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Tolmetin-induced thrombocytopenia.

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Preliminary criteria for remission in rheumatoid
To the Editor:
The report by the Subcommittee for Criteria of
Remission in Rheumatoid Arthritis of the American Rheumatism Association (Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 24: 1308-13 15,
1981) represents a significant effort which is to be highly
commended. I appreciate the sentiment of the physician who
commented from the floor at the ARA meeting in Boston
that no committee could tell him how to decide whether his
patient was in remission, but his comment seems to me to
have completely missed the point. Unless physicians A, B, C
. . . X can agree on what the term “remission” means, then
it is guaranteed that we will be miscommunicating more
often than not. In fact, a wide variation in concepts of
remission was noted by the subcommittee in their reference
to the “absolutists” and the “relativists.”
There are two important points to bring out. First,
the definition of remission will be of future significance only
if the criteria have operational validity. In their report of a
retrospective test on a sample of patients judged to be in
remission by informed observers, the committee demonstrated a reasonable consistency of collective judgment in
defining how individual physicians determine remission.
This is an important first step, but the more critical test will
be in applying the criteria in a prospective study to carefully
evaluate their ability to predict the long-term consequences
of abatement of the disease symptoms. Until this is accomplished, the actual validity of the criteria, either individually
or collectively, cannot be fully evaluated.
Second, I question whether “partial remission” is an
appropriate term. It would appear that the subcommittee has
proposed criteria that define remission and partial remission
in terms of levels of activity of the disease process. This
seems quite appropriate and, if proven to predict future
course accurately, would be extremely useful. However,
“partial remission” implies an assessment at a given date
that describes the patient’s disease status relative to a prior
observation. If patient X had had the disease for several
years, had improved spontaneously or as a consequence of
treatment, but had not gone into complete remission, this
patient would be referred to as being in “partial remission.”
However, patient Z, who recently had had onset of rheumatoid arthritis and had mild disease without progression,
would be properly described as a patient with recent onset of
arthritis who (still) has mildly active disease. It would be
inappropriate to describe patient Z as being in “partial
remission,” even though hidher level of disease activity
might be the same as for patient X.
Therefore, it seems more reasonable to propose that
in testing their operational effectiveness, the criteria should
Arthritis and Rheumatism, Vol. 25, No. 9 (September 1982)
be considered as defining levels of activity which can be
tested prospectively by patient followup to determine longterm outcome, both in assessing the natural history of the
disease and its modification by modern treatment.
John T. Sharp, MD
Director, Joe and Betty Alpert
Arthritis Cznter
Professor of Medicine
University of Colorado
School of Medicine
Denver, CO
Tolmetin-induced thrombocytopenia
To the Editor:
To1metin sodium is a nonsteroidal antiinflammatory
drug that has been approved for use in juvenile rheumatoid
arthritis (JRA). The Pediatric Rheumatology Collaborative
Study Group (1) compared tolmetin with aspirin. No serious
side effects occurred in either treatment group, although
abnormal liver function test results were associated with the
aspirin-treated group. Specifically, there were no episodes of
thrombocytopenia or significant bone marrow suppression in
the tolmetin-treated group. I report here an episode of
presumed tolmetin-induced thrombocytopenia in a young
girl with seronegative polyarticular JRA.
A 4-year-old white girl had a history of approximately 1 year of polyarticular swelling that involved her metatarsophalangeal, metacarpophalangeal, and distal interphalangeal joints, as well as her wrists, ankles, elbows, knees, and
shoulders. Her back and hips were not involved. Morning
stiffness decreased with activity, and her mother noted
decreased range of motion associated with swelling and pain
in multiple joints. Therapy had been limited to salicylates.
There was no history indicative of a more diffuse
connective tissue disease (rash, photosensitivity, Raynaud’s
phenomenon, spiking fevers, pleurisy, eye inflammation,
etc.). Physical examination results were indicative of active
synovitis in multiple joints. Results of all of the following
tests were normal or negative: slit-lamp examination, complete blood count (CBC), platelet count, antinuclear antibody (ANA), rheumatoid factor, and urinalysis. The highest
erythrocyte sedimentation rate was 27 mm/hour. Salicylate
levels were within therapeutic range while she was taking
aspirin. Aspirin therapy was changed to tolmetin therapy (15
mg/kg given as 100 mg tolmetin 3 times per day).
