WBR0156

Author	[[PageAuthor::William J Gibson (Reviewed by Yazan Daaboul, M.D.)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Pharmacology
Sub Category	SubCategory::Musculoskeletal/Rheumatology
Prompt	[[Prompt::A 43-year-old woman presents to her primary care physician for increasingly severe joint pain and fatigue over the past three months. She complains of joint stiffness in the morning, which improves throughout the day. She describes her pain as a persistent, dull pain that “hurts all over”. On physical examination, the physician notes mild joint swelling around the knee and ulnar deviation of the fingers. Laboratory testing reveals a positive ELISA for anti-IgG antibodies. The patient is started on a first-line disease-modifying drug, but three weeks later is found to be critically leukopenic. Which of the following medications can be used to quickly reverse the effects of the administered drug?]]
Answer A	AnswerA::Infliximab
Answer A Explanation	[[AnswerAExp::Infliximab is a monoclonal antibody directed against TNF-alpha, indicated for RA, Crohn’s disease, and ankylosing spondylitis. All anti-TNF-alpha agents increase the risk of TB re-activation. While Infliximab can be used to treat RA, it cannot rescue the toxic effects of methotrexate.]]
Answer B	AnswerB::Reduced Vitamin B9
Answer B Explanation	[[AnswerBExp::Leucovorin is equivalent to activated folinic acid, a reduced form of folic acid (vitamin B9). It can be administered to “rescue” the effects of methotrexate in cases of severe adverse drug events, such as leukopenia.]]
Answer C	AnswerC::Vitamin K
Answer C Explanation	[[AnswerCExp::Vitamin K is used to reverse the effects of warfarin.]]
Answer D	AnswerD::Protamine sulfate
Answer D Explanation	[[AnswerDExp::Protamine sulfate is used to reverse the effects of heparin.]]
Answer E	AnswerE::Folic acid
Answer E Explanation	[[AnswerEExp::Folic acid (vitamin B9) may be administered routinely with methotrexate to reduce nausea and mouth ulcers associated with methotrexate administration. Unlike leucovorin, folic acid cannot overcome methotrexate-induced inhibition of the dihydrofolate reductase enzyme and is not helpful in severe adverse events.]]
Right Answer	RightAnswer::B
Explanation	[[Explanation::Rheumatoid arthritis (RA) is an autoimmune inflammatory disease which commonly presents as systemic joint pain. A positive rheumatoid factor (anti AgG antibody) is 80% sensitive and 90% specific for RA. RA is two to three times more prevalent in females than males. Rheumatoid arthritis tend to affect the MCP and PIP joint of the hand and spares the DIP, resulting in swelling of the MCP joint that can cause ulnar deviation of the fingers observed in this patient. RA is treated with a combination of analgesics and disease-modifying antirheumatic drugs (DMARDs). The first-line disease modifying drug for RA is methotrexate. Methotrexate competitively inhibits folic acid binding to dihydrofolate reductase, a cellular enzyme responsible for the conversion of dihydrofolic acid to tetrahydrofolic acid. Cells require tetrahydrofolic acid to make thymidine, one of the four critical nucleosides in DNA synthesis. Without thymidine, fast-growing cells can no longer replicate DNA and die. Leucovorin is equivalent to folinic acid, an active reduced form of folic acid. It can be administered to “rescue” the effects of methotrexate. Methotrexate competitively inhibits folic acid binding to dihydrofolate reductase. While folic acid administration along with methotrexate may be helpful to prevent other adverse drug events such as GI distress or mucosal ulcers, folic acid administration cannot overcome severe effects associated with methotrexate-induced inhibition of dihydrofolate reductase such as leukopenia. On the other hand, leucovorin administration bypasses this step in thymidine synthesis and thereby reverses the effect of methotrexate-induced leukopenia much more rapidly and effectively. Educational Objective: Leucovorin (folinic acid or reduced form of vitamin B9) can be used to “rescue” methotrexate-induced leukopenia. References: Tishler M, Caspi D, Fishel B, et al. The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis & Rheumatology. 1988;31(7):906-8. Shiroky J, Neville C, Esdaile JM, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. results of a multicenter randomized, double-blind, placebo-controlled trial. Arthritis and Rheumatism. 1993;36(6):795-803. Shiroky J, Allegra C, Inghirami G, et al. High dose intravenous methotrexate with leucovorin rescue in rheumatoid arthritis. J Rheumatol. 1988;15(2):251-5. Stoller RG, Kaplan HG, Cummings FJ, Calabresi P. A clinical and pharmacological study of high-dose methotrexate with minimal leucovorin rescue. Cancer Res. 1979;39(3):908-12. First Aid 2014 Page 403]]
Approved	Approved::Yes
Keyword	WBRKeyword::Rheumatoid arthritis, WBRKeyword::RA, WBRKeyword::Methotrexate, WBRKeyword::Methotrexate-induced leukopenia, WBRKeyword::Side effect, WBRKeyword::Adverse event, WBRKeyword::Adverse drug reaction, WBRKeyword::Myelosuppression, WBRKeyword::Leukopenia, WBRKeyword::Drug, WBRKeyword::Rescue, WBRKeyword::Folinic acid, WBRKeyword::Vitamin B
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