Yeong-Jian Jan Wu

Insights into the poor prognosis of allopurinol-induced severe cutaneous adverse reactions: the impact of renal insufficiency, high plasma levels of oxypurinol and granulysin

Objective Allopurinol, an antihyperuricaemic agent, is one of the common causes of life-threatening severe cutaneous adverse reactions (SCAR), including drug rash with eosinophilia and systemic symptoms (DRESS), Stevens–Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). The prognostic factors for allopurinol-related SCAR remain unclear. This study aimed to investigate the relationship of dosing, renal function, plasma levels of oxypurinol and granulysin (a cytotoxic protein of SJS/TEN), the disease severity and mortality in allopurinol-SCAR. Methods We prospectively enrolled 48 patients with allopurinol-SCAR (26 SJS/TEN and 22 DRESS) and 138 allopurinol-tolerant controls from 2007 to 2012. The human leucocyte antigen (HLA)-B*58:01 status, plasma concentrations of oxypurinol and granulysin were determined. Results In this cohort, HLA-B*58:01 was strongly associated with allopurinol-SCAR (p<0.001, OR (95% CI) 109 (25 to 481)); however, the initial/maintenance dosages showed no relationship with the disease. Poor renal function was significantly associated with the delayed clearance of plasma oxypurinol, and increased the risk of allopurinol-SCAR (p<0.001, OR (95% CI) 8.0 (3.9 to 17)). Sustained high levels of oxypurinol after allopurinol withdrawal correlated with the poor prognosis of allopurinol-SCAR. In particular, the increased plasma levels of oxypurinol and granulysin linked to the high mortality of allopurinol-SJS/TEN (p<0.01), and strongly associated with prolonged cutaneous reactions in allopurinol-DRESS (p<0.05). Conclusions Impaired renal function and increased plasma levels of oxypurinol and granulysin correlated with the poor prognosis of allopurinol-SCAR. Allopurinol prescription is suggested to be avoided in subjects with renal insufficiency and HLA-B*58:01 carriers. An early intervention to increase the clearance of plasma oxypurinol may improve the prognosis of allopurinol-SCAR.

Salmonella septic arthritis in systemic lupus erythematosus and other systemic diseases.

Salmonella infection is an important problem in immunocompromised patients. The synovium is a particular metastatic focus ofSalmonella infection and can result in many disabilities of life. Systemic lupus erythematosus (SLE) patients were highly susceptible toSalmonella infection. In the past 6 years, 41 patients withSalmonella septic arthritis have been treated in our hospital. Eleven patients had an underlying systemic disease of SLE which presented with a distinctive clinical course. Alcoholic liver disease (six cases) was another common underlying systemic disease. The most frequent predisposing articular factor was avascular necrosis (16 cases). The hip joint was the most commonly involved site.Salmonella group B was the most common serotype (30/41). Seventy-three per cent (8/11) of the SLE group had involvement of two or more joints compared with only three out of 30 patients in the non-SLE group. The sex differentiation shows a predominance of young females (10/11) in the SLE group and middle-aged males in the non-SLE group. Moreover, in the SLE group, all 11 patients shared the risk of lupus nephritis and steroid use. Ten patients hadSalmonella group B bacteraemia and five had urinary tract infections simultaneously. In the non-SLE group, there were 10 patients with a history of steroid use, three with antecedent enteritis, 12 with bacteraemia, and three with necrotising fasciitis. Seven patients in each of the groups had a recurrent course. However, three patients in the non-SLE group had died during the episode of septic arthritis.

