Kanako Kitahara

Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis

Purpose of reviewThe calcineurin inhibitors cyclosporine and tacrolimus are important treatments for patients with active rheumatoid arthritis, especially in cases of resistance or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Here, we discuss the mechanism, efficacy and safety of cyclosporine and tacrolimus in the treatment of rheumatoid arthritis. Recent findingsRecent clinical trials of cyclosporine have shown the advantages of its combination with methotrexate, glucocorticoids and leflunomide in the treatment of active rheumatoid arthritis. In Japan, tacrolimus monotherapy was found to be quite effective and combination therapy with methotrexate had positive results in an American study. The inhibitory effects of both drugs not only on T lymphocytes, but also on human osteoclast formation, have been demonstrated in basic studies. SummaryCyclosporine and tacrolimus are clinically available disease-modifying antirheumatic drugs. Numerous clinical studies have shown the usefulness of these calcineurin inhibitors in monotherapy and also when combined with methotrexate. Although these drugs have similar effects, there are some differences in adverse reactions.

Literature survey on epidemiology and pathology of gangliocytic paraganglioma

BackgroundAlthough gangliocytic paraganglioma (GP) has generally been regarded as a neuroendocrine tumor, its origin remains unclear. We therefore aimed to investigate the details of this disease by carefully analyzing and extracting common features of the disease as presented in selected publications.MethodsWe searched for English and Japanese cases of GP using the PubMed and IgakuChuoZasshi databases on August 2010. We then extracted and sampled raw data from the selected publications and performed appropriate statistical analyses. Additionally, we evaluated the expression of hormone receptors based on our previously reported case.Results192 patients with GP were retrieved from the databases. Patient ages ranged from 15 y to 84 y (mean: 52.3 y). The gender ratio was 114:76 (male to female, 2 not reported). Maximum diameter of the tumors ranged from 5.5 mm to 100 mm (mean: 25.0 mm). The duodenum (90.1%, 173/192) was found to be the most common site of the disease. In 173 patients with duodenal GP, gastrointestinal bleeding (45.1%, 78/173) was found to be the most common symptom of the disease, followed by abdominal pain (42.8%, 74/173), and anemia (14.5%, 25/173). Rate of lymph node metastasis was 6.9% (12/173). Our statistical analysis indicated that significant differences were found for gender between GP within the submucosal layer and exceeding the submucosal layer. Furthermore, our immunohistochemical evaluation showed that both epithelioid and pancreatic islet cells showed positive reactivity for progesterone receptors.ConclusionsOur literature survey revealed that there were many more cases of GP exceeding the submucosal layer than were expected. Meanwhile, our statistical analyses and immunohistochemical evaluation supported the following two hypotheses. First, vertical growth of GP might be affected by progesterone exposure. Second, the origin of GP might be pancreatic islet cells. However, it is strongly suspected that our data have been affected by publication bias and to confirm these hypotheses, further investigation is required.

Adiponectin stimulates IL-8 production by rheumatoid synovial fibroblasts

The adipokines are linked not only to metabolic regulation, but also to immune responses. Adiponectin, but not leptin or resistin induced interleukin-8 production from rheumatoid synovial fibroblasts (RSF). The culture supernatant of RSF treated with adiponectin induced chemotaxis, although adiponectin itself had no such effect. Addition of antibody against adiponectin, and inhibition of adiponectin receptor gene decreased adiponectin-induced IL-8 production. Nuclear translocation of nuclear factor-kappa B was increased by adiponectin. The induction of interleukin-8 was inhibited by mitogen-activated protein kinase inhibitors. These findings suggest that adiponectin contributes to the pathogenesis of rheumatoid arthritis.

