Michael I. Shiman

Autoreactive T cells in the immune pathogenesis of pemphigus vulgaris

Pemphigus vulgaris is a life‐threatening autoimmune blistering disease caused by anti‐desmoglein IgG autoantibodies that finally lead to acantholysis presenting clinically as progressive blistering. Whilst the production of pathogenic antibodies is key to the development of pemphigus vulgaris, many immunological steps are required prior to autoantibody induction. We review advances in the understanding of these immunologic processes with a focus on human leucocyte antigen polymorphisms and antigen recognition, epitope spreading, central and peripheral tolerance, T helper differentiation, induction of pro‐ and anti‐inflammatory cytokines and T‐cell regulation of B cells. Targeting autoaggressive T cells as regulators and stimulators of B‐cell antibody production should allow for more specific therapeutic immune interventions, avoiding the global immunosuppression seen with many commonly used immunosuppressants in pemphigus vulgaris.

Venous ulcers: A reappraisal analyzing the effects of neuropathy, muscle involvement, and range of motion upon gait and calf muscle function

Chronic venous insufficiency is a complex disease that can result in severe sequelae including venous ulceration. Though the exact progression from chronic venous insufficiency to venous ulcer remains unclear, the high cost and burden of this disease on patients and society is quite clear. Sustained ambulatory venous pressures or venous hypertension plays an integral role in the development of venous ulceration and involves the failure of the calf muscle pump system. Standard of care involves compression therapy to assist the calf muscle pump. However, several cofactors may contribute to or exacerbate this disease and understanding their impact may provide insight into new treatment modalities. Nerve involvement, which may result in neuropathic pain and muscle dysfunction, alterations in mobility and a decrease in range of motion may lead to gait alterations all affecting calf muscle pump function. In this paper, we analyze these cofactors and discuss possible treatment options to target them. Physicians treating this disease should be aware of the numerous factors involved in its development. Exploring new treatment options may 1 day lessen the burden and suffering caused by venous insufficiency.

An update on the management of acne vulgaris

Acne vulgaris is a common skin disorder that can affect individuals from childhood to adulthood, most often occurring in the teenage years. Acne can have a significant physical, emotional, and social impact on an individual. Many different treatment options are available for the treatment of acne vulgaris. Commonly used topical treatments include benzoyl peroxide, antibiotics, sulfur and sodium sulfacetamide, azelaic acid, and retinoids. Systemic treatment is frequently used and includes the use of systemic antibiotics, oral contraceptives, antiandrogens, and retinoids. Other treatment modalities exist such as the use of superficial chemical peels as well as using laser and light devices for the treatment of acne. With the multitude of treatment options and the rapidly expanding newer technologies available to clinicians, it is important to review and be aware of the current literature and studies regarding the treatment of acne vulgaris.

The Use of Antioxidants in Radiotherapy-Induced Skin Toxicity

Radiation-induced skin damage is one of the most common complications of radiotherapy. In order to combat these side effects, patients often turn to alternative therapies, which often include antioxidants. Antioxidants such as those in the polyphenol chemical class, xanthine derivatives, tocepherol, sucralfate, and ascorbate have been studied for their use in either preventing or treating radiotherapy-induced skin damage. Apart from their known role as free radical scavengers, some of these antioxidants appear to alter cytokine release affecting cutaneous and systemic changes. We review the role of antioxidants in treating and preventing radiation-induced skin damage as well as the possible complications of using such therapy.

Potential Role of Human Growth Hormone in Melanoma Growth Promotion

BACKGROUND Human growth hormone (HGH) and insulin-like growth factor-1 (IGF-1) have been shown to play a role in the malignant transformation and progression of a variety of cancers. HGH is also known to upregulate molecular signaling pathways implicated in the pathogenesis of melanoma. Although HGH has previously been implicated in promoting the clinical growth of both benign and malignant melanocytic neoplasms, to our knowledge there are no conclusive studies demonstrating an increased risk of melanoma following HGH therapy. Nevertheless, there are reports of melanoma developing subsequent to HGH coadministered with either other hormones or following irradiation. OBSERVATION A 49-year-old white man presented with a new pigmented papule that was diagnosed as melanoma. The patient reported using HGH for 3 months prior to the diagnosis. His 51-year-old wife, who also was white, had also been using exogenous HGH for 3 months and had been diagnosed as having a melanoma 2 weeks prior. CONCLUSIONS Given the unlikelihood of 2 unrelated people developing melanoma within a short time span, it is reasonable to assume that a common environmental component (HGH or other shared exposure) contributed to the development of both melanomas. Because of the increased use of exogenous HGH as an antiaging agent, it is important to be aware of the growth-promoting effects of this hormone. Until better data are available that determines the true risk of exogenous HGH, its use as an antiaging agent merits increased surveillance.

