Methotrexate

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)

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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.

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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.

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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.

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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

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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.

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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.