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Progressive multifocal leukoencephalopathy (PML) is one of the rare but lethal infectious complication in patients with SLE, manifesting progressive central nervous demyelination caused by JC virus (JCV). There have been no effective antiviral agents so far; however, immune checkpoint inhibitors (ICI) have been demonstrated as potential treatments by reinvigorating antiviral T-cell activity against JC virus. To date, sixteen PML cases treated with anti-PD-1 have been reported; however, there was no report addressing the use of ICI in patients with concomitant PML and rheumatic disease, possibly due to the concern for possible autoimmune disease flare-up. In addition, treatment outcomes of these ICI-treated cases were heterogeneous. Experiences from these cases suggested that high disease burden, JC viral load in CSF, and severe immunosuppression status at baseline may predict poor response to treatment. Our case, a 62-year-old woman with long-standing SLE, turned out to have a delayed but effective response to prolonged ICI treatment despite of her high JC viral load and immunosuppressed status caused by high-dose steroid and rituximab. To our knowledge, this is the first case report with SLE complicated with PML clinically improved by pembrolizumab treatment without consequent immune related adverse events (irAE). Considering the lethal nature of PML and absence of effective medication, ICI is a reasonable consideration in patients with SLE and progressive PML.

Recent emerging evidences indicate that dysfunction of metabolic remodeling underlies aberrant T cell immune responses in systemic lupus erythematosus (SLE). However, how these aberrant immune activation and metabolic dysfunction interact in lupus patients are not fully understood. This study was undertaken to investigate the expression of HIF-1α, a regulator of metabolic reprogramming, in T cells from SLE. Our results demonstrated that HIF-1α expression is increased in CD4 T cells from SLE patients both in intracellular staining and quantitative real-time PCR analysis. In addition, there is enhanced HIF-1α expression in Th17-skewing murine T cells, and lentivirus-mediated HIF-1α overexpression promotes Th17 differentiation. Moreover, HIF-1α gene expression is positively correlated with the expression of glycolysis- and IL-17-associated genes in SLE patients. These results indicate that HIF-1α expression is increased in T cells from SLE patients, and is associated with enhanced Th17 pathway, implicating HIF-1α contributes to the activation of Th17 cells in SLE, and represents a potential novel therapeutic target.

Aims: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This analysis investigated the cost-effectiveness of the second-line treatment with tofacitinib, ...

Background/Purpose: Chronic periodontitis (CP) and rheumatoid arthritis (RA) are the most common chronic inflammatory diseases and their immunopathogenesis is similar. The aim of this study was to evaluate the effect of non-surgical periodontal treatment on the serum levels of RA-related inflammatory markers in patients with chronic periodontitis. Methods: Thirty-one Taiwanese adults with CP were included. Demographics and periodontal parameters, including probing depth, clinical attachment level, and number of remaining teeth in the oral cavity, were recorded. All subjects received non-surgical periodontal treatment such as scaling and subgingival root planing. Serum samples were collected before and after the treatment. Serum levels of anti-citrullinated protein antibodies (ACPA), rheumatoid factor, tumor necrosis factor-α (TNF-α), C-reactive protein, interleukin-1β (IL-1β), and Interleukin-6 (IL-6) were measured using an enzyme-linked immunosorbent assay. Results: Non-surgical periodontal treatment significantly reduced the serum ACPA (p = 0.015) and TNF-α levels (p = 0.026) in CP patients, particularly in patients with generalized CP. Furthermore, there was a significant and positive correlation between the number of extracted teeth and the reduction in the serum ACPA (p = 0.05) and IL-1β levels (p = 0.029) after non-surgical periodontal treatment. Conclusion: Non-surgical periodontal therapy may aid in the control of RA-related inflammatory markers in patients with CP. A large-scale study with well-defined populations is needed to clarify the benefit of non-surgical periodontal therapy. Keywords: Periodontitis, Anti-citrullinated protein antibodies, Tumor necrosis factor-α, Non-surgical periodontal treatment

OBJECTIVES: This study aims to evaluate the efficacy and safety profile of opinercept for rheumatoid arthritis (RA) patients undergoing disease- modifying anti-rheumatic drugs (DMARDs) therapy. PATIENTS AND METHODS: A total of 98 patients with active RA (17 males, 81 females; mean age 58.6±12.2 years; range, 24.3 to 85.3 years) were randomized into opinercept plus DMARDs (OD group) or placebo plus DMARDs (PD group), in a 24-week treatment period. Primary outcome was American College of Rheumatology score (ACR20) at week 24. Other exploratory endpoints included ACR50, ACR70 and disease activity score-28 (DAS28) at week 12 and 24, tender/swollen joint counts, pain, Health Assessment Questionnaire-Disability Index, erythrocyte sedimentation rate, and C-reactive protein level. Incidence of adverse events (AEs), vital signs and physical findings, and laboratory test results were also evaluated. RESULTS: Patients in OD group showed significantly higher achievement percentage of ACR20 at week 24 than the PD group (76.6% vs. 30.3%, p

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in rheumatoid arthritis (RA), primarily due to its ability to promote apoptosis in synoviocytes and infiltrating lymphocytes. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory arthritis. We created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited T-cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL receptor (TRAIL-R)-knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R knockout mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T-cell activation. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing inflammatory arthritis and shed light on the development of effective new therapies for autoimmune inflammatory diseases.

Objectives SLE is an autoimmune disease characterized by aberrant autoantibody production and immune dysfunctions. Whether the anti-CMV immunity is impaired in SLE patients is poorly understood. We investigated the specific anti-viral T-cell response in SLE patients with CMV infection and its possible impacts on clinical manifestations in lupus. Methods CD28 null T-cell percentages were measured by flow cytometry in 89 SLE patients and 58 healthy controls. A specific anti-CMV CD8 T-cell response was assessed ex vivo by the production of intracellular cytokines in response to CMV phosphoprotein 65 (pp65) by flow cytometry. Clinical manifestations and immune parameters were analysed in SLE patients according to their CMV serostatus. Results CD28 null T cells were significantly expanded in SLE patients. When the anti-CMV pp65 CD8 polyfunctional T cell response was analysed, as defined by production of at least three of four functional cytokines or effectors (intracellular IFN-γ, IL-2, TNF-α and surface CD107a), the results demonstrated that it was not impaired in SLE patients. In contrast, when comparing clinical manifestations, there were lower anti-ds-DNA levels and decreased SLEDAI in SLE patients with CMV infection. Furthermore, the expansion of CD4+CD28 null T cells was negatively associated with anti-ds-DNA levels and SLEDAI in these lupus patients. Conclusion In SLE patients with CMV infection, the specific anti-CMV CD8 T-cell response is preserved but is associated with decreased disease activity and lower anti-DNA levels among these patients, suggesting CMV infection may mitigate lupus activity.