Adiponectin stimulates prostaglandin E2 production in rheumatoid arthritis synovial fibroblasts

OBJECTIVE Adipokines may influence inflammatory and/or immune responses. This study was undertaken to examine whether adiponectin affects the production of prostaglandin E(2) (PGE(2)) by rheumatoid arthritis synovial fibroblasts (RASFs). METHODS Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. Fibroblast-like cells from the third or fourth passage were used as RASFs. Expression of adiponectin receptor messenger RNA (mRNA) and protein was detected. PGE(2) (converted from arachidonic acid) was measured by enzyme-linked immunosorbent assay (ELISA). Expression of mRNA and protein for cyclooxygenase 2 (COX-2) and membrane-associated PGE synthase 1 (mPGES-1), key enzymes involved in PGE(2) synthesis, was detected in RASFs. The effects of RNA interference (RNAi) targeting the adiponectin receptor genes and the receptor signal inhibitors were examined. The influence of adiponectin on NF-kappaB activation in RASFs was measured with an ELISA kit. RESULTS Adiponectin receptors were detected in RASFs. Adiponectin increased both COX-2 and mPGES-1 mRNA and protein expression by RASFs in a time- and concentration-dependent manner. PGE(2) production by RASFs was also increased by the addition of adiponectin, and this increase was inhibited by RNAi for the adiponectin receptor gene, or coincubation with the receptor signal inhibitors. Enhancement of NF-kappaB activation by adiponectin as well as by interleukin-1beta was observed in RASFs. CONCLUSION Our findings indicate that adiponectin induces COX-2 and mPGES-1 expression, resulting in the enhancement of PGE(2) production by RASFs. Thus, adiponectin may play a role in the pathogenesis of synovitis in RA patients.

Pulmonary tumor thrombotic microangiopathy induced by gastric carcinoma: Morphometric and immunohistochemical analysis of six autopsy cases

BackgroundPulmonary tumor thrombotic microangiopathy (PTTM) has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM.MethodsAutopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho University Omori Medical Center from 2000 to 2006. And then, tissue sections of extracted cases were prepared for not only light microscopic observation but morphometric analysis with the use of selected PTTM cases.ResultsSix autopsies involved PTTM and clinicopathological data of them were summarized. There was a significant negative association between pulmonary arterial diameter and stenosis rate in four cases. Although all cases showed an increase of stenosis rate to some degree, the degree of stenosis rate varied from case to case. Significant differences were found for average stenosis rate between the under 100 micrometer group or the 100 to 300 micrometer group and the 300 micrometer group in four cases. However, no significant differences were found for average stenosis rate between the under 100 micrometer group and the 100 to 300 micrometer group in all cases. Meanwhile, all cases showed positive reactivity for tissue factor (TF), five showed positive reactivity for vascular endothelial growth factor (VEGF), and three showed positive reactivity for osteopontin (OPN).ConclusionsIn the present study, we revealed that the degree of luminal narrowing of the pulmonary arteries varied from case to case, and our results suggested that pulmonary hypertension in PTTM occurs in selected cases which have a widespread pulmonary lesion with severe luminal narrowing in the smaller arteries. Furthermore, our immunohistochemical examination indicated that gastric carcinoma indicating PTTM shows a higher TF-positive rate than typical gastric carcinoma. However, it remains still obscuring whether gastric carcinoma indicating PTTM shows a higher VEGF or OPN-positive rate as determined by immunohistochemistry.Virtual SlidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9204869075191730.

