Edward W. Cowen

Awareness of skin cancer by kidney transplant patients

BACKGROUND Skin cancer is the most common malignancy occurring after kidney transplantation. OBJECTIVE Our purpose was to identify the skin problems of kidney transplant recipients, the extent of their awareness of skin cancer, and interest in skin cancer screenings. METHODS One hundred twenty-two patients were administered an oral questionnaire during regular follow-up at a renal transplant clinic. RESULTS The average time from transplantation was 3.1 years. Thirty-nine percent of patients reported skin problems, including warts, fungal infection, and skin cancer. Forty-one percent of patients were unable to recall specific skin cancer education, and 52% expressed an interest in skin cancer screening. Twenty-seven percent of patients had seen a dermatologist since their transplant, but only 14% were followed up regularly by a dermatologist. CONCLUSION We believe the need for continuing skin cancer education and early detection and treatment of skin lesions establishes an important role for the dermatologist on the transplant recipients health care team.

Minocycline-Induced Drug Hypersensitivity Syndrome Followed by Multiple Autoimmune Sequelae

BACKGROUND Drug hypersensitivity syndrome (DHS) is a severe, multisystem adverse drug reaction that may occur following the use of numerous medications, including anticonvulsants, sulfonamides, and minocycline hydrochloride. Long-term autoimmune sequelae of DHS have been reported, including hypothyroidism. OBSERVATIONS A 15-year-old female adolescent developed DHS 4 weeks after starting minocycline therapy for acne vulgaris. Seven weeks later she developed autoimmune hyperthyroidism (Graves disease), and 7 months after discontinuing minocycline therapy she developed autoimmune type 1 diabetes mellitus. In addition, she developed elevated titers of several markers of systemic autoimmune disease, including antinuclear, anti-Sjögren syndrome A, and anti-Smith antibodies. CONCLUSIONS Minocycline-associated DHS may be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and elevated markers of systemic autoimmunity. Long-term follow-up is needed in patients with DHS to determine the natural history of DHS-associated sequelae.

An unusually aggressive trichoblastoma

Trichogenic tumors are neoplasms of the hair germ cell that usually exhibit benign behavior. We describe a case of a large invasive trichoblastoma requiring Mohs micrographic surgery for its removal. Immunohistochemical studies performed demonstrate overlapping features of this trichogenic tumor with basal cell carcinoma.

Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity

Chronic graft-versus-host disease (cGVHD) remains a major cause of non-relapse morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Currently there are no accepted measures of cGVHD activity to aid in clinical management and disease staging. We analyzed clinical markers of inflammation in the sera of patients with established cGVHD and correlated those with definitions of disease activity. In all, 189 adults with cGVHD (33% moderate and 66% severe according to National Institutes of Health (NIH) global scoring) were consecutively enrolled onto a cross-sectional prospective cGVHD natural history study. At the time of evaluation, 80% were receiving systemic immunosuppression and failed a median of four prior systemic therapies (PST) for their cGVHD. Lower albumin (P<0.0001), higher C-reactive protein (P=0.043), higher platelets (P=0.030) and higher number of PST (P<0.0001) were associated with active disease defined as clinicians intention to intensify or alter systemic therapy due to the lack of response. Higher platelet count (P=0.021) and higher number of PST (P<0.0001) were associated with more severe diseased defined by NIH global score. This study identified common laboratory indicators of inflammation that can serve as markers of cGVHD activity and severity.

Localization of Sclerotic-type Chronic Graft-vs-Host Disease to Sites of Skin Injury Potential Insight Into the Mechanism of Isomorphic and Isotopic Responses

BACKGROUND The mechanisms responsible for the variable manifestations of chronic cutaneous graft-vs-host disease (cGVHD) are poorly understood. Localization of sclerotic-type chronic graft-vs-host disease to sites of skin injury (isomorphic and isotopic responses), a recognized phenomenon in morphea, suggests a potential common pathway between cGVHD and other sclerotic skin conditions. OBSERVATIONS Four cases of sclerotic-type cGVHD developed at the site of disparate skin injuries (ionizing radiotherapy, repeated needle sticks, central catheter site, and varicella-zoster virus infection). We review the spectrum of previously reported cases of sclerotic and nonsclerotic cGVHD relating to external forces on the skin. CONCLUSIONS Localization of sclerotic-type cGVHD may occur after many types of skin injury, including UV and ionizing radiotherapy, needle sticks, viral infection, and pressure or friction. Recognition of this phenomenon may be helpful for the early diagnosis of sclerotic disease. Recent insights into the immunological consequences of minor skin injury may provide important clues to the underlying pathogenesis of cGVHD-mediated skin disease.

