Epidemiology and prognostic factors for mycosis fungoides and Sézary syndrome in a multi-ethnic Asian cohort: a 12-year review.

BACKGROUND: Limited information exists regarding survival of Asian patients with mycosis fungoides (MF) and Sézary syndrome (SS). OBJECTIVE: To evaluate the epidemiology, outcome and prognostic factors of these patients. METHODS: A retrospective review of MF/SS cases diagnosed from 2000 to 2011 at a tertiary referral dermatology centre in Singapore was performed. RESULTS: Of 246 patients, 63% were male and the median age at diagnosis was 49 years. 73.2% were Chinese, 12.6% Indian, 6.9% Malay and 7.3% Caucasian. A total of 239 patients (97.2%) had MF and seven had SS. Median follow-up duration was 6.3 years, and median duration of symptoms at diagnosis was 13 months. For patients with MF, the majority had early disease (92.8% stage IA-IIA). 3.8% were stage IIB, 1.7% stage III and 1.7% stage IV. Complete response to treatment occurred in 78.2%, partial response in 9.6%, persistent but non-progressive disease in 10.0% and disease progression in 4.1% of patients. Large cell transformation occurred in 4.1% of patients. Mean overall survival during this study was 12.7 years, with death occurring in 2.5% of patients (all ≥stage IIB at diagnosis). For patients with SS, 71.4% presented with stage IVA disease, 28.6% stage IVB. Complete response to treatment occurred in 14.2%, persistent but non-progressive disease in 28.6% and disease progression in 57.2% of patients. Mean overall survival was 3.3 years within this study, with death occurring in 42.9% of SS patients. Prognostic factors associated with favourable recurrence-free survival were male gender (P = 0.008), early disease stage (T1) at diagnosis (P < 0.001) and absence of maintenance treatment after remission (P = 0.01). CONCLUSION: Compared to Caucasian and East Asian cohorts, MF in South-East Asians was diagnosed at a younger age and associated with lower mortality, largely due to greater prevalence of hypopigmented MF.

Vitamin D levels in 87 Asian patients with cutaneous lupus erythematosus: a case-control study.

BACKGROUND: Cutaneous lupus erythematosus (CLE) is an autoimmune disease, often exacerbated by sun exposure. Patients are encouraged to avoid sun exposure, therefore predisposing them to vitamin D deficiency. AIM: To investigate the prevalence of and risk factors for vitamin D deficiency in patients with CLE. METHODS: Total serum 25-hydroxy vitamin D (25(OH)D) was measured in 87 consecutive patients with CLE and in 79 controls. Clinical characteristics, disease severity, medications used and lifestyle factors were analysed and compared to determine risk factors for inadequate (25(OH)D), defined as a serum (25(OH)D) level of < 20 µg/L. RESULTS: We found that 51% (n = 44) of the patients with CLE had 25(OH)D levels of < 20 µg/L compared with 73% (n = 58) of the controls (P < 0.01). No significant differences in (25(OH)D) levels were found between cases and controls with regard to age, sex, ethnicity, smoking, sun exposure, sunblock use or vitamin D supplementation. Treatment with antimalarials showed a statistically significant association with lower vitamin D levels. CONCLUSION: Low levels of vitamin D were found in both patients with CLE and controls. Despite being on vitamin D supplementation and living in an equatorial location, our Asian patients with CLE still had low levels of vitamin D. It is therefore important to ensure adequate vitamin D supplementation in patients with CLE, especially for those who are on antimalarial therapy.

Mortality of bullous pemphigoid in Singapore: risk factors and causes of death in 359 patients seen at the National Skin Centre.

