"Thalidomide and Analogues: Potential for Immunomodulation of Inflammatory and Neoplastic Dermatologic Disorders"Ladizinski, B; Shannon, EJ; SANCHEZ, MR; Levis, WR
Thalidomide and analogues are a class of immunomodulatory drugs or IMiDS Thalidomide was initially approved by the U S Food and Drug Administation for treatment of erythema nodosum in leprosy and is now approved for multiple myeloma as well A second generation IMiD, lenalidomide, is also approved for multiple myeloma and refractory myelodysplastic syndrome Discovery of this class of drugs has been serendipitous and empirical, as the drug targets have been unknown In this review, the authors integrate recent identification of drug targets of IMiDS, which include the inducible form of nitric oxide synthase (iNOS), Rho GTPase and caspase-1, with the developments in the understanding of the molecular biology of human inflammatory, infectious and neoplastic skin disorders Because thalidomide reemerged through leprosy, the original disease classified by the T cell, the authors have also emphasized advances in the understanding of T-cell subsets in human skin disorders.
"Neurosarcoidosis: presentations and management"Terushkin, Vitaly; Stern, Barney J; Judson, Marc A; Hagiwara, Mari; Pramanik, Bidyut; SANCHEZ, MIGUEL; Prystowsky, Stephen
BACKGROUND: Sarcoidosis affects the central nervous system more frequently than previously appreciated. The diagnosis of neurosarcoidosis is often delayed, potentially leading to serious complications. Symptoms, when present, are not specific, may be subtle and resemble those of other neurologic diseases. REVIEW SUMMARY: During the past decade, significant progress has been made in understanding the epidemiology and pathophysiology of neurosarcoidosis, as well as the ability to diagnose and treat this disease. Studies have shown that the optimal diagnostic imaging modality for neurosarcoidosis is magnetic resonance imaging with gadolinium as it enhances visualization of granulomatous infiltration in neural tissue. Subclinical neurosarcoidosis may not be uncommon in patients with sarcoidosis. It is now evident that neurosarcoidosis does not invariably present as a catastrophic event. Adverse effects associated with high-dose systemic corticosteroids, the standard therapy, have discouraged practitioners from initiating treatment in the absence of significant symptomatic neurologic disease. However, other immunosuppressive agents as well newer biologic agents have emerged as an effective, well-tolerated therapeutic alternative to corticosteroids, which are often effective in corticosteroid-recalcitrant cases. CONCLUSION: Neurologists should be aware of the varying presentations of neurosarcoidosis since early recognition of neurologic involvement in patients with undiagnosed or proven sarcoidosis is currently possible and critical to the prevention of disabling complications.
"Dendritic cells in the pathogenesis of sarcoidosis"Zaba, Lisa C; Smith, Gideon P; SANCHEZ, MIGUEL; Prystowsky, Stephen D
GRANTS:GM07739/GM/NIGMS NIH HHS/United States
Sarcoidosis is a noncaseating granulomatous disease, likely of autoimmune etiology, that causes inflammation and tissue damage in multiple organs, most commonly the lung, but also skin, and lymph nodes. Reduced dendritic cell (DC) function in sarcoidosis peripheral blood compared with peripheral blood from control subjects suggests that blunted end organ cellular immunity may contribute to sarcoidosis pathogenesis. Successful treatment of sarcoidosis with tumor necrosis factor (TNF) inhibitors, which modulate DC maturation and migration, has also been reported. Together, these observations suggest that DCs may be important mediators of sarcoidosis immunology. This review focuses on the phenotype and function of DCs in the lung, skin, blood, and lymph node of patients with sarcoidosis. We conclude that DCs in end organs are phenotypically and functionally immature (anergic), while DCs in the lymph node are mature and polarize pathogenic Th1 T cells. The success of TNF inhibitors is thus likely secondary to inhibition of DC-mediated Th1 polarization in the lymph node.
"Rapidly eruptive, treatment-resistant, nodular Kaposi's sarcoma in an acquired immunodeficiency syndrome (AIDS) patient on highly active antiretroviral therapy"Chang, Caroline A; SANCHEZ, MIGUEL R; Karen, Julie K; Rosenman, Karla S; Prystowsky, Stephen D
"Linear psoriasis"Chien, Peter Jr; Rosenman, Karla; Cheung, Wang; Wang, Nadia; SANCHEZ, MIGUEL
A 33-year-old man presented with verrucous, red-brown papules, which coalesced into linear plaques on the right buttock, waist, thigh, and genitals. A skin biopsy was consistent with psoriasis, and the unilateral distribution in a linear pattern led to a diagnosis of linear psoriasis, which is a rare variant of psoriasis. Although histopathologically it can be difficult to distinguish from inflammatory linear verrucous epidermal nevus (ILVEN), linear psoriasis presents in adulthood and responds to conventional topical antipsoriatic therapies.
