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.

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.

Reappraisal of histologic features of the acute cutaneous graft-versus-host reaction based on an allogeneic rodent model.

We employed a rat model of complete major histocompatibility complex-mismatched allogeneic bone marrow transplantation to better characterize the histologic expression of the acute cutaneous graft-versus-host reaction (GVHR), compared with changes due to the preparative regimen. Cyclosporin A abolished the development of this GVHR. Low levels of dyskeratotic cells were present in all groups (allogeneic and syngeneic transplants with and without cyclosporin A) and, alone, were insufficient to diagnose a cutaneous GVHR. A consistent histologic feature of the GVHR was significant lymphoid infiltration of the dermis. The pattern of cytotoxic folliculitis involved follicular epithelium above the entry of sebaceous glands. Immunostain for major histocompatibility complex class II, IA, and IE antigens revealed that dendritic cells within the follicle were limited to this upper region and that lower follicular epithelium did not upregulate expression with evolution of the GVHR. Based on this model, we conclude 1) that the diagnostic scheme for the acute cutaneous GVHR should include lymphoid infiltration of the dermis, 2) that the preparative regimen (including total body irradiation) induces persistent low levels of dyskeratotic cells (two to three cells/linear mm of epidermis), and 3) that the pattern of follicular involvement may relate to the distribution of dendritic cells and to an inability of lower follicular epithelium to upregulate major histocompatibility complex class II antigens.

Clinical, laboratory, and histopathologic indicators of the development of progressive acute graft-versus-host disease.

Graft-versus-host disease (GvHD) is the major cause of morbidity and mortality following bone marrow transplantation (BMT). The goal of this study of 69 cyclosporin-treated, allogeneic BMT patients was to identify early clinical, laboratory, or histopathologic indicators of the development of progressive, fatal GvHD. Peak values within 100 d of allogeneic BMT for total bilirubin, stool volume in a day, clinical stage of cutaneous GvHD (based on extent of rash), and overall clinical stage of GvHD (based on a combination of graft-versus-host reactions in the skin, liver, and gastrointestinal tract) were most useful (p less than 0.05, by logistic regression) in identifying those patients with clinically progressive and fatal GvHD. Peak values for each of these parameters were reached an average of 40 d or less after BMT. Each unit increase in peak clinical stage of rash (e.g., stage 2 versus stage 3) was associated with an odds ratio incremental risk of 5.8 for clinical progression of GvHD, and each tenfold increase in peak total bilirubin (e.g., 2 mg/dl versus 20 mg/dl) or stool output in a day (e.g., 100 cm3/d versus 1000 cm3/d) was associated with an incremental risk of 8.4 and 10.6, respectively, for a fatal outcome from GvHD. Number of exocytosed lymphocytes and dyskeratotic epidermal keratinocytes (DEK) per linear millimeter of epidermis, the presence of follicular involvement, and the degree of dermal perivascular lymphocytic infiltration in 121 skin biopsy specimens were not associated with the development of progressive or fatal GvHD. Pretransplant total body irradiation was associated (p = 0.03, by Mann-Whitney U testing) with an increased number of DEK in skin biopsy specimens taken less than 20 d after BMT. This study demonstrates that monitoring of total bilirubin, stool output, extent of rash, and overall clinical stage of GvHD is most useful during the first 40 d after BMT in formulating the prognosis of early acute GvHD in allogeneic BMT patients receiving cyclosporin.

Cutaneous graft-versus-host reaction lacks evidence of cutaneous cytomegalovirus by the immunoperoxidase technique.

Sixty skin biopsy specimens from 21 bone-marrow transplant patients were evaluated for the presence of cytomegalovirus (CMV) using two monoclonal antibodies to early and late antigens. Each patient had at least one biopsy showing an acute graft-versus-host reaction (GVHR), grade 2, and one positive culture for CMV from blood, bone marrow or urine. In no case could CMV antigens be identified in biopsies showing an acute or chronic cutaneous GVHR or in any other of the skin biopsies obtained from these patients. While CMV may play a role in immunologic events culminating in graft-versus-host disease (GVHD), this immunoperoxidase study did not reveal evidence of viral antigens in tissue displaying features of cutaneous GVHR.

Predominant CD8+ infiltrate in limb biopsies of individuals with filarial lymphedema and elephantiasis.

