October 26, 2013.\u00a0http:\/\/dx.doi.org\/10.1016\/.\u00a0S0140-6736(13)61941-8.\u00a0\u00a0<\/p>\n
<\/p>\n
Randomised controlled trials of the eff ect of stopping\u00a0treatment are rare, but in The Lancet Josef Smolen and\u00a0colleagues1 report results showing that it is possible to\u00a0stop a risky and expensive treatment for many patients\u00a0with rheumatoid arthritis once an initial response has\u00a0been obtained. Newly diagnosed adult patients were\u00a0treated fi rst with either methotrexate plus placebo\u00a0(n=517) or methotrexate plus the biological drug\u00a0adalimumab (n=515), a fully human monoclonal\u00a0antibody that binds to tumour necrosis factor (TNF),\u00a0preventing it from activating TNF receptors.<\/p>\n
More\u00a0patients in the methotrexate plus adalimumab group\u00a0(207 of 466 [44%] completers, 40% of patients\u00a0randomised) attained a predefi ned low disease activity\u00a0target (28-joint disease activity score with C-reactive\u00a0protein [DAS28] <3\u00b72) at weeks 22 and 26 compared\u00a0with methotrexate alone (112 of 460 [24%] completers,\u00a022% of patients randomised).1,2<\/p>\n
Patients with low disease activity in the methotrexate\u00a0plus adalimumab group were then randomly\u00a0allocated to continue this treatment, or to switch to\u00a0methotrexate plus placebo. Patients who achieved\u00a0the target with methotrexate monotherapy\u00a0continued that regimen. The primary endpoint\u00a0was a composite measure of DAS28 of less than\u00a03\u00b72 at week 78 and radiographic non-progression\u00a0from baseline to week 78, compared between\u00a0adalimumab-continuation and methotrexatemonotherapy,\u00a0and was achieved by more patients in\u00a0the adalimumab-continuation group (73 of 105 [70%])\u00a0than the methotrexate-monotherapy group (61 of\u00a0112 [54%]; mean diff erence 15% [95% CI 2\u201328]). However,\u00a0importantly, outcomes for clinical symptoms and\u00a0radio graphic progression were assessed in all groups at\u00a0week 78\u2014by which time patients who withdrew adalimumab\u00a0mostly maintained their good responses.<\/p>\n
This study\u2014the OPTIMA trial\u2014was very large\u00a0(more than 1000 patients at 161 sites), and in our\u00a0opinion excellently done, properly analysed, and\u00a0appropriately interpreted. And yet we fi nd ourselves\u00a0interpreting the result in a wider context than the\u00a0investigators, who comment that withdrawal of the\u00a0biological agent might be an option for most patients\u00a0with early rheumatoid arthritis who achieve initial\u00a0disease control. We think this study raises three other\u00a0questions: did the patients need to take biological\u00a0therapy in the fi rst place? Was there another treatment\u00a0eff ect hidden within the trial results? And how\u00a0should the cost-eff ectiveness of biological therapy be\u00a0calculated?<\/p>\n
The initial control group of this study was\u00a0methotrexate plus placebo, but scientifi c literature on\u00a0the treatment of newly diagnosed rheumatoid arthritis,\u00a0some reported since OPTIMA was designed, very\u00a0strongly suggests that methotrexate monotherapy is\u00a0an inadequate and old fashioned therapy. Combination\u00a0therapy, particularly including glucocorticoids\u00a0(which we advocate in our practice) would be a more\u00a0appropriate comparator group,3\u20136 and some would\u00a0argue that a so-called treat-to-target policy of dose\u00a0escalation would be even more eff ective (although its\u00a0cost-eff ectiveness has not yet been shown).6,7 Indeed,\u00a0these combination therapies have been shown to\u00a0produce treatment eff ects very similar to biological\u00a0therapies. We would no longer off er monotherapy\u00a0with methotrexate to our patients except in rare\u00a0circumstances. Trial comparisons should compare new\u00a0treatments to the best available alternative, but many\u00a0do not. Showing that a new treatment is better than an\u00a0old treatment that has been superseded does not add\u00a0useful knowledge.<\/p>\n
Other treatments were used in OPTIMA; in particular,\u00a0more than 40% of patients were treated with glucocorticoids\u00a0during the fi rst 26 weeks of the study. As is\u00a0common in most trial reports, the random allocation\u00a0of patients meant that roughly equal proportions of\u00a0patients were taking glucocorticoids in each group, and\u00a0hence the trial interpretation often ignores this aspect\u00a0of treatment. But the evidence shows an additional\u00a0eff ect of glucocorticoids added to other disease\u00a0modifying therapies,3\u20136 such as methotrexate. Might it\u00a0be that the therapeutic benefi ts are also heightened in\u00a0those patients taking glucocorticoids at the same time\u00a0as biological therapies? The data from this and other\u00a0studies of biological therapies should be analysed from\u00a0this point of view.<\/p>\n
How do we estimate the cost-eff ectiveness of<\/p>\n
expensive treatments such as biological therapy?<\/p>\n
