Background Methotrexate is known to cause folate deficiency which can be manifested early on as macrocytosis in a complete blood count. Some clinical manifestations of folate deficiency such as cytopenia, anorexia, stomatitis, and gastrointestinal intolerance are also observed during low dose methotrexate (MTX) treatment in various forms of arthritis.

Objectives The purpose of this study was to determine the effectiveness of daily folinic acid supplementation in reversing macrocytosis noted in some patients with rheumatoid arthritis (RA) and psoriatric arthritis (PsA) treated with low dose methotrexate and folic acid and to see if it altered the disease modifying activity of the drug.

Methods Twenty-eight patients were studied. There were 20 women and eight men with an age range of 34–82 years. Twenty-four patients had RA and four had PsA. They were all treated with low dose MTX between 5–15 mg. weekly and folic acid two mg. orally daily, as well as a nonsteroidal antiinflammatory drug and in some patients low dose oral prednisone. Additionally, 16 patients took hydroxychloroquine sulfate, eight patients sulfasalazine, and two patients auranofin. All patients had normal thyroid function. Twenty-three patients (82%) developed macrocytosis after an interval of three to four years on MTX and folic acid. A favourable response was noted in two patients by reversal of their macrocytosis when their daily folic acid dose was increased to three mg. For 21 patients the folic acid was discontinued and supplemented orally with five mg. folinic acid daily. Of the five patients who did not develop macrocytosis, four took weekly MTX of seven and a half mg. or less. One took 15 mg. MTX weekly but also received intramuscular testosterone every three weeks for hypogonadism.

Results Patients were followed for three to seven years. Of the 21 patients on folinic acid supplementation, 20 (95%) had a reversal of their macrocytosis in 12–15 months. There was no exacerbation of their underlying arthritis. This was determined by joint count, tenderness, limitation of motion and flexion contractures of affected joints. When the folinic acid was discontinued and folic acid reinstituted, macrocytosis recurred in two to three years in five patients and responded to another course of folinic acid. Eight patients who had active disease from the onset continued to have active disease and six were subsequently given etanercept injections. The remaining 13 patients continued to show improvement of all parameters of disease activity. The one non-respondent had active PsA.

Conclusion These observations suggest that reversal of macrocytosis can be accomplished with daily use of five mg. folinic acid without diminishing the effectiveness of low dose MTX in patients with RA and PsA.