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Published on 16 September 2009

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Dawn of a new era in rheumatoid arthritis treatment

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New classes of drugs for rheumatoid arthritis and new concepts have shifted the treatment paradigm from controlling pain and inflammation to preventing joint destruction

Rhonda Siddall
BSc(Hons)

Rheumatoid arthritis (RA) is a painful and destructive inflammatory condition that affects around 1% of the population. Of these, around 15% have severe disease. RA is three times more prevalent in women than in men. It can develop at any age, but it usually starts between the ages of 40 and 60.[1]

The disease is characterised by inflammation of the synovial tissue of the peripheral joints, leading to the debilitating symptoms of RA: swelling, stiffness, pain and progressive joint destruction. Inflammatory disease can also occur outside the joints. Rheumatoid arthritis can have a severe impact on quality of life, and it is estimated that 40% of people with RA will have stopped working within five years of diagnosis.1 One of the key challenges in RA treatment is posed by the fact that the disease is a heterogenous disorder, with its many clinical features differing between and even within individuals. Response to therapy is also variable between individuals. Against this background, new treatment options are welcome to aid the achievement of the ultimate goal of RA treatment-remission.

There is no cure for rheumatoid arthritis. Treatment
aims to prevent or to control joint damage, to prevent functional impairment and to minimise pain. The early initiation of disease-modifying antirheumatic drugs (DMARDs) is recommended, preferably before the first radiographic evidence of erosions, and methotrexate (MTX) should be used first-line in patients at risk of developing persistent disease, according to European treatment guidelines.[1]

Professor Paul Emery, arc Professor of Rheumatology
and Clinical Director (Rheumatology) at Leeds Teaching Hospitals Trust in the UK, said: “Even though the objective of treatment is to achieve remission, many patients do not achieve long-term remission of rheumatoid arthritis with methotrexate monotherapy, and only around 10% of patients who do not respond to MTX monotherapy are likely to respond to other
conventional DMARDs.” Recent trials have shown that new DMARDs and DMARD combinations slow disease progression and that biological treatments result in rapid and sustained disease control associated with the prevention of joint destruction. New, effective treatments for RA and new concepts have led to a shift in practice, with an emphasis now on treating arthritis as early as possible to achieve remission. The treatment paradigm for rheumatoid arthritis has now developed from controlling pain and inflammation to preventing joint destruction.

Treating RA

Treatment options for RA include a combination of pharmacological and nonpharmacological interventions, including surgery, physiotherapy, occupational therapy, nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids,
analgesics and disease-modifying drugs (DMARDs). Only DMARDs (and glucocorticoids, to some extent) can delay or stop inflammation and joint destruction.[2]

Conventional DMARDs such as methotrexate (MTX)
and sulfasalazine (SFZ) have been the mainstay of treatment for decades. More recently, biological drugs have been developed to target the cytokine mediators, such as tumour necrosis factor (TNF), interleukin (IL)-1 and IL-6, involved in the inflammatory cascade. Anti-TNF agents, the most established biological drugs for RA treatment, are effective for both the improvement of symptomatic disease and for the prevention of structural damage in patients with RA who have active disease in spite of treatment with conventional DMARDs, including methotrexate.

EULAR treatment guidelines recommend that anti-
TNF therapy be considered instead of, or in addition to, treatment with conventional DMARDs for patients who do not achieve a satisfactory clinical response to one conventional DMARD. EULAR guidelines also state that anti-TNF agents may be appropriate first-line therapy in patients with severe disease or for those in whom conventional DMARDs are contraindicated.[3] But around a third of RA patients do not respond adequately to anti-TNF therapy, so new treatments are a welcome addition to the treatment armamentarium.

Professor Josef Smolen from the Division of Rheumatology,
Medical University of Vienna in Austria, said:“The many patients who obtain insufficient responses to established and novel treatments indicated a need to search for further therapies and treatment principles to increase response rates, and to achieve high frequencies of remission.”

New biological treatments
Three new classes of biological agents have been approved recently for the treatment of rheumatoid arthritis: rituximab (MabThera), abatacept (Orencia) and tocilizumab (RoActemra). The PEGylated anti-TNF certolizumab pegol (Cimzia) also received a CHMP positive opinion in June for the treatment of moderate to severe rheumatoid arthritis in adults in combination with methotrexate when response to DMARD therapy has been inadequate. Certolizumab pegol monotherapy
is recommended in case of intolerance to MTX or when continued treatment with MTX is inappropriate. European marketing authorisation subsequent to a positive CHMP opinion follows, usually within a few months.

By the end of this year, it is anticipated that a new anti-TNF – the first pegylated anti-TNF – and a new class of RA drug, the IL-6 inhibitor tocilizumab, will be launched in Europe. Moreover, data presented at this year’s 10th Annual Congress of the European League Against Rheumatism (EULAR) meeting in Copenhagen in June suggests that using rituximab earlier in the
treatment of RA could be justified.

EULAR 2009
Certolizumab pegol
Two-year data presented at EULAR showed that certolizumab
pegol maintained efficacy in rheumatoid arthritis when used as add-on therapy to methotrexate. Certolizumab pegol showed improvements in RA symptoms as early as the first week of treatment and early inhibition of progression of structural joint damage in the RAPID 1 trial published last year.[4] The latest
results from an open-label extension study to RAPID 1,
presented at EULAR, showed that treatment improvements were sustained for two years in patients maintained on 400 mg certolizumab every two weeks and methotrexate.

A separate analysis also presented at EULAR showed that patients receiving certolizumab whose symptoms were controlled as early as six weeks had significantly better control of symptoms after a year of treatment compared with patients whose symptoms responded later at 12 weeks. RAPID 1 lead investigator Professor Edward Keystone of Mount Sinai Hospital,
Toronto, said: “It is important to know that a new treatment has a sustained effect.”

The one-year results from RAPID 1 showed that the American College of Rheumatology (ACR) ACR20 response rates in patients receiving 200 mg and 400 mg of certolizumab pegol were 58.8% and 60.8%, respectively, compared with 13.6% for placebo in patients who had previously failed to respond to methotrexate. Latest results from the two-year open-label extension study showed that ACR20 response rates in patients who completed treatment with certolizumab pegol 200 mg or 400 mg every two weeks were 68.2% and 69.5%, respectively, at 100 weeks. ACR50 response rates were 55.2% and 51.5%, respectively. Serious adverse events occurred in a fifth of patients, with 7% affected by serious infections. Two cases of
tuberculosis were reported, but there were no reports of opportunistic infections.

Rituximab
New data presented at EULAR from the IMAGE study
showed that rituximab in combination with methotrexate
was more effective than methotrexate alone at slowing joint damage when taken at the early stages of rheumatoid arthritis.

Rheumatologist Professor John Isaacs of Newcastle University’s Institute of Cellular Medicine said: “These data show the efficacy of using rituximab earlier in the RA treatment pathway.” Rituximab is currently licensed for use in combination with methotrexate to treat adults with severe rheumatoid arthritis who have failed anti-TNFs.

The IMAGE study presented by Dr Paul-Peter Tak from the Academic Medical Centre at the University of Amsterdam in the Netherlands showed that 2 x 1,000 mg rituximab plus methotrexate achieved superior clinical and radiological responses compared with methotrexate alone in patients with early active rheumatoid arthritis (RA) who were naive to methotrexate. Lower doses of rituximab (2 x 500 mg) were also studied. Dr Tak said: “Our findings showed significantly improved clinical outcomes and inhibition of joint damage with rituximab at higher doses that could be seen by six months. The lower doses improved clinical but not radiological outcomes.”

ACR20, ACR50 and ACR70 responses were 80%, 64.8% and 46.8% in the higher-dose RTX group, compared with 64.3%, 41.8% and 24.9%, respectively, in the placebo plus methotrexate group (p < 0.0001). Mean change in mTSS was 0.359 in the higher-dose RTX group and 1.079 in the placebo/MTX group (p < 0.001). The percentage of patients with a change in mTSS was 63.5%, versus 53.4% in the higher-dose RTX and placebo/MTX groups, respectively (p < 0.05). The percentage of serious adverse events was similar across the treatment groups.

Tocilizumab
Data reported at EULAR showed that tocilizumab plus methotrexate was more effective than methotrexate monotherapy in preventing worsening joint damage in RA patients and that a significant proportion of patients achieved disease remission. Dr Joel Kremer from the Center for Rheumatology, Albany, New York, and colleagues examined the efficacy of adding tocilizumab to methotrexate in patients with moderate to severe RA who had responded inadequately to methotrexate in the phase III Tocilizumab Safety and the Prevention of Structural Joint Damage (LITHE) trial. Dr Kremer
said: “There was significant inhibition of radiographic progression at week 52 in tocilizumab-treated patients compared with the methotrexate-treated only group. Methotrexate slowed radiographic progression but not to the same degree as tocilizumab.”

Significantly more patients treated with 8 mg/kg tocilizumab achieved remission at six months compared with those treated with methotrexate alone (33% versus 4%), and these rates continued to increase over time to a year (47% versus 8%). Professor Smolen presented data from an interim analysis of two open-label, long-term extension studies that included patients who had completed one of four 24-week controlled studies of tocilizumab as monotherapy or with DMARDs.

This suggested that efficacy with long-term tocilizumab therapy was maintained over time on multiple outcome measures in a broad population of RA patients. In this study, efficacy was assessed across three groups: patients who had had an inadequate response to DMARDs (DMARD-IR), those who had an inadequate response to anti-TNFs (TNF-IR) and those who were DMARD-naive (monotherapy).

These groups were treated with tocilizumab 8 mg/kg every four weeks for up to 2.5 years. At 132 weeks, 66.7% of DMARD-IR patients had achieved an ACR50 response and 43.9% had achieved an ACR70 response. Overall, 19% maintained an ACR70 response for 24 consecutive weeks. Similar results were obtained in the other two groups. Remission rates were maintained or increased over time. Tocilizumab was generally well tolerated. The most commonly reported adverse events
were upper respiratory infection, nasopharyngitis, headache and hypertension.

Abatacept
Data presented by Dr Kremer showed that abatacept plus methotrexate given to RA patients who had not adequately responded to methotrexate maintained efficacy through five years of treatment.

Patients completing the Abatacept in Inadequate responders to Methotrexate (AIM) trial were eligible to enter an open-label, long-term extension period. Patients received abatacept ~10 mg/kg plus MTX.

Of the 433 and 219 patients randomised initially and treated with abatacept or placebo, 378 and 161, respectively, entered the long-term extension study.

Of the patients originally randomised to abatacept, 70.4% remained on treatment at year five. The types and incidence of adverse events and serious adverse events were similar in the double-blind period and the five-year cumulative period, and ACR response rates were also sustained.

References
1. National Institute for Health and Clinical Excellence (NICE) clinical guideline 79. Rheumatoid arthritis. April 2009. http://guidance.nice.org.uk/CG79/NiceGuidance/doc/English
2. Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet 2007;370:1861-74.
3. Combe B, et al. EULAR recommendations for the management of early arthritis. Ann Rheum Dis 2007;66:34-45.
4. Keystone E. Arthritis Rheum 2008;58:3319-29.



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