Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome.

BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are rare, severe cutaneous adverse reactions usually triggered by medications. In addition to tertiary-level supportive care, various systemic therapies have been used including glucocorticoids, intravenous immunoglobulins (IVIGs), cyclosporin, N-acetylcysteine, thalidomide, infliximab, etanercept, and plasmapheresis. There is an unmet need to understand the efficacy of these interventions. OBJECTIVES: To assess the effects of systemic therapies (medicines delivered orally, intramuscularly, or intravenously) for the treatment of SJS, TEN, and SJS/TEN overlap syndrome. SEARCH METHODS: We searched the following databases up to March 2021: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched five clinical trial registers, the reference lists of all included studies and of key review articles, and a number of drug manufacturer websites. We searched for errata or retractions of included studies. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) and prospective observational comparative studies of participants of any age with a clinical diagnosis of SJS, TEN, or SJS/TEN overlap syndrome. We included all systemic therapies studied to date and permitted comparisons between each therapy, as well as between therapy and placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as specified by Cochrane. Our primary outcomes were SJS/TEN-specific mortality and adverse effects leading to discontinuation of SJS/TEN therapy. Secondary outcomes included time to complete re-epithelialisation, intensive care unit length of stay, total hospital length of stay, illness sequelae, and other adverse effects attributed to systemic therapy. We rated the certainty of the evidence for each outcome using GRADE. MAIN RESULTS: We included nine studies with a total of 308 participants (131 males and 155 females) from seven countries. We included two studies in the quantitative meta-analysis. We included three RCTs and six prospective, controlled observational studies. Sample sizes ranged from 10 to 91. Most studies did not report study duration or time to follow-up. Two studies reported a mean SCORe of Toxic Epidermal Necrosis (SCORTEN) of 3 and 1.9. Seven studies did not report SCORTEN, although four of these studies reported average or ranges of body surface area (BSA) (means ranging from 44% to 51%). Two studies were set in burns units, two in dermatology wards, one in an intensive care unit, one in a paediatric ward, and three in unspecified inpatient units. Seven studies reported a mean age, which ranged from 29 to 56 years. Two studies included paediatric participants (23 children). We assessed the results from one of three RCTs as low risk of bias in all domains, one as high, and one as some concerns. We judged the results from all six prospective observational comparative studies to be at a high risk of bias. We downgraded the certainty of the evidence because of serious risk of bias concerns and for imprecision due to small numbers of participants. The interventions assessed included systemic corticosteroids, tumour necrosis factor-alpha (TNF-alpha) inhibitors, cyclosporin, thalidomide, N-acetylcysteine, IVIG, and supportive care. No data were available for the main comparisons of interest as specified in the review protocol: etanercept versus cyclosporin, etanercept versus IVIG, IVIG versus supportive care, IVIG versus cyclosporin, and cyclosporin versus corticosteroids. Corticosteroids versus no corticosteroids It is uncertain if there is any difference between corticosteroids (methylprednisolone 4 mg/kg/day for two more days after fever had subsided and no new lesions had developed) and no corticosteroids on disease-specific mortality (risk ratio (RR) 2.55, 95% confidence interval (CI) 0.72 to 9.03; 2 studies; 56 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. IVIG versus no IVIG It is uncertain if there is any difference between IVIG (0.2 to 0.5 g/kg cumulative dose over three days) and no IVIG in risk of disease-specific mortality (RR 0.33, 95% CI 0.04 to 2.91); time to complete re-epithelialisation (mean difference (MD) -2.93 days, 95% CI -4.4 to -1.46); or length of hospital stay (MD -2.00 days, 95% CI -5.81 to 1.81). All results in this comparison were based on one study with 36 participants, and very low-certainty evidence. Adverse effects leading to discontinuation of therapy were not reported. Etanercept (TNF-alpha inhibitor) versus corticosteroids Etanercept (25 mg (50 mg if weight > 65 kg) twice weekly "until skin lesions healed") may reduce disease-specific mortality compared to corticosteroids (intravenous prednisolone 1 to 1.5 mg/kg/day "until skin lesions healed") (RR 0.51, 95% CI 0.16 to 1.63; 1 study; 91 participants; low-certainty evidence); however, the CIs were consistent with possible benefit and possible harm. Serious adverse events, such as sepsis and respiratory failure, were reported in 5 of 48 participants with etanercept and 9 of 43 participants with corticosteroids, but it was not clear if they led to discontinuation of therapy. Time to complete re-epithelialisation and length of hospital stay were not reported. Cyclosporin versus IVIG  It is uncertain if there is any difference between cyclosporin (3 mg/kg/day or intravenous 1 mg/kg/day until complete re-epithelialisation, then tapered off (10 mg/day reduction every 48 hours)) and IVIG (continuous infusion 0.75 g/kg/day for 4 days (total dose 3 g/kg) in participants with normal renal function) in risk of disease-specific mortality (RR 0.13, 95% CI 0.02 to 0.98, 1 study; 22 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. No studies measured intensive care unit length of stay. AUTHORS' CONCLUSIONS: When compared to corticosteroids, etanercept may result in mortality reduction. For the following comparisons, the certainty of the evidence for disease-specific mortality is very low: corticosteroids versus no corticosteroids,  IVIG versus no IVIG and cyclosporin versus IVIG. There is a need for more multicentric studies, focused on the most important clinical comparisons, to provide reliable answers about the best treatments for SJS/TEN.

