Mechanism of action:

• Effects G1 and S phases all cell cycle.

• Folate antagonist, inhibits denovo purines and pyrimidines.

• Secondary to interference with thymidine DNA nucleotide metabolism cell cycle arrest.

• Selective inhibitor of dihydrate folate reductase and lymphocyte proliferation.

• At lower doses, as used in neuromuscular diseases, methotrexate's immunomodulatory mechanism is not well understood. It is believed to include increased T-cell apoptosis, alteration of cell adhesion molecule gene expression, and modulation of humoral and cytokine responses.

• Reduce his production (from a tree cytokines: IL-1 and IL-6.

Uses:

• Second or third line option in dermatomyositis, polymyositis and CIDP.

• Systemic and nonsystemic vasculitic neuropathy, sarcoidosis, MMN, MG and immune mediated necrotizing myopathy.

• Psoriasis: Benefit in 25% in 3.2 weeks with high doses and 9.9 weeks with low doses.

• The most extensive neuromuscular studies of methotrexate have been in MG, although with conflicting results. A smaller, randomized, assessor-blinded study compared the steroid sparing effect of weekly methotrexate versus daily azathioprine. After 2 years, they were substantial and comfortable decreases in daily prednisone dosing and QMG scores in both groups. These findings indicate similar long-term efficacy and tolerability for methotrexate and azathioprine and MG, but with a cost advantage for methotrexate, which is relevant in financially constrained health systems. Also, the study reaffirmed the long latency of clinical benefit from azathioprine and indicated that methotrexate's steroid sparing effect may start at 10 months.

• In IMNM consensus guidelines recommends the use of methotrexate plus prednisone.

• For CIDP, randomized double blinded, placebo controlled pilot clinical trial of methotrexate was negative.

Adverse events:

• Hepatotoxicity, ILD-pulmonary fibrosis (check anti-Jo 1), if anti-Jo 1 is positive do not give methotrexate.

• Infection, neoplasia, infertility, bone marrow suppression with leukopenia, alopecia, GI: Nausea, vomiting, diarrhea. Fatigue, rash, dizziness, ulcerative stomatitis and teratogenicity.

Treatment regimen:

• P.o. at 7.5 mg/week follow-up in renal insufficiency. Given 3 divided doses every 12 hours. Usually given on Saturday a.m. and p.m. and Sunday a.m. p.o. max doses 25 mg/week. Patients are treated concomitantly with folate 5 mg a week.

• Subcutaneous at 20 to 50 mg weekly.

Monitor: LFTs, platelets, WBC. Patient with pulmonary symptoms: Hold treatment, investigate if it is infectious cause or secondary to pulmonary fibrosis (chest x-ray, CT chest, PFTs, pulmonary consult).

7.5-20 mg PO weekly, single dose or divided dosing

3-12 mo

Hepatoxicity, pulmonary fibrosis, infection, malignancy, infertility, leucopenia, alopecia, gastric irritation, stomatitis, teratogenicity

Monthly: CBC and LFTs