Literature survey on epidemiology and pathology of cardiac fibroma

BackgroundAlthough cardiac fibroma has been regarded as benign tumor, it presents various symptoms and may lead to death. Unfortunately, only a few studies have reported the epidemiology, embryology, and histopathology of the tumor, and the factors predicting poorer outcome are still obscured.MethodsIn July 2011 we searched for English and Japanese cases of cardiac fibroma using the PubMed and IgakuChuoZasshi databases. We then extracted and sampled raw data from the selected publications in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) style as much as was possible.ResultsDetails of a total of 178 patients with cardiac fibroma were retrieved. The mean age was 11.4 years (median: 2.8 years). Tumor sizes ranged from 8.0 to 150.0 mm (mean 53.1 mm). The left ventricle was found to be the most common site associated with the tumor at a rate of 57.3%, followed by the right ventricle, and interventricular septum. The highest mortality was found in patients with septal involvement (58.6%). In all, 111 patients survived among the 160 patients with a recorded outcome. A younger age of the patient at the time of diagnosis was associated with a decreased survival rate. In addition, a significant positive association was found between ages for patients younger than 17 years of age and the diameter of the tumor at the time of diagnosis (r = 0.341, P = 0.006).ConclusionsBoth the younger age of patients at the time of diagnosis and septal involvement can be regarded as factors significantly indicating a poor prognosis. Furthermore, our statistical analyses support the following hypotheses. First, the high ratio of tumor-to-heart size may generate low cardiac output and therefore lead to poor outcome. Second, the ratio of the sites where cardiac fibroma occurred corresponds with the ratio of the muscular weight of the cardiac chamber. Third, cardiac fibroma involving the interventricular septum more frequently induces conduction system disease.

Clinical value of second- and third-generation assays of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis

Anti-cyclic citrullinated peptide (CCP) antibodies are useful for the diagnosis of rheumatoid arthritis (RA) because of their higher specificity.1 First-generation anti-CCP (CCP1) ELISAs were based on synthetic peptides derived from human filaggrin.2 The second-generation anti-CCP (CCP2) test, which contains epitopes selected from libraries of citrullinated peptides, performs better than anti-CCP1.3 4 Recently, a third-generation anti-CCP (CCP3) test was introduced. We compare the performance of the anti-CCP3 test with that of two anti-CCP2 tests, and assess their value in diagnosing RA. A total of 502 participants were studied: 227 patients fulfilling the American College of Rheumatology criteria for RA,5 173 patients with non-RA autoimmune diseases (details are indicated …

Leiomyosarcoma with partial rhabdomyoblastic differentiation: First case report of primary cardiac origin

BackgroundLeiomyosarcoma occurring as a primary cardiac tumor has been known as an extremely rare condition. Previous studies of leiomyosarcoma with rhabdomyoblastic differentiation have conducted to those arisen from another site, and they indicated a poorer prognosis of this tumor.Case presentationA 69-year-old woman was referred to our hospital for an operation concerning umbilical hernia. Subsequent imaging examinations before an operation indicated the presence of primary cardiac malignant tumor due to its atypical shape. And then, it was surgically removed. Histopathologically, tumor cells consisted of two different types: spindle and polyhedral cells. Immunohistochemically, it is interesting to note that 2.1% of spindle cells and 23.1% of polyhedral cells showed positive reactivity for myogenin. Furthermore, we performed double-immunostaining for alpha-smooth muscle actin (SMA) and myogenin. The rates of alpha-SMA and myogenin double negative, alpha-SMA single positive, myogenin single positive, and alpha-SMA and myogenin double positive in spindle cells were estimated as 69.1%, 28.8%, 1.1% and 1.0%, respectively. In contrast, the rates in polyhedral cells were estimated as 76.9%, 0.0%, 23.1%, and 0.0%, respectively.ConclusionOur immunohistochemical evaluation suggested that rhabdomyoblastic differentiation in leiomyosarcoma might be generated not only by de novo generation from mesenchymal cells. To the best of our knowledge, this is the first case of primary cardiac leiomyosarcoma with partial rhabdomyoblastic differentiation.

