Methotrexate

Methotrexate (MTX)

  • Antimetabolite, structurally similar to folic acid with chemotherapeutic & immunosuppressive properties 
  • Pregnancy Category X

Availability 

  • Oral (most reliable peak plasma level), Intramuscular, Intravenous, sub-cutaneous, intralesional, intrathecal

Dose

  • Start with a test dose of 5-10 mg, then increase by 2.5-5 mg q2weeks until 10-15 mg (up to 30 mg)
  • Once dermatosis controlled, taper to lowest effective dose (some dermatoses require higher doses e.g. dermatomyositis, pityriasis rubra pilaris, neutrophilic dermatoses 25-35mg weekly, & some require low doses e.g. pityriasis lichenoides et varioliformis acuta, ~2.5-5 mg weekly) 
  • Takes ~3-4 weeks for effect to be seen & 2-3 months for full effect
  • Folic acid effect on methotrexate efficacy controversial
  • Folic acid 5 mg weekly or 1 mg daily (except methotrexate day) decreases gastrointestinal, liver, hematologic, & mucosal side effects

Antiproliferative

  • Methotrexate is a folate analog: competitive & irreversible inhibition of dihydrofolate reductase & competitive but partially reversible binding of thymidylate synthetase, inhibiting synthesis of thymidylate & purine nucleotides needed for deoxyribonucleic acid (DNA) & ribonucleic acid (RNA) synthesis with a net effect of cellular division inhibition during S phase of cell cycle
  • Note: rescue therapy in cases of methotrexate acute hematologic toxicity; Folinic acid “leucovorin” can be used (overcomes dihydrofolate reductase), & thymidine (overcomes dihydrofolate reductase & thymidylate synthetase,)

Anti-inflammatory

  • Increased adenosine (by inhibiting 5-Aminoimidazole-4-carboxamide ribonucleotide transformylase) leading to decreased function of neutrophils, lymphocytes, & monocytes
  • Decreased Adenyl methionine

Immunosuppressant

  • Decreased T & B lymphocyte proliferation, migration & subsequent antibody production

  • Good gastrointestinal absorption (exception: decreased absorption with diary intake in children)
  • Does not cross blood brain barrier
  • Half-life ~10-27 hours 
  • Metabolized intracellularly + liver to polyglutamated form (cause of toxicity)
  • Excreted renally

Food & drug administration (FDA)

  • Malignancies (including cutaneous lymphomas/Sézary syndrome)
  • Rheumatoid arthritis
  • Psoriatic arthritis
  • Psoriasis:
    • >20% total body surface area
    • Pustular
    • Erythrodermic
    • Interferes with employment
    • Lack of response to phototherapy/ systemic retinoids

Off label

  • Papulosquamous (pityriasis rubra pilaris needs higher doses, pityriasis lichenoides et varioliformis acuta (PLEVA) & pityriasis lichenoides chronica (PLC) respond well to low doses)
  • Immunobullous
  • Autoimmune connective tissue diseases (dermatomyositis requires higher doses)
  • Vasculitis
  • Neutrophilic dermatoses (higher doses)
  • Intralesional: keratoacanthoma, keloids

Pediatrics

Consistent efficacy:

  • Psoriasis
  • Atopic dermatitis
  • Dermatomyositis
  • Systemic lupus erythematosus
  • Localized scleroderma
  • Pemphigus

Absolute

  • Hypersensitivity
  • Pregnancy
  • Lactation

Relative

  • Unreliable patient (including excessive alcohol intake >100 g/week)
  • Metabolic: Diabetes, Obesity
  • Liver: abnormal liver function tests, hepatitis nonalcoholic steatohepatitis (NASH), cirrhosis
  • Severe hematologic abnormalities
  • Active infection, history of severe infection, Tuberculosis reactivation
  • Immunodeficiency
  • Decreased renal function
  • Planning pregnancy (females or males)

Respiratory

  • Idiosyncratic acute pneumonitis
  • Rheumatoid arthritis patients > psoriasis
  • If symptomatic: do chest X-Ray, otherwise no screening indicated

Gastrointestinal

  • Nausea, vomiting
  • Diarrhea & ulcerative stomatitis; may need to discontinue methotrexate
  • To decrease gastrointestinal side effects: give folic acid, split dose to twice daily, switch to subcutaneous route, with ulcerative stomatitis +/- Folinic acid 2.5-5mg 8-12 hours after methotrexate

