Rheumatology 2001; 40: 699-702
© 2001 British Society for Rheumatology
Report |
WHO Collaborating Centre consensus meeting on anti-cytokine therapy in rheumatoid arthritis
University of Leeds, Rheumatology and Rehabilitation Research Unit, 36 Clarendon Road, Leeds LS2 9NZ, UK,
1 CH Université de Liège, WHO Collaborating Centre, Bone and Cartilage Unit, 45 Quai Godefroid Kurth, 4020 Liège,
2 University of Brussels, Rheumatology, Erasmus Hospital, 88 Route De Lennik, 1070 Brussels, Belgium,
3 University Hospital, Department of Rheumatology, Building 1, C4-R, 2300 RC, Leiden, The Netherlands,
4 Department of Rheumatology, Lindenstrasse 2, 83043 Bad Aibling,
5 University of Magdeburg, Klinik für Rheumatologie, D-39245 Vogelsang, Germany,
6 CH Université de Liège, Sart-Tilman, 4000 Liège, Belgium,
7 Hospital Universitario La Paz, Rheumatology Unit, Paseo la Castellana 261, 28046 Madrid, Spain,
8 IRCCS Policlinico San Matteo, Rheumatology Department, Piazzale Golgi, 27100 Pavia, Italy,
9 Anti-inflammatory, Wyeth-Ayerst Research, 145 King of Prussia Road, Saint Davids, PA 19087-4588, USA,
10 Hôpital Lapeyronie, Service d’Immuno-Rhumatologie, 371 avenue du Doyen Gaston Giraud, 34295 Montpellier Cx 5, France,
11 Kings College Hospital, Clinical and Academic Rheumatology, East Dulwich Grove, London SE22 8PT, UK,
12 Istituto Ortopedico Toscano ‘P. Palagi’, Via Michelangelo 41, 50122 Firenze, Italy and
13 Global Strategic Marketing, Wyeth-Ayerst Pharmaceuticals, 555 East Lancaster Avenue, PO Box 8299, Philadelphia, PA 19101-8299, USA
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Abstract |
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 Top Abstract IntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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Severe adult rheumatoid arthritis is a cause of progressive disability and increased mortality across Europe. A cure for the disease remains elusive, but control of symptoms and maintenance of individual independence is possible. Anti-cytokine therapies offer a new approach to disease management. They are effective after the failure of full doses of methotrexate, and are at least as effective as methotrexate in retarding the progression of radiological changes. Until more is known about the long-term safety and efficacy of these drugs they should be reserved for patients with severe disease who are progressing despite adequate doses of methotrexate or other disease-modifying anti-rheumatic drugs. They should be continued until therapeutic failure or intolerance. A comprehensive health economic evaluation is needed to optimally direct the use of these drugs. This should be undertaken when long-term safety and efficacy studies are completed.
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Introduction |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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Two anti-tumour necrosis factor (TNF) agents have been granted marketing authorization by the European Medicines Evaluation Agency. These products are Remicade (infliximab), a chimaeric murine monoclonal anti-TNF, and Enbrel (etanercept), a P75–TNF receptor fusion protein. For each product there is a common data sheet or SmPC [1, 2] across the member states of the European Union. As a result, it was felt appropriate to have an approach to patient management which was common across Europe and which could be agreed by different nationalities, relating to the initiation and treatment of patients with these agents. To achieve this objective, a consensus meeting was held under the auspices of the WHO Collaborating Centre for Rheumatic Diseases, Liège, Belgium.
This document deals only with the therapy of adult rheumatoid arthritis (RA) and is the consensus of a representative group of rheumatologists practising within the European Union. It does not address the therapy of juvenile RA as only one of the two drugs is approved for use in children. Patients must be involved in the choice of treatment and management of this chronic disease. Approaches to patient participation have been well described for other chronic diseases, such as asthma and back pain [3]. The same principles apply to the treatment of RA.
RA is an important disease. It has an overall prevalence of around 1%. The prevalence of severe RA in the population is lower, at 0.23 [4], and the annual incidence of disease leads to severe disability in 1 in 10000 patients. Some 16% of patients have marked functional loss after 5 yr of conventional treatment [5]. Severe disease produces increased mortality and considerable morbidity with substantial costs to individuals.
Whilst once considered virtually untreatable, the effectiveness of traditional disease-modifying anti-rheumatic drugs (DMARDs) in altering the disease process is now convincingly established. The introduction of the anti-TNF therapies has taken this effectiveness one stage further. Their introduction has been the result of rapid drug development from animal models less than 10 yr ago to phase IV studies of outcome today. At both a theoretical and a practical level, these observations have confirmed the central role of cytokines, particularly TNF-
, in the pathogenesis of RA.
Studies have demonstrated the efficacy of cytokine blockade in treating the symptoms and signs of disease and additionally have demonstrated the prevention of progression of structural damage [6–12]. The availability of such agents represents a major advance in the management of this potentially crippling disease. However, such therapies have complex actions with several potential important side-effects. Therefore, they require a specialized monitoring assessment from physicians experienced in using immunomodulatory drugs in RA. Administration via intravenous infusion may require dedicated facilities to be set aside and patient education to be established for subcutaneous self-administration. Their exact place in the standard management of patients with RA has yet to be agreed. Earlier consensus statements were developed shortly after drug approvals and did not reflect the latest information on the impact on radiological progression of disease [13, 14].
This document represents a conservative first step in Europe towards providing guidance on integrating these drugs into everyday clinical practice.