DIRA, DITRA, and New Insights Into Pathways of Skin Inflammation: What’s in a Name?

Dermatology has a long-standing affinity for acronyms. From AGEP (acute generalized exanthematous pustulosis) to XP (xeroderma pigmentosum), acronyms have become a part of our dermatology lexicon, perhaps occasionally to the consternation of our colleagues in other specialties. In this issue, Brau-Javier et al1 describe a patient with a severe pustular skin disease called “DIRA”—an acronym for “deficiency of the interleukin 1 (IL-1) receptor antagonist,” which we first described in 9 pediatric patients in 2009.2 As its name suggests, DIRA is a new autoinflammatory disease linked to activation of the IL-1 pathway (Figure), joining the ranks of other IL-1–associated conditions with a prominent dermatologic component, foremost the cryopyrin-associated periodic fever syndromes (CAPS)—familial cold–induced autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID).3 Figure The pathogenesis of DIRA (deficiency of the interleukin 1 [IL-1] receptor [IL-1R] antagonist) and DITRA (deficiency of the IL-36 receptor [IL-36R] antagonist). Loss of the IL-1R antagonist leads to unopposed proinflammatory signaling by IL-1α ... CAPS is caused by gain of function mutations that lead to oversecretion of the well-established fever causing cytokine IL-1Β, and all 3 disorders manifest in the skin as neutrophilic urticaria. In contrast, DIRA presents in the neonatal period with a severe neutrophilic “pustular” skin eruption, skin pathergy, and nail dystrophy, as well as elevated acute-phase reactants, sterile osteomyelitis, and periostitis. DIRA is caused by loss of function of the IL-1 receptor (IL-1R) antagonist, the first endogenous cytokine receptor antagonist identified that blocks IL-1 signaling (Figure). Absence of the IL-1R antagonist results in unopposed proinflammatory signaling via the cytokines IL-1α and IL-1β on the IL-1R type I (IL-1R1). DIRA is a rare condition that you may never encounter in your practice, so why bother filing away another acronym in the deep recesses of your dermatologic cortex? First, as Brau-Javier et al1 demonstrate, just as with CAPS, DIRA is exquisitely responsive to IL-1 blockade. Responses are similar to those seen following anti–IL-1 treatment for NOMID, the most severe form of CAPS; children who have been ill since infancy now feel well for the first time; others confined to wheelchairs because of disabling joint pain are able to walk; and growth curves begin to arc upward again for the first time in years. Interleukin 1–blocking therapy is now the standard of care for CAPS, and 3 Food and Drug Administration–approved agents, anakinra, rilonacept, and canakinumab, are currently available that provide targeted inhibition of IL-1 signaling.4 Second, understanding DIRA may yield new insights into the mechanism of other challenging pustular skin conditions. The cutaneous and systemic features of DIRA bear similarity to features seen in pustular psoriasis and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), suggesting that IL-1 signaling may play a role in these conditions as well.

Homeostatic Tissue Responses in Skin Biopsies from NOMID Patients with Constitutive Overproduction of IL-1β

