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The effect of long-term sulfasalazine therapy on type II collagen-induced arthritis in rats.

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45 1
LETTERS
The early use of disease-modifying antirheumatic
drugs in rheumatoid arthritis
To the Editor:
At the recent annual meeting of the American College of Rheumatology, I attended the combined meeting of
the antirheumatic therapy and epidemiologyhealth services
research study groups. It was a provocative and stimulating
meeting in which all but 1 panelist presented data suggesting
that early rheumatoid arthritis (RA) should be vigorously treated with disease-modifying antirheumatic drugs
(DMARDs), rather than with nonsteroidal antiinflammatory
drugs (NSAIDs) alone. I am concerned about “turning the
pyramid upside down.”
The panel presented evidence showing that NSAIDs
are more toxic than previously thought and, in some instances, cause significant gastrointestinal bleeding. However, evidence was also presented suggesting that DMARDs
are not as effective in altering the long-term (i.e., >10 years)
loss of functional capacity as previously believed. No data
were presented indicating that RA patients treated with
DMARDs early in the course of the disease are better off 10
years later than are patients treated with the present conventional therapy. In my opinion, the proposal to prescribe
DMARDs early in the course of RA is a reasonable but
unproven hypothesis that should be vigorously tested.
In the 1950s, when I received my medical training,
general internists treated cancer patients who needed chemotherapy. We felt comfortable using drugs such as nitrogen
mustard, and we did not refer such patients to subspecialists.
During the last 10-15 years, however, I have promptly
referred such patients to an oncologist because I am not
familiar with the current multiple drug regimens in use. In
my experience, only rheumatologists prescribe and feel
comfortable administering parenteral gold, methotrexate, or
immunosuppressive drugs to RA patients. If the early use of
DMARDs becomes the standard of care for RA patients,
such patients would then be referred to rheumatologists soon
after the diagnosis was made. Since the majority of patients
with early RA are not currently being treated by rheumatologists, one result of this change in therapy would be a large
increase in the number of RA patients being cared for by
rheumatologists. More patients and more laboratory monitoring for the effects of DMARDs also means more income
for rheumatologists.
I do not believe that any of the panel members
considered this possibility. Indeed, since the panel consisted
of individuals in full-time academic positions, or clinicians
with well-established practices who probably are already too
busy to treat more patients, their incomes would not change.
We all, however, are concerned about the number and
quality of young physicians entering rheumatology. We want
our fellows to do well both professionally and financially.
We might, therefore, have an unrecognized bias in favor of
early treatment of RA with what are presently “second-line”
drugs.
The possibility that practice patterns may change if
DMARDs are used to treat patients with early RA is no
reason not to take the proposal seriously. It is a reason,
however, to devise and perform appropriate scientific stud-
ies before an exciting, but unproven, proposal becomes
standard practice.
Because the panel was almost unanimous in their
suggestions and enthusiasm, I am concerned that many of
the physicians who were in the audience will begin to
prescribe DMARDs early in the course of RA, without
waiting for comprehensive studies to be performed to establish their long-term efficacy.
Edward S. Mongan, MD
Rancho Los Amigos Medical Center
Downey, CA
The effect of long-term sulfasalazine therapy on
type I1 collagen-induced arthritis in rats
To the Editor:
We read with interest the article by Bjork et a1 (l),
who reported a correlation between the serum hyaluronate
(HA) concentration and the severity of disease in 2 experimental models of arthritis in rats. They also noted that
sulfasalazine, 100 mg/kg given subcutaneously on weekdays,
did not modify the clinical course or the levels of serum HA
in adjuvant arthritic rats. Since the articular features of type
I1 collagen-induced arthritis (CIA) in rats resemble those of
adjuvant arthritis (2), we report our findings on extended
treatment with sulfasalazine in established CIA.
