Report on Anti-TNF - June 2004 by Fergus Rogers (Director NASS):

In the last few years readers of AS News have followed the reports in the developments of a new form of treatment for some rheumatic diseases, including ankylosing spondylitis. These are called TNF blockers or anti-TNF drugs and two of them have now received a Europe-wide license. They were first used in rheumatoid arthritis (RA) simply because there are more RA sufferers than AS, therefore, not unnaturally the first trials were on patients with rheumatoid arthritis.

Over the last few years, trials in Europe and North America, based on treatment regimes as set out in the manufacturers’ recommendations, have been conducted on the use of these biologic agents for ankylosing spondylitis and a few other rheumatic diseases. These trials have demonstrated conclusively, that in many cases, there are both clinical improvements and in a few studies, improvements in Magnetic Resonance Imaging (MRI) parallel to the clinical improvement. The evidence suggests that there is reason to suspect that in AS, the drug is even more effective than it is in RA, especially as it is recognised that AS has a limited response to anti-inflammatory drugs.

The first to be issued with a European-wide license in 2003 was Remicade produced by Schering-Plough. This drug is delivered to the patients, in hospital, by infusion over a two-hour period, approximately every six weeks. The second drug, Enbrel was licensed for AS in 2004 and is manufactured by Wyeth and is delivered twice a week by self-injection subcutaneously (beneath the skin). The drugs, therefore, being delivered to the patients own home every few weeks. These medications can, in the UK, only be prescribed by rheumatologists, and their use will be severely limited by the health authorities because they are exceedingly expensive and the long-term effects are not yet known. This expense relates to long scientific development time and the fact that they are made by a biological method which is slow and costly. Because of this cost topic, many Primary Care Trusts (PCT) in this country are at the moment resisting its use, or not increasing the hospitals drug budget to take the additional costs into consideration. There is, however, direct evidence of postcode prescribing in rheumatoid arthritis, so we predict there could be the same problems in AS. Some PCTs are claiming that they are not obliged to provide the medication for people with AS as the National Institute for Clinical Excellence, NICE, has not yet passed these drugs for this indication: it will not look at it until 2005 and make their announcement in 2006. However they are wrong, as there was a health service circular, HSC/1999/176, which stated that the fact that NICE had not approved the drug was no reasons for it being withheld, when the physician is of the opinion that it should be used. This was confirmed in the House of Lords on 3rd April 2001 by the then Parliamentary Under-Secretary of State. The reason why there were questions in the House at that time, was because it was licensed to be used in RA and NICE had not at the time reviewed it. This is exactly the situation where AS is today, three years later.

There is undoubtedly a cost effective case to be made in favour of its use when one considers those patients who have such severe disease, that they either are, or more importantly, about to lose their occupations because of their disease severity. In addition, there are considerable days, sick leave lost per year, in many of the employed AS population. Research so far indicates that very few working days are lost after the commencement of anti-TNF treatment. By balancing the cost to the state in social security benefits, against the cost of using the medication, the case is made for its use. In addition, one should take into consideration the possible surgical implications, sometimes associated with severe disease. There is, for example, spinal surgery in a small number of patients, as well as hip replacement in 6% of the AS population. There are also a number of other surgical problems such as knees and jaw joint replacement, a number of which could probably be avoided with the appropriate use of anti-TNF. There can, in many cases of AS, be considerable additional costs in treating some of the well-known side effects, mainly gastrointestinal, associated with non-steroidal anti-inflammatory agents.

The British Society for Rheumatology (BSR), in the last few months of 2003 and in the first few months of 2004, held regular meetings of a working party to produce guidelines for prescribing anti-TNF blockers in adults with ankylosing spondylitis. As the Director of NASS, I was privileged to be on that working party. The other ten members are all experienced in the management of patients with AS and have a familiarity with the use of TNF blocking agents. All of the research papers that had been published over the last three years, up until that date, were reviewed and their findings collated and recommendations added. The report which followed was presented at the BSR annual meeting which was held in April 2004. We are awaiting a response from their rheumatology colleagues and when that has been received and noted, the final recommendations will be published in one of the main rheumatology journals.

However, basically the recommendations are that everybody should be tested and treated for the TB germ if they have previously had TB or in contact with other people who have had the disease. This is because, in very few cases, there is evidence that TB has been reactivated as a result of this treatment. It is recommended that pregnant women should not be treated but this is only a precaution, as nothing is known. Also people with active significant infection, as well as certain types of heart complications, and certain types of disease process affecting the central or peripheral nervous system should all be excluded. All patients must meet the modified New York criteria for AS, after taking reasonable measures to ensure that the symptoms are not due to alternative causes such as spinal fracture, disc disease and fibromyalgia. The doctor must also be of the opinion that all other forms of medication have failed, which includes anti-inflammatory drugs and disease modifying agents, such as methotrexate. The patient must also have reached a score of more than 4 on what is known as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and spinal pain score during the previous week, measuring more than 4 on the Visual Analogue Scale (VAS).

Fortunately, beneficial effects have also been noted in Crohn’s disease, when associated with AS, as well as in cases of psoriasis, where separate guidelines have been drawn up. Some observers have also noticed that there seems to be a beneficial effect on osteoporosis, a condition which can also be associated with AS, even at a young age. It looks that by switching off the inflammatory process, there is an increase in bone formation. This means that anti-TNF may make a contribution to a reduction of spinal fracture in later life. There is no evidence yet to suggest that uveitis or iritis benefits. However, as the above conditions frequently overlap with AS, it means that some patients can have two or three conditions benefiting from the same treatment.

The report also includes circumstances under which the drugs are withdrawn, examples being when there are severe, adverse effects, and inefficacy indicated by a failure of the BASDAI score to improve by 50% or a fall by more than 2 units, and VAS to reduce by 2 units, after three months of therapy.

It is not yet known if there is an appropriate time to withdraw the medication and what the effects are. However, one study has suggested that 64% of cases flared, which means that one-third did not flare after withdrawal.

The BSR are encouraging all rheumatologists to log the names of all patients on TNF, with their patients permission. This is known as the British Society for Rheumatology Biologics Registry (BSRBR), and reports regularly during the course of treatment. This would allow them to pick up quickly on any adverse reactions, not already known, especially as any long-term downstream consequences are not yet known. This reporting is in addition to the existing practice known as the Yellow Card system. The working party recognises that, as further evidence becomes available, the guidelines will be reviewed and revised periodically. This, therefore, means that the information on this website might change from time to time. There is, for example, a third manufacturer whose anti-TNF drug may also be available for treating AS within the next two years.