Elizabeth A. Abel

Drugs in exacerbation of psoriasis.

Drugs that have been associated with the precipitation or exacerbation of psoriasis include lithium, beta adrenergic receptor blocking agents, and antimalarials. The withdrawal of corticosteroids has been reported to activate pustular psoriasis. Nonsteroidal anti-inflammatory drugs, such as indomethacin, have recently been reported to exacerbate psoriasis, although additional well-controlled studies are still needed. Drugs used for treatment of psoriasis will sometimes cause a flare because of irritation, phototoxicity, or hypersensitivity reaction resulting in a Koebner phenomenon. Because psoriasis is a very complex disease and its activity is often unpredictable, clinical studies on adverse drug effects on psoriasis have been difficult to conduct. This review evaluates clinical, histologic, and biochemical evidence in the literature for drug-associated onset or exacerbation of psoriasis.

Mycosis fungoides and the Sézary syndrome: Pathology, staging, and treatment

Mycosis fungoides and the Sézary syndrome are forms of cutaneous T-cell lymphoma. Mycosis fungoides is an uncommon disease: only about 500 new cases are diagnosed in the United States annually. The median age of onset is 55 years and there is a 2:1 male predominance. The etiology of mycosis fungoides is unknown. Although occupational exposures have been implicated, case control studies fail to support this hypothesis. Mycosis fungoides is typified by cutaneous plaques which may evolve into tumors over the course of time. It is often preceded by a lengthy pre-mycotic phase prior to the time of definitive diagnosis. In its earliest diagnostic phase, there may only be slightly scaling patches with a limited distribution. Indurated lesions evolve into plaques, which may become more generalized in their distribution. As the severity of skin involvement increases, there is an increasing likelihood of spread to extracutaneous sites. The pathology of this disease is marked by involvement of the epidermis (Pautrier microabscesses). Immunologic studies characterize these cells as belonging to the helper T-cell subset. Genotypic analysis demonstrates monoclonal rearrangements of the T-cell receptors of the infiltrating cells. The staging system for mycosis fungoides considers the extent of skin involvement, presence of lymph node or visceral disease, and detection of abnormal cells in the peripheral blood. Patients with disease limited to the skin (90% of newly diagnosed cases) are treated best with topical or cutaneous therapies. Common modalities include psoralen photochemotherapy (PUVA), topical chemotherapy (nitrogen mustard) and total skin electron beam therapy. Both topical nitrogen mustard and electron beam therapy have good initial response rates (73% and 100%) and may achieve long-term disease-free survival, especially in patients with initially limited disease. Even if the response is incomplete or relapse occurs, substantial and very important palliation is generally achieved with topical therapy. Recurrent or resistant cutaneous disease will require the use of sequential topical treatment. The median survival time of patients who present with disease limited to the skin is greater than 10 years, and many deaths in this group are from intercurrent causes, especially in patients with limited or generalized plaque disease. If cutaneous tumors are present, the majority of these patients will eventually die from disease-related causes. The prognosis of patients who develop extracutaneous disease is exceedingly poor (median survival time, approximately 1 year).(ABSTRACT TRUNCATED AT 400 WORDS)

Leu-8 and Leu-9 antigen phenotypes" Immunologic criteria for the distinction of mycosis fungoides from cutaneous inflammation

The distinction of mycosis fungoides from reactive cutaneous inflammation can be difficult. Unfortunately, since many reactive processes exhibit predominantly a mature helper T cell phenotype similar to that expressed by most cases of mycosis fungoides, standard immunologic marker studies have not been very helpful in differential diagnosis. To determine whether novel immunophenotypic criteria could be developed that correlate with the diagnosis of cutaneous involvement by mycosis fungoides, we studied the expression of Leu-8 and Leu-9 antigens by T cells in forty-one skin biopsy specimens from twenty-seven patients with mycosis fungoides and thirty-four skin biopsy specimens from thirty-three controls with a variety of benign cutaneous diseases. These antigens are expressed by the majority of normal T cells in the blood and lymphoid tissues but are often absent in T cell lymphomas or expressed by only a minority of tumor cells. Semiquantitative grading of the percentage of Leu-8+ and Leu-9+ T cells in our patients revealed that deficiency of these antigens (i.e., expression by less than or equal to 33% of T cells) was more prevalent among mycosis fungoides patients than among controls and became more specific for mycosis fungoides as the percentage of Leu-8+ and Leu-9+ T cells decreased. In initial biopsies, less than or equal to 33% of T cells were Leu-8+ in 82% of mycosis fungoides patients versus 15% of controls, while less than or equal to 10% of T cells were Leu-8+ in 52% of mycosis fungoides patients versus only 3% of controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Mycosis fungoides: management with topical nitrogen mustard.

