Soo-Jin Chung

Reactivation of hepatitis B viral infection in inactive HBsAg carriers following anti-tumor necrosis factor-α therapy.

Objective. To investigate whether anti-tumor necrosis factor-α (TNF-α) therapy can influence the reactivation of hepatitis B virus (HBV) infection in inactive HBsAg carriers. Methods. The medical records of 103 patients [59 with ankylosing spondylitis (AS), 41 with rheumatoid arthritis (RA), 2 with juvenile RA, and 1 with psoriatic arthritis] who had been treated with anti-TNF-α therapy were reviewed retrospectively. Data on seropositivity of HBV, HBV load, and serum aminotransferases prior to and after initiation of anti-TNF-α therapy were obtained. Results. Eight patients were inactive HBsAg carriers, and all of them had normal liver function and undetectable HBV load prior to anti-TNF-α therapy. Reactivation of hepatitis B occurred in 1 patient during the course of anti-TNF-α therapy. After the third infusion of infliximab 5 mg/kg at Week 6, a blood test showed that the patient had normal liver function. When the patient returned for the fourth infusion of infliximab at Week 14, a blood test showed markedly elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels (457 and 1054 IU/l, respectively) and increased viral DNA by HBV polymerase chain reaction (PCR). The fourth infliximab infusion was canceled, and entecavir 0.5 mg/day was prescribed. Then AST/ALT levels began to decrease and returned to normal range after 3 months. Followup HBV PCR showed negative results. Conclusion. We found 1 HBV reactivation case among 8 inactive HBsAg carriers following anti-TNF-α therapy. This finding supports the prophylactic use of antiviral agents in HBV carriers, even if they have normal liver function or an undetectable viral load.

Gallic acid, a natural polyphenolic acid, induces apoptosis and inhibits proinflammatory gene expressions in rheumatoid arthritis fibroblast-like synoviocytes

OBJECTIVES To investigate whether gallic acid (3, 4, 5-trihydroxybenzoic acid), a natural polyphenolic acid found in gall nuts, sumac, oak bark, tea leaves, grapes and wine, has pro-apoptotic and anti-inflammatory effects on fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS Viability of RA FLS was assessed using a MTT assay after gallic acid treatment. Apoptosis was assessed by TUNEL assay and caspase-3 activity was determined by a colorimetric assay. The levels of apoptosis-related proteins including Bcl-2, p-Akt, p53, and Bax were determined using western blot analyses, and the mRNA expressions of various pro-inflammatory mediators were measured using quantitative real-time PCR. RESULTS Cell viability of RA FLS was significantly decreased by treatment with 10 or more μM of gallic acid. Gallic acid treatment at the concentrations that do not affect cell viability (0.1 and 1 μM) induced cellular apoptosis of RA FLS. Treatment with 0.1 and 1 μM of gallic acid also resulted in a significant increase in caspase-3 activity and regulated the productions of Bcl-2, Bax, p53 and pAkt. The mRNA expression levels of pro-inflammatory cytokines (IL-1β, IL-6), chemokines (CCL-2/MCP-1, CCL-7/MCP-3), cyclooxygenase-2, and matrix metalloproteinase-9 from RA FLS were suppressed by the gallic acid treatment in dose-dependent manners. CONCLUSION Gallic acid treatment was found to induce apoptosis of RA FLS through regulation of apoptosis-related protein expressions and to reduce the expression of pro-inflammatory genes in RA FLS. These data suggest that pro-apoptotic and anti-inflammatory activities of gallic acid may be used as a possible therapeutic option for RA.

Liver X receptor agonist prevents the evolution of collagen-induced arthritis in mice

OBJECTIVE Liver X receptors (LXRs) have been characterized as regulators of macrophage inflammatory pathways. Synthetic LXR agonists inhibit the macrophage response to bacterial pathogens and antagonize the induction of a number of pro-inflammatory genes. The aim of this study was to investigate the preventive effects of synthetic LXR agonist, GW3965, treatment on the evolution of arthritis and inflammatory response in a murine CIA model. METHODS Intradermal injection of bovine type II CIA in DBA/1 mice. Along with the induction of CIA, mice were treated with oral GW3965 (0.1, 0.3 or 1.0 mg/kg/day) or vehicle from Day 1 to Day 40. Clinical assessment for arthritis scores and histopathological assessment of joint sections were performed. The expression of inflammatory mediators was evaluated by immunohistochemical staining. Serum pro-inflammatory cytokine levels were determined using ELISA. RESULTS The CIA incidence was 100% on Day 27 and the severity progressed until Day 35 with histological features of cartilage erosion in vehicle-treated mice. GW3965 treatment significantly reduced the arthritis incidence and attenuated the clinical and histological severity, compared with vehicle-treated mice. GW3965 treatment also significantly reduced inflammatory mediator production in joint sections and serum pro-inflammatory cytokine levels in a dose-dependent manner. CONCLUSIONS These results indicate that activation of LXRs suppresses the onset of CIA and reduces inflammation and joint destruction in CIA mice. The data could suggest that LXR treatment is an effective prophylactic approach to suppress the evolution of synovitis and resultant joint destruction observed in RA.

