Dr Elspeth Wise outlines the requisite criteria for offering biological therapies to patients with rheumatoid arthritis

The management of rheumatoid arthritis (RA) is becoming increasingly complex as our understanding of the inflammatory process occurring in joints evolves. New potential targets for treatment are being identified and drugs are being developed specifically to affect certain steps in the inflammatory cascade.

These biological agents are often expensive because of the cost of their development and production, which is why guidance published by NICE is essential to prevent any variation in prescribing. As these agents affect the body’s inflammatory response, they also increase the risk of infections. There is also concern that biological agents could increase the risk of malignancy, and a national register has therefore been created to monitor their use and side-effects.1

This article reviews the current management of RA as recommended by NICE and, in particular, indicates where its latest guidance (Technology Appraisal 247) on the use of tocilizumab fits into the treatment pathway.2

Measuring disease activity

The effect of any treatment for RA is assessed using a disease activity score (DAS); NICE recommends the use of the DAS28 score. This is a complex calculation that combines the number of tender/swollen joints, a patient’s inflammatory markers (e.g. erythrocyte sedimentation rate), and the patient’s own evaluation of their general health. It is called DAS28 as only 28 different joints are checked during the scoring.
A score of:3

  • >5.1 is regarded as high disease activity
  • <3.2 is regarded as low disease activity
  • <2.6 suggests that a patient’s disease has gone into remission.

Initial presentation

In 2009, NICE published Clinical Guideline 79 on the management of RA in adults.4 The NICE recommendations highlighted the importance of early referral for any patient with possible inflammatory joint disease.4 This is because joint damage occurs at an early stage and can be detected when patients are seen at their initial presentation in secondary care. This damage cannot be reversed, but can be stopped by adequate treatment and so early diagnosis and appropriate management is essential.

The current initial management of RA, as advised by NICE, is to start treatment with disease-modifying anti-rheumatic drugs (DMARDs).4 Two of these agents should be used in combination if possible, with methotrexate as one of the drugs, and the doses escalated to an effective dose as soon as possible. Glucocorticoids can be used concurrently to help control symptoms while the DMARD treatment is taking effect.4 This combination therapy should be trialled for 6 months with treatment for at least 2 months at the recognised standard drug doses for both agents.5 Disease-modifying anti-rheumatic drug monotherapy can be used if combination therapy is inappropriate.4

Methotrexate is favoured because studies have shown that early tight control of arthritis symptoms using this drug can significantly reduce disease activity.6 Methotrexate is known to cause pneumonitis and so all patients should receive a chest X-ray and pulmonary function tests prior to starting treatment, as arranged by their rheumatologist.7 If a patient on methotrexate develops a dry cough or increasing shortness of breath, their methotrexate should be stopped and specialist advice sought as soon as possible. From a primary care perspective, healthcare professionals must be aware that methotrexate is a folate antagonist and therefore must be co-prescribed with folic acid (5 mg) in order to prevent deficiency.7 The folic acid supplement should not be taken on the same day as the methotrexate dose. Clinicians must also ensure that trimethoprim and co-trimoxazole are not prescribed to these patients as they increase the anti-folate effect of methotrexate.7 The British National Formulary highlights an interaction with non-steroidal anti-inflammatory drugs,8 but this is rarely clinically significant and most patients can take them together safely.


Biological therapy

If a patient with RA has received a combination of DMARDs for 6 months with at least 2 months at the recognised standard doses and their disease activity remains high (i.e. a DAS28 score ?5.1 measured on at least two occasions, 1 month apart), he or she is eligible to receive biological therapy.5

Originally, NICE recommended adalimumab, etanercept, and infliximab as first-line biological agents, but later guidance added both certolizumab pegol and golimumab as possible treatment options.5,9,10 These five therapies are anti-tumour necrosis factor alpha (TNF-?) agents that inhibit TNF-?, a cytokine in the inflammatory cascade.

