Efficacy and safety of remibrutinib, a selective potent oral BTK inhibitor, in Sjögren's syndrome: results from a randomised, double-blind, placebo-controlled phase 2 trial.

OBJECTIVES: To evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren's syndrome (SjS) in a phase 2 randomised, double-blind trial (NCT04035668; LOUiSSE (LOU064 in Sjögren's Syndrome) study). METHODS: Eligible patients fulfilling 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive for anti-Ro/Sjögren's syndrome-related antigen A antibodies, with moderate-to-severe disease activity (EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (based on weighted score) ≥ 5, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) ≥ 5) received remibrutinib (100 mg) either one or two times a day, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles. RESULTS: Remibrutinib significantly improved ESSDAI score in patients with SjS over 24 weeks compared with placebo (ΔESSDAI -2.86, p=0.003). No treatment effect was observed in ESSPRI score (ΔESSPRI 0.17, p=0.663). There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Remibrutinib had a favourable safety profile in patients with SjS over 24 weeks. Remibrutinib induced significant changes in gene expression in blood, and serum protein abundance compared with placebo. CONCLUSIONS: These data show preliminary efficacy and favourable safety of remibrutinib in a phase 2 trial for SjS.

Recommendations for psoriatic arthritis management: A joint position paper of the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology.

In Taiwan, the incidence and prevalence of psoriatic arthritis (PsA) have risen significantly in recent years. Moreover, data from the Taiwan National Health Insurance Research Database (NHIRD) show that more than 85% of PsA patients are treated with just non-steroidal anti-inflammatory drugs (NSAIDs) and/or conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Taiwanese clinicians have also expressed concerns regarding uncertainties in the diagnosis of PsA and the delayed, interrupted, and/or tapered use of biologics, as well as differences in therapeutic preferences between and within dermatologists and rheumatologists. To address these issues, the Taiwan Rheumatology Association and the Taiwanese Association for Psoriasis and Skin Immunology jointly convened a committee of 28 clinicians from the fields of rheumatology, dermatology, orthopedics, and rehabilitation, to develop evidence-based consensus recommendations for the practical management of PsA in Taiwan. A total of six overarching principles and 13 recommendations were developed and approved, as well as a treatment algorithm with four separate tracks for axial PsA, peripheral PsA, enthesitis, and dactylitis. Psoriasis (PsO) management was not discussed here, as the Taiwanese Dermatological Association has recently published a comprehensive consensus statement on the management of PsO. Together, these recommendations provide an up-to-date, evidence-based framework for PsA care in Taiwan.

Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis.

OBJECTIVE: To evaluate the associations between (1) antidrug antibody (ADAb) and therapeutic response, (2) ADAb and serum drug trough levels and (3) serum drug levels and therapeutic responses in rheumatoid arthritis (RA) patients receiving adalimumab or etanercept. Secondarily, we aim (1) to evaluate the concordance between radioimmunoassay and bridging ELISA for ADAb assessment and to evaluate the correlation between two different ELISA methods for detecting drug levels, and (2) to determine the optimal cut-off drug levels for good European League Against Rheumatism (EULAR) response. METHODS: ADAb levels were determined by bridging ELISA and radioimmunoassay, and drug levels evaluated using sandwich ELISA among 36 adalimumab-treated patients and 34 etanercept-treated patients at the 6th and 12th month. The optimal cut-off drug levels for EULAR responses were determined by receiver-operating characteristic curve analysis. RESULTS: ADAb was detected in 10 (27.8%) and 13 (36.1%) of adalimumab-treated patients after 12-month therapy using bridging ELISA and radioimmunoassay respectively, but not detected in any of etanercept-treated patients. The presence of ADAb was associated with lower EULAR response and lower drug levels compared with those without ADAb (both p<0.001). Drug trough levels were positively associated with DAS28 decrement (ΔDAS28) (all p<0.001). The optimal cut-off trough levels for adalimumab were 1.274 µg/mL and 1.046 µg/mL, and those for etanercept were 1.242 µg/mL and 0.800 µg/mL for good EULAR response assessed at the 6th and 12th month, respectively. CONCLUSIONS: ADAb levels were inversely correlated with therapeutic response and drug levels. The positive correlation between drug levels and ΔDAS28 indicates that drug monitoring would be useful to evaluate therapeutic response of TNF-α inhibitors.

