Linda K. Martin

Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus

Our scientific knowledge of pemphigus has dramatically progressed in recent years. However, despite the availability of various therapeutic options for the treatment of inflammatory diseases, only a few multicenter controlled trials have helped to define effective therapies in pemphigus. A major obstacle in comparing therapeutic outcomes between centers is the lack of generally accepted definitions and measurements for the clinical evaluation of patients with pemphigus. Common terms and end points of pemphigus are needed so that experts in the field can accurately measure and assess disease extent, activity, severity, and therapeutic response, and thus facilitate and advance clinical trials. This consensus statement from the International Pemphigus Committee represents 2 years of collaborative efforts to attain mutually acceptable common definitions for pemphigus. These should assist in development of consistent reporting of outcomes in future studies.

A systematic review of randomized controlled trials for pemphigus vulgaris and pemphigus foliaceus.

BACKGROUND A range of interventions has been described for the treatment of pemphigus; however, the optimal therapeutic strategy has not been established. OBJECTIVE We sought to evaluate the safety and efficacy of interventions for pemphigus vulgaris and pemphigus foliaceus. METHODS We undertook a systematic review and meta-analysis according to the methodology of the Cochrane Collaboration. We selected randomized controlled trials including participants with the diagnosis of pemphigus vulgaris or pemphigus foliaceus confirmed with clinical, histopathological, and immunofluorescence criteria. All interventions were considered. Primary outcomes studied were remission and mortality. Secondary outcomes included disease control, relapse, pemphigus severity score, time to disease control, cumulative glucocorticoid dose, serum antibody titers, adverse events, and quality of life. RESULTS Eleven studies with a total of 404 participants were identified. Interventions assessed included prednisolone dose regimen, pulsed dexamethasone, azathioprine, cyclophosphamide, cyclosporine, dapsone, mycophenolate, plasma exchange, topical epidermal growth factor, and traditional Chinese medicine. We found some interventions to be superior for certain outcomes, although we were unable to conclude which treatments are superior overall. LIMITATIONS Many interventions for pemphigus have not been evaluated in controlled trials. All studies were insufficiently powered to establish definitive results. CONCLUSIONS There is inadequate evidence available at present to ascertain the optimal therapy for pemphigus vulgaris and pemphigus foliaceus. Further randomized controlled trials are required.

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.

Reticular Variant of Mid-Dermal Elastolysis

A 49-year-old man presented with a 20-year history of an asymptomatic reticular eruption on his upper trunk. On examination, there were well-demarcated orange-red patches with reticular margins and irregular central atrophy on the lateral chest and proximal upper limbs. Skin biopsies showed histological evidence of elastophagocytosis with scant lymphocytic inflammation. Elastin stains demonstrated focal loss of elastic fibers in the reticular dermis, consistent with mid-dermal elastolysis. Mid-dermal elastolysis is a rare disorder characterized by focal loss of elastic tissue in the mid-dermis. The etiology remains obscure. Reticular presentations of mid-dermal elastolysis have rarely been described and extend the clinical spectrum of dermal elastolytic disorders.

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.

Fabry disease in a heterozygote presenting as hand ischaemia and painful acroparaesthesia.

A 48‐year‐old woman presented with acute unilateral ischaemia of the left hand. She had a background of chronic peripheral neuropathic pain, palpitations, anaemia and an episode of superficial thrombophlebitis. Physical examination revealed non‐blanching purple discoloration of her left fingers and her left thumb, index finger and thenar eminance appeared ischaemic. Digital subtraction angiography of the left hand demonstrated reduced flow. Skin punch biopsy histology was unremarkable. The diagnosis of Fabry disease was made on urine lipid profile analysis and confirmed by reduced peripheral blood leukocyte α‐galactosidase A activity.

Naevus of Ota presenting in two generations: a mother and daughter

© 2008 The Authors JEADV 2009, 23, 70–110 Journal compilation

Cutaneous Mycobacterium neoaurum infection causing scarring alopecia in an immunocompetent host

expression. Griffiths classified PRP into five types based on clinical features, age at onset and prognosis: classical adult (type I), atypical adult (type II), classical juvenile (type III), circumscribed juvenile (type IV) and atypical juvenile (type V). Most familial cases belong to type V and present at birth or in the first few years of life with widespread scaly erythema and follicular papules. Palmoplantar keratoderma ranges from mild thickening to pronounced keratoderma resulting in a contracted sclerodermoid appearance. The daughters in our case have some features of type V PRP but lack palmoplantar keratoderma. Type V PRP also tends to run a chronic course but the disorder has mostly cleared in the older daughter and we anticipate that the second daughter’s PRP will follow the same benign course. Despite these discrepancies, the pattern of disease in these daughters still fits best with type V as compared with type III or IV. We have considered other diagnoses for the daughters, the most plausible being very extensive seborrhoeic dermatitis. However, the congenital onset and the rare occurrence of clinical features compatible with PRP affecting two neonates in one family suggests that the family history must be relevant. The histological findings also support a diagnosis of PRP. Congenital PRP has been reported only twice previously and may be aetiologically significant. We speculate that maternal transmission of circulating factors may cause a PRP phenotype which improves as maternal factors decline. This would explain the congenital presentation and time course of the daughters’ condition in our case. Theories based on maternal transmission as opposed to genetics would also explain how a mother with type I PRP had two daughters with type V PRP.

Pemphigus: Directions for the future.

E leven randomized controlled trials of the treatment of pemphigus have been published in the last 20 years, yet the optimal treatment for this serious condition remains elusive. So varied are the interventions, trial methodologies, patient groups, and outcome measures published, what role does a systematic review play in untangling the disparate treatment options? A systematic review, particularly within the rigorous methodological confines of the Cochrane Collaboration guidelines, provides three main benefits to our understanding of the management of pemphigus. First, it meticulously identifies and synthesizes the available evidence. Second, in the circumstances in which several trials examine the same intervention, the review allows meta-analysis of the data. Third, and perhaps most importantly, the review highlights the difficulty of performing research in this area and points the way to future research in profitable directions. The crux of the difficulty of researching pemphigus is its rarity. An incidence of only 1 to 16 per million population per annum means that all but the largest single centers are unable to recruit sufficient numbers of patients for adequate analysis. For example, assuming a baseline remission rate of 75% (as seen in the largest randomized controlled trial to date), to demonstrate a 20% difference between interventions with 80% power, a study of more than 196 patients is required. This calculation does not allow for withdrawals, so in reality an even higher number would be required. The implications of this are important. Studies that are underpowered add little to our knowledge of treatment options; the results are not statistically significant regardless of

Plaque-like cutaneous mucinosis: case report and literature review.

Midline mucinosis was observed in a 14-year-old man, which was confined to the midline of the back and appeared as asymptomatic, nonindurated, hyperpigmented plaques. Skin biopsies showed prominent interstitial mucinosis with perivascular lymphocytic infiltration. A literature review of plaque-like mucinosis revealed 14 previous cases with this distinct presentation that may overlap with reticular erythematous mucinosis and connective tissue disease. Midline mucinosis has been previously reported in prepubertal children but is rare.