"Pseudoxanthoma elasticum"Gonzalez, Mercedes E; Votava, Henry J; Lipkin, George; SANCHEZ, MIGUEL
Pseudoxanthoma elasticum is an incurable, autosomal-recessive, genetic disorder that is caused by mutations in the ABCC6 gene. It is characterized by progressive mineralization and fragmentation of the elastic fibers in the skin, retina, and blood vessels. The characteristic cutaneous features bring the patient to medical attention, but morbidity is related to the degree of extracutaneous involvement. The disease is progressive with phenotypic variability and no definite genotype-phenotype correlation. Treatment is supportive and is directed at prevention and early detection of adverse ocular and cardiovascular sequelae. We present two siblings with pseudoxanthoma elasticum, who have considerable differences in disease related morbidity, which highlights intra-familiar phenotypic heterogeneity.
"Neurovascular hamartoma"Lee, Arnold; Heidary, Noushin; Altiner, Ahmet; Votava, Henry; Kamino, Hideko; SANCHEZ, MIGUEL
A 29-year-old man presented with a large, asymptomatic, brown, hyperpigmented, depressed plaque over his left upper back, which included the scapular area, since childhood. Histopathological analyses of the biopsy specimens was consistent with a rare entity known as neurovascular hamartoma. This uncommon lesion has been reported in two publications, either as a possible marker of the malignant rhabdoid tumor or as a hamartomatous tongue lesion in children. Due to its possible association with the aggressive and often fatal rhabdoid tumor, periodic examination of this lesion may be warranted.
"Sarcoidosis of the skin: a review for the pulmonologist"Lodha, Saurabh; SANCHEZ, MIGUEL; Prystowsky, Stephen
With vastly heterogeneous morphologic manifestations, sarcoidosis is one of the 'great imitators' of medicine. Because there is no specific confirmatory test, the diagnosis rests on clinical acumen coupled with supportive information from tissue or blood evaluation and the exclusion of other diseases. The characteristic histologic pattern of noncaseating, epithelioid cell granulomas is not always present in skin lesions, which may be visually distinctive or diverse in appearance. As a result of their high incidence of respiratory disease, patients with sarcoidosis frequently seek care from pulmonologists who may become their primary health-care providers. Physicians who treat patients with sarcoidosis should be aware of the disease's diverse organ manifestations, but particularly those appearing on the skin because these can be disfiguring, have prognostic importance, and may not be readily diagnosed even by skin specialists. In this comprehensive review, we sought to illustrate this diversity and to update the diagnostic approach, histologic spectrum, and therapeutic strategies involved in cutaneous sarcoidosis.
"Fixed cutaneous sporotrichosis"Mahlberg, Matthew J; Patel, Rishi; Rosenman, Karla; Cheung, Wang; Wang, Nadia; SANCHEZ, MIGUEL
Sporotrichosis is a subcutaneous mycosis that is caused by Sporothrix schenckii. Whereas the most common clinical presentation is the lymphocutaneous form, the fixed cutaneous form is not uncommon. Important clues from the clinical history, such as travel and occupation, can help to raise the suspicion of this infection in the differential diagnosis. However, histopathologic and tissue culture, which often require multiple specimens, are necessary to confirm the diagnosis. We present a patient with fixed cutaneous sporotrichosis whose delayed diagnosis led to appreciable scars and morbidity.
"Cutaneous piloleiomyomata"Smith, Gideon; Heidary, Noushin; Patel, Rishi; Rosenman, Karla; Meehan, Shane A; Kamino, Hideko; SANCHEZ, MIGUEL
A 49-year-old man presented with an eight-month history of intermittently painful, subcutaneous nodules that were increasing in size, number, and pain intensity. A biopsy specimen showed smooth muscle proliferation, which also stained positive for actin, and was consistent with piloleiomyoma. The patient was placed initially on gabapentin and then nifedipine with very limited success in pain control. The lesions continued to proliferate, and the patient was referred to surgery for excision.