In 34 individuals with a spectrum of clinical manifestations of Bancroftian filariasis, we investigated whether immunoperoxidase-stained, random, superficial dermal biopsies could further elucidate the nature of the diffuse damage to superficial lymphatics that had been recently demonstrated by radionuclide lymphoscintigraphy. A total of 78% and 68% of limbs from patients with clinical disease and asymptomatic microfilaremia, respectively, contained EN4+PAL-E- lymphatic vessels that were abnormally dilated. The majority of subjects, regardless of clinical classification, had a CD3+ perivascular but not a perilymphatic infiltrate in tissues and no parasites were present. In contrast to those individuals with asymptomatic infection, a striking predominance of CD8+ T cells was found in the tissue of individuals with clinical disease. Tissue pathology consistent with cutaneous bacterial infection was not observed. The prominent perivenular and pericapillary mononuclear infiltrates likely indicate, in light of current understanding of lymphocyte recirculation, the extravasation of lymphocytes from the vascular circulation into the inflamed filarial tissue.

Transient acantholytic dermatosis in immunocompromised febrile patients with cancer.

A focal acantholytic dermatosis resembling transient acantholytic dermatosis (TAD) clinically and histologically occurred in four immunocompromised and persistently febrile patients with various malignant neoplasms. No pathologic organism was isolated in cultures from blood or from the actual skin lesions. The rash resolved over several days, coinciding with defervescence. As do authors of other reports of TAD, we believe that the etiology of TAD is related to heat, persistent fever, and/or sweating.

Cytomegalovirus is predictably present in perineal ulcers from immunosuppressed patients.

We examined five consecutive skin biopsy specimens taken from perineal ulcers on immunosuppressed patients. Examination of hematoxylin-eosin-stained sections in conjunction with immunohistochemistry using monoclonal antibodies to early and late viral antigens resulted in identification of cytomegalovirus in all specimens. Cells containing cytomegalovirus were present in the ulcer base and papillary dermis. Herpes simplex virus was identified in three of five specimens. This series demonstrates that cytomegalovirus is predictably present in perineal ulcers from immunocompromised patients, but does not establish this virus as the cause of the ulcers.

Histologic features of paraneoplastic pemphigus.

BACKGROUND: We describe the histopathologic features of paraneoplastic pemphigus, a recently described autoimmune mucocutaneous disease associated with neoplasia. Complete evaluation for paraneoplastic pemphigus requires identification of the characteristic mucocutaneous eruption, tissue specimens for routine histologic and direct immunofluorescence evaluation, and identification of circulating autoantibodies with a unique specificity. Immunoprecipitation from keratinocytes reveals a characteristic complex of four proteins with the circulating antibodies. Various neoplasms have been identified in patients with paraneoplastic pemphigus. OBSERVATIONS: We reviewed 16 skin and oral mucous membrane biopsy specimens from six patients with paraneoplastic pemphigus confirmed by fulfillment of all criteria. Major features include epidermal acantholysis, suprabasal cleft formation, dyskeratotic keratinocytes, vacuolar change of the basilar epidermis, and epidermal exocytosis of inflammatory cells. Seven (44%) of 16 specimens displayed a unique combination of suprabasal acantholysis and dyskeratotic keratinocytes throughout the epidermis. These histologic findings correspond to those of the characteristic clinical lesions that are described as having features of pemphigus and erythema multiforme. CONCLUSIONS: Paraneoplastic pemphigus represents a unique clinical, histologic, and immunologic disease characterized by autoantibody production to desmoplakin I and desmoplakin II, bullous pemphigoid antigen, and, possibly, other antigens in the desmosomal complex. Recognition of the histologic features should prompt immunopathologic confirmation and evaluation for an occult neoplasm.

Characterization of the dermal infiltrate in human immunodeficiency virus-infected patients with psoriasis.

