Dr Elspeth Wise discusses the technology appraisals on the use of biological therapies in the management of rheumatoid arthritis


Rheumatoid arthritis (RA )is an autoimmune condition that presents predominantly as an inflammatory arthritis affecting synovial joints, although other systems can be involved. It affects around 1% of the UK population with women being nearly three times more likely to develop the condition than men.1,2 The 2009 NICE guideline on the management of RA recommended using a combination of clinical features and laboratory investigations for diagnosing this disease rather than the more traditional criteria that are often used in studies.3 It advised GPs to refer patients presenting with:3

  • suspected persistent synovitis of undetermined cause. Urgent referral should take place if:
  • the small joints of the hands and feet are affected
  • more than one joint is affected
  • there has been a delay of 3 months or longer between onset of symptoms and seeking medical advice.

The aim of early referral is to allow appropriate treatment to be started as soon as possible in order to prevent joint damage. Prior to the use of magnetic resonance imaging and ultrasound, it was thought that around 20% of patients had evidence of joint damage at presentation. Now, with these more sophisticated techniques being available both for studies and in routine clinical practice, it appears that around 80% of affected people actually have joint damage when first seen by rheumatology specialists.4 It is believed that early aggressive treatment prevents this damage from progressing and may actually help RA to regress.

Pharmacological management of rheumatoid arthritis

Initial pharmacological management of RA is with a combination of non-steroidal inflammatory agents, steroids, analgesics, and disease-modifying anti-rheumatic drugs (DMARDs). The traditional/conventional DMARDs that have been part of managing RA for decades include: methotrexate, sulfasalazine, leflunomide, ciclosporin, azathioprine, hydroxychloroquine, gold, and penicillamine.1–5 The way in which they have been used has changed over recent years, and in particular with the publication of the NICE guideline,3 which recommended a much more aggressive treatment approach than had previously been used.

A combination of DMARDs (one of which should be methotrexate) is now recommended as first-line treatment, with doses being rapidly escalated until they reach a clinically effective dose.3 Patients will generally try two or three of these agents before moving on to the next stage, which is treatment with the newer biological therapies.

Biological drugs

Over recent years, biological drugs have been developed for the treatment of RA. Their use is becoming more and more widespread not only in rheumatology but also in other fields. It is estimated that around 6% of all UK patients with RA are receiving these agents.5 Biological drugs target different parts of the inflammatory cascade including tumour necrosis factor-? (TNF-?), B cells, T-cell activation, and interleukin 6 (IL-6).

In August 2010, NICE issued two sets of guidance relating to the management of rheumatoid arthritis (RA):

  • Technology Appraisal (TA) 195 on Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor is a part review of TA36, and a review of TA126 and TA1411
  • TA198 on Tocilizumab for the treatment of rheumatoid arthritis, is the first time that NICE has issued advice regarding this therapy.6

Earlier in 2010, NICE published TA186 on Certolizumab pegol for the treatment of rheumatoid arthritis.7

These new TAs on the use of the biological drugs now take into account what treatment to offer to patients who fail to respond to their first biologic agent, generally a TNF inhibitor.

Adalimumab, etanercept, infliximab, rituximab, and abatacept
The NICE guidance suggests using rituximab (in combination with methotrexate) first of all if patients with severe RA have not responded to, or are intolerant of, other DMARDs including at least one TNF inhibitor. Treatment should only be continued if patients demonstrate an adequate response (an improvement in disease activity score [DAS28] of 1.2 or more) and if this is maintained.1

Adults with severe active RA who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they have a contraindication to rituximab, or when rituximab is withdrawn because of an adverse event, are now allowed to progress onto trying adalimumab, etanercept, infliximab, or abatacept. Again, an adequate response must be shown to occur and must be maintained.1

All of these above drugs should be given with methotrexate if possible. However if the patient has a contraindication or if methotrexate is withdrawn because of an adverse event, adalimumab monotherapy and etanercept monotherapy are treatment options.

Certolizumab pegol
In TA186, NICE recommends certolizumab pegol if:7

  • it is used as described for other TNF inhibitor treatments in TA195 and
  • the manufacturer provides the first 12 weeks of certolizumab pegol (10 pre-loaded 200-mg syringes) free of charge to all patients starting treatment.

Tocilizumab
NICE recommends that tocilizumab in combination with methotrexate, is used for patients with moderate to severe active RA who have not responded adequately to one or more TNF inhibitors and who have:7

  • not responded to rituximab or
  • in whom rituximab is contraindicated or when rituximab is withdrawn because of an adverse effect.

