Dr Joanna Robson (left) and Dr Raashid Luqmani discuss the recommendations on lowering the DAS-28 threshold and assessing the number of swollen and tender joints


Rheumatoid arthritis (RA) is an important disease with a UK prevalence of approximately 400,000.1 Those affected can have significant functional impairment with 30% of individuals becoming severely disabled after 10 years.2 The total costs of RA in the UK are between £3.8 billion and £4.8 billion.2,3

Treatment of RA has traditionally been with disease-modifying anti-rheumatic drugs (DMARDs), which are now given in combination for swift control of disease activity and reduction in joint damage.4 However, there is still a significant minority of patients who fail to respond to DMARDs alone, and for these patients biological therapy has revolutionised the outlook.5

Tumour necrosis factor-? therapies

The anti-tumour necrosis factor (TNF)-? therapies used in RA include:6,7

  • infliximab, a chimeric monoclonal antibody to anti-TNF-?
  • adalimumab, a humanised antibody against anti-TNF-?
  • etanercept, a recombinant human TNF-? receptor fusion protein
  • certolizumab pegol, a TNF-? specific Fab’ fragment of a humanised monoclonal antibody.

The anti-TNF-? therapies are similar in efficacy, eliciting a response in 70% of patients who fail on DMARD treatment.2,6,7

Measuring disease activity in rheumatoid arthritis

In order to assess response to therapy, it is necessary to determine the disease activity accurately before and after treatment. In patients with RA, this is achieved by measuring:2

  • the number of swollen and tender joints
  • inflammatory markers, such as the erythrocyte sedimentation rate or C-reactive protein
  • the patient’s assessment of general health, using a visual analogue score (VAS).2

The above factors are used to calculate a composite score called the disease activity score (DAS).8 This score has been refined and now only requires 28 joints to be assessed—in the hands, wrists, elbows, shoulders, and knees—it is called the DAS-28 and correlates well with disease outcomes.9

The European League Against Rheumatism (EULAR) used the DAS-28 to define patients with severe (DAS-28 >5.1) or moderate (DAS-28 >3.2) disease activity and those who are in remission. This organisation also defined response to treatment based on the reduction in DAS-28, as shown in Table 1.10 These criteria have been validated and are widely accepted.11

Table 1: EULAR response criteria10
  DAS-28
Change in DAS-28 >5.1 ?5.1 and >3.2 ?3.2
>1.2 Moderate Moderate Good
>0.6 and ?1.2 None Moderate Moderate
?0.6 None None None
EULAR=European League Against Rheumatism; DAS-28=disease activity score
Deighton C, Hyrich K, Ding T et al. BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. Rheumatology 2010; 49 (6): 1197–1199. Reproduced with permission.

Eligibility criteria for use of biological therapies

Original BSR recommendations
The British Society for Rheumatology (BSR) first produced recommendations on the use of anti-TNF-? therapies in 2001.12 Because of the higher cost of biological therapies in comparison with combination DMARDs, the BSR was mindful of the need to consider financial as well as clinical issues when making its recommendations.12 (NB current cost comparisons of DMARDs versus biological therapies are listed in Table 2, below).

At the time, there was also limited evidence of anti-TNF-? efficacy in patients with moderate disease activity, so the BSR set the threshold for the DAS-28 to be >5.1—measured on two occasions 1 month apart—and included the need to fail two DMARDs, one of which being methotrexate. A trial of DMARD therapy was defined as being of 6 months, with 2 months at the standard dose, unless toxicity limited the duration or dose of treatment. After biological treatment was commenced, a reduction in DAS-28 by 1.2 points within 6 months was required or therapy had to be stopped.12 This was a simplification of the EULAR response criteria shown in Table 1 (above).

The BSR recommendations on the eligibility criteria for the use of biological therapy were subsequently adopted unchanged by NICE in its guidance on the use of adalimumab, etanercept, and infliximab in the treatment of RA.6

Updated BSR recommendations
Evidence-based modifications to the original BSR recommendations have now been produced by the BSR and the British Health Professionals in Rheumatology (BHPR).10 This update is directed at healthcare providers within rheumatology and also those with responsibility for wider healthcare provision and allocation of resources. It is hoped that these recommendations will be adopted by NICE in future technology appraisals and guidelines. The key differences and similarities between the initial BSR guideline published in 2001, NICE Technology Appraisal 130, and the latest BSR recommendations are shown in Table 3 (below).