Sixty 12-week-old inbred, female Furth Wistar rats
(Iffa Credo, Lyon, France), weighing 155-185 gm, were
immunized with human native type I1 collagen, as previously
described (3). All animals that developed polyarthritis were
randomly assigned to 2 groups on day 28. The treatment
group (n = 18) was given sulfasalazine, 80 mg/kg (suspended
in 1% carboxymethylcellulose), and the control group (n =
17) received the vehicle only. Throughout the study, the
compounds were administered on weekdays, by gastric
intubation. Peripheral arthritis was evaluated blindly 3 times
weekly, using a clinical score with a maximum value of 12.
Radiographic examinations were performed on days 30, 60,
and 150. Each radiograph was graded 0-3 for the presence
and severity of the following parameters: 1) tibiotarsal and
tarsal joint space alterations of the uninjected hind paw, 2)
tarsal and calcaneal periostitis of the front paw, and 3)
lesions of the tail (spondylodiscitis).
Sulfasalazine displayed beneficial activity on peripheral arthritis, as judged by the clinical score. This effect was
delayed, being first detectable on day 56. The difference
between the 2 groups became significant (P < 0.05 by
chi-square test) on day 80. Moreover, spontaneous inflammatory relapses occurred later and were less frequent in the
treatment group than in the control group (days 12CL140
versus days 80-120, and 22% versus 53%, respectively).
Radiographic analysis indicated that sulfasalazine was effective in attenuating the development of joint space destruction without affecting periosteal reaction and aseptic spondylodiscitis. Finally, the drug appeared to be more effective on
the lesions related to synovitis than on those related to
ossifying processes (4).
In our experiment, sulfasalazine functioned as a
slow-acting antirheumatic drug (SAARD). In contrast to our
LETTERS
452
results, earlier studies (5-7) reported a lack of sensitivity of
CIA to SAARDs. However, those studies were conducted
over short-term treatment periods. For instance, Bjork et a1
(1) performed their experiment over 23 days. If they had
conducted their study for the length of time we did, it is
possible that sulfasalazine might have produced a similar
effect on adjuvant arthritis. The dosage regimens and routes
of administration that were used might also have contributed
to this discrepancy.
Furthermore, a beneficial effect of sulfasalazine on
active ankylosing spondylitis has been emphasized (8,9).
Since CIA bears some resemblance to the latter disease (4),
it is noteworthy that in our study, periosteal new bone
formation and caudal lesions failed to respond to this drug.
B. Bannwarth, MD
P. Gillet, MD
P. Fener, MD
P. Netter, MD
A. Gaucher, MD
Clinique Rhumatologique
URA CNRS 1288
Vandoeuvre, France
1. Bjork J, Kleinau S, Tengblad A, Smedeghd G: Elevated levels of
serum hyaluronate and correlation with disease activity in experimental models of arthritis. Arthritis Rheum 32:306-311,1989
2. Stuart JM, Myers LK, Townes AS, Kang AH: Effect of cyclophosphamide, hydrocortisone, and levamisole on collageninduced arthritis in rats. Arthritis Rheum 24:790-794, 1981
3. Gillet P, Bannwarth B, Netter P, Morel 0, Pere P, Gaucher A:
Experimental autoimmune spondylodiscitis associated with type
I1 collagen induced arthritis. J Rheumatol 14:856-857,1987
4. Gillet P, Bannwarth B, Charritre G, Leroux P, Fener P, Netter
P, Hartmann DJ, Pere P, Gaucher A: Studies on type I1 collagen
induced arthritis in rats: an experimental model of peripheral and
axial enthesopathy. J Rheumatol 16:721-728, 1989
5. McCune WJ, Trentham DE, David JR: Gold does not alter the
arthritic, humoral, or cellular responses in rats with type I1
collagen-induced arthritis. Arthritis Rheum 23:932-936, 1980
6. Sloboda AE, Birnbaum JE, Oronsky AL, Kerwar SS: Studies on
type I1 collagen-induced polyarthritis in rats: effect of antiinflarnmatory and antirheumatic agents. Arthritis Rheum 24:616-624,
1981
7. Jones SA, Kennedy AJ, Roberts NA: Assessment of drugs for
activity in established type I1 collagen arthritis. Agents Actions
12:650-655,1982
8. Dougados M, Boumier P, Amor B: Sulfasalazine in ankylosing
spondylitis: a double blind controlled study in 60 patients. Br
Med J 292:911-914, 1986
9. Nissila M, Lehtinen K, Leirisalo-Rep0 M, Luukkainen R, Mutru
0, Yli-Kerttula U: Sulfasalazine in the treatment of ankylosing
spondylitis: a twenty-six-week, placebo-controlled clinical trial.