We investigated the dermal inflammatory cell infiltrates of psoriatic lesions from nine human immunodeficiency virus-infected patients and nine age-, sex-, and site-matched control specimens. The study was retrospective and observer blinded. T lymphocytes were quantitated using UCHL-1, a pan-T-cell monoclonal antibody, and plasma cell number was estimated in hematoxylin-eosin-stained sections. Differences in both variables reached statistical significance. There were fewer T cells and the number of plasma cells was significantly higher in specimens from the human immunodeficiency virus-positive individuals in comparison with control specimens. As plasma cells are readily identified on hematoxylin-eosin-stained sections, their presence in skin biopsy specimens from psoriatic leisons should arouse suspicion of human immunodeficiency virus infection. The depletion of helper/inducer T lymphocytes by the human immunodeficiency virus may promote the presence of plasma cells in cutaneous inflammatory infiltrates.

Histologic comparison of autologous graft-vs-host reaction and cutaneous eruption of lymphocyte recovery.

BACKGROUND AND DESIGN: The cutaneous eruptions due to allogeneic graft-vs-host disease, autologous graft-vs-host disease, and lymphocyte recovery occur in the setting of peripheral leukocyte reconstitution after marrow aplasia. Since the eruptions of lymphocyte recovery (ELR) and autologous graft-vs-host disease develop in the presence of histocompatibility, we question whether reliable histologic differentiation is possible. To this end, we performed a retrospective, blind analysis of 38 skin biopsy specimens obtained from patients who received autologous marrow transplants or intensive chemotherapy alone for various malignant neoplasms. RESULTS: In 31% of the cases, we were unable to distinguish between an ELR and a grade 2 graft-vs-host reaction. In 40% of the ELR specimens, a significant number of dyskeratotic keratinocytes were present, leading to the false interpretation of a grade 2 graft-vs-host reaction. Satellite cell necrosis was observed in both groups. The patterns of dyskeratotic keratinocytes were similar; one ELR specimen displayed prominent follicular involvement. Most ELR specimens were consistent with grade 1 graft-vs-host reaction changes. CONCLUSIONS: These findings indicate that the presence of dyskeratotic keratinocytes is not specific for a graft-vs-host reaction and that cutaneous eruptions after autologous marrow transplantation are best considered an ELR.

Prurigo pigmentosa. Report of a case and review of the literature.

Prurigo pigmentosa is an uncommon skin disease first reported from Japan where it has gained recognition as distinct cutaneous disease characterized by rapid response to dapsone therapy. Recently, a few reports of prurigo pigmentosa have appeared in the western literature. American-born white man and review the literature pertaining to this unique entity.

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.

Observations and proposed mechanism of N,N',N''-triethylenethiophosphoramide (thiotepa)-induced hyperpigmentation.

After receiving N,N',N''-triethylenethiophosphoramide (thiotepa) and cyclophosphamide intravenously, five women with metastatic adenocarcinoma of the breast developed a patterned hyperpigmentation confined to skin occluded by adhesive-containing materials. Determinations of thiotepa concentrations in occluded and nonoccluded skin, plasma, bandage with adhesive, and gauze containing sweat were performed. The results suggest that this alkylating agent is excreted onto the skin surface in sweat, accumulates beneath adhesive-containing bandages and electrocardiogram pads, and exerts a local toxic effect resulting in hyperpigmentation.

Intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor causes a cutaneous eruption.

The intravenous administration of recombinant human granulocyte-macrophage colony-stimulating factor to three patients with leukemia who were receiving marrow aplasia-inducing chemotherapy resulted in the development of wide-spread erythematous macules and papules. The course of the eruption paralleled the time of infusion of the granulocyte-macrophage colony-stimulating factor. Skin biopsy specimens taken from two of the eruptions displayed characteristic changes consisting of a variable mixture of granulocytes and lymphocytes, increased number and size of dermal macrophages, mild to moderate epidermal exocytosis, intercellular edema, and rare dyskeratotic keratinocytes. Immunophenotypic analysis of one specimen was notable for keratinocyte intercellular adhesion molecule-1 expression. Administration of the recombinant human cytokine in pharmacologic doses is postulated to induce changes in the immunologic status of the skin, resulting in the expression of a cutaneous eruption.

Lichen planus-like histopathologic characteristics in the cutaneous graft-vs-host reaction. Prognostic significance independent of time course after allogeneic bone marrow transplantation.