Aim To review the published studies that dose down and then discontinue biologic therapy in patients with rheumatoid arthritis (RA), particularly concerning the criteria for such dosing and the impact on clinical outcomes. Methods Published studies conducted in patients with RA that sequentially decreased the dose and then discontinued therapy were included if one or more of the following biologic disease modifying antirheumatic drugs (bDMARDs) was evaluated: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab or tocilizumab. Results Five studies qualified for inclusion. The populations of patients with RA were heterogeneous among the studies; patients were required to have low disease activity (LDA) or to be in remission prior to dose titration. Approximately 25-65% of patients successfully decreased and in some cases, discontinued the bDMARD. However, the flare rate was higher than for the patients who remained on a standard dose. The only variable that predicted relapse in more than one study was down-titration of the bDMARD dose. Conclusion In patients who have achieved LDA or remission, down-titration and discontinuation of bDMARD therapy may be attempted, with careful monitoring. However, it is likely that some patients will flare, and it is not known how to predict these patients.

Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-α blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-α blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-α blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose- and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-α blockage therapy occurred at early time points after HBV infection. In addition, TNF-α blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1highCD127low exhausted T cells. Furthermore, TNF-α blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-α blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-α blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-α-blocking agents.

Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-α blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-α blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-α blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose- and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-α blockage therapy occurred at early time points after HBV infection. In addition, TNF-α blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1(high)CD127(low) exhausted T cells. Furthermore, TNF-α blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-α blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-α blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-α-blocking agents.

Objective.The aim of this population-based study is to examine the adverse events (AE) associated with longitudinal systemic glucocorticoid (GC) use among an ethnic Chinese systemic lupus erythematosus (SLE) cohort.Methods.Our study subjects were patients with newly diagnosed SLE aged 18 and older who received at least 1 prescription of systemic GC between 2001 and 2012 from Taiwan’s National Health Insurance Research Database (NHIRD). The earliest prescription date of systemic GC for each subject was defined as the index date. For each subject, we calculated the average prednisolone-equivalent dose and the medication possession ratio (MPR) of GC use every 90 days for each patient after the index date. Patients with a diagnosis of AE (defined by the International Classification of Diseases-9-Clinical Modification diagnosis code) during the followup were also identified from the NHIRD. Generalized estimating equations adjusted for propensity score were applied to examine the association between longitudinal GC use and risks of prespecified AE (musculoskeletal, gastrointestinal, ophthalmologic, infectious, cardiovascular, neuropsychiatric, metabolic, and dermatologic diseases).Results.We identified 11,288 patients with SLE (mean followup: 6.28 yrs). Higher doses and higher MPR of GC were associated with increased risk of osteonecrosis [adjusted OR (aOR) 2.87–9.09]. Similar results were found regarding the risk of osteoporosis (aOR 1.71–3.67), bacterial infection (aOR 2.12–3.89), Cushingoid syndrome (aOR 6.51–62.03), and sleep disorder (aOR 1.42–3.59).Conclusion.To our knowledge, this is the first study to show that the dose and intensity of longitudinal use of GC were both associated with risk of AE among a nationwide Asian SLE cohort.

Background Chronic hepatitis B (CHB) patients display Toll-like receptor 9 (TLR9)-dependent defective immune responses. We aimed to study TLR9 expression on CHB patients and its alteration during therapy. Methods We compared TLR9 expression on fresh peripheral CD14+ monocytes from a cohort of 97 CHB patients and 35 HBsAg-negative, anti-HCV-negative controls, during pegylated interferon or entecavir therapy. TLR9 expression on liver tissue was also investigated. Results Compared with controls, peripheral CD14+ monocytes of CHB patients displayed reduced expression of TLR9 mean fluorescence intensity (MFI; 9.90 ±3.64 versus 7.95 ±3.61; P=0.007) independent of age, gender and alanine aminotransferase (ALT; -2.09, 95% CI -3.568, -0.613; P=0.006). Furthermore, age, gender, ALT, HBeAg status, quantitative HBsAg (qHBsAg) or HBV DNA did not predict the TLR9 expression ( P=0.863). Hepatic TLR9 messenger RNA (mRNA) was significantly reduced in 54 patients compared with 3 controls (0.45 ±0.32 versus 1-fold). Using response-guided therapy by qHBsAg levels and pretreatment TLR9 MFI as a reference, TLR9 MFI restored to a mean of 1.7- to 2.7-fold in pegylated interferon responders and reduced to a mean of 0.6-to 0.7-fold in non-responders starting from treatment week 12. Among 10 entecavir-treated patients, TLR9 MFI gradually restored to a mean of 1.2- to 2.1-fold starting from treatment week 48. Conclusions CHB patients display reduced TLR9 expression on peripheral CD14+ monocytes, which is independent of host and viral markers, and on liver tissue. Responders to pegylated interferon and those under entecavir demonstrate restoration of TLR9 expression. On-treatment TLR9 expression on peripheral monocytes might predict response to pegylated interferon therapy.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of the joints. Objectives This research aims to estimate the economic burden of RA in Taiwan. Methods The National Health Insurance Research Database (NHIRD), a claims-based dataset encompassing 99 % of Taiwan’s population, was applied. We used a micro-costing approach for direct healthcare costs and indirect social costs by estimating the quantities and prices of cost categories. Direct costs included surgeries, hospitalizations, medical devices and materials, laboratory tests, and drugs. The costs and quantities of the direct economic burden were calculated based on 2011 data of NHIRD. We identified RA patients and a control cohort matched 1:4 on demographic and clinical covariates to calculate the incremental cost related to RA. Indirect costs were evaluated by missed work (absenteeism) and worker productivity (presenteeism). For the indirect burden, we estimated the rate of absenteeism and presenteeism from a patient survey. Costs were presented in US dollars (US$1 = 30 TWD). Results A total of 41,269 RA patients were included in the database with incremental total direct cost of US$86,413,971 and indirect cost of US$138,492,987. This resulted in an average incremental direct cost of US$2050 per RA patient. Within direct costs, the largest burdens were associated with drugs (US$73,028,944), laboratory tests (US$6,132,395), and hospitalizations (US$3,208,559). For indirect costs, absenteeism costs and presenteeism costs were US$16,059,681 and US$114,291,687, respectively. Conclusions The economic burden of RA in Taiwan is driven by indirect healthcare costs, most notably presenteeism. Electronic supplementary material The online version of this article (doi:10.1007/s40801-016-0063-8) contains supplementary material, which is available to authorized users.

Helicobacter pylori infection is associated with chronic gastritis, peptic ulcer, gastric carcinoma, and gastric mucosa-associated lymphoid tissue lymphomas. Apoptosis induced by microbial infections is implicated in the pathogenesis of H. pylori infection. Enhanced gastric epithelial cell apoptosis during H. pylori infection was suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells. Human gastric epithelial cells sensitized to H. pylori confer susceptibility to TRAIL-mediated apoptosis via modulation of death-receptor signaling. The induction of TRAIL sensitivity by H. pylori is dependent upon the activation of caspase-8 and its downstream pathway. H. pylori induces caspase-8 activation via enhanced assembly of the TRAIL death-inducing signaling complex through downregulation of cellular FLICE-inhibitory protein. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, significant increases in CCR6+ CD3+ T cell infiltration in the gastric mucosa was observed, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These mechanisms initiate chemokine-mediated T lymphocyte trafficking into inflamed epithelium and induce mucosal injury during Helicobacter infection. This article will review recent findings on the interactions of H. pylori with host-epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation and mucosal damage.

