**4. Methotrexate**

MTX is the most commonly used systemic agent for psoriasis and, because it has been available for 35 years, most dermatologists are comfortable with its use. It is considered as an longstanding effective oral medication for the treatment of various types of psoriasis [98, 99]. Generally psoriasis treatment is mainly depends on the PASI score. For mild psoriasis patients, doctors prescribed topical therapy and phototherapy. For moderate to severe disease who have at least 5% of their skin covered with psoriasis are treated with oral medications like MTX, cyclosporine. [100]. Folate supplementation along with MTX reduces the incidence of megaloblastic anemia, hepatotoxicity, and gastrointestinal intolerance [101].

#### **4.1 History**

Anti-metabolites mimic substances required for normal biochemical reactions and thus interfere with normal functions of the cell, including cell division. They may masquerade as purines (e.g., azathioprine), pyrimidines (e.g., 5-flourouracil) and folic acid analogs essential for purine and pyrimidine synthesis, (e.g., MTX). Methotrexate, formerly known as aminopterin, has been widely used in the treatment of cancer and autoimmune diseases [102]. It was first developed in the 1940s when scientists were investigating the effects of folic acid on cancer, particularly childhood leukemia [103]. MTX is an analog of folic acid that inhibits cellular proliferation inducing folate coenzyme deficiencies [104]. When MTX was incidentally noted to improve psoriatic lesions in the 1960s it became clear that it possessed anti-inflammatory properties in addition to its antiproliferative effects [105–107]. Anti-inflammatory actions of MTX is accomplished by inhibiting dihydrofolate reductase which eventually diminishes the de novo synthesis of purines and pyrimidines and increases the catabolism of AMP and adenosine to IMP and inosine. Increased catabolism leads to accumulation of adenosine which confers anti-inflammatory effects of MTX [108].

### **4.2 Chemical structure of methotrexate**

(2S)-2-[[4-[[2,4-bis (azanyl)pteridin-6-yl]methyl-methylamino]phenyl]carbonylamino] pentanedioic acid.
