Methotrexate is an antimetabolite that works by inhibiting dihydrofolic reductase. This enzyme is important in the production of DNA. Methotrexate targets rapidly growing cells such as inflammatory cells in rheumatoid arthritis or psoriasis. Methotrexate was originally used as a cancer drug for malignancies including acute lymphoblastic leukemia and lymphomas.

Methotrexate and wound healing

Methotrexate is an antimetabolite that works by inhibiting dihydrofolic reductase.  This enzyme is important in the production of DNA.  Methotrexate targets rapidly growing cells such as inflammatory cells in rheumatoid arthritis or psoriasis.  Methotrexate was originally used as a cancer drug for malignancies including acute lymphoblastic leukemia and lymphomas. 

My first patient has a severe deformity of the right foot that includes plantar fat pad atrophy and multiple plantar, forefoot bursae.  Rheumatoid nodules are prevalent on the bottom of the foot.  If you think of a foot with multiple ping pong balls on the bottom of the foot, then you have the right mind’s eye vision of this foot.  I had corrected her left foot 3 years ago by performing a pan-metatarsal head resection (Hoffman procedure) and bunionectomy.  She came back to us with a great result on the left and wanted to pursue correction of the right foot.  In an elective case, when the patient is in active treatment using methotrexate, we have the distinct advantage to work directly with the patient’s rheumatologist.  His suggestion is to discontinue the methotrexate three weeks prior to the surgery and restart it 2 weeks following the surgery. 

Surgery should be thought of as premeditated trauma.  The body can’t tell the difference between a fireplace log and a scalpel blade.  Trauma is trauma.  The response to a traumatic wound is always the same; stop the bleeding, become inflamed, close the wound and remodel the wound.  But when a patient has methotrexate on-board, that typical cascade of wound healing is interrupted.  Hemostasis (stop the bleeding) occurs, but there is no inflammation.  Inflammation in a wound in the beacon that calls for the cellular and chemical response that sends the necessary components to the wound to begin the process of healing.  Knowing that methotrexate affects cells with rapid turn over, we can then assume that methotrexate will have a direct effect on inflammatory cells.  Methotrexate essentially stops healing. 

My second case was not elective.  The patient is a 60 y/o female referred to our critical limb care center (wound center).  She had a 5-year history of vasculitis that was in remission with continued use of methotrexate.  She had visited a vein center to have a few spider veins treated by multiple injections (a technique called sclerotherapy).  6 weeks after her sclerotherapy, she had multiple, nonhealing wounds of the right ankle where the solution used in the injections had extravasated (escaped) from the vein.  My assumption is that the sclerotherapy was poorly performed.  In a healthy patient, the extravasation would have been accommodated by healthy cells adjacent to the vein.  But in this case, the sclerosing solution simply sclerosed the tissue surround the vein.  In a healthy patient, the inflammatory response to this problem would have initiated healing.  But since the patient was taking methotrexate, there was no inflammatory response, and subsequently no healing. 

My sclerotherapy patient had tried in the past to get off of her methotrexate but was not able to do so.  She told me that when she did try, she had a terrible time getting readjusted to her dose.  So our goal was to heal this wound while keeping the patient on her methotrexate.  She’s 8 weeks now into her treatment.  The smaller wounds have healed with the use of a topical enzymatic agent called Santyl.  The larger wounds are responding to the use of Oasis, a matrix of collagen made from the submucosa of pig intestine.  Oasis acts as both a cover and scaffold for the fibroblasts in the wound.  A few more weeks and I think we’ll have her healed.

Does methotrexate influence healing?  Absolutely.  If you’re taking methotrexate, be sure to tell each of your doctors.

Jeff

Jeffrey A. Oster, DPM
Medical Advisor
Myfootshop.com

Updated 9/23/2021