Coma blisters in two postoperative patients.

Coma blisters are self-limited cutaneous bullae that occur in the setting of loss of consciousness because of a drug, illness, or accident, with the most common settings being barbiturate overdose and neurological disorders. The etiology behind coma blisters is poorly understood and is not related to underlying infections or autoimmune conditions. The clinical presentation consists of bullae, erosions, and violaceous plaques usually involving sites of pressure. The skin lesions usually occur within 48-72 hours of the start of a coma and resolve within 2-4 weeks. We present one case of a 5-month-old infant with severe valvular disease who required surgical repair. He was placed on extra corporeal membrane oxygenation and developed multiple tense coma blisters during the course of therapy. Skin biopsy revealed a noninflammatory subepidermal blister with necrosis of the overlying epidermis and necrosis of the eccrine ducts. We also present a second case of an 18-year-old female patient who underwent surgical resection of a benign mandibular tumor. She subsequently developed bullae on both arms 4 days after surgery. The skin biopsy showed a necrotic epidermis, a subepidermal blister, and diffuse necrosis of the eccrine coils.

Primary localized cutaneous nodular amyloidosis associated with CREST (calcinosis, Raynaud's phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) syndrome

and telangiectasia) syndrome Primary localized cutaneous amyloidosis (PLCA) is a rare condition that presents with the deposition of amyloid material in the skin, withno evidence of systemic involvement. Primary localized cutaneous nodular amyloidosis (PLCNA) is the rarest type of cutaneous amyloidosis. Of the three subdivisions of localized amyloidosis, macular and lichenoid subtypes show keratin-derived amyloid, whereas the nodular subtype is believed to be derived from plasma cells. Several disorders, including systemic sclerosis, primary biliary cirrhosis, systemic lupus erythematosus, Sjogren’s syndrome, and rheumatoid arthritis, have been associated with PLCA. Summers and Kendrick recently presented the first case of PLCNA with the CREST variant (calcinosis, Raynaud’s phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) of systemic sclerosis. To our knowledge, we report the second case of this association. An 83-year-old woman presented with multiple, shiny, skin-colored nodules on the legs bilaterally that had been present for 25 years (Fig. 1a,b). The lesions had been asymptomatic and had recently begun to enlarge and develop several satellite nodules. Findings on physical examination revealed sclerodactyly, as well as a few scattered telangiectasias on the lips and pulp of the fingers. A biopsy specimen of the nodules showed diffuse eosinophilic aggregates of amorphous material in the superficial portion of the dermis, accentuated around vascular channels and adnexal structures (Fig. 2). Plasma cells within amyloid material were prominent. Congo red stain revealed an apple-green birefringence under polarized light. Deposits were positive for both Ak and Aj. Laboratory results showed a normal serum protein electrophoresis and a positive antinuclear antibody(ANA)withatiterof‡1:1280.ANAshowed an anticentromere antibody pattern, suggestive of the CREST variantof scleroderma. Based on the patient’s clinical, pathologic, and laboratory data, she was diagnosed with PLCNA and CREST syndrome. The amyloid fibrils in PLCNA consist of immunoglobulin light chains which are referred to as amyloid L (AL) type. These chains are produced by a clonal plasma cell population. This is in contrast with the amyloid A (AA) type which is associated with secondary amyloidosis and is derived from an acute-phase reactant secondary to long-standing inflammation. As the lesions in PLCNA may contain numerous plasma cells, they are best considered as isolated plasmacytomas. In conclusion, we believe that there is an association between PLCNA and the CREST variant of systemic sclerosis. First, PLCNA has been described in association with autoimmune connective tissue disorders. Second, association Figure 1 (a) Multiple, shiny, skin-colored nodules on the patient’s lower extremities. (b) Telangiectasias on the patient’s fingertips as a part of CREST (calcinosis, Raynaud’s phenomenon, esophageal motility disorders, sclerodactyly, and telangiectasia) syndrome

Cutaneous aspergillosis masquerading as Sweet's syndrome in a patient with acute myelogenous leukemia.

