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Transient fall in serum salicylate levels following intraarticular injection of steroid in patients with rheumatoid arthritis.

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345
-
BRIEF REPORT
TRANSIENT FALL IN SERUM SALICYLATE LEVELS FOLLOWING
INTRAARTICULAR INJECTION OF STEROID IN PATIENTS WITH
RHEUMATOID ARTHRITIS
PHILIP A. BAER, ABRAHAM SHORE, and ROBERT L. IKEMAN
Our study of 13 hospitalized patients with rheumatoid arthritis examined the effect of intraarticular
injection of steroid on serum salicylate levels. A mean decrease in serum salicylate levels of 42 f 14.5% was observed in 12 patients within 12-36 hours post-injection (P < 0.005). This interaction, though transient,
may be very significant clinically. It may lead to erroneous conclusions concerning patient compliance, unwarranted increases in salicylate dosage and resultant toxicity, and delay of appropriate therapeutic maneuvers.
Acetylsalicylic acid (ASA) traditionally has
been employed as the antiinflammatory agent of first
choice in patients with rheumatoid arthritis (RA).
Significant advantages of ASA therapy, compared
with other nonsteroidal antiinflammatory drugs, are
the ready availability of serum salicylate measurements in the clinical setting, accurate dose titration,
and the detection of interactions between salicylates
and other drugs.
Recently, we witnessed frequent, unexplained
-
From the Rheumatic Disease Unit, Wellesley Hospital and
the Division of General Pediatrics, The Hospital for Sick Children,
University of Toronto, Ontario, Canada.
Philip A. Baer, MD, FRCP(C): Chief Rheumatology Fellow, Rheumatic Disease Program, Wellesley Hospital, University of
Toronto, and Fellow, Canadian Arthritis Society; Abraham Shore,
MD, FRCP(C): Assistant Professor of Pediatrics and Medicine,
University of Toronto, and Associate, Canadian Arthritis Society;
Robert L. Ikeman, MD, FRCP(C): Rheumatology Fellow, Rheumatic Disease Program, University of Toronto, and Fellow, Canadian Arthritis Society.
Address reprint requests to Abraham Shore, MD, Box 151,
Research Institute, The Hospital for Sick Children, 555 University
Avenue, Toronto, Ontario, Canada MSG 1x8.
Submitted for publication April 24, 1986; accepted in revised form August 12, 1986.
Arthritis and Rheumatism, Vol. 30, No. 3 (March 1987)
fluctuations in serum salicylate levels in patients with
RA who were admitted to our Rheumatic Disease Unit
because of a disease flare. Such patients often receive
intraarticular injection of steroids (11s)as part of their
therapy. Because of the known interaction between
oral corticosteroids and salicylates (l), we undertook a
study of the effects of IIS on serum salicylate levels in
these patients.
Patients and methods. Patients admitted to the
Rheumatic Disease Unit of Wellesley Hospital were
entered into this study if they had a diagnosis of
definite or classic RA (2), had been treated with a
constant dose of ASA for at least 6 weeks prior to
admission, had received 1 or more IIS to control active
synovitis, and gave informed consent to participate in
the study.
Patients enrolled in the study were maintained
on their admission dose of ASA, administered in 3
divided doses daily: 8 AM, 2 PM, and 8 PM. Other
medications, including oral prednisone, were continued without dosage modification. Patients always received IIS injections between 6 PM and 8 PM, and all
IIS injections were given within 2 weeks of hospital
admission. Blood was drawn for serum salicylate level
measurement immediately prior to IIS and at 24-hour
intervals after IIS, starting 12 hours post-IIS. Post-IIS
serum samples were always drawn in the morning,
immediately preceding the 8 AM dose of ASA. Serum
salicylate levels were determined by the method of
Trinder (3). In our laboratory, this method is accurate
to within *3% for salicylate levels in the range of
600-2,000 pmolesfliter. Statistical analysis was carried
out using the Wilcoxon rank sum test.
