CYTOTOXIC AND IMMUNOSUPPRESSIVE AGENTS
Cytotoxic and immunosuppressive drugs, which inhibit the synthesis or action of crucial cellular macromole-cules, such as nucleic acids, are used in three broad cat-egories of skin disease: hyperproliferative disorders, such as psoriasis; immunological disorders, such as au-toimmune bullous diseases; and skin neoplasms.
Methotrexate is approved for use in severe disabling psoriasis recalcitrant to other less toxic treatments. The standard regimen is similar to low-dose therapy used for the treatment of rheumatoid arthritis . Although toxicities are similar to those described in the treatment of other diseases, hepatic cirrhosis and unexpected pancytopenia are of special concern given the chronicity of treatment.
Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent that blocks de novo purine synthesis by noncompetitively in-hibiting the enzyme inosine monophosphate dehydro-genase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo the guanosine nucleotides required for DNA and RNA synthesis.
MPA has been used for decades as a systemic treatment for moderate to severe psoriasis. MMF was developed to increase the bioavailability of MPA.
MMF is rapidly and completely cleaved to form MPA, the active metabolite, after oral administration. MPA is converted in the liver and kidney to an inactive glucuronide. However, certain tissues, such as the epi-dermis, express a glucuronidase that converts the inac-tive glucuronide back to the active agent. The half-life of MPA is approximately 18 hours; 90 to 95% of the my-cophenolate dose is excreted in the urine.
MMF is indicated for the prophylaxis of organ rejec-tion in patients receiving renal, hepatic, and cardiac transplants; it is often used in combination with other immunosuppressive agents for this indication. In derma-tology, MMF is particularly useful as monotherapy, or as a steroid-sparing agent, for treatment of autoimmune blistering diseases (bullous pemphigoid and pemphi-gus). It may also be useful for the treatment of inflam-matory skin diseases mediated by neutrophilic infiltra-tion, such as pyoderma gangrenosum, and psoriasis.
The principal advantage of MMF over alternative systemic immunosuppressive agents (e.g., methotrexate, cyclosporine) is its relative lack of hepatotoxicity and nephrotoxicity. Adverse effects produced by MMF most commonly include nausea, abdominal cramps, diarrhea, and possibly an increased incidence of viral and bacte-rial infections. Whether MMF may be associated with an increased long-term risk of lymphoma or other ma-lignancies is controversial; however, any such risk is likely to be lower in patients treated for skin disease with MMF monotherapy than in transplant patients treated with combination immunosuppressive therapy.
6-Thioguanine is a purine analogue structurally related to 6-mercaptopurine and azathioprine. Thioguanine in-terferes with several enzymes required for de novo purine synthesis, and its metabolites are incorporated into DNA and RNA, further impeding nucleic acid syn-thesis. The mechanism of action of thioguanine in psori-asis is not clearly understood; it has been hypothesized to affect the proliferation and trafficking of lympho-cytes as well as the proliferation of keratinocytes.
Absorption of orally administered 6-thioguanine is slow and incomplete; only approximately 30% of the oral dose is achieved in the plasma, peak levels being reached after 8 hours. Thioguanine is extensively me-tabolized prior to excretion. The elimination half-life is on the order of 80 minutes.
Although 6-thioguanine is chiefly used in che-motherapy for acute myelocytic leukemia and other marrow-based malignancies, lower doses are very effec-tive for moderate to severe psoriasis, particularly in patients who cannot tolerate alternative systemic agents such as methotrexate and cyclosporine.
Dose-related myelosuppression is the major adverse effect produced by 6-thioguanine. Patients deficient in thiopurine methyltransferase (TPMT), a cytosolic en-zyme required for metabolism of 6-thioguanine, are at heightened risk. Other adverse effects include gastroin-testinal complaints and elevations of liver transami-nases. There have been rare reports of more serious he-patotoxicity, including acute hepatitis, acute cholestasis, and hepatic venoocclusive disease.