T-helper immune phenotype may underlie 'paradoxical' tumour necrosis factor-α inhibitor therapy-related psoriasiform dermatitis.

BACKGROUND: Therapeutics targeting tumour necrosis factor (TNF)-α are effective for psoriasis; however, in patients treated for other disorders, psoriasis may worsen and psoriasiform dermatitis (PsoD) may arise. T helper (Th) cytokines in psoriasis upregulate keratin (K)17, which modulates TNF-α transduction, leading to vascular adhesion molecule upregulation and lymphocytic extravasation. AIM: We investigated Th phenotype and expression of K17, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 in psoriasis and anti-TNF-α-related PsoD. METHODS: Skin biopsies from patients with psoriasis unresponsive to TNF-α inhibitor therapy (n = 11), PsoD-related to TNF-α inhibition (n = 9), untreated psoriasis (n = 9) or atopic dermatitis (AD; n = 9) were immunohistochemically analysed for Th1, Th2, Th17 and Th22. Expression of K17, ICAM-1 and VCAM-1 was also examined. RESULTS: Anti-TNF-α-unresponsive psoriasis and anti-TNF-α-related PsoD showed decreased Th1 : Th2 raio and increased Th17 : Th1 ratio compared with untreated psoriasis. Anti-TNF-α-unresponsive psoriasis had significantly fewer Th1 (4% vs. 12%) and more Th17 (51% vs. 20%) cells than untreated psoriasis. No difference in Th22 cells was identified. K17 was present in all cases of untreated psoriasis and anti-TNF-α-related PsoD, 91% of anti-TNF-α-unresponsive psoriasis, and only 22% of AD. VCAM-1 and ICAM-1 in anti-TNF-α-related PsoD was akin to untreated psoriasis, but decreased in anti-TNF-α-unresponsive psoriasis. CONCLUSIONS: These findings further the current understanding of the anti-TNF-α-related psoriasiform phenotype and support a rationale for therapeutic targeting of interleukin-17 and TNF-α in combination.

Cardiac and vascular metal deposition with high mortality in nephrogenic systemic fibrosis.

Nephrogenic systemic fibrosis is a severe disabling disease that can follow gadolinium-based contrast exposure. In this study we analyzed the clinical and laboratory records of patients with nephrogenic systemic fibrosis who had a history of exposure to gadolinium-based contrast media and identified their cardiac and vascular events. At autopsy, we found that the heart, blood vessels, and skin of three patients who died of cardiac and/or vascular complications had appreciable amounts of gadolinium, iron, and aluminum as measured by inductively coupled plasma-mass spectrometry and confirmed by x-ray fluorescence. Of the 32 patients with nephrogenic systemic fibrosis studied, 10 died at a median of 112 days after diagnosis. Cardiovascular events contributed to the mortality of 9 patients and included congestive heart failure, recurrent arrhythmias, hypotension, stroke, limb ischemia, posterior ischemic optic neuropathy and sudden death. Our results show that increased cardiac and vascular complications along with short survival in nephrogenic systemic fibrosis are associated with metal accumulation in the heart, blood vessels, and skin of these patients.

Histological study of necrolytic acral erythema.

Described in 1996, necrolytic acral erythema remains the sole diagnostic cutaneous marker for hepatitis C virus infection. To date only eight cases have been described in literature, a fact that makes full histological description and appreciation of the disease process inadequate. Thirty necrolytic acral erythema cases were biopsied and detailed histological description was performed by three separate dermatopathologists who were blinded as to clinical presentation. Clinicopathological correlation was used to evaluate the disease progress. In the early stage, there is moderate regular acanthosis with variable spongiosis and inflammation, progressing to a picture resembling nummular eczema. In its fully evolved form, necrolytic acral erythema shows psoriasiform epidermal hyperplasia with marked papillomatosis. Associated findings include parakeratosis, focal hypergranulosis, subcorneal pustule, epidermal pallor, necrotic keratinocytes, which sometimes become confluent in the upper epidermis and/or track along the acrosyringia, vascular ectasia and papillary dermal inflammation. Late stage samples display some remaining acanthosis with variable inflammation. Pigment incontinence is seen in all stages.