The impact of systemic lupus erythematosus on women's sexual functioning.

INTRODUCTION: The effect of systemic lupus erythematosus (SLE) on women's sexual functioning has been rarely assessed. AIM: The aim of this study is to evaluate the impact of SLE on women's sexual functioning. METHODS: A total of 302 consecutive female outpatients with SLE were provided with a questionnaire composed of the Female Sexual Function Index (FSFI), questions for sociodemographic characteristics and comorbidities. Similarly, 2,159 hospital female employees were assessed as the control group. In patients, data of SLE duration and Sjögren's syndrome were derived from the chart records and the disease activity was assessed using the SLE Disease Activity Index 2000. MAIN OUTCOME MEASURES: The FSFI scores were compared between the patients and the controls. Correlates of the FSFI scores were determined in the patients. RESULTS: Of 302 eligible patients, 92.4% (279/302) responded, in addition to 73.2% (1,580/2,159) of controls. Ninety-five percent (255/268) of the respondent patients were in no-to-mild SLE disease activity. Among the respondents, 171 (61.3%) patients and 930 (58.9%) controls were sexually active in the previous month, P = 0.446. Of the sexually active patients, 52.5% (85/162) had impaired sexual function (the FSFI total score < 26.55) and so did 47.1% (408/867) of the sexually active controls, P = 0.206. With adjustment of age group, marital status and education level, patients had lower FSFI scores than controls only in the domains of lubrication and pain. Significant risk factors for lower FSFI scores in the patients included persistent activity or flare of SLE, menstrual cycle disturbances, and vascular disease. With further adjustment of other risk factors, only vascular disease remained significant as a risk factor for impaired sexual function (odds ratio = 5.7; 95% confidence interval 1.6-20.1). CONCLUSION: When not in an exacerbation period, the impact of SLE on women's sexual functioning is not great and is related to vascular factors.

Increased Risk of Sjögren's Syndrome in Patients with Obsessive-Compulsive Disorder: A Nationwide Population-Based Cohort Study.

Obsessive-compulsive disorder (OCD) includes a wide range of symptoms and is often associated with comorbidities. Although psychiatric involvement may be an early manifestation of Sjögren's syndrome (SS), only a few studies have demonstrated the relationship between OCD and SS. This is a nationwide cohort study identifying the risk of SS in OCD patients. We studied a longitudinal health insurance database for the period from 1999 to 2013. The study group was OCD patients with at least three outpatient visits or one hospitalization. The comparison cohort was matched by age and sex, as well as comorbidities. We calculated the risk of Sjögren's syndrome using Cox proportional hazard regression models. We performed a propensity score match for confounders and effect modifiers between the two groups. The propensity score probability was estimated through logistic regression. Primary outcome was the incidental SS. A total of 1678 patients with OCD (49% women, mean age: 35.6 years) and 3356 controls were followed up, resulting in 13,077 and 25,856 person-years, respectively. The hazard ratio for developing SS was 3.31 (95% C.I.: 1.74-6.28) in patients with OCD, compared to those without OCD after adjusting for age, sex, and comorbidities. Furthermore, the risk of SS significantly increased over the 2-year follow-up period after OCD diagnosis. We concluded that risk of SS is significantly increased in patients with OCD compared to those without OCD. Clinically, Sjögren's symptoms in OCD patients should be regularly assessed.

Monitoring by viral load and quantitative hepatitis B surface antigen in patients with hepatitis B virus infection receiving immunosuppressive therapy.

