Michael T. Goldfarb

CTLA4Ig-mediated blockade of T-cell costimulation in patients with psoriasis vulgaris

Engagement of the B7 family of molecules on antigen-presenting cells with their T cell-associated ligands, CD28 and CD152 (cytotoxic T lymphocyte-associated antigen-4 [CTLA-4]), provides a pivotal costimulatory signal in T-cell activation. We investigated the role of the CD28/CD152 pathway in psoriasis in a 26-week, phase I, open-label dose-escalation study. The importance of this pathway in the generation of humoral immune responses to T cell-dependent neoantigens, bacteriophage phiX174 and keyhole limpet hemocyanin, was also evaluated. Forty-three patients with stable psoriasis vulgaris received 4 infusions of the soluble chimeric protein CTLA4Ig (BMS-188667). Forty-six percent of all study patients achieved a 50% or greater sustained improvement in clinical disease activity, with progressively greater effects observed in the highest-dosing cohorts. Improvement in these patients was associated with quantitative reduction in epidermal hyperplasia, which correlated with quantitative reduction in skin-infiltrating T cells. No markedly increased rate of intralesional T-cell apoptosis was identified, suggesting that the decreased number of lesional T cells was probably likely attributable to an inhibition of T-cell proliferation, T-cell recruitment, and/or apoptosis of antigen-specific T cells at extralesional sites. Altered antibody responses to T cell-dependent neoantigens were observed, but immunologic tolerance to these antigens was not demonstrated. This study illustrates the importance of the CD28/CD152 pathway in the pathogenesis of psoriasis and suggests a potential therapeutic use for this novel immunomodulatory approach in an array of T cell-mediated diseases.

Oral cyclosporine for severe chronic idiopathic urticaria and angioedema

Three patients with chronic urticaria, two of whom also had angioedema, were treated with oral cyclosporine, 6 mg/kg per day. In each patient, complete resolution of symptoms occurred within the first week of therapy; however, all patients eventually had to stop therapy as a result of side effects. On stopping therapy, all side effects resolved and the urticaria and angioedema recurred. Although cyclosporine therapy is not an appropriate treatment of urticaria, the results of this preliminary study suggest that cyclosporine and related drugs should be investigated in the treatment of mast cell-mediated diseases.

Acitretin improves psoriasis in a dose-dependent fashion

Acitretin, a metabolite of etretinate, was given to 38 patients for the treatment of psoriasis. During the first 8 weeks patients received either placebo, 10 mg, 25 mg, 50 mg, or 75 mg of acitretin daily in a double-blind manner. The dosages of 10 mg and 25 mg daily did not achieve any statistically significant improvement in psoriasis over placebo; however, both the 50 and 75 mg dosages were statistically significantly better than placebo. Side effects were primarily mucocutaneous and occurred in most patients receiving 25 mg or more of acitretin daily. After the double-blind period, patients continued treatment in an open fashion until they had received a total of 24 weeks of acitretin therapy. Most patients received 50 mg of acitretin daily, which adequately cleared their psoriasis. After approximately 3 months without acitretin, most patients required retreatment. Subsequent 24-week courses of therapy were generally effective and well tolerated. The most common laboratory abnormalities were elevations of triglyceride, cholesterol, and liver transaminase levels. The efficacy and side effects of acitretin appear to be similar to those of etretinate; the principal advantage of acitretin is its shorter half-life. Although acitretin is a potent teratogen, its rapid elimination makes it a viable treatment for psoriasis among women of childbearing potential.

Side-effect profile of acitretin therapy in psoriasis

Acitretin, the principal and free acid metabolite of etretinate, was used to treat patients with stable, plaque-type psoriasis. For the first 8 weeks, 38 patients received placebo or acitretin, 10, 25, 50, or 75 mg daily, in a double-blind manner. After the double-blind phase, the patients were allowed to continue for a total of 6 months of acitretin therapy at an average dosage of 50 mg/day. When the patients flared after stopping therapy, an additional 6-month course of acitretin therapy was offered. Acitretin, which was as effective as etretinate, had to be given at a dosage of 50 mg/day or more to obtain a significant benefit. Side effects frequently occurred in patients receiving acitretin, 25 mg/day or more, but were generally mild and did not warrant discontinuation of therapy. They were similar to those of etretinate therapy; cheilitis, peeling of palms and soles, and alopecia occurred most frequently. The most common abnormal laboratory test results were elevations in serum triglycerides and, to a lesser extent, serum cholesterol and liver transaminase levels. Acitretin, in view of its much shorter half-life and similar efficacy and side-effect profile compared with etretinate, may be a preferable therapy for psoriasis, especially in women of childbearing age.