Arthritis Rheum 31:1111-1116,1988
Reply
To the Editor:
The results referred to by Bannwarth et a1 on the
beneficial effects of sulfasalazine in the type I1 collageninduced arthritis (CIA) model are very interesting in that
they observed both a therapeutic and a remission-inducing
effect. Their approach toward doing long-term drug studies in
CIA will undoubtedly result in additional important findings.
In our study on the correlation between serum hyaluronic acid (HA) levels and arthritis severity (l), we treated 1
group of adjuvant arthritic rats with sulfasalazine, 100 mgkg
given on weekdays. No beneficial effect on either arthritis
scores or serum HA levels was seen over the 23-day experimental period. The possibility of a clinical effect with a longer
period of treatment is only a matter of speculation, but we
doubt that such an effect would occur since the inflammation in
the adjuvant arthritis model subsides within 35-40 days (2).
Although the articular features of adjuvant arthritis
and CIA are similar, it is important to bear in mind that they
are considered to be different models with distinct pathogenic mechanisms (3,4). So far, we have no experience with
studying the effect of sulfasalazine in the rat model of CIA,
but in the mouse model of CIA, a beneficial effect is seen
with sulfasalazine treatment early in the course of the
disease (5). This would seem to contradict the results of
Bannwarth et al, who saw an effect only at the late stage of
the disease. However, we believe this discrepancy reflects
the heterogeneity in CIA depending on the animal species
used, the source of type I1 collagen used for immunization,
and the strain of susceptible animal. Thus, the clinical
picture of CIA can vary considerably between different
strains of rats ( 6 ) , and an immunomodulatory drug has been
shown to have different effects on CIA in Lewis rats depending on the source of type I1 collagen (rat or bovine) used for
immunization (7).
Considering these differences together with differences in administration protocols, it is not surprising that
different drug effects are sometimes reported by researchers
in different laboratories. Still, the type I1 collagen-induced
arthritis model is currently one of the best models of
rheumatoid arthritis, and its use will undoubtedly serve to
further unravel the mechanisms behind autoimmune reactions and increase our knowledge of the action of diseasemodifying drugs such as sulfasalazine.
J. Bjork, PhD
G. Smedegkd, PhD
Pharmacia LEO Therapeutics AB
Uppsala, Sweden
1. Bjork J, Kleinau S, Tengblad A, Smedegird G: Elevated levels of
serum hyaluronate and correlation with disease activity in experimental models of arthritis. Arthritis Rheum 32:306-311, 1989
2. Van Arman CG: Pathway to adjuvant arthritis. Fed Proc 35:
2442-2446, 1976
3. Stuart JM, Townes AS, Kang AH: Collagen autoimmune arthritis. Annu Rev Immunol2:199-218, 1984
4. Cang YH, Iizuka Y: Adjuvant polyarthritis. V11. Differences in
immunopathogenisis between type 11 collagen arthritis and adjuvant arthritis. Agents Actions 15529-534, 1984
5. Holmdahl R, Klareskog L, Rubin K, Bjork J, Smedegird G,
Jonsson R, Anderson M: Role of T lymphocytes in murine
collagen induced arthritis. Agents Actions 19:295-305, 1986
6. Larsson P, Kleinau S, Holmdahl R, Klareskog L: Homologous
type I1 collagen-induced arthritis in rats: characterization of the
disease and demonstration of clinically distinct forms of arthritis
in two strains of rats after immunization with the same collagen
preparation. Arthritis Rheum (in press)
7. Kleinau S, Larsson P, Bjork J, Holmdahl R, Klareskog L:
Linomide, a new immunomodulatory drug, shows different ef-
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