Association of Genetic Variants of RANK, RANKL, and OPG with Ankylosing Spondylitis Clinical Features in Taiwanese.

Ankylosing spondylitis (AS) is a chronic inflammatory disease that leads to spinal ankylosis. The receptor activator of the nuclear factor-kappa (RANK), RANK ligand, and osteoprotegerin (OPG) (RANK/RANKL/OPG) pathway plays critical roles in bone metabolism and the immune system. The current study was aimed at investigating whether six single-nucleotide polymorphisms (SNPs) within the RANK, RANKL, and OPG genes essential for bone homeostasis are associated with AS. Genotype distributions, allele and haplotype frequencies, were compared between 1120 AS patients and 1435 healthy controls and among AS patients with stratification by syndesmophyte formation, onset age, and HLA-B27 positivity. We found that RANKL SNPs were associated with AS syndesmophyte formation. Notably, the RANKL SNP haplotype rs7984870C/rs9533155G/rs9525641C was negatively associated with AS susceptibility and appeared to protect against syndesmophyte formation in AS. Functionally, RANKL promoter SNPs (rs9525641 C/T and rs9533155 G/C) affected DNA-protein complex formation and promoter activity in promoter reporter analyses. The OPG SNP haplotype rs2073618G/rs3102735T was significantly associated with HLA-B27 negativity in AS patients. Furthermore, AS patients with syndesmophyte formation had significantly lower levels of soluble RANKL levels than those without syndesmophyte formation. Our data suggested a role for RANKL in AS susceptibility and severity.

Hypersensitivity and Cardiovascular Risks Related to Allopurinol and Febuxostat Therapy in Asians: A Population-Based Cohort Study and Meta-Analysis.

The safety of newer xanthine oxidase inhibitor febuxostat compared to allopurinol remains unclear. To compare the risks of allopurinol hypersensitivity and febuxostat hypersensitivity and cardiovascular diseases (CVDs) in Asians, we conducted a population-based cohort study enrolling patients receiving allopurinol or febuxostat from Chang Gung Memorial Hospital Health System across Taiwan during 2012-2016 and further performed a meta-analysis incorporating two recent studies. Among the 61,539 users, a corresponding 12,007 and 5,680 patients were identified as new users. The overall incidence of febuxostat hypersensitivity was significantly lower than allopurinol hypersensitivity (0.2 vs. 2.7 per 1,000 new users; P < 0.001). There were 33 allopurinol-hypersensitivity reactions (including 18 severe cutaneous adverse drug reactions), and only one patient developed febuxostat-maculopapular exanthema. Moreover, febuxostat did not statistically increase the risk of CVD (hazard ratio (HR), 1.16; P = 0.152) and related death (HR, 1.49; P = 0.496) compared to allopurinol. The result of the meta-analysis also showed a consistent result. In conclusion, the incidence and severity of febuxostat-hypersensitivity are lower than with allopurinol. Febuxostat did not show an increased risk of CVD and related death.

Rhein, An Anthraquinone Drug, Suppresses the NLRP3 Inflammasome and Macrophage Activation in Urate Crystal-Induced Gouty Inflammation.

Rhein, an anthraquinone drug, is a widely used traditional Chinese medicine. Rhein is a major bioactive metabolite of diacerein which has been approved for treating osteoarthritis with a good safety profile in humans. Gouty arthritis is an inflammatory disease characterized by urate crystal-induced NLRP3 inflammasome activation with up-regulated caspase-1 protease and IL-1 ß in macrophages. Inhibition of the NLRP3 inflammasome formation has been considered as a potential therapeutic avenue for treating or preventing many inflammatory diseases. This study aimed to evaluate the anti-inflammatory effects of rhein on gouty arthritis. Rhein within the physiological levels of humans showed no toxicity on the cell viability and differentiation, but significantly decreased the production of IL-1 ß , TNF- α and caspase-1 protease in urate crystal-activated macrophages. Compared to medium controls, rhein at the therapeutic concentration (2.5 µ g/mL) effectively inhibited IL-1 ß production by 47% ( P=0.002 ). Rhein did not affect the mRNA levels of CASP1, NLRP3 and ASC, but suppressed the protein expression and enzyme activity of caspase-1. Immunofluorescence confocal microscopy further revealed that rhein suppressed the aggregation of ASC speck and inhibited the formation of NLRP3 inflammasome. Rhein of 5 µ g/mL significantly decreased the ASC speck to 36% ( P=0.0011 ), and reduced the NLRP3 aggregates to 37.5% ( P=0.014 ). Our data demonstrate that rhein possesses pharmacological activity to suppress caspase-1 protease activity and IL-1 ß production by interfering with the formation of NLRP3 multiprotein complex. These results suggest that rhein has therapeutic potential for treating NLRP3 inflammasome-mediated diseases such as gouty arthritis.