Retention of DAS-28 usage
The main criticism of the DAS-28 as a measure of disease activity has been the inclusion of subjective components, for example, the number of tender joints and the patient’s VAS, which can be altered by other factors. Despite this, the DAS-28 is able to differentiate patients with RA who have high and low disease activity far better than any of the other published single or composite indices;14 furthermore, longitudinal cohort studies have demonstrated that high DAS-28 scores correlate well with radiographic damage.15

The overwhelming majority of patients with RA who have a DAS-28 >5.1 at 1 month prior to baseline will also have a score of >5.1 at baseline,16 and so the need for two assessments a month apart is no longer recommended in the updated BSR and BHPR recommendations.10

Reduction in the threshold of DAS-28
In the absence of biological therapy, patients with RA who have moderate disease activity (DAS-28 values between 3.2 and 5.1) have as much progression in joint damage and reduction in function and quality of life as those with DAS-28 scores of above 5.1.10,17–20 There is also now evidence to support the effectiveness of anti-TNF-? therapy in this particular group of patients; significant improvements in disease activity and outcomes as measured using the Health Assessment Questionnaire (HAQ) have been achieved, comparable to individuals with DAS-28 values >5.1.21–23

The new BSR recommendations therefore suggest a reduction in the threshold for treatment with biological therapy to a DAS-28 score of >3.2, while introducing a minimum number of three swollen and three tender joints.10

Measuring response
The NICE guidelines state that patients can continue anti-TNF-? treatment only if there is an adequate response at 6 months, as defined by a drop in DAS-28 of 1.2 points.4,6 As biological therapy has become more widely available, patients’ initial scores are often only just above 5.1, in contrast to the higher scores seen historically when biological agents were first introduced. This can lead to a struggle to demonstrate an adequate reduction in disease activity with treatment. These patients would, however, still be classified as moderate responders using the original EULAR response criteria. The authors of the BSR and BHPR recommendations10 urge a return to the use of this method of assessment, which has been validated in patients with RA. Interruptions to anti-TNF-? treatment through infections or operations should also be taken into consideration before treatment is stopped because these disruptions may explain the apparently inadequate response.

Table 2: Comparison of average cost of DMARDs and biologicals for 1 year6,7,13
DMARD therapy Biological therapy
sulfasalazine £49 adalimumab* £9295
sulfasalazine £110 etanercept* £9295
hydroxychloroquine £64 infliximab £11,330 (minimum)
combination DMARD therapy £223 certolizumab £10,367 for the first year, £9295 thereafter
*Can be given as monotherapy or with methotrexate
†Should be given with methotrexate
‡NICE approved patient access scheme, first 12 weeks free to NHS
DMARD=disease-modifying anti-rheumatic drug
Table 3: Comparison between BSR and BHPR 2010 recommendations and previous BSR recommendations and NICE Technology Appraisal 130 on eligibility for biological therapy6,7,10,12
Criteria for use of biological therapy BSR 2010 recommendations BSR 2001 recommendations and NICE Technology Appraisal 130

Initiation

DAS-28 >3.2 on one occasion
PLUS ?3 swollen joints
PLUS ?3 tender joints
DAS-28 >5.1, on two occasions 1 month apart
Trial of two DMARDs (including methotrexate)
Continuation Continue treatment at 6 months if there is a good or moderate EULAR response Continue treatment at 6 months only if there is an improvement in DAS-28 of ?1.2
Monitoring After initial assessment, monitor with DAS-28 every 6 months and withdraw therapy if response is not maintained
BSR=British Society for Rheumatology; BHPR=British Health Professionals in Rheumatology; DAS-28=disease activity score-28; DMARD=disease-modifying anti-rheumatic drug; EULAR=European League Against Rheumatism

Impact of the BSR and BHPR recommendations

Lowering the DAS-28 threshold
A detailed cost analysis was outside the remit of this updated BSR and BHPR guidance, however, it was noted that in European countries with DAS-28 thresholds of 3.