BACKGROUND: Bullous pemphigoid (BP) is the most common autoimmune-mediated subepidermal blistering skin disease and is associated with significant morbidity and mortality. OBJECTIVES: To determine the 3-year mortality rate, risk factors and causes of death in patients with BP in Singapore, compared with the general population. METHODS: We conducted a retrospective cohort study of all newly diagnosed patients with BP seen at the National Skin Centre from 1 April 2004 to 31 December 2009. Demographic and clinical data on comorbidities and treatment were recorded. Mortality information was obtained from the National Registry of Diseases. RESULTS: In total 359 patients were included in our study. The 1-, 2-, 3-year mortality rates were 26·7%, 38·4% and 45·7%, respectively. The 3-year standardized mortality risk for patients with BP was 2·74 (95% confidence interval 2·34-3·19) times higher than for the age- and sex-matched general population. Parkinson disease, heart failure and chronic renal disease were associated with increased mortality, while combination treatment with low-to-moderate-dose corticoste-roids and immunomodulatory agents such as doxycycline and/or nicotinamide was associated with lower mortality. Overall, infections were the most common cause of death (59·8%), with the main causes of death being pneumonia (42·7%), cardiovascular disease (14·6%) and stroke (11·6%). CONCLUSIONS: This study confirms an increased 3-year mortality rate for patients with BP in Singapore. Risk factors for increased mortality include medical comorbidities, especially neurological, cardiac and renal diseases. Treatment with combination therapy, including the use of low-to-moderate-dose corticosteroid, appeared to decrease mortality risk in patients with BP.

Filaggrin mutations are associated with recurrent skin infection in Singaporean Chinese patients with atopic dermatitis.

BACKGROUND: Loss-of-function (null) mutations within the filaggrin (FLG) gene are a strong risk factor for atopic dermatitis (AD). We hypothesized that the absence or reduction of the filaggrin protein could compromise skin barrier and increase patients' susceptibility to recurrent skin infection. OBJECTIVES: To investigate the association between FLG-null mutations and the risk of recurrent skin infection among a series of patients with AD in Singapore. METHODS: This study included 228 Singaporean Chinese patients with AD with at least 1year of follow-up at the time of recruitment between January 2008 and December 2009 at the National Skin Centre in Singapore. Each patient had their medical records reviewed for history of skin infection in the preceding year and was genotyped for 22 FLG-null mutations. RESULTS: Compared with those without the FLG-null mutations, patients with AD who had FLG mutation(s) had approximately a seven times increased risk of more than four episodes of skin infection requiring antibiotics in the past year (odds ratio 6·74; 95% confidence interval 2·29-19·79). This risk was much greater in those with mild or moderate disease, and was present in both users and nonusers of oral steroids. CONCLUSION: This study highlights a novel association between FLG-null mutations and an increased susceptibility to recurrent bacterial skin infection among patients with AD.

Lymphomatoid papulosis: is a second lymphoma commoner among East Asians?

BACKGROUND: Lymphomatoid papulosis (LyP) is a low-grade cutaneous lymphoma, which lies within the spectrum of primary cutaneous CD30-positive lymphoproliferative disorders. Around 10-20% of LyP cases are associated with a second lymphoma. AIM: To analyse a cohort of Asian patients with LyP, diagnosed from 1987 to 2007 at the National Skin Centre (NSC), Singapore, in terms of epidemiology, treatment and association with a second lymphoma. METHODS: Patients were identified through the NSC clinical and histological databases. RESULTS: During this period, 13 patients were diagnosed with LyP based on clinicopathological criteria. The mean age at diagnosis was 41 years, the male : female ratio was 2.3 : 1, and 92% of the patients were Chinese. Recurrent papulonecrotic lesions were present for a mean of 3 years before diagnosis. Treatment of LyP comprised monotherapy (n = 4) or combination therapy (n = 9) using corticosteroids, oral antibiotics, methotrexate and/or phototherapy. Mean duration of follow-up was 6.4 years. Eight patients (61.5%) were diagnosed with a second lymphoma, either before (n = 2), concurrently with (n = 1) or after (n = 5) the diagnosis of LyP. Mycosis fungoides (MF) was the commonest lymphoma (78%, n = 7), followed by primary cutaneous anaplastic large-cell lymphoma (12%, n = 2). There was one death (mortality rate 7.7%), which occurred in a patient who had developed stage IIA MF after LyP, which subsequently progressed to systemic T-cell lymphoma. CONCLUSIONS: LyP is a chronic, relapsing disease with considerable morbidity, but an overall good prognosis. A strikingly large proportion of our Asian patients (61.5%) had a second lymphoma, compared with previous studies. This emphasizes the importance of regular lifetime surveillance for associated lymphomas in all patients with LyP.

Wide spectrum of filaggrin-null mutations in atopic dermatitis highlights differences between Singaporean Chinese and European populations.