BACKGROUND: The discrimination between acute and chronic graft-vs-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) is important because the treatment regimens and prognosis differ. OBJECTIVES: To identify whether accepted histopathologic criteria of a graft-vs-host reaction (GVHR) alone or in combination accurately reflect clinical phase of disease, to correlate patterns with clinical outcome, and to identify any concordance between inflammation and epidermal changes of a GVHR. DESIGN: Skin biopsy specimens were analyzed according to histologically defined standards. SETTING: This study was performed in a tertiary care hospital. PATIENTS: One hundred seventy-three skin biopsy specimens (10 days before to 1326 days after BMT) from 83 patients undergoing allogeneic BMT for various malignant neoplasms were selected for study. A consecutive 12-month sample was used. MAIN OUTCOME MEASURES: The main measures in this study were statistical correlations between histopathologic findings and time after BMT, the outcome of BMT, and the correlations between selected histopathologic criteria. RESULTS: Fully evolved histologic features of chronic lichenoid GVHR in the specimens occurred across a wide time range (33-832 days after BMT) and were associated with a 5.6-fold increased risk for death (P = .02) from GVHD. Histologic features of acute GVHR in the specimens also occurred across a wide time range (14-481 days after BMT) and were associated with a 2.2-fold increased risk for death; this finding was not statistically significant (P = .11). Inflammation of the upper dermis was significantly associated with acanthosis and epidermal cell necrosis (P < .001 and P < .001, respectively, for bandlike pattern), confirming the importance of this finding as a criterion for the diagnosis of a GVHR. Blinded evaluation of a subset of specimens for the diagnosis of acute vs chronic GVHR resulted in wide interobserver variation. CONCLUSIONS: This study demonstrates the following: specific histologic parameters in skin biopsy specimens do not consistently separate acute from chronic GVHD as defined by days after BMT; independent of time course, fully evolved histopathologic characteristics of a lichen planus-like GVHR is associated with a greater likelihood of death from GVHD; and identification of upper dermal inflammation correlates with the epidermal features of GVHR and should be included in the diagnostic scheme.

Cutaneous eruptions of lymphocyte recovery.

Macular and papular eruptions are ascribed to various causes, often drug-related hypersensitivity or toxicity. We observed patients with cutaneous eruptions during hospital admissions for induction or augmentation chemotherapy in the treatment of leukemia. In 10 of 14 patients, macular and papular eruptions occurred in a strikingly similar pattern, at the earliest recovery of peripheral lymphocytes, after chemotherapy-induced nadir of the leukocyte count. A concomitant sharp, transient rise in temperature accompanied the eruption of lymphocyte recovery. Skin biopsy specimens were obtained from 8 of these 10 patients and showed a superficial, perivascular mononuclear cell infiltrate. Immunohistochemical analysis of the cellular infiltrate was performed. The rash of lymphocyte recovery may be due to the actual return of immunocompetent lymphocytes to the peripheral circulation and skin after the chemotherapy-induced nadir of the leukocyte count. These observations suggest that macular and papular eruptions relate to specific immunologic events.

Interleukin 2 and granulocyte-macrophage colony-stimulating factor induce a perivascular lymphocytic infiltrate in a skin explant model.

Cutaneous eruptions displaying perivascular inflammatory cell infiltrates histologically may develop with the intravenous administration of cytokines. Similar findings are seen spontaneously in some patients on recovery of peripheral blood lymphocytes after profound marrow aplasia. To investigate the production of a cutaneous perivascular infiltrate further, the ability of several cytokines to induce a perivascular lymphocytic infiltrate was studied in vitro using a skin explant model. A skin biopsy specimen obtained at the time of peripheral blood lymphocyte recovery after chemotherapy-induced marrow aplasia (n = 10) was divided and incubated for 3 days with and without a series of cytokines plus various peripheral blood mononuclear cell populations. Skin incubated with interleukin 2 and granulocyte-macrophage colony-stimulating factor induced a perivascular lymphocytic infiltrate, while control samples did not. Immunophenotypic analysis revealed that the lymphocytes were predominantly CD3+/CD4+. An infiltrate was not observed when skin was incubated with cytokines alone, without the addition of simultaneously isolated peripheral lymphocytes. A perivascular pattern was not observed with the addition of interferon gamma. Only interferon gamma induced keratinocyte intercellular adhesion molecule 1 expression in experimental tissue. Certain cytokines that affect a range of cell types are capable of inducing a common cutaneous histologic pattern, the perivascular lymphocytic infiltrate.