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Editorial
Why Are Only 50% of Courses of Anti-Tumor Necrosis Factor Agents Continued for Only 2 Years in Some Settings? Need for Longterm Observations in Standard Care to Complement Clinical Trials
THEODORE PINCUS, MD,
Vanderbilt University Medical Center, Nashville, Tennessee;
YUSUF YAZICI, MD, RONALD van VOLLENHOVEN, MD, Supported in part by grants from the Arthritis Foundation and the Jack C. Massey Foundation. Address reprint requests to Dr. T. Pincus, Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500. In this issue of The Journal, Duclos, Gausec, Dougados, and colleagues at the Cochin Hospital in Paris report analyses of the largest series of courses of anti-tumor necrosis factor (anti-TNF) agents at one site in patients with inflammatory arthritides1. The proportion of 975 courses that were continued in 770 patients at 6, 12, and 24 months was 64%, 50%, and 39%, respectively. No significant differences were seen between the 3 available agents, etanercept, infliximab, and adalimumab. Courses of anti-TNF agents were continued longer in the 38% of patients with ankylosing spondylitis than in the 57% of patients with rheumatoid arthritis, and courses were continued longer if no concomitant disease modifying antirheumatic drug (DMARD), including methotrexate (MTX), was taken1. The authors recognize that results in their report, termed the "Cochin report," differ from those reported in clinical trials1, in which a combination of anti-TNF agent with MTX invariably had greater efficacy than either agent as monotherapy2-4. Further, a study from Sweden indicated continuation of 88% of etanercept plus MTX courses at 24 months versus 73% of etanercept-only courses at 24 months, and 57% of infliximab plus MTX courses versus 35% of infliximab courses5. Perhaps DMARD therapy serves as a marker for more severe clinical status and is often discontinued when the patient is improved in the Cochin clinical setting. In contrast, many rheumatologists, including the authors of this editorial, continue MTX in most patients who take anti-TNF agents, generally indefinitely6. In some senses, the question about the use of concomitant DMARD with anti-TNF therapies addresses physician attitudes and actions as well as patient status. If reports of clinical trials and results in some clinical settings indicate that anti-TNF agents have had greater apparent efficacy compared to findings of the Cochin report, as recognized by the authors1, we may ask why 50% of courses they studied were continued for 2 years or less: 1. The Cochin report data may not be generalizable The authors note that some rheumatology centers have reported high remission rates in patients treated with anti-TNF agents in standard clinical care5,7,8. In a study of 200 patients in The Netherlands, 50% of courses of anti-TNF therapy were continued for 37 months7. In reports from Sweden 77% of etanercept courses were continued after 20 months9 and 24 months10. Analyses in Germany suggested that continuation after 12 months was about 75%11. An abstract from Denmark8 indicated that 70% of courses of anti-TNF agents were continued for 1 year, and 50% for 134 weeks. A recent abstract from Sweden indicated continuation at 24 months of 72% of etanercept courses, 59% of infliximab courses, and 50% of adalimumab courses; however, continuation of first courses of the 3 anti-TNF agents was similar, at 80%, after 1 year12. Stern and Wolfe reported that 75% of courses of infliximab were continued for 2 years in 2 cohorts from Dallas and the entire United States13, although these patients may be selected for returning mailed questionnaires every 6 months. Taken together these reports suggest somewhat higher rates of continuation of anti-TNF agents in other clinical settings versus those seen in the Cochin study, although results are in a range similar to other studies. Continuation rates may also in part reflect attitudes and actions of rheumatologists and patients, which may differ widely in different clinical settings. The Cochin database does not include analyses of MTX courses. Reports from the United States in 199014 and in 199215 indicated that 50% of courses of MTX were continued over 5 years, and more recently in one setting, that 80% of courses were continued over 5 years6. Although it is not possible to gain definitive information from comparisons of data from different settings and different eras, these reports may suggest higher rates of continuation of MTX courses versus those seen for anti-TNF agents in the Cochin report. 2. Many patients treated with anti-TNF agents already had extensive joint damage Patients with RA usually have some degree of ongoing reversible inflammatory activity indefinitely, so most can benefit from antiinflammatory therapies even after many years of disease. However, currently many patients treated with TNF agents have significant longterm joint damage (in addition to inflammatory activity16) that will not necessarily respond to anti-TNF therapy. Moreover, patients who have irreversible longterm joint damage often are less likely to experience control of pain and other symptoms compared with patients with reversible damage. In the Paris study no association between disease duration and continuation of courses was seen; however, duration of disease is a poor surrogate for joint damage. Rheumatology clinical trials generally exclude people in functional "class IV" RA17, but this status is unusual in ambulatory patients at this time in an era of total joint replacement. Nonetheless, many of the patients may have extensive joint damage. It is unfortunate that measures of damage generally are not included in clinical trials, and results are not analyzed according to the presence or absence of significant damage to possibly serve as an exclusion criterion or potentially adjust for joint damage. 3. Some patients who receive anti-TNF agents have fibromyalgia as their primary clinical problem About 10–20% of patients with RA may have extensive fibromyalgia (FM)18, which will reduce or eliminate the likelihood of substantial improvement and lead to discontinuation within 1 or 2 years of therapy. Again, the presence of FM generally is not considered in inclusion or exclusion criteria for RA clinical trials. Most rheumatologists might be unlikely to enroll a patient with extensive FM in a trial. Nonetheless, no adjustment is made for FM in reporting results of clinical trials. 