"Raynaud's phenomenon: pathogenesis and management"Bakst, Richard; Merola, Joseph F; Franks, Andrew G Jr; SANCHEZ, MIGUEL
Raynaud's phenomenon is a common clinical disorder for which patients frequently seek the expertise and care of dermatologists. It is manifested by recurrent vasospasm of the fingers and toes, often associated with exposure to cold temperature or emotional stress. The phenomenon is named after Maurice Raynaud, who, as a medical student, defined the first case in 1862 as episodic, symmetric, acral vasospasm characterized by pallor, cyanosis, suffusion, and a sense of fullness or tautness, which may be painful. Despite more than 140 years of research, the pathophysiology of Raynaud's phenomenon continues to elude investigators. Accordingly, although many pharmacologic treatments have been reported, there is still no cure or gold standard therapy. Further, response to treatment varies and is difficult to predict. Recently, there has been renewed interest in finding the pathogenetic mechanisms of Raynaud's phenomenon, an effort that has led to more potential targeted therapeutics. The purpose of this review is to discuss recent breakthroughs in the pathogenesis and treatment of Raynaud's phenomenon.
"Epidermodysplasia verruciformis in the setting of HIV infection"Chen, Peter Jr; Kamino, Hideko; Walters, Ruth F; Rosenman, Karla; Pomeranz, Miriam K; SANCHEZ, MIGUEL
A 56-year-old man with human immunodeficiency virus infection presented with pink-to-hypopigmented, thin, flat-topped papules coalescent to plaques on the trunk and extremities for five years. The histopathologic findings were consistent with flat warts resembling epidermodysplasia verruciformis. Typically an inherited condition, this entity has also been observed in the setting of immunosuppression; the risk of developing non-melanoma skin cancers is of concern. Treatment options vary considerably, but often the lesions will recur upon cessation of therapy.
"Invasive squamous-cell carcinoma and arsenical keratoses"Elmariah, Sarina B; Anolik, Robert; Walters, Ruth F; Rosenman, Karla; Pomeranz, Miriam K; SANCHEZ, MIGUEL R
A 42-year-old man presented with a six-month history of a slowly-enlarging ulcer on his right sole, a 30-year history of altered pigmentation of the trunk and extremities, and hyperkeratotic papules of the palms and soles. Histopathologic examination showed an invasive squamous-cell carcinoma of the right sole and hyperkeratosis with keratinocyte atypia of the left finger and left lateral foot. The clinical and histopathologic findings are consistent with chronic arsenicism, which most commonly occurs in the setting of drinking contaminated water or after occupational exposure. Evaluation should include a physical examination, basic laboratory work-up, and measurement of a 24-hour urine arsenic concentration. Vigilant surveillance for the development of cutaneous malignancies is required. Oral retinoids may be helpful in reducing hyperkeratosis secondary to chronic arsenicism.
"Trichoepithelioma"Johnson, Hillary; Robles, Mirin; Kamino, Hideko; Walters, Ruth F; Lee, Arnold; SANCHEZ, MIGUEL
A 29-year-old man presented with a long-standing history of asymptomatic, skin-colored, facial papules and nodules. Histopathologic examination of a representative papule demonstrated trichoepithelioma. The patient had a history of a brother with a similar phenotype, which suggests a diagnosis of familial trichoepithelioma. Linkage and mutational analyses support genetic heterogeneity of familial trichoepithelioma, possibly sharing a clinical spectrum with Brooke-Spiegler syndrome and familial cylindromatosis since each entity has been associated with mutations the CYLD gene.
"Cutaneous umbilical endometriosis"Lee, Arnold; Tran, Hien T; Walters, Ruth F; Yee, Herman; Rosenman, Karla; SANCHEZ, MIGUEL R
A 35-year-old woman presented with a four-month history of a tender umbilical nodule that bleeds during her menstrual period. Physical examination showed a hyperpigmented umbilical nodule. A biopsy specimen showed fibrotic dermis with increased numbers of blood vessels and scattered glandular structures with areas of hemosiderin deposition consistent with a diagnosis of endometriosis. Cutaneous umbilical endometriosis is rare, with an estimated incidence of 0.5 to 1.0 percent. Although anti-gonadotropin medications, such as danazol, have been used for symptomatic control, but surgical excision is the treatment of choice owing to the possibility of malignant degeneration of cutaneous endometriosis.
