A 40-year-old woman comes to the office for follow-up. The patient has a 4-year history of rheumatoid arthritis and has been taking a disease-modifying therapy. She reports significant improvement in joint pain and stiffness with treatment and can now perform daily activities without difficulty. The patient has no other medical conditions and does not use tobacco, alcohol, or illicit drugs. She consumes a balanced diet and exercises most days of the week. Vital signs are normal. Physical examination shows no significant joint swelling, erythema, or tenderness. Laboratory results are as follows:
| Complete blood count | |
| Hemoglobin | 11.2 g/dL |
| Mean corpuscular volume | 108 µm3 |
| Platelets | 226,000/mm3 |
| Leukocytes | 7,800/mm3 |
| Serum chemistry | |
| Sodium | 140 mEq/L |
| Potassium | 4.0 mEq/L |
| Bicarbonate | 24 mEq/L |
| Creatinine | 0.8 mg/dL |
| Calcium | 9.6 mg/dL |
| Glucose | 98 mg/dL |
Laboratory studies were within normal limits 6 months ago. Which of the following is the most likely additional adverse effect of this patient's pharmacotherapy?
Disease-modifying antirheumatic drugs | ||
Agent | Mechanism | Adverse effects |
Methotrexate |
|
|
Leflunomide |
|
|
Hydroxychloroquine |
|
|
Sulfasalazine |
|
|
TNF inhibitors |
| |
IL-1 = interleukin 1;TNF = tumor necrosis factor. | ||
This patient with rheumatoid arthritis (RA) is on disease-modifying antirheumatic drug (DMARD) therapy, which improves long-term joint function and is initiated as soon as practical after diagnosis. Methotrexate is the preferred first-line DMARD for most patients with RA.
However, this patient now has macrocytic anemia (mean corpuscular volume >100 µm3), a potential adverse effect of methotrexate. Methotrexate inhibits dihydrofolate reductase, which can lead to cellular folate depletion. Hematologic effects can range from mild macrocytosis to severe pancytopenia. Methotrexate is also associated with hepatotoxicity, especially in patients with comorbid liver disease. Mild elevations in hepatic transaminases are common, and chronic liver disease and cirrhosis may occur over time. Other adverse effects of methotrexate include nausea, stomatitis, rash, interstitial lung disease, alopecia, and fever.
Therefore, patients on methotrexate should have regular monitoring with complete blood counts and hepatic function markers (eg, serum albumin, transaminases). Much of the toxicity of methotrexate, including hepatotoxicity, can be mitigated by concurrent administration of folic (or folinic) acid, which does not reduce the effectiveness of the drug. Due to the risk of hepatotoxicity, patients should avoid alcohol intake while on treatment.
(Choice B) Calcineurin inhibitors (eg, cyclosporine, tacrolimus) are associated with neurotoxicity; manifestations include headache, seizures, tremor, encephalopathy, and peripheral pain. However, these medications do not commonly cause macrocytic anemia and are rarely used for RA.
(Choice C) Glucocorticoids (eg, prednisone) are used in acute management of RA. Major adverse effects include Cushing syndrome, osteoporosis, adrenocortical atrophy, and poor wound healing; however, they do not commonly cause macrocytosis. Unlike DMARDs, glucocorticoids do not alter the course of joint destruction and are not continued chronically in most patients.
(Choice D) Hydroxychloroquine is an antimalarial DMARD that is well tolerated in management of RA and other autoimmune disorders. It can cause irreversible retinal toxicity and warrants regular ophthalmologic examination. Hematologic effects are uncommon.
(Choice E) Tumor necrosis factor (TNF) inhibitors (eg, etanercept, adalimumab) are large-molecule biologic DMARDs that are very effective in the treatment of RA. They have potent immunosuppressive qualities and are associated with increased risk for reactivation of latent tuberculosis. TNF inhibitors commonly cause neutropenia, but macrocytic anemia is not a common effect.
Educational objective:
Methotrexate is a disease-modifying antirheumatic drug used for rheumatoid arthritis. Macrocytic anemia and hepatotoxicity are common adverse effects. The toxicity of methotrexate (including hepatotoxicity) can be mitigated by the administration of folic acid, which does not reduce the effectiveness of the drug.