Hepatic

  • Hepatotoxicity, may lead to fibrosis & cirrhosis
  • More common on psoriasis patients due to obesity & non-alcoholic steatohepatitis (NASH)
  • Risk factors: Obesity, diabetes, hyperlipidemia, non-alcoholic steatohepatitis (NASH), alcohol/hepatotoxic medications, active liver disease, abnormal liver function test, family history of liver disease
  • Testing: serum procollagen III, fibroscan, liver biopsy

Genitourinary

  • Reversible oligospermia
  • Teratogenicity (pregnancy category X, avoid pregnancy x 3 months in males & 1 menstrual cycle in females) 
  • Renal toxicity (high doses > 50 mg)

Hematologic

  • Idiosyncratic pancytopenia (leading cause of death), risk highest early during treatment course 4-6 weeks
  • Risk factors: older age, decreased renal function, drugs that potentiate methotrexate activity, lack of folate supplement

Infections

  • Risk of opportunistic infections

Dermatologic

  • Hypersensitivity/ toxic epidermal necrolysis,
  • Diffuse hyperpigmentation/nail hyperpigmentation
  • Alopecia
  • Flag sign
  • Phototoxicity
  • Acral erythema 
  • Toxic erythema of chemotherapy / neutrophil eccrine hidradenitis
  • Vasculitis
  • Nodulosis in rheumatoid arthritis patients
  • Ulceration in psoriatic plaques
  • Recall phenomena at radiation site
  • Pseudolymphoma

Malignancy

  • Reports of lymphoma

Inhibitors of folic acid pathway

  • Sulfonamide
  • Dapsone
  • Trimethoprim
  • Fluorouracil

Increase Free methotrexate level (via decreased   kidney excretion, protein binding displacement, or increased intracellular levels)

  • Sulfonamides
  • Tetracyclines
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Salicylates
  • Phenytoin

Synergic hepatotoxicity

  • Alcohol
  • Systemic retinoids

Note

Folic acid pathway & its inhibitors in detail:

  • Folate to Dihydrofolate (enzyme: Dihydropteroate synthetase, inhibited by sulfonamides & dapsone)
  • Dihydrofolate to Tetrahydrofolate (enzyme: Dihydrofolate reductase, inhibited by methotrexate & Trimethoprim) 
  • Tetrahydrofolate to deoxyribonucleic acid (DNA) (enzyme: thymidylate synthetase, inhibited by methotrexate & fluorouracil)

Baseline

  • Complete blood count, chemistry profile, liver function tests, Urinalysis
  • Pregnancy test
  • Hepatitis B & C virus, human immunodeficiency virus, (HIV), +/- Tuberculin skin test (optional)
  • Liver biopsy to consider if high risk features present (better to avoid methotrexate)

Follow-up

  • Complete blood count, chemistry profile, liver function tests weekly x4 weeks, then monthly x 3 months, then every 3months thereafter

Liver follow-up (controversial subject):

  • If low risk patient: annual fibroscan after a year of methotrexate. Liver biopsy (controversial) after cumulative dose of 3.5-4 g then subsequent biopsies after each accumulated 1.5 g 
  • If high risk: avoid methotrexate, or liver biopsy within 6-12 months of methotrexate, repeat at 1-1.5g cumulative dose or every 6months if mild fibrosis IIIa on fibroscan
  • If 5/9 abnormal Liver function tests in the past 12 months can test with:
    • Procollagen III
    • Fibroscan
    • Liver biopsy (Gold standard)
    • Liver ultrasound
    • Radionucleotide scan

If liver function tests increasing

  • < 2-fold, repeat liver function tests in 2-3 weeks
  • > 2-fold but < 3-fold, decrease methotrexate dose
  • > 3-fold, discontinue methotrexate

Indications to discontinue methotrexate

  • Pregnancy
  • Cytopenia: white blood cells < 3.5, Platelets < 100,000
  • Liver function test > 3-fold
  • Patients with moderate-severe fibrosis & cirrhosis on liver biopsy
  • Hypoalbuminemia
  • Diarrhea
  • Ulcerative stomatitis
  • Severe active infection