Guidance
2 Clinical need and practice
The problem addressed
2.1 Tumour necrosis factor (TNF)‑alpha inhibitors are recommended as treatment options for people with severe rheumatoid arthritis (disease activity score [DAS28] greater than 5.1) whose disease does not respond to intensive conventional therapy (a combination of conventional disease-modifying antirheumatic drugs [DMARDs]).
2.2 In some people, the disease does not respond to treatment with TNF‑alpha inhibitors or stops responding over time. This can be related to the formation of antibodies to TNF‑alpha inhibitors and fluctuations in circulating TNF‑alpha inhibitor levels. Therefore, laboratory tests that measure the levels of these antibodies and the circulating drug could help clinicians understand the reasons for non-response (for example, to exclude poor adherence). This information could guide decisions on which treatment to offer next. Currently, although there is considerable interest in therapeutic drug monitoring, treatment decisions are usually based on clinical judgement alone.
2.3 Therapeutic monitoring of TNF-alpha inhibitors could also potentially benefit people whose rheumatoid arthritis has a sustained response to these drugs and who could be considered for dose reduction. Reducing the dose of TNF‑alpha inhibitor is expected to lower the risk of unnecessary side effects such as serious infections, and lower the cost of treatment, without negatively affecting outcomes. Currently, dose reduction is not routine NHS practice and if carried out, it is usually based only on clinical assessment and patient history.
2.4 The purpose of this assessment is to evaluate the clinical effectiveness and cost effectiveness of using enzyme-linked immunosorbent assay (ELISA) tests (Promonitor, IDKmonitor, LISA-TRACKER, RIDASCREEN, MabTrack, and tests used by Sanquin Diagnostic Services). These are used to measure circulating drug levels and antidrug antibodies to monitor response to TNF‑alpha inhibitors (adalimumab, etanercept, infliximab, certolizumab pegol and golimumab) in people with rheumatoid arthritis who:
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have reached their treatment target (remission or low disease activity)
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have disease that has not responded to TNF‑alpha inhibitors (primary non-response)
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have disease that has stopped responding to TNF‑alpha inhibitors (secondary non-response).
The condition
2.5 Rheumatoid arthritis is a chronic systemic autoimmune disease, primarily causing inflammation, pain and stiffness (synovitis) in the joints. It affects approximately 0.8% of the population (around 500,000 people in the UK; Symmons et al. 2002). The disease affects about 2 to 3 times more women than men.
2.6 The course of rheumatoid arthritis varies considerably from person to person, but often results in substantial morbidity, impaired physical activity, poor quality of life, and reduced life expectancy. It is marked by relapses (when the disease flares up) and remission (when there are few or no signs or symptoms). Rheumatoid arthritis is currently incurable, and people will remain on treatment for the rest of their lives.
The care pathways
2.7 Initial diagnosis and management of rheumatoid arthritis, including monitoring of treatment response, are covered in NICE's guideline on rheumatoid arthritis.
2.8 People with active rheumatoid arthritis should have treatment with the aim of disease remission or low disease activity. Monitoring treatment response allows treatment adjustments to be made. In current clinical practice, the DAS28 and the European League Against Rheumatism (EULAR) response classification system (which is based on the DAS28) are most commonly used to monitor disease activity.
2.9 People with rheumatoid arthritis whose disease does not respond to intensive conventional therapy (a combination of conventional DMARDs), and whose disease is severe (DAS28 greater than 5.1), may have treatment with biological therapy. This includes the TNF‑alpha inhibitors adalimumab, etanercept, infliximab, certolizumab pegol and golimumab.
2.10 Treatment with a TNF‑alpha inhibitor should only be continued if there is an adequate response (using EULAR criteria) 6 months after starting therapy. Treatment should be withdrawn if an adequate EULAR response is not maintained.
2.11 Currently, monitoring response to TNF‑alpha inhibitors is usually based only on clinical assessment and patient history. A monitoring review appointment generally takes place 6 months after reaching the treatment target (remission or low disease activity) to ensure it has been maintained. Monitoring should continue every 6 to 12 months to assess disease activity, treatment response, functioning, quality of life, comorbidities, complications and the need for surgery, and to arrange multidisciplinary referrals.
2.12 Treatment options for people whose disease does not respond to treatment with TNF-alpha inhibitors or stops responding over time include switching to another TNF‑alpha inhibitor or switching to treatment with a different mechanism of action.
2.13 Currently, dose reduction of TNF‑alpha inhibitors in people whose disease is in sustained remission or has low disease activity is not part of routine NHS practice in England and is not covered in NICE guidance. However, dose reduction is already being done in some centres, and there is interest in developing local treatment protocols for dose reduction in the UK. Also, the EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological DMARDs recommend reducing the dose of biological DMARDs if a person's disease is in persistent remission after reducing their dose of glucocorticoids, especially if this treatment is combined with a conventional DMARD.