The Impact of Suspension of Dermatology On-Call Services.

BACKGROUND: Dermatological conditions are commonly seen in the emergency department and inpatient wards. The ability to access dermatology on-call services improves the accuracy of diagnosis and management of common and sometimes life-threatening conditions. Limitations of dermatologist availability led to the suspension of the dermatology on-call service for 3 months in Ottawa, Canada. OBJECTIVES: Our objective was to assess the impact of this call suspension on patient care and the need for a dermatology on-call service at our hospital, as perceived by nondermatologist physicians at our center. METHODS: A survey was sent to all departments at The Ottawa Hospital, addressed to staff physicians and residents. Participation was entirely voluntary. Descriptive statistics were used to analyze survey responses. RESULTS: A total of 105 physicians completed the survey including staff physicians (85%) and resident trainees (15%). The most represented specialties were emergency medicine (N = 21), general internal medicine (N = 19), nephrology (N = 17), neurology (N = 13), and plastic surgery (N = 13). Over half of the respondents felt that the lack of dermatology on-call service impacted the care of their patients by a moderate or great extent. Over half reported performing dermatology-related clinical work during the call suspension and two-thirds of these individuals reported feeling uncomfortable or very uncomfortable doing so. Most (94%) participants felt that an on-call dermatology service was useful and 57% deemed it essential. CONCLUSION: Our survey results demonstrate a significant impact of the suspension of a dermatology on-call service, as perceived by nondermatologist physicians. Hospitals need to recognize the importance of on-call dermatology consultations and provide support for divisions to enable this service to continue.

Management of Common Side Effects of Apremilast.

Apremilast is a relatively new therapy for the treatment of moderate to severe plaque psoriasis in adults. While this medication is considered safe with a very low risk of serious side effects, a few common (≥5% of patients) mild to moderate side effects have been reported, including diarrhea, nausea, headache, and nasopharyngitis. Not addressing these symptoms may lead to medication nonadherence and unnecessary discontinuation of therapy. These side effects are often easily managed with interventions available to the practicing dermatologist, and in only rare instances will these side effects require dose adjustment or discontinuation of therapy. The purpose of this article is to review common side effects of apremilast at its approved dose of 30 mg orally twice daily (BID) and to provide clear, simple recommendations for their management in dermatological practice.

Brief Report: Increase in Melanoma Incidence in Ontario.

BACKGROUND: Melanoma is a serious, potentially lethal disease. It is one of very few common cancers whose incidence is rising in North America. OBJECTIVES: The objective of this study was to examine trends in melanoma incidence in Ontario, Canada's most populous province, over the past 20 years. METHODS: Using data from the Ontario Cancer Registry (OCR), this retrospective cohort examined all incident cases of melanoma in Ontario from 1990 to 2012. Generalized linear modeling was used to evaluate changes in melanoma incidence over time, adjusting for age and sex using direct standardization with the 1991 Canadian census population. Tests for trend for changes in the distribution of cases by age, sex, socioeconomic status, and rurality status were also calculated. RESULTS: Our results show a statistically significant increasing incidence of melanoma in Ontario from 9.3 cases per 100 000 in 1990 to 18.0 cases per 100 000 in 2012 ( P for trend <.001, adjusted for age and sex). Incidence rates show stabilization from 2010 to 2012. CONCLUSION: Our study reveals a marked increase in melanoma incidence in Ontario, more than doubling over the past 20 years but with a stabilization more recently. Adequate availability of dermatology services may be important to ensure satisfactory care for the increased caseload and to ensure that cases may detected at an early stage with a good prognosis.