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Which patients are appropriate for anti-cytokine therapy? |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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The stage of disease at which a disease-modifying drug is administered depends on a variety of judgements. At one end of the treatment spectrum are patients with early disease who have had no other therapy, and at the other end are patients who have exhausted all DMARD options. Where should anti-TNF therapy be placed in this spectrum?
Should anti-cytokine therapy be used in early disease at diagnosis?
The group felt that there was good evidence that anti-TNF therapy is effective in early disease, a large randomized study having demonstrated that etanercept produced significantly faster disease suppression than methotrexate 20 mg per week [9]. This faster mode of action resulted in early differences between the two groups and a significant improvement in the radiological erosion rate at 12 months. However, the difference was not significant for the total Sharp score. The assessment of function demonstrated that the cumulative ACR was significantly better in the etanercept group, but overall the Health Assessment Questionnaire score was not significantly different. In a post hoc analysis of the ATTRACT study [11]: comparing infliximab with placebo in partially treated methotrexate patients, those with a disease duration of less than 3 yr responded no differently to patients with disease of longer duration.
Clearly, anti-cytokine therapy works faster, at least as well as and, in some measures, better than methotrexate. However, until long-term safety studies and health economic analyses are complete, it is difficult to justify the broad introduction of these drugs in early disease before methotrexate.
Having answered this question, the committee was then asked to identify which patients with established disease should receive the anti-TNF therapies.
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Patients with established disease: who is eligible for anti-cytokine therapy? |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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The consensus group felt that appropriate patients were those in whom active inflammation continued despite adequate exposure to effective DMARDs. An adequate course of DMARD was defined as a course of methotrexate at a dose of at least 20 mg per week for 3 months or a lesser dose if limited by toxicity. In patients who had suffered methotrexate toxicity without adequate exposure to the DMARD effect, a trial of a second DMARD (e.g. sulphasalazine) should be undertaken.
What is unacceptable disease activity?
The definition of disease activity used in the clinical trials was too restrictive for clinical practice. The consensus group felt that unacceptable disease activity could be defined as five swollen joints plus an elevated acute-phase response, i.e. erythrocyte sedimentation rate 
28 mm/h or C-reactive protein 20 mg/l. This is approximately equivalent to a disease activity score (DAS) of >3.2. Thus, TNF- blockers are indicated in patients with RA and active disease as defined and who have failed an adequate course of DMARD therapy as defined above.
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Assessing success or failure of anti-TNF therapies |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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Currently the evidence suggests that long-term blockade of TNF is required. Given the high cost of these agents, only those patients who are truly benefiting should receive them. Patients who are not benefiting should be exposed to the agent for a minimum amount of time. Once the therapy has been initiated according to the criteria above, it is necessary to have some objective measures for deciding when to cease anti-TNF therapy.
Criteria for measuring success/failure
It was felt strongly by the committee that the response criteria should correspond to the entry criteria (for identifying DMARD failures). Thus, as patients are admitted to the study on the basis of swollen joints and acute-phase response, these should be the measures by which effectiveness is judged.
Definition of successful therapy
Successful therapy is defined as a 20% reduction in swollen joint count together with a 20% reduction in disease phase response. This would be equivalent with a reduction in the DAS by 1.2 or a total score or reduction of 
3.2.
Definition of failure of anti-TNF therapy
Treatment failure would be defined as a failure to reach the endpoints defined above for successive therapy by 12 weeks.
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Contraindications |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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The contraindications for anti-cytokine therapy recommended by the group are as follows: (i) hypersensitivity to the active substance or any of the excipients; (ii) sepsis or risk of sepsis; and (iii) the presence of active infection.
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Precautions |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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Prescribers should refer to the individual SmPCs for precautions for the use of anti-TNF agents.
Serious infections have been reported in patients during treatment with anti-TNF cytokines. In many cases this may have been related to underlying diseases, e.g. diabetes or congestive heart failure. Patients who develop infections should be closely monitored, and if the infection becomes serious treatment should be stopped.
Caution should be exercised in the presence of optical neuritis, multiple sclerosis and blood dyscrasia.
Reactivation of tuberculosis has been observed with the use of one anti-TNF agent. It is not known if this is a class effect, so caution should be exercised in patients with a history of tuberculosis.
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Monitoring |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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No specific laboratory tests are required. Periodic clinical evaluation should be carried out by a physician experienced in treating patients with RA with immunotherapy.
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Conclusion |
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TopAbstractIntroductionWhich patients are appropriate...Patients with established...Assessing success or failure...ContraindicationsPrecautionsMonitoringConclusionReferences |
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Anti-cytokine, and in particular anti-TNF therapy represents a significant scientific and clinical advance in the understanding and treatment of RA. It provides rapid symptomatic relief after the failure of methotrexate and other DMARDs in advanced disease. Anti-cytokine agents are at least as effective as methotrexate in early disease. Evidence is now emerging that they slow the radiological progression of disease, but it is too early to determine whether or not they alter the course of the disease. They are very well tolerated and serious side-effects are uncommon, but do occur. Supervision by a physician experienced in the treatment of RA with immunomodulatory drugs is advisable. A comprehensive health economics evaluation will be dependent on the availability of long-term clinical data. On present evidence, our recommendation is that these drugs be used after the failure of at least one DMARD given at a clinically effective dose. They should be continued indefinitely or until there are intolerable side-effects or therapeutic failure.
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Acknowledgments |
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The authors would like to acknowledge Karl Knight and Ayse Baxter (PharmaCom) for their assistance with this paper.
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Notes |
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Correspondence to: P. Emery, Rheumatology and Rehabilitation Research Unit, University of Leeds, 36 Clarendon Road, Leeds LS2 9NZ, UK.
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References |
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