Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor

Rheumatoid arthritis is a chronic and progressive disabling condition characterised by inflammation of the synovial tissue of the joints. It may cause tenderness and stiffness of joints and their progressive destruction, and symptoms including pain and fatigue. It is estimated that 580,000 people in England and Wales, approximately 1% of the population, have rheumatoid arthritis. Of these, approximately 15% have severe disease. Rheumatoid arthritis affects three times as many women as men and has a peak age of onset of 40 to 70 years.

In rheumatoid arthritis, the synovial membrane thickens because of an increased number of synovial cells, infiltration by white blood cells and formation of new blood vessels. Synovial fluid increases within the joint cavity, and bone mineral density adjacent to the joint reduces. Erosions of the bone may occur at the margin of the joint where synovial tissue meets cartilage and bone, and this can lead to irreversible damage to the structure and function of the joint.

Inflammatory disease involving areas other than the joints can also occur. Dryness of the eyes and mouth and the formation of rheumatoid nodules may affect up to one third of people with rheumatoid arthritis. More severe inflammatory manifestations may lead to fibrosis in the lungs and inflammation affecting the lining of the heart, lungs and blood vessels. Ischaemic heart disease and cardiac failure are more common in people with rheumatoid arthritis than in those without this condition. Osteoporosis is also more common because of reduced mobility, inflammation and/or the side effects of drugs used to treat rheumatoid arthritis, particularly corticosteroids. Corticosteroid use can also contribute to an increased risk of infection and diabetes mellitus.

Internationally agreed criteria for the diagnosis of rheumatoid arthritis (American College of Rheumatology [ACR] 1987) require four of the following features:

• joint stiffness in the morning exceeding 1 hour

• physician-observed arthritis of three or more areas with soft tissue swelling

• arthritis involving hand joints

• symmetrical arthritis

• rheumatoid skin nodules

• a positive blood test for rheumatoid factor

• radiographic changes typical of rheumatoid disease.

A diagnosis requires that, with the exception of the last criterion, all criteria must be present for a minimum of 6 weeks. However, clinicians sometimes diagnose rheumatoid arthritis without reference to these criteria.

The course of rheumatoid arthritis varies, and the following factors indicate poor prognosis: the presence of antibodies to rheumatoid factor or cyclic citrullinated peptide (CCP); high erythrocyte sedimentation rate or concentrations of C-reactive protein; early radiographic evidence of erosions; and the presence of swollen and tender joints. Within 2 years of diagnosis, people with rheumatoid arthritis may experience moderate disability, and after 10 years 30% are severely disabled. Approximately one third of people with rheumatoid arthritis stop work because of the disease. Rheumatoid arthritis is associated with a reduced life expectancy; for example, a 50-year-old woman with rheumatoid arthritis is expected to die 4 years earlier than a 50-year-old woman without rheumatoid arthritis.

The aim of treatment is to induce remission of disease, control pain and inflammation, and reduce or prevent joint damage, disability and loss of function, thereby improving quality of life. Treatment involves a combination of pharmacological and non-pharmacological interventions. Pharmacological treatment includes various combinations of non-steroidal anti-inflammatory drugs (NSAIDs), analgesics, corticosteroids and disease modifying anti-rheumatic drugs (DMARDs). DMARDs reduce symptoms and slow progression of structural damage. DMARDs may be classified as conventional (for example methotrexate or sulfasalazine) or biological. Biological DMARDs include, but are not limited to, the TNF inhibitors adalimumab, etanercept and infliximab, as well as rituximab and abatacept. Non-pharmacological interventions include orthopaedic surgery, physiotherapy and occupational therapy.

NICE's guideline on rheumatoid arthritis in adults (now replaced by NICE's guideline on rheumatoid arthritis in adults: management) recommends the use of a combination of conventional DMARDs (including methotrexate and at least one other conventional DMARD plus short-term glucocorticoids) as first-line treatment, beginning ideally within 3 months of the onset of persistent symptoms. When combination therapy is not appropriate (for example, in people with methotrexate intolerance), the guideline recommends monotherapy with a conventional DMARD with quick escalation to a clinically effective dose.

The TNF inhibitors adalimumab, etanercept or infliximab, (NICE's technology appraisal guidance on adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis [2007] now replaced by NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed) and certolizumab pegol (NICE's technology appraisal guidance on certolizumab pegol for the treatment of rheumatoid arthritis [2010] now replaced by NICE's technology appraisal guidance on adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for rheumatoid arthritis not previously treated with DMARDs or after conventional DMARDs only have failed), each in combination with methotrexate, are recommended as options for the treatment of adults with active rheumatoid arthritis who have a disease activity score (DAS28) greater than 5.1 and whose rheumatoid arthritis has failed to respond to at least two conventional DMARDs, including methotrexate. If a patient does not tolerate methotrexate or if treatment with methotrexate is considered to be inappropriate, adalimumab, etanercept and certolizumab pegol may be given as monotherapy. Treatment should be withdrawn if response is not adequate within 6 months (as defined by an improvement in DAS28 score of more than 1.2 points) or if response is not maintained. Response to treatment should be monitored at least every 6 months. An alternative TNF inhibitor may be considered when treatment with a first TNF inhibitor is withdrawn because of an adverse event before the initial 6-month assessment.

Several tools have been developed to assess the response to treatment in rheumatoid arthritis. The American College of Rheumatology (ACR) response criteria (ACR20, 50 and 70) require a specified improvement in the percentage (20%, 50% or 70% respectively) of tender joints, swollen joints, global assessments, pain, disability and circulating inflammatory markers (for example, erythrocyte sedimentation rate). The disease activity score (DAS) is an alternative scoring system developed in Europe. It is calculated using a formula that includes counts for tender and swollen joints (53 and 44 joints respectively), an evaluation of general health by the patient (on a scale of 0 to 100) and a measure of circulating inflammatory markers. DAS28 is similar to DAS but uses only 28 joints for assessment. A DAS28 score greater than 5.1 indicates high disease activity, between 3.2 and 5.1 moderate disease activity, and less than 3.2 low disease activity. A score of less than 2.6 indicates disease remission. An improvement in DAS28 score of 0.6 or less is considered a poor response, and improvements greater than 1.2 points indicate a good response. The European League Against Rheumatism (EULAR) response criteria are based on the DAS measure. The Stanford Health Assessment Questionnaire (HAQ) comprises one component of the ACR criteria and scores the ability to perform daily activities; it ranges from 0 (least disability) to 3 (most severe disability). The modified Sharp score measures joint damage as assessed radiographically, and is scored on joint-space narrowing and erosions.