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Rapid Responses to:
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Electronic letters published:
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif){kind=icon}
Excellent systematic reviews of clinical trials may not be useful for patient care
Oral Methotrexate Is The Way to Go In The Treatment Of RA
Comparative Effectiveness of Biologics to Methotrexate
The Uncertainty of Effective Treatment for RA May Lie with the Investigators
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Theodore Pincus, MD NYU Hospital for Joint Diseases, New York, NY, Yusuf Yazici, MD, NYU Hospital for Joint Diseases, New York, NY;Tuulikki Sokka, MD, PhD, Jyväskylä Central Hospital, Jyväskylä, and Medcare Oy, Äänekoski, Finland
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tedpincus{at}gmail.com Theodore Pincus, et al.
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A systematic review of disease-modifying anti-rheumatic drugs and biological agents for rheumatoid arthritis [(Ann Intern Med 148, 124-134 (2008)] concludes that methotrexate, leflunomide and sulfasalazine have equivalent efficacy to one another and to biological agents. The methodology is excellent, but this information may be misleading, ironically resulting from methodologic limitations of clinical trials and systematic reviews Although such limitations are acknowledged, “best evidence” remains sought virtually exclusively from primary outcomes of trials, ignoring observational and trial data that may be more informative. Methotrexate appears considerably more effective than leflunomide or sulfasalazine in clinical care, despite apparent similarities in clinical trials. A 1990 meta-analysis of 61 trials indicating indistinguishable efficacy for methotrexate gold and penicillamine (1). However, a 1992 report of 532 patients from 7 clinical settings indicated that methotrexate courses were continued by about 50% of patients after 5 years, in contrast to 20% for gold and penicillamine, explained in part by short time-frame, inflexible dosages, and patient selection in clinical trials (2). More recently, courses of methotrexate were continued by 80% of patients 5 years after initiation in one practice (3), suggesting that weekly low-dose methotrexate (in contrast to high-dose methotrexate for neoplasia) is one of the safest and most effective medications in clinical medicine. It is disheartening that observational data are ignored 15 years after specific limitations of clinical trial data and meta-analysis for treatment of rheumatoid arthritis were reported. An international database of about 6,000 patients in 20 countries indicates that methotrexate is taken by 86% of patients, sulfasalazine by 46%, leflunomide by 22%, any biologic agent by 24% (4). Clinical trial results are examined only for primary outcome endpoints, ignoring strong evidence that most efficacy of any agent in rheumatoid arthritis is achieved within 3-6 months of any treatment. This phenomenon is consistent with evidence from 4 clinical trials [FinRACO, TICORA, BeST, CAMERA [see reference(5)] that targeted intense monitoring with changes every 3 months toward low activity or remission appears more important in outcome than any specific agent. Yet the systematic review focuses almost exclusively on agents, rather than strategy. Donahue et al may properly argue their systematic review is directed to evaluation of agents rather than to patient care. However, the Annals of Internal Medicine, the official journal of the American College of Physicians (fewer than 5% of whom are rheumatologists) might also select reports beyond methodologically rigorous compendia toward better patient care. References: (1) Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two metaanalyses. Arthritis Rheum. 1990;33:1449-61. (2) Pincus T, Marcum SB, Callahan LF. Long-term drug therapy for rheumatoid arthritis in seven rheumatology private practices: II. Second -line drugs and prednisone. J Rheumatol. 1992;19:1885-94. (3) Yazici Y, Sokka T, Kautiainen H, Swearingen C, Kulman I, Pincus T. Long term safety of methotrexate in routine clinical care: discontinuation is unusual and rarely the result of laboratory abnormalities. Ann Rheum Dis. 2005;64:207-11. (4) Sokka T, Kautiainen H, Toloza S, Makinen H, Verstappen SMM, Hetland ML et al. QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries. Ann Rheum Dis. 2007;66:1491-96. (5) Verstappen SMM, Jacobs JWG, van der Veen MJ, Heurkens AHM, Schenk Y, Ter Borg EJ et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66:1443-49. Conflict of Interest:None declared |
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Daniel Arkfeld, MD USC Keck School fo Medicine
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arkfeld{at}usc.edu Daniel Arkfeld
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It is with interest that I read the rapid response article entitled "Comparative Effectiveness of Biologics to Methotrexate " by Anastassiadesnti et al. In this commentary,they focused on the use of injectable methotrexate implying that it is the preferential form for a RA comparison study. It is this that I beg to differ. Oral methotrexate is the preferred form of this DMARD by the vast majority of rheumatologists. The average weekly dose of Methotrexate is between 15 to 20mgs in most studies which is a very tolerable and effective dose. Injectable methotrexate is reserved for specific situations such as the following: 1. GI intolerance 2. To improve compliance if given in a clinic situation 3. At higher doses to improve efficacy and tolerability 4. Cost savings(injectable methotrexate can be less expensive) However, it is important to be cautious with the injectible forms due to the possibility of misdosing, the increased risk of dose relateed side effects,and the risk of miscarriage or birth defects for the clinic nurse who is administering the methotrexate should they get pregnant. In conclusion, oral methotrexate is the preferred form in most patients. I concur with Donahue et al in "Systematic Review: Comparative Effectiveness and Harms of Disease-Modifying Medications for Rheumatoid Arthritis" in their methodology. Oral methotrexate is tried and true and the agent of choice for clinical RA studies. Conflict of Interest:None declared |
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Tassos Anastassiades, MD, PhD, FRCPC Division of Rheumatology, Department of Medicine, Queen's University, Kingston ON, Tanveer Towheed MD, FRCPC, Henry Averns MB, ChB, FRCP, Mala Joneja MD, FRCPC, Isaac Dwosh MD, FRCPC
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anastass{at}post.queensu.ca Tassos Anastassiades, et al.