OBJECTIVES: Hepatitis B virus reactivation in patients on immunosuppressive therapy is a critical issue. We aimed to verify the monitoring strategies of hepatitis B virus DNA and quantitative hepatitis B surface antigen in patients receiving therapies with moderate risk. METHODS: We enrolled 25 patients with autoimmune diseases receiving immunosuppressive therapy. Liver function, hepatitis B virus DNA, and quantitative hepatitis B surface antigen were followed-up every 2 months for 24 months. The hepatitis B virus reactivation was defined as hepatitis B virus DNA reappearance or increase of >1 log IU/mL. RESULTS: Patients who were hepatitis B surface antigen positive with (n = 12) or without (n = 6) antiviral prophylaxis and hepatitis B surface antigen negative (n = 7) were analyzed, and the reactivation rates were 0%, 50% and 14%, respectively. Antiviral prophylaxis prevented hepatitis B virus reactivation in hepatitis B surface antigen-positive patients (P = 0.025). Administration of high-risk steroid doses was the sole factor related to the sign of quantitative hepatitis B surface antigen increase of >0.5 log IU/mL in the first 12 months (P = 0.035, risk ratio = 0.098, 95% confidence interval = 0.011-0.847). Furthermore, no patient experienced hepatic decompensation or failure. CONCLUSION: Monitoring hepatitis B virus DNA and quantitative hepatitis B surface antigen every 2 months is safe. However, antiviral prophylaxis can prevent hepatitis B virus reactivation. For patients under steroid therapy in high-risk doses, quantitative hepatitis B surface antigen increase of >0.5 log IU/mL may signify hepatitis B virus reactivation.

Secukinumab Demonstrates Sustained Efficacy and Safety in a Taiwanese Subpopulation With Active Ankylosing Spondylitis: Four-Year Results From a Phase 3 Study, MEASURE 1.

Objectives: To present the long-term (4-year) efficacy and safety of secukinumab in Taiwanese patients with active AS in the MEASURE 1 extension study. Methods: This post hoc analysis reports data from Taiwanese patients originally randomized to subcutaneous secukinumab 150 or 75mg or placebo every 4 weeks (following intravenous loading dose) who were invited to enter the 3-year extension study. Assessments at Week 208 included ASAS20/40 responses and other clinically relevant endpoints. Efficacy data are presented as observed. Safety analyses included all patients who received ≥1 dose of secukinumab. Results: Of the 57 Taiwanese patients in the core trial, 48 entered the extension study and 87.5% patients (42/48) completed 4 years of treatment. Thirteen Taiwanese patients (including placebo-switchers) were escalated from 75 to 150mg (approved dose) at some point starting from Week 172. ASAS20/40 responses were sustained through 4 years in the Taiwanese patients who were originally randomized to secukinumab 150mg. Clinical responses were improved in those patients who received dose-escalation from 75 to 150mg during the study. No unexpected safety signals were reported. Conclusion: Secukinumab 150mg demonstrated sustained efficacy over 4 years in Taiwanese patients with active ankylosing spondylitis. The safety profile of secukinumab was consistent with previous reports. ClinicalTrialsgov identifier: NCT01863732.

Clinical practice recommendations for the use of imaging in the diagnosis and management of axial spondyloarthritis in Taiwan.

OBJECTIVE: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease bearing challenges in early diagnosis. To improve clinical diagnosis and management of axSpA, recommendations were developed with current axSpA classification criteria and recent advances in medical imaging applications. METHODS: A systematic literature review was conducted by 10 rheumatologists and radiologists in Taiwan to retrieve research evidence on the utilization of imaging modalities, including conventional radiography (CR), magnetic resonance imaging (MRI), computed tomography (CT), ultrasound (US), quantitative sacroiliac scintigraphy (QSS), and dual-energy X-ray absorptiometry (DXA). The panel of experts proposed six key issues on the role of imaging in early diagnosis of axSpA, monitoring of disease activity and structural changes, predicting treatment effects, and assessing complications such as osteoporosis and spinal fracture. The consensus was established on the basis of research evidence, clinical experiences and expert opinions. For each recommendation statement, the level of evidence was evaluated, the strength of recommendation was graded and the final level of agreement was determined through voting. RESULTS: In total, four overarching principles and 13 recommendations were formulated. These recommendations outlined different imaging approaches in the diagnosis and management of axSpA disease progression. Considering CT is easy to perform when MRI is less available in Taiwan, the expert panel proposed a concise and practical diagnostic scheme to strengthen the valuable role of MRI and CT in the diagnostic evaluation of axSpA without evident radiographic features. CONCLUSION: These modified recommendations provide guidance for rheumatologists, radiologists and healthcare professionals on timely diagnosis of axSpA and disease management with appropriate imaging modalities.