Aim: Rheumatoid arthritis (RA) is an important rheumatologic disease in Asia-Pacific countries, as in other parts of the world. However, limited information is available regarding RA therapy in this region. The Asia-Pacific Study in Patients to be Treated With Etanercept or an Alternative Listed DMARD (APPEAL) compared efficacy and safety of etanercept (ETN) + methotrexate (MTX) versus usual disease-modifying anti-rheumatic drugs (DMARDs) + MTX (reflecting regional practice) in subjects with moderate to severe RA from multiple Asia-Pacific countries. Method: In this open-label, active-comparator, parallel-design, multicenter study, subjects (n = 300) in the Asia-Pacific region were randomized to ETN + MTX (n = 197) or DMARD + MTX (n = 103). The primary efficacy endpoint was the American College of Rheumatology (ACR) response (ACR-N) area under the curve (AUC) over 16 weeks. Results: Baseline characteristics were similar between groups. At Week 16, ACR-N AUC indicated a significantly greater response with ETN + MTX compared with DMARD + MTX (mean difference –145.3; P

Background/aims Hepatitis B infection is a well-known cause of hepatocellular carcinoma (HCC). This study aims to investigate the role that the co-stimulatory molecule CD28 and co-inhibitory molecule programmed death-1 (PD-1) play in compromising the function of tumour-infiltrating lymphocytes (TIL) in hepatitis B virus (HBV)-related HCC. Methods A total of 45 patients with HBV-related HCC were enrolled during the period February 2008 to March 2010. The immune phenotype and the expression of PD-1, CD28 and CD127 in TIL in biopsy specimens and in peripheral blood lymphocytes (PBL) from the same patients were analysed by flow cytometry. Results Among the 45 patients, there was a male predominance (80%) and the mean age was 50 ± 13.68 years (range: 29-71). The majority of TIL were CD45RO(+) CD69(+). PD-1 expression was higher and CD28 and CD127 expression levels were lower in TIL than in PBL. The prevalence of portal vein thrombosis was 40%. Furthermore, tumour thrombosis invasion into the portal vein correlated with the expression level of the PD-1 co-inhibitory molecule. Conclusion PD-1(+) tumour-infiltrating lymphocytes correlate with portal vein thrombosis and might serve as a potential prognostic marker of and a novel therapeutic target for HBV-related HCC.

Helicobacter pylori infection is associated with an inflammatory response in the gastric mucosa, leading to chronic gastritis, peptic ulcers, gastric carcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphomas. Recent studies have shown that apoptosis of gastric epithelial cells is increased during H. pylori infection. Apoptosis induced by microbial infections are factors implicated in the pathogenesis of H. pylori infection. The enhanced gastric epithelial cell apoptosis in H. pylori infection has been suggested to play an important role in the pathogenesis of chronic gastritis and gastric pathology. In addition to directly triggering apoptosis, H. pylori induces sensitivity to tumor-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in gastric epithelial cells via modulation of TRAIL apoptosis signaling. Moreover, H. pylori infection induces infiltration of T lymphocytes and triggers inflammation to augment apoptosis. In H. pylori infection, there was significantly increased CCR6(+)CD3(+ )T-cell infiltration in the gastric mucosa, and the CCR6 ligand, CCL20 chemokine, was selectively expressed in inflamed gastric tissues. These results implicate that the interaction between CCL20 and CCR6 may play a role in recruiting T cells to the sites of inflammation in the gastric mucosa during Helicobacter infection. Through these mechanisms, chemokine-mediated T lymphocyte trafficking into inflamed epithelium is initiated and the mucosal injury in Helicobacter infection is induced. This article will review the recent novel findings on the interactions of H. pylori with diverse host epithelial signaling pathways and events involved in the initiation of gastric pathology, including gastric inflammation, mucosal damage and development of MALT lymphomas.

Background Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is characterized by multifocality of the tumors, which often scatter over the mucosa of the stomach and adjacent upper gastrointestinal tract, and is therefore theoretically not curable by surgical resection. Methods We conducted a long-term follow-up study of 14 patients who received surgical treatment for gastric MALT lymphoma. Tissues from the surgical margins of the resected stomach were analyzed by polymerase chain reaction-based amplification of the complementarity-determining region 3 of the IgH gene for the presence of residual tumors. T (11;18)(q21;q21), a marker of Helicobacter pylori-independent MALT lymphoma, was analyzed by reverse transcription polymerase chain reaction. All living patients were restaged, and rebiopsied if suspicious lesions were identified. Results At a median follow-up of 11.5 years, only 1 patient had evidence of tumor recurrence. Three patients with molecularly proven residual tumors in the surgical margin remained disease-free at 9.6 to 11.6 years. Five patients with t(11;18)(q21;q21) in the tumor cells were disease-free at 9.2 to 12.6 years. Conclusion Our results indicate that surgical resection is a highly curative treatment for gastric MALT lymphoma, even for patients with residual tumor cells in the surgical margins, and for patients with H. pylori-independent tumors. A revisit of surgical treatment for gastric MALT lymphoma is mandatory.

Summary Decoy receptor 3 (DcR3/TR6) is a decoy receptor for the Fas ligand (FasL) and can inhibit FasL-induced apoptosis. It has been reported recently that DcR3 can induce T cell activation via co-stimulation of T cells, suggesting that DcR3 may be involved in the pathophysiology of autoimmune diseases. This study aims to analyse the serum DcR3 in patients with systemic lupus erythematosus (SLE) and to investigate the role of DcR3 in the pathogenesis of SLE. Significantly elevated serum DcR3 was observed in SLE patients, and the mean serum DcR3 level was significantly higher for those with active disease [SLE disease activity index (SLEDAI) ≥ 10] compared with that in patients with inactive disease (SLEDAI

Purpose: To search for novel disease-specific markers in gastric juice by investigating the protein concentrations and components in gastric juice from patients with various gastroduodenal diseases. Experimental Design: Protein concentrations and pH values in fasting gastric juice were examined in 120 healthy subjects and 39 gastric ulcer, 38 duodenal ulcer, and 31 gastric cancer patients. The protein components in gastric juice were studied by two-dimensional PAGE and mass spectrometric analysis. Results: Protein concentrations in gastric juice of patients with gastric ulcers and gastric cancer were significantly higher than those in healthy subjects (1.06 and 2.61 mg/mL versus 0.48 mg/mL; P = 0.001 and P < 0.001, respectively), and duodenal ulcer patients had lower gastric juice protein concentrations compared with healthy subjects (0.26 versus 0.48 mg/mL; P < 0.05). Gastric hypoacidity and advanced age were independent factors affecting the protein concentrations in gastric juice with odds ratios of 32.9 (95% confidence interval, 11.8-90.9) and 3.2 (95% confidence interval, 1.3-8.3), respectively. Each electrophoresis images of gastric juice could be classified into one of three patterns: basic band, specific band, or nonspecific band. The frequencies of specific band pattern in healthy subjects, gastric ulcer, duodenal ulcer, and gastric cancer patients were 6%, 42%, 6%, and 93%, respectively. Proteomic analysis revealed that α1-antitrypsin precursor was the principal peptide in the specific band. Conclusions: α1-antitrypsin precursor in gastric juice is a novel biomarker for gastric cancer and ulcer. A noninvasive method to obtain gastric juice followed by proteomic analysis may serve as a new tool to screen for gastric malignancies.

