reported that vascular endothelial growth factor (VEGF) was one of them. We investigated milk VEGF isoforms, their functions, and VEGF receptors on mammary gland epithelial cells (MEC). The VEGF concentration in human milk was 74.3+/-34.9ng/ml on the first day after delivery, and rapidly decreased in a couple of days to 6.2+/-2.3ng/ml on the fifth day, and matured milk maintained about 4ng/ml. In an MTT assay, human milk accelerated HUVEC proliferation and MV303, a neutralizing antibody of VEGF, blocked 17.3 % of the effect. Immunoprecipitation and Western blotting showed that VEGF121 and VEGF165 were contained in human colostrums, and RT-PCR of human MEC confirmed that VEGF121, VEGF165 and VEGF189 were present. By immunostaining of human breast tissues, RT-PCR of MEC from human colostrum and measurement of the VEGF concentrations of conditioned media of cultured human MEC, it was confirmed that VEGF was produced by MEC. MEC was also expressed VEGF receptors, flt-1 and Flk-1/KDR. These results speculate us that the existence of autocrine or paracrine system within breast tissue via VEGF receptors on MEC and have a role in lactation.