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