Taiwan Rheumatology Association consensus recommendations for the management of axial spondyloarthritis.

AIM: To establish guidelines for the clinical management of axial spondyloarthritis that take into account local issues and clinical practice concerns for Taiwan. METHOD: Overarching principles and recommendations were established by consensus among a panel of rheumatology and rehabilitation experts, based on analysis of the most up-to-date clinical evidence and the clinical experience of panelists. All Overarching Principles and Recommendations were graded according to the standards developed by the Oxford Centre for Evidence Based Medicine, and further evaluated and modified using the Delphi method. RESULTS: The guidelines specifically address issues such as local medical considerations, National Health Insurance reimbursement, and management of extra-articular manifestations. CONCLUSION: It is hoped that this will help to optimize clinical management outcomes for axial spondyloarthritis in Taiwan.

Expression of intracellular transforming growth factor-beta1 in CD4+CD25+ cells in patients with systemic lupus erythematosus.

BACKGROUND AND PURPOSE: The CD4+CD25+ regulatory T (Treg) cells exert immunoregulatory functions in various autoimmune diseases, in part through transforming growth factor-beta1 (TGF-beta1), and can be expanded by TGF-beta1 stimulation in normal subjects. This study aimed to examine intrinsic TGF-beta1 expression and the response to TGF-beta1 stimulation of this CD4+CD25+ subset in patients with systemic lupus erythematosus (SLE). METHODS: Flow cytometry with multicolor staining of CD4+, CD25+, and TGF-beta1 was used to quantify the percentage of CD4+CD25+ T cells in fresh peripheral blood and TGF-beta1-stimulated peripheral blood mononuclear cell (PBMC) cultures, and their corresponding intracellular TGF-beta1 expression. RESULTS: In fresh peripheral blood, we found that decreased percentages of CD4+CD25+/CD4+ in SLE patients were associated with disease activity and renal involvement. Intracellular TGF-beta1 expression of CD4+CD25+ cells was significantly elevated in SLE compared with matched controls (p<0.001). In addition, there was significant negative correlation between TGF-beta1 expression and percentage of CD4+CD25+ cells present (r = -0.432, p=0.004). Nevertheless, in ex vivo unstimulated PBMC cultures, the percentage and intracellular TGF-beta1 expression of CD4+CD25+ cells of SLE were normalized to the levels of the control group. In TGF-beta1-stimulated PBMC cultures, CD4+CD25+ cells and their intracellular TGF-beta1 expression were significantly increased (p<0.001), both in SLE and controls. Moreover, the increments in the percentage of CD4+CD25+ cells and intracellular TGF-beta1 expression by TGF-beta1 stimulation were comparable in SLE and controls, and were not significantly influenced by disease activity or renal involvement in SLE. CONCLUSIONS: CD4+CD25+ cells were deficient in peripheral blood but not impaired either in intrinsic TGF-beta1 expression or in response to TGF-beta1 stimulation in patients with SLE. This study suggests that TGF-beta1, by inducing CD4+CD25+ cells, has potential clinical application in treating SLE.

Elevated serum anti-endothelial cell autoantibodies titer is associated with lupus nephritis in patients with systemic lupus erythematosus.