Infections in polymyositis and dermatomyositis: analysis of 192 cases

OBJECTIVES To estimate the incidence, characteristics and predictors of infections in patients with PM and DM. METHODS The medical records of 192 PM/DM patients followed up in a tertiary teaching medical centre from 1999 to 2008 were retrospectively reviewed. RESULTS Seventy-six episodes of major infection, defined as infections requiring>1 week of treatment with anti-microbial agents, occurred in 53 (27.6%) patients, and 15 (7.8%) patients had two or more episodes. The incidence rate of major infections was 11.1 episodes per 100 patient-years in PM/DM patients. Aspiration pneumonia [n (%)=16 (21.1)] was the leading cause of major infections, followed by opportunistic infection [n (%)=14 (18.4)]. A variety of pathogens were isolated, mainly including Staphylococcus aureus, Klebsiella, Escherichia coli, Salmonella and Mycobacterium. Overall patient survival rates were 85.0% at 1 year, 78.0% at 5 years and 78.0% at 10 years. However, after one episode of major infection, survival rates decreased to 84.7% at 30 days and 68.3% at 1 year. Multivariate analysis indicated that independent predictors of major infection were age>45 years at PM/DM onset [odds ratio (OR) 5.26; 95% CI 2.01, 13.77; P=0.001], presence of arthritis/arthalgia (OR 2.59; 95% CI 1.12, 6.02; P=0.027), co-present interstitial lung disease (OR 7.24; 95% CI 2.67, 19.65; P<0.001), current use of AZA (OR 6.07; 95% CI 2.39, 15.42; P<0.001) or IVIG (OR 6.33; 95% CI 1.50, 26.77; P=0.012). CONCLUSIONS This study underlines the high frequency of major infections in PM/DM, which is significantly detrimental to patient survival rates. Close follow-up of PM/DM patients with risk factors for developing major infections is mandatory.

A transmembrane polymorphism in FcγRIIb ( FCGR2B ) is associated with the production of anti-cyclic citrullinated peptide autoantibodies in Taiwanese RA

The aim of the current study was to determine whether the FcγRIIb 187-Ile/Thr polymorphism is a predisposition factor for subtypes of RA defined by disease severity and production of autoantibodies against cyclic citrullinated peptides (anti-CCPs) in Taiwanese RA patients. Genotype distributions and allele frequencies of FcγRIIb 187-Ile/Thr were compared between 562 normal healthy controls and 640 RA patients as stratified by clinical parameters and autoantibodies. Significant enrichment of 187-Ile allele was observed in RA patients positive for anti-CCP antibodies as compared with the anti-CCP negative RA patients (P=0.001, OR 1.652 (95% CI 1.210–2.257)) or as compared with the normal controls (P=0.005, OR 1.348 (95% CI 1.092–1.664)). In addition, 187-Ile allele was found to be enriched in RA patients positive for rheumatoid factor (RF) compared to the RF negative RA patients (P=0.024, OR 1.562 (95% CI 1.059–2.303)). Furthermore, the homozygotes were enriched in destructive male RA patients (P=0.035; OR 2.038 (95% CI 1.046–3.973)) and the 187-Ile allele was associated with early-onset of RA in Taiwanese patients (P=0.045, OR 1.548 (95% CI 1.007–2.379)). Thus, FcγRIIb SNP 187-Ile/Thr may influence the RA phenotypes in Taiwanese RA.

Gout in systemic lupus erythematosus and overlap syndrome – a hospital-based study

AbstractThe negative association between gout and rheumatoid arthritis is widely accepted, and gout is also speculated to be rare in systemic lupus erythematosus (SLE), as only a few sporadic cases have been reported. From 1985 to 2001 we encountered 15 lupus patients at Chang-Gung Memorial Hospital, including two with lupus–scleroderma and one with lupus–scleroderma–polymyositis overlap syndrome coexisting with gout. This study retrospectively analyses the clinical and laboratory characteristics of these patients. A lower female predominance is found, and most patients developed gout after the onset of SLE, although gout preceded SLE in two cases. Measurement of serum uric acid and 24-h urine uric acid found all of the patients to be hyperuricaemic and underexcretors of uric acid. Furthermore, most of the patients (14/15) were receiving diuretics. Also, many had hypertension and serious cardiovascular diseases. Renal impairment during gouty attacks seemed to be a predisposing factor for developing end-stage renal disease. Gouty arthritis usually occurred during relative SLE inactivity, podagra was frequent, and tophi were found in a few patients. Compared with the unselected population of SLE patients, the cases studied here had a higher incidence of chronic arthritis, malar rash, haematologic disorder, photosensitivity, serositis and neurologic disorder. Renal disease in the patients sampled was frequently membranous nephropathy.

Haemophilus influenzae pericarditis with tamponade as the initial presentation of systemic lupus erythematosus.

Although cardiac tamponade is an important and emergent complication of systemic lupus erythematosus (SLE), purulent pericarditis is rare despite the high frequency of pericardial effusion in SLE. We describe the first SLE case of Haemophilus influenzae type‐f pericarditis with cardiac tamponade with SLE as the initial presentation. The pathophysiology and therapy are discussed.