Galectin-3, a member of the β-galactoside-binding lectin family, expresses in many different immune cells and modulates broad biological functions including cell adhesion, cell activation, cell growth, apoptosis, and inflammation. However, the role of galectin-3 in mucosal immunity or inflammatory bowel diseases is still not clear. We demonstrate here that galectin-3 knockout mice have more severe disease activity in the dextran sulfate sodium (DSS)-induced colitis model, indicating that galectin-3 may protect from inflammation in DSS-induced colitis. Furthermore, treating with galectin-3 reduced body weight loss, shortened colonic length, and ameliorated mucosal inflammation in mice having DSS-induced colitis. However, the protective effects of galectin-3 were eliminated by the administration of anti-CD25 mAb. In addition, primary T cells treated with galectin-3 ex vivo induced the expression of FOXP3, ICOS, and PD-1 with a Treg cell phenotype having a suppression function. Moreover, adoptive transfer of galectin-3-treated T cells reduced bowel inflammation and colitis in the T cell transfer colitis model. In conclusion, our results indicate that galectin-3 inhibited colonic mucosa inflammation and reduced disease severity by inducing regulatory T cells, suggesting that it is a potential therapeutic approach in inflammatory bowel disease.Galectin-3 offers protection from inflammation in experimental colitis. Galectin-3 knockout mice have more severe disease activity in DSS-induced colitis. Adoptive transfer of galectin-3-treated T cells reduced bowel inflammation. Galectin-3 inhibited colonic mucosa inflammation by inducing regulatory T cells. Galectin-3 is a potential therapeutic approach in inflammatory bowel disease.

It was reported that patients with systemic lupus erythematosus (SLE) exhibited increased levels of anticardiolipin (anti-CL) antibodies, a class of antiphospholipid antibodies associated with thrombosis. β2-glycoprotein I (β2GPI) has been considered as the actual target antigen for anti-CL antibodies. This study investigates the association of periodontal infection with anti-CL antibodies in patients with SLE.Fifty-three SLE female patients and 56 healthy female volunteers were recruited in this case-control study. All participants received periodontal examinations. The presence of Porphyromonas gingivalis and Treponema denticola in saliva and plaque samples was detected by polymerase chain reaction. Levels of serum anti-CL and anti-β2GPI antibodies were examined using enzyme-linked immunosorbent assay.Patients with SLE exhibited more periodontal attachment loss and increased titers of serum anti-CL and anti-β2GPI antibodies compared with healthy controls. Patients with active SLE who harbored P. gingivalis or P. gingivalis together with T. denticola intraorally exhibited significantly higher anti-CL and anti-β2GPI antibodies than those without these bacteria. Anti-CL and anti-β2GPI antibody levels correlated positively with clinical attachment level. Furthermore, increased anti-β2GPI antibody levels were significantly associated with C-reactive protein and erythrocyte sedimentation rate.Elevated anti-CL and anti-β2GPI antibody levels were associated with periodontopathic bacteria and periodontal breakdown in patients with SLE. Periodontitis might be a modifiable risk factor for SLE.

Discovertebral erosion with pseudoarthrosis is a well-known complication in ankylosing spondylitis but it is seldom mentioned in psoriatic arthritis. We report a 53-year-old woman with an 8-year history of pso-riatic arthritis who developed severe low back pain followed by sudden onset of numbness in the lower limbs, weakness and dysesthesia. Abnormal contour of L1 and L2 vertebrae and intervertebral disc space was noted during radiologic examination. Pseudoarthrosis was suspected based on extensive osseous re-sorption and reactive sclerosis about the discovertebral junction on magnetic resonance imaging study. She underwent emergency operation due to spinal instability with neurologic deficit. Pseudoarthrosis was confirmed intraoperatively. No evidence of infection or neoplasms was found. This case shows that pseudoarthrosis can be complicated in patients with psoriatic arthritis, and this possibility should be considered in patients with previously quiescent disease.

Summary Background : The host genetic factors that determine the clinical outcomes of Helicobacter pylori-infected individuals remain unclear. Aim : To elucidate the risks of host interleukin-1 (IL-1) genetic polymorphisms and H. pylori infection in the development of gastric cancer. Methods : In a case–control study of 164 controls and 142 patients with gastric cancer, the IL-1B-511 biallelic polymorphisms and the IL-1RN penta-allelic variable number of tandem repeats were genotyped. Results : The carriage of IL-1RN*2, male gender, old age and H. pylori infection independently increased the risk of gastric cancer, with odds ratios of 3.3 [95% confidence interval (CI), 1.4–7.7], 2.1 (95% CI, 1.2–3.8), 5.3 (95% CI, 3.1–9.0) and 2.2 (95% CI, 1.3–3.8), respectively. H. pylori-infected individuals who were carriers of IL-1RN*2 showed increased risks of both intestinal and diffuse types of gastric cancer, with odds ratios of 11.0 and 8.7, respectively. In addition, these individuals also had a higher score of intestinal metaplasia in the corpus than did uninfected non-carriers. Conclusions : This study is the first to verify IL-1RN*2 as an independent factor governing the development of gastric cancer in Asian individuals. A combination of H. pylori testing and host genotyping may target the eradication of H. pylori to high-risk individuals.

Lupus cystitis was rare but frequently resulted in obstructive uropathy and had a strong association with gastrointestinal(GI) symptoms. We treated six patients with systemic lupus erythematosus(SLE) and obstructive uropathy from January 1996 to December 2001 in a university hospital. Evidence of cystitis was obtained from cystoscopic biopsy or the presence of thickened bladder wall in image study. Similar to other reports, five patients had GI manifestations such as abdominal pain, nausea/vomiting, diarrhoea or ileus. In addition, mesenteric lymphadenopathy or pancreatitis was noted in three patients. Two patients had been treated for idiopathic thrombocytopenicpurpura (ITP), four and 20 years ago, respectively. All six patients had antibodies to double-stranded DNA (dsDNA). Five patients each had antibodies to cardiolipin (IgG aCL) or SSA. The high prevalence of anti-SSA had also been reported in Chinese lupus patients with intestinal pseudo-obstruction, a clinical manifestation frequently associated with bilateral ureterohydronephrosis. Two patients died of intractable infection after the surgical procedures for persistent ureterohydronephrosis and both patients had antibodies to ribosomal P proteins. Lupus cystitis might not be so rare in Chinese patients with SLE. The diagnosis should be kept in mind when lupus patients have urinary and/or GI symptoms.

