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Cost-Effectiveness of Biologics as First-Line Treatment of Rheumatoid Arthritis: Case Closed?

Maarten Boers, MSc, MD, PhD
[+] Article, Author, and Disclosure Information

From VU University Medical Center, Amsterdam, The Netherlands.

Potential Conflicts of Interest:Consultancies: M. Boers (Roche, Nitec, Mapi Values, GlaxoSmithKline). Honoraria: M. Boers (Sanofi, Novartis, Merck, Astra, Nicox, Savient, Combinatorx, Astellas MedImmune, Schering-Plough).

Requests for Single Reprints: Maarten Boers, MSc, MD, PhD, Department of Epidemiology and Biostatistics, VU University Medical Center, PK 6Z 185, Box 7057, 1007 MB, Amsterdam, the Netherlands; e-mail, eb@vumc.nl.

Ann Intern Med. 2009;151(9):668-669. doi:10.7326/0003-4819-151-9-200911030-00013
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Rheumatoid arthritis (RA) is an autoimmune, multisystem disease characterized by chronic inflammation and, ultimately, destruction of joints. Left unchecked, it leads to a high burden of disease, early loss of work capacity, major morbidity, and increased mortality. The concept of a window of opportunity—that early and aggressive treatment could prevent many of the long-term consequences of the disease—was introduced in the early 1990s (1). The drugs available at that time, including disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids, were tested in different combination strategies and proven through tight-control strategies to be effective in both the short and the long term. Treatment of RA received a subsequent boost from the introduction of new biologic therapies, beginning with tumor necrosis factor (TNF)-α inhibitors and recently followed by agents that modulate other targets. With 1 exception, all have shown great efficacy that matches that of optimum conventional combination therapies, as well as a good safety profile and ease of use.

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Comment to Editorial: Cost-Effectiveness of Biologics as First-Line Treatment of Rheumatoid Arthritis (Ann Intern Med 2009 151:668-669)
Posted on November 19, 2009
Axel Finckh
Geneva University Hospital
Conflict of Interest: None Declared

Dr Maarten Boers writes elegantly about our cost-effectiveness study. We appreciate his ideas but some require comment(1). He feels, "curiously, the investigators shy away from a firm conclusion, instead stating that the cost-effectiveness of early biologics is still uncertain." We feel that the case cannot be closed for at least three major reasons: 1. The long-term impact of very early initiation of aggressive antirheumatic therapy, and biologic therapy, in particular, is largely unknown. These include the long-term impact on mortality, the need for joint replacement and the rate of disability decades after the initiation of these therapeutic strategies. 2. Other parameters profoundly impact the cost-effectiveness ratio of these therapeutic strategies, the major ones being the availability of effective alternatives after failure of several biologics, the price of these agents, the induction of long-term drug-free remission and the ability to identify responders to biologics before treatment initiation. Because of these uncertainties, a firm conclusion is not justified. Rather, our findings support the use of aggressive DMARDs before biologics in very early RA from a cost-effectiveness perspective. The study identifies the key parameters that are uncertain and drive the results, and which should be studied to improve future decisions.

We calibrated estimates of the published literature against real patients from the National Data Bank for Rheumatic Diseases (NDB). Such calibration techniques are appropriate and commonly applied in cost- effectiveness studies. Calibration in an another unrelated data set would further validate the model. However, at present, significant circularity is unlikely given that the patient populations used to derive most of the parameters and those used to calibrate the model are largely different.

Finally, Dr Boers takes issue with the model and its treatment of glucocorticoids and feels that including them in only the NSAID strategy arm is "medically inappropriate." Glucocorticoids are effective and clinically useful. In the doses originally used for rheumatoid arthritis, the benefits were outweighed by serious and sometimes fatal long-term effects, increased susceptibility to infection, osteoporosis, obesity, hypertension, or glucose intolerance. The long-term risk/benefit ratio of lower doses is debated(2), and in North America, more likely to be used to put out "fires" rather than long-term. Adding steroids to the DMARD strategy would, as Dr Boers points out, likely to be a conservative bias with respect to the findings(3).


1. Finckh A, Bansback N, Marra CA, Anis AH, Michaud K, Lubin S, et al. Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost- effectiveness analysis. Ann Intern Med 2009;151(9):612-21.

2. Da Silva JA, Jacobs JW, Kirwan JR, Boers M, Saag KG, Ines LB, et al. Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 2006;65(3):285-93.

3. Maillefert JF. Appropriate and inappropriate use of oral glucocorticoid therapy in rheumatoid arthritis. Joint Bone Spine 2006;73(3):234-5.

Conflict of Interest:

None declared

response to dr. Finckh
Posted on December 13, 2009
Maarten Boers
VU University Medical Center
Conflict of Interest: None Declared

I think dr Finkh and I agree on most of the issues, but we differ in the wording of our conclusions. Scientifically it is wise to avoid firm conclusions in the face of shaky evidence. A model can never fully replace reality, and we probably need another 10 years of additional experience with biologics to be fully certain. Nevertheless, when we trust the model and it points unmistakably in one direction, we shouldn't be afraid to clearly communicate what it shows. This is especially important in the area of biologics in RA, where intense marketing pressure exists to push opinions in the other direction. In his reaction, dr Finkh uses a whole paragraph to describe the uncertainties inherent in modeling to conclude with the sentence I would have liked to have seen in the original article: "our findings support the use of aggressive DMARDs before biologics in very early RA from a cost-effectiveness perspective." It would have been even better if he would have said: "our findings CLEARLY support..." etc.

In his response to the glucocorticoid question, I feel dr Finkh is side-stepping my point that not modeling glucocorticoids is an unfortunate omission in the study. That glucocorticoids "in the doses originally used" (i.e., high doses) have many side effects is stating the obvious. He misrepresents our review on the published evidence of the safety of low- dose glucocorticoids (1) when he uses it to conclude that "the long term risk/benefit ratio of lower doses is debated." In fact, what we showed was that the popular conviction on the unacceptable harm of long-term low-dose glucocorticoid therapy in RA is based on poor quality or even nonexistent data; and that the, admittedly limited, good quality data that is available actually supports the contrary view that harms are limited and manageable. Together with strong evidence on benefit it follows that the role of this class of drugs in RA should no longer be ignored. Thus the study's value would have been greatly enhanced by including glucocorticoids explicitly in the model.

In contrast to dr. Finkh's belief, data shows practitioners in the field have already got the message: current glucocorticoid use in RA in North America is dynamic, but these drugs are not being used only to "put out fires" but applied for extended periods in many patients(2).


1. Da Silva JA, Jacobs JW, Kirwan JR, et al. Safety of low dose glucocorticoids treatment in rheumatoid arthritis: published evidence and prospective trial data. Ann Rheum Dis 2006;65:285-93.

2. Caplan C, Wolfe F, Russell AS, et al. Corticosteroid use in rheumatoid arthritis: prevalence, predictors, correlates, and outcomes. J Rheumatol 2007;34:696-705.

Conflict of Interest:

None declared

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