Clinical experience with infliximab among Filipino patients with rheumatic diseases

Aim: To describe the clinical experience with infliximab among Filipino patients with rheumatic diseases, specifically disease indications, dose regimens, clinical response, and adverse events. Methods: We reviewed the data on Filipino patients who were given infliximab by rheumatologists for a rheumatic disease indication. The case report form included demographic profile, underlying rheumatic disease, comorbidities, concurrent medications, dose and frequency of infliximab, physicians’ assessment of clinical response, and adverse events. The frequency of doses, intervals between doses, and discontinuation status were recorded. Results: Included were 64 patients (35 females), with a mean age of 44 years. Most (41%) had rheumatoid arthritis, followed by psoriasis/psoriatic arthritis (31.2%) and ankylosing spondylitis (17.2%). Average disease duration from diagnosis to initiation of infliximab therapy was 7.6 years ± 6.7 SD. Among 35 patients, the interval between maintenance infusions ranged from 6 to 13.6 weeks, with a mean of 8.27 weeks. Clinical response was good to excellent in more than 80% of patients. Discontinuation rate was 10.9% and 28.1% at 3 and 12 months, respectively. Infusion‐related adverse events were mild and transient, and 14 (21.8%) cases of infection resolved with appropriate therapy. Infliximab was temporarily withheld in five (7.8%) patients with active tuberculosis. Summary: These findings substantiate the superior clinical efficacy of infliximab and manageable adverse events among Filipinos with rheumatic diseases. It also demonstrates dose regimens in clinical practice in a third world setting with limited resources.     

ER-27319, an acridone-related compound, inhibits release of antigen-induced allergic mediators from mast cells by selective inhibition of Fcɛ receptor I-mediated activation of Syk

Engagement of the mast cell high-affinity receptor for immunoglobulin E (IgE), FcRI, induces tyrosine phosphorylation of Syk, a non-receptor tyrosine kinase, that has been demonstrated as critical for degranulation. Herein we describe a synthetic compound, ER-27319, as a potent and selective inhibitor of antigen or anti-IgE-mediated degranulation of rodent and human mast cells. ER-27319 affected neither Lyn kinase activity nor the antigen-induced phosphorylation of the FcRI but did effectively inhibit the tyrosine phosphorylation of Syk and thus its activity. As a consequence, tyrosine phosphorylation of phospholipase C-γ1, generation of inositol phosphates, release of arachidonic acid, and secretion of histamine and tumor necrosis factor α were also inhibited. ER-27319 did not inhibit the anti-CD3-induced tyrosine phosphorylation of phospholipase C-γ1 in Jurkat T cells, demonstrating a specificity for Syk-induced signals. In contrast the tyrosine phosphorylation and activation of Syk, induced by in vitro incubation with the phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) of FcRI γ subunit or by antigen activation of RBL-2H3 cells, was specifically inhibited by ER-27319. However, when ER-27319 was added to immunoprecipitated Syk, derived from activated cells, no effect was seen on Syk activity. ER-27319 did not inhibit the tyrosine phosphorylation of Syk induced by activation in the presence of Igβ ITAM or the anti-IgM-induced phosphorylation of Syk in human peripheral B cells. Therefore, ER-27319 selectively interferes with the FcRI γ phospho-ITAM activation of Syk in vitro and in intact cells. These results confirm the importance of Syk in FcRI-mediated responses in mast cells and demonstrate the mast cell selectivity and therapeutic potential of ER-27319 in the treatment of allergic disease.     

Growth velocity and interleukin 6 concentrations in juvenile idiopathic arthritis

OBJECTIVE: .To evaluate associations of growth velocity with inflammatory markers and cumulative dose of glucocorticoid in a cohort of patients with juvenile idiopathic arthritis (JIA) followed during 1 year. METHODS: Seventy-nine patients were evaluated. Disease activity was evaluated by a pediatric rheumatologist. Anthropometric data were classified according to the World Health Organization standards. Tanner growth velocity curves were used; values below the Z-score < or = -2 were considered low growth velocity. Serum concentrations of interleukin 6 (IL-6) were measured by ELISA, and values > 1 pg/ml were considered elevated. RESULTS: The prevalence of low growth velocity was 25.3%, and it was associated with active disease on followup visit, elevated IL-6, erythrocyte sedimentation rate and C-reactive protein, and higher cumulative glucocorticoid doses. In the multiple linear regression with growth velocity as the dependent variable, only elevated IL-6 level was independently and negatively associated with growth velocity. CONCLUSION: Low growth velocity is highly prevalent in children with JIA. Elevated IL-6 levels seem to have an important negative influence on growth in these children, while total glucocorticoid exposure appears to be a secondary factor.     

Associations Between Complex PCI and Prasugrel or Clopidogrel Use in Patients With Acute Coronary Syndrome Who Undergo PCI: From the PROMETHEUS Study

Background

Potent P2Y₁₂ inhibitors might offer enhanced benefit against thrombotic events in complex percutaneous coronary intervention (PCI). We examined prasugrel use and outcomes according to PCI complexity, as well as analyzing treatment effects according to thienopyridine type.

