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Toxicity of combination therapies in rheumatoid arthritisComment on the article by Willkens et al.

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ARTHRITIS & RHEUMATISM
Vol. 39, No. 8, August 1996, pp 1435-1440
8 1996, American College of Rheumatology
1435
LETTERS
Joint and connective tissue ultrasonography in the
evaluation of shoulder pain: comment on the article
by Manger and Kalden
To the Editor:
Manger and Kalden’s article on joint and connective
tissue ultrasonography (USG) (1) is of great interest for both
the present and future practice of rheumatology. We were very
happy to read, for the first time, about the “rheumatologic”
applications of musculoskeletal USG in such a prestigious
journal, and do hope to see more articles like this one in the
near future.
Although Manger and Kalden intentionally left out
other uses of USG in clinical rheumatology, we wonder why a
very important and proven indication for the in-office use of
USG-the evaluation of shoulder pain-was not mentioned.
Shoulder pain is a common rheumatologic symptom (reported
by up to 25% of the elderly), yet much of its pathophysiology
is still unknown. However, it is known that the lesions are
frequently found in the surrounding soft tissues, namely, the
rotator cuff and bicipital tendon. For this reason, more than
90% of these patients have unremarkable results on shoulder
plain radiography.
USG has been proposed by many authors as a noninvasive, rapid, and inexpensive diagnostic method for screening
patients with shoulder pain (2-5). Disadvantages of the
method include its long learning curve, and that the results
depend on the explorer’s experience. USG can detect areas of
edema, tendonitis, partial tears, full thickness tears, bursitis,
and calcifications, as well as bicipital tenosynovitis and dislocation (3). The main technical pitfall of USG is the inability to
image the rotator cuff beneath the acromion. Fortunately,
rotator cuff tears are rarely isolated in this location, and passive
maneuvers often allow otherwise-hidden parts of the cuff to be
imaged (5).
When arthritis of the shoulder is the potential diagnosis, USG can easily discriminate between a simple effusion and
the presence of proliferative synovitis (3). In addition, USG
can help to guide the needle when difficult aspirations are
anticipated, and may even facilitate the performance of a
biopsy. Thus, when assessing a patient with a painful shoulder,
USG is a very useful tool for the rheumatologist to formulate
an accurate diagnosis and to establish a prompt therapeutic
approach.
In conclusion, we, as well as others, hope that USG will
soon become an everyday in-office working tool for the rheumatologist, as it already is for the cardiologist, gastroenterologist, gynecologist, and urologist.
Jacqueline Uson
Esperanza Naredo
Lucia Maryordomo
Prosalud International Clinic
Madrid, Spain
1. Manger B, Kalden J R Joint and connective tissue ultrasonography-a rheumatologic bedside procedure? A German experience.
Arthritis Rheum 38:736-742, 1995
2. Soble MG, Kaye AD, Guay RC: Rotator cuff tear: clinical experience with sonographic detection. Radiology 173:319-321, 1989
3. Van Holsbeeck M, Introcaso J H Musculoskeletal Ultrasound. St.
Louis, Mosby Year Book, 1991
4. Van Moppes FI, Veldkamp 0, Roorda J: Role of shoulder ultrasonography in the evaluation of the painful shoulder. Eur J Radio1
19:142-146, 1995
5. Middleton W, Reinus W, Melson GL, Totty WG, Murphy W A
Pitfalls of rotator cuff sonography. AJR Am J Roentgen01146:555560, 1986
To the Editor:
We fully agree with Dr. Uson and coworkers that
musculoskeletal USG is an extremely helpful diagnostic procedure in the hands of an experienced examiner. However,
USG in clinical rheumatology has been used more widely in
some European countries than in North America or in other
parts of the world. There are also variations in who is applying
this diagnostic procedure.
We have tried to argue that USG should be viewed as
an extension of the physical examination and be performed by
the same physician. Therefore, the main intent of our article
was to point out clinical situations in which USG has proven
helpful for a rheumatologist, rather than going over wellestablished indications such as shoulder pain. There is no
doubt that the shoulder is a domain of this technique, and that
ultrasound has almost completely replaced arthrography using
radiopaque contrast material. Rotator cuff tears, tenosynovitis,
and other soft tissue changes are easily detected by USG.
In contrast to Uson et al, however, we believe that
differentiation between older effusions and edematous pannus
tissue can be extremely difficult, and sometimes such alterations have to be described neutrally as “inflammatory process’’ (Backhaus M, Manger B: unpublished communication).
We concur with Uson et a1 in the hope that this discussion
leads to an increased awareness of this useful technology
among rheumatologists in the future.
Bernhard Manger, MD
Joachim R. Kalden, MD
Friedrich-Alexander-University Erlangen-Nuremberg
Erlangen, Germany
Toxicity of combination therapies in rheumatoid
arthritis: comment on the article by Willkens et a1
To the Editor:
Efficacy is rightly the primary outcome of interest in
combination studies of the treatment of rheumatoid arthritis;
however, the potential increased risk of adverse effects posed
by such combination therapy is also of considerable clinical
importance. Willkens and colleagues concluded that the combination of methotrexate (MTX) and azathioprine (AZA)is
not associated with more toxicity than is treatment with single
agents (Willkens RF, Sharp JT, Stablein D, Marks C, Wort-
1436
LETTERS
mann R: Comparison of azathioprine, methotrexate, and the
combination of the two in the treatment of rheumatoid arthritis: a forty-eight-week controlled clinical trial with radiologic
outcome assessment. Arthritis Rheum 38:1799-1806, 1995).