A multi-centre, double-blind, randomised parallel-group study was conducted to compare the efficacy and safety between etodolac SR and diclofenac in treating patients with osteoarthritis of the knee. Thirty-two patients receiving etodolac SR (400 mg/day) and 32 patients receiving diclofenac (100 mg/day) were included for analyses. After receiving the study treatment, etodolac SR and diclofenac were shown to produce comparable improvement in pain relief as measured by a 10-cm visual analogue scale. There was no statistically significant difference observed between groups for the degree of functional impairment or the amount of paracetamol taken. The etodolac SR treatment group showed fewer incidents of adverse event. In addition, fewer gastrointestinal symptoms were observed in the etodolac SR treatment group. A statistically higher percentage of etodolac SR-treated patients were better tolerated to the study treatment compared with the diclofenac-treated patients. Etodolac SR-treated patients also took fewer antacids than the diclofenac-treated patients during the treatment period. In conclusion, etodolac SR is an effective treatment with fewer side-effects than diclofenac for patients with osteoarthritis of the knee.

Background and aims: A subset of non-ulcer dyspepsia (NUD) disorders can evolve into peptic ulcer disease. This prospective study attempted to determine the independent risk factors for ulcer formation in NUD patients, and compared the natural history of Helicobacter pylori positive and negative NUD subjects. Methods: From May 1997 to April 1999, consecutive NUD patients were enrolled into the study. Endoscopy was performed routinely on enrolment, at the end of the second and 12th months, and whenever there was a dyspepsia attack. Patients were prospectively followed up for two years. Results: Peptic ulcers occurred in 16 of 209 NUD patients during the two year follow up period. Multivariate analysis of 13 host and bacterial factors demonstrated that advanced age (odds ratio 2.90), H pylori infection (odds ratio 3.59), and use of non-steroidal anti-inflammatory drugs (NSAID; odds ratio 4.46) were independently significant in predicting subsequent peptic ulcer development. NUD patients with all three risk factors had a 75% (3/4) risk of developing peptic ulcer but the ulcer incidence in patients without any of the risk parameters was only 1.2% (1/84). The resolution rate of symptoms in the H pylori positive NUD patients was similar to the H pylori negative patients (57.9% v 49.1%; 95% confidence interval (CI) −5 to 22). However, rates for subsequent peptic ulcer and erosion development were significantly higher in H pylori positive patients than in H pylori negative patients (ulcer 12.6% v 3.5%, 95% CI 1–16; erosion 23.2% v 12.3%, 95% CI 1–21). Conclusion: A small but significant proportion of NUD patients develop peptic ulcer after long term follow up. H pylori infection, NSAID use, and advanced age are independent risk factors for subsequent ulcer formation. Follow up endoscopy is strongly indicated for an NUD patient with multiple risk factors for ulcer formation when symptoms recur.

OBJECTIVE Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) is involved in macrophage activation, neutrophil motility and osteoclast differentiation. However, the role of PSTPIP2 in inflammation and autoinflammatory diseases is still not clear. In this study, we generated PSTPIP2 knockout (Pstpip2(-/-)) mice to investigate its phenotype and role in autoinflammatory diseases. METHODS We constructed a Pstpip2-targeting vector and generated Pstpip2(-/-) mice. The phenotype and immunopathology of Pstpip2(-/-) mice were analysed. RESULTS All Pstpip2(-/-) mice developed paw swelling, synovitis, hyperostosis and osteitis, resembling SAPHO syndrome, an inflammatory disorder of the bone, skin and joints. Multifocal osteomyelitis was found in inflamed paws, with increased macrophage and marked neutrophil infiltrations in the bone, joint and skin. Profound osteolytic lesions with markedly decreased bone volume density developed in paws and limbs. Neutrophil-attracting chemokines and IL-1β were markedly elevated in inflamed tissues. CONCLUSION Our study suggests that PSTPIP2 could play a role in innate immunity and development of autoinflammatory bone disorders, and may be associated with the pathogenesis of human SAPHO syndrome.

We recently showed that Helicobacter pylori (HP)-positive gastric ‘pure' diffuse large B-cell lymphoma (DLBCL) may respond to HP eradication therapy. However, whether these HP-related ‘pure' DLBCL of the stomach may differ fundamentally from those unrelated to HP remains unclear. In this study, we compared the clinicopathologic features of these two groups of patients who had been uniformly treated by conventional chemotherapy. Forty-six patients were designated HP-positive and 49 were HP-negative by conventional criteria. HP-positive patients had a lower International Prognostic Index score (0–1, 65% vs 43%, P=0.029), a lower clinical stage (I-IIE1, 70% vs 39%, P=0.003), a better tumor response to chemotherapy (complete pathologic response, 76% vs 47%, P=0.004) and significantly superior 5-year event-free survival (EFS) (71.7% vs 31.8%, P

Background: Although the eradication of Helicobacter pylori infection benefits patients with gastric or duodenal ulcers, the value of eradicating the infection in the patients with functional dyspepsia (FD) remains controversial. Aims: To determine whether eradicating H. pylori can prevent the subsequent development of ulcers or relieve the symptoms of functional dyspepsia patients. Methods: In a double-blind, placebo-controlled trial, 161 patients infected with H. pylori who had functional dyspepsia were randomly assigned to 7 days of treatment with a lansoprazole-based triple therapy or placebo and then followed for 1 year. The main outcome measures were the development of peptic ulcers and the resolution of symptoms. Results: H. pylori was eradicated in 63 out of 81 patients (78%) in the treatment group and none of the 80 patients (0%) in the placebo group. During the follow-up period, two patients in the treatment group and six patients in the placebo group developed peptic ulcers at repeat endoscopy (2.5% vs. 7.5%; 95% CI: –12 to 2). The reduction in ulcer rates was statistically significant in the ‘ulcer-like’ sub-group (0% vs. 16.7%; 95% CI: –32 to –2), but not in the ‘dysmotility-like’ and ‘unclassifiable’ sub-groups. Regarding symptom response, the resolution rates of symptoms were similar between the treatment and placebo groups (58.0% vs. 55.0%, 95% CI: –12 to 18). Additionally, no significant differences existed in the symptom responses between the treatment and control arms in each of the dyspepsia sub-groups. Conclusions: Eradicating H. pylori can prevent the subsequent development of peptic ulcers in the patients with ‘ulcer-like’ functional dyspepsia. However, this approach does not significantly reduce the symptoms of functional dyspepsia patients.