BACKGROUND: Null mutations in the filaggrin gene (FLG) cause ichthyosis vulgaris (IV) and predispose to atopic dermatitis (AD). Cohort studies in Europe and Japan have reported an FLG mutation carrier frequency of between 14% and 56%, but the prevalent European FLG mutations are rare or absent in Chinese patients with IV and AD. OBJECTIVES: To investigate further the spectrum of FLG-null mutations in Chinese patients and to compare it with that in other populations. METHODS: We conducted comprehensive FLG genetic analysis in a discovery cohort of 92 Singaporean Chinese individuals with IV and/or moderate-to-severe AD. All detected FLG mutations were then screened in a cohort of 425 patients with AD and 440 normal controls. Results In total, 22 FLG-null mutations, of which 14 are novel, were identified in this study; the combined null FLG genotype of 17 mutations detected in cases and controls showed strong association with AD [Fisher's exact test; P = 5·3 × 10⁻9; odds ratio (OR) 3·3], palmar hyperlinearity (Fisher's exact test; P = 9·0 × 10⁻¹5; OR 5·8), keratosis pilaris (Fisher's exact test; P = 0·001; OR 4·7) and with increased severity of AD (permutation test; P = 0·0063). CONCLUSIONS: This study emphasizes the wider genetic landscape of FLG-null mutations in Asia that is slowly emerging.

TAK1 regulates SCF expression to modulate PKBα activity that protects keratinocytes from ROS-induced apoptosis.

Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor ß-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)α pro-survival pathway in a cell-autonomous manner to protect keratinocytes from ROS-mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-α treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c-Kit/PKBα signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBα pathway exhibited increased ROS production and TNF-α- or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology.

A case of paraneoplastic pemphigus associated with Castleman's disease presenting as erosive lichen planus.

Paraneoplastic pemphigus (PNP) is a debilitating chronic blistering mucocutaneous disease associated with an underlying neoplasm and a poor prognosis. We present a patient who had been diagnosed and treated for recalcitrant erosive mucocutaneous lichen planus for 3 years with little success. Further investigations established the diagnosis of PNP with underlying Castleman's disease. This case highlights the importance of repeated investigations to exclude PNP in patients with recalcitrant mucosal erosions, especially if atypical features are present.

Prevalence and molecular characteristics of Staphylococcus aureus isolates colonizing patients with atopic dermatitis and their close contacts in Singapore.

BACKGROUND: Staphylococcus aureus colonization is an established pathogenic factor for disease flare in atopic dermatitis (AD). OBJECTIVES: We conducted a study to investigate the colonization of S. aureus in patients with AD and their close contacts in order to evaluate the possibility of intrafamilial transmission. We sought to determine the distribution of the bacterial virulence factors and their correlation with disease severity. METHODS: Nasal swabs and skin swabs (patients with AD only) were taken from patients with AD aged 2-21 years and their close contacts, seen at the National Skin Centre from January to March 2007. All S. aureus isolates were typed using multilocus variable-number tandem-repeat fingerprinting (MLVF) and screened for virulence factors via polymerase chain reaction (PCR) analysis. AD severity was determined by the SCORAD index. RESULTS: A total of 34 patients with AD and 55 close contacts were recruited. Thirty-one (91%) patients were colonized with S. aureus. Twenty-five (45%) of their close contacts were also colonized, and MLVF showed a high concordance of S. aureus isolates in index patients and their close contacts. On multivariate analysis, patients with a moderate SCORAD were more likely to be colonized by enterotoxin B-positive S. aureus (P = 0.027). No virulence factor was significantly associated with a severe SCORAD. CONCLUSIONS: The prevalence of S. aureus colonization was high among patients with AD and their close contacts. However, no predominant isolate of S. aureus was found to be associated with AD. The presence of superantigen B is possibly associated with moderate rather than severe disease in our population.

Generalized granuloma annulare associated with gastrointestinal stromal tumour: case report and review of clinical features and management.

The paraneoplastic variant of granuloma annulare (GA) is a rare cutaneous manifestation of underlying malignancy that is most commonly associated with systemic lymphoma. We report an interesting case of a patient with gastrointestinal stromal tumour (GIST) of the stomach presenting with extensive generalized GA. GIST was diagnosed 2 months after the diagnosis of GA. Resolution of the GA was seen 1 month after surgical excision of GIST. The close correlation of the clinical courses of these two rare diseases suggests that their coexistence was more than a coincidental finding. This case highlights the importance of excluding paraneoplastic GA, especially in cases where the skin manifestations are extensive and resistant to treatment.

