Topical clobetasol for the treatment of toxic epidermal necrolysis: study protocol for a randomized controlled trial.

BackgroundToxic epidermal necrolysis (TEN) is a rare systemic allergic drug eruption with high patient mortality. Currently, no established treatments have been shown to be effective for TEN beyond supportive care. Prior studies of systemic corticosteroids have yielded conflicting data, with some showing a possible benefit and others reporting in increased mortality. However, topical steroids have shown promise for treatment of ocular sequelae of TEN, such as scarring and vision loss. We have designed a randomized controlled trial to evaluate topical clobetasol for treatment of the epidermal manifestations of TEN. In addition, we propose genetic studies to characterize the TEN transcriptome and alterations in cutaneous gene expression that might occur following topical steroid treatment.Methods/designThis split-body randomized, double-blind, placebo-controlled Phase IIa proof-of-concept trial will evaluate the safety and efficacy of once-daily topical clobetasol applied to the skin of patients with TEN. This multicenter trial will recruit a total of 15 patients between the ages of 12 and 85 from the University of California Davis Medical Center and Shriners Hospital for Children inpatient burn units. Designated treatment areas on opposite sides of the body will be treated with blinded clobetasol 0.05% ointment or control petrolatum ointment daily for 14 days. On day 3 of therapy, a biopsy will be taken from the treated area for genetic studies. The primary study aims will be to establish the safety of topical clobetasol treatment and determine the time to cessation of skin detachment for the control and clobetasol-treated areas. Secondary endpoints will evaluate efficacy using parameters such as time to 90% re-epithelialization and percentage of affected skin at 0, 3, 6, 9, 12 and 15 days. Genomic DNA and RNA will be obtained from biopsy samples, to characterize the TEN transcriptome and identify changes in gene expression after topical steroid treatment.DiscussionTopical steroids have shown promise for treating ocular complications of TEN, but to date have not been evaluated for cutaneous manifestations of the disease. This trial will investigate clinical and molecular outcomes of topical clobetasol application and hopefully provide insight into the disease pathophysiology.Trial registrationClinicalTrials.gov NCT02319616. https://clinicaltrials.gov/ct2/show/NCT02351037

65 Year Old Woman with Hemoptysis: a Case Report/review of Literature Discussing Scleroderma,vasculitis, & Malignancy

A 66 year-old Hispanic Caucasian lady with a 14 year history of diffuse scleroderma and bilateral stage II-B invasive breast cancer presented for evaluation of a vasculitic rash and hemoptysis. On examination vital signs were stable and cardiovascular exam was normal. Pulmonary exam revealed coarse crackles to the mid-lung fields bilaterally with bronchial breath sounds at the left apex. Abdominal exam was benign with no hepatosplenomegaly. Musculoskeletal exam revealed bilateral sclerodactyly with modified Rodnan Skin Score of 14 and contractures of the digits. There was a large punched-out ulceration over the right third metacarpophalangeal joint measuring 1x0.7x0.2 cm with desiccated tendon in the base. Multiple similar ulcers were noted over other joints, and on the legs she had a petechial rash consistent with leukocytoclastic vasculitis. CT thorax revealed multiple lung nodules and masses, bilateral lower lobe honeycombing, bibasilar reticular changes with traction bronchiectasis, ground glass opacities in bilateral upper lobes with multiple calcified granulomata with cavitation. Laboratory evaluation revealed normocytic anemia, ESR 23 mm/hr, CRP 14 mg/dL, c-ANCA titer of 1:640, with proteinase-3 antibody of 39.9 U/mL. Anti-nuclear antibody was positive at a titer of 1:160 homogenous pattern and additional serologic testing revealed positive RNA polymerase III antibody at 33.4 units. Differential diagnosis included infections causing cavitating pneumonias, granulomatosis with polyangiitis and other ANCA-associated vasculitides, and primary or secondary malignant lung lesions. The patient underwent left thoracoscopic wedge resection of the left lower lobe. Gram stain, acid fast and fungal stains with cultures were all negative. Histopathology demonstrated background fibrosis, cyst formation, and bronchial metaplasia consistent with scleroderma-associated lung disease. Additionally, areas of necrotizing granulomatous inflammation and vasculitis were seen consistent with focal vasculitis. Subjacent to the pleura atypical epithelial proliferation was seen and these cells stained diffusely positive for MAK-6, GATA-3, estrogen receptor and mammoglobulin. Taken together the findings were consistent with RNAP III-positive diffuse scleroderma with associated breast cancer, presenting with lung metastases and ANCA-associated vasculitis consistent with limited GPA. The patient was treated with pulse-dose glucocorticoids for 3 days followed by prednisone 60 mg daily along with Rituximab for her ANCA-associated vasculitis. The breast cancer was treated with anastrazole 1 mg daily. She is currently doing well. This case emphasizes the now well-recognized co-temporal relationship between scleroderma and malignancy, and the emerging pathophysiologic understanding of the relationship between autoantigen mutations in malignant tissues and autoimmune triggering