The Pharmaceutical Journal
Vol 272 No 7305 p818-819
26 June 2004

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European Congress of Rheumatology

TNF remains target for arthritis drugs

Although blocking tumour necrosis factor was a big step forward, both medically and scientifically, for most patients with rheumatoid arthritis, it is certainly not a cure, Marc Feldman, head of the Kennedy Institute of Rheumatology division, Imperial College, London, said at a press briefing. Together with Sir Ravinder Maini (also from Imperial College), Professor Feldman discovered and developed anti-TNF therapy, also known as cytokine inhibitors. A 40 per cent remission in two years is the best result that has been reported so far (see TEMPO trial results below) but that still leaves many people with active disease, Professor Feldman said.

Other problems with current anti-TNF therapy includes the significant stress it can put on the health budget (cost may be as high as €15,000 per year per patient), the fact that the drugs are only available in an injectable form and the small increased risk of infection. Consequently, cheaper and more convenient options must be looked for in the future, Professor Feldman said, before outlining some of the latest research.

Investigations are being carried out into drugs that reduce the traffic of white blood cells into the joints (caused by TNF) and drugs that prevent angiogenesis (in rheumatoid arthritis the amount of diseased tissue is much larger than normal tissue and new blood vessels grow to feed this mass of tissue). Other mechanisms being looked at include blocking extracellular cell signals that activate TNF production and having intracellular enzymes that regulate TNF.

Small molecules that can be taken orally, and either have anti-TNF effects or can augment the effects of such drugs, are also being investigated but often these are found to have toxic effects, Professor Feldman said.

Professor Maini added that, in most cases, an intervention within the first three to six months of rheumatoid arthritis with the standard drugs that are available (not including biological therapies — ie, anti-TNF drugs) can bring about significant control of the disease, so that signs and symptoms are abolished and function is restored. It is important to intervene in rheumatoid diseases early because a six- to nine-month delay can cause a significant problem in controlling the disease process.

Josef Smolen, president of the European League Against Rheumatism, said that because of the insidious nature of rheumatoid arthritis, it is important to alert GPs and the public to the disease. By the time a patient seeks help, three or four months may have elapsed, he added. However, Professor Maini thinks that the answer lies more in public education on self-examination of joints with respect to swelling — “the average GP with 5,000 patients may not see rheumatoid arthritis cases often enough,” he explained.

Although a good prognosis can be expected with early intervention, in around 20 to 30 per cent of patients with rheumatoid arthritis the disease continues despite the best available standard drugs. It is for these patients that biological therapies provide an important option and 70 per cent of patients who are exposed to these anti-TNF drugs will show significant improvement, Professor Maini said. However, we are still learning how best to use these remedies. We need a clearer understanding of how they work and who will benefit most from them. In addition, the long-term efficacy and safety of anti-TNFs are still not known, he warned.

Four treatment strategies for RA compared

Patients receiving initial treatment with a combination of methotrexate, sulfasalazine and prednisolone or methotrexate plus infliximab (Remicade) have less radiological damage compared with those receiving sequential monotherapy or step-up therapy, according to the first-year results of a multicentre trial. During the trial 508 patients with newly diagnosed rheumatoid arthritis were randomised to receive one of the following treatment strategies:

· Group one: Sequential monotherapy (initial methotrexate, switching to sulfasalazine and then leflunomide)
· Group two: Step-up therapy (methotrexate followed by the addition of sulfasalazine and a further addition of hydroxychoroquine if necessary)
· Group three: Methotrexate with sulfasalazine and prednisolone
· Group four: Infliximab plus methotrexate

In group one, 27 per cent of patients did not show any radiological progression, compared with 29, 37 and 46 per cent of patients in groups two, three and four, respectively (P=0.007). There was no significant difference in the incidence of adverse effects between the four groups.

“The question remains: should all patients with newly diagnosed rheumatoid arthritis need to be treated with combinations of drugs or the new and expensive TNF-blocking agents right away, or should these be reserved for patients who do not respond to more traditional anti-inflammatory drugs, such as methotrexate,” one of the researchers said.

TEMPO results show promise at two years

Two-year results From TEMPO (trial of etanercept and methotrexate with radiographic patient outcomes) confirm that the combination of methotrexate and etanercept is more effective than either drug used alone (PJ, 6 March, p273). After two years’ treatment, 40.7 per cent of patients (n=682) receiving both drugs achieved remission compared with 15.9 and 23.3 per cent of those treated with methotrexate or etanercept alone, respectively (P<0.05).

In addition, a higher proportion of patients in the combination group remained in the study compared with the other two groups. There were no new safety findings and the rate of infections in those on combination therapy did not increase, say the researchers.