Intralesional injection of mumps or Candida skin test antigens: a novel immunotherapy for warts.

BACKGROUND: Warts are common and induce physical and emotional discomfort. Numerous therapies exist, yet none is optimal. Despite theoretical advantages, immunotherapeutic modalities are often neglected as first-line wart therapies. OBJECTIVE: To compare treatment with intralesional skin test antigen injection of 1 wart vs cryotherapy of all warts. DESIGN: Pilot study. SETTING: University dermatology outpatient clinic. PATIENTS: A total of 115 consecutive patients with at least 1 nongenital wart. INTERVENTIONS: Patients with warts were tested for immunity to mumps and Candida using commercial antigens. Nonresponders received cryotherapy and immune individuals received cryotherapy or intralesional injection of 1 antiserum. RESULTS: Thirty-four (30%) of the 115 patients did not respond to the test injections and 81 (70%) had detectable immunity. Of the immune group, 26 (32%) received cryotherapy, 45 (56%) received intralesional mumps antiserum, and 10 (12%) received intralesional Candida antiserum. Of the anergic patients, 28 (82%) were treated with cryotherapy; 6 (18%) refused cryotherapy. Of the 39 patients who were treated with immunotherapy and completed the protocol, 29 (74%) had complete clearing of the treated wart. Fourteen (78%) of 18 patients with complete resolution of their immunotherapy-treated wart also had resolution of untreated, distant warts. CONCLUSIONS: Intralesional injection of mumps or Candida antigens into warts of immune individuals represents effective treatment. Observation of clearing of anatomically distinct and distant warts suggests acquisition of human papillomavirus-directed immunity in some patients. We conclude that this novel approach to immunotherapy may serve as first-line treatment in immune individuals with multiple or large warts and as second-line treatment in immune patients for whom cryotherapy fails.

Yellow eyelids heralding lymphoma.

Yellow eyelids are an uncommon finding but can be cosmetically disfiguring to a patient. There are a variety of causes of yellow eyelids. A case study as well as the differential diagnosis of yellow eyelids are presented.

Granuloma annulare: another manifestation of Bartonella infection?

Granuloma annulare (GA) is a common cutaneous eruption whose pathogenesis remains unknown. Recent literature has suggested a relation between Borrelia infection and GA, a relation that has not been widely accepted. Earlier works attempted unsuccessfully to implicate various other infectious agents. Some reports have demonstrated the increased frequency of GA in patients with human immunodeficiency virus infection, again raising the possibility of an infectious etiology. Using polymerase chain reaction amplification, we examined 19 biopsy specimens from 19 patients with GA (14 with classic palisading GA and 5 with an interstitial pattern) for the presence of a 153-base pair sequence specific for Bartonella henselae or Bartonella quintana. None of our patients were known to be human immunodeficiency virus-positive. These primers failed to detect B. henselae and B. quintana DNA in any of the specimens examined. Our findings do not support the hypothesis that GA represents a granulomatous reaction pattern to cutaneous Bartonella infection. Nevertheless, we cannot exclude the possibility that there may be a relation in other geographic locations or in immunocompromised patients or that GA represents an autosensitization reaction in response to a distant site of infection. Additional studies are needed to address these hypotheses.

Immunofluorescent microscopic investigation of the distal arrector pili: a demonstration of the spatial relationship between alpha5beta1 integrin and fibronectin.

Currently there is limited knowledge regarding the anatomy of the distal arrector pili (AP) muscle. A previous study implicated fibronectin and alpha5beta1 integrin binding as the anchor between the AP and the extracellular matrix (ECM). The purpose of this study was to strengthen this hypothesis. Serial frozen sections of human scalp skin were double-labeled via immunofluorescent staining for alpha5beta1 with fluorescein and fibronectin with rhodamine, followed by fluorescent microscopy. Granular staining for alpha5beta1 with fluorescein and smooth staining for fibronectin with rhodamine were seen at the periphery of the AP muscle bundles and along the distal fibers. Precise co-localization of alpha5beta1 and fibronectin was observed at the AP-ECM interface by means of a dual filter. Analysis of variance was used on the relative density of staining for each epitope. Staining for both epitopes was significantly brighter at the distal fibers than at the middle or proximal portions of the muscle. A computerized three-dimensional reconstruction provides a detailed picture of the microanatomy of the distal AP, which allows mathematical evaluation of the forces of contraction. The anatomic co-localization between alpha5beta1 and fibronectin strengthens our hypothesis that interaction of these epitopes mediates the attachment of the distal AP to the ECM.

