What's next after anti-TNF?

Published on 01 April 2009
Source: Arthritis Today

Paul Emery

What’s the future for the treatment of rheumatoid arthritis in the wake of anti-TNF therapy and now, other exciting new drugs? Leading rheumatoid arthritis expert and Arthritis Research UK Professor of Rheumatology at the University of Leeds, Paul Emery, shares his views with Jane Tadman.

Arthritis Research UK’s greatest achievement in its seventy years of existence has undoubtedly been its development and pioneering of anti-TNF therapy for rheumatoid arthritis (RA). Since this new class of drugs first appeared in the late 1990s, others are now following, prompting the possibility of - if not a cure as such - then the prospect of doctors being able to induce and maintain patients in a state of remission.

Articles in leading journals like The Lancet excitedly talk about how remission has become the goal of managing early RA, and that this aim needs now to be included in the design of clinical trials. The same article also concedes that there are several definitions of what remission actually means.

Arthritis Research UK Professor of Rheumatology, Paul Emery, who has been the lead investigator in a number of international Phase III, multi-centre clinical trials of new RA drugs, explains:

“For the first time it is feasible to talk realistically about remission as the primary outcome for people with newly diagnosed arthritis. However with more patients achieving a remission state the definition of remission itself has been re-examined.

“If we were talking about remission in cancer, it would mean that you have no detectable disease and eradication of the tumour. In RA we conventionally define remission as clinical remission where there may still be underlying disease, so we are now discussing true remission, which is defined by sensitive imaging (ultrasound or MRI) and no disease progression over time. It is still possible to have no symptoms but yet have significant sub-clinical disease. Conversely some patients still have pain but no underlying disease; this is often the case with patients who are treated late.”

Could the term “being in remission” ever mean that a patient remains free of disease - once they have come off drugs? At the moment, the standard way of inducing remission is to step up drugs in order to suppress inflammation. More recently there has been a change to remission-induction using anti-TNF as first therapy in controlled studies and subsequently to stop it when patients are in remission reducing to a maintenance dose of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate.

To Professor Emery, the mere suggestion that being in remission could mean being off medication is evidence of how far treatments for RA have come in the past few years. “Until recently it would never have occurred to doctors that remission would mean that a patient can come off drugs. That is a huge step forward, but that’s the way we are going, so there’s now an evolving definition of the term remission. At some point it might mean that a patient is completely well and the therapy can be stopped.”

Paul Emery and patientThe results from several recent clinical studies have provided evidence of the effectiveness of anti-TNF in early RA, and that people with early disease respond much better than patients with late-stage RA. The multi-centre COMET trial of patients who had had RA for between three months and two years showed that 50 per cent of them, on a combination of etanercept and methotrexate, attained clinical remission after a year, compared to 28 per cent of patients on methotrexate. Another trial, called TEMPO, showed that 40 per cent and 19 per cent of patients respectively were in remission after taking etanercept and methotrexate, but these patients had had RA for on average seven years.

“Anti-TNF works in most patients if they are treated early enough.”

Of course, in the UK, such discussion of inducing remission or treatment of early RA with anti-TNF therapy remains entirely hypothetical outside clinical trials. TNF blockade works in more people with arthritis when they are treated early enough, but current guidelines from the government’s health watchdog the National Institute for Health and Clinical Excellence (NICE) mean that only those people with severe RA who have failed on at least two DMARDs are eligible for this class of drugs.

“If cost was not an issue we would be treating most patients with early RA with anti-TNF therapy, as the effect is greater than with standard DMARDs,” says Paul Emery. “Anti-TNF works in most patients if they are treated early enough.”

This is not a universal view, and also begs the question whether it would be appropriate for all patients with early RA who have the condition fairly mildly and whether they would actually benefit from such an approach.

Professor Emery has little doubt what most patients would choose. “If you were given the opportunity to go into remission and have a chance to stop your therapy, but had to take more powerful drugs at the beginning, would you take it? This becomes especially relevant when COMET shows no increase in toxicity. It’s a question of relative benefit, and RA, true RA, is a really nasty disease. Anti-TNF makes a difference to people’s quality of life.”