Malignancy in dermatomyositis and polymyositis: analysis of 192 patients.

This study aims to investigate the prevalence and predictive risk factors of malignancy in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 192 PM/DM patients followed up in a medical center between January 2000 and December 2013 were reviewed. Among the 192 patients, 33 patients (17.2 %) had associated cancer. Both PM and DM are significantly associated with cancer, although the risk of cancer appears to be somewhat higher among patients with DM (23.0 %) than among those with PM (8.9 %). Nasopharyngeal cancer (30.3 %) and breast cancer (18.2 %) comprised the most common malignant diseases associated with PM/DM. Univariate analysis showed that an older age at PM/DM onset, heliotrope rash, Gottron's sign, dysphagia, and low creatine phosphokinase (CPK) level were associated with increased malignancy. Multivariate analysis revealed that independent predictors of malignancy in PM/DM were age >40 years at PM/DM onset (adjusted OR 3.44; 95 % CI 1.08-10.98; p = 0.037) and heliotrope rash (adjusted OR 2.96; 95 % CI 1.04-8.43; p = 0.042). During the follow-up period, 66 (34.4 %) patients died and the overall patient survival rates were 83.1 % at 1 year, 78.9 % at 2 years, 74.2 % at 5 years, and 65.5 % at 10 years. This study demonstrates a high frequency of malignancy (17.2 %) in DM/PM patients. Nasopharyngeal cancer and breast cancer were the most common cancer types in DM/PM patients in our study. Cancer screening should be offered to patients with newly diagnosed DM/PM. Moreover, all patients should be evaluated for the possibility of an underlying malignancy during treatment.

Impact of the HLA-B(*)58:01 Allele and Renal Impairment on Allopurinol-Induced Cutaneous Adverse Reactions.

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.

Survival analysis of patients with dermatomyositis and polymyositis: analysis of 192 Chinese cases.

To estimate the mortality rate and identify factors predicting survival in patients with polymyositis (PM) and dermatomyositis (DM). The medical records of 192 PM/DM patients who were treated at Chang Gung Memorial Hospital from 1999 through 2008 were retrospectively reviewed. The Taiwan National Death Registry (1999-2008) was used to obtain their survival status. Thirty-one (16.1%) of the 192 patients with PM/DM had an associated malignancy; 41 (21.4%) had interstitial lung disease (ILD). During the follow-up period, 55 (28.6%) patients died and the overall cumulative survival rate was 79.3% at 1 year, 75.7% at 2 years, 69.9% at 5 years, and 66.2% at 10 years. In univariate analysis, older age at PM/DM onset, anemia, thrombocytopenia, leukopenia, diabetes mellitus, ILD, cancer, and non-use of azathioprine were associated with higher mortality (p = 0.0172, 0.0484, <0.0001, 0.0008, 0.0001, 0.0036, 0.0010, and 0.0019, respectively). In multivariate Cox regression analysis, thrombocytopenia (hazard ratio [HR] 4.94, 95% confidence interval [CI] 2.60-9.37, p < 0.0001), diabetes mellitus (HR 2.57, 95% CI 1.38-4.80, p < 0.0001), cancer (HR 2.30, 95% CI 1.26-4.22, p = 0.0030), and ILD (HR 1.98, 95% CI 1.11-3.51, p = 0.0182) were positively associated with mortality. Use of azathioprine (HR 0.35, 95% CI 0.16-0.74, p = 0.0064) was negatively associated with mortality. This study confirmed the high mortality rate (28.6%) in PM/DM patients. Survival time was significantly reduced in patients with thrombocytopenia, diabetes mellitus, ILD, and cancer patients than in those without these conditions.