LETTERS 1447

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Haldane JBS: The estimation and significance of the logarithm of ratio of frequencies. Ann Hum Genet 20:309-311, 1955 Medsger TA, Dawson WN, Masi AT: The epidemiology of polymyositis. Am J Med 48:715-723, 1970 Garlepp MJ, Dawkins RL, McDonald B, Black KA: Polymyosi- tis, lmmunogenetics in Rheumatology. Edited by RL Dawkins, FT Christiansen, PJ Zilko. Amsterdam, Excerpta Medica. 1982 Mehra NK, Taneja V, Kailash S, Raizada N, Vaidya MC: Distribution of HLA antigens in a sample of the North Indian Hindu population. Tissue Antigens 2754-74, 1986 Panayi GS, Wooley P, Batchelor JR: Genetic basis of rheumatoid disease: HLA antigens, disease manifestations and toxic reac- tions to drugs. Br Med J 2:13261328, 1978 Hirsch TJ, Enlow RW, Bias WB, Arnett FC: HLA D related (DR) antigens in various kinds of myositis. Hum Immunol 31181-186. 1981

Comment on the article by Morgan et al

To the Editor: My experience with the effect of folic acid supple-

mentation on the toxicity of low-dose methotrexate (MTX) in patients with rheumatoid arthritis was different from that noted by Morgan et a1 (Morgan SL, Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, Alarcon GS: The effect of folk acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33:9-18, 1990).

Approximately 1 year ago, I noted that inclusion of folic acid supplementation in the treatment regimen of my patients receiving low-dose MTX did in fact reduce the toxicity of MTX; however, in virtually every case, the efficacy of MTX was diminished significantly. In patients whose disease was in remission while they were taking low-dose MTX, a disease flare usually began within 2-3 weeks after the initiation of folic acid therapy. The flare subsided approximately 3-6 weeks after withdrawal of the folic acid therapy, without alteration of the MTX dosage.

The average oral or intramuscular dosage of MTX was 5-12 mg administered weekly, and the dosage of folic acid vaned from 4 mg to 8 mg per week, given as either a I-mg daily dose or as a single total dose each week. The dosage schedule of the folic acid did not seem to alter the diminished efficacy of the MTX.

The patients who were treated with folic acid did in fact notice less toxicity in terms of reduced hair loss, mouth ulcers, and gastrointestinal manifestations. However, there was a significant increase in rheumatoid arthritis symptoms and objective measurements; specifically, there was an increase in the erythrocyte sedimentation rate, a significant increase in synovial thickening of the involved joints, and a marked increase in joint pain and morning stiffness.

Initially, I thought it might be appropriate to treat every patient receiving low-dose MTX with folic acid in order to avoid MTX side effects; however, at this time, I am reserving the use of folic acid only for those patients who have significant toxicity to MTX, and I am holding the dosage level to the smallest amount possible in order not to diminish the effect of MTX.

Alfred Miller, MD Oak Hills Medical Building San Antonio, TX

Reply To the Editor:

The deterioration in clinical efficacy of methotrexate (MTX) therapy with folic acid supplementation has not been observed by us ( I ) , and our experience is the same as that of Wilke and Krall(2). In his letter, Dr. Miller does not specify the number of patients in his study or mention other factors such as alterations in prednisone or nonsteroidal anti- inflammatory drug dosage, which might also affect disease activity. The patients in our study continued to take usual dosages of aspirin and/or nonsteroidal antiinflammatory drugs and/or prednisone (5 10 mglday). Moreover, Miller’s evaluation of his patients’ disease activity seems to have been subjective and not systematic. Our experience in the use of folic acid supplementation in our MTX-treated pa- tients since the published trial ( I ) seems to be similar to our study results. We have not observed worsening of disease activity in folate-supplemented, MTX-treated, rheumatoid arthritis patients.

An important factor in this combination therapy is undoubtedly the ratio of the folate to MTX, as well as the vitamin form selected for folic acid supplementation. The patients in our trial were asked to discontinue the concom- itant use of folate-containing vitamins. Such vitamin use could have raised total folate intake. The trials of concomi- tant folinic acid and MTX administration (3-5) have shown a definite trend toward a lack of efficacy and diminished toxicity with larger doses of folinic acid (i.e., folinic acid: MTX ratios greater than 1: 1). It is likely that such a critical optimal ratio also exists for folic acid/MTX therapy, even though folic acid in its fully oxidized form cannot readily bypass the inhibition of dihydrofolate reductase by MTX and serve as a cofactor in I-carbon-transfer reactions.

Finally, the administration of folic acid in a single dose on the day of MTX administration could potentially interfere with the absorption of MTX. The optimum dosing interval for combination therapy has not been determined. The challenge of such combination therapy will be to identify biochemical measurements that can quantify and monitor the optimal state of folate supplementation, while allowing enough folate antagonism for efficacy.

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Sarah L. Morgan, MD, MS, RD, FACP The University of Alabama at Birmingham Birmingham, A L

Morgan SL. Baggott JE, Vaughn WH, Young PK, Austin JV, Krumdieck CL, Alarc6n GS: The effect of folk acid supplemen- tation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 339-18, 1990 Wilke WS, Krall PL: Resistant rheumatoid arthritis: what to do when conservative therapy doesn’t work. Postgrad Med 75:69- 77. 1984 Tishler M, Caspi D, Fishel B, Yaron M: The effects of leucovorin (folinic acid) on methotrexate therapy in rheumatoid arthritis patients. Arthritis Rheum 3 1:906-908, 1988 Hanrahan PS, Russell AS: Concurrent use of folinic acid and methotrexate in rheumatoid arthritis. J Rheumatol IS: 1078-1080, 1988 Buckley LM, Cooper SM, Vacek PM: The use of leucovorin after low-dose methotrexate in patients with rheumatoid arthritis (abstract). Arthritis Rheum 31 (suppl I):R3, 1988