Failure of detection of mucin in the clear halos around the epidermotropic lymphocytes in mycosis fungoides.

Epidermotropic lymphocytes in mycosis fungoides typically reside in clear lacunae. The material forming this space is unknown. Thirty specimens from 30 patients with mycosis fungoides were stained with alcian blue, modified Mowry's colloidal iron and mucicarmine to determine if some form of mucin could be identified. Using these stains, no form of mucin was noted in the lacunae surrounding the epidermotropic lymphocytes of mycosis fungoides. The cause of the clear spaces around epidermotropic lymphocytes in mycosis fungoides remains unexplained, but is unlikely to represent mucin deposition.

The microanatomy of the distal arrector pili: possible role for alpha1beta1 and alpha5beta1 integrins in mediating cell-cell adhesion and anchorage to the extracellular matrix.

The arrector pili (AP) muscle is a small band of smooth muscle that attaches proximally to the bulge area of the pilosebaceous apparatus in the reticular dermis and extends up toward the epidermis. The distal anatomy of the AP and the anchorage mechanism allowing hair erection have not been previously described. Integrins are likely candidates mediating this attachment. Immunohistochemical techniques were used to determine the distribution of the following integrins: alpha1, alpha2, alpha3, alpha4, alpha5, alpha6 and beta1 as well as fibronectin. Frozen human scalp tissue was sectioned in traditional planes, obliquely and horizontally to visualize microanatomy in three dimensions. Histological examination revealed that the distal portions of smooth muscle fibers splay extensively between collagen bundles of the upper dermis. Integrin subunits alpha1, alpha5 and beta1 were expressed by the AP muscle. Analysis of the relative density of immunoreactivity in digitized sections revealed increased alpha5 subunit expression at the extracellular matrix (ECM)-muscle interface. These data suggest that anchorage of the AP muscle to the ECM is via alpha5beta1 integrin and alpha1beta1 integrin functions in muscle cell-cell adhesion. Extensive splaying of smooth muscle fibers may allow increased surface area contact between the ECM and smooth muscle cells expressing peripherally situated alpha5 integrin.

Etretinate therapy for refractory sclerodermatous chronic graft-versus-host disease.

Chronic graft-versus-host disease (GVHD) is the most common late complication of allogeneic bone marrow transplantation (BMT). The sclerodermatous form of the disease is often refractory to standard treatment modalities. Based on reports of response to etretinate, a synthetic retinoid, among patients with scleroderma, we have added etretinate to the treatment regimen of 32 patients with refractory sclerodermatous chronic GVHD. This case series is comprised mainly of patients who had chronic GVHD of long duration (median of 30 months before the initiation of etretinate). Most had failed to respond to three or more agents before etretinate treatment was started. Clinical response was assessed after 3 months of therapy. Five patients did not complete a 3-month trial. Among the 27 patients evaluable for response, 20 showed improvement including softening of the skin, flattening of cutaneous lesions, increased range of motion, and improved performance status. Four showed no response after 3 months of therapy and 3 had progression of their sclerosis. Overall, etretinate has been fairly well tolerated in our patients, with skin breakdown and/or ulceration leading to its discontinuation in 6 patients. We believe the results in our patients are encouraging and suggest that further evaluation of etretinate in the treatment of sclerodermatous chronic GVHD is warranted.

The lymphocytic infiltrate in acute cutaneous allogeneic graft-versus-host reactions lacks evidence for phenotypic restriction in donor-derived cells.

