Methotrexate-induced pancytopenia more common than expected

The risk of pancytopenia with methotrexate may be higher than has been assumed until now, a group of UK researchers write in the July issue of Rheumatology. “The importance of routine blood monitoring cannot be emphasized enough,” they comment. “Methotrexate needs to be monitored in the long term, even when the patient has been on a stable dose for many months.”

Dr Anita Lim and colleagues at the Norfolk and Norwich University Hospital, UK, report on their experience with 25 cases in 5 years the largest reported individual case series, they note. Pancytopenia affects all three blood cell lines, and was defined in the study as a white blood cell count <3.5x109/L, hemoglobin <11 g/dL, and platelet count <130x109/L. Lim, who is currently at the Singapore National University Hospital, tells rheumawire that the main message from their findings is: "Be vigilant for this late but potentially fatal complication.""Blood monitoring should be continued indefinitely for the duration of treatment, because hematological toxicity can occur even after many months or years, as we discovered in our cohort," Lim says. In their series, the mean duration of treatment when pancytopenia was discovered was 36 months, but three severe cases were identified after 84, 87, and 96 months of treatment, and three less-severe cases were discovered after 78, 93, and 120 months of treatment. Of the 25 patients with this side effect, seven died (28% mortality)five from sepsis and two from acute myeloid leukemia. "There is no place for complacency, and one cannot say a patient has been on methotrexate for many years and has never had any problems, therefore blood monitoring can be discontinued," Lim comments.Six of the cases were identified in patients who had not been undergoing regular blood monitoring; all six were in residential or nursing homes, the authors note. Another nine cases were identified by routine blood monitoring, as recommended by the British Rheumatology Society guidelines. (These advocate fortnightly full blood count [FBC] and liver-function test for the first six weeks and after each dose increment, and then suggest that once the dose is stabilized, FBC be carried out monthly.)On presentation, one patient had an acute coronary syndrome secondary to anemia, seven had bleeding, nine had concomitant sepsis, and ten had oral mucositis. Nearly half (12 patients) were taking folic- or folinic-acid supplements. The authors comment that although folic-acid supplementation has been shown to reduce liver toxicity, as well as mucosal and gastrointestinal side effects, there have been no studies showing that it has an unequivocal protective effect on hematological toxicity, and they suggest that these specific tissues may have a distinctive susceptibility. Nevertheless, they suggest that folic-acid supplementation, 5 mg weekly, should be considered in all patients taking methotrexate. Lim tells rheumawire that potential risk factors include renal impairment; age over 75 years; low serum albumin (particularly <28 g/dL); pre-existing folate deficiency and poor nutritional status; polypharmacy, with its risk of drug interactions; and dosing errors, especially in view of its once-weekly dosing. She adds: "Sepsis is a major cause of death, particularly when pancytopenia is profound/severe; patients on methotrexate who develop infections should stop the drug."More common than expectedThe researchers were prompted to conduct their retrospective review after they noticed increasing hospital admissions for methotrexate-related pancytopenia at their hospital. They found records on 25 patients admitted between 1999 and 2004. The catchment population served by the hospital is 550 000 people. To estimate the prevalence of this side effect, Lim et al used data from the Norfolk Arthritis Register, which puts the prevalence of rheumatoid arthritis (RA) at 0.8%, and records that between 1999 and 2004, about 25% of patients with RA received methotrexate. (They note, however, that methotrexate is also used for other inflammatory conditions. In their series of 25 patients, 19 had RA; the others were taking methotrexate for RA with lupus [1 patient], Wegener's granulomatosis [3 patients], psoriatic arthritis [1 patient], and giant cell arteritis [1 patient].) From these figures, Lim et al estimate the prevalence of methotrexate-induced pancytopenia in their cohort to be approximately 1.9%. The authors note that a previous report estimated the prevalence of all hematological toxicities at 3% in methotrexate-treated RA patients. However, in addition to pancytopenia, this study included leucopenia, thrombocytopenia, and megaloblastic anemia. "This suggests that pancytopenia caused by methotrexate is underestimated, as we more commonly see leucopenia, thrombocytopenia, etc, on their own," Lim explains."In our experience, methotrexate-induced pancytopenia is more common than expected, and is probably underreported," the researchers conclude. (Source: Lim AY, Gaffney K, Scott DG. Methotrexate-induced pancytopenia: Serious and under-reported? Our experience of 25 cases in 5 years. Rheumatology 2005; 44:1051-1055: Weinblatt ME. Toxicity of low dose methotrexate in rheumatoid arthritis. J Rheumatol 1985; Suppl 12:35-39: Joint and Bone: August 2005.)