Serum immunoglobulin G (IgG) antibody tests are used extensively. We attempted to find out whether the titers of anti-Helicobacter pylori IgG antibody correlated with the degree of macroscopic gastrointestinal damage, the severity of antral gastritis, and the density of antral H. pylori colonization in symptomatic patients. Peripyloric antral biopsy specimens were obtained from 50 consecutive patients with dyspepsia undergoing upper gastrointestinal endoscopy. The macroscopic gastrointestinal damage and the histologic grades of antral gastritis were scored by a modified Lanza scale and Sydney system, respectively. In addition, the densities of antral H. pylori colonization were graded semiquantitatively. Serum IgG antibodies to H. pylori were measured by enzyme-linked immunosorbent assay. Thirty-six (M/F = 29/7) of the 50 patients had H. pylori infection documented by histologic examination or rapid urease test or both. Among the subjects, the IgG antibody titers to H. pylori correlated significantly with the grades of antral polymorphonuclear cell infiltration (p = 0.002) and antral bacterial density (p = 0.01) but not with endoscopic scores, the grades of mononuclear cell infiltration, mucosal atrophy, or intestinal metaplasia (p > 0.05). In addition, endoscopic scores also were found to be significantly correlated with antral bacterial density (p = 0.049) and the grade of polymorphonuclear cell infiltration (p = 0.012). We therefore conclude that high titers of IgG antibody to H. pylori in patients with dyspepsia indicate dense H. pylori colonization and severe antral polymorphonuclear cell infiltration. However, it cannot replace endoscopic examination to evaluate the degree of macroscopic gastrointestinal damage.

Growth arrest-specific protein 6 (Gas6) is a serum protein involved in granulocyte, platelet and endothelium interaction, and is implicated in both anti-inflammatory response as well as platelet/leukocytes activation. We investigated serum Gas6 level in different clinical manifestations of systemic lupus erythematosus (SLE). Data were collected in 83 patients with SLE and 40 non-lupus controls. The Gas6 levels were detected by enzyme-linked immunosorbent assay. Our results demonstrated that the Gas6 level was higher in SLE patients as compared to the non-lupus control subjects (SLE vs. non-lupus control, median [inter-quartile range (IQR)] 22.67 [19.40–28.60] vs. 18.97 [16.05–20.62] ng/mL, p

Background The OuTcomes Associated with taPering biologics among patiEnts with Rheumatoid arthritis (TAPER) study is a multicenter retrospective chart review to assess real-world implication of the Taiwan National Health Insurance Administration policy on tapering and withdrawing biologics in stable rheumatoid arthritis (RA) patients. Objectives To assess the clinical and health resource utilization (HRU) outcomes associated with dose tapering and withdrawing of biologics among stable RA patients. Methods Medical chart data were collected from RA patients tapering adalimumab (ADA) or etanercept (ETN) who had been on the treatment for ≥2 years prior to tapering. RA disease flares and HRU were assessed for the 6-month pre-tapering period, and for the 6-month short-term and up to 18-month longer-term post-tapering periods. A flare was defined a priori as any of the following: 1) an increase in DAS28 ≥1.2; 2) an increase in the number of swollen/tender joints; or 3) use of injectable steroids during outpatient or emergency room (ER) visits. Results Data were collected from medical charts of 261 patients (ADA=106, 40.6%; ETN=155, 59.4%). The majority were female (76.2%), with a mean age of 57.2±13.0 years, and an average RA duration of 10.1±5.6 years. Hypertension (31.4%), osteoporosis (19.2%), other autoimmune diseases (16.9%), and dyslipidemia (14.2%) were the most common comorbidities. More than half of the patients had a longer-term follow-up between one year and18 months (58.6%: ADA=62, 40.5%; ETN=91, 59.5%). The majority of ADA patients were tapered to 40mg every three weeks (63.6%) or 40mg every four weeks (30.8%); most ETN patients were tapered to 25mg every 5 days (49.4%) or once a week (30.5%). Greater proportions of patients had an RA flare post-tapering (pre-tapering: 20.7%; post-tapering short-term: 44.1%; post-tapering longer-term: 73.9%). When compared to the pre-tapering period, the mean RA flare events per patient per year increased substantially post-tapering (pre-tapering: 0.5; post-tapering short-term: 1.2; post-tapering longer-term: 1.6, all p Conclusions Tapering biologic agents among stable RA patients may lead to an increase in RA flare and an increase in outpatient visits. Disclosure of Interest C. Chang: None declared, K. Chen: None declared, Y. Chen: None declared, T. Cheng: None declared, P. Hsu: None declared, N. Lai: None declared, J. Lan: None declared, C. Lee: None declared, S. Lee: None declared, H. Lin: None declared, G. Tsay: None declared, J. Yen: None declared, C. Tsai Shareholder of: AbbVie, Employee of: AbbVie, Y. Bao Shareholder of: AbbVie, Employee of: AbbVie, M. Skup Shareholder of: AbbVie, Employee of: AbbVie, M. Yang Employee of: Analysis Group, E. Wu Employee of: Analysis Group, V. Garg Shareholder of: AbbVie, Employee of: AbbVie

Background The OuTcomes Associated with taPering biologics among patiEnts with Rheumatoid arthritis (TAPER) is a retrospective chart review study to assess real-world implication of Taiwan policy on tapering/withdrawing biologics in stable rheumatoid arthritis (RA) patients. 1 Objectives To assess RA flare rates before and after anti-TNF dose tapering and to identify predictors of flaring upon tapering. Methods Medical chart data were collected from RA patients tapering adalimumab (ADA) or etanercept (ETN) (methods described elsewhere). 1 RA flares were assessed for 6-month pre-tapering, and for short-term (6 months) and longer-term (12 to 18 months) post-tapering. Three alternative flare definitions were used: 1) TAPER: defined a priori the Institutional Review Board submission as a) increase in DAS28≥1.2, b) increase in number of swollen/tender joints, or c) use of injectable steroids during outpatient/ER visits; 2) OMERACT: a) increase in DAS28>1.2, or b) increase in DAS28>0.6 if prior DAS28≥3.2; and 3) Taiwan National Health Insurance Administration: a) increase in DAS28≥1.2 and b) erythrocyte sedimentation rate (ESR) >25mm/h and c) increase in ESR>25%. Logistic regression models were developed to identify factors significantly associated with post-tapering flare. Results Data came from medical charts of 261 patients (ADA=40.6%; ETN=59.4%). More than half patients had a 12- to 18-month follow-up (58.6%: ADA=40.5%; ETN=59.5%). All three flare criteria showed that a greater proportion of patients had flare post-tapering (see table). During the short-term post-tapering, the risk factors of flaring included a longer disease duration (odds ratio=1.05, p=0.049) and having prior concomitant therapy on Cox-2 inhibitors (OR=2.61, p=0.003); being in remission (DAS28 Conclusions Careful considerations are needed when tapering a biologic in stable RA patients in order to avoid potentially increased risk of disease flaring. This could include assessing disease duration and remission status prior to tapering, and whether there is a flare within 6-month of tapering when considering for in long-term. References J Rheum Dis 2015;18(Suppl1):22 Disclosure of Interest C. Chang: None declared, K. Chen: None declared, Y. Chen: None declared, T. Cheng: None declared, P. Hsu: None declared, N. Lai: None declared, J. Lan: None declared, C. Lee: None declared, S. Lee: None declared, H. Lin: None declared, G. Tsay: None declared, J. Yen: None declared, C. Tsai Shareholder of: AbbVie, Employee of: AbbVie, V. Garg Shareholder of: AbbVie, Employee of: AbbVie, Y. Bao Shareholder of: AbbVie, Employee of: AbbVie, M. Yang Employee of: Analysis Group, E. Wu Employee of: Analysis Group

