Supriya S. Venugopal

A phase II randomized vehicle-controlled trial of intradermal allogeneic fibroblasts for recessive dystrophic epidermolysis bullosa

BACKGROUND Chronic wounds are a major source of morbidity and mortality in generalized severe recessive dystrophic epidermolysis bullosa (RDEB-GS). OBJECTIVE This was a phase II double-blinded randomized controlled trial of intralesional allogeneic cultured fibroblasts in suspension solution versus suspension solution alone for wound healing in RDEB-GS. METHODS Adult patients with RDEB-GS were screened for chronic ulcers and reduced collagen VII expression. Up to 6 pairs of symmetric wounds were measured and biopsied at baseline, then randomized to cultured allogeneic fibroblasts in a crystalloid suspension solution with 2% albumin or suspension solution alone. Ulcer size, collagen VII protein and messenger RNA expression, anchoring fibril numbers, morphology, and inflammatory markers were measured at 2 weeks and at 3, 6, and 12 months. RESULTS All wounds healed significantly more rapidly with fibroblasts and vehicle injections, with an area decrease of 50% by 12 weeks, compared with noninjected wounds. Collagen VII expression increased to a similar degree in both study arms in wounds from 3 of 5 patients. LIMITATIONS The number of patients with RDEB-GS who met inclusion criteria was a limitation, as was 1 trial center rather than multicenter. CONCLUSIONS The injection of both allogeneic fibroblasts and suspension solution alone improved wound healing in chronic nonhealing RDEB-GS wounds independently of collagen VII regeneration. This may provide feasible therapy for wound healing in patients with RDEB-GS.

Recalcitrant Cutaneous Warts Treated With Recombinant Quadrivalent Human Papillomavirus Vaccine (Types 6, 11, 16, and 18) in a Developmentally Delayed, 31-Year-Old White Man

A 31-year-old white man with developmental delay and a history of epilepsy was seen in February 2008 with multiple warts on his hands that had been present for several years. He had previously been treated with podophyllin, 2 different concentrations of salicylic acid (25% and 40%), and oral cimetidine, and his regular medications included lamotrigine, valproate, topiramate, and levetiracetam. He denied other risk factors for human immunodeficiency virus (HIV) or AIDS and lived at home with his parents. He also denied a history of other autoimmune conditions and allergies and had no relevant family history of other illnesses or dermatologic conditions. On examination, we found that he had multiple hyperkeratotic warty lesions on the dorsal and palmar aspects of his hands bilaterally (Figure 1). In addition, he had multiple warts on his chin, both knees, and right third metatarsophalangeal joint. In total, he had about 30 warts, the largest of which was on the right thumb. Several additional treatments were tried, including cryotherapy and 6 weeks of nightly application of imiquimod cream. We considered acitretin therapy, but this was not initiated owing to his neurologists’ concerns about potential interactions with his antiepileptic medications. Owing to the persistence and extensive nature of the warts, we performed a complete blood cell count; tests for electrolyte, urea, creatinine, and fasting glucose levels; liver function tests; thyroid function tests; and an HIV screen, the results of which were all normal. No human papillomavirus (HPV) typing was performed. A genetic underlying immune deficiency was thought to be very unlikely, given his relatively older age at presentation. The patient denied having a sexual partner, and no genital warts were found on examination. The patient and his family also denied a history of genital warts. THERAPEUTIC CHALLENGE

Diagnosis and clinical features of pemphigus vulgaris.

Autoimmune bullous diseases are associated with autoimmunity against structural components that maintain cell-cell and cell-matrix adhesion in the skin and mucous membranes. They include those where the skin blisters at the basement membrane zone and those where the skin blisters within the epidermis (pemphigus vulgaris, pemphigus foliaceus, and other subtypes of pemphigus). The variants of pemphigus are determined according to the level of intraepidermal split formation. There are 5 main variants of pemphigus: pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus. This review focuses only on pemphigus vulgaris.

Diagnosis and Clinical Features of Pemphigus Vulgaris

Autoimmune bullous diseases are associated with autoimmunity against structural components that maintain cell-cell and cell-matrix adhesion in the skin and mucous membranes. They include those where the skin blisters at the basement membrane zone and those where the skin blisters within the epidermis (pemphigus vulgaris, pemphigus foliaceus, and other subtypes of pemphigus). The variants of pemphigus are determined according to the level of intraepidermal split formation. There are 5 main variants of pemphigus: pemphigus vulgaris, pemphigus foliaceus, pemphigus erythematosus, drug-induced pemphigus, and paraneoplastic pemphigus. This review focuses only on pemphigus vulgaris.

Development of a quality-of-life instrument for autoimmune bullous disease: The autoimmune bullous disease quality of life questionnaire