Age-associated changes in functional response to CXCR3 and CXCR5 chemokine receptors in human osteoblasts

The expression and functional activity of CXC chemokine receptors were evaluated in human osteoblasts (OB) obtained post-trauma from old donors compared to very young donors. It was found that CXCR1 and CXCR4 were only expressed by old but not young donors' cells. In contrast, CXCR3 and CXCR5 were expressed by both young and old donors. We functionally evaluated CXCR3/CXCL10 and CXCR5/CXCL13 receptor/ligand pairs by analysing cell proliferation and the release of N-acetyl-β-D-glucosaminidase (NAG), an enzyme that degrades glycosaminoglycans and hyaluronic acid. CXCL10 and CXCL13 induced a dose-dependent increase of cell proliferation in OB from young donors while cell proliferation of OB in old donors was not affected. By contrast, CXCL10 and CXCL13 induced a significantly higher NAG release in OB from old donors compared to young ones. These data demonstrate a significant age-dependent difference in the response of OB to CXCL10 and CXCL13 stimulation. These chemokines induce an inverse response of OB from old and young donors, which suggests a role of ageing in the modulation of cellular response of bone cells. This revised version was published online in July 2006 with corrections to the Cover Date.     

Early life stress enhances the vulnerability to chronic psychosocial stress and experimental colitis in adult mice

Early life stress enhances the vulnerability to both mood and chronic inflammatory disorders, suggesting a link between these stress-related disorders. To study this, we exposed male C57BL/6 mice to early life stress [maternal separation (MS), 3 h/d, d 1-14] and to adult chronic psychosocial stress [chronic subordinate colony housing (CSC)] and measured changes in neuroendocrine parameters and in the severity of a chemically induced colitis. In both unseparated and MS mice, 19 d of CSC exposure resulted in a transient decrease in body weight gain, increased anxiety-related behavior, and decreased vasopressin mRNA expression in the hypothalamic paraventricular nucleus compared with respective nonstressed mice. However, only CSC-stressed MS mice showed elevated CRH mRNA expression in the paraventricular nucleus and reduced plasma corticosterone. Subsequent treatment with dextran sulfate sodium (1%, 7 d) resulted in a more severe colonic inflammation in MS compared with unseparated mice. This was indicated by an increased histological damage score and increased TNF secretion (nonstressed MS mice), more severe body weight loss and inflammatory reduction in colon length (CSC-stressed MS mice), and increased interferon-gamma secretion (nonstressed and CSC-stressed MS mice). In conclusion, early life stress and subsequent exposure to chronic psychosocial stress in adulthood induced neuroendocrine abnormalities, which likely contributed to enhanced vulnerability to chemically induced colitis. The combined use of MS and CSC represents a potential animal model providing novel (patho)physiological insights into the complex interactions between neuroendocrine and inflammatory actions upon chronic stress exposure. These findings may further help to reveal mechanisms of hypocortisolemic disorders.     

Toll-like receptor-4 deficiency attenuates doxorubicin-induced cardiomyopathy in mice

BACKGROUND: Cardiac inflammation and generation of oxidative stress are known to contribute to doxorubicin (Dox)-induced cardiomyopathy. Toll-like receptors (TLRs) are a part of the innate immune system and are involved in cardiac stress reactions. Since TLR4 might play a relevant role in cardiac inflammatory signalling, we investigated whether or not TLR4 is involved in Dox-induced cardiotoxicity. METHODS AND RESULTS: Five days after a single injection of Dox (20 mg/kg; i.p.), left ventricular pressure-volume loops were measured in wild-type and TLR4-deficient mice (TLR4-/-) Dox-treated and control mice. Analyses of possible pathophysiological mechanisms were performed in left ventricular tissue and isolated myocytes, respectively. Dox injection resulted in an impairment of left ventricular function and neurohumoral activation, indexed by increased ET-1 expression. This was further associated with an increase in cardiac oxidative stress, inflammation and apoptosis, as indicated by an up-regulation of cardiac lipid peroxidation, TNF-alpha expression and enhanced content of TUNEL-positive cells. In contrast, TLR4-/- Dox mice showed improved left ventricular function with reduced oxidative and inflammatory stress response including reduced cardiac apoptosis. These results were found to be associated with an increase of GATA-4 expression. CONCLUSIONS: TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in Dox-induced cardiomyopathy.     

Estrogens,but not androgens,regulate expression and functional activity of oxytocin receptor in rabbit epididymis

Previous binding and contractility studies indicate that oxytocin (OT) receptors are present in rabbit epididymis. To investigate the effect of changing endocrine milieu on OT responsiveness, we induced hypogonadism (hypo) in rabbits with a single administration of a long-acting GnRH analog, triptorelin, and we replaced hypogonadal rabbits with different sex steroids. After 2 months from triptorelin administration, testosterone (T) plasma levels were decreased and OT responsiveness abolished. Administration of T to hypo rabbits restored T plasma levels but not OT sensitivity. Because Western blot analysis indicated that both estrogen receptors and aromatase are expressed in the epididymis, we treated hypo rabbits with estradiol valerate (E2v). E2v not only completely restored OT responsiveness but also even amplified it. Accordingly, Northern and Western blot analysis indicated that both OT receptor gene and protein were strongly induced by E2v but not by T. Surprisingly, also the class I estrogen receptor antagonist, tamoxifen restored OT sensitivity in hypo rabbits. To verify whether endogenous estradiol is involved in the regulation of OT receptor responsiveness, we treated intact rabbits with an aromatase inhibitor, letrozole. Blocking aromatase activity almost completely abolished OT sensitivity. These findings suggest a new function of estrogens in the male: regulation of OT responsiveness in epididymis.