On a return visit approximately 4 weeks later, her
mother stated that the patient had improved dramatically
within 72 hours of the start of tolmetin treatment and had
become progressively more physically active during the
following weeks. A week before the next visit (after about 8
weeks of tolmetin therapy), bruises were noted on the legs,
arms, and back. The patient had continued taking the
medication and was feeling fine, with little, if any, joint pain
or stiffness. By examination, there was no lymphadenopathy
or organomegaly, but she had several ecchymoses on her
forearms, legs, and back, as well as active synovitis with a
little tenderness to palpation. CBC results included a normal
hemoglobin and white count, but a platelet count yielded
36,000 mm3 with only occasional large platelets on the
smear. Results of a repeat ANA were still negative; permission for a bone marrow examination was refused.
The tolmetin was stopped, and the patient was
observed. Within a few days, her platelet count had risen to
43,000 mm3, and no new ecchymoses formed. Two weeks
after tolmetin treatment was stopped, the platelet count was
207,000 mm3; it has remained normal. She has subsequently
started taking salicylates again, and there has been no
recurrence of the bruising; periodic platelet counts have
remained over 200,000 mm3.
Nonsteroidal antiinflammatory drugs have only rarely been associated with blood dyscrasias (2). On the package
insert for tolmetin “a few cases of granulocytopenia” are
listed under the adverse reactions section, but there is no
mention of thrombocytopenia. The dose of tolmetin that was
used for our patient was well within the dosage range
recommended by the manufacturer (3), but she developed
thrombocytopenia that only responded to discontinuation of
tolmetin therapy. Physicians should watch for this potential
complication of tolmetin when this drug is given to children.
Jack M. Lockhart, MD
Department of Medicine
Section of Rheumatology
Gundersen Clinic, Ltd
La Crosse, WI
Levinson JE, Baum J, Brewer E, Fink C, Hanson V ,
Schaller J: Comparison of tolmetin sodium and aspirin
for treatment of juvenile rheumatoid arthritis. J Pediatr
91:799-804, 1977
Paulus HE, Furst DE: Aspirin and non-steroidal antiinflammatory drugs, Arthritis and Allied Conditions.
Ninth edition. Edited by DJ McCarty. Philadelphia, Lea
& Febiger, 1979, pp 331-354
Physicians’ Desk Reference. 35th edition. Oradell, NJ,
Medical Economics Company, 1981, p 1120
Unconventional arthritis therapies
To the Editor:
Unfortunately, conventional drug therapy for osteoarthritis (OA), rheumatoid arthritis (RA), and ankylosing
spondylitis (AS) often fails to provide satisfactory relief to
patients. Frustrated by persistent symptoms and/or disease
progression, many desperate patients turn to unconventional
remedies (1). We have followed 6 patients during the past 5
years who traveled to certain clinics run by nonrheumatologists and returned with drugs given for their “RA.” Toxico-
Figure 1. Drugs dispensed to patients as (clockwise from upper
left): “indomethacin” (actually a steroid), “DMSO” (dipyrone),
“naproxam” (a steroid), and a “muscle relaxant” (diazepam).
logic analysis of these drugs revealed alarming results and
indicated unsuspected potential hazards for patients.
Patient I is a 49-year-old married, white man who
had 20 years of polyarthralgias for which aspirin was prescribed; there was no relief of his symptoms. In January
1978, wheelchair-bound with severe pain, he visited a clinic
in Mexicali, Mexico, where a diagnosis of “RA” allegedly
was made. He was given 10 yellow capsules (every 2 hours)
and 3 white and 1 green tablets (3 times a day) (Figure 1).
Functional capacity returned within 4 hours. We evaluated
the patient in February 1980. Results of physical examination, joint radiographs, erythrocyte sedimentation rate
(ESR), rheumatoid factor (RF), and fluorescent antinuclear
antibody tests were all negative or normal. Toxicologic
analysis of medications revealed that the yellow capsule
contained a steroid, the white tablet another steroid preparation, and the green tablet diazepam (Table 1 ) . The patient
was subsequently given prednisone (10 mg per day) and
diazepam (2 mg, 3 times per day) in an attempt to duplicate
therapy; the attempt, however, was unsuccessful.
Patient 2 is a 63-year-old married, white man, who
underwent fusion of his lumbosacral spine in 1963 and
complained of subsequent back pain. Because of persistent
pain and arthralgias he sought evaluation at a clinic in
Mexicali, Mexico. There he was given a green tablet said to
be “indomethacin 25 mg,” a white tablet said to be “diazepam,” and a yellow capsule “for nerves” (Figure I), the
combination of which resulted in a rapid resolution of joint
pain with weight gain. He requested evaluation by us in
November 1979 for complaints of vague arthralgias without
synovitis. He was slightly cushingoid, without synovitis, had
normal joint motion, and was thought to have osteoarthritis.
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induced, thrombocytopenic, tolmetin
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