Results. Twelve adults (8 women, 4 men) with
RA and 1 child (female) with seropositive juvenile RA
346
BRIEF REPORTS
Table 1. Effects of intraarticular injection of steroid (11s) on serum salicylate levels in 13 patients
Salicylate level (pmoleslliter)
Patient*
1
2
3
4A
4B
5
6
7
8
9
10
11
12
13
Agelsex
Prednisone
(mglday)t
Pre-IIS
5O/F
33lF
711M
5.0
-
1,914
1,900
1,540
551F
551F
-
1.640
2.5
5.0
5.0
10.0
-
1,420
980
1,420
1,240
1,540
1,420
1,850
1,500
1,105
1,580
57lM
631M
711M
301F
471F
731M
571F
601F
121F
Post-11s
(12
hours)
Post-11s
(36
hours)$
Post-11s
750
750
1,536
1,650
980
750
900
1,395
1,000
1,040
1,420
860
475
1,010
1,290
1,607
1,571
1,280
520
1,210
980
1,425
1,790
1,750
1,OOo
1,360
ND
1,760
1,460
ND
1,125
1,400
750
900
1,280
1,280
ND
1,540
2,170
ND
1,285
ND
(60
hours)$
* Patient 4 received 2 separate courses of IIS, 1 week apart.
t - = no prednisone.
$
ND
=
not done.
were entered in this study. The mean age was 52 years,
(range 12-73). The mean ASA dose was 3.925 gm/day
(range 1.625-5.2). Five patients were receiving a stable, long-term, daily dose of oral prednisone. The
mean oral prednisone dose for these 5 patients was
5.5 mg/day (range 2.5-10). The mean 11s dose given to
the 13 patients was 130 mg of methylprednisolone
acetate (range 60-240), injected into 1 or more joints
simultaneously. One patient had 2 courses of 11s given
1 week apart.
In 12 of the 13 patients, and in 13 of 14 11s
courses, a marked fall in serum salicylate levels was
observed at some point (Table 1). The mean maximum
decrease from pre-IIS levels was 42 2 14.5% (range
22-63). The nadir occurred at 12 hours post-IIS in 9
patients, at 36 hours post-IIS in 3 patients, and as late
as 108 hours post-IIS in 1 patient (results not shown).
By 12 hours post-IIS, the mean serum salicylate level
for all patients had fallen 31% from baseline levels
(1,504 ? 277 pmolesfliter pre-11s versus 1,037 ? 342
pmoles/liter; P < 0.005). Of the 5 patients who were
taking oral steroids, 4 experienced a transient fall in
salicylate levels post-11s. The amount of decline in
serum salicylate levels following 11s was no different
in this group of 5 patients receiving oral prednisone
than that observed in the 8 patients not receiving
continuous, low-dose oral prednisone.
Five patients had at least 2 serial serum salicylate level measurements, at 12-hour intervals (before
the 8 AM and 8 PM doses), for 48-72 hours prior to
receiving 11s. Baseline variability in serum salicylate
levels in these patients was < 10% for each individual
(results not shown). The baseline values shown in
Table 1 for these 5 patients were always those obtained just prior to the 11s injection.
Patient 4, who received 2 separate courses of
IIS, had a decrease in serum salicylate levels on both
occasions which was maximal at 36 hours post-11s. In
this patient, the second series of 11s injections resulted
in a much lower serum salicylate level (520 versus
1,280 pmoles/liter at 36 hours post-11s).
Nine courses of 11s resulted in a fall of >30% in
serum salicylate levels within 36 hours. In 8 of these 9
courses, the serum salicylate levels returned to
baseline (pre-11s) levels within 60 hours following
injection.
Discussion. The ability of oral corticosteroids to
alter serum salicylate levels has been well documented. Klinenberg and Miller reported 4 cases in
which withdrawal of oral steroids caused a rise in
serum salicylate levels in patients receiving a steady
dose of salicylate preparations (1). In 3 patients,
salicylate levels were subtherapeutic, with ASA doses
as high as 7.2 gm/day, and rose into the therapeutic
range only after steroids were tapered or discontinued.
Clinical salicylate toxicity occurred in 1 patient when
prednisone was tapered, with a documented, marked
increase in serum salicylate levels. Similar results
were noted in 2 other studies ( 4 3 .
The mechanism of this interaction is uncertain.
347
BRIEF REPORTS
Steroids do increase the glomerular filtration rate
when they are given over a short course, and also
when they are administered on a long-term basis (6).
