Toxic response to topical fluorouracil in two rheumatoid arthritis patients receiving low-dose weekly methotrexate.код для вставкиСкачать
LETTERS mented skin rash covered 80% of her body and scalp. The ANA had become positive with a titer of 1:32, and the antiSS-A was again positive. A skin biopsy specimen obtained on October 24, 1985 for immunofluorescence studies revealed moderate numbers of cytoid bodies in the papillary dermis, which stained for IgG and IgM. Heavy fibrinogen was seen in a thready pattern along the basement membrane zone. The immunofluorescent changes were consistent with SLE. The hematologic abnormalities and lymphadenopathy responded to 1 week of high-dose p a r e n t e d steroids, but the hypopigmentation persisted. The presence of SS-A antibody may be the single most important serologic contraindication to PUVA therapy, in patients with or without a history of SLE. The antibody has been reported in as many as 50% of SLE patients and 60% of “ANA negative” SLE patients (2). SS-A correlates significantly with unclassified connective tissue disease (3), with SLE photosensitivity, and with SCLE ( 4 3 . SCLE is a clinical syndrome characterized by annular a n d o r psoriasiform skin lesions, frequent photosensitivity (4), and variable degrees of SLE involvement. Patients with SCLE manifest the most severe reactions to PUVA therapy. FANA testing, if done using certain human cell lines as substrates, may effectively screen for SS-A antibody (usually present in these patients), but specific identification, as with double diffusion in agar, must follow. FANA testing with mouse kidney or liver as substrate will not detect this antibody. However, since only 1 in 1,OOO hospitalized patients without apparent rheumatic disease were found to have the SS-A antibody (6), specific screening for SS-A antibody may not be indicated in FANA negative patients in the absence of apparent rheumatic disease. In our patient and in the patient of Dowdy et al, PUVA appears to have exacerbated serologic and/or other clinical features of underlying SLE, in addition to triggering the skin lesions of SCLE. The patient reported by Dowdy et al developed hypocomplementemia and antibodies to double-stranded DNA; our patient, with preexisting inflammatory polyarthritis and leukopenia, developed lymphadenopathy and thrombocytopenia after PUVA therapy. She had previously developed thrombocytopenia during the administration of ultraviolet B light. As reviewed by Dowdy et al ( I ) , there are reports describing PUVA-induced positive FANA, creating concern that PUVA may be capable of producing SLE. In none of these reports, however, did patients develop clinical signs of SLE. Our patient did become FANA positive following PUVA therapy, but she already had SS-A antibodies, as well as clinical signs of an unclassified connective tissue disease. Interestingly, in animals with lupus, ultraviolet A light (without psoralens) actually diminishes the disease activity; long-term low-dose irradiation improved immune function and prolonged life in the SS-A-negative (New Zealand black x New Zealand white)F, mouse model of lupus (7). The findings in our patient, in conjunction with the report by Dowdy et a1 and other reports in the literature, support the following recommendations. First, the presence of SS-A antibodies is a contraindication to PUVA therapy. Second, a negative FANA result on mouse or rat kidney substrate does not exclude the presence of SS-A antibody, and in patients with clinical signs or symptoms of connective tissue disease, it should be followed up with specific SS-A 303 antibody testing. Conversely, a positive FANA result on any substrate does not establish the presence of SS-A antibody, but is an indication for SS-A antibody testing prior to PUVA therapy. Third, although PUVA therapy can unmask SLE, there is no substantive evidence to indicate that it causes it. Fourth, because the rashes of psoriasis and SCLE cannot always be distinguished in the acute phase (S), photosensitivity in any patient with psoriasis may be reason to test for the presence of SS-A antibodies. Hugh McGrath, Jr., MD Eve Scopelitis, MD Lee T. Nesbitt, Jr., MD Louisiana State University School of Medicine New Orleans, LA 1. Dowdy MJ, Nigra TP, Barth WF: Subacute cutaneous lupus 2. 3. 4. 5. 6. 7. 