NICE Guidelines on Anti-tumor Necrosis Factor Therapy for RA

David L Scott; Sophia Steer


Nat Clin Pract Rheumatol. 2009;5(1):16-17. 


The UK National Institute for Health and Clinical Excellence (NICE) utilizes the available evidence to provide guidance on the efficacy and cost-effectiveness of existing health technologies. NICE advisors decide that a technology is of value to society when its cost falls beneath a certain threshold—conventionally under £30,000 (approximately $50,000) per quality-adjusted life year. NICE can work only with the available evidence. In many cases, this evidence is neither good nor complete, but the quality of the evidence is not something that NICE can influence directly. Its proponents believe that NICE is far more than a system for rationing expensive treatments.[1] Its critics, however, argue that rationing is its central business, and that NICE often deprives patients from receiving the effective treatments they wish to have.[2]

In the field of rheumatology, NICE has focused mainly on treatment with biologic agents—the tumor necrosis factor (TNF) inhibitors, human interleukin-1 receptor antagonists, anti-B-cell antibodies and CD4+ T-cell costimulation modulators. NICE has previously recommended the use of anti-TNF agents to treat rheumatoid arthritis (RA), psoriatic arthritis and ankylosing spondylitis, as well as rituximab for RA. It has not approved anakinra or abatacept for RA therapy on the basis of cost-effectiveness analyses.

In 2007, NICE updated its guidance on the use of TNF inhibitors for the treatment of RA.[3] The institute confirmed its earlier view that anti-TNF agents should be restricted to patients who have failed treatment with two DMARDs and who continue to have high disease activity (28-joint Disease Activity Score ≥5.1). In reaching their decision, NICE advisors highlighted the diversity of published data on the cost-effectiveness of TNF inhibitors in RA,[4] but concluded that, on balance, the evidence suggests this treatment approach falls within the threshold for acceptability. However, NICE refrained from recommending TNF inhibitors for treating early RA.

Neither of these recommendations is particularly controversial, as it is generally accepted that anti-TNF therapy is likely to be less cost-effective in patients with low levels of disease activity than in those with increased disease activity.[5,6] Furthermore, there is some evidence that intensive use of conventional DMARDs in early RA has similar efficacy to TNF inhibitors administered with methotrexate. This rationale was confirmed in the only head-to-head trial of TNF inhibitors and intensive conventional treatment, which showed comparability between these management strategies.[7] Although NICE noted the subtle advantages of the early use of biologic agents, such as their tolerability, ease of use and ability to induce drug-free remissions, these points were not included within its conventional economic analyses.

By contrast, a recommendation in the guidelines with regard to switching TNF inhibitors has aroused extensive controversy and debate, and is the subject of ongoing appeals. While NICE accepts that it is reasonable to switch TNF inhibitors in patients who experience toxicity, it specifically recommends that when patients stop taking one TNF inhibitor for lack of effect, they should not start another.

Switching TNF inhibitors exemplifies the problems facing NICE; it has to balance pressures regarding the best use of high-cost treatments with the needs of patients suffering from a severe long-term disorder and the concerns of specialists who have many years of experience of switching TNF inhibitors. Although the evidence for and against switching is incomplete, prior to the recent NICE guidelines many centers in the UK followed a policy of switching to a second or even a third TNF inhibitor after the first was stopped. In addition, most commentators recommend switching when a TNF inhibitor is discontinued.[8,9,10]

The open-label ReAct (Research in Active Rheumatoid Arthritis) study showed that, following adalimumab therapy, 41% of TNF inhibitor-naive patients (n = 5,711) had a 50% improvement in symptoms according to the American College of Rheumatology criteria (ACR50) .[11] Furthermore, 33% of 899 patients who had previously received a TNF inhibitor had an ACR50 response. Within the group of patients in whom switching had occurred, those who switched because of toxicity had lower ACR50 responses than patients who switched due to adverse events (25% vs 38%). These findings were replicated for ACR20 and ACR70 responses. Data from other trials, open-label studies and registries confirm that switching TNF inhibitors is effective, but seems to be less beneficial than treatment with the first TNF inhibitor.[12,13,14,15]

Rheumatologists believe these findings confirm the efficacy of switching TNF inhibitors. From a health economics perspective, however, if primary TNF inhibition lies towards the upper limits of cost-effectiveness, switching anti-TNF agents in patients where no benefit is noted could fall into the realm of the unaffordable. The key question, however, is whether this treatment approach is effective enough to meet the NICE threshold of cost-effectiveness. The cost-effectiveness model adopted by NICE is founded on a theoretical assessment of what happens without biologic agents:[16] its evidence base is relatively thin. Furthermore, the guidance focuses on medical costs without taking into account the societal costs, which is likely to reduce the apparent cost-effectiveness of these therapies.

In addition, the new guidance on TNF inhibitors from NICE could be criticized in several other ways. The rationale for using high 28-joint Disease Activity Scores to define eligibility for treatment, instead of the definitions of active RA used in the pivotal trials on anti-TNF therapy for RA, is debatable. Furthermore, the threshold at which the quality-adjusted life year is considered to be cost-effective is based on judgment rather than evidence, creating an inconsistency in the arguments about evidence-based decision-making.

Rather than focus on criticizing the NICE guidance, however, it might be more rewarding to improve the evidence base on which its decisions depend. Ultimately, all specialists will need to make the case for patients having access to high-cost treatments, and this is an area in which rheumatologists need to take leading roles. Demonstrating that these treatments are effective is, by itself, not enough—we also have to show that conventional treatments can result in unacceptable outcomes; this is an issue for the rheumatology community to tackle without delay.

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