Cytotoxic And Immunosuppressant Drugs

Cytotoxic and immunosuppressive drugs are used in dermatology for immunologically mediated diseases such as psoriasis, the autoimmune blistering diseases, and leukocytoclastic vasculitis. These agents are discussed in detail in Chapters 51 and 52.

Antimetabolites methotrexate The antimetabolite methotrexate suppresses immunocompetent cells in the skin, and it also decreases the expression of cutaneous lymphocyte-associated antigen (CLA)-positive T cells and endothelial cell E-selectin, which may account for its efficacy in psoriasis. It is useful in treating a number of other dermatological conditions, including pityriasis lichenoides et varioliformis, lymphomatoid papulosis, sarcoidosis, pemphigus vulgaris, pityriasis rubra pilaris, lupus erythematosus, dermatomyositis, and cutaneous T-cell lymphoma.

Methotrexate (rheumatrex, others) is equally effective as orally administered cyclosporine for the treatment of moderate-to-severe chronic plaque psoriasis. Methotrexate is used often in combination with phototherapy and photochemotherapy or other systemic agents, and it also may be useful in combination with the biologics. A usual starting dose for methotrexate therapy is 5-7.5 mg/week (maximum of 15 mg/week). This dose may be increased gradually to 20-30 mg/week if needed. Widely used regimens include three oral doses given at 12-hour intervals once weekly or weekly intramuscular injections. Doses must be decreased for patients with impaired renal clearance. Methotrexate should never be coadministered with trimethoprim-sulfamethoxazole, probenecid, salicylates, or other drugs that can compete with it for protein binding and thereby raise plasma concentrations to levels that may result in bone marrow suppression. Fatalities have occurred because of concurrent treatment with methotrexate and nonsteroidal anti-inflammatory agents.

Methotrexate exerts significant antiproliferative effects on the bone marrow; therefore, complete blood counts should be monitored. Folinic acid (leucovorin) can be used to rescue patients with hematologic crises caused by methotrexate-induced bone marrow suppression. Careful monitoring of liver function tests is necessary but may not be adequate to identify early hepatic fibrosis in patients receiving chronic methotrexate therapy. Liver biopsy is recommended when the cumulative dose reaches 1-1.5 g. A baseline liver biopsy also is recommended for patients with increased potential risk for hepatic fibrosis, such as a history of alcohol abuse or infection with hepatitis B or C. Patients with significantly abnormal liver function tests, symptomatic liver disease, or evidence of hepatic fibrosis should not use this drug. Pregnancy and lactation are absolute contraindications to methotrexate use.

Azathioprine (Imuran) is discussed in detail in Chapters 38 and 52. In dermatologic practice, the drug is used as a steroid-sparing agent for autoimmune and inflammatory dermatoses, including pemphigus vulgaris, bullous pemphigoid, dermatomyositis, atopic dermatitis, chronic actinic dermatitis, lupus erythematosus, psoriasis, pyoderma gangrenosum, and Behfet's disease. The usual starting dose is 1-2 mg/kg/day. Since it often takes 6-8 weeks to achieve therapeutic effect, azathioprine often is started early in the course of disease management. Careful laboratory monitoring is important. Thiopurine S-methyltransferase is critical for the metabolism of azathioprine to nontoxic metabolites. Homozygous deficiency of this enzyme may raise plasma levels of the drug and cause myelosuppression, and some experts advocate measuring this enzyme before initiating azathioprine therapy (see Chapter 38).

Fluorouracil (5-FU) interferes with DNA synthesis by blocking the methylation of deoxyuridylic acid to thymidylic acid. Topical formulations (carac, efudex, fluoroplex) are used in multiple actinic keratoses, actinic cheilitis, Bowen's disease, and superficial basal cell carcinomas not amenable to other treatments.

Fluorouracil is applied twice daily for 2-4 weeks. The treated areas may become severely inflamed during treatment, but the inflammation subsides after the drug is stopped. Intralesional injection of 5-FU has been used for keratoacanthomas, warts, and porokeratoses.

alkylating agents Cyclophosphamide (cytoxan, neosar) is an effective cytotoxic and immunosuppressive agent.

Both oral and intravenous preparations of cyclophosphamide are used in dermatology. Cyclophos-phamide is FDA-approved for treatment of advanced cutaneous T-cell lymphoma. other uses include treatment of pemphigus vulgaris, bullous pemphigoid, cicatricial pemphigoid, paraneoplastic pemphigus, pyoderma gangrenosum, toxic epidermal necrolysis, Wegener's granulomatosis, polyarteritis nodosa, Churg-Strauss angiitis, Behfet's disease, scleromyxedema, and cytophagic histiocytic panni-culitis. The usual oral dose is 2-3 mg/kg/day in divided doses, and there is often a 4-6-week delay in onset of action. Alternatively, intravenous pulse administration of cyclophosphamide may offer advantages, including lower cumulative dose and a decreased risk of bladder cancer.