BACKGROUND AND PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease associated with endothelial dysfunction and the existence of multiple species of autoantibodies. However, the association between endothelial dysfunction and renal manifestations remains unclear in Taiwanese SLE patients. METHODS: Serum samples were collected from SLE patients with biopsy-proven lupus nephritis (n = 32), stable SLE patients (n = 32) and healthy controls (n = 32). The SLE Disease Activity Index (SLEDAI) of SLE patients was scored, and levels of anti-endothelial cell antibodies (AECA) and anti-endothelial activities in serum samples were measured by cell-enzyme-linked immunosorbent assay and crystal violet assay, respectively, using cultured human endothelial EA.hy926 cells. RESULTS: Significantly higher AECA (p<0.001) and anti-endothelial activities (p<0.001) were found in sera from patients with lupus nephritis compared with that from stable SLE patients or controls. Moreover, AECA titers (p<0.001) and anti-endothelial activities (p<0.001) were strongly correlated with SLEDAI scores in these patients. CONCLUSION: The strong correlations of AECA and anti-endothelial activity with lupus nephritis activity support an endothelial origin for renal complications in Taiwanese SLE patients.

Primary Sjögren's syndrome complicated with cryoglobulinemic glomerulonephritis, myocarditis, and multi-organ involvement.

Glomerulonephritis in primary Sjögren's syndrome is rarely reported. Cryoglobulinemic glomerulonephritis with the presence of cryoglobulin deposition in the glomerular capillary lumen in primary Sjögren's syndrome is extremely rare. A 51-year-old woman with primary Sjögren's syndrome for > 10 years complained of fever, hypertension, and proteinuria. In addition, novel manifestations, including myocarditis with heart failure, pericardial effusion, and polyneuropathy (sensory motor neuropathy) were also noted. Cryoglobulinemia test was positive, and kidney biopsy results were consistent with cryoglobulinemic glomerulonephritis. There were no symptoms associated with systemic lupus erythematosus or other connective tissue disease. Treatment with monthly methylprednisolone and cyclophosphamide pulse therapy for 6 months resulted in resolution of proteinuria, heart failure, and neurologic symptoms.

Prolonged survival after single lung transplantation for pulmonary hypertension secondary to systemic lupus erythematosus.

Pulmonary hypertension is one of the life-threatening complications of systemic lupus erythematosus, but these patients are often excluded from lung transplantation candidacy due to the nature of underlying multiple system involvement. We report a long-term survival after single lung transplantation in a case of systemic lupus erythematosus with severe pulmonary hypertension. It suggests that single lung transplantation may be considered in such patients, especially in condition of limited donor organ supply.

PTEN overexpression attenuates angiogenic processes of endothelial cells by blockade of endothelin-1/endothelin B receptor signaling.

Arteriovenous (AV) graft is frequently used as vascular access in hemodialysis patients. However, clotting or thrombosis of AV grafts often occurs and requires surgical removal. At present, the molecular pathogenesis underlying thrombosis of AV graft is not clear. The PTEN/Akt signaling has been implicated in the pathogenesis of vascular diseases. In this study, elevated PTEN expression and concomitant Akt inactivation was observed in endothelium of atherosclerotic brachial arteries from hemodialysis patients. To investigate whether PTEN upregulation affects endothelial function, adenovirus-mediated PTEN (Ad-PTEN) overexpression was performed in aorta rings and cultured endothelial cells. It was found that PTEN overexpression potently inhibited the microvessel sprouting in aorta rings and the angiogenic activities of endothelial cells including migration and tube formation. On the contrary, PTEN knockdown by RNA interference promoted the endothelial migration and reversed the Ad-PTEN-induced inhibition of endothelial migration. Expression analysis showed that PTEN overexpression attenuated the expression of endothelin-1 (ET-1) and endothelin B receptor (ETBR) in endothelial cells at transcriptional levels. However, exogenous ET-1 supply only partially reversed the PTEN-induced inhibition of migration and tube formation. This was delineated due to that PTEN overexpression also perturbed endothelial nitric oxide synthase (eNOS) activation and vascular endothelial growth factor (VEGF) release. In summary, PTEN upregulation induces endothelial dysfunction by attenuating the availability and signaling of multiple angiogenic pathways in endothelial cells, thereby may contribute to thrombosis of AV graft.

