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The availability of new therapies such as tocilizumab is key in improving the management of rheumatoid arthritis
Unit of Clinical Pharmacy
Hôpital Cochin – APHP
Rheumatoid arthritis (RA) is a chronic disease with alternating phases of remission and relapse. When arthritis is “active”, there are joint pains, synovitis and a biological inflammatory syndrome. This activity is measured with the DAS (disease activity score) or the DAS 28, which includes the ESR (erythrocytes sedimentation rate), the tender joint count, swollen joint count and the evaluation of the disease made by the patient. A treatment can then be introduced with the intent to put the disease into remission.
The use of biologic therapy in the treatment of RA has widely exploded in recent years. The anti-TNF (tumour necrosis factor) alpha agents were the first pharmacological class developed and used in this indication. Rituximab, abatacept and anakinra completed the therapeutic spectrum for physicians. All these molecules have demonstrated their efficacy. In clinical trials, the efficacy of drugs in treatment of RA is most often assessed by the American College of Rheumatology 20 criteria (x% of patients who reach the ACR20 criteria have at least 20% improvement of their disease). Tolerance is another important element to consider in clinical trials because it is often a cause of drug discontinuation in clinical care.
However, after a while patients will no longer respond to each of these treatments or have a major intolerance that requires disruption of treatment. Tocilizumab (TCZ), a new biotherapy with a different pharmacological action is a new option for patients in therapeutic failure.
Concept of treatment failure
When the Disease Modifying Anti-Rheumatics Drugs Agents (DMARDs) such as methotrexate (MTX) are not enough for patients with rheumatoid arthritis, starting a TNF therapy is recommended. Three anti-TNF alpha agents are available in Europe: infliximab and adalimumab-both antibodies directed against TNF alpha-and etanercept, which is a soluble receptor of TNF alpha.
The clinical trial ATTRACT, a phase III placebo-controlled trial, evaluated infliximab in combination with MTX in patients with RA after a prior treatment with MTX alone. The results showed an efficacy depending on the ACR20 criteria to 54 weeks for 52% of patients. Infliximab is an effective molecule but nearly half of patients do not respond, or do not sustain a response. Adalimumab and etanercept gave similar results. In addition, data from clinical trials, which are made on a limited population and therefore not representative of all patients, most probably overestimate the effectiveness of anti-TNF agents and underestimate the frequent side-effects. In case of failure or intolerance to an anti-TNF agent, it is possible to use another anti-TNF agent. Etanercept should be preferred if it has not yet been tested because of its mode of action, which is different from the other two.[5,6]
When the anti-TNF alpha agents are not effective or not indicated, rituximab and abatacept are then possible options. To date, no phase III trial has directly compared these two molecules together. Like the anti-TNF alpha agents, molecules are effective in RA but only for a limited number of patients.
Rituximab is an anti-CD20 antibody that induces a depletion of the B cells involved in pathological inflammation. It was the first of three drugs marketed for this indication. The WA 17042 pivotal study showed that 51% of patients reach ACR20 at 24 weeks following treatment with rituximab and MTX after an inadequate response to anti-TNF therapies. A recent observational study suggests that using rituximab is more effective than switching an anti-TNF agent to another anti-TNF agent when the motive to stop was an ineffective treatment.
Abatacept inhibits T cell activation by blocking co-stimulation mediated by the ligand CD80/86 on antigen-presenting cells. Abatacept was also evaluated in patients failing therapy with anti-TNF agents in the pivotal phase III trial IM10029. After 24 weeks, 50.4% of patients had an ACR20 response. This effect seems to remain at two years, according to other studies.[8,9] It is interesting to note that an academic and direct comparative study has shown after six months an increased tolerance statistically significant with abatacept compared with infliximab in patients with an inadequate response to MTX. From all these data, we note that the biotherapies have greatly improved the quality of life of patients suffering from RA and the prognosis of the disease, but also that the effectiveness is incomplete, as it is about 50% for each of these drugs.
Tocilizumab: a new biotherapy
TCZ received its European licence in January 2009 from the European Medicines Agency. It is a humanised antibody directed against the receptor for IL-6, a proinflammatory cytokine implicated in the pathogenesis of some autoimmune diseases including rheumatoid arthritis.TCZ is licensed as monotherapy or in combination with a DMARD in rheumatoid arthritis at the dose of 8mg/kg every four weeks. TCZ has demonstrated efficacy in several phase III studies in patients naïve of biotherapy (study OPTION, TOWARD and AMBITION).
One of its pivotal studies (RADIATE) comparing TCZ + MTX with MTX alone has evaluated the efficacy in 499 patients with an inadequate response to one or more TNF alpha antagonists. ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8mg/kg, 4mg/kg and control groups. No study has directly compared TCZ with anti-TNF alpha agents. Serious side-effects of tocilizumab were identified during clinical trials such as severe infections, hypersensitivity, neutropenia, increased hepatic transaminases, and thrombocytopenia. They have to motivate a dose reduction or the disruption of the treatment.
During the last 10 years, rheumatology has seen a significant change with biotherapies. The clinical development in this area remains fully active, as evident by TCZ. However, RA is a severe chronic disease that can not always get in remission despite these new available treatments. Physicians will sometimes have to use several successive lines of treatment to relieve their patients. Indeed, the simultaneous use of two different biotherapies is probably more harmful than it is effective and is not currently planned to get a higher rate of responders.
It is widely accepted that anti-TNF alpha agents should be used first if RA is not controlled with the DMARDs. TNF antagonists have demonstrated for several years their good risk/benefit ratio. Therefore, it is appropriate that the clinical development of the other biotherapies demonstrates, at the least, efficiency after one or more anti-TNF agents, not only in naïve patients.
It may seem surprising that a new biotherapy such as TCZ is not directly compared with abatacept or rituximab, which have been indicated for several years in this situation and for which we have a good knowledge. In fact, the inter-individual variability of response to biotherapy and the lack of reliable predictive factors of this response accounts for such strategy. Indeed, a non-response to rituximab does not prejudge the response that a patient will then get with abatacept and vice versa. To date, we are not yet able to choose a priority treatment that is most effective when treating RA patients. There are no recommendations to use one biotherapy over another.
In this context, TCZ can not be compared to rituximab or abatacept if a clinical benefit is established. Clinical trials of TCZ including the RADIATE study validated that the inhibition of IL-6 pathway is effective in the treatment of RA.
In future, observational studies regarding TCZ in larger population of patients would be useful to confirm that some of them benefit from an improvement in second- or third-line treatment. Although TCZ is indicated for patients after only one DMARD, it must still be evaluated as part of its post-marketing phase (phase IV). Patients for whom the risk/benefit ratio is then the largest are those that are in a therapeutic impasse. In clinical care, it is likely that TCZ will be first used in this particular population, because many patients did not respond to all other biotherapy – so TCZ is their only alternative.
As RA is a chronic disease that occurs in young adults, and the biotherapies have limited effectiveness over time, the availability of new therapies such as TCZ is important to improve the management of this disabling disease.
1. D Aletaha et al. Ann Rheum Dis Oct 2008;67:1360–4.
2. P-T Fan et al. Ann Acad Med Singapore 2007;36:128–34.
3. Jack D. Lancet 1999 Jun 19;353(9170):2132.
4. Caporali R et al. Autoimmun Rev 2009 Jan;8(3):274–80.
5. Karlsson JA et al. Rheumatology (Oxford). 2008 Apr;47(4):507–13.
6. Navarro-Sarabia F et al. BMC Musculoskelet Disord 2009 Jul 23;10:91.
7. Finckh A et al. Ann Rheum Dis 2009 May 15. Epub ahead of print.
8. Genovese MC et al. N Engl J Med 2005 Sep 15;353(11):1114–23.
9. Genovese MC et al. Ann Rheum Dis 2008 Apr;67(4):547–54.
10. Schiff M et al. Ann Rheum Dis 2008 Aug;67(8):1096–103.
11. Park JY et al. Bull NYU Hosp Jt Dis 2007;65 Suppl 1:S4–10
12. Emery P et al. Ann Rheum Dis 2008 Nov;67(11):1516–23.
13. Weinblatt M et al. Ann Rheum Dis 2007 Feb;66(2):228–34.