Scrofuloderma from the acromioclavicular joint presenting as a chronic ulcer in an immunocompetent host.

A 53-year-old woman presented with a chronic, non-healing painless ulcer over her right clavicular area of a two-month duration. Skin biopsy, microbiological and radiological investigations confirmed the diagnosis of scrofuloderma arising from an underlying tuberculous infection of her acromioclavicular joint. She was treated successfully with anti-tuberculosis therapy with complete healing of the ulcer. Awareness of this uncommon presentation of osteoarticular tuberculosis may assist in earlier diagnosis.

Impetigo herpetiformis--a rare dermatosis of pregnancy associated with prenatal complications.

INTRODUCTION: We describe a patient who developed an acute generalised pustular eruption associated with pyrexia at 33 weeks of gestation. CLINICAL PICTURE: Her condition was complicated by preterm labour, requiring an emergency caesarean section delivery. A diagnosis of impetigo herpetiformis was made on clinicopathological grounds. TREATMENT: Initial treatment with topical and systemic corticosteroids failed and oral methotrexate was added. OUTCOME: She responded well to this therapy and required only 2 doses of weekly methotrexate. CONCLUSION: Impetigo herpetiformis is a rare dermatosis of pregnancy that requires early recognition and treatment to prevent maternal and fetal morbidity. Combination therapy using oral corticosteroids and short-term methotrexate is effective.

Latex sensitisation in healthcare workers in Singapore.

INTRODUCTION: Epidemiological data on latex sensitisation among Asian healthcare workers is lacking. The aim of the study is to determine the rate of latex sensitisation in our healthcare workers. MATERIALS AND METHODS: We recruited 313 healthcare workers, of which 46.6% were operating theatre staff and 53.4% were non-operating theatre staff. Seventy-one administrative staff served as controls. All participants answered a self-administered questionnaire relating to latex exposure and glove-related symptoms. Latex sensitisation was determined by skin prick testing to latex and latex-specific IgE detection. RESULTS: The prevalence of latex sensitisation among healthcare workers was 9.6%, with no difference between operating theatre and nonoperating theatre staff. Glove-related symptoms were reported in 13.7% of all healthcare workers, of which 22.9% were sensitised to latex. Only 26.7% of latex-sensitised healthcare workers had glove-related symptoms while the rest were asymptomatic. The most common symptoms were itch and hand eczema but the most important discriminating symptom was contact urticaria. Personal history of atopy was more common in sensitised healthcare workers (40.0%) compared to non-sensitised workers (31.8%). Only 1 out of 9 (11.2%) symptomatic latex-sensitised subjects had sought previous medical attention for the problem. CONCLUSIONS: Latex sensitisation among healthcare workers in Singapore should be considered a significant occupational health risk, as it is in the West. Increased screening and awareness of this problem is essential to identify those at risk.

Study on the efficacy of ELA-Max (4% liposomal lidocaine) compared with EMLA cream (eutectic mixture of local anesthetics) using thermosensory threshold analysis in adult volunteers.

BACKGROUND: ELA-Max and EMLA cream are topical anesthetics that have been shown to have similar anesthetic efficacy in previous studies. OBJECTIVE: To evaluate the analgesic efficacy of ELA-Max in comparison with EMLA cream using a novel method of thermosensory threshold analysis. METHODS: A thermosensory analyzer was used to assess warmth- and heat-induced pain thresholds. RESULTS: No statistically significant difference was found in pain thresholds using either formulation. However, EMLA cream increased the heat-induced pain threshold to a greater extent than ELA-Max. Thermosensory measurement and analysis was well tolerated and no adverse events were encountered. CONCLUSIONS: EMLA cream may be superior to ELA-Max for heat-induced pain. This study suggests that thermosensory measurement may be another suitable tool for future topical anesthetic efficacy studies.

Secondary syphilis presenting as a lichen planus-like rash.

We describe a case of secondary syphilis in a 29-year-old man who presented with a severely pruritic lichen planus-like eruption that mimicked a lichenoid drug eruption histologically. Although uncommon, syphilis should be considered in the differential diagnosis of any lichenoid eruption.