Tricuspid flow propagation velocity predicts exercise tolerance and readmission in patients with systemic lupus erythematosus.

BACKGROUND: Evaluating right ventricular dysfunction, pulmonary artery systolic pressure (PASP), and exercise tolerance is critical in patients with systemic lupus erythematosus (SLE) because of the high mortality rate in such patients with pulmonary arterial hypertension (PAH). The aim of this study was to use the flow propagation velocity (FPV) of early diastolic tricuspid inflow to evaluate exercise tolerance and PAH severity and to predict readmission in patients with SLE. METHODS: A total of 66 patients with SLE with or without PAH and 30 healthy control subjects were enrolled. Controls were age-matched to patients with SLE and without PAH. All patients completed the 6-minute walking distance (6MWD) test and underwent standard echocardiography. Tricuspid FPV was measured in the modified parasternal short-axis view using the color M-mode technique. PAH was defined as PASP > 35 mm Hg using the tricuspid regurgitant method. RESULTS: Patients with SLE and PAH had significantly lower tricuspid FPVs and 6MWDs than patients in the other 2 groups (both P values < .001). Tricuspid FPV was well correlated with 6MWD (r = 0.748, P < .001). In multivariate analysis, right atrial pressure was the only independent factor affecting tricuspid FPV (R(2) = 0.394, P < .001), and 6MWD was affected only by tricuspid FPV and PASP (R(2) = 0.629, P < .001). Patients with SLE who had been readmitted had lower tricuspid FPVs than those who had not (P = .035). Furthermore, FPV > or = 35.4 cm/s predicted 6MWD > or = 350 m and a lower 1-year readmission rate with good sensitivity and specificity. CONCLUSION: The tricuspid FPV technique provides a simple method for predicting exercise tolerance, the severity of PAH, and readmission among patients with SLE.

Right heart function and scleroderma: insights from tricuspid annular plane systolic excursion.

OBJECTIVE: The purpose of this study was to evaluate the use of echocardiographic parameters as predictors of rehospitalization in scleroderma patients. METHODS: Echocardiographic studies were conducted in 38 patients with systolic scleroderma (SSc) to assess cardiopulmonary function. Forty-five age-matched volunteers without any sign of heart failure served as the control group. Transmitral flow pattern, tricuspid annular plane systolic excursion (TAPSE), left ventricular ejection fraction (LVEF), and right ventricular ejection fraction (RVEF) were evaluated. All patients were subsequently followed for one year. RESULTS: Peak transmitral early-diastolic velocity (mitral E) and TAPSE measurements were significantly different between SSc and control patients (mitral E: 74.1 +/- 16.3 vs. 83.5 +/- 17.0 cm/s with P = 0.012; TAPSE: 2.4 +/- 0.43 vs. 1.9 +/- 0.39 cm with P < 0.0001). LVEF was similar, but RVEF was lower in the SSc group (LVEF: 61.7 +/- 9.7 vs. 61.7 +/- 5.8% with P = 0.962; RVEF: 49.6 +/- 6.8 vs. 39.2 +/- 6.7% with P < 0.0001). A strong correlation was found between TAPSE and RVEF. A TAPSE less than 1.96 cm indicted a RVEF less than 40% with a sensitivity of 81% and specificity of 78%. Contrary to expectation, pulmonary artery systolic pressure (PASP) did not correlate well with RV function (r = 0.261, r2= 0.068, P = 0.016). Finally, the frequency of rehospitalization was inversely correlated with RVEF and TAPSE in SSc patients. CONCLUSIONS: We can predict the rehospitalization rate of SSc patients by TAPSE and RVEF, suggesting the involvement of heart, skin, lung, and other organs in scleroderma patients.

Right heart function in systemic lupus erythematosus: insights from myocardial Doppler tissue imaging.