Erythema Multiforme in Children and Mycoplasma pneumoniae Aetiology.

Erythema multiforme (EM) in children is understudied and confused with Stevens-Johnson syndrome (SJS) despite their being separate diseases with unique aetiologies and clinical presentations. The goal of this study was to determine the prevalence of Mycoplasma pneumoniae in paediatric patients with EM minor, EM major (EMM), and SJS. This retrospective cohort at The Hospital for Sick Children accrued all cases of EM minor, EMM, and SJS from 1999 to 2013. Sixty-five cases were identified: 20 of EM minor, 23 of EMM, and 22 of SJS. Aetiologies were attributed in 58% of cases: 79% infection and 21% drug aetiology. Sixty-one percent of patients with EMM were M pneumoniae positive, compared with 14% of those with SJS and 22% of those with EM minor (P < .01). M pneumoniae patients were older at presentation (P = .03) and more frequently had sore throat (P < .01) and atypical targets with central blistering (P < .01). These findings suggest that M pneumoniae should be suspected and treated until laboratory confirmation becomes available in patients presenting with atypical target lesions with central blistering.

Laryngoscope manipulation by experienced versus novice laryngoscopists.

PURPOSE: During endotracheal intubation using a Macintosh laryngoscope blade, it has been recommended by some that the best laryngeal view is achieved with a laryngoscope handle angle of 45º from horizontal; however, this may be unnecessary. Novices are rarely taught specifically how or where to grip the laryngoscope handle. This study compared the angle and grip of the laryngoscope handle by experienced vs novice laryngoscopists to determine whether basic differences could be identified that might aid in teaching the nuances of skillful laryngoscope manipulation. METHODS: Laryngoscopists were photographed performing tracheal intubation for elective surgical patients (22 experienced laryngoscopists) and an airway trainer mannequin (22 experienced and 21 novice layngoscopists). The photographs were analyzed for laryngoscope handle angle from horizontal, eye-scope distance, and eye-scope angle. Airway trainer photographs were also assessed for hand rotational angle and distance from the laryngoscope base. RESULTS: The average laryngoscope handle angle for patient tracheal intubations was 23.7º (95% confidence interval [CI]: 21.1 to 26.2), significantly less than 45º (P < 0.001). Compared with novices, experts gripped the laryngoscope handle closer to the hinge at rest and at best laryngeal view (P = 0.001 and P = 0.003, respectively), held the laryngoscope in their fingers vs the palm of their hand (P = 0.005), and used greater eye-scope distances (P = 0.005) for airway trainer intubations. Expert technique was unchanged with patient vs airway trainer laryngoscopy. CONCLUSION: Experienced laryngoscopists used laryngoscope handle angles less than 45º from horizontal for routine intubations. Compared with novices, experts gripped the laryngoscope closer to the hinge and held the laryngoscope more in their fingers vs the palm of their hand. Sharing these important points with novices early in their instruction may improve technique and skill acquisition.

Anthropometric measures and the risk of endometrial cancer, overall and by tumor microsatellite status and histological subtype.

Obesity is an established risk factor for endometrial cancer, but this association is not well understood for subtypes of endometrial cancer. We evaluated the association of recent and adult-life obesity with subtypes of endometrial cancer based on microsatellite status (microsatellite-stable (MSS) vs. microsatellite-instable (MSI)) and histology (type I vs. type II). Analyses were based on a population-based case-control study (524 cases and 1,032 controls) conducted in Alberta, Canada (2002-2006) and included the following groupings of subtypes: MSS = 337 and MSI = 130; type I = 458 and type II = 66. Logistic and polytomous logistic regression were used to estimate odds ratios and 95% confidence intervals for overall endometrial cancer and subtypes of endometrial cancer, respectively. The risks of all subtypes of endometrial cancer, except type II, increased with an increase in all of the anthropometric characteristics examined. The risks for MSI tumors were suggestively stronger than those for MSS tumors; the risk with high (≥30) body mass index (weight (kg)/height (m)(2)) was significantly stronger for MSI tumors (odds ratio = 4.96, 95% confidence interval: 2.76, 8.91) than for MSS tumors (odds ratio = 2.33, 95% confidence interval: 1.66, 3.28) (P-heterogeneity = 0.02). Obesity is associated with most subtypes of endometrial cancer, and further studies are warranted to elucidate the biological mechanisms underlying the stronger risk for the MSI subtype with a high body mass index.