Their cost is an order of magnitude greater than<\/p>\n
those of combinations of standard treatment plus<\/p>\n
glucocorticoids. In most countries, biological therapy<\/p>\n
is only reimbursed when methotrexate and one other<\/p>\n
traditional antirheumatic drug have failed. In the UK,<\/p>\n
the National Institute for Health and Care Excellence<\/p>\n
(NICE) has applied the clinical trial outcomes from<\/p>\n
biological therapy to a mathematical model of costs<\/p>\n
and benefi ts, resulting in a strict reimbursement rule<\/p>\n
compared with many other European countries.8<\/p>\n
And even in NICE\u2019s analysis cost-eff ectiveness of<\/p>\n
biological agents might be exaggerated, because the<\/p>\n
model compares biological agents with methotrexate<\/p>\n
monotherapy rather than the more eff ective<\/p>\n
combination therapy. In this situation, were healthcare<\/p>\n
providers to change the practice for initial<\/p>\n
treatment of rheumatoid arthritis on the basis of<\/p>\n
OPTIMA, all patients with early rheumatoid arthritis<\/p>\n
would receive biological treatment, and less than half<\/p>\n
would reach the low disease activity target allowing<\/p>\n
them to stop after 6 months. Costs would skyrocket.<\/p>\n
At a time of constraint in health-care budgets,<\/p>\n
health-care providers should spend their money<\/p>\n
wisely, and NICE should reset its economic model<\/p>\n
for rheumatoid arthritis to include the outcomes of<\/p>\n
modern combination therapy, treatment which it<\/p>\n
itself recommends.9 For many patients, the intelligent<\/p>\n
use of combination therapy including glucocorticoids<\/p>\n
will eliminate the need for early biological therapy.<\/p>\n
For patients who do need biological therapy and then<\/p>\n
achieve stable low disease activity, the OPTIMA results<\/p>\n
suggest it might be reasonable to consider switching<\/p>\n
back to non-biological treatment.<\/p>\n
We congratulate Smolen and colleagues for tackling<\/p>\n
the problem of treating rheumatoid arthritis from a<\/p>\n
new standpoint, for showing how a trial of stopping<\/p>\n
treatment can be so informative, and for providing<\/p>\n
a very useful opportunity for re-evaluating the best<\/p>\n
possible role of routine combination therapy in the early<\/p>\n
stages of this important disease.<\/p>\n
*John R Kirwan, Maarten Boers<\/p>\n
University of Bristol Academic Rheumatology Unit, Bristol Royal<\/p>\n
Infi rmary, Bristol BS8 2UR, UK (JRK); and Department of<\/p>\n
Epidemiology and Biostatistics, VU University Medical Center,<\/p>\n
Amsterdam, Netherlands (MB)<\/p>\n
john.kirwan@bristol.ac.uk<\/p>\n
We declare that we have no confl icts of interest.<\/p>\n
1 Smolen JS, Emery P, Fleischmann R, et al. Adjustment of therapy in<\/p>\n
rheumatoid arthritis on the basis of achievement of stable low disease<\/p>\n
activity with adalimumab plus methotrexate or methotrexate alone: the<\/p>\n
randomised controlled OPTIMA trial. Lancet 2013; published online Oct 26.<\/p>\n
http:\/\/dx.doi.org\/10.1016\/S0140-6736(13)61751-1.<\/p>\n
2 Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and<\/p>\n
radiographic consequences of achieving stable low disease activity and<\/p>\n
remission with adalimumab plus methotrexate or methotrexate alone in<\/p>\n
early rheumatoid arthritis: 26-week results from the randomised,<\/p>\n
controlled OPTIMA study. Ann Rheum Dis 2013; 72: 64\u201371.<\/p>\n
3 Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Comparison<\/p>\n
of treatment strategies in early rheumatoid arthritis: a randomized trial.<\/p>\n
Ann Intern Med 2007; 146: 406\u201315.<\/p>\n
4 M\u00f6tt\u00f6nen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of<\/p>\n
combination therapy with single-drug therapy in early rheumatoid<\/p>\n
arthritis: a randomised trial. Lancet 1999; 353: 1568\u201373.<\/p>\n
5 Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in<\/p>\n
a methotrexate-based, tight control strategy for early rheumatoid arthritis:<\/p>\n
a randomized trial. Ann Intern Med 2012; 156: 329\u201339.<\/p>\n
6 Kirwan JR, Bijlsma JWJ, Boers M, Shea B. Eff ects of glucocorticoids on<\/p>\n
radiological progression in rheumatoid arthritis. Cochrane Database Syst Rev<\/p>\n
2007; 1: CD006356.<\/p>\n
7 Kirwan JR. Combination therapy including glucocorticoids: the new gold<\/p>\n
standard for early treatment in rheumatoid arthritis? Ann Intern Med 2012;<\/p>\n
156: 390\u201391.<\/p>\n
8 NICE. Adalimumab, etanercept and infl iximab for the treatment of<\/p>\n
rheumatoid arthritis. Technology appraisals, TA 130\u2014issues October, 2007.<\/p>\n
http:\/\/www.nice.org.uk\/TA130 (accessed Sept 25, 2013).<\/p>\n
9 National Collaborating Centre for Chronic Conditions. Rheumatoid<\/p>\n
arthritis: national clinical guideline for management and treatment in<\/p>\n
adults. London: Royal College of Physicians, 2009.<\/p>\n","protected":false},"excerpt":{"rendered":"
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