8. erythematosus during PUVA therapy for psoriasis: case report and review of the literature. Arthritis Rheum 32:343-346, 1989 Maddison PJ, Provost ‘IT, Reichlin M: Serological findings in patients with “ANA negative” systemic lupus erythematosus. Medicine (Baltimore) 60:87-94, 1981 Scopelitis E, Perez M, Biundo JJ: Anti-SSA (Ro) antibody: a connective tissue disease marker. J Rheumatol 12:1105-1 108, 1985 Sontheimer RD, Maddison PJ, Reichlin M, Jordon RE, Stastny P, Gilliam JN: Serologic and HLA associations in subacute cutaneous lupus erythematosus, a clinical subset of lupus erythematosus. Ann Intern Med 97:664-671, 1982 Mond CB, Peterson MGE, Rothfield NF: Correlation of anti-Ro antibody with photosensitivity rash in systemic lupus erythematows patients. Arthritis Rheum 32:202-204, 1989 Maddison P, Mogavero H, Provost TT: The clinical significance of autoantibodies to a soluble cytoplasmic antigen in systemic lupus erythematosus and other connective tissue diseases. J Rheumatol6:18%195, 1979 McGrath H Jr, Bak E, Michalski JP: Ultraviolet-A light prolongs survival and improves immune function in (New Zealand black x New Zealand white)F, hybrid mice. Arthritis Rheum 30557-561, 1987 Mills JL, McDuffie FC, Muller SA, Jordon RE: Development of photosensitivity and an SLE-like syndrome in a patient with psoriasis. Arch Dermatol 114:1177-1181, 1978 Toxic response to topical fluorouracil in two rheumatoid arthritis patients receiving low-dose, weekly methotrexate To the Editor: Methotrexate (MTX) is a commonly accepted treatment of rheumatoid arthritis (RA). The major factor limiting its use is the development of toxicity (1-3). We wish to report a toxic response that resulted from the use of topical fluorouracil in 2 patients with RA who had been receiving low-dose, weekly MTX. The first patient, a 72-year-old man with an 8-year history of seropositive rheumatoid arthritis, had been treated with oral, weekly MTX (7.5 mglweek) for 6 months. Treatment was begun with 2% fluorouracil cream topically, twice daily, for actinic keratosis. Within 3 days, he noted erythema, blister formation, and necrosis. Use of the cream LETTERS 304 was stopped, but MTX was continued and over the next 3 weeks, the lesion healed with only mild residual scarring. The second patient, a 51-year-old man with a 3-year history of RA, had been treated with MTX at a dosage of 12.5 mglweek for 14 months when he was referred for treatment of actinic keratosis. Treatment was also begun with 2% fluorouracil cream topically, twice daily. Within 48 hours, he noted extreme erythema, prompting his discontinuation of the use of the cream. Nevertheless, the erythema progressed to ulceration and necrosis. The lesions eventually healed over the next 2 weeks. Fluorouracil is frequently used as a topical treatment of a number of premalignant and malignant cutaneous conditions. Its primary mechanism of action appears to be secondary to inhibition of the methylation reaction catalyzed by thymidylate synthetase, which transfers a methyl group from N', N '"methylene tetrahydrofolic acid to deoxyuridylic acid (4). MTX, by interfering with the activity of dihydrofolate reductase (9, also interferes with the synthesis of pyrimidines. This may explain the observed synergistic toxicity. Based on these findings, it would appear that caution is required when these 2 drugs are used simultaneously in the treatment of RA patients. Warren D. Blackburn, Jr., MD Graciela S. Alarcon, MD, MPH The University of Alabama at Birmingham Birmingham, AL 1. Tugwell P, Bennett K , Gent M: Methotrexate in rheumatoid 2. 3. 4. 5. arthritis: indications, contraindications, efficacy, and safety. Ann Intern Med 107:358-366, 1987 Guyton-Gispen J , Alarcon GS, Johnson J , Acton R, Barger B , Koopman W: Toxicity to methotrexate in rheumatoid arthritis. J Rheumatol 14:74-77, 1987 Alarc6n GS, Tracy IC, Blackburn W D Jr: Methotrexate in rheumatoid arthritis: toxic effects as the major factor in limiting long-term treatment. Arthritis Rheum 32:671476, 1989 Reyes P, Heidelberger C: Fluorinated pyrimidines. Mol Pharmacol 1:14-30, 1969 Johns DG, Bertino JR: Folate antagonists, Cancer Medicine. Edited by JF Holland, E Frei 111. Philadelphia, Lea & Febiger, 1973 New Manuscripts to be Sent to Dr. Peter H. Schur as of April 1 Dr. Peter H. Schur will officially assume the full responsibilities of Editor, Arthritis and Rheumatism, on July 1, 1990. However, as part of the transition from the Editorship of Dr. William J. Koopman, Dr. Schur will handle the review process for all new manuscripts submitted on or after April 1, 1990. Any manuscripts submitted on or after this date should be sent to Peter H. Schur, MD, Editor, Arthritis and Rheumatism, Arthritis and Rheumatism Editorial Office, Richardson Fuller Building, 221 Longwood Avenue, Boston, MA 02115.