The technique of treatment, response rate, freedom from relapse, survival, and complications of therapy in 123 patients treated with topical nitrogen mustard (HN2) for cutaneous mycosis fungoides (MF) at Stanford University Medical Center are reviewed. Patients were treated with HN2 in an aqueous or ointment base with equal efficacy. Response rates depended on the extent of skin involvement. In limited plaque (T1) disease, complete and overall response rates were 51% and 88%, respectively, while in generalized plaque (T2) disease they were 26% and 69%. No patients with tumorous involvement (T3) achieved complete skin clearance and all 13 of these patients developed progression of disease. Only two of nine patients with erythrodema (T4) achieved a complete response (CR), and both later relapsed. After achieving a CR, 40% of patients with T1 disease and 60% with T2 disease later relapsed; however, subsequent therapies, including repeat courses of topical HN2, often were successful in achieving later skin clearance. Overall, 42% of T1 patients and 31% of T2 patients were without evidence of MF at last follow-up. When death occurred, it was usually unrelated to MF in the T1 group. However, half of the deaths of patients with T2 disease were attributable to MF. Among the 22 patients with T3 or T4 disease, 80% of deaths were attributable to MF. The most common complication observed was a cutaneous hypersensitivity reaction, which occurred much more commonly with the aqueous than the ointment preparation. Fourteen patients (11%) developed subsequent cutaneous malignancies.

Leu-8/CD7 antigen expression by CD3+ T cells: Comparative analysis of skin and blood in mycosis fungoides/Sézary syndrome relative to normal blood values

Deficiencies of Leu-8 and CD7 antigens are exhibited by CD3+ T cells in the skin lesions of most patients with mycosis fungoides/Sézary syndrome. To determine whether these antigenic abnormalities are limited to involved skin, we studied Leu-8/CD7 expression in 21 skin lesions of mycosis fungoides/Sézary syndrome obtained from 16 patients and compared them with their peripheral blood leukocytes obtained concurrently. There was no correlation between Leu-8/CD7 values in skin lesions versus blood. Blood values were relatively uniform; most patients had 50% or greater of CD3+, Leu-8+ T cells and CD3+, CD7+ T cells. In contrast, skin values were highly heterogeneous; most patients lacked expression of Leu-8 or CD7 by the majority of lesional CD3+ T cells. Furthermore, Leu-8/CD7 antigen deficiency was present in lesional skin in one patient with mycosis fungoides but not in her concurrently sampled pityriasis lichenoides chronica or blood. These findings suggest that Leu-8/CD7 antigen deficiencies in skin lesions of mycosis fungoides/Sézary syndrome do not represent generalized antigenic abnormalities of CD3+ T cells in other body compartments and that within the skin, these deficiencies are disease specific within individual patients with more than one dermatosis. Comparative peripheral blood immunophenotyping of the patients with mycosis fungoides/Sézary syndrome and of the control subjects indicated that the control ranges of CD3+/Leu-8+ and CD3+/CD7+ T cells (33% or greater) extend lower than reported previously (60% or greater) and suggested that leukemic involvement in patients with mycosis fungoides/Sézary syndrome may correlate with percentages of CD3+, Leu8+ and/or CD3+, CD7+ T cells that fall below the revised control range.

Cutaneous malignancies and metastatic squamous cell carcinoma following topical therapies for mycosis fungoides

Specific treatments for mycosis fungoides, including electron beam irradiation, topical mechlorethamine, and psoralen plus ultraviolet A (PUVA) may be associated with the development of skin cancers after a variable latency period. Because these treatments are often not curative, topical therapies for mycosis fungoides, administered sequentially or concomitantly, are being used increasingly in order to control recurrent disease. This report documents the development of multiple cutaneous tumors, including squamous cell carcinoma, basal cell carcinoma, actinic keratoses, keratoacanthomas, and one case of lentigo maligna, in seven patients who received topical therapies for mycosis fungoides. In contrast to the usual latency period between ionizing radiation therapy and the development of skin cancer, two of our patients who had received prior PUVA therapy developed multiple skin tumors upon completion of electron beam irradiation. The development of metastatic squamous cell carcinoma in two of the other seven patients with multiple cutaneous neoplasms suggests that this potential hazard must be considered in the evaluation and treatment of patients with mycosis fungoides.

Cutaneous manifestations of immunosuppression in organ transplant recipients

Skin disease is a significant cause of morbidity in chronically immunosuppressed patients, including organ transplant recipients. Cutaneous drug reactions may be caused by immunosuppressive therapy that commonly includes corticosteroids, cyclosporine, azathioprine, and antithymocyte and antilymphocyte globulins. Immunosuppressive drugs can also potentiate the effects of other carcinogens, such as ultraviolet radiation, that cause premalignant lesions and squamous cell carcinoma. The risk of Kaposis sarcoma is increased in these immunosuppressed patients, particularly in renal transplant recipients. Oncogenic viruses such as the Epstein-Barr virus have been associated with the development of non-Hodgkins lymphoma in transplant recipients. In transplant patients human papillomavirus infections may be predisposed to malignant transformation, particularly at genital sites. Opportunistic infections caused by bacteria, fungi, viruses, or protozoa are the most common cause of death in transplant recipients. Skin manifestations of infection in immunosuppressed patients may be an important clue to their presence.