4. Selection for patients with severe inflammatory activity into clinical trials Most early trials of anti-TNF agents selected incomplete responders to MTX to continue MTX with the biologic agent or a placebo. This "add-on" trial design19 might be expected to select for patients who have more severe inflammatory activity than the general population of patients seen in clinics. Indeed, in some settings, only a small minority of patients seen were eligible for such trials20-22. Patients with higher levels of inflammatory activity might be more likely to respond to an intervention that reduces inflammation. Therefore, a higher proportion of patients who meet eligibility criteria for clinical trials would be expected to respond to any therapy. 5. Availability of 3 anti-TNF agents Three anti-TNF therapies are available, so that a patient or clinician who is unhappy with one anti-TNF agent can switch to another agent. Therefore, an analysis of continuation of any anti-TNF agent might be of considerable interest, i.e., what is the likelihood of someone who begins anti-TNF to continue to take any anti-TNF agent? For example, in a report from Sweden, treatment with any TNF agent was continued in 84% of patients after 2 years and 75% after 5 years12. In the Cochin report1, only 205 of the 770 patients appeared to have more than one course of an anti-TNF agent, so most of the data appear to reflect results with any anti-TNF agent. 6. Expense of anti-TNF agents The expense of anti-TNF agents may inhibit their being continued over long periods. In general, once administrative hurdles to administer anti-TNF agents are overcome, the therapy is continued, particularly if there is a good response. However, some patients in the USA attribute discontinuation to financial reasons. The Cochin report does not mention possible financial influences on discontinuation of therapies. The Cochin observations reinforce the importance of data from observational studies in standard clinical care to supplement data from clinical trials. Essays concerning limitations of randomized controlled clinical trials conducted in various disciplines have been published23-26, including several editorials in The Journal27-30. Patient selection, short timeframe, fixed dosage schedules, and many other limitations may explain why results in clinical care may differ from those in clinical trials. It is recognized that many different designs other than the randomized clinical trial are needed in research concerning clinical care31-34. Nonetheless, in the rheumatology and general medical communities, the limitations of clinical trials remain underrecognized, while their results remain overemphasized as almost the only source of "evidence-based medicine"30. Data from clinical trials cannot be used by the rheumatologist to choose a specific agent when managing an individual patient with RA, as many choices are supported by "evidence." Therefore, longterm analyses, such as those performed by the Cochin group, are required to inform clinicians concerning the optimal management of individual patients. Databases or registers to study longterm outcomes of RA have been established in many locales, including the United States35-39, United Kingdom40, Germany11,41, Norway42, Sweden9,12,43,44, Finland45, Denmark8,46, and elsewhere. In longitudinal databases of patients with RA, it may be of value to include a measure of joint damage such as joint deformity on radiographic and/or physical examination, as well as assessment of the presence of FM. Further, such studies should include patients treated with MTX, and all patients with RA, including those with suspected disease. Indeed, a longterm observational study is most informative if all consecutive patients are included, rather than a selection for any particular therapy47. Anti-TNF agents provide a major advance to the rheumatology community — the senior author of this editorial has reported that 37% of his patients with RA have been treated with biologic agents48. Since many patients with severe disease activity will require anti-TNF therapy, TNF agents will invariably appear superior to MTX and other DMARD in randomized trials in which a combination of anti-TNF and MTX is compared to MTX monotherapy. Nonetheless, many patients may be adequately treated with MTX — the highest reported levels of remission in the rheumatology literature are seen in the FinRACo49 and TICORA50 trials in patients who did not receive anti-TNF therapy, and longterm minimal radiographic progression has been documented in many patients prior to anti-TNF therapy51,52. The most important principle in standard clinical care of RA at this time is not necessarily which agent is used, but how early "tight control" is established50,53. Frequent visits that include quantitative assessments54 are helpful to recognize which patients are responders or nonresponders to different DMARD, so that anti-TNF therapy may be initiated prior to substantial damage. The Cochin group has accomplished much. Further studies from these and additional databases from many locales, including standard clinical care, will further inform rheumatologists in their efforts to improve outcomes for patients with RA.
2. Klareskog L, van der Heijde D, de Jager JP, et al. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004;363:675-81. [MEDLINE] 3. Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54:26-37. [MEDLINE] 4. St. Clair EW, van der Heijde DMFM, Smolen JS, et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004;50:3432-43. [MEDLINE] 5. Kristensen L, Geborek P, Saxne T. Adherence to therapy of etanercept and infliximab during first anti-TNF treatment course in rheumatoid arthritis patients [abstract]. Ann Rheum Dis 2005;64 Suppl III:431. 6. 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. [MEDLINE] 7. Flendrie M, Creemers MCW, Welsing PMJ, den Broeder AA, van Riel PLCM. Survival during treatment with tumor necrosis factor blocking agents in rheumatoid arthritis. Ann Rheum Dis 2003;62 Suppl II:ii30-ii33. 8. Ostergaard M, Unkerskov J, Krogh NS, et al. Poor remission rates but long drug survival in rheumatoid arthritis patients treated with infliximab or etanercept — results from the nationwide Danish "Danbio" database [abstract]. Ann Rheum Dis 2005;64 Suppl III:59. 9. Geborek P, Crnkic M, Petersson IF, Saxne T. 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