The NICE guidance emphasises that patients who are already receiving tocilizumab for RA should have the option to continue until they and their consider it appropriate to stop.6

Dosage and administration
These drugs differ in their mode, frequency of administration, and in their licensed usage.1,8

Patients can be taught to self administer adalimumab and etanercept, which are both given as subcutaneous injections. Adalimumab is given fortnightly but can be increased to a weekly dose if the patient is not taking methotrexate. Etanercept can given once or twice weekly.1,8 Infliximab is administered as an intravenous infusion, generally every 8 weeks depending on how the patient responds.1,8

Rituximab and abatacept are newer agents that affect different areas of the inflammatory cascade. Rituximab acts by depleting B cells and is given as two intravenous infusions 2 weeks apart. If patients respond to rituximab the course can be repeated.8 Abatacept acts by blocking full T-cell activation and is given as an intravenous infusion over 30 minutes every 4 weeks. Both of these agents should also be given in combination with methotrexate.8

Certolizumab pegol is given in combination with methotrexate subcutaneously in maintenance doses of 200 mg every 2 weeks. It can also be taken as monotherapy in case of intolerance to methotrexate or if methotrexate is inappropriate.7

Tocilizumab is a monoclonal antibody, which acts by inhibiting IL-6. Treatment is given as an intravenous infusion over an hour every 4 weeks and is usually given in combination with methotrexate.7 The recommended dosage is 8 mg/kg, given once every 4 weeks after the loading regimen.6,7

Implications for GPs

Tumour necrosis factor inhibitors have revolutionised the management of RA. Patients who appear to have not responded to DMARDs now have other options to try, and very often these are successful at controlling their disease. These three pieces of guidance (TA186, TA195, and TA198) have clarified how to treat patients who have not responded to their first TNF inhibitor and allows for patients to try two or three different treatments; this choice should be welcomed.

The use of biological agents will become more and more widespread. Therefore, GPs must be aware of the potential side-effects and how to manage them. The biological therapies are generally well tolerated, but they are strong immunosuppressants so sepsis must always be considered as a potential cause of any presenting symptoms.8 It must be remembered that the usual symptoms of a raised temperature and systemic upset may not be present and, if there is any concern, to contact the prescribing physician for advice. There is also concern over a theoretical increased risk of cancer in patients on biological treatments although no definite link has been seen as yet.

All biological agents are hospital prescribed and because of this, their use may not be recorded in the patient’s notes.9 It is worth considering coding the patient as being immunosuppressed and adding an alert to their records if at all possible.

Conclusion

These three technology appraisals offer hope to patients with severe rheumatoid arthritis. They now have a multitude of options available should they fail to respond to their initial treatment. It is imperative that GPs are aware if patients are receiving biologics and that they have knowledge on possible side-effects.

References

  1. National Institute for Health and Care Excellence. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. Technology Appraisal 195. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA195
  2. Symmons D, Turner G, Webb R et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology 2002; 41 (7): 793–800.
  3. National Institute for Health and Care Excellence. Rheumatoid arthritis: national clinical guideline for management and treatment in adults. Clinical Guideline 79. London: NICE, 2009. Available at: www.nice.org.uk/CG79
  4. Emery P. Treatment of rheumatoid arthritis. BMJ 2006; 332: 152–155.
  5. Arthritis Research UK. Hands on. An update on DMARDs and biologics. Summer 2010, No 6. Arthritis Research UK. Available at: www.arthritisresearchuk.org/arthritis_information/information_for_medical_profes/hands_on,_syn_and_topical_revi.aspx
  6. National Institute for Health and Care Excellence. Tocilizumab for the treatment of rheumatoid arthritis. Technology Appraisal 198. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA198
  7. National Institute for Health and Care Excellence. Certolozumab pegol for the treatment of rheumatoid arthritis. Technology Appraisal 186. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA186
  8. British National Formulary. BNF 60. September 2010. London: British Medical Association and the Royal Pharmaceutical Society of Great Britain, 2010.
  9. Wise E, Burdon A, Nicholl K et al. Documentation of anti-TNF therapy in primary care health records. Oral presentation presented at the British Society of Rheumatology Annual Meeting; May 8–11, 2007; Birmingham. G
Guidelines in Practice will feature an article on the British Society for Rheumatology and British Health Professionals in Rheumatology guideline on eligibility criteria for first biological therapy in the November issue of the journal