The correlation between increased serum concentrations of interleukin-6 family cytokines and disease activity in rheumatoid arthritis patients.

Purpose This study was performed to determine whether the serum concentrations of interleukin (IL)-6 family cytokines are elevated in patients with rheumatoid arthritis (RA) and to investigate the relationship between IL-6 family cytokine levels and disease activity in RA patients. Materials and Methods We obtained serum samples from 40 patients with RA and 40 age- and sex-matched healthy controls, and we assessed the clinical parameters of disease activity, including the 28-joint disease activity score (DAS28) and C-reactive protein (CRP) levels. Serum samples from five patients with high disease activity (DAS28 > 5.1) were also collected at the eighth week of treatment. Serum concentrations of IL-6, IL-11, and leukemia inhibitory factor (LIF) were measured using an enzyme-linked immunosorbent assay (ELISA). Results Serum concentrations of IL-6 family cytokines, including IL-6, IL-11, and LIF, were significantly elevated in patients with RA compared to those of healthy controls. Although there was no significant relationship between IL-6 family cytokine levels and DAS28, the IL-6 levels of patients with RA showed a significant correlation with CRP levels. After eight weeks of medical treatment in patients with high disease activity, a decrease in DAS28 was associated with a significant decrease in the serum concentrations of IL-6 and IL-11. Conclusion The serum concentrations of IL-6 family cytokines were significantly elevated in patients with RA, and they decreased with medical treatment. These findings suggest a possible role for IL-6 family cytokines in the pathogenesis of RA.

Bone and Cartilage Turnover Markers, Bone Mineral Density, and Radiographic Damage in Men with Ankylosing Spondylitis

Purpose To determine the levels of bone and cartilage turnover markers in men with ankylosing spondylitis (AS) and to investigate their associations with disease activity, bone mineral density, and radiographic damage of the spine. Patients and Methods This cross-sectional study enrolled 35 men with newly diagnosed AS. The bone mineral densities (BMD) of their lumbar spines and proximal femurs, Bath AS Disease Activity Index (BASDAI), and Bath AS Radiographic Index (BASRI) were evaluated. Urinary C-terminal telopeptide fragments of type I collagen (CTX-I) and type II collagen (CTX-II) levels were determined by enzyme-linked immunosorbent assay, and serum levels of bone-specific alkaline phosphatase (BALP) and osteocalcin were determined by an enzyme immunoassay. Levels of biochemical markers were compared with those of 70 age-matched healthy men. Results Patients with AS had significantly higher mean urinary CTX-I and CTX-II levels than control subjects (p < 0.05). Elevated urinary CTX-I levels correlated well with BASDAI, femoral BMD, and femoral T score (p < 0.05), and elevated urinary CTX-II levels correlated well with spinal BASRI (p < 0.05) in patients with AS. Mean serum BALP and osteocalcin levels did not differ between patients and controls and did not show any significant correlations with BMD, BASDAI, or BASRI in men with AS. Conclusions Elevated CTX-I reflects disease activity and loss of femoral BMD while elevated CTX-II levels correlate well with radiographic damage of the spine, suggesting the usefulness of these markers for monitoring disease activity, loss of BMD, and radiographic damage in men with AS.

Pro-inflammatory effect of leptin on peripheral blood mononuclear cells of patients with ankylosing spondylitis.

OBJECTIVES This study was performed to investigate whether leptin mRNA expression is increased from peripheral blood mononuclear cells (PBMCs) of patients with active ankylosing spondylitis (AS) and whether it stimulates the production of pro-inflammatory cytokines. METHODS Twenty patients with active AS were enrolled and their Bath AS disease activity index (BASDAI) and levels of acute phase reactants were measured. Leptin, interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha mRNA expressions and their protein productions were determined in PBMCs of patients with AS using semi-quantitative reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay. Then, the results were compared with those from 20 healthy controls, as were clinical and laboratory parameters reflecting disease activity. The changes of pro-inflammatory cytokine productions from PBMCs in response to leptin stimulation were also determined. RESULTS Leptin, IL-6 and TNF-alpha mRNA expressions of PMBCs from patients with AS were significantly higher than controls. Similar significances were also found in the measurements for leptin and cytokine levels of supernatants, and leptin levels correlated well with IL-6 expression (r=0.871, p<0.001) and BASDAI (r=0.691, p<0.001) in patients with AS. Stimulation of PBMCs by exogenous leptin significantly increased the production of IL-6 and TNF-alpha in PBMCs from patients with AS in a dose-dependent fashion and these increases were much exacerbated compared to controls. CONCLUSION Our results shows that leptin production is increased and its stimulation of PBMCs significantly increased the production of pro-inflammatory cytokines in patients with active AS, suggesting its pro-inflammatory effect in pathogenesis of AS.