What intervention is most likely to relieve symptoms in a 57-year-old man with unintentional weight loss, shortness of breath, fatigue, and macrocytic anemia, taking losartan, methotrexate, and cetirizine (hydroxyzine), with a history of hypertension, systemic lupus erythematosus (SLE), and seasonal allergies?

From the Guidelines

Discontinuation of methotrexate is most likely to relieve this patient's symptoms, as the patient is presenting with signs and symptoms consistent with methotrexate toxicity, which can occur with long-term use of this medication for autoimmune conditions like lupus. The patient's macrocytic anemia, unintentional weight loss, shortness of breath, and fatigue are all consistent with methotrexate toxicity, which is a known side effect of this medication 1. Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, leading to impaired DNA synthesis, and this can manifest as macrocytic anemia, mucosal inflammation, gastrointestinal disturbances, fatigue, and hyperpigmentation of the skin. Some key points to consider in this patient's management include:

• The patient's medication regimen, including losartan, methotrexate, and cetirizine (hydroxyzine), and how these medications may be contributing to his symptoms
• The patient's history of hypertension, systemic lupus erythematosus (SLE), and seasonal allergies, and how these conditions may be impacting his overall health
• The importance of evaluating the patient for potential folate or vitamin B12 supplementation to address the macrocytic anemia after discontinuing methotrexate, as recommended by multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders 1
• The need for the physician to discuss alternative medications for managing the patient's lupus and counsel him on reducing alcohol intake, as this combination is particularly harmful while taking methotrexate. Given the potential for methotrexate toxicity, discontinuation of this medication is the most appropriate course of action to relieve the patient's symptoms and prevent further complications, as supported by the recommendations for the use of methotrexate in rheumatic disorders 1.

From the FDA Drug Label

Leucovorin is indicated to diminish the toxicity and counteract the effect of inadvertently administered overdosages of methotrexate. Symptoms commonly reported following oral overdose include those symptoms and signs reported at pharmacologic doses, particularly hematologic and gastrointestinal reaction For example, leukopenia, thrombocytopenia, anemia, pancytopenia, bone marrow suppression, mucositis, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration, gastrointestinal bleeding.

The patient's symptoms, such as macrocytic anemia, fatigue, and shortness of breath, may be related to methotrexate toxicity.

• The most likely intervention to relieve these symptoms is leucovorin administration, as it is indicated to counteract the effects of methotrexate overdosage 2.
• Monitoring of the serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin.

From the Research

Patient Symptoms and Medications

The patient is a 57-year-old man with unintentional weight loss, shortness of breath, fatigue, and macrocytic anemia, taking losartan, methotrexate, and cetirizine (hydroxyzine), with a history of hypertension, systemic lupus erythematosus (SLE), and seasonal allergies.

Potential Causes of Symptoms

• Macrocytic anemia can be caused by a deficiency in vitamin B12 or folate, which may be related to the patient's methotrexate treatment 3, 4.
• Methotrexate toxicity is a potential cause of the patient's symptoms, particularly macrocytic anemia, and can be exacerbated by factors such as dosing errors, metabolic syndrome, hypoalbuminemia, renal dysfunction, and lack of folate supplementation 3.
• SLE can also cause anemia, with a study finding that 93.33% of patients with SLE presented with anemia, including iron deficiency anemia, anemia of chronic disease, and hemolytic anemia 5.

Potential Interventions

• Discontinuing methotrexate and starting vitamin B12 and folate supplements may help alleviate the patient's symptoms, as seen in a case report where a patient's illness resolved with cessation of methotrexate and sulfasalazine, leucovorin treatment, and vitamin B12 repletion 3.
• Continuing folic acid supplementation may help prevent methotrexate toxicity and improve treatment outcomes, with a study finding that patients who continued folic acid supplementation had lower rates of discontinuation due to adverse effects 6.
• Adding methylprednisolone to vitamin B12 treatment may be effective in treating combined megaloblastic and immunohemolytic anemia, as seen in a case report where this treatment successfully improved hemoglobin and erythrocyte concentration 4.

Folate Supplementation and Methotrexate Treatment

• Folate supplementation has been shown to improve continuation rates of methotrexate treatment by reducing adverse effects such as liver function test abnormalities and gastrointestinal intolerance 7.
• Folate supplements do not appear to significantly reduce the effectiveness of methotrexate in treating rheumatoid arthritis, and may also help offset the elevation in plasma homocysteine associated with methotrexate use, potentially reducing the risk of cardiovascular disease 7.