The Use of Cyclosporine in Dermatology

in Sweet's syndrome and pyoderma gangrenosum, however, in subcorneal pustular dermatosis they are found in the upper layers of the epidermis. Sweet syndrome is also referred to as acute febrile neutrophilic dermatosis. It is a condition of unknown etiology characterized by pyrexia, elevated neutrophil count, painful erythematous cutaneous lesions, and usually prompt clinical improvement is seen following corticosteroid systemic therapy. The standard therapy for Sweet's syndrome is prednisone or prednisolone at an initial dose of 0.5 mg/kg to 1.5 mg/kg of body weight per day, and gradual reduction is recommended for the following 2 to 4 weeks. Sweet's syndrome can be associated with other conditions such as Acute Myeloid Leukemia (AML).

The tendency of Sweet's syndrome to relapse was the rationale for trying cyclosporine as a first-line treatment. Several cases have been reported demonstrating the efficacy of cyclosporine for the treatment of Sweet's syndrome.^66-70

Cyclosporine had been used in 3 settings: as initial monotherapy, a second line therapy after the failure of other first-line treatments (steroids) or as a corticosteroid-sparing agent. The initial oral dose has ranged from 2 mg/kg/day to 4 mg/kg/day, to as high as 10 mg/kg/day for the acute presentation; this dose is continued for the first 10 days and then reduced gradually and discontinued at day 21. Patients should be closely monitored due to the side effects.^68,69

Cyclosporine has been shown to inhibit neutrophil chemotaxis and, more importantly, impair neutrophil migration into infective and sterile inflammatory foci in vivo. Monocyte functions are also modulated by cyclosporine and it has been shown in vitro to inhibit antigen presentation and suppress monocyte activation. Even though, Sweet's syndrome is predominantly a neutrophilic, inhibition of cytokine release by mature T-helper lymphocyte and decrease of effector found in cytotoxic lymphocytes has been reported. The mode of acting of cyclosporine in this disease may be related to these effects.^66,69,70

Furthermore, it has been suggested that interleukin 1 (IL-1) might play a key role in Sweet's syndrome. IL-1 possesses endogenous pyrogen activity, is chemotactic to neutrophils, induces neutrophil leucocytosis and stimulates synthesis of prostaglandin E2. Cyclosporine has been shown inhibit the release of Il-1.⁷⁰

Cutaneous Lupus Erythematosus
Cutaneous lupus erythematosus includes wide variety of skin lesions. Discoid lupus erythematosus are erythematous, scaly papules and plaques on sun-exposed areas that can leave scarring; of these, fewer 10% will develop systemic disease. Systemic lupus erythematosus can produce malar erythema and widespread maculopapular lesions on the skin. Between these 2 entities, there is a wide spectrum of cutaneous manifestations: annular, psoriasiform (subacute lupus erythematosus), poikiloderma-like, lichenoid, panniculitis, verrucous, or bullous skin lesions.^71-73

Cyclosporine has been used for concomitant treatment of systemic lupus erythematosus or as a third line therapy for cutaneous disease. In these settings cyclosporine is given after antimalarials, dapsone, oral prednisone, and/or retinoids have failed.⁷¹ The recommended dose is between 2.5 mg/kg/day and 5 mg/kg/day, usually starting at a dose of 4 mg/kg/day to 5 mg/ kg/day, and as the patient responds the dose can be decreased.⁷¹

In a clinical trial of 59 patients with systemic lupus erythematosus where other immunosuppressants failed, 75% improved when treated with cyclosporine, which included skin lesions, and patients were able to maintain the treatment for 2 years. Cyclosporine also improved lupus nephritis; thus there is no evidence of worsening the lupus associated renal disease. In some patients, however, it elevated the blood pressure; this is the most frequent reason for discontinuation of the therapy.⁷⁴

In some cases, a combination of cyclosporine and other immunosuppressant drugs can allow a reduction in the dose of both medications, for example, the combination of cyclosporine and corticosteroids as a steroid-sparing agent⁷³; cyclosporine and methotrexate have also been reported to be useful and safe,⁷⁵ though most of the reports are case series, and further controlled studies are needed.

Cyclosporine is also useful when lupus is associated with another inflammatory skin disease, such as lichen planus⁷⁶ or psoriasis.⁷⁷ Although these diseases have different clinical and histopathological features, cyclosporine has proven to be a beneficial treatment in many of them. Thus, cyclosporine can be used to treat refractory cutaneous lupus with or without systemic involvement. The recommended doses are between 2.5 mg/kg/day and 5 mg/kg/day and can be maintained for 2 years. Also, the combination with corticosteroids and other immunosuppressant drugs have proven to be beneficial.

Dermatomyositis
Dermatomyositis is an autoimmune disease of the skin and muscles. Skin lesions involve Gottron's papules, heliotrope rash, periungal telangiectasias, and/or facial erythema and edema.^78,79 The disease is usually associated with muscle weakness and elevated skeletal muscle enzymes. However, dermatomyositis sine myositis (or amyopathic, ie, without muscle involvement and with the characteristic skin lesions) is well recognized.⁸⁰ Prognosis is dependent upon the development of internal malignancy, interstitial lung disease, or clinical muscle weakness, which can be profound.

Cyclosporine is used to treat dermatomyositis as a steroid-sparing agent; the first-line therapy is glucocorticosteroids in high doses (1 mg to 2 mg/kg/day), usually associated with another immunosuppressant treatment like methotrexate or azathioprine. Cyclosporine can be and has been used as a second-line therapy, ^81-83 and for refractory dermatomyositis unresponsive to methotrexate and azathioprine treatment. In a clinical trial com-