Yu Asanuma

Inflammatory Mediators and Premature Coronary Atherosclerosis in Rheumatoid Arthritis

OBJECTIVE Rheumatoid arthritis (RA) is an inflammatory disease associated with premature atherosclerosis. We hypothesized that mediators of inflammation associated with atherosclerosis in other populations (interleukin-6 [IL-6], tumor necrosis factor alpha [TNFalpha], serum amyloid A [SAA], vascular endothelial growth factor, neutrophil count, IL-1alpha, E-selectin, intercellular adhesion molecule 1 [ICAM-1], myeloperoxidase [MPO], matrix metalloproteinase 9, and vascular cell adhesion molecule 1) would be increased and associated with the severity of coronary atherosclerosis in patients with RA. METHODS Clinical variables, concentrations of inflammatory mediators, and coronary artery calcification were measured in 169 patients with RA and 92 control subjects. Differences in concentrations of inflammatory mediators were compared using median quantile regression. The relationship of inflammatory mediators with the severity of coronary calcification in RA and control subjects was examined using proportional odds logistic regression, allowing for interaction with disease status. Models were adjusted for traditional cardiovascular risk factors. RESULTS Median serum concentrations of IL-6, SAA, ICAM-1, E-selectin, TNFalpha, and MPO and peripheral blood neutrophil count were higher in patients with RA than controls (all P < 0.05), independent of Framingham risk score and diabetes mellitus (DM). IL-6 (main effect odds ratio [OR] 1.72; 95% confidence interval [95% CI] 1.12, 2.66) and TNFalpha (main effect OR 1.49; 95% CI 1.16, 1.90) concentrations were significantly associated with higher amounts of coronary calcium, independent of Framingham risk score and DM, and such main effects significantly differed from controls (P = 0.001 and 0.03 for interaction, respectively). CONCLUSION TNFalpha and IL-6 are significantly associated with the severity of subclinical atherosclerosis, independent of Framingham risk score, in RA.

Marked Induction of c-Maf Protein during Th17 Cell Differentiation and Its Implication in Memory Th Cell Development

Until recently, effector T helper (Th) cells have been classified into two subsets, Th1 and Th2 cells. Since the discovery of Th17 cells, which produce IL-17, much attention has been given to Th17 cells, mainly because they have been implicated in the pathogenesis of various inflammatory diseases. We have performed transcriptome analysis combined with factor analysis and revealed that the expression level of c-Maf, which is considered to be important for Th2 differentiation, increases significantly during the course of Th17 differentiation. The IL-23 receptor (IL-23R), which is important for Th17 cells, is among putative transcriptional targets of c-Maf. Interestingly, the analysis of c-Maf transgenic Th cells revealed that the overexpression of c-Maf did not lead to the acceleration of the early stage of Th17 differentiation but rather to the expansion of memory phenotype cells, particularly with Th1 and Th17 traits. Consistently, mouse wild-type memory Th cells expressed higher mRNA levels of c-Maf, IL-23R, IL-17, and IFN-γ than control cells; in contrast, Maf−/− memory Th cells expressed lower mRNA levels of those molecules. Thus, we propose that c-Maf is important for the development of memory Th cells, particularly memory Th17 cells and Th1 cells.

Analysis of cytokine production patterns of peripheral blood mononuclear cells from a rheumatoid arthritis patient successfully treated with rituximab

We had a rheumatoid arthritis (RA) patient resistant to multiple drugs and who developed panniculitis due to etanercept treatment, then responded fairly well to rituximab. Intracellular staining of cytokines in the peripheral blood mononuclear cells before and after rituximab administration revealed that the cytokine production, representative of T-helper (Th)1-, Th2-, and Th17-type responses, decreased abruptly after the treatment. Interestingly, this timing coincided with that of the manifestation of the beneficial effect. This relationship may provide useful insight into the mechanism of action of the drug and hence about the pathogenesis of RA.

Effects of C‐reactive Protein and Homocysteine on Cytokine Production: Modulation by Pravastatin

Objective C-reactive protein (CRP) and homocysteine are markers of cardiovascular risk that may have inflammatory effects. HMG coenzyme A reductase inhibitors (statins) have anti-inflammatory effects in vitro, but it is not clear if such responses in vivo are secondary to lipid lowering. We examined the hypothesis that CRP and homocysteine would stimulate cytokine release in human whole blood and that short-term treatment with a statin would inhibit it. Methods The time course of IL-6 and MCP-1 production was determined in whole blood incubated with saline, 1 µg/mL lipopolysaccaride (LPS), 50 and 100 µM/L DL-homocysteine, and 5 µg/mL human recombinant CRP for 24 hours at 37°C under 5% CO2 atmosphere. Cytokine responses were determined in blood drawn from 15 healthy volunteers before and after administration of pravastatin 40 mg daily for 2 days. Results Both human recombinant CRP and LPS significantly increased the production of IL-6 and MCP-1 in whole blood samples more than 4-fold (P < 0.001) but homocysteine did not. Oral administration of pravastatin, 40mg daily for 2 days, decreased CRP-stimulated IL-6 production by approximately 20% (P = 0.02) 6 hours after incubation, but did not affect MCP-1 production (P = 0.69). Pravastatin treatment did not affect LPS-stimulated MCP-1 but increased IL-6 modestly. Conclusions CRP stimulated the production of the proatherogenic mediators MCP-1 and IL-6 in human whole blood, but homocysteine did not. CRP-stimulated production of IL-6, but not MCP-1, was modestly attenuated by short-term treatment with pravastatin.

Vasculo-Behçet’s disease with non-traumatic subcapsular hematoma of the kidney and aneurysmal dilatations of the celiac and superior mesenteric arteries

We report a patient with vasculo-Behçet’s disease treated successfully with a high dose of prednisolone. In 2002, the patient was diagnosed with vasculo-Behçet’s disease. He was admitted to our hospital because of sudden-onset right lower back pain in June 2006. Upon admission, abdominal angiography revealed aneurysmal dilatations of the celiac and superior mesenteric arteries. He was treated promptly with high-dose prednisolone, after which the aneurysms displayed no further enlargement. As we believe this case to be quite rare, we report this case with a literature review in support of this characterization.

Relationship Between Corticosteroid Therapy and Atherosclerosis in Patients With Systemic Lupus Erythematosus

Clinical Pharmacology & Therapeutics (2003) 73, P91–P91; doi:

Reduction in C‐reactive protein stimulated interleukin‐6 production by an hmg coenzyme‐a reductase inhibitor (statin)

Clinical Pharmacology & Therapeutics (2003) 73, P3–P3; doi: