Methotrexate is a folic acid analogue that inhibits dihydrofolate reductase and is used to treat various inflammatory and proliferative skin conditions. It can be administered orally, intravenously, intramuscularly or subcutaneously. It is well distributed throughout the body except in the brain. Around 50% is bound to plasma proteins and it has a terminal half-life of 10-27 hours. It works by inhibiting DNA synthesis and blocking T cell migration. Common side effects include gastrointestinal upset and hepatotoxicity. It is contraindicated in pregnancy due to risk of teratogenicity. Monitoring for toxicity and supplementing with folic acid can help reduce adverse effects.

1. By : Dr. Kriti Maheshwari
1st year Resident (M.D. DVL)
Methotrexate in Dermatology

2.  Structure : Methotrexate (4-amino-N10methyl
pteroylglutamic acid) is a potent competitive
antagonist (inhibitor) of the enzyme dihydrofolate
reductase. It is structurally similar to folic acid, the
natural substrate for this enzyme.
 Absorption and distribution:
- MTX can be administered orally, intravenously,
intramuscularly, or subcutaneously.
- Concurrent food intake, especially milk-based
meals, may reduce bioavailability in children.
However, in adults the drug is unaffected by
concurrent food ingestion.
- The drug is well distributed throughout the body
except in the brain, penetrating the blood–brain
barrier poorly

3.  Metabolism and Excretion :
- Once absorbed, the level of MTX in the plasma
has a triphasic reduction.
- The first phase occurs rapidly (0.75 h) and
reflects distribution of the drug throughout the
body.
- The second phase of the plasma level reduction
is represented by renal excretion and occurs over
2–4 hours.
- The third phase represents the terminal half-life
and varies between 10 and 27 hours. This phase
shows a slow release of MTX, primarily bound to
dihydrofolate reductase, from the tissues.
- 50% of MTX is bound to plasma proteins.

4. Mechanism Of Action
 DNA synthesis effects: inhibition of cell division being
specific for the S phase (DNA synthesis)
 T cell effects: blocks migration of activated T cells into
certain tissues
 Immunosuppresive effects : Suppresion of primary
and secodary antibody responses
 Anti inflammatory effects: mediated by adenosine
(which is anti inflammatory)
 Concurrent use of folic acid with MTX: controversial
role
- may decrease risk of GI side effects and
pancytopenia

5. Clinical Uses
 FDA Approved Indications :
- Psoriasis
- Sezary syndrome.
 Off label uses:
 Proliferative dermatoses : Pityriasis rubra pilaris, PLEVA, Reiter’s
disease
 Immunobullous dermatoses : Pemphigus vulgaris, Bullous
pemphigoid, Cicatricial pemphigoid, Epidermolysis bullosa acquisita.
 Autoimmune connective tissue diseases : Dermatomyositis,
Subacute cutaneous lupus erythematosus, Systemic lupus
erythematosus, Systemic scleroderma, Morphea/localized
scleroderma, Scleredema diabeticorum.
 Vasculitis – neutrophilic dermatoses : Leukocytoclastic vasculitis,
Cutaneous PAN, Behcet’s disease, Kawasaki disease, Pyoderma
gangrenosum.
 Dermatitis : Atopic dermatitis

6. Contraindications
 Absolute : Pregnancy (Category X), Lactation.
 Relative :
- Unreliable patients
- Decreased renal function
- DM, obesity
- Hepatic diseases: active hepatitis, cirrhosis, h/o
liver disease
- Severe haematological abnormality
- Man/ woman contemplating conception
- Active infection.
- Immunodeficiency syndromes.

7. Indications of MTX therapy of
psoriasis
 Erythrodermic psoriasis.
 Psoriatic arthritis: not responsive to conventional
therapy.
 Pustular psoriasis: generalized or debilitating
localized disease.
 Psoriasis that adversely affects ability to maintain
employment.
 Extensive, severe plaque psoriasis: not
responsive to conventional therapy (usually >
20% surface involvement).
 Lack of response to phototherapy (PUVA and
UVB) or retinoids.

8. Adverse Effects
 Hepatotoxicity : PIIINP serum test to help assess
hepatic fibrosis
 Pulmonary toxicity – acute pneumonitis, pulmonary
fibrosis.
 Haematologic effects - pancytopenia
 Malignancy induction - lymphomas
 GI effects – diarrhoea, vomiting, ulcerative stomatitis
(Stop MTX)
 Potent teratogen and abortifacient
 Oligospermia
 Renal toxicity on high dose treatment
 Others: mild alopecia, headache, fatigue, dizziness,
potentially phototoxic.

9. Metotrexate Toxicity
 C/F – commonly pancytopenia, deranged LFT
 Rare – SJS, burning sensation of skin.
 Treatment – Leucovorin (or folinic acid) given
within 12 hours of last MTX dose.

10. Drug Interactions

11. Therapeutic Guidelines
 2 regimens
Single weekly
dose
-3 divided doses/week over
a 24 hr period (eg. 8am and
8pm on the 1st day and 8am
on the 2nd day)
-k/a Weinstein frost regimen.
-Adv : reduced GI upset
- Disadv : increased risk of
hepatic fibrosis.
-Generally , starting dose is 5-10mg/week
-Max dose – 25mg/week

12. Other Antifolate agents
 Also act by inhibiting dihydrofolate reductase
(DHFR).
 Proguanil: Malaria - prevention and treatment
 Trimethoprim: treatment & prophylaxis
for pneumocystis jiroveci
pneumonia, malaria and toxoplasmosis.
 Pyrimethamine: used in malaria, toxoplasmosis
 Pemetrexed : used in non small cell lung
carcinoma and mesothelioma

13. Thank you