The lymphocytic subtypes effecting allogeneic graft-versus-host disease (GVHD) are unknown. We studied 35 skin biopsy specimens from 19 women transplanted with bone marrow from men for patterns and time course of infiltration of the skin by Y chromosome-bearing lymphocytes using in situ hybridization. Immunophenotypic analysis was performed on serial sections. Significant numbers of donor cells were first observed by day 13 after bone marrow transplantation (BMT), although a few cells were noted at earlier time points. The quantity of donor lymphocytes in the dermis correlated with the diagnosis of GVHD. For specimens with grade 1 features, only rare cells bore the Y chromosome, whereas the majority of lymphocytes in grade 2 tissues, whether heavily inflamed or not, contained the Y chromosome. These lymphocytes were predominantly CD4+ with fewer CD8+ and CD56+ cells in the dermis and epidermis. No concentration of a specific subtype in the epidermal compartment was observed. These data do not support the observation that a cutaneous graft-versus-host reaction (GVHR) is mediated primarily by CD8+ lymphocytes. Several effector cell populations may mediate a cutaneous GVHR with further variation over time and in BMTs between different individuals.

Cutaneous lymphoplasmacytic lymphoma.

We report a case of cutaneous lymphoplasmacytic lymphoma with multiple recurrences. The patient's disease has been controlled with local radiotherapy, excision, and low dose chemotherapy. During the 9 years of his disease, he has not experienced extracutaneous involvement. This case demonstrates the indolent nature that may characterize cutaneous extramedullary plasmacytomas.

Nonneoplastic disorders of the eccrine glands.

Eccrine glands are uniquely susceptible to a variety of pathologic processes. Alteration in the rate of sweat secretion manifests as hypohidrosis and hyperhidrosis. Obstruction of the eccrine duct leads to miliaria. The excretion of drugs into eccrine sweat may be a contributory factor in neutrophilic eccrine hidradenitis (NEH), syringosquamous metaplasia (SSM), coma bulla, and erythema multiforme (EM). Alterations in the electrolyte composition of eccrine sweat can be observed in several systemic diseases, most notably cystic fibrosis. This article summarizes current knowledge of eccrine gland pathophysiology.

Solar ultraviolet radiation exposure does not appear to exacerbate HIV infection in homosexual men. The Multicenter AIDS Cohort Study.

OBJECTIVE: To determine the effect of sun exposure on HIV progression. DESIGN: Cross-sectional survey nested within a longitudinal cohort study. SETTING: The Multicenter AIDS Cohort Study. PARTICIPANTS: A total of 1155 white HIV-seronegative and 496 white HIV-seropositive homosexual men, of whom 142 seroconverted during the study. MAIN OUTCOME MEASURES: T-helper lymphocyte decline and AIDS. RESULTS: No positive correlation was found between the development of AIDS or loss of T-helper lymphocytes and (i) phenotypic characteristics associated with enhanced ultraviolet radiation (UVR) sensitivity (hair or eye color, skin type), or (ii) reported UVR exposure (sun lamp/tanning bed use, frequency of beach vacations, sunscreen use), or (iii) composite score of UVR sensitivity and exposure history. The composite scores and individual measures of risk were not correlated with rate of T-helper lymphocyte decline (slope) based upon rank correlation (correlation coefficient, 0.04; P = 0.32). In fact, individuals purposefully seeking the sun had slower T-helper lymphocyte declines. Sensitivity to UVR was also not significantly associated with AIDS [odds ratio (OR), 1.11 per unit of higher composite score; 95% confidence interval (CI), 0.66-1.88; P = 0.63]. Among individuals who were HIV-infected at baseline, those who have been purposely seeking sun exposure were less likely to have AIDS (OR, 0.67; 95% CI, 0.39-1.11; P = 0.12). CONCLUSIONS: These data suggest that phenotypic characteristics of high UVR sensitivity and exposure are not highly correlated with decline in T-helper lymphocyte count or with progression to AIDS.

Ultraviolet therapy of HIV-infected individuals: a panel discussion.

Patients infected with the human immunodeficiency virus (HIV) frequently develop skin diseases that are responsive to ultraviolet (UV) radiation. Studies on the effects of UV on HIV and on the immune system in vitro and in transgenic animals have raised questions regarding the safety of UV exposure in these patients. In this article, invited experts address issues concerning the safety of ultraviolet therapy in HIV-infected patients by discussing their clinical and/or research experience.