Case Presentation: A 70-year-old male with medical history significant for rheumatoid arthritis presented to the emergency department with several days of odynophagia, oral ulcers, skin lesions and epistaxis. He was treated for foot cellulitis with TMP-SMX for one week prior to admission. The patient had been receiving 10 mg SQ weekly injectable MTX for Rheumatoid Arthritis. However, he had not been taking folateOn the exam, the patient was afebrile. He had stomatitis and oral bleeding. Skin exam revealed erythematous papules, plaques with dusky erosions scattered on arms, chest, abdomen, legs, and his right foot. His labs showed pancytopenia and eosinophilia. His folate level was 2.88 ng/ml (normal range >3.10 ng/ml). His MTX was held, and the patient was started on intravenous (IV) folate.He quickly developed worsening anemia and thrombocytopenia and he received supportive platelet and RBC transfusions. His course was notable for neutropenic fever that improved with antibiotics. His hematopoietic cell lines eventually recovered with folate supplementation and his pancytopenia was resolved 9 days post-admission.

Discussion: Methotrexate (MTX) is known to inhibit Dihydrofolate Reductase (DHFR), an enzyme needed to replenish folate in nucleic acid synthesis. MTX therapy can be either low dose (LDMTX) as seen in Rheumatoid Arthritis patients and our patient or high dose (HDMTX) as used in chemotherapy regimens. Supplemental folate is vital when using LDMTX and folinic acid is essential while on HDMTX to prevent bone marrow suppression. MTX’s effect on non-immune cells causes several other toxicities including stomatitis and gastro-intestinal symptoms. Less common manifestations of MTX toxicity include an increased risk of lymphoproliferative disorder, skin erosions, as observed in our patient, and skin cancer.Trimethoprim like MTX, is a folate depleting drug which inhibits DHFR increasing the risk of bone marrow toxicity when added to MTX. In addition, Sulfamethoxazole inhibits MTX renal excretion which further increases the risk for methotrexate toxicityMTX is usually well tolerated in patients taking trimethoprim-sulfamethoxazole prophylaxis (usually as one double-strength tablet three times weekly, such as on a Monday-Wednesday-Friday regimen), but this combination should be avoided when the antibiotic is used in a twice-daily regimen for treatment of an active infection. Significant bone marrow and other toxicities have been observed with use of a daily sulfa antibiotic regimen as seen in our patient

Conclusions: Twice daily TMP-SMX is contra-indicated in combination with MTX and folate supplementation is crucial while using MTX.

IMAGE 1: Stomatitis

IMAGE 2: Dusky erosions