Methotrexate

Immunosuppressive cytostatic drug (antimetabolite; folic acid antagonist) of importance for rheumatology and dermatology. According to the German and European S3 guidelines, it is suitable as a conventional standard therapy, especially for the long-term treatment of severe and moderate symptoms. After fumaric acid esters, it is the conventional systemic therapy form most frequently used by dermatologists in Germany.

Primarily used as a cytostatic in the chemotherapy of malignant hematological diseases and metastatic epithelial tumors, also as an immunosuppressant in rheumatic diseases.

In dermatology, MTX is mainly used in severe therapy-resistant psoriasis (chronic active psoriasis vulgaris, localized and generalized pustular psoriasis, arthropathic psoriasis) and circumscribed scleroderma as well as Reiter's syndrome.

Further indications: dermatomyositis/polymyositis; lupus erythematosus; mycosis fungoides; Wegener's granulomatosis; polyarteritis nodosa; granuloma gangraenescens nasi; bullous pemphigoid; pemphigus foliaceus; pemphigus vegetans; pemphigus vulgaris; steroid-resistant sarcoidosis; atopic eczema; alopecia areata, cutaneous T-cell lymphomas.

Severe alcoholism with hepatopathy, hepatitis (viral), non-alcohol-related steatosis hepatis, impaired renal insufficiency especially with concomitant use of other nephrotoxic drugs (e.g. NSAIDs, here: lowering the MTX dose), poor compliance, polymorbidity.

MTX should be temporarily interrupted in case of: vomiting, diarrhea, acute infections, stomatitis, gastrointestinal ulcers.

Vaccination therapy against inactivated vaccines may be restricted.

MTX should be discontinued 3 months before a live vaccination.

Methotrexate systemic:

• "Low-dose" MTX therapy (e.g. for psoriasis): 7.5-10 -25 mg/week as shock therapy (once a week orally, i.v., i.m. s.c.) or as interval therapy 3 or 4 times 2.5 mg p.o. at 12-hour intervals, e.g. on Mondays and Tuesdays (so-called Weinstein-Frost regimen).
• MTX: subcutaneous dose vs. oral dose. Due to the better efficacy and better bioavailability, s.c. therapy using an autoinjector (e.g. metex pen) is increasingly preferred to oral therapy.
• In children, a dosage adjusted according to body weight or body surface area is recommended (10-15mg/sqm KOF/week).
• In combination with TNF-alpha antagonists, a lower dose of 7.5-10.0mg/week is recommended.)

Methotrexate topical (n. Wohlrab J et al)

• Methotrexate remains galenically stable in a concentration of up to 0.5% in base cream DAC and can be incorporated without any problems. When applied to a limited area of skin, no relevant systemic bioavailability is apparent. The indication is for localized foci of mycosis fungoides as well as lymphomatoid papulosis.
• Rp.: Methotrexate (acid form) 0.25/0.5 in base cream DAC ad 100.0
• S.: 1 x daily thinly on the affected areas. Use a finger stick.

• Pneumological ADR:
  • Pneumonia (acute onset with dyspnea, fever<38°C, tachypnea, signs of interstitial or alveolar infiltration, leukocytosis < 15,000, negative blood and sputum culture, restriction disorder)
  • Pulmonary fibrosis,
• Hematologic ADR:
  • Blood count disorders
  • Cutaneous methotrexate-related lymphoproliferative diseases are rare (see also Post-transplant lymphoproliferative disease - MTX-LPD). Up to 80% of cases are EBER-positive, suggesting that EBV activation under immunosuppression is involved in the pathogenesis of MTX-LPD (Fujita Y et al. 2025).
• Gatrointestinal ADRs:
  • gastrointestinal disorders
  • Gastrointestinal ulcers
• Hepatologic and nephrologic ADRs:
  • Liver or kidney damage
• Dermatologic ADRs:
  • pruritus
  • diffuse alopecia
  • purpura
  • urticaria
  • Lyell syndrome medicinal
  • photosensitization
  • stomatitis
  • vasculitis
  • acral localized ulcer of the skin
• Other ADRs:
  • Hyperuricemia
  • Disturbance of ovulation and spermatogenesis
  • osteoporosis
• Remark: For the treatment of overdoses and acute toxicities, the immediate administration of the antidote Leukovorin (5-formyl-tetrahydrofolate) is recommended. Dose: 10 ^mg/m2 KO i.v. or orally.