An explorative study evaluates the efficacy of Helicobacter pylori (HP) eradication (HPE) therapy on early-stage gastric diffuse large B-cell lymphomas (DLBCLs) without features of mucosa-associated lymphoid tissue (MALT), the pure (de novo) DLBCLs, in comparison with its efficacy on high-grade transformed gastric MALT lymphomas, the DLBCL(MALT). In total, 50 patients of stage IE/IIE1 HP-positive gastric DLBCLs with frontline HPE treatment were included. HP infection was successfully eradicated in 100% (16/16) of the pure (de novo) DLBCL patients and 94.1% (32/34) of the DLBCL(MALT) patients. In total, 68.8% (11/16) of pure (de novo) DLBCL patients and 56.3% (18/32) of DLBCL(MALT) patients achieved complete pathologic remission (pCR) after HPE therapy. The median time to pCR was 2.1 months (95% confidence interval, 0.6%-3.7%) for pure (de novo) DLBCLs and 5.0 months (95% confidence interval, 2.8%-7.5%; P = .024) for DLBCL(MALT). At a median follow-up of 7.7 years, all patients with pCR after HPE therapy were alive and free of lymphomas, except for one patient with pure (de novo) DLBCL who died of lung cancer. Similar to DLBCL(MALT), a substantial portion of early-stage HP-positive gastric pure (de novo) DLBCLs remains HP-dependent and responds to antibiotic treatment. Prospective studies to validate the findings are warranted.

The growth arrest-specific 6 (GAS6) gene product participates in platelet activation and granulocyte interaction with the endothelium. Our case–control study aimed to determine whether polymorphism of GAS6 was associated with predisposing risk or specific clinical manifestations of systemic lupus erythematosus (SLE). Two of the single-nucleotide polymorphisms (SNPs) of the GAS6 gene, GAS6 834 + 7G/A (rs8191974) and GAS6 +1332C/T (rs1803628), were investigated in 83 SLE patients and 89 non-lupus control subjects. We demonstrated that among lupus patients, the GAS6 +1332 T allele was more prevalent in patients with cutaneous vasculitis (allele T 41.7 % in patients with cutaneous vasculitis compared with 18.3 % in patients without vasculitis, odds ratio (OR) 3.2, 95 % confidence interval 1.3–8.0, p = 0.016). In conclusion, GAS6 polymorphism is positively associated with cutaneous vasculitis in SLE patients, which suggests that GAS6 polymorphism could be a genetic marker for SLE with cutaneous vasculitis.

Aims Effective cytokines can drive the commitment of naive T cells to regulate immune response after antigen-mediated activation. Aims are to elucidate the clinical role of serum IL-27 and IL-6 in the different stages of naive hepatitis B virus (HBV)-infected patients. Methods Samples with well-characterized clinical profiles were assessed from 395 HBV-infected patients including chronic hepatitis B (CHB) group in 291 patients, liver cirrhosis (LC) group in 57 patients, hepatocellular carcinoma (HCC) group in 47 patients. Another 139 non-HBV infected individuals were enrolled as control group (CG) including 104 with normal liver function (NF) and 35 with liver dysfunction (LD). Results The HBV-infected group and separated groups presented significantly higher IL-27 and IL-6 expression than the CG or subgroups of CG. In contrast to IL-27, IL-6 showed significant differences with deteriorating liver condition compared with LC or HCC with CHB groups. Furthermore, IL-6, rather than IL-27, showed significant statistical differences in patients with advanced liver disease compared with those of mild or moderate to severe liver disease and in patients with terminal stage HCC compared with those of early to intermediate or advanced stage HCC. The data associated with liver function, including Albumin, Bilirubin, INR, Platelet and AFP levels, were significantly correlated to IL-6 expression, but had weak correlation to IL-27 expression in HBV patients. Conclusion Serum IL-27 can trigger immune response to prevent hepatic injury in different clinical-pathologic stages of HBV-infected patients earlier, but IL-6 may play an extremely important role to determine the liver progression.

Background Annexin-A7 (ANXA7) exhibits biological and genetic properties expected of a tumor suppressor gene and may play a role in cancer progression. However, the ANXA7 expression in different histological subtypes of gastric adenocarcinomas and its correlation with invasive potentials has not been elucidated. Methods Immunohistochemical staining of ANXA7 for 84 primary gastric adenocarcinomas was performed, and data was correlated with clinicopathological parameters of patients. Results The ANXA7 expression was well correlated with the grade of differentiation of primary tumors. Its expression was detected in 100% (8/8), 64.9% (24/37), 66.7% (2/3), 31.9% (13/31), 0% (0/3), and 0% (0/2) of well-differentiated tubular, moderately-differentiated tubular, papillary, poorly differentiated, signet-ring cell, and mucinous adenocarcinoma, respectively. According to the Lauren's classification, the ANXA7 expression was higher in intestinal type than in diffuse type tumor (71.9% vs. 6.1%, P = 0.003). The loss of expression of ANXA7 expression was significantly related to distant metastasis (P = 0.04). However, there were no significant associations between the ANXA7 expression and survival of cancer patients (P = 0.159). Conclusions A striking correlation between ANXA7 expression and cell differentiation of gastric cancer was observed. The loss of expression of ANXA7 is associated with distant metastasis. J. Surg. Oncol. 2008;97:609–614. © 2008 Wiley-Liss, Inc.

Hepatitis C virus (HCV) infection is frequently associated with anti-SSA/Ro and anti-SSB/La autoantibodies. The objective of this study is to examine the prevalence of anti-SSA/Ro and anti-SSB/La autoantibodies in HCV-infected patients and their possible associations with HLA-DRB1 polymorphism in Chinese patients in Taiwan. About 288 HCV-infected patients were recruited for autoantibody detection and HLA-DRB1 typing. Anti-SSA/Ro and anti-SSB/La autoantibodies were detected in 12.8 and 9.7% of HCV-infected patients. Anti-SSA/Ro antibody was positively associated with age over 55 [p = 0.04; odds ratio = 2.17; 95% confidence interval (CI), 1.03–4.57]. Anti-SSB/La antibody was negatively associated with HLA-DR2 carriage (p = 0.024; odds ratio = 0.30; 95% CI, 0.10–0.90). No significant correlation was found between autoantibody production and gender, autoimmune manifestation, presence of cirrhosis, or hepatocellular carcinoma in HCV infection. In conclusion, anti-SSA/Ro and anti-SSB/La antibodies present frequently in HCV-infected patients. Anti-SSB/La antibody is negatively associated with HLA-DR2 in HCV-infected patients in Taiwan.

e19520 Background: We recently showed that gastric “pure” diffuse large B-cell lymphoma (DLBCL) as well as DLBCL with histologic evidence of mucosa-associated lymphoid tissue (DLBCL[MALT]) remains ...