The autoinflammatory disorder, Neonatal-onset Multisystem Inflammatory Disease (NOMID) is the most severe phenotype of disorders caused by mutations in CIAS1 that result in increased production and secretion of active IL-1β. NOMID patients present with systemic and organ-specific inflammation of the skin, central nervous system and bone, and respond dramatically to treatment with IL-1 blocking agents. We compared the cellular infiltrates and transcriptome of skin biopsies from patients with NOMID (n = 14) before treatment (lesional (LS) and non-lesional (pre-NL) skin) and after treatment (post-NL) with the IL-1 blocker anakinra (recombinant IL-1 receptor antagonist, Kineret®, Swedish Orphan Biovitrum AB, SOBI), to normal skin (n = 5) to assess tissue responses in the context of untreated and treated disease. Abundant neutrophils distinguish LS skin from pre-NL and post-NL skin. CD11c+ dermal dendritic cells and CD163+ macrophages expressed activated caspase-1 and are a likely source of cutaneous IL-1 production. Treatment with anakinra led to the disappearance of neutrophils, but CD3+ T cells and HLA-DR+ cells remained elevated. Among the upregulated genes IL-6, IL-8, TNF, IL-17A, CCL20, and the neutrophil defensins DEFA1 and DEFA3 were differentially regulated in LS tissues (compared to normal skin). Important significantly downregulated pathways in LS skin included IL-1R/TLR signaling, type I and II cytokine receptor signaling, mitochondrial dysfunction, and antigen presentation. The differential expression and regulation of microRNAs and pathways involved in post-transcriptional modification were suggestive of epigenetic modification in the chronically inflamed tissue. Overall, the dysregulated genes and pathways suggest extensive “adaptive” mechanisms to control inflammation and maintain tissue homeostasis, likely triggered by chronic IL-1 release in the skin of patients with NOMID.

Comparative analysis of FoxP3 + regulatory T cells in the target tissues and blood in chronic graft versus host disease

Activation and migration of regulatory T cells (Treg) into tissue is critical in control of inflammation, but has not been examined extensively in chronic graft versus host disease (cGVHD). In parallel studies of tissues and blood, we determined that FoxP3+ T cells increased in proportion to T effectors (Teff) in tissue infiltrates in oral and cutaneous lichenoid cGVHD. These FoxP3+ cells expressed distinguishing phenotypic and functional markers of Treg (CD3+, CD4+, CD27+, ICOS+ and CD39+), not found on FoxP3− Teff. Both Teff and FoxP3+ Treg expressed T-bet and the chemokine receptor CXCR3, however, consistent with a common mechanism of chemokine-mediated migration into tissue. Furthermore, functional markers (ICOS and CD39) and chemokine receptors (CXCR3) were both present in a higher proportion of FoxP3+ cells in tissues than in peripheral blood, consistent with recruitment and activation of Treg in cGVHD target tissues. Finally, the ‘activated’ CD45RA−FoxP3hi subset of Treg cells, which highly express functional markers, were found in comparable frequencies in cGVHD patients and normal controls, despite a significant deficit in naive ‘resting’ Treg. These findings are consistent with Treg capacity to upregulate functional markers and traffick into tissue in cGVHD.

Malnutrition in patients with chronic GVHD.

Malnutrition is a known complication of chronic GVHD (cGVHD), but has not been well described in the context of organ-specific manifestations and the recent National Institutes of Health (NIH) criteria. Here, 210 cGVHD patients were analyzed, in a cross-sectional study design, for demographics, transplant-related history, clinical assessments, symptoms, function, quality-of-life, laboratory values and survival in order to determine their associations with nutritional status. Most patients had long-standing, moderate or severe cGVHD and had failed many lines of therapy. Twenty-nine percent (60/210) of subjects were malnourished, using the subjective Patient-Generated Subjective Global Assessment (PG-SGA) questionnaire and evaluation. No demographic or transplant characteristics were associated with malnutrition; cGVHD of the lungs, gastrointestinal (GI) tract and mouth, NIH global score, cGVHD symptoms, worse functioning, low albumin, poorer survival and low BMI were associated with malnutrition. A predictive model was developed from all variables of significance: cGVHD of the lungs, GI tract, mouth and BMI accurately predicted 84.2% of malnourished patients as well as 87.2% of well-nourished patients. The PG-SGA questionnaire may be a useful tool in diagnosing nutritional deficits in cGVHD patients undergoing one-time evaluations. Longitudinal prospective studies should assess the utility of nutritional support interventions in cGVHD.

The isomorphic response in morphealike chronic graft-vs-host disease.

The isomorphic response of Koebner, also known as the Koebner phenomenon, is a well-recognized dermatologic manifestation first described in psoriasis. The isomorphic response occurs when a dermatologic disease develops at a site of normal-appearing skin that is injured in some manner.1 Chronic graft-versus-host disease (cGvHD) is a multisystem disorder that commonly affects the skin and may present with protean manifestations. Sclerotic cGvHD features are categorized as lichen sclerosus-like, morphea-like, or sclerosis involving the subcutaneous tissue and fascia.2 Morphea-like lesions of cGvHD are characterized by localized dyspigmented indurated plaques of skin thickening.