Genetic variants of PPAR-gamma coactivator 1B augment NLRP3-mediated inflammation in gouty arthritis

Objective. Gout is characterized by recurrent attacks of arthritis with hyperuricaemia and urate crystal-induced inflammation. Although urate transporters are known as risk factors, the immunogenetics of gouty inflammation remains unclear. This study aimed to investigate the genetic association between immune/metabolism regulators and gout. Methods. We enrolled 448 gout patients and 943 population controls from Taiwan; all were Han Chinese. We screened association between gout and 22 variants of candidate genes, including NLRP3, caspase 1, peroxisome proliferator-activated receptor-&ggr;, proliferator-activated receptor-&ggr; coactivator 1&agr; (PPARGC1A) and 1&bgr; (PPARGC1B). The association was validated by replication and combined-sample analyses. Functional assays were performed by quantitative PCR, ELISA, siRNA knockdown and transfection using THP-1 cells, peripheral blood mononuclear cells and synovial cells from patients. Results. Gouty arthritis exhibited significant association with variants of peroxisome PPARGC1B, which included a missense single nucleotide polymorphism, rs45520937 [P = 6.66 × 10−9; odds ratio (95% CI): 1.85 (1.51, 2.28)]. Expression of PPARGC1B and NLRP3 was induced in urate crystal-activated THP-1, peripheral blood mononuclear cells and synovial cells from gout patients in acute stage. siRNA knockdown of PPARGC1B upregulated NLRP3 in urate crystal-activated macrophages. Compared with the wild-type carriers, patients with the risk A allele of rs45520937 showed statistically increased NLRP3 (P = 0.044) and plasma IL-1&bgr; (P = 0.006). Transfection of PPARGC1B cDNA with rs45520937 A allele to macrophages significantly augmented the expression of NLRP3 and IL-1&bgr;. Conclusion. Genetic variants of PPARGC1B are significantly associated with gout, and a missense single nucleotide polymorphism, rs45520937, augments NLRP3 and IL-1&bgr; expression. These data suggest that variants of PPARGC1B, a regulator of metabolism and inflammation, contribute to the pathogenesis of gouty arthritis.

SAT0282 Frequency and Predictors of Attainment of The Lupus Low Disease Activity State (LLDAS) in A Cross Sectional Study of Sle Patients in The Asia Pacific

Background Systemic lupus erythematosus (SLE) is a heterogeneous disease characterised by fluctuating disease activity. A low disease activity endpoint, the Lupus Low Disease Activity State (LLDAS), was recently reported and retrospective validation showed that time spent in LLDAS translated into reduced damage accrual (Franklyn, Ann Rheum Dis, 2015). A large prospective study to validate LLDAS in a multiethnic cohort of lupus patients from the Asia Pacific Region is underway. Objectives To describe the frequency and identify the predictors of fulfilling criteria for LLDAS in baseline visit data from a large multinational multiethnic cohort of patients with SLE in nine Asia Pacific countries. Methods Prospectively collected baseline visit data from 1846 SLE patients enrolled in a longitudinal study were analysed cross sectionally against the recently published definition of LLDAS, and patient characteristics associated with LLDAS attainment determined. Results LLDAS criteria were met by 44% of patients at a single baseline visit. Stepwise multivariable logistic regression revealed that patients with shorter disease duration were less likely to be in LLDAS (OR 0.31, 95% CI 0.19–0.49, p<0.001). Likewise, discoid rash (OR 0.66, 95% CI 0.49–0.89, p=0.006), renal disease (OR 0.60, 95% CI 0.48–0.75, p<0.001), elevated double stranded DNA (OR 0.65, 95% CI 0.53–0.81, p<0.001) or hypocomplementaemia (OR 0.52, 95% CI 0.40–0.67, p<0.001) were negatively associated with LLDAS attainment. Significant differences in LLDAS attainment between countries were observed, and higher national social wealth as measured by the Gross Domestic Product per capita was positively associated with LLDAS (OR 1.57, 95% CI 1.25–1.98, p<0.001). Conclusions Low disease activity was observed in less than half of SLE patients at a single point in time. Disease duration and phenotype, as well as national social wealth, were predictive of LLDAS attainment. Disclosure of Interest None declared