Unfortunately, they do not provide details of the statistical
analysis on which this conclusion was based.
They report 83 adverse events in 38 patients receiving
combination therapy, compared with 37 events (21 patients)
and 40 events (26 patients) in the AZA and MTX groups,
respectively. The majority of the serious adverse events (11 of
18) occurred in the group receiving combination therapy.
Similarly, therapeutic intervention was required for 33 adverse
events occurring in the combination therapy group, compared
with 18 and 14 such events in the AZA and MTX groups,
respectively.
It would be useful if the authors could provide details
of the analysis which led them to conclude that the combination of MTX and AZA was not associated with more toxicity
than the individual agents.
C. Michael Stein, MB ChB, MRCP (UK)
Vanderbilt University School of Medicine
Nashville, TN
Results of controlled study of combination therapy
with azathioprine and methotrexate in the treatment
of rheumatoid arthritis revisited comment on the
article by Willkens et a1
To the Editor:
Willkens and his co-authors are to be congratulated on
their multiclinic controlled study comparing M A , MTX, and
a combination of the 2 in the treatment of rheumatoid arthritis
(1,2). The authors chose the most conservative interpretation
of their results, which seems appropriate since one should
always attempt to disprove the hypothesis. The hypothesis in
their trial is that 2 remittive agents are more effective than 1.
However, unless their data are carefully scrutinized, the casual
reader (most of us) will gain the mistaken impression that
there is no value in using MTX and AZA together.
First, the combination was tested against AZA and
MTX often given in lager doses. At week 18, 14% of the
patients receiving the combination were escalated to sham
dosage level 111, while more than one-third of patients receiving AZA or MTX received real dosage increases. The authors
stated that few patients receiving combination therapy (- 14%)
had disease that was active enough to earn promotion to level
111, suggesting that combination therapy was clearly better than
either drug used alone.
Even with these larger doses, twice as many patients
receiving MTX were “crossed over” at week 24 (10, compared
with 5 patients receiving the combination).
Second, every mean point for 48 weeks in all 4 primary
response variables used to assess treatment results (number of
tender joints, number of swollen joints, patient and physician
global assessments) were in favor of combination therapy
(Figure 2 in ref. 2). The P value here must approach infinity!
How much better would the results have been if a more
realistic combination dosage schedule had been used?
Third, both MA-treated and combination-treated pa-
tients had a larger dropout rate, largely due to the gastrointestinal toxicity of M A . About 25% of patients with rheumatoid arthritis cannot stomach this drug. Intent-to-treat analysis,
while esthetically pleasing, heavily penalizes both of these
treatment groups.
Last, too few serial radiographs were available over too
short a time for any meaningful analysis.
The study by Willkens et a1 is commendable as far as it
goes. The authors have confirmed that the toxicity of the
combined regimen is reasonable (3). I can only agree “that
additional controlled trials with higher doses of these drugs”
(2) are needed.
Daniel J. McCarty, MD
Milwaukee, WZ
Willkens RF, Urowitz MB, Stablein DM, McKendry RJR Jr, Berger
RG, Box JH, Fiechtner JJ, Fudman EJ, Hudson NP, Marks CR,
Brooks R, Rooney TW, Rubin BR, Schmid FR, Segal AM, Thomas
JW, Goldstein AG, Yunus MB, Wortmann RL, Sherrer YRS:
Comparison of azathioprine, methotrexate, and the combination of
both in the treatment of rheumatoid arthritis: a controlled clinical
trial. Arthritis Rheum 35:849-856, 1992
Willkens RF, Sharp JT, Stablein DM, Marks C, Wortmann R
Comparison of azathioprine, methotrexate, and the combination of
the two in the treatment of rheumatoid arthritis: a forty-eight-week
controlled clinical trial with radiologic outcome assessment. Arthritis Rheum 38:1799-1806, 1995
McCarty DJ, Harman JG, Grassanovich JL, Qian C, Klein J P
Combination drug therapy of seropositive rheumatoid arthritis. J
Rheumatol22:1631-1635, 1995
Reply
To the Editor:
We refer Dr. Stein to an earlier manuscript in which
adverse experiences after the initial randomization are reported (Willkens RF, Urowitz MB, Stablein DM, McKendry
RJR Jr, Berger RG, Box JH, Feichtner JJ, Fudman EJ,
Hudson NP, Marks CR, Brooks R, Rooney TW, Rubin BR,
Schmid FR, Segal AM, Thomas JW, Goldstein AG, Yunus
MB, Wortmann RL, Sherrer YRS: Comparison of azathioprine, methotrexate, and the combination of both in the
treatment of rheumatoid arthritis: a controlled clinical trial.
Arthritis Rheum 35849-856, 1992). Table 1 summarizes
adverse experience results as described in the second 24-weektime period.
Thus, no difference is apparent in the overall frequency
Table 1. Summary of adverse events after week 24 of treatment with
azathioprine (AZA) and methotrexate (MTX), alone or in combination, in rheumatoid arthritis patients
h Y
Serious
Severe
No. (%) taking
combination
(n = 57)
No. (%) taking
AZA
(n = 39)
No. (%) taking
MTX
(n = 52)
P*
38 (67)
11 (19)
5 (9)
21 (54)
4 (10)
6 (15)
26 (50)
3 (6)
2 (4)
0.19
0.09
0.29
* By chi-square with 2 degrees of freedom.
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