Guidelines questioned as not based on practice

Guidelines for the management of musculoskeletal conditions are needed because the best outcomes are not being achieved, according to Anthony Woolf, professor of rheumatology, Royal Cornwall Hospital, Truro. “We know that there is inadequate symptom control,” he said. But where guidelines are available (eg, for rheumatoid arthritis and osteoporosis) they are not always followed and this means therapies are not being used consistently. Part of the problem is that people are not always aware that guidelines exist, Professor Woolf said.

However, according to Maarten Boers, head of the department of clinical epidemiology and biostatistics, VU University medical centre, Amsterdam, existing guidelines are weakened because they are based on data from trials not designed to answer the questions that clinicians ask in practice. There is little drug data from independent sources and this means the questions being answered are those that drug companies like to see answered, he said.

These are important questions, Professor Boers acknowledged, but other information is needed. For example, trial data on toxicity is poor. If you want to know if a treatment is toxic in practice, most important information comes from observational studies and not from randomised controlled trials, he said.

Furthermore, the trials that are performed are usually short (eg, 12-week) and only show that one drug is better than another. “Questions rarely move beyond phase 3. What we need is the answer to the question: if I do everything right, will this drug usually work in my patient, who is older, sicker, has co-morbidities, may be less active than the subjects in trials or is using other drugs?” Professor Boers told The Journal. Other examples of questions that require evidence-based answers include: Which drug do we use first? If we start patients on a high dose, do they like it? Do they continue using it? Professor Boers called for good explanatory long-term trials to answer the questions posed in developing guidelines.

Where guidelines exist, producing a patient guide to them should become standard practice, Professor Boers added. “If you cannot explain the guidelines in patient terms then they are useless because it is patients who will have to follow them. You can say ‘I want you to do this or that’, but it is the patients who are, or who are not, going to do it,” he said.

Patients want help to assess information

A European survey shows that only 40 per cent of people with arthritis or rheumatism think they are fairly well informed about their condition. Self management is an important concept, especially if you have a long-term condition like arthritis. We need, therefore, to be able to indicate to people where they can get good quality, independent information, Neil Betteridge, Arthritis Care, said. But health care professionals also need to be increasingly flexible and recognise the role that patients want them to play. Although many patients are becoming effective health care consumers, some will still want the old (“grateful recipient”) model — they still want to be told what to do, Mr Betteridge added.

Health professionals now have to be both an information source and an information manager for patients. According to Maarten Boers, VU University medical centre, Amsterdam, information management means being able to appraise critically increasing amounts of literature, including trial data presented by patients. However, Professor Boers said that many health professionals are poor at critically appraising the literature and most patients have none of these skills at all. The only advantage patients have is the motivation to go through the information because it concerns their own disease.

The answer is to learn and maintain basic critical appraisal skills. This helps in making evidence-based choices and explaining information to patients. “If you read an article but you cannot assess it critically, you are not being a good health professional,” Professor Boers said.

Zoledronic acid may be of benefit in arthritis

Osteoclasts may be viable therapeutic targets in rheumatoid arthritis, according to Steve Jarrett, academic unit of musculoskeletal disease, Leeds University. A a six-month proof of concept study has revealed a 61 per cent decrease in mean change in hand and wrist erosions (measured using magnetic resonance imaging) in patients given two 5mg infusions of zoledronic acid, compared with placebo (n=39, P=0.18).

There was a 13-week interval between the two injections, and disease duration in patients included in the study ranged from 0.4 to 20.6 months. The main side effects complained of were flu-like symptoms.

Although osteoclasts play a central role in the development of bone erosions, past evaluations of bisphosphonates in rheumatoid arthritis have shown limited benefit. However, previous trial results may have been affected by the poor potency or bioavailability of the compounds studied. Zoledronic acid is a third generation bisphosphonate, of high potency.

The new evidence warrants further trials, the researchers say.

Conference in brief

Genes linked to osteoarthritis
Researchers at Oxford University have associated the genetic risk of osteoarthritis with three genes that encode for cell signalling proteins. Before this discovery, it was assumed that the defective genes were linked to joint structure rather than the homeostatic processes that maintain cartilage and bone.

TNF blockers give pain control in ankylosing spondylitis
A Norwegian observational study comparing clinical responses to TNF blockers shows that these drugs produce better pain control and improved physical function in patients with ankylosing spondylitis compared with those with rheumatoid arthritis.

Hyaluronic acid reduces costs
A French observational study shows that within six months of treatment, the cost of management of patients with mild-to-moderate knee osteoarthritis given three, weekly injections of a highly purified sodium salt of hyaluronic acid was significantly reduced. In France, 30,000 hyaluronic acid treatments were prescribed last year.