Methotrexate (MTX) is a widely used medication for treating various conditions, including rheumatoid arthritis, psoriasis, and certain cancers. While it offers significant therapeutic benefits, it's associated with a range of side effects, including hair loss, also known as alopecia. This article explores the causes, treatment, and management of methotrexate-induced alopecia, providing comprehensive information for patients and healthcare professionals.
Methotrexate is an immunosuppressant and chemotherapy drug. It is used to treat cancers of the blood, bone, breasts, and lungs. It is also an antirheumatic drug used to relieve symptoms of rheumatoid arthritis, psoriasis, and other autoimmune conditions. Low-dose methotrexate (MTX) is the backbone of treatment for extensive psoriasis vulgaris not responding to topical therapy. Since its introduction for the treatment of psoriasis in the 1970s, its short- and long-term side effect profile has been extensively studied. Over the years, low-dose methotrexate (MTX) therapy has become an important way of psoriasis management with a relatively safe side effect profile.
Hair loss is a distressing side effect that can occur with methotrexate treatment. While not everyone experiences it, understanding the underlying mechanisms and potential management strategies is crucial.
Hair loss with MTX has been reported mostly with high-dose MTX used in chemotherapy. In rheumatoid arthritis patients, the Arthritis Foundation notes that approximately 1% to 3% of people taking methotrexate experience hair loss. However, studies of psoriasis patients show a higher rate of hair loss, approximately 3% to 10%. More recent research has found higher rates. One study found that 9.2 percent of people with early RA had hair loss over one year of taking methotrexate. According to a 2019 study, researchers discovered that hair loss - particularly among females - occurred at a rate of 29.4%.
Methotrexate works by interfering with folic acid, which is essential for cell reproduction, particularly in rapidly dividing cells. The mechanism of action of MTX at higher doses is primarily cytotoxic and antiproliferative. At high extracellular concentrations, MTX also enters cells through high-capacity, low-affinity processes such as passive diffusion in addition to being transported intracellularly through reduced folate carrier (RFC) giving its higher intracellular concentration. At higher doses (>30 mg/m[2]), MTX primarily acts by inhibiting DNA and RNA synthesis during the S phase of the cell cycle in the rapidly dividing cells.
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At lower doses, the mechanism of action of MTX is primarily by inhibition of 5aminoimidazole4carboxamide ribonucleotide (AICAR) transformylase domain of the bifunctional enzyme AICAR transformylase/inosine monophosphate cyclohydrolase (ATIC). Inhibition of this metabolic pathway results in increased levels of extracellular adenosine. Since hair follicles are among the body's rapidly dividing cells, they are susceptible to the effects of methotrexate. This can lead to hair thinning or loss.
Methotrexate is known to cause anagen effluvium but only at high doses (>1 g/m[2]) used in cancer chemotherapy. Anagen effluvium refers to abrupt loss of hair in their growing phase due to any event which causes sudden stoppage of the metabolic or mitotic activity of the hair follicle. Anagen effluvium is of two types, namely dystrophic anagen effluvium and loose anagen syndrome. Dystrophic anagen effluvium occurs commonly due to chemotherapeutic agents but can also occur in case of protein-energy malnutrition, pemphigus, alopecia areata, and various heavy metal poisoning.
Explanation of such bizarre reactions lies in the polymorphisms in the genes for MTX regulating intracellular uptake and enzyme inhibition which are known to render individuals susceptible to toxicity. Many polymorphisms to such effect have been detected: (i) MTX is transported intracellularly by the RFC. A polymorphism leading to substitution of arginine for histidine at codon 27 of the RFC protein has been identified (RFC G80A), and studies suggest that this polymorphism had higher plasma MTX levels and higher intracellular polyglutamated MTX levels than patients with other genotypes. (ii) A tandem repeat sequence within 5′-untranslated region of the TYMS gene, containing a variable number of 28 base-pair repeats, has been identified which function as enhancers, and with increased number of repeat sequences, both mRNA expression and enzyme activity are increased. (iii) Methyltetrahydrofolate enzyme is a central regulatory enzyme in the folate pathway which catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Toxicogenic index for MTX is a sum of homozygous variant genotype for four SNPs (MTHFR C677T, ATIC C347G, the TYMS 28-bp tandem repeat, and a SNP within serine hydroxymethyltransferase, C1420T). Despite MTX being a relatively safe drug in long-term management of psoriasis, idiosyncratic reactions such as the one being reported are occasionally witnessed during the clinical practice. Therefore, wherever possible, prior genetic testing for polymorphisms must be undertaken to identify individuals who are at higher risk of developing such complications.