IMPORTANCE Quality-of-life (QOL) evaluation is an increasingly important outcome measure in dermatology, with disease-specific QOL instruments being the most sensitive to changes in disease status. OBJECTIVE To develop a QOL instrument specific to autoimmune bullous disease (AIBD). DESIGN A comprehensive item generation process was used to build a 45-item pilot Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire, distributed to 70 patients with AIBD. Experts in bullous disease refined the pilot ABQOL before factor analysis was performed to yield the final ABQOL questionnaire of 17 questions. We evaluated validity and reliability across a range of indices. SETTING Australian dermatology outpatient clinics and private dermatology practices. PATIENTS AND EXPOSURE: Patients with a histological diagnosis of AIBD. MAIN OUTCOMES AND MEASURES The development of an AIBD-specific QOL instrument. RESULTS Face and content validity were established through the comprehensive patient interview process and expert review. In terms of convergent validity, the ABQOL was found to have a moderate correlation with scores on the Dermatology Life Quality Index (R = 0.63) and the General Health subscale of the 36-Item Short Form Health Survey (R = 0.69; P = .009) and low correlation with the Pemphigus Disease Area Index (R = 0.42) and Autoimmune Bullous Disease Skin Disorder Intensity Score (R = 0.48). In terms of discriminant validity, the ABQOL was found to be more sensitive than the Dermatology Life Quality Index (P = .02). The ABQOL was also found to be a reliable instrument evaluated by internal consistency (Cronbach α coefficient, 0.84) and test-retest reliability (mean percentage variation, 0.92). CONCLUSIONS AND RELEVANCE The ABQOL has been shown to be a valid and reliable instrument that may serve as an end point in clinical trials. Future work should include incorporating patient weighting on questions to further increase content validity and translation of the measure to other languages. CLINICAL TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12612000750886.

Treatment of Skin Cancers in Epidermolysis Bullosa

Squamous cell carcinomas (SCCs) are highly aggressive in patients with epidermolysis bullosa (EB). Non-ultraviolet-related SCCs are the leading cause of death in patients with recessive dystrophic EB, particularly recessive dystrophic EB-generalized severe subtype (RDEB-GS). The mechanism of SCC development in patients with RDEB continues to be investigated and several theories have been reported in the literature.

The development and validation of the Treatment of Autoimmune Bullous Disease Quality of Life questionnaire, a tool to measure the quality of life impacts of treatments used in patients with autoimmune blistering disease

Treatments for autoimmune blistering diseases have significant risk of medical complications and quality of life impacts during treatment, and it is difficult to differentiate these impacts from disease burden or the effects of treatment.

Diffuse melanosis cutis: A systematic review of the literature

BACKGROUND Diffuse melanosis cutis (DMC) is a rare presentation of metastatic melanoma characterized by a progressive blue-gray discoloration of the skin and mucous membranes. OBJECTIVE To foster a better understanding of the clinical presentation, histological findings, and pathophysiology underlying DMC. METHODS A systematic review of the literature was completed utilizing MEDLINE, CINAHL, Embase, and Google. Data were extracted using a protocol-driven spread sheet with all statistical analyses completed using SPSS. RESULTS The review identified 68 original cases of DMC. The mean time from diagnosis of melanoma until development of DMC was 11.48 months (95% confidence interval [CI]: 0-48.16). The mean time to death following the onset of DMC was 4.43 months (95% CI: 0.00-11.11). Histological findings were relatively consistent demonstrating intracellular and extracellular melanin deposition in the dermis, with a pronounced perivascular distribution. The pathophysiological mechanisms underlying DMC could not be definitively elucidated; however, it is hypothesized that the melanin precursors, melanin, and melanosomes liberated by cytolytic metastatic melanoma deposits are phagocytosed by dermal histiocytes, manifesting clinically as diffuse melanosis. LIMITATIONS The cross-sectional nature of case reports, paucity of cases of DMC, and heterogeneity in reporting limit any conclusions being drawn regarding the pathophysiology of DMC definitively. CONCLUSION DMC heralds a poor prognosis for patients with metastatic melanoma and affected patients should be made aware of the implications of this condition on survival.

A pilot comparison study of four clinician-rated atopic dermatitis severity scales

There are multiple severity outcome measures for atopic dermatitis (AD). There is a need to compare the reliability of these measures.

Development, reliability, and validity of a novel Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI)

BACKGROUND There is a lack of validated standardized outcome measures for epidermolysis bullosa (EB) that can separate activity from damage. OBJECTIVE We sought to develop and validate an instrument for inherited EB of all ages and subtypes, the EB Disease Activity and Scarring Index (EBDASI), which scores activity responsive to therapy separately from scarring. METHODS The EBDASI was validated by comparing its reliability and validity against the Birmingham EB Severity (BEBS) score (partially validated with activity mixed with scarring), using the Physician Global Assessment (PGA) scale as a reference measurement. Sixteen patients with EB (7 EB simplex, 5 dominant dystrophic EB [DDEB], 2 junctional EB, and 2 recessive dystrophic EB) were assessed by 5 EB experts using the EBDASI, BEBS, and PGA, and data from 9 additional patients assessed on an ad hoc basis during routine patient clinic were also included. RESULTS For interrater reliability, the overall total score intraclass correlation coefficients (95% confidence intervals) were: EBDASI 0.964 (0.929-0.986), BEBS 0.852 (0.730-0.937), and PGA 0.873 (0.765-0.946). For intrarater reliability, the intraclass correlation coefficients were: EBDASI 0.994 (0.976-0.998), BEBS 0.926 (0.748-0.981), and PGA 0.932 (0.764-0.982). The EBDASI had a higher correlation with PGA (ρ = 0.871) than BEBS with PGA (ρ = 0.852). Intraclass correlation coefficients scatterplots showed the EBDASI was better at distinguishing milder forms of EB, with better correlations at higher severity scores than the BEBS. LIMITATIONS A limited number of patients were recruited for this study. An independent study will be required to demonstrate the responsiveness of the EBDASI. CONCLUSION The EBDASI demonstrated excellent reliability and validity, as compared with 2 other outcome measures.