• Note! Serious side effects (e.g. leukopenia) can occur with low endogenous folic acid depots (often in older patients) even at a dosage of 15-25 mg/week after 1-2 weeks of therapy; continuous monitoring of serum MTX levels is recommended here! Simultaneous administration of folic acid (analogous dose as MTX).

Increase in toxicity due to:

• Decreased renal excretion with concomitant administration of aminoglycosides, sulfonamides, cephalosporins, ciclosporin A, cisplatin, penicillin, amoxicillin, mezlocillin, antiphlogistics, omeprazole, probenecid, colchicine.
• Additive synergistic toxicity with concomitant administration of trimethoprim/sulfmethoxazole, pyrimethamine.
• Displacement of MTX from plasma binding with concomitant administration of ASA, ethanol, barbiturates, phenytoin, retinoids, sulfonamides, tetracyclines, sulfonylureas.
• Increased hepatoxicity with concomitant administration of ethanol, retinoids.

• Before starting therapy (routine laboratory, hepatitis serology, pregnancy test, HIV serology) and in intervals of 4 weeks control of blood, liver and kidney parameters (in polymorbid patients possibly more closely; after longer monitoring without complications 8-week control appointments are sufficient).
• Before any systemic therapy (of psoriasis) it is recommended to perform an "Interferon-gamma Release Assay -IGRA - e.g. Quantiferon -TB-Gold-Test).
• Medical history regarding the amount of usual alcohol consumption, previous liver diseases, previous or current use of hepatotoxic drugs, drug abuse, membership in an HIV risk group. Family history of liver disease, diabetes, overweight! Men and women must use effective contraception during therapy and up to 3 months after discontinuing the preparation!
• Based on the data of a meta-analysis, the task force of the US-American "National Psoriasis Foundation" continues to recommend the performance of a liver biopsy in case of clinical suspicion of liver structural damage or additional risk factors. Even with high cumulative total doses, a liver biopsy may be justified under certain circumstances according to the above recommendations. This does not appear necessary to us. Instead, we recommend regular monitoring of liver function by laboratory and imaging procedures (sonography).
• Combination therapies
  • The combination therapy "MTX with other immunomdoulators (e.g. fumaric acid esters) or immunosuppressive drugs" is considered by some authors to be contra-induced. Our experience with the combination MTX/fumaric acid ester can be described as good, especially in the case of psoriasis arthropathica (regular laboratory checks!).
  • The combination therapy "MTX with biologicals (e.g. Enbrel)" is standard.
• Use of MTX for fertility:
  • Women: Safe contraceptive measures must be continued for 3 months after stopping the therapy!
  • Men: Fertility restrictions are documented. The changes are reversible. It is recommended to wait 3 months before a planned conception. Attention should be drawn to the possibility of cryopreservation of sperm!
• In psoriatic patients who have received both PUVA and a high-dose methotrexate therapy, the risk of lymphoma should increase 4-fold!
• For patients suffering from gastrointestinal complaints, the (very well tolerated) subcutaneous injection method (pre-filled syringes) is recommended.
• Folic acid administration during MTX therapy: The additional administration of folic acid is handled differently in Europe and America. In Europe, MTX therapy is often carried out without folic acid administration. An additional folic acid dose is only given in case of MTX intolerance or serologically proven folic acid deficiency (macrocytosis, hyperchromasia in the blood count). Other signs of folic acid deficiency are inflammation of the mucous membranes (oral mucosa). In these cases, MTX therapy can be interrupted for a short time and folic acid can be administered in high doses until it subsides (e.g. 3 times/day 1 tbl. of folican). Subsequently, continuation of the MTX therapy (but simultaneously with folic acid). In the USA, folic acid is mainly given after each MTX intake or MTX injection (usually 24 hours after the first dose). However, there are different dosage recommendations:
  • Usually 5 mg folic acid (e.g. 1 tablet of Folsan) 24 hours after MTX (independent of the MTX dose) is the usual dose.
  • Alternatively, adjust the folic acid dose to the MTX dose (e.g. 15 mg MTX and 15 mg folic acid equivalent).
• There are also differences with regard to the time of substitution: in America 24 hours after MTX administration or daily intake (1 mg/day) (in Germany 5 mg tablets are used). In Europe (especially in Germany), many rheumatology centres do not give folic acid until 48 hours after the treatment. Background: the action of MTX is essentially based on a blockade of the folic acid metabolism, MTX and its metabolite remain in the body for 48 hours until elimination. MTX itself remains in the body for about 24 hours, the metabolite also for another 24 hours. Folic acid applications that are too early should cancel the effect or lead to a weakening of MTX.

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