Methotrexate

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Indications

  • Psoriasis
    • Severe psoriasis.
    • Chronic plaque psoriasis (>10–15% BSA or interference with employment or social functioning).
    • Pustular psoriasis (generalized or localized).
    • Erythrodermic psoriasis
    • Psoriatic arthritis (moderate to severe).
    • Severe nail psoriasis.
    • Psoriasis not responding to topical treatments, photo(chemo)therapy and/or systemic retinoids.
  • Off label
    • Immunobullous disorders:
      • Pemphigus, bullous pemphigoid : 7.5 and 12.5 mg weekly.
      • Cicatricial pemphigoid: 5–25 mg weekly.
      • Epidermolysis bullosa acquisita.
    • Connective tissue diseases:
      • Dermatomyositis : 25 mg weekly.
      • Lupus erythematosus.
      • Scleroderma.
    • ِِِِِAtopic eczema.
  • Others
    • Pyoderma gangrenosum and Sweet syndrome : 25–35 mg per wk.
    • Sarcoidosis.
    • Cutaneous Crohn disease.
    • Chronic idiopathic urticaria.
    • Keratoacanthomas (intralesional).
    • Keloids.
    • Lymphomatoid papulosis.
    • Mycosis fungoides.
    • Sézary syndrome.
    • Pityriasis rubra pilaris :1.5–2 times higher than doses of psoriasis.
    • PLEVA (2.5–5 mg per week)

Monitoring

Baseline

  • Examination
    • Careful history and physical examination.
    • Identification of patients at increased risk for toxicity.
    • Recording concomitant medications that may interact with methotrexate.
  • Labs
    • CBC.
    • Urea, creatinine, and LFTs.
    • Serologic tests for hepatitis B, C
    • Pregnancy test and test for HIV in selected patients.

Liver biopsy is only indicated in patients with a history of significant liver disease , the first liver biopsy in a psoriatic patient might be delayed until 1.5 g cumulative dose is reached in lower-risk patients.

Follow Up

Every 1–2 weeks for 4–8 weeks following the last dose escalation; thereafter the frequency can be gradually reduced to 3‐monthly.

  • CBC.
  • Liver function tests.
  • Renal function tests.

Side effects

  • Hepatotoxicity.
  • Pulmonary toxicity :
    • Acute pneumonitis (can occur with extremely small doses of MTX, and can be life-threatening ).
    • Pulmonary fbrosis .
  • Hematologic toxicity :
    • Pancytopenia.
  • Gastrointestinal effects :
    • Nausea , anorexia ,Diarrhea, vomiting, and ulcerative stomatitis.
  • Renal Toxicity : (with high doses)
  • Others :
    • Alopecia.
    • Headaches.
    • Fatigue.
    • Dizziness.
    • Acral erythema.
    • Cutaneous ulceration.
    • Osteopathy.

Contraindications

Absolute

  • Pregnancy and lactation.

Relative

  • Elevated liver enzymes.
  • Chronic liver disease.
  • Excessive alcohol intake.
  • Active infection.
  • Immunodeficiency.
  • Abnormalities in renal function.
  • The desire to get pregnant.
  • Recent vaccination with a live vaccine.
  • Obesity.
  • Diabetes mellitus.
  • Unreliable patient.

Drug interactions

  • Drugs that elevate MTX blood levels:
    • NSAIDs.
    • Salicylates.
    • Sulfonamides.
    • Chloramphenicol.
    • Phenothiazines .
    • Phenytoin.
    • Tetracyclines.
    • Penicillins.
    • Ciprofloxacin.
  • Drugs increase intracellular accumulationc of MTX.
    • Dipyridamole.
    • Probenecid .
  • Drugs increase the risk for pancytopenia with concomitant use :
    • Trimethoprim.
    • Sulfonamides.
    • Dapsone.
  • Drugs cause synergistic liver damage in combination with MTX:
    • Systemic retinoids.
    • Alcohol .
  • Reduced absorption from gut: digoxin (absorption reduced by MTX), neomycin.
  • Diminished renal excretion:
    • Ciprofloxacin.
    • NSAIDs .
    • Omeprazole.
    • Penicillins.
    • Probenecid.
    • Sulphonamides.
  • Increased renal excretion:
    • acetazolamide.
  • Cumulative toxicity :
    • Tetracyclines.
    • Acitretin.
    • Clozapine.
    • Ciclosporin.
    • Cisplatin.
    • leflunomide.
    • Alcohol.
  • plasma levels increased by MTX :
    • Theophylline.

Pregnancy and lactation

  • Category X; men and women considering conception should discontinue methotrexate for 3 months before attempting to conceive.
  • Mothers receiving methotrexate should not breast-feed

Precautions

  • In case of liver enzymes exceeds x2 normal, they must be checked more frequently; if results exceed x3 normal, consider dose reduction; if exceeds x5 normal, discontinue.
  • If the white blood cell count (WBC) is < 3500/mm3, the platelet count is <100 000/mm3, or there is an increase over twice the upper normal value for liver transaminase levels, discontinue or reduce the dosage of MTX, then restart at a lower dose after a 2–3-week.
  • Take a liver biopsy when the cumulative dose is about 2 g (liver function tests can be normal in the presence of hepatic toxicity ).
  • To detect hepatic fibrosis:
    • Liver biopsy.
    • Procollagen III aminopeptide ( unreliable in patients with psoriatic arthritis or other inflammatory diseases ).
    • FibroSpect II.
    • FibroTest.
    • FibroScan ( unreliable in obese patients).
  • Caution is indicated and significant dose reduction necessary if used in patients with decreased renal function.
  • Sun protection may be needed.
  • Folic acid therapy (1–5 mg orally daily, based on symptoms) except for the day of methotrexate dosing.
  • After discontinuing MTX, wait at least one ovulatory cycle before attempting to become pregnant.
  • After discontinuing MTX, Men must wait 3 months before attempting to have partner become pregnant.
  • A chest X-ray should be done only if the patient develops symptoms suggesting pneumonitis.
  • Alcoholic beverages may increase some of the side effects, so it should be restricted to less than 20 g/day.

Drug info

  • Anitodote :
    • High doses of folinic acid (leucovorin calcium or thymidine):15 mg/m2 intravenously every 6 hours until the serum methotrexate level becomes undetectable.
  • When maximal benefit is reached : MTX may be tapered by 2.5 mg/week to determine the lowest possible dosage that maintains disease control.
  • For patients with intramuscular route : increase the interval between doses to 2 weeks or more.
  • Most psoriatic patients treated with MTX respond, typically demonstrating an initial response within 1–4 weeks. Full therapeutic benefit usually occurs within 2–3 months.
  • The risk of liver damage is low for patients whose cumulative dosage is <1.5 g.
  • The presence of ulcerative stomatitis or severe diarrhea requires cessation of the MTX therapy.
  • More frequent investigations are needed if laboratory values are abnormal or with high-risk patients.
  • Most optimal timing for laboratory tests is 5–6 days after the preceding methotrexate dose.

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