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-γ, proliferator-activated receptor-γ coactivator 1α ( PPARGC1A ) and 1ß ( 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-1ß (P = 0.006). Transfection of PPARGC1B cDNA with rs45520937 A allele to macrophages significantly augmented the expression of NLRP3 and IL-1ß. Conclusion: Genetic variants of PPARGC1B are significantly associated with gout, and a missense single nucleotide polymorphism, rs45520937, augments NLRP3 and IL-1ß expression. These data suggest that variants of PPARGC1B , a regulator of metabolism and inflammation, contribute to the pathogenesis of gouty arthritis.

Methotrexate-induced epidermal necrosis: A case series of 24 patients.

BACKGROUND: Methotrexate-induced epidermal necrosis (MEN) is a rare but life-threatening cutaneous reaction that mimics Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To investigate the clinicopathology, risk factors, and prognostic factors of MEN. METHODS: We enrolled 24 patients with MEN and 150 controls and analyzed the demographics, pathology, and plasma concentrations of methotrexate (MTX). RESULTS: Patients with MEN showed extensive skin necrosis (mean, 33.2% total body surface area) but no target lesions. The histopathology displayed keratinocyte dystrophy. Early signs of MEN included painful skin erosions, oral ulcers, and leukopenia/thrombocytopenia. Although 79.2% patients received leucovorin treatment, there was 16.7% mortality. Risk factors for MEN included older age (>60 years), chronic kidney disease, and high initial dosage of MTX without folic acid supplementation. Renal insufficiency delayed MTX clearance. Severe renal disease and leukopenia predicted poor prognosis in MEN, but none of the SCORe of Toxic Epidermal Necrosis criteria were associated with mortality of MEN. LIMITATIONS: The study was limited by the small sample size. CONCLUSION: MEN exhibited distinct clinicopathologic features from SJS/TEN. Recognition of the early signs and prognostic factors is important, because the rapid institution of leucovorin may be helpful. To reduce the risk of MEN, physicians should avoid prescribing MTX to high-risk patients and titrate the dosage slowly upward with folic acid supplementation.

Early application of low-level laser may reduce the incidence of postherpetic neuralgia (PHN).

BACKGROUND: Postherpetic neuralgia (PHN) is difficult to treat, and currently there are no available treatments that effectively reduce its incidence. Low-level laser therapy (LLLT) has been proposed for indirect virus deactivation in treating recurrent herpes simplex infections. OBJECTIVE: This study seeks to investigate whether LLLT could reduce the incidence of PHN. METHODS: We retrospectively reviewed the incidence of PHN at the first, third, and sixth months after rash outbreak in 3 groups: the acute group of patients who received LLLT during the first 5 days; the subacute group of patients who received LLLT during days 6 to 14 of the eruption; and the control group of patients who did not receive LLLT. RESULTS: There were 48, 48, and 154 patients in the acute, subacute, and control groups, respectively. After adjusting for confounding factors, including age, sex, and use of famciclovir, the incidence of PHN was significantly lower in the acute group versus the control group after 1 month (odds ratio [OR] 0.21, P = .006, 95% confidence interval [CI] 0.068-0.632), 3 months (OR 0.112, P = .038, 95% CI 0.014-0.886), and 6 months (OR 0.123, P = .021, 95% CI 0-0.606). The subacute group only had a lower incidence (OR 0.187, P = .032, 95% CI 0.041-0.865) after 3 months when compared with the control group. LIMITATIONS: This is a retrospective study lacking double-blind randomization, and the placebo effect may be a major concern. Lack of standardized and prospective evaluation measures is also a limitation of this study. CONCLUSION: Applying LLLT within the first 5 days of herpes zoster eruption significantly reduced the incidence of PHN. LLLT may have the potential to prevent PHN, but further well-designed randomized controlled trials are required.

Genetic variants associated with phenytoin-related severe cutaneous adverse reactions.