Cyclophosphamide has many adverse effects, including the risk of secondary malignancy and myelosuppression, and thus is used only in the most severe, recalcitrant dermatological diseases. The secondary malignancies have included bladder, myeloproliferative, and lymphoproliferative malignancies and have been seen with the use of cyclophosphamide alone or in combination with other antineoplastic drugs.

Mechlorethamine hydrochloride (mustargen) and carmustine (bischloronitrosourea, BCNU, bicnu) are used topically to treat cutaneous T-cell lymphoma. Both can be applied as a solution or in ointment form. It is important to monitor complete blood counts and liver function tests because systemic absorption can cause bone marrow suppression and hepatitis. other side effects include allergic contact dermatitis, irritant dermatitis, secondary cutaneous malignancies, and pigmentary changes. Carmustine also can cause erythema and posttreatment telangiectasias.

calcineurin inhibitors Cyclosporine (sandimmune, neoral, sangcya) is a potent immunosuppressant isolated from the fungus Tolypocladium inflatum. Its mechanism of action is discussed in Chapter 52. The presence of calcineurin in Langerhans' cells, mast cells, and keratinocytes may explain the therapeutic efficacy of cyclosporine and the other calcineurin inhibitors (e.g., tacrolimus and pimecrolimus; see below). Cyclosporine is FDA-approved for the treatment of psoriasis. other cutaneous disorders that typically respond well to cyclosporine are atopic dermatitis, alopecia areata, epidermolysis bullosa acquisita, pemphigus vulgaris, bullous pemphigoid, lichen planus, and pyoderma gangrenosum. The usual initial oral dose is 3-5 mg/kg/day given in divided doses.

Hypertension and renal dysfunction are the major adverse effects associated with the use of cyclosporine. These risks can be minimized by monitoring serum creatinine (which should not rise more than 30% above baseline), calculating creatinine clearance or glomerular filtration rate in patients on long-term therapy or with a rising creatinine, maintaining a daily dose of less than 5 mg/kg, and regular monitoring of blood pressure. Alternation with other therapeutic modalities may diminish cyclosporine toxicity. Laboratory monitoring during therapy is essential. Cyclosporine is not mutagenic. However, as with other immunosuppressive agents, patients with psoriasis treated with cyclosporine are at increased risk of cutaneous, solid organ, and lymphoproliferative malignancies. The risk of cutaneous malignancies is compounded if patients have received phototherapy with PUVA.

Tacrolimus (fk506, prograf), a metabolite of Streptomyces tsukubaensis, is a potent macrolide immunosuppressant traditionally used to prevent kidney, liver, and heart allograft rejection (see Chapter 52). Like cyclosporine, tacrolimus works mainly by inhibiting early activation of T lymphocytes, thereby inhibiting the release of IL-2, suppressing humoral and cell-mediated immune responses, and suppressing mediator release from mast cells and basophils. In contrast to cyclosporine, this effect is mediated by binding to intracellular FK506-binding protein 12, generating a complex that inhibits the phosphatase activity of calcineurin.

Tacrolimus is available in oral and topical forms for the treatment of skin disease. Systemic tacrolimus has shown some efficacy in the treatment of inflammatory skin diseases such as psoriasis, pyoderma gangrenosum, and Beh├žet's disease. When administered systemically, the most common side effects are hypertension, nephrotoxicity, neurotoxicity, GI symptoms, hyperglycemia, and hyperlipidemia. Topical formulations of tacrolimus penetrate into the epidermis.

In commercially available topical formulations (0.03% and 0.1%), tacrolimus ointment (protoptic) is effective in and approved for the treatment of atopic dermatitis in adults (0.03% and 0.1%) and children (0.03%). Other uses in dermatology include intertriginous psoriasis, vitiligo, mucosal lichen planus, graft-versus-host disease, allergic contact dermatitis, and rosacea. It is applied to the affected area twice a day and generally is well tolerated.

A major benefit of topical tacrolimus compared with topical glucocorticoids is that tacrolimus does not cause skin atrophy and therefore can be used safely in locations such as the face and intertriginous areas. Common side effects at the site of application are transient erythema, burning, and pruritus, which tend to improve with continued treatment. Systemic absorption generally is very low and decreases with resolution of the dermatitis. However, topical tacrolimus should be used with extreme caution in patients with Netherton's syndrome because these patients have been shown to develop elevated blood levels of the drug after topical application. It is recommended that patients using tacrolimus use sunscreen and avoid excessive UV exposure.

Pimecrolimus 1% cream (elidel), a macrolide derived from azomycin, is FDA-approved for the treatment of atopic dermatitis in patients >2 years of age. Its mechanism of action and side effect profile are similar to those of tacrolimus. Burning, while occurring in some patients, appears to be less common with pimecrolimus than with tacrolimus. In addition, pimecrolimus has less systemic absorption. Similar precautions with regard to UV exposure should be taken during treatment with pimecrolimus.

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