Tacrolimus down-regulates chemokine expressions on rheumatoid synovial fibroblasts: screening by a DNA microarray

ObjectiveAlthough the effects of tacrolimus on T cells are well-known, direct effects on rheumatoid synovial fibroblasts (RSF) remain unclear. We studied the effects of tacrolimus on RSF by a DNA microarray analysis.Materials and methodsTacrolimus and interleukin (IL)-1β were added to cultured RSF. Total RNA was prepared from the cells and the gene expression profile was analyzed by a DNA microarray screening system. mRNA expressions influenced by tacrolimus in the screening system were confirmed by real-time PCR. The effects of tacrolimus on nuclear translocation of nuclear factor-κB (NF-κB) were also examined.ResultsThe mRNA expressions of CCL3, CCL4, and CXCL8 were up-regulated by IL-1β and down-regulated by tacrolimus. The levels of these IL-1β-induced chemokines in culture supernatant were decreased by a therapeutic concentration of tacrolimus. Tumor necrosis factor-α as well as IL-1β induced these chemokines, while tacrolimus inhibited their production and mRNA expression. Chemotaxis of polymorphonuclear cells in response to IL-1β was also inhibited by tacrolimus. Nuclear translocation of p50 and p65 NF-κB in response to IL-1β was decreased by tacrolimus.ConclusionIL-1β-induced chemokine expressions were down-regulated by tacrolimus, suggesting that tacrolimus exerts its anti-inflammatory effect partly through inhibiting chemokine production by RSF.

FRI0030 Jak2/stat3 is a major pathway of leptin-induced interleukin-6 production by rheumatoid synovial fibroblasts

Background Since proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, play major pathophysiological roles in rheumatoid arthritis (RA), their inhibitors have recently been developed as potent biological anti-rheumatic drugs. However, they are not curative and the effects are still partial, with many patients failing to respond. Leptin is the product of the ob gene, and is a peptide hormone synthesized almost exclusively by adipocytes that regulates appetite and energy expenditure. It is also suggested that leptin may contribute to inflammation and autoimmunity. We previously reported that serum leptin level was elevated in patients with RA [1]. Accordingly, we examined the direct effects of leptin on cultured rheumatoid synovial fibroblasts (RSFs) in the present study. Objectives To determine the effects of leptin on the production of proinflammatory cytokines by RSFs. Methods Synovial tissue was obtained at total knee replacement operation from patients with RA who gave consent. RSFs were harvested from the synovial tissues of these patients. Leptin receptor mRNAs were detected by reverse transcription–polymerase chain reaction. Productions of mRNA by RSFs and protein concentrations of TNF-α, IL-1β, and IL-6 in the culture medium were detected by real-time PCR and ELISA kit, respectively. Small interfering RNA (siRNA) was transfected into RSFs to down-regulate the expression of leptin receptor. Effects of inhibitors of janus kinase 2 (JAK2), phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK) on IL-6 production were evaluated. Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in RSFs were determined by Western blot analysis. This study was approved (No. 19021) by Ethics Committee of Toho University School of Medicine. Results We detected leptin receptor mRNAs in RSFs. Expressions of IL-1β and IL-6 mRNAs were enhanced in a concentration-dependent manner by addition of leptin to RSFs. IL-6 secretion by RSFs showed an increase after leptin stimulation, while IL-1β did not increase in the culture media. Leptin-induced production of IL-6 by RSFs was decreased after exposure to siRNA targeting leptin receptor (Ob-Rb). A JAK2 inhibitor, but not PI3K and MAPK inhibitors, decreased leptin-induced IL-6 production. Enhanced phosphorylation of STAT3 was observed in RSFs after stimulation by leptin. Conclusions Leptin possibly acts as a proinflammatory cytokine that up-regulates IL-6 production in RSFs via activation of JAK2/STAT3 in RSFs. Leptin and JAK/STAT pathway may represent a new alternative therapeutic target in the treatment of RA. References Yoshino T, Kusunoki N, Tanaka N, Kaneko K, Kusunoki Y, Endo H, Hasunuma T, Kawai S. Elevated serum levels of resistin, leptin, and adiponectin are associated with C-reactive protein and also other clinical conditions in rheumatoid arthritis. Intern Med. 2011;50:269. Disclosure of Interest None Declared