The purpose of this study was to use Doppler tissue imaging to evaluate heart function and to investigate the correlation between Doppler imaging and pulmonary artery systolic pressure (PASP) and right ventricular (RV) ejection fraction (EF) in patients with systemic lupus erythematosus (SLE). Standard echocardiography and 2-dimensional and color Doppler imaging were used to assess cardiac function in patients given the diagnosis of SLE (n = 40) and healthy control subjects (n = 45). Half of the patients with SLE also presented with pulmonary hypertension (PH). Significant differences in PASP and RV EF (RVEF) were found between the control and SLE groups. The peak systolic velocity of tricuspid annulus was significantly lower in patients with SLE than in the control group. The calculated myocardial performance index of the RV, septum, and left ventricular lateral wall were significantly higher in patients with SLE than in the control group. Bivariate correlation analysis revealed a significant correlation among PASP, RVEF, and systolic tricuspid annular velocity. There was a significant correlation between each of these 3 parameters and the 6-minute walk distance in patients with SLE. Patients with SLE and PH had a significantly shorter 6-minute walk distance than patients with SLE without PH. Furthermore, in patients with SLE and PH, RVEF and systolic tricuspid annular velocity were lower than in the control subjects and patients with SLE without PH. Patients with SLE and PH had a longer isovolumic relaxation time and a higher myocardial performance index of RV than those without PH. Finally, by simple linear regression analysis, we found a significant positive relation between RVEF and systolic tricuspid annular velocity, but a negative relationship between PASP and systolic tricuspid annular velocity. These findings demonstrate that in patients with SLE, systolic tricuspid annular velocity determined by echocardiography and Doppler imaging can be used to assess RV function and PASP. Furthermore, systolic tricuspid annular velocity reflects exercise tolerance in patients with SLE and the length of the isovolumic relaxation time represents the progression of PH.

Gene transfer of pro-opiomelanocortin prohormone suppressed the growth and metastasis of melanoma: involvement of alpha-melanocyte-stimulating hormone-mediated inhibition of the nuclear factor kappaB/cyclooxygenase-2 pathway.

Pro-opiomelanocortin (POMC) is a prohormone of various neuropeptides, including corticotropin, alpha-melanocyte-stimulating hormone (alpha-MSH), and beta-endorphin (beta-EP). POMC neuropeptides are potent inflammation inhibitors and immunosuppressants and may exert opposite influences during tumorigenesis. However, the role of POMC expression in carcinogenesis remains elusive. We evaluated the antineoplastic potential of POMC gene delivery in a syngenic B16-F10 melanoma model. Adenovirus-mediated POMC gene delivery in B16-F10 cells increased the release of POMC neuropeptides in cultured media, which differentially regulated the secretion of pro- and anti-inflammatory cytokines in lymphocytes. POMC gene transfer significantly reduced the anchorage-independent growth of melanoma cells. Moreover, pre- or post-treatment with POMC gene delivery effectively retarded the melanoma growth in mice. Intravenous injection of POMC-transduced B16-F10 cells resulted in reduced foci formation in lung by 60 to 70% of control. The reduced metastasis of POMC-transduced B16-F10 cells could be attributed to their attenuated migratory and adhesive capabilities. POMC gene delivery reduced the cyclooxygenase-2 (COX-2) expression and prostaglandin (PG) E(2) synthesis in melanoma cells and tumor tissues. In addition, application of NS-398, a selective COX-2 inhibitor, mimicked the antineoplastic functions of POMC gene transfer in melanoma. The POMC-mediated COX-2 down-regulation was correlated with its inhibition of nuclear factor kappaB (NFkappaB) activities. Exogenous supply of alpha-MSH inhibited NFkappaB activities, whereas application of the alpha-MSH antagonist growth hormone-releasing peptide-6 (GHRP-6) abolished the POMC-induced inhibition of NFkappaB activities and melanoma growth in mice. In summary, POMC gene delivery suppresses melanoma via alpha-MSH-induced inhibition of NFkappaB/COX-2 pathway, thereby constituting a novel therapy for melanoma.