Case-control study of lifetime alcohol consumption and endometrial cancer risk.

PURPOSE: Alcohol consumption is hypothesized to increase the risk of endometrial cancer by increasing circulating estrogen levels. This study sought to investigate the association between lifetime alcohol consumption and endometrial cancer risk. METHODS: We recruited 514 incident endometrial cancer cases and 962 frequency age-matched controls in this population-based case-control study in Alberta, Canada, from 2002 to 2006. Participants completed in-person interviews querying lifetime alcohol consumption and other relevant health and lifestyle factors. Participants reported the usual number of drinks of beer, wine, and liquor consumed; this information was compiled for each drinking pattern reported over the lifetime to estimate average lifetime exposure to alcohol. RESULTS: Lifetime average alcohol consumption was relatively low (median intake: 3.9 g/day for cases, 4.9 g/day for controls). Compared with lifetime abstainers, women consuming >2.68 and ≤8.04 g/day alcohol and >8.04 g/day alcohol on average over the lifetime showed 38 and 35 % lower risks of endometrial cancer, respectively (p trend = 0.023). In addition, average lifetime consumption of all types of alcohol was associated with decreased risks. There was no evidence for effect modification by body mass index, physical activity, menopausal status, and hormone replacement therapy use combined and effects did not differ by type of endometrial cancer (type I or II). CONCLUSION: This study provides epidemiologic evidence for an inverse association between relatively modest lifetime average alcohol consumption (approximately 1/4 to 1/2 drink/day) and endometrial cancer risk. The direction of this relation is consistent with previous studies that examined similar levels of alcohol intake.

A neonate with Langerhans cell histiocytosis presenting as blueberry muffin rash: Case report and review of the literature.

In our case report, we discuss a 1-day-old boy presenting with blueberry muffin syndrome diagnosed with Langerhans cell histiocytosis. The diagnosis complicated by an initial difficult-to-interpret biopsy showing only a hint of perifollicular CD1a-positive cells; however, given our team's strong clinical suspicion of Langerhans cell histiocytosis, a second biopsy of a more mature lesion was done and showed typical histopathology. This case introduces the possibility of perifollicular Langerhans cells early in this condition, demonstrates the importance of appropriate biopsy site selection, and highlights the importance of maintaining a high degree of suspicion when there is poor clinicopathologic correlation. Our case report contains a comprehensive table which reviews the systemic and cutaneous clinical features, as well as the laboratory, pathology, and imaging findings for the differential diagnoses of blueberry muffin baby.

A Case of Colocalized Vitiligo and Psoriasis.

BACKGROUND: Psoriasis and vitiligo are common dermatologic conditions with underlying autoimmune etiologies. There are few reports of concomitant and colocalized disease. Several theories have been proposed to explain this rare presentation. OBJECTIVE: The objective of this study was to present a rare case of a concomitant and colocalized presentation of vitiligo and psoriasis. METHODS: Case report. RESULTS: A 72-year-old male was referred for treatment of a 30-year history of psoriasis and 5-year history of colocalized vitiligo. The patient had no other underlying autoimmune diseases including psoriatic arthritis. CONCLUSION: Clinicians should be aware of the possible concomitance and colocalization of psoriasis and vitiligo. Further research is needed to elucidate the common pathways leading to the concomitance and colocalization of these diseases.

Case-control study of inflammatory markers and the risk of endometrial cancer.

