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IIn its guidance published in October 2007, NICE describes rheumatoid arthritis (RA) as ‘a chronic progressive and disabling condition characterised by inflammation of the synovial tissue of the joints’.1 It affects all aspects of the patient’s life, from family and social circles to education and employment, with an estimated one-third of people with RA giving up work as a result of the disease.1

Inflammation of the synovial tissue in joints is characteristic of RA, and causes pain, swelling, and stiffness, and can lead to joint destruction. In its severest form, RA causes relentless pain and swelling, affecting approximately 15% of people with the disease. This results in severe disability and loss of function.1

In the UK, between 0.5% and 1% of people have RA, making it the most common inflammatory polyarthropathy. A recent technology appraisal from NICE reports that approximately 400,000 people in England and Wales have RA.1

Management of rheumatoid arthritis

Management of RA is holistic and multidisciplinary. Physical therapy and surgical intervention are considered alongside pharmacology. Treatment has several key aims. These include:

• controlling joint pain and inflammation
• reducing joint damage, disability, and loss of function
• improving quality of life.1

Pharmacological treatment

There are several agents available for conventional drug therapy for RA, involving various combinations of:1

• non-steroidal anti-inflammatory drugs
• analgesics
• corticosteroids
• disease-modifying anti-rheumatic drugs (DMARDs).

Based on the evidence, patients with RA should be treated with DMARDs soon after diagnosis. When this treatment is delayed, patients may have worse outcomes. The DMARDs aim to ameliorate symptoms and slow the progress of structural damage. There are several in use and they are conventionally used in sequence, the order of which depends on the patient and the prescribing doctor. Current best practice advocates initial treatment with methotrexate. It is becoming more common for DMARDS to be used in combination.1

When treatment with DMARDs has failed to achieve an improvement in the patient’s condition, the only available option until now has been to control symptoms with steroids and analgesics. These patients have the greatest level of unmet medical need, and are also responsible for the greatest proportion of direct medical costs. It is this group that may benefit from treatment with biologic therapies.1

Anti-TNF-α therapy

Tumour necrosis factor alpha (TNF-α), a pro-inflammatory mediator, has been identified as a key molecule in the pathogenesis of RA. Overexpression of TNF-α is one cause of the damaging inflammatory processes that occur in bone and synovium.1

Currently, three TNF-α inhibitors are licensed for use in the UK for the treatment of RA—infliximab, etanercept, and adalimumab. They are only licensed to be used when treatment with two standard DMARDs (including methotrexate unless contraindicated) has failed. The patient must also have a disease activity score including a 28-joint count (DAS28)2 of more than 5.1 on two occasions a month apart. The DAS is a standardised method of assessing disease activity and measures the number of swollen joints, the number of tender joints, the erythrocyte sedimentation rate, and the patient’s global assessment. A formula is then used to calculate the DAS; this can range from remission (less than 2.6), to active disease (greater than 5.1).3

Rituximab for rheumatoid arthritis

Most cases of RA respond well to one of the three licensed agents, but there is a group of patients for whom this is not the case, and, until recently, nothing more could be done than try one of the other DMARDs. Experience has shown that of those patients who do not respond to one TNF-α inhibitor, 30% or more will also be unresponsive to an alternative one.4 This means that there is a relatively large number of patients who have responded neither to DMARDs nor to TNF-α inhibitor therapy. What can be done to help them?

Rituximab is a genetically engineered chimeric monoclonal antibody that depletes the B-cell population by targeting cells bearing the CD20 surface marker. In combination with methotrexate, rituximab is licensed for the treatment of adults with severe active RA who have shown an inadequate response to, or are intolerant of, other DMARDs, including one or more TNF-α inhibitor therapies. A course of rituximab comprises two intravenous infusions of 1000 mg each, which are given 2 weeks apart.5

Rituximab differs from other TNF-α inhibitors in that it is an antibody that specifically attacks B lymphocytes, as opposed to disabling the pro-inflammatory cytokine TNF. This explains its effectiveness in those cases unresponsive to TNF-α inhibitors. Rituximab was originally developed for the treatment of B cell lymphomas.6

The other interesting feature of rituximab is that repeat courses of treatment (rituximab plus methotrexate) should be given no more frequently than every 6 months after the initial injections.5

Possible adverse effects of rituximab

The drug will be prescribed and monitored by specialist rheumatology units, but GPs should be aware of any adverse effects. There may be initial effects from the infusions, including fever, and chest symptoms such as cough and breathlessness. Immunisations are not effective for some time after treatment with rituximab as a result of depletion of B cells, and if immunisations are scheduled, it is worth advising patients to complete the course before rituximab is given. Live vaccines are not recommended in patients receiving rituximab; for example, yellow fever vaccine. However, if a live vaccine has to be used, such as rubella, the risks and benefits must be assessed for each patient individually.