The short-term effects of intravenous steroids on
glomerular filtration persist for 24-36 hours (7). A
study by Klinenberg and Miller of renal salicylate
clearance in 5 patients revealed a mean increase of
26% in free salicylate clearance, following hydrocortisone administration in 4 of the subjects (1).
Systemic absorption of steroid following 11s
has previously been demonstrated in patients with RA
(8). Systemic effects included improvement in measures of global joint inflammation and blunted response to hypoglycemia. Suppression of plasma
cortisol levels persisted for 3 to 6 days after 11s
injection. These systemic effects were observed in
patients given a mean dose of 80 mg of methylprednisolone acetate, compared with the mean dose of 130
mg given in the present study.
Our findings indicate that intraarticular injections of steroid also cause transient depression of
serum salicylate levels in patients who receive constant doses of ASA. This effect was noted even in
patients already receiving oral steroids on a long-term
basis. In contrast, a subgroup of our patients whose
serum salicylate levels were determined serially, while
in the hospital And receiving a steady dose of ASA
prior to IIS, showed little baseline variability in serum
salicylate levels. Keystone et a1 have previously demonstrated that steady-state serum salicylate levels
show little hour-to-hour fluctuatiotl in hospitalized
patients with RA who were receiving enteric-coated
ASA, whether the ASA was administered in 2, 3, or 4
divided doses per day (9).
All of our serum samples were drawn at the
same time of day (8 AM), immediately prior to the
morning ASA dose. Thus, the post-IIS depression of
serum salicylate levels in our patients appears genuine, rather than a reflection of variant dosage intervals
or tablet strengths. The likely mechanism of this
interaction is accelerated renal clearance of salicylate,
as described in studies with oral steroids. Further
studies, including measurements of urine salicylate
levels and of glomerular filtration rate post-IIS, would
be required to confirm this mechanism.
The time from IIS injection to the nadir of
serum salicylate levels is most often 12-36 hours, after
which recovery begins. This corresponds to the duration of increased glomerular filtration rate after a single
dose of intravenous steroid (7). The short duration of
this 11s-mediated salicylate level depression is also
comparable with the duration of plasma cortisol suppression after 11s (8).
Unrecognized, the effect of IAS on serum
salicylate levels may lead to erroneous conclusions
concerning patient compliance, or to an unwarranted
increase in salicylate dosage. Most often, RA patients
receive 11s when their disease has flared. Usually, all
medications are reviewed at this time, and salicylate
level studies are ordered. Failure to appreciate the
interaction between 11s and serum salicylate may thus
lead to serious salicylate intoxication. Delays in appropriate alterations to a failed regimen of therapy
may also ensue, because clinicians are usually unwilling to initiate such changes unless salicylate levels are
first optimized.
REFERENCES
1. Klinenberg JR, Miller F: Effect of corticosteroids on
blood salicylate concentration. JAMA 194:131-134, 1965
2. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
1958 revision of diagnostic criteria for rheumatoid arthri-
tis. Bull Rheum Dis 9:175-176, 1958
3. Trinder P: Rapid determination of salicylate in biologic
fluids. Biochem J 57:301-303, 1954
4. Muirden KD, Barraclough DRE: Drug interactions in the
management of rheumatoid arthritis. Aust NZ J Med
(suppl) 6:14-17, 1976
5. Graham GG, Champion GD, Day RO, Paul1 PD: Patterns
of plasma concentrations and urinary excretion of salicylate in rheurfiatoid arthritis. Clin Pharmacol Ther 22:
410420, 1977
6. George CRP: Non-specific enhancement of glomerular
filtration by corticosteroids. Lancet II:72&729, 1974
7. Webel ML, Donadio JV, Woods JE, Maher FT: Effect of
a large dose of methylprednisolone on renal function. J
Lab Clin Med 80:765-771, 1972
8. Koehler BE, Urowitz MB, Killinger DW: The systemic
effects of intra-articular corticosteroid. J Rheumatol
1:117-125, 1974
9. Keystone EC, Paton TW, Littlejohn G, Verdeja A, Piper
S, Wright LA, Goldsmith CH: Steady-state plasma levels
of salicylate in patients with rheumatoid arthritis: effects
of dosing internal and tablet strength. Can Med Assoc J
1271282-286, 1982
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