"Advances in the genetics of sarcoidosis"Smith, G; Brownell, I; SANCHEZ, M; Prystowsky, S
Sarcoidosis is an uncommon disease of granulomatous inflammation. Genetic predisposition to sarcoidosis is indicated by observations of familial clustering, increased concordance in monozygotic twins over other siblings, and variations in susceptibility and disease presentation among different ethnic groups. Published studies on sarcoidosis have investigated a variety of genetic associations. These studies used techniques ranging from classic human lymphocyte antigen genotype correlations to genome-wide linkage scans. Results have both supported and refuted disease associations with a number of genes potentially involved in the pathogenesis of sarcoidosis. Here, we review representative studies concerning the genetics of sarcoidosis. While investigations to date have failed to identify a unifying genetic signature associated with sarcoidosis, numerous studies have identified genetic associations with disease subtypes or within specific populations. These studies suggest that genetic susceptibility to sarcoidosis is complex and polygenic in nature. Future studies will help clarify the genetics of sarcoidosis and allow for the development of diagnostic, prognostic and therapeutic technologies.
"Steroid-responsive facial eruption with cornoid lamellae--a possible new entity"Tran, Hien; Bossenbroek, Nicole M; Rosenman, Karla; Meehan, Shane A; SANCHEZ, MIGUEL; Prystowsky, Stephen
The histopathologic presence of a cornoid lamella is often associated with a diagnosis of porokeratosis. However, this feature is not pathognomonic for porokeratosis and can be found in a number of other dermatologic conditions, which include seborrheic keratosis, verruca vulgaris, actinic keratosis, squamous-cell carcinoma in situ, basal-cell carcinoma, milia, and scar. Notably, the etiology of none of these entities is inflammatory. Wade and Ackerman consider cornoid lamellation to be a distinctive histopathologic reaction pattern that reflects the disordered progression of epidermal cells during cornification. As such, this pattern is not specific for any given disease process. We report a case in which the lesions appeared inflammatory clinically as well as histopathologically, did not resemble porokeratosis despite the presence of cornoid lamellae, and responded to topical glucocorticoids.
"A systemic type I 5 alpha-reductase inhibitor is ineffective in the treatment of acne vulgaris"Leyden, J; Bergfeld, W; Drake, L; Dunlap, F; Goldman, MP; Gottlieb, AB; Heffernan, MP; Hickman, JG; Hordinsky, M; Jarrett, M; Kang, S; Lucky, A; Peck, G; Phillips, T; Rapaport, M; Roberts, J; Savin, R; Sawaya, ME; Shalita, A; Shavin, J; Shaw, JC; Stein, L; Stewart, D; Strauss, J; Swinehart, J; Swinyer, L; Thiboutot, D; Washenik, K; Weinstein, G; Whiting, D; Pappas, F; SANCHEZ, M; Terranella, L; Waldstreicher, J
Excessive sebum production is a central aspect of the pathophysiology of acne vulgaris. Sebaceous gland function is under androgen control and it is hypothesized that dihydrotestosterone is formed by the action of 5 alpha-reductase. Type I is the Controlling isoenzyme. This study describes a 3-month, multicenter, randomized, placebo-controlled clinical trial witha potent, selective inhibitor of type I 5 alpha-reductase used alone and in combination with systemic minocycline. Inhibition of type I 5 alpha-reductase was not associated with clinical improvement of acne when used alone and did not enhance the clinical benefit of systemic minocycline. These results indicate the need for further work at the molecular level to better understand the action of androgens on sebaceous gland function.
"New and re-emerging cutaneous infectious diseases in Latin America and other geographic areas"Bravo, F; SANCHEZ, MR
Due to environmental factors and inadequate public health measures in many developing countries, new tropical infections, as well as infections that were previously isolated to remote locales, are becoming more prevalent in several areas of Latin America. This article discusses some tropical infections and infestations with predominantly cutaneous manifestations. Previously uncommon diseases such as gnathostomiasis, mycobacteria ulcerans infection, paederus dermatitis, Balamuthia mandrillaris infection, and human T-lymphotrophic virus I dermatitis are increasingly being reported. Well-known tropical infections such as bartonellosis, leishmaniasis, chromomycosis, larva migrans, and larva currens are also becoming more prevalent. On the other hand, the incidence of Hansen's disease, the quintessential tropical infection, is dwindling all over the globe thanks to a highly effective eradication campaign launched by the World Health Organization. Because of increased immigration and tourist travel, the number of cases of these diseases in the United States may escalate.