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Toxic response to topical fluorouracil in two rheumatoid arthritis patients receiving low-dose weekly methotrexate.

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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
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
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,
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,
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
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
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,
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.
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receiving, two, patients, dose, fluorouracil, low, weekly, toxic, topical, response, arthritis, methotrexate, rheumatoid
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