In February 2012, NICE reviewed its guidance on tocilizumab, and placed it alongside the anti-TNF-? agents as a first-line and also a second-line option.2 Tocilizumab acts by inhibiting interleukin-6, a different cytokine in the inflammatory cascade and is administered as an intravenous infusion. Similar to certolizumab pegol and golimumab, the use of tocilizumab is subject to an agreed discount with the manufacturer (patient access scheme) remaining in place.2,9,10

The choice of agent depends on cost, mode and frequency of administration, and whether or not a patient is able to take methotrexate. If methotrexate is contraindicated or not tolerated, then monotherapy with adalimumab, etanercept, or certolizumab pegol can be offered.5,9 If the patient can take methotrexate, any agent can be chosen. Use of a combination of methotrexate and a biological agent is preferred as it reduces side-effects and improves efficacy. If the patient experiences an adverse event to their first biological agent, they are eligible to try an alternative agent.5

For patients to be eligible for a continuation of biological therapy following a 6-month trial period, an adequate response in disease activity must be demonstrated. This is defined as an improvement in DAS 28 of ?1.2 points.2,5,9,10 If patients remain on the medication, their progress needs to be monitored at 6-monthly intervals as a minimum and their improvement must be maintained.

Treatment failure following the first biological agent

If a patient fails to respond adequately to their first anti-TNF-? agent or tocilizumab (i.e. did not achieve an improvement of their DAS28 by ?1.2 points), they can be offered rituximab.11 This is a monoclonal antibody directed against a protein found on the surface of some types of B cells. Rituximab causes the depletion of B cells, which reduces the activation of the inflammatory process. Rituximab must be used alongside methotrexate and is given at about 6-monthly intervals. Because of its action on B cells, rituximab should not be given to patients who are at increased risk of infections.11

If patients are unable to try rituximab then a second anti-TNF-? agent, abatacept (a T-cell modulator), or tocilizumab can be offered.11 As described previously, these drugs can only be continued if an adequate response is demonstrated. If a patient fails to respond to both first- and second-line treatment with biological agents then their treatment becomes complicated, and they may be referred to tertiary centres for the use of more novel agents, often in a trial context.

If a patient’s RA appears to be stable at any point in the treatment process, it is possible to try reducing treatment.4 It is well recognised that some cases of RA seems to ‘burn out’ and so disease-modifying treatment then becomes unnecessary.4,12


Conclusion

The management of RA is a complex clinical area and the aim of treatment has changed over the years from trying to control symptoms only to modifying the disease process. The classical joint deformities, which we have been taught about at medical school will hopefully become a thing of the past as tight aggressive control of the disease prevents these from developing. As a GP, it is essential that we are aware of biological agents and that they can cause significant immune suppression. Healthcare professionals should ensure that they record this on patient medical records and that they seek appropriate specialist help if they have any concerns relating to patients who receive this treatment.

View the Guidelines summary of the NICE guideline on Rheumatoid arthritis: the management of rheumatoid arthritis in adults at: egln.co.uk/link/8784

  1. University of Manchester Musculoskeletal Research Group website. British Society for Rheumatology Biologics Register.
    www.medicine.manchester.ac.uk/musculoskeletal/research/arc/clinicalepidemiology/pharmacoepidemiology/bsrbr (accessed 5 March 2012).
  2. National Institute for Health and Care Excellence. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198). Technology Appraisal 247. London: NICE, 2012. Available at: www.nice.org.uk/guidance/TA247nhs_accreditation
  3. National Rheumatoid Arthritis Society website. The DAS28 score. www.nras.org.uk/about_rheumatoid_arthritis/established_disease/managing_well/the_das28_score.aspx (accessed 5 March 2012).
  4. 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/CG79nhs_accreditation
  5. National Institute for Health and Care Excellence. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. Technology Appraisal 130. London: NICE, 2010. Available at: www.nice.org.uk/TA130nhs_accreditation
  6. Grigor C, Capell H, Stirling A et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364 (9430): 263–269.
  7. British Society for Rheumatology and British Health Professionals in Rheumatology. Quick reference guideline for monitoring of disease modifying anti-rheumatic drug (DMARD) therapy. Available at: www.rheumatology.org.uk/includes/documents/cm_docs/2009/d/dmard_grid_november_2009.pdf
  8. British National Formulary. BNF 62. London: Royal Pharmaceutical Society, 2011.
  9. National Institute for Health and Care Excellence. Certolizumab pegol for the treatment of rheumatoid arthritis. Technology Appraisal 186. London: NICE, 2010. Available at: www.nice.org.uk/TA186 nhs_accreditation
  10. National Institute for Health and Care Excellence. Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. Technology Appraisal 225. London: NICE, 2011. Available at: www.nice.org.uk/TA225nhs_accreditation
  11. 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/TA195 nhs_accreditation
  12. Symmons D, Hazes J, Silman A. Cases of early inflammatory polyarthritis should not be classified as having rheumatoid arthritis. J Rheumatol 2003; 30 (5): 902–904. G