“Inducing remission in late stage RA is a real possibility”

Treatment could be even better than it is and clinical trials have produced better data than seen in routine clinical practice, he believes; in other words, there’s a big lag between trial results and what patients actually get. However, it should be stressed that with more than 70 per cent of people with RA responding well to anti-TNF therapy in early disease, the possibility of inducing remission in patients with late stage as well as early RA is also very real (see case study).

The argument that putting all new cases of RA onto anti-TNF therapy would be eye-wateringly expensive (the drugs cost about £12,000 a year per patient) is countered by the fact that many of these patients would be able to stay in employment. At the moment, four out of ten people in work with RA lose their jobs within five years, and one in seven give up work within a year of diagnosis.

Keeping people with RA in work is now the basis of campaigning by patient groups, pharmaceutical companies and professional bodies in the UK, and almost 50 nursing and medical organisations have pledged to consider supporting people of working age to stay in employment, using job retention as a critical outcome measure. Paul Emery, as next President of EULAR (from June 2009), (the European League Against Rheumatism) a European-wide organisation representing patients, health professionals and research bodies, is very much involved in this.

He adds: “Anti-TNF is used more widely in mainland Europe and also in the US, where there is private medical insurance and greater freedom for doctors to prescribe, and certainly NICE is having a major impact on the use of the therapy in the UK. But the success of clinical studies showing the effectiveness of anti-TNF on early RA will put pressure on NICE to look at this issue.”

The sheer number of new RA drugs currently in the pipeline could also pressurise NICE into looking afresh at how people with early RA should ideally be treated.

The imminent licensing of another very promising new RA drug, tocilizumab, aimed not only at people who have either failed on or not responded to not only to anti-TNF therapy but also a DMARD such as methotrexate or sulfasalazine, raises more interesting questions for NICE. What will be the pecking order of drugs if tocilizumab and anti-TNF therapy are the same price, for example?

Sequential use of anti-TNF therapy

Another unresolved issue is the so-called sequential use of anti-TNF drugs. NICE has decided to review its controversial guidance on the “sequential use” of anti-TNF therapy. Its previous draft guidelines had recommended that RA patients who failed on anti-TNF should not be allowed to try a second, but the watchdog is now re-considering the decision in the light of outcry from campaigning groups.

Paul Emery believes that rheumatologists should be able to decide on sequential prescribing. “I wouldn’t try it on everyone, but we have treated people who had no response after the first anti-TNF but then went into remission with another. However, if you have a patient that has failed on two anti-TNF therapies you would be less inclined to treat with a third….”

Whatever the current inadequacies of the treatment of RA, the strides made improving it have been massive over the past 20 years. “Then, if you failed on two DMARDs, there was nothing else, you just ran out of drugs,” points out Paul Emery. “Now we have a greater understanding of how we can use methotrexate in larger doses, and of course we have now more effective treatments like anti-TNF, which has been the stimulus for other new drugs.”

Professor Emery predicts that in another 20 years time all new cases of inflammatory arthritis will be rapidly assessed and the concept of “individualised medicine” will come into play, with treatment more targeted and tailored towards individual needs. In the meantime, he concludes: “We’ve come a long way!”

New RA drugs in the pipeline

Tocilizumab: expected to be licensed in the UK in October 2009, the drug is also currently awaiting NICE approval. Brand name RoActemra, it is the first interleukin-6 (IL-6) receptor-inhibiting monoclonal antibody developed for the treatment of RA, and has a different mode of action to anti-TNF therapy. Following several multi-centre Phase III trials which demonstrated impressive effectiveness, it is expected to be licensed for RA patients who fail on other drugs, including methotrexate and anti-TNF therapy. 

Certilizumab-pegol: brand name Cimzia, it is a new anti-TNF therapy currently going through the NICE approval process, with a decision expected by February 2010. Phase III trials have shown the drug effectively prevents joint damage when combined with methotrexate. It is already approved in the US for Crohn’s disease. 

Golimumab: following positive Phase III trials results, it is now awaiting licensing in the USA and Europe for the treatment of RA, psoriatic arthritis and ankylosing spondylitis.It has recently been referred for review by NICE for methotrexate-naïve RA patients.

Ofatumumab: Phase III clinical trials into this B-cell therapy also known as Humax-CD20 are underway, for both methotrexate and anti-TNF failures. It is also in long-term trials for non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia.

Ocrelizumab: this drug, which also targets B-cells, is currently in Phase III trials for rheumatoid arthritis, lupus and multiple sclerosis.