To the Editor, Aspergillosis may present as primary cutaneous lesions or as secondary cutaneous emboli.1 The former typically appear as plaques with black crust, while the latter consists of necrotic papules and plaques, often with ulceration and rapid progression. Pulmonary disease with multiple, bilateral cavitating infiltrates and nodules may appear in those with disseminated cutaneous emboli.1 In hosts with neutropenia or an immunocompromised status, such as our patient, the fungus can disseminate widely. Here we present a case of a 68-year-old male with newly diagnosed acute myelogenous leukemia (AML) who developed multiple pink Sweet’s-like papules; the tissue stained positive with Gomori methenamine silver (GMS) stain, consistent with aspergillosis. A 68-year-old male with newly diagnosed AML status post-induction chemotherapy presented with a 2-day history of multiple, painful skin lesions that were indurated and erythematous. The lesions were distributed on his right finger, right neck, right foot and left cheek and spread to his left leg, left neck and occiput. Over the next few days, he developed left eye pain, periorbital swelling, decreased visual acuity and left-sided nasal congestion. Associated symptoms included recent neutropenic febrile episodes, night sweats, chills, shortness of breath and progressive fatigue. Physical examination at this time revealed rounded, well-defined pink papules with central pustules that were tender to palpation (Fig. 1). Two lesions had a blackish, eschar-like appearance in the center surrounded by an erythematous base (Fig. 2) and one lesion contained a central Fig. 1. Discrete erythematous papule and macule on the left posterior thigh.

Post-kala-azar dermal leishmaniasis in HIV-infected patients with AIDS: a report of two cases diagnosed in the USA

Post‐kala‐azar dermal leishmaniasis (PKDL) is an uncommon complication of visceral leishmaniasis (VL) but is emerging as an increasingly frequent and serious complication of acquired immunodeficiency syndrome (AIDS). It manifests as a macular, morbilliform, or nodular eruption in a patient who has recovered from VL.

Letter to the editor: Application of dapsone 5% gel in a patient with dermatitis herpetiformis.

