Neil H. Shear

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

14 Dermatological drugs, topical agents, and cosmetics

Publisher Summary This chapter examines the dermatological drugs, topical agents, and cosmetics. Botulinum toxin A is used for the treatment of facial rhytides by producing weakness or paralysis of the associated muscles, and in the treatment of hyperhidrosis. Transient adverse effects, such as temporary bruising, discomfort, incomplete muscle paralysis, or headache, can occur. Focal weakness was the only adverse event that occurred significantly more often with botulinum toxin A than control. It is found that although p –phenylenediamine (PPD) and toluene-2,5-diamine are the most frequently reported hair dye allergens, allergic contact dermatitis from direct dyes for hair coloration is unusual. Two patients with a history of PPD allergic contact dermatitis had positive patch tests to HC Yellow 7, 4 amino-3-nitrophenol and HC Red B54 in hair dyes. The main adverse effects associated with finasteride are loss of libido, erectile dysfunction, and reduced ejaculate volume. In clinical trials, 4.4% of patients treated with finasteride and 2.2% of patients taking placebo experienced sexual adverse effects. Systemic and topical psoralens plus ultraviolet A irradiation (PUVA therapy) are well-established treatments for vitiligo. Adverse effects of PUVA therapy include nonmelanoma skin cancer and PUVA-induced lentigines. It is found that lentigines are common among PUVA-treated patients with psoriasis, but rare in patients with vitiligo.

Ciprofloxacin skin testing: A retrospective study

RATIONALE: Limited information is available regarding the validity of procedures to diagnose allergic adverse drug reactions (ADRs) associated with fluoroquinolones (FQ). A retrospective study was undertaken to examine the clinical utility of ciprofloxacin (CP) skin testing. MATERIALS AND METHODS: A review of 135 charts from patients seen with suspected FQ associated ADRs between 1996-2001 was con- ducted at the Sunnybrook Drug Safety Clinic. Skin testing (prick and intradermal) was performed to CP (0.0001 mg/ml to 0.1 mg/ml) and levofloxacin (0.0001 mg/ml to 0.1 mg/ml) and oral challenge with CP (250 rag) and/or another FQ was administered following the negative skin tests. RESULTS: False positive reactions were associated with concentrations >0.05 mg/ml. 5/135 (4%) tested positive on the skin testing; 2 to levofloxacin and 3 to CP. 20/135 (15%) were positive on the oral challenge; however, only 9 (7%) subjects had reactions consisting of a rash and/or breathing difficulties within the time frame for an immediate or accelerated reaction (between 0 and 72 hours). The other 11 (8%) false negative reactions were potentially non-allergic (eg, pruritus, lightheadedness). There was a significant relationship between the original reaction history (indicative or non-indicative of immediate hypersensitivity) and positive oral challenge outcomes (true false negative or non-specific reactions) (P=0.0014, 95% CI). The negative predictive value for this test was deter- mined to be 93.1%, which is comparable to the negative predictive value for penicillin, the gold standard for skin testing. CONCLUSIONS: Skin testing should be pursued as a diagnostic tool for suspected allergic ADRs associated with FQ antibiotics.

Practical Approach to Diagnosis and Management of Cutaneous Adverse Drug Reactions

Drug eruptions have a wide spectrum of clinical manifestations, are caused by various drugs, and result from varied pathophysiological mechanisms. Hence, their diagnosis and management is challenging. Drug eruptions can range from a mild, simple eruption involving only the skin to severe complex eruptions with systemic involvement, such as toxic epidermal necrolysis. Systemic involvement should be explored even in a mild cutaneous eruption due to a drug since the severity of skin manifestation does not necessarily mirror the severity of the systemic involvement. This chapter aims to provide a practical approach to a patient with a suspected drug eruption.

Pharmacogenetics and Pharmacogenomics II: Genetic Determinants of Drug Responses and Adverse Drug Reactions

The ability to predict efficacy and safety is crucial for drug discovery and development. To date, there are only a few genetic biomarkers whose clinical validity in predicting drug response has been clearly established; for example, HER-2/neu-positivity in breast cancer as a predictor of response to trastuzumab (Herceptin) [1]. Patient variability in response to medications can range from failure to demonstrate an expected therapeutic effect to development of an adverse reaction, resulting in significant patient morbidity and mortality, as well as increasing healthcare costs. In order to optimize treatment response and decrease adverse drug reactions, pharmacogenetics and pharmacogenomics are being increasingly utilized. Pharmacogenetics is the study of genetic variation and its effects on the response to drugs, vaccines, or other pharmaceutical agents [2]. Pharmacogenomics more broadly involves genome-wide analysis of the genetic determinants of drug efficacy and toxicity. Primary candidate genes of interest include those encoding for drug receptors, metabolizing enzymes, and transporters. However, selection of optimal drug therapy may also involve disease susceptibility genes indirectly affecting drug responses [3].

The utility of skin testing in suspected clindamycin allergy

RATIONALE: Skin testing has been validated for lgE-mediated reactions associated with penicillin but little information exists regarding this form of testing for other drugs. We explored the clinical utility of clindamycin prick testing and intradermal testing in patients with immediate or delayed reactions to clindamycin. METHODS: A total of 34 subjects with histories of reactions associated with clindamycin (14 accelerated reactions, 11 delayed, and 8 not documented) underwent prick and intradermal skin testing to clindamycin (0.15 mg/ml to 15 mg/ml) between 1999 and 2001. Subjects with negative skin testing received a single oral dose of clindamycin. RESULTS: Although none of the 34 prick and intradermal tests per- formed were positive, a significant number of patients [11/34 (32%)] had reactions to the oral challenge lie, immediate reactions (n=l) and accelerated reactions (n= 10)]. Sensitivity of the prick and intradermal testing was determined to be 0%, specificity 100%, positive predictive value 0%, and negative predictive value 68%. CONCLUSIONS: Our experience highlights the low clinical utility of prick and intradermal testing for allergic and cutaneous reactions associated with clindamycin. We caution against the use of clindamycin skin testing as a diagnostic tool in this setting. Although a single oral challenge appears to be highly predictive it should be used selectively given the potential for significant morbidity incurred by induced reactions.