DERBY, UK – A group of British clinicians led by Chris Deighton, MD, of Derbyshire Royal Infirmary in Derby, UK, charge that the British Society for Rheumatology (BSR) and National Institute for Health and Clinical Excellence (NICE) guidelines for prescribing of TNF inhibitors for rheumatoid arthritis (RA) are too rigid and need to be updated annually to keep pace with emerging data on the appropriate use of these agents.

In an editorial in the June issue of Rheumatology, Dr. Deighton, along with Drs. E. George, P.D.W. Kiely, J. Ledingham, R.A. Luqmani, and D.G.I. Scott, contend that the present guidelines are unduly restrictive because they require preassessment, failure of at least two disease-modifying antirheumatic drugs (DMARDs), and a Disease Activity Score (DAS) 28 of >5.1.¹ The authors call for input from other physicians on the need for changes to the guidelines. "Guidelines will never please everybody all of the time. They need to be evidence based, but where evidence is lacking, they must be informed by the advice and opinions of practitioners who will use them. This will ensure broad acceptability. Most importantly, we need these drugs to reach those patients who are most likely to benefit from them," they write. 

In 2003, the BSR began updating the original 2001 guidelines. NICE, however, incorporated the unchanged guidelines into their Health Technology Appraisal on the grounds that there was little evidence for changing the treatment eligibility criteria. Dr. Deighton writes that the BSR updates were presented in April 2004 with few changes due to limited feedback from doctors and drug companies. He argues that as a result, the updated guidelines, published in 2005,² are far behind those of other countries, including the US and Ireland. Dr. Deighton contends that, due to fast-moving research in this area, an ongoing review of TNF inhibitor treatment guidelines would be more appropriate.

"What is needed is an ongoing review of the BSR guidelines so that we are in an evidence-based position to appropriately adjust the guidelines in the future, in a way which NICE will find acceptable," the researchers conclude. "Important ammunition in persuading NICE that more RA patients should be eligible for anti-TNF will also rely on strong health economic data."

To preassess or not to preassess?

The 2005 guidelines suggest that a patient should have a DAS of >5.1 on two occasions a month apart. In actuality, Dr. Deighton writes, nurses often state that this is a cruel delay of the inevitable, since everybody who fulfills the criteria at 1 month prior to baseline continues in a similar vein at baseline. Furthermore, patients may deteriorate over the course of the month's delay, and their doctors are reluctant to intervene in case this jeopardizes their chances of fulfilling the criteria at the second visit.

"Preassessment in my view is a waste of valuable time during which the patient needlessly struggles for a month," Dr. Deighton told CIAOMed. "The overwhelming majority of patients who fulfill the criteria at preassessment go on to fulfill them at baseline, but will have deteriorated during that month. My opinion is it should be scrapped, and we are hoping to publish on this soon."

The authors also question the practice of making newly diagnosed RA patients eligible for TNF inhibitors if they cannot tolerate their first two DMARDs, and suggest that consideration be given to making methotrexate failure alone sufficient for TNF inhibitor eligibility.

Deighton recommends SDAI rather than DAS28 

The rationale of using a DAS28 of >5.1 was to select patients with ongoing active disease, as opposed to those experiencing a single flare, Dr. Deighton notes. Other national societies and representative bodies use a much lower level of 3.2 or set no specified level at all.

"DAS needs to be replaced by something simpler, more responsive to change, and valid for demonstrating eligibility for the drug and response to the drug," Dr. Deighton told CIAOMed. "We need some objective measure, or funding authorities will not pay. I think the Simplified Disease Activity Index has many advantages of the DAS, and more data is emerging on this measure. [As to] whether it is the best method of assessment will be the source of heated debate."

Another question posed by the new editorial is whether failing to decrease the DAS by >1.2 after 3 months is sufficient grounds for withdrawing therapy. Some patients show benefit from anti-TNF therapy that is not captured by DAS, such as a decrease in fatigue or an increase in well-being, the editorialists point out, but nonresponders do need to be identified so that "expensive and unhelpful medication can be stopped." Going forward, targeted administration based on cytokine profiling or biomarkers may help, they write.

Sir Ravinder N. Maini, MB, professor emeritus of rheumatology at Imperial College in London, UK, agreed with the editorial. "The guidelines for anti-TNF treatment of RA as laid down by NICE were appropriate in 2002, but are too rigid and are likely depriving deserving patients of this treatment in 2006,"  Sir Maini said. He was awarded the 2003 Lasker Award for Clinical Research with colleague Marc Feldmann, MD, for identifying TNF as the key proinflammatory cytokine in RA and helping to pave the way for the development of anti-TNF therapy.

Sir Maini challenged the British guideline requirements for a DAS of >5.1 on two occasions a month apart and for patients to have failed at least two DMARDs. "Both these criteria are now inappropriate for patients most likely to benefit from this intervention," he told CIAOMed. "The arbiter for intervention should be defined by criteria that permits inclusion of patients who are 'suffering' and likely to experience the greatest deterioration in function and its consequences in the future; eg, work disability, co-morbidity, and the need for joint surgery. This decision is best made by a clinical judgment, albeit evidence-based, that is responsive to need."

Dr. Deighton adds, "[I]n the UK we have to convince a government-appointed body (NICE) that interventions are cost effective. For us in the UK, therefore, the biggest issue is making these expensive anti-TNF drugs available to those patients who stand to gain the greatest chance of benefit, and to ensure that NICE agrees with us so that patients will receive funding from the National Health Service for these treatments."

References

1. Deighton CM, George E, Kiely PDW, et al. Updating the British Society for Rheumatology guidelines for anti-tumour necrosis factor alpha therapy in adult rheumatoid arthritis (again). Rheumatology. 2006;45:649-652.
2. Ledingham J, Deighton C. Update in the British Society for Rheumatology guidelines for prescribing TNF-a blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology. 2005;44:157-163.