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Hypotension With Oliguriaa Side-Effect of Azathioprine.

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Looking at Figures 2 and 3 on page 540 of the
March 1981 issue, if the normal range for anti-ssDNA
antibodies would include at least one standard deviation above the mean were at 10 ng, ‘”I anti-Ig bound
to ssDNA, the percent positives with active SLE
would be 66% or greater. It would appear, therefore,
that antibodies to ssDNA are prevalent in connective
tissue diseases but occur in the highest concentrations
in active SLE.
The appropriate upper limits of normal for that
assay is not the same as for the anti-dsDNA assay.
Although others have presented a great deal of evidence that antibodies specific for the helical form of
dsDNA do exist, these are indeed rare and are almost
always accompanied by high titers of anti-ssDNA.
The ease and reproducibility of assays using ssDNA as
antigen appear to make it a better candidate for use in
clinical laboratories where there is great difficulty in
having reproducible assays for the detection of antibodies to dsDNA. The use of the Crithidia luciliae
titers which correlate with antibodies to dsDNA also
correlate with the titer of antibodies to ssDNA (2). It
seems reasonable to give attention to anti-ssDNA (3).
Professor of Medicine
UCLA School of Medicine
Los Angeles, CA 90024
1. Fish F, Ziff M: A sensitive sold phase microradioimmunoassay for anti-double stranded DNA antibodies. Arthritis Kheum 24:534-543, 1981
2. Chiang M, Chia D, Barnett EV: Evaluation of fluorescent antinuclear antibody assays, Crithidia luciliae and
anti-ss-DNA binding capacity in the diagnosis of four
rheumatic diseases. J Rheumatol
3. Barnett EV: Role of DNA structure in determining
sensitivity and specificity of anti-DNA antibody tests. J
Rheumatol 5:363-364, 1978
D-penicillamine: before, during, or after?
To the Editor:
Patients with rheumatoid arthritis have traditionally been directed to consume their oral medications with meals in order to minimize gastrointestinal
side effects. D-penicillamine (PCA), now an accepted
form of therapy for rheumatoid arthritis, may interact
with foods or their trace metal contents, resulting in
less than complete absorption of the active agent ( I ) .
Jaffe ( 2 ) recommends that PCA be given approximately 1 % hours after meals and 1 hour from other medications. How many patients taking penicillamine are
currently being instructed in this fashion?
While attending a recent seminar in which 70%
of the participants were rheumatologists, a questionnaire was distributed. Three questions were asked:
1. Do you use PCA in therapy of rheumatic disease?
2. If “yes,” do you instruct the patient to take PCA
with meals?
3. If “no” to question number 2, do you instruct the
patient to take PCA on an empty stomach?
Of 53 respondents, 11 (21%) instructed the patient to
take PCA with meals. Seventeen (32%) gave no instructions, while 25 (47%) instructed the patient according to Jaffe’s recommendations.
In light of the above information, the reader
may reconsider how many penicillamine “failures,”
particularly with the new lower dosage schedules now
in use, may be actually due to inactivation of PCA
prior to absorption of the concomitant ingestion of
foods which may be rich in trace metals such as iron,
copper, or zinc. There is little doubt that PCA-induced
cupruresis is strikingly inhibited with simultaneous
iron administration (3). Other agents such as vitamin C
interact in vitro with PCA and also should probably
not be administered simultaneously (4).
It is apparent from the above data that time
spent carefully counselling the patient regarding penicillamine administration is well worth the effort.
Germantown Hospital
Philadelphia, PA
1. Jaffe IA: Personal communication
2 . Jaffe 1A: D-penicillamine. Bull Rheum Dis 28:948-953,
3. Lyle WH, Pearcey DF, Hui M: Inhibition of penicillamine: induced cupruresis by oral iron. Proc R SOCMed
70:48-49, 1977
4. Jaffee IA: Personal communication
Hypotension with oliguria: a side-effect of
To the Editor:
Since its introduction in mid-1960, azathioprine has found wide use in a variety of rheumatic
conditions. Many of its side effects are well recognized
including myelosuppression, infection, and malignancy.
Hypersensitivity reactions to azathioprine have
also been recognized to include fever and rash. We
describe 2 patients who experienced profound hypo-
tension in association with fever and leukocytosis
when rechallenged with azathioprine.