NICE recommendations

In NICE technology appraisal 126, released in 2007, NICE has considered the evidence for the clinical effectiveness of rituximab and the health economics of its use. Recommendations include:5

• giving rituximab, in combination with methotrexate, as a treatment for adults with severe active RA, who have had an inadequate response to, or are intolerant of other DMARDs—including previous treatment with at least one TNF-α inhibitor
• continuing treatment with rituximab plus methotrexate only if there is an adequate response following initiation of therapy—an adequate response is defined as an improvement in the DAS28 of 1.2 points or more. Repeat courses of treatment (rituximab plus methotrexate) should be given no more frequently than every 6 months
• making specialist physicians, experienced in the diagnosis and treatment of RA, responsible for initiating, supervising, and administering treatment with rituximab plus methotrexate—they should also assess the treatment response.

Implication for GPs

This new NICE approval means that those patients with RA who are resistant to all other treatments and yet are severely affected, should now be offered rituximab. Evidence suggests that this should improve their DAS and health outcomes and make a huge difference to the quality of their lives.

Key points for GPs

Aims of treatment are to control the symptoms of RA—joint pain with swelling, stiffness, and inflammation—reduce damage and disability with loss of function, and maintain or improve quality of life Conventional therapy involves NSAIDs, pain killers, corticosteroids, and DMARDs in various combinations—treatment with DMARDS should be started soon after diagnosis If these therapies fail to achieve an improvement in a patient’s condition, therapy with TNF-α inhibitors will be started by the local specialised rheumatology unit The patient’s DAS28 should be measured on two occasions a month apart — this is usually done in the rheumatology department Rituximab, in combination with methotrexate, is licensed for the treatment of adults with severe active RA who have demonstrated an inadequate response to, or are intolerant of, other DMARDs, including one or more TNF-α inhibitors GPs need to be aware that immunisations are not effective for some time after completion of the treatment with rituximab as the therapy depletes B cells

RA=rheumatoid arthritis; NSAIDs=non-steroidal anti-inflammatory drugs; DMARDs=disease-modifying anti-rheumatic drugs; TNF-α=tumour necrosis factor alpha; DAS28=disease activity score including a 28-joint count

Practice-based commissioning take home messages

written by Dr David Jenner, NHS Alliance PBC Lead Rituximab is only recommended for use in a subset of the approximate 1% of the general population with RA—those adults with severe active RA who have responded neither to conventional DMARDs nor to at least one TNF-α inhibitor NICE states its prescription and administration should be undertaken only by specialist physicians. It provides a costing template to help estimate the costs1 Rituximab is administered by intravenous infusion and it should be decided with local rheumatology specialists whether this can be administered in a local community setting or in hospital If it can be safely administered in a local community setting, expensive hospital admission tariff charges can be avoided Tariff prices:2 rheumatology outpatient = £224 (new), £99 (follow-up); rheumatology elective day case = £1338 (cost of drug excluded)

RA=rheumatoid arthritis; DMARDs=disease-modifying anti-rheumatic drugs; TNF-α= tumour necrosis factor alpha 1www.nice.org.uk 2

References

1. National Institute for Health and Care Excellence. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. Technology appraisal 130. London: NICE, 2007.
2. Prevoo M, van’t Hof M, Kuper H et al. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38 (1): 44–48.
3. van Riel P, van Gestrel A, van der Putte L. Development and validation of response criteria in rheumatoid arthritis: steps towards an international consensus on prognostic markers. Br J Rheumatol 1996; 35 (2): 4–7.
4. Criscione L, St Clair E. Tumour necrosis alpha antagonists for the treatment of rheumatic diseases. Curr Opin Rheumatol 2002; 14 (3): 204–211.
5. National Institute for Health and Care Excellence. Rituximab for the treatment of rheumatoid arthritis. Technology appraisal 126. London: NICE, 2007.
6. National Institute for Health and Care Excellence. Rituximab for the treatment of follicular lymphoma. Technology appraisal 110. London: NICE, 2006.G

Dr Louise Warburton
GPwSI in musculoskeletal medicine and rheumatology
GP in Shropshire
Member of the Primary Care Rheumatology Society steering committee