Objective Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has recently been shown to induce costimulation of mouse T cells in conjunction with signals from the T cell receptor. This study was undertaken to investigate TRAIL-induced costimulation of human T cells in order to determine the role of TRAIL-induced T cell activation in human systemic lupus erythematosus (SLE). Methods An in vitro T cell stimulation system with immobilized anti-CD3 and recombinant TRAIL receptor DR4-Fc proteins was used to activate human T cells purified from healthy individuals and from patients with SLE. The T cells were stimulated in vitro to assay their proliferation response by 3H-thymidine incorporation, and their cytokine production by enzyme-linked immunosorbent assay. Activation of p38 MAPK after TRAIL stimulation was detected with specific anti–phospho-p38 MAPK monoclonal antibodies in Western blots. Results Enhanced T cell proliferation and increased interleukin-2 and interferon-γ (IFNγ) production were demonstrated in human T cells after stimulation with immobilized DR4-Fc and anti-CD3 in vitro. TRAIL engagement selectively activated human CD4, rather than CD8, T cells and augmented IFNγ production. Activation of p38 MAPK was detected after TRAIL-induced T cell activation. T cells isolated from patients with SLE demonstrated a stronger response to TRAIL-induced costimulation, in terms of proliferation and increased up-regulation of CD25 after activation, when compared with T cells from healthy subjects. Conclusion TRAIL engagement induces costimulation of human CD4 T cells via a p38 MAPK–dependent pathway. The results suggest that enhanced reactivity of T cells to autoantigens as a result of TRAIL-induced costimulation may play a role in the development of human autoimmune diseases.

Standard triple therapy remains an important option for eradicating Helicobacter pylori (Hp) in developing countries because of its relatively low cost. However, salvage therapies after failure of this regimen remain undefined. The authors therefore investigate the efficacy of 1-week quadruple therapy as a second-line treatment of Hp infection after failure of standard triple therapy. Seventy-eight patients who failed Hp eradication using a 2-week bismuth-based triple therapy were enrolled and received a course of 1-week quadruple therapy (lansoprazole, 30 mg twice daily; bismuth subcitrate, 120 mg four times daily; clarithromycin, 500 mg twice daily; and amoxicillin, 1,000 mg twice daily) as a salvage regimen. The Hp status was reassessed 7 weeks after cessation of therapy. Among the 78 patients, Hp eradication was achieved in 65 (83%, 95% confidence interval = 75-91%) by intention-to-treat analysis. Only five (6%) patients had side effects, and all (100%) showed good drug compliance. Multivariate analysis disclosed that coffee drinking was an independent factor for treatment failure (odds ratio = 5.3, 95% confidence interval = 1.2-23.6, p = 0.028). The authors therefore conclude that their 1-week quadruple therapy is an effective salvage regimen for Hp infection after failure of standard triple therapy in the population examined. The benefits of this regimen include the high eradication rate, the short duration of treatment, fewer side effects, and good drug compliance. Coffee consumption possibly is an important factor in failure of the rescue regimen. The mechanisms underlying the association between coffee drinking and eradication failure require further research.

Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r(2)=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4(+) T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). An efficient control of virus infections requires the coordinated actions of both innate and adaptive immune responses. In order to define the role of innate immunity effectors against HBV, viral clearance was studied in a panel of immunodeficient mouse strains by the hydrodynamic injection approach. Our results demonstrate that HBV viral clearance is not changed in IFN-α/β receptor (IFNAR), RIG-I, MDA5, MYD88, NLRP3, ASC, and IL-1R knock-out mice, indicating that these innate immunity effectors are not required for HBV clearance. In contrast, HBV persists in the absence of tumor necrosis factor-alpha (TNF-α) or in mice treated with the soluble TNF receptor blocker, Etanercept. In these mice, there was an increase in PD-1-expressing CD8+ T-cells and an increase of serum HBV DNA, HBV core, and surface antigen expression as well as viral replication within the liver. Furthermore, the induction of TNF-α in clearing HBV is dependent on the HBV core, and TNF blockage eliminated HBV core-induced viral clearance effects. Finally, the intra-hepatic leukocytes (IHLs), but not the hepatocytes, are the cell source responsible for TNF-α production induced by HBcAg. These results provide evidences for TNF-α mediated innate immune mechanisms in HBV clearance and explain the mechanism of HBV reactivation during therapy with TNF blockage agents.

At present, there is no study that simultaneously addresses the apparent differences between bacterial and host factors in patients with bleeding and nonbleeding Helicobacter pylori-related ulcer diseases. Therefore, we designed this prospective study to evaluate whether there are identifiable differences between the two groups of patients whose H. pylori-related peptic ulcer diseases present with bleeding or dyspepsia. From July 1996 to November 1996, consecutive patients presenting with upper gastrointestinal bleeding or dyspepsia were enrolled if H. pylori-related ulcer diseases were confirmed. Fifteen clinical, endoscopic, histologic, and serologic factors were tested for association with ulcer bleeding by a logistic regression analysis. In the study period, bleeding occurred in 39 out of 119 patients with H. pylori-related peptic ulcer diseases. Multivariate analysis showed that ingestion of nonsteroidal antiinflammatory drugs (NSAIDs; p = 0.0156; odds ratio = 5:4), ulcer size ≥ 1 cm (p = 0.0033; odds ratio = 4:2), and low bacterial density (p = 0.0030; odds ratio = 4:1) were independent factors associated with the risk of bleeding. There were no associations between ulcer bleeding and age, sex, smoking, alcohol consumption, the histologic grade of gastritis, location and number of ulcers, and the cytotoxin-associated gene (CagA) status of H. pylori strain. Therefore, we concluded that H. pylori-related ulcer patients who use NSAIDs or have large ulcers are more likely to present with upper gastrointestinal bleeding; that the CagA-bearing strains are not associated with the development of bleeding complication in patients with peptic ulcer diseases; and that the exact reason concerning the association between low bacterial density and ulcer bleeding merits further investigation.

Chronic hepatitis C virus (HCV) infection is associated with immunological abnormality, including circulating immune complexes, production of autoantibodies, and concurrent autoimmune disorders.1,2 Both viral and host factors may contribute to the development of autoantibodies and rheumatological manifestations. In this study we investigated the production of autoantibodies in patients with HCV in order to determine a possible link between the polymorphic HLA-DRB1 allele(s) and autoantibody production in chronic HCV infection. We analysed HLA-DR polymorphisms in 288 HCV infected subjects in the Department of Internal Medicine, National Taiwan University Hospital. All patients were assayed for their serum autoantibodies with detection of antinuclear antibodies (ANA), rheumatoid factor (RF), antithyroid antibodies (antithyroglobulin (ATG) and antimicrosomal (AMG) antibodies), and antineutrophil cytoplasmic antibodies (ANCA). The HLA-DR polymorphisms were genotyped by polymerase chain reaction and sequence-specific …