Managing hair loss due to methotrexate involves a multifaceted approach, including medical interventions, lifestyle adjustments, and supportive care.
Alopecia totalis (AT) and alopecia universalis (AU) are the most debilitating types of alopecia areata (AA) as they incur severe changes to a patient’s quality of life. A 19-year-old man came with the chief complaint of baldness on the scalp, hair, eyebrows, eyelashes, moustache, beard, and axillary hair without itch nor pain. Three years previous, there was a couple of coin-size baldness on the top and back of the head, with no itch and pain sensation. In one-year time, baldness on the scalp became widespread, accompanied by the loss of eyebrows, eyelashes, moustache, beard, and axillary hair. The patient went for treatment and was given topical and oral medication and injections at the scalp. There was a temporary improvement as the growth of small and fine hair at the injection site lasted about six months, but they fell out again. Furthermore, the patient did not continue the therapy. This patient was diagnosed as AU with unknown precipitating factors. As injections were painful and uncomfortable, we decided to give the topical minoxidil treatment and combined it with systemic therapy of methotrexate and corticosteroids. He was given combination therapy of oral 15 mg methotrexate per week, 16 mg methylprednisolone per day, and topical treatment with minoxidil 5%. Additionally, we gave a 5 mg folic acid supplementation on the off-days of oral methotrexate dose. Three months after treatment, we observed no significant improvement in hair growth. However, the trichoscopy examination revealed white and black short vellus hair growth. After six months of observations, there was an improvement marked with terminal hair growth. Methotrexate and topical minoxidil were continued. After nine months of observations, there was improvement shown as a decrease in the SALT score to 41%, indicating high responsiveness to therapy marked with 59% hair growth compared to the pre-treatment state. Hair growth was also seen in the eyebrows, eyelashes, moustaches, and beards. This case report showed the effective and promising results with the use of combinations of systemic methotrexate, corticosteroids, and topical minoxidil.
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Explanation of such bizarre reactions lies in the polymorphisms in the genes for MTX regulating intracellular uptake and enzyme inhibition which are known to render individuals susceptible to toxicity. Many polymorphisms to such effect have been detected: (i) MTX is transported intracellularly by the RFC. A polymorphism leading to substitution of arginine for histidine at codon 27 of the RFC protein has been identified (RFC G80A), and studies suggest that this polymorphism had higher plasma MTX levels and higher intracellular polyglutamated MTX levels than patients with other genotypes.5,6 A tandem repeat sequence within 5′-untranslated region of the TYMS gene, containing a variable number of 28 base-pair repeats, has been identified which function as enhancers, and with increased number of repeat sequences, both mRNA expression and enzyme activity are increased.7 Methyltetrahydrofolate enzyme is a central regulatory enzyme in the folate pathway which catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. Toxicogenic index for MTX is a sum of homozygous variant genotype for four SNPs (MTHFR C677T, ATIC C347G, the TYMS 28-bp tandem repeat, and a SNP within serine hydroxymethyltransferase, C1420T). Despite MTX being a relatively safe drug in long-term management of psoriasis, idiosyncratic reactions such as the one being reported are occasionally witnessed during the clinical practice. Therefore, wherever possible, prior genetic testing for polymorphisms must be undertaken to identify individuals who are at higher risk of developing such complications.
It's important to distinguish methotrexate-induced hair loss from other potential causes, as this can influence the management approach.
If you’re noticing hair loss while taking methotrexate, you might be wondering how best to care for your hair - and whether it’s still safe to style or dye it as you normally would. A rheumatologist can help you navigate these changes. They can offer guidance based on your RA symptoms, treatment plan, and any other health conditions you may have.
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