Patient I. A 56-year-old man with severe psoriatic arthritis and spondylitis associated with debility
and weight loss was admitted to the Wellesley Hospital with an exacerbation of his spondylitis. Nonsteroidal antiinflammatory agents were without benefit, and
administration of prednisone was followed by a perforated ulcer. Methotrexate was started but was quickly
terminated because of an exacerbation of the skin
condition with each dose. Azathioprine (Imuran), 75
mglday, was initiated. After 7 days of therapy, the
patient experienced general malaise and shaking chills
and developed a fever of 393°C. A complete blood
count revealed a leukocytosis of 30,100 cells/mm3.
Azathioprine was stopped, samples of blood and urine
were drawn for cultures, and antibiotic therapy was
begun with tobramycin and cefamandole. Within 48
hours, the malaise subsided and the fever abated. The
total white blood cell count began to fall until it was
18,700 cells/mm3. All cultures were negative.
Because of persistent skin and joint disease, the
patient was rechallenged with azathioprine 50 mg/day .
After 2 doses, general malaise recurred and his blood
pressure fell from 120/80 to 60/40 mm Hg. His white
blood cell count again rose to 54,400 cells/mm'. The
patient became oliguric, and the serum creatinine rose
from 0.7 mg/dl to 2.8 mg/dl. Azathioprine was discontinued and intravenous fluids were administered. Over
a period of 48 hours, his blood pressure gradually
returned to normal, and renal function returned to
normal over several days after stopping the azathioprine.
Patient 2. A 62-year-old man with severe, longstanding rheumatoid arthritis that was unresponsive to
prednisone, gold, chloroquine, and penicillamine was
started on azathioprine (Irnuran) 75 mg/day as an
outpatient. After 8 days of therapy, fever up to 39.4"C
and leukocytosis developed, and the azathioprine was
stopped. Multiple blood and urine cultures proved to
be negative. The patient's symptoms gradually resolved over 7 days. A rechallenge with one dose of 75
mglazathioprine was undertaken, but within 12 hours,
the temperature rose to 38.5"C and hypotension of 721
48 and leukocytosis with a total count of 37,000 cells/
mm3 occurred. Oliguria ensued and the serum creatinine rose over 48 hours from 0.8 to 2.1 mg/dl. The
patient was treated with ancef, gentamicin, and intravenous steroids. Again, all cultures proved to be
negative. Over several days clinical and biochemical
improvement occurred.
Both patients described had severe inflamma-
tory arthritis relatively refractory to the usual disease
suppressants. Shortly after commencing azathioprine
therapy, both patients developed high fever and leukocytosis in the absence of proven sepsis. On rechallenge with azathioprine, both promptly redeveloped
fever, severe leukocytosis, profound hypotension, and
oliguria without evidence of sepsis. The episodes
resolved over several days with cessation of the drug.
We believe that the profound hypotension resulting in
oliguria represents a previously unreported side-effect
of azathioprine. In view of the seriousness of this
reaction, we recommend that patients who develop
fever and leukocytosis (in the absence of proven
sepsis) shortly after initiation of azathioprine not be
rechallenged with the drug.
Rheumatic Disease Unit
Suite 655-Turner Wing
160 Wellesley Street East
Toronto, Ontario M4Y 153
Condensing osteitis of the clavicle
To the Editor:
In 1974, Brower et a1 (1) reported two cases of
well-defined clinical, radiologic, and histologic features that described a new entity: condensing osteitis
of the clavicle. We have observed a patient with
similar clinical, radiologic, scintigraphic, and histologic features.
A 34-year-old housewife was seen who had
been knitting on an automatic machine for the past 10
years. Three years before admission, she developed
pains in the right supraclavicular area. The pain increased selectively with abduction of the arm. Four
months prior to examination, a deformity without
other inflammatory signs appeared in the right sternoclavicular joint.
The physical examination showed a thickened
internal third of the right clavicle, with selective pain
on flexion and abduction of the arm. The results of
routine laboratory tests were all normal. The chest
tomogram (Figure 1) showed thickening and sclerosis
of the internal third of the right clavicle without
involvement of the sternoclavicular joint. Pyrophosphate scintigraphy of the bone showed an increased
isotope uptake in the internal third of the right clavicle.
A biopsy of the clavicle, sternum, and synovial tissue
showed a nonspecific osteitis of the clavicle.
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effect, side, hypotension, oliguria, azathioprine
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