How should we manage low-dose methotrexate-induced pancytopenia in patients with rheumatoid arthritis?

Low-dose methotrexate (ld-MTX) that is administered during rheumatoid arthritis (RA) treatment has hematological adverse effects such as pancytopenia, although rare. Although well-established and widely used for hematological adverse effects caused by high-dose MTX, leucovorin (folinic acid) treatment does not have an agreed-upon administration for ld-MTX-induced pancytopenia. Here, we aimed to figure out whether there was any difference in response time between the regimens with and without folinic acid prescribed to our patients who developed pancytopenia while on MTX therapy, and to identify risk factors for its development. Our cases were collectively assessed together with other rare cases available in the literature that were reported in a similar manner with an explicitly indicated response time, in days. Thereupon, we looked for any difference in response time between the regimens with and without folinic acid. In total, ten of our patients experienced pancytopenia while on ld-MTX treatment. Mean day on which hematological response was achieved was as follows: 7 days in one patient on folic acid monotherapy, 6 days in three patients on granulocyte-colony stimulating factor (G-CSF) monotherapy, 4.5 days in two patients on leucovorin monotherapy, and 4 days in the remaining three patients who were treated with G-CSF + folinic acid/leucovorin. When we collectively evaluated our patients and the patients with an explicitly stated response duration in the literature (15 patients) and compared regimens including folinic acid to those without folinic acid, duration until response/recovery from pancytopenia was significantly shorter in folinic acid group than that in the group without folinic acid (5.47 ± 2.9 days vs 10 ± 3.77 days, p = 0.002). Treatment modalities including folinic acid (leucovorin) either with or without G-CSF result in a shorter recovery/response time compared to other agents. Leucovorin should definitely be considered and applied in rescue therapy for ld-MTX-associated side effects.