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In the clearly written Systematic Review of Comparative Effectiveness of Disease-Modifying Medications for Rheumatoid Arthritis, the authors review monotherapy vs monotherapy (including the biological vs the synthetic DMARDs), combination therapy vs monotherapy and combination therapy . In each of these group comparisons, methotrexate is included as a chief comparator drug, for outcomes such an ACR response (e.g. ACR 20), HAQ, SF-36 or a radiological erosion score. Although the authors do not specify the route(s) that methotrexate was administered in the trials reviewed, generally speaking, oral methotrexate has been used as the comparator preparation for the clinical trials involving the biological agents, which are, of course, parenterally administered. It has been known for a long time that parenterally (IM or SC) administered methotrexate is likely more effective than the orally administered compound (1). This difference has been primarily explained by the reduced bioavailability of the oral methotrexate. In one study, the mean bioavailability of oral methotrexate (median dose 30 mg weekly) was just 0.64 (statistically significant) compared to SC administration (2). It is not unusual to see patients with rheumatoid arthritis respond to SC methotrexate, when they failed to respond to oral dosing, and in some Centers SC administration is employed routinely. Splitting high oral doses improves the bioavailability but both the split and single dose had lower bioavailability compared to SC administration (3). In the recently published guidelines for methotrexate therapy for rheumatoid arthritis, a switch from oral to IM or SC is recommended for patients with poor compliance, inadequate effectiveness or gastrointestinal side effects (4). It stands to reason that a regulatory agency evaluating a SC- administered new drug (such as a biological), in comparison to an older “comparator” drug (such as methotrexate) would require that the same route of administration be used, if possible. Patently, the argument for comparing the SC-administered biologic to oral methotrexate is that the oral route is the most common method of administration. However, it can also be argued that if a SC-administered biological were to be compared to SC-administered methotrexate differences in outcomes such as ACR responses and erosion scores might be blunted and could prove to be clinically insignificant in many instances. Obviously, pharmaceutical sponsorship would be difficult to obtain for these types of studies. We feel that regulatory agencies should re-consider this issue and the limitations of using only oral methotrexate as the “comparator” for the biologics should be emphasized in critical reviews of this literature. References 1. Hamilton RA, Kremer JM. Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis. Br J Rheum. 1997;36:86-90. 2. Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Bioavailability of higher dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol. 2005;31:645-8. 3. Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, van de Laar M. Splitting high-dose oral methotrexate improves bioavailability: a pharmacokinetic study in patients with rheumatoid arthritis. J Rheumatol. 2006;33:481-5. 4. Pavy S, Constantin A, Pham T, Gossec L, Maillefert JF, Cantagrel A et al. Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine 2006;73:388-95. Conflict of Interest:None declared |
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Stephanie M Lacson, Rheumatology Fellow MD USC Keck School of Medicine, Daniel G. Arkfeld
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slacson{at}usc.edu Stephanie M Lacson, et al.
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We were very interested to read the article by Donahue et al, and appreciate the intention to examine the evidence regarding therapeutic options for rheumatoid arthritis. The authors conclude their review by stating that the current evidence is limited, with no one treatment regimen proven to be more effective. As Donahue et al. acknowledge, it is often difficult to apply findings from randomized controlled trials to practice in the community due to the selection bias. This was demonstrated by Kievit et al.(1) who examined the efficacy of anti-TNF agents between patients in randomized controlled trials and patients in the community, with patients showing greater achievement of ACR 20 than patients in clinical practice. At the end of the day, the clinician has to choose the best treatment option for each patient, and unfortunately we do not have enough evidence to make the choice obvious. We agree with the authors that we need more studies with greater applicability to the general population. Not only should we look at traditional DMARDs versus TNF agents, but other agents like rituximab and abatacept also merit further investigation. With the new emerging therapies, such as IL-6 blockade, there will be more uncertainty which will necessitate more well-designed clinical trials. 1. Kievit W et al. The efficacy of anti-TNF in rheumatoid arthritis, a comparison between randomized controlled trials and clinical practice. Annals of Rheumatic Diseases 2007; 66; 1473-1478. Conflict of Interest:None declared |
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