Cyclosporine as maintenance therapy in patients with severe psoriasis

BACKGROUND Low-dose cyclosporine therapy for severe plaque psoriasis is effective. Most side effects can be controlled by patient monitoring, with appropriate dose adjustment or pharmacologic intervention, or both, if indicated. Prevention or reversibility of laboratory and chemical abnormalities may be achieved by discontinuation of therapy after the induction of clearing. However, relapse occurs rapidly on discontinuation. Maintenance therapy with cyclosporine after induction has not been fully evaluated. OBJECTIVE Our purpose was to compare a regimen of 3.0 mg/kg per day of oral cyclosporine with placebo in maintaining remission or improvement in patients with psoriasis. METHODS After a 16-week unblinded induction phase in which 181 patients received cyclosporine, 5.0 mg/kg per day (an increase up to 6.0 mg/kg per day and a decrease to 3.0 mg/kg per day were allowed, if required, to achieve efficacy or tolerability, respectively), those patients showing a 70% decrease or more in involved body surface area (BSA) entered the 24-week maintenance phase and were randomly assigned to either placebo, cyclosporine, 1.5 mg/kg per day, or cyclosporine, 3.0 mg/kg per day. Patients were considered to have had a relapse when BSA returned to 50% or more of the prestudy baseline value. Clinical efficacy, adverse effects, and laboratory values were monitored regularly throughout both study phases. RESULTS During induction, cyclosporine at approximately 5.0 mg/kg per day produced a reduction in BSA of 70% or more in 86% of the patients. During maintenance, the median time to relapse was 6 weeks in both the placebo and cyclosporine 1.5 mg/kg per day groups, but was longer than the 24-week maintenance period in the 3.0 mg/kg per day group (p < 0.001 vs placebo). By the end of the maintenance period, 42% of the patients in the 3.0 mg/kg per day cyclosporine group had a relapse compared with 84% in the placebo group. Changes in laboratory values associated with the higher induction dosage generally exhibited partial or complete return toward mean prestudy baseline values during the maintenance phase, with the greatest degree of normalization in the placebo group. CONCLUSION Cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day.

PUVA treatment of erythrodermic and plaque type mycosis fungoides

Five patients with plaque type mycosis fungoides (MF) and five patients with erythrodermic MF responded favorably to oral psoralen photochemotherapy (PUVA). The mean total UVA irradiation dose was less for erythrodermic than for plaque type MF, but the mean number of treatments to achieve clearing was greater in the erythrodermic patients. Histologic examination at clearing revealed persistence of an inflammatory infiltrate in the lower dermis in most cases. Subsequent recurrent lesions in five patients revealed a more extensive dermal inflammatory infiltrate, although findings were not always diagnostic of MF due to a lack of epidermal involvement. Resumption of more intensive PUVA therapy again resulted in clinical clearing in all five patients. The follow-up period for six patients who received long-term PUVA maintenance ranged from 1 1/2 to 3 1/2 years. During PUVA therapy, five of ten patients developed epithelial malignancies or premalignancies, and one patient developed a malignant fibrous histiocytoma. Most of these patients had received prior treatment with electron beam and topical nitrogen mustard.

Immunohistology of pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica: Evidence for their interrelationship with lymphomatoid papulosis

Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica are idiopathic, papular eruptions that exhibit certain clinicopathologic similarities to each other and to lymphomatoid papulosis. In order to determine if these disorders are also similar immunologically, we studied the immunopathology of five biopsy specimens from three cases of pityriasis lichenoides et varioliformis acuta and three biopsy specimens from three cases of pityriasis lichenoides chronica. We then compared them to our prior immunohistologic study of nine cases of lymphomatoid papulosis. Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica both exhibited a dermal and epidermal infiltrate of CD4+ and CD8+ T cells expressing activation antigens. These were admixed with numerous macrophages. The lesional epidermis was diffusely human lymphocyte antigen (HLA)-DR+ and contained decreased CD1+ dendritic cells. Endothelial cells were also HLA-DR+. Cells bearing the phenotypes of B cells, follicular dendritic cells, or natural killer/killer cells were essentially absent. Except for the lack of large atypical cells, the results resembled those described previously for lymphomatoid papulosis. These findings indicate that pityriasis lichenoides chronica, pityriasis lichenoides et varioliformis acuta, and lymphomatoid papulosis share several immunohistologic features. Together with certain clinicopathologic similarities, they are consistent with the hypothesis that these three disorders are interrelated.