Chronic inflammation may be important in endometrial cancer etiology. Several established endometrial cancer risk factors, particularly obesity, are hypothesized to operate through this pathway by increasing proinflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and acute-phase protein C-reactive protein (CRP). This study sought to investigate the association between inflammatory markers and the risk of endometrial cancer (types I and II). We recruited 519 incident endometrial cancer cases and 964 frequency age-matched controls in this population-based case-control study in Alberta (Canada) from 2002 to 2006. Participants completed in-person interviews, were assessed for anthropometric measures, and provided 8-h fasting blood samples either preoperatively or postoperatively. Blood was analyzed for the concentrations of TNF-α, IL-6, and CRP by immunoassay. Endometrial cancer cases had consistently higher mean levels of TNF-α, IL-6, and CRP compared with controls in these predominantly postmenopausal women. After adjusting for age, all markers were associated with statistically significant increased risks for endometrial cancer; however, after multivariable adjustment, only the risk from CRP remained elevated (odds ratio=1.22, 95% confidence interval: 1.02-1.47). Similarly, upon stratification by cancer type, only CRP was associated positively with an increased risk for type I endometrial cancer (odds ratio=1.25, 95% confidence interval: 1.03-1.52). All markers were associated with an elevated risk for the more rare and aggressive type II cancers; however, these findings were statistically nonsignificant, likely because of the small number of cases in this group. In conclusion, we found epidemiologic evidence for an association between CRP and the risk of endometrial cancer, which was slightly stronger for type I cancer. No associations emerged for TNF-α and IL-6.

A cross-sectional study of breast cancer biomarkers among shift working nurses.

Objectives In 2007, the International Agency for Research on Cancer classified long-term shift work as a probable carcinogen, with the strongest evidence for breast cancer. One proposed mechanism involves night-time light exposure and decreases in melatonin, a circadian rhythmic hormone. It is hypothesised that melatonin influences patterns of sex hormone production that in turn influence breast cancer risk. This study sought to investigate the relationships of shift work history, 6-sulfatoxymelatonin (aMTs-6, the primary melatonin metabolite) and sex hormone levels among shift working nurses. Design This is a cross-sectional biomarker study. Setting 94 premenopausal nurses who work a full-time rotating shift schedule at one Ontario hospital were recruited for this study; 82 completed follow-up. Primary and secondary outcome measures Study participants provided morning void urine and fasting blood samples for the assessment of aMTs-6 and sex hormone (oestradiol, oestrone, progesterone, prolactin) levels, respectively. These data were collected at two time points (summer and winter) such that relationships between melatonin and sex hormones could be assessed with respect to two time frames of interest (acute and cross-seasonal). Results An inverse relationship between aMTs-6 and oestradiol was suggested in the winter (ß=-0.18, p=0.04), but this result was not statistically significant in multivariate modelling that adjusted for age, body mass index and menstrual cycle. Likewise, while oestradiol, oestrone and progesterone levels increased with greater years of shift work history (all p<0.05), these associations were attenuated after confounder adjustment. Conclusions These results do not support the proposed relationship between melatonin and sex hormone levels as biomarkers on the pathway of shift work and breast cancer but emphasise the importance of adjusting for confounders in modelling.

Case-control study of markers of insulin resistance and endometrial cancer risk.

Markers of insulin resistance such as the adiponectin:leptin ratio (A:L) and the homeostasis model assessment ratio (HOMA-IR) are associated with obesity and hyperinsulinemia, both established risk factors for endometrial cancer, and may therefore be informative regarding endometrial cancer risk. This study investigated the association between endometrial cancer risk and markers of insulin resistance, namely adiponectin, leptin, the A:L ratio, insulin, fasting glucose, and the HOMA-IR. We analyzed data from 541 incident endometrial cancer cases and 961 frequency age-matched controls in a population-based case-control study in Alberta, Canada from 2002 to 2006. Participants completed interview-administered questionnaires were assessed for anthropometric measures, and provided 8-h fasting blood samples either pre- or postoperatively. Blood was analyzed for concentrations of leptin, adiponectin, and insulin by immunoassay, and fasting plasma glucose levels were determined by fluorimetric quantitative determination. Compared with the lowest quartile, the highest quartile of insulin and HOMA-IR was associated with 64% (95% confidence intervals (CI): 1.12-2.40) and 72% (95% CI: 1.17-2.53) increased risks of endometrial cancer, respectively, and the highest quartile of adiponectin was associated with a 45% (95% CI: 0.37-0.80) decreased risk after multivariable adjustments. Null associations were observed between fasting glucose, leptin and A:L, and endometrial cancer risk. This population-based study provides evidence for a role of insulin resistance in endometrial cancer etiology and may provide one possible pathway whereby obesity increases the risk of this common cancer. Interventions aimed at decreasing both obesity and insulin resistance may decrease endometrial cancer risk.