Faculty Bibliography

BACKGROUND: Limited options are available for the treatment of brittle nail syndrome. OBJECTIVE: To assess the efficacy and safety of topical cyclosporine emulsion (CsAE) versus emulsion (vehicle) alone in the treatment of brittle nail syndrome. RESULTS: Twenty-four patients were randomized to topical CsAE emulsion or emulsion (vehicle) for 24 weeks. Four fingernails of each patient were included; the 2 most severe brittle nails and the second most normal nail were treated with the same medication. The fourth nail, the most normal nail, remained untreated and was used to assess nail growth. The prespecified primary endpoint was change from baseline in Physician Global Assessment (PGA) score (0 to 5 scale) at each follow-up visit. Safety evaluations were conducted at each visit. RESULTS: In the intent-to-treat population (n=12 for each treatment arm), the PGA score for treated nails improved from baseline (CsAE, 0.7 to 1.4; emulsion, 0.7 to 1.5; P<0.05 for each), with no significant between-group differences. Untreated nails did not improve in overall appearance (0.0 to 0.3 grade; P>0.05). Statistically and clinically significant improvement from baseline was reported for nail length/appearance in both CsAE and vehicle groups. LIMITATIONS: Sample size was relatively small. The difference in PGA between treated and untreated nails was not analyzed. Baseline disease severity may have been too mild, limiting detection of efficacy. CONCLUSIONS: Both CsAE and emulsion vehicle applied topically appeared to improve signs and symptoms of brittle nail syndrome and were well tolerated. These findings warrant corroboration in a larger population and inclusion of comparison with an inactive control and a higher concentration of CsAE, the former which may help in distinguishing the efficacy of vehicle emulsion from CsAE.

BACKGROUND: Dysregulated hedgehog signaling is the pivotal molecular abnormality underlying basal-cell carcinomas. Vismodegib is a new orally administered hedgehog-pathway inhibitor that produces objective responses in locally advanced and metastatic basal-cell carcinomas. METHODS: We tested the anti-basal-cell carcinoma efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the basal-cell nevus syndrome at three clinical centers from September 2009 through January 2011. The primary end point was reduction in the incidence of new basal-cell carcinomas that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary end points included reduction in the size of existing basal-cell carcinomas. RESULTS: In 41 patients followed for a mean of 8 months (range, 1 to 15) after enrollment, the per-patient rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases per group per year, P<0.001), as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant basal-cell carcinomas (-65% vs. -11%, P=0.003). In some patients, all basal-cell carcinomas clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 adverse events of loss of taste, muscle cramps, hair loss, and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events. At 1 month, vismodegib use had reduced the hedgehog target-gene expression by basal-cell carcinoma by 90% (P<0.001) and diminished tumor-cell proliferation, but apoptosis was not affected. No residual basal-cell carcinoma was detectable in 83% of biopsy samples taken from sites of clinically regressed basal-cell carcinomas. CONCLUSIONS: Vismodegib reduces the basal-cell carcinoma tumor burden and blocks growth of new basal-cell carcinomas in patients with the basal-cell nevus syndrome. The adverse events associated with treatment led to discontinuation in over half of treated patients. (Funded by Genentech and others; ClinicalTrials.gov number, NCT00957229.).

Cutaneous drug eruptions are a common adverse reaction to medication. Creation of a drug calendar that covers a two-week span prior to the onset of rash is useful to identify the culprit agent. However, the creation of a drug calendar is often labor intensive. We developed an electronic version of a drug calendar that has considerably increased the ease and efficiency of completing a dermatology consultation.

Psoriasis affects approximately 2 percent of the population. Approximately 30-45 percent of those affected first experience symptoms during childhood or adolescence. Although biologics have proven to be a relatively safe and effective treatment option for adults with psoriasis, limited information is available regarding the use of biologic agents in pediatric patients with psoriasis. The authors attempt to assess and summarize the available data on the use of biologic agents in patients under the age of 18, regardless of the indication, as well as to examine the limited available data on the use of biologics for psoriasis in the pediatric population. In doing so, the authors aim to provide guidance on the safety and efficacy of biologic therapies in pediatric patients with psoriasis. The authors' findings suggest that biologic agents should be considered for use solely in children with psoriasis that is refractory to conventional therapies, including children currently with severe, widespread, refractory pustular, plaque or psoriatic arthritis. Of all the currently available biologics, etanercept appears to have resulted in fewer and less severe side effects compared to infliximab in the juvenile rheumatoid arthritis population. In addition, while biologics are generally safe and effective in the pediatric population, serious adverse events (including infection), have been reported in the literature and should be taken into account before beginning treatment with any biologic agent. The physician and parents of the patient must carefully consider the risk-benefit ratio when deciding whether to use these medications. Additional randomized, controlled trials are needed to adequately assess the safety and efficacy of biologic medications for childhood psoriasis.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a de novo heterozygous point mutation G608G (GGC>GGT) within exon 11 of LMNA gene encoding A-type nuclear lamins. This mutation elicits an internal deletion of 50 amino acids in the carboxyl-terminus of prelamin A. The truncated protein, progerin, retains a farnesylated cysteine at its carboxyl terminus, a modification involved in HGPS pathogenesis. Inhibition of protein farnesylation has been shown to improve abnormal nuclear morphology and phenotype in cellular and animal models of HGPS. We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.