Topical tretinoin therapy: Its use in photoaged skin

Tretinoin cream has been used extensively to reverse the changes of photoaging. It is the first topical therapy to undergo controlled clinical testing and proved to be efficacious. These results have been substantiated with photography, histopathologic examination, and skin surface replicas. The mechanism of action of retinoic acid is unknown, but it may bind to a specific receptor that alters the gene expression of the cell. Therapy is most successful when a liberal amount of tretinoin 0.1% cream is applied to the skin daily. Tretinoin cream has an excellent safety record; a local cutaneous hypervitaminosis A reaction is the only common problem.

The safety of etretinate as long-term therapy for psoriasis: Results of the Etretinate Follow-up Study

BACKGROUND Etretinate is an aromatic retinoid given orally to treat severe psoriasis, a chronic disease that often requires long-term therapy. OBJECTIVE We assessed the safety of long-term therapy with etretinate for psoriasis. METHODS This 5-year prospective study of a cohort of 956 patients with psoriasis treated with etretinate assessed the frequency of adverse events in relation to total use and in relation to the frequency of these events in control populations. RESULTS Our data do not provide evidence for an increased risk of cardiovascular disease, cancer, diabetes, or inflammatory bowel disease in association with long-term etretinate use. Although some patients reported that joint problems improved with the use of etretinate, a greater number associated the use of etretinate with joint problems. CONCLUSION With proper patient selection and monitoring, long-term etretinate therapy (up to 4 years) does not appear to be accompanied by a substantial increased risk of major adverse effects.

The role of fish oil in psoriasis : a randomized, double-blind, placebo-controlled study to evaluate the effect of fish oil and topical corticosteroid therapy in psoriasis

ABSTRACT: In a randomized, double‐blind, placebo‐controlled study, patients received 10 fish or olive oil capsules three times daily for the whole study in addition to applying betamethasone diproprionate to their psoriatic plaques for the first 3 weeks. Most patients gradually worsened upon discontinuation of corticosteroids. Using survival analysis methods, no significant difference was found between the fish and olive oil groups. The authors attempt to put the role of fish oil in the therapy of psoriasis into perspective and discuss the efficacy of fish oil when used alone versus in combination therapy.

Topical tretinoin: its use in daily practice to reverse photoageing

The effect of 0.1% tretinoin cream for the treatment of photoageing was studied in a double‐blind, placebo‐controlled trial. All patients applied tretinoin cream to one forearm and the vehicle cream to the other, and half of the patients also applied tretinoin cream to the face and the other half used the vehicle cream. Tretinoin treatment produced an improvement in the signs of extrinsic ageing conipared with the vehicle‐treated areas. Fine wrinkling was improved most, although coarse wrinkling, brown spots, tactile roughness and overall skin colour also showed clear improvement. The majority of lentigines and sun‐induced freckles showed some reduction in coloration with extended treatment. It is important when using tretinoin that the treatment procedure is carefully explained to the patients and that they are warned about a retinoid reaction. It should be stressed that improvement is gradual and that regular application of the cream must continue even after improvement has been achieved. Patients should be assured that there is no evidence of carcinogenicity in humans. Although no teratogenic effects of tretinoin have been reported when applied topically, it is not advisable to use the cream when trying to conceive or when pregnant.

The Use of Sulfasalazine in Atrophie Blanche

Abstract: Atrophie blanche can be a chronic condition for which there is no satisfactory treatment. Two patients with atrophie blanche who had not responded to various therapeutic modalities were given a trial of sulfasalazine 1 g three times daily. The ulcers healed within 3 months in both cases. In view of these positive results, patients should be treated with sulfasalazine to determine the efficacy of this drug in atrophie blanche.

Effects of oral meclofenamate therapy in psoriasis

One hundred three patients entered a study to evaluate the effects of oral meclofenamate sodium therapy on psoriasis. The first 4 weeks of the study were double-blind, with patients receiving either meclofenamate or placebo. Most patients receiving meclofenamate had no change in their psoriasis, in comparison with their pretherapy condition. There was no difference in the response of the psoriasis between the group taking meclofenamate and the group taking placebo. Eighty-nine patients continued in a 4-week open trial of meclofenamate. Approximately one third of the patients showed improvement, but this result appeared to be related to the open trial design. Since oral meclofenamate therapy was not associated with frequent worsening of psoriasis, it is an appropriate treatment for psoriatic arthritis.