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Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A or methotrexateComment on the article by Pasero et al.

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LETTERS
79 1
Slow progression of joint damage in early rheumatoid
arthritis treated with cyclosporin A or methotrexate:
comment on the article by Pasero et a1
To the Editor:
I read with interest the article by Pasero et a1 on the
use of cyclosporin A to reduce the progression of joint damage
in early rheumatoid arthritis (RA) (1) and am concerned about
the implications this work may have with regard to RA
treatment; the conclusion a reader may reach is that in order to
prevent joint destruction, cyclosporin A should be chosen over
traditional disease-modifying antirheumatic drugs
(DMARDs). By design, this “control,” DMARD-treated
group in Pasero and coworkers’ study included patients who
received a number of different therapeutic regimens (antimalarial agents, oral gold, parenteral gold salts, sulfasalazine,
D-penicillamine, methotrexate [MTX]) which were used sequentially (oral gold/antimalarials followed, if unsuccessful, by
injectable gold/sulfasalazine followed, if unsuccessful, by
D-penicillamine followed, if unsuccessful, by MTX) and at the
dosages recommended by the manufacturers for the treatment
of RA.
I am not too surprised at the study results, considering
the fact that patients randomized to the control group were not
treated from the outset with a single “potent” DMARD at an
optimal dose (e.g., MTX escalated to 20 mdweek); in fact, in
a study of patients with established RA treated with either oral
gold, MTX, or the combination of the two, those patients
treated with either MTX alone or MTX and oral gold demonstrated a slower rate of disease progression than those treated
with oral gold only (2). Some other published studies have
yielded similar data while others have not; in a meta-analysis
our group conducted several years ago, MTX was shown to be
superior to parenteral gold salts (3), and it subsequently was
shown to be superior to oral gold as well (4).
It has been stated that if MTX is used earlier in the
disease process it may actually halt the progression of the
disease as demonstrated radiographically. O u r group has
recently had the opportunity to study a group of 24 RA
patients in whom MTX was used as the first DMARD;
preliminary analyses of the data suggest that disease progression is more likely to occur if erosions were already
present at the time of initiation of MTX treatment (69% of
patients versus 27%; P < 0.05).
The report by Pasero et a1 fails to provide a fair
comparison between MTX and cyclosporin A with regard to
efficacy in slowing or preventing disease progression in RA.
First, MTX was not used at the highest recommended dosage,
and second, it was only ured after (all) other (likely less potent)
DMARDs had failed. Neither of these considerations was
noted in the article.
Graciela S. Alarcon, MD, M P H
The University of Alabama at Birmingham
Pasero G, Priolo F, Marubini E, Fantini F, Ferraccioli G, Magaro
M, Marcolongo R, Oriente P, Pipitone V, Portioli I, Tirri G, Trotta
F, Della Casa-Alberighi 0: Slow progression of joint damage in
early rheumatoid arthritis treated with cyclosporin A. Arthritis
Rheum 39:1006-1015, 1996
Lopez-MCndez A, Daniel WW, Reading JC, Ward JR, Alarcon GS:
Radiographic assessment of disease progression in rheumatoid
arthritis patients enrolled in the Cooperative Systematic Studies of
the Rheumatic Diseases Program randomized clinical trial of
methotrexate, auranofin, or a combination of the two. Arthritis
Rheum 36:1364-1369, 1993
Alarcon GS, Lopez-Mendez A, Walter J, Boerbooms AMT, Russell
AS, Furst DE, Rau R, Drosos AA, Bartolucci AA: Radiographic
evidence of disease progression in methotrexate treated and nonmethotrexate disease modifying antirheumatic drug treated rheumatoid arthritis patients: a meta-analysis. J Rheumatol 19:18681873, 1992
Bannwarth B, Labat L, Moride Y, Schaeverbeke T: Methotrexate in
rheumatoid arthritis: an update. Drugs 47:25-SO, 1994
To the Editor:
In reply to Dr. Alarc6n’s letter, we would like to point
out that the intention of our article was not to argue that
cyclosporin A should necessarily be chosen over traditional
DMARDs for the prevention of joint destruction in early RA.
As we stressed in the Discussion section, our interest was in
obtaining data that would provide a better understanding of
the potential effects of cyclosporin A in controlling joint
damage over time in relation to survival with treatment, given
the known limitations of conventional antirheumatic treatments in this respect (1-3).
The feasibility of such a pragmatic study (4) was clearly
influenced by the treatment practices followed by the investigators at the time the trial was planned. The study design
required the selection of one of the DMARDs available at the
time, as initial control treatment. When the Italian Rheumatologist Study Group on Rheumatoid Arthritis (Gruppo Reumatologi Italiani Studio Artrite Reumatoide [GRISAR]) study
began, MTX was not widely used in early R A by rheumatologists in Europe (5,6); furthermore, it was not available for the
treatment of R A in Italy.
Moreover, when the trial was started, there was no
evidence that MTX might delay radiologic progression any
more than the other DMARDs: Nordstrom et a1 (7) had not
found any decrease in radiologic progression during MTX
treatment compared with the period prior to MTX treatment.
It was not until later that Jeurissen et a1 (8) showed some
evidence that MTX led to decreased radiologic progression
compared with azathioprine, a finding that was subsequently
substantiated in 1993 (9,lO). Therefore, our inclusion of MTX
as just one further DMARD was totally consistent with the
clinical practice of the time, as was the sequence of drugs used
in the control group (and here we would like to point that we
did state that MTX was used after the other DMARDs).
We certainly do not question the role and value of
MTX in RA, although we would like to clarify some points.
The studies published to date comparing radiologic effects of
MTX versus other DMARDs (3,s)have not necessarily used
the most efficacious reference drug of the time as the comparison treatment, since all published studies have shown that no
effect on joint damage can be expected from auranofin,
D-penicillamine, antimalarial agents, or azathioprine (6) yet
these drugs continue to be used for comparison. Furthermore,
it has also been shown that the effects of MTX are the same as
those of parenteral gold (11). In o u r study, even when the 61
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progressive, articles, joint, arthritis, damage, methotrexatecomment, cyclosporin, slow, treated, early, rheumatoid, pasero
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