IMPORTANCE: The antiepileptic drug phenytoin can cause cutaneous adverse reactions, ranging from maculopapular exanthema to severe cutaneous adverse reactions, which include drug reactions with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The pharmacogenomic basis of phenytoin-related severe cutaneous adverse reactions remains unknown. OBJECTIVE: To investigate the genetic factors associated with phenytoin-related severe cutaneous adverse reactions. DESIGN, SETTING, AND PARTICIPANTS: Case-control study conducted in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n=61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n=44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia. A genome-wide association study (GWAS), direct sequencing of the associated loci, and replication analysis were conducted using the samples from Taiwan. The initial GWAS included samples of 60 cases with phenytoin-related severe cutaneous adverse reactions and 412 population controls from Taiwan. The results were validated in (1) 30 cases with severe cutaneous adverse reactions and 130 phenytoin-tolerant controls from Taiwan, (2) 9 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis and 2869 population controls from Japan, and (3) 6 cases and 374 population controls from Malaysia. MAIN OUTCOMES AND MEASURES: Specific genetic factors associated with phenytoin-related severe cutaneous adverse reactions. RESULTS: The GWAS discovered a cluster of 16 single-nucleotide polymorphisms in CYP2C genes at 10q23.33 that reached genome-wide significance. Direct sequencing of CYP2C identified missense variant rs1057910 (CYP2C9*3) that showed significant association with phenytoin-related severe cutaneous adverse reactions (odds ratio, 12; 95% CI, 6.6-20; P=1.1 × 10(-17)). The statistically significant association between CYP2C9*3 and phenytoin-related severe cutaneous adverse reactions was observed in additional samples from Taiwan, Japan, and Malaysia. A meta-analysis using the data from the 3 populations showed an overall odds ratio of 11 (95% CI, 6.2-18; z=8.58; P < .00001) for CYP2C9*3 association with phenytoin-related severe cutaneous adverse reactions. Delayed clearance of plasma phenytoin was detected in patients with severe cutaneous adverse reactions, especially CYP2C9*3 carriers, providing a functional link of the associated variants to the disease. CONCLUSIONS AND RELEVANCE: This study identified CYP2C variants, including CYP2C9*3, known to reduce drug clearance, as important genetic factors associated with phenytoin-related severe cutaneous adverse reactions.

A Review of the Systemic Treatment of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are uncommon but life-threatening diseases mostly caused by drugs. Although various systemic immunomodulating agents have been used, their therapeutic efficacy has been inconsistent. This study aimed to provide an evidence-based review of systemic immunomodulating treatments for SJS/TEN. We reviewed 13 systematic review and meta-analysis articles published in the last 10 years. The use of systemic corticosteroids and IVIg is still controversial. An increasing number of studies have suggested the effectiveness of cyclosporine and biologic anti-TNF-α in recent years. There were also some promising results of combination treatments. Further large-scale randomized controlled trials are required to provide more definitive evidence of the effectiveness of these treatments. The pathogenesis of SJS/TEN has been elucidated in recent years and advances in the understanding of SJS/TEN may inspire the discovery of potential therapeutic targets.

Cutaneous normolipemic plane xanthoma with supraglottic involvement in a patient with hand-Schüller-Christian Disease: a case report.

Normolipemic plane xanthoma (NPX) is a histiocytic disorder characterized by yellow-orange plaques in the periorbital areas, neck, upper trunk, and flexural folds. Association with systemic disease or paraproteinemia has been reported previously, but rarely with Langerhans cell histiocytosis (LCH). We report a case of Hand-Schüller-Christian disease (a type of LCH) in a patient who developed NPX with supraglottic involvement. NPX developed after several courses of chemotherapy and the supraglottic xanthoma occurred about 2 years later. The coexistence of LCH and non-LCH histiocytic lesions in this patient could be a result of chemotherapy-induced changes or may be just coincidental.

Bullous pemphigoid in a renal transplant recipient: a case report and review of the literature.

Bullous pemphigoid (BP) is an autoimmune disease with chronic, recurrent bullous eruptions. BP has been reported to be associated with drugs, physical stimuli, malignancies, and immune abnormalities. Its association with renal transplant is rare and only four cases have been reported. We present a case of BP in a 52-year-old man with chronic hepatitis B and C infection who underwent a cadaveric renal transplant 13 years earlier. His graft was still functioning well when BP appeared. The occurrence of BP in our patient might be a result of drugs (furosemide or tacrolimus), viruses, or renal allograft. As the patient was receiving regular T-cell immunosuppressant therapy, his BP lesions were recalcitrant to corticosteroid treatment. We discuss the pathogenesis and treatment of such patients.

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.

Metastasis of mediastinal epithelioid angiosarcoma to the finger.

Epithelioid angiosarcoma (EA) is a rare malignant, vascular tumor that is usually observed in middle-aged and elderly males. Cutaneous metastasis of EA is extremely rare. We report the case of a 41-year-old woman presenting with a painful bluish, bulla-like lesion on the distal extent of the left third finger. The patient had recently been diagnosed with mediastinal EA with disseminated metastases. The skin biopsy specimen revealed metastatic EA. This is thought to be the first reported metastasis of EA to the finger. Whenever a patient has metastatic disease, acrometastases should be considered in the differential diagnosis of inflammatory lesions of the digits and a skin biopsy should be performed.

The Function of HLA-B*13:01 Involved in the Pathomechanism of Dapsone-Induced Severe Cutaneous Adverse Reactions.

Dapsone-induced hypersensitivity reactions may cause severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). It has been reported that HLA-B*13:01 is strongly associated with dapsone-induced hypersensitivity reactions among leprosy patients. However, the phenotype specificity and detailed immune mechanism of HLA-B*13:01 remain unclear. We investigated the genetic predisposition, HLA-B*13:01 function, and cytotoxic T cells involved in the pathogenesis of dapsone-induced severe cutaneous adverse reactions. We enrolled patients from Taiwan and Malaysia with DRESS and maculopapular eruption with chronic inflammatory dermatoses. Our results showed that the HLA-B*13:01 allele was present in 85.7% (6/7) of patients with dapsone DRESS (odds ratio = 49.64, 95% confidence interval = 5.89-418.13; corrected P = 2.92 × 10-4) but in only 10.8% (73/677) of general population control individuals in Taiwan. The level of granulysin, the severe cutaneous adverse reaction-specific cytotoxic protein released from cytotoxic T cells, was increased in both the plasma of DRESS patients (36.14 ± 9.02 ng/ml, P < 0.05) and in vitro lymphocyte activation test (71.4%, 5/7 patients) compared with healthy control individuals. Furthermore, dapsone-specific cytotoxic T cells were significantly activated when co-cultured with HLA-B*13:01-expressing antigen presenting cells in the presence of dapsone (3.9-fold increase, compared with cells with no HLA-B*13:01 expression; P < 0.01). This study indicates that HLA-B*13:01 is strongly associated with dapsone DRESS and describes a functional role for the HLA-restricted immune mechanism induced by dapsone.

Fas/Fas ligand mediates keratinocyte death in sunitinib-induced hand-foot skin reaction.

Sunitinib, a multitargeted receptor Y kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among the 29 biomarkers examined, soluble FasL (sFasL) showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with those of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40 mg kg(-1) per day) for 4 weeks to mice caused the maximally affected skin area with an erosion-to-ulceration response to tape-stripping. The skin biopsies of mice administered sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR.

Association between gout and vertigo in a Taiwanese population.

There are reports of an association between benign paroxysmal positional vertigo and hyperuricemia. We sought to determine the risk of vertigo among patients with gout compared with the general population, using a nationwide Taiwanese population-based claims database. Our study cohort consisted of patients with a diagnosis of gout disorders in 2004 (N = 18773). Four age- and gender-matched controls for every patient in the study cohort were selected using random sampling as the comparison cohort (N = 75092). All subjects were followed from the date of cohort entry until they developed vertigo or to the end of 2006. Cox proportional hazard regressions were performed to evaluate the 3-year vertigo-free survival rates. Of the total sample, 2563 (incidence, 10.09 per 1000 person-years) had vertigo during the 3-year follow-up period: 570 (incidence, 11.78 per 1000 person-years) from the study cohort and 1993 (incidence, 9.69 per 1000 person-years) from the comparison cohort. The adjusted hazard ratios (HR) of peripheral and central vertigo in patients with gout compared with controls during the 2-3-year follow-up were 1.17 (95% confidence interval [CI] = 1.05-1.29, p = 0.003) and 1.08 (95% CI = 0.86-1.36, p = 0.53), respectively. This is the first population-based study performed to suggest that patients with gout may have an increased risk of peripheral vertigo but not central vertigo. Benign paroxysmal positional vertigo may be the reason for the observed association; however, future studies are required to further ascertain the relationship between gout and the various causes of peripheral vertigo.