Dermatitis Herpetiformis (DH) is a rare, blistering skin disease described by Duhring in 1884.[1] DH is strongly associated with the HLA-DQ2 phenotype, a gateway in which dietary gluten reaches inflammatory cells and stimulates an autoimmune process. The etiopathogenesis involves IgA anti-endomysial antibodies directed against tissue transglutaminase (TG); the presumed skin autoantigen is epidermal TG. IgA/TG immune complexes form locally within the papillary dermis leading to neutrophil chemotaxis and degranulation (which forms neutrophilic abscesses), proteolytic cleavage disrupting the lamina lucida, and blister subepidermal blister formation.[2] Current standard-of-care for DH is oral dapsone and a gluten-free diet. We describe a teenage patient in whom resolution of lesions was achieved with adjuvant use of topical dapsone 5% gel (aczone), the first case in the literature. A 14-year-old male had been suffering recurrent eruptions of blisters on his chest and arms for 16 months. He had been diagnosed with direct immunofluorescent proven DH based on granular IgA deposition in the upper papillary dermis. Though distinguishing LABD (linear IgA bullous dermatosis) from DH is often clinically impossible, the finding of IgA in a granular pattern at the dermoepidermal junction with accentuation in the dermal papillae was specific for DH in our patient. Upon an exacerbated eruption of blisters on the chest and shoulders, the patient presented to our clinic. On physical examination he presented with multiple, welldefined, pink keratotic papules, plaques and diffuse, hypopigmented macules and patches on the chest and shoulders, equally distributed on the left and right side. Primary lesions were counted before treatment and numbered 33 on the left side and 34 on the right side of the chest, respectively. The patient did not maintain a gluten-free diet and was receiving daily oral dapsone (25 mg). Twice daily application of topical dapsone (Aczone gel, 5%) was initiated on the right side of the patient’s chest and Aquaphor ointment to the left. Two physicians were blinded to which side received the medication. The patient was asked to follow up in four weeks. Over the following three days the patient’s skin lesions did not improve on either side of the chest. The oral dosage of dapsone was modified to 25 mg and 50 mg on alternating days. The patient continued to apply the topical products unilaterally as originally prescribed. On a follow-up visit four weeks later, the blinded physicians observed improvement of the lesions on the right side of his chest in comparison to the left. Physical exam demonstrated two remaining ulcerated vesicles on the right chest and five on the left without signs of erosion. It was also noted that relative to the left side, the skin on the right side was significantly smoother. The patient was then allowed to expand usage of topical dapsone to all affected areas and had similar improvements. There have been no reports on treating dermatitis herpetiformis using topical dapsone and the current standard-ofcare remains oral dapsone. Most clinical remissions are related to dietary gluten restriction, however, the gluten-free diet is inconvenient and unacceptable to some patients. Oral dapsone (diaminodiphenylsulfone) is the current treatment and the most effective sulfone but many physicians would prefer a non-systemic treatment choice. Though patients intolerant to dapsone may consider therapy with sulfapyridines, there is significant risk for nephrolithiasis and some patients may not respond at any dose. Although this patient had received oral and topical dapsone simultaneously, he only applied topical dapsone 5% gel to the right side, the same side which demonstrated significant improvement of the lesions. The left side where aquaphor was applied did not show the same level of improvement at four-week follow-up. High doses of oral dapsone simply increase toxicity while providing minimal benefit. The main side effects associated with oral dapsone may be classified as toxic/pharmacologic or idiosyncratic/allergic; these range from hemolytic anemia, the most common complication within 2 weeks after starting therapy, to nephritis and renal failure, precluding the need for strict monitoring of renal function tests.[3] Hemolytic anemia occurs in virtually every patient on oral therapy and may even occur in breastfed infants since dapsone is secreted in breast milk. A notable complication, especially in patients with glucose-6-phophate dehydrogenase (G6PD) deficiency, is hemolysis and methemoglobinemia due to oxidative stress from the hydroxylamine metabolite.[4] Adverse effects of dapsone are generally dose-dependent and are more commonly observed in patients with comorbid conditions such as anemia and cardiopulmonary disease.[3] Other rare complications include agranulocytosis early on, as well as a systemic drug hypersensitivity syndrome, a serious complication that requires medication withdrawal and systemic corticosteroid administration.[5] Regular follow-up visits and routine laboratory monitoring of blood counts are needed for patients receiving treatment with oral dapsone, especially during the first 3 months.[5] Dapsone is clinically useful in diseases containing neutrophilic infiltrates. Dapsone inhibits neutrophil myeloperoxidase, decreasing the damage from the neutrophil respiratory burst pathway mediated by this enzyme. The anti-inflammatory properties of topical dapsone benefit patients with acne and could also hinder the immunologic cascade and accompanying inflammatory process that occurs in DH. We attribute the efficacy of topical dapsone to a local inhibition of neutrophil chemotaxis to N-formyl-methionyl-leucyl-phenylalanine and interference of the CD11b/CD18-mediated neutrophil binding that induces chemoattractant signal transduction and inhibits leukotrienes. IgA adherence may also be inhibited though it remains to be proven.[5] Concerning our review of the literature, we conclude that there is therapeutic explanation for the moderate therapeutic effects seen from use of topical dapsone in DH. Using topical dapsone alone or in combination with a lower dose of oral dapsone is preferable to high doses of oral dapsone. Additionally, facial disease may prove refractory to oral dapsone therapy; topical dapsone gel may provide a more tolerable alternative than breaking facial vesicles and applying a potent corticosteroid gel. In order to further study the utility of topical dapsone in DH, a more extensive trial of topical dapsone is warranted. In summary, aczone appears to be a promising therapeutic agent for patients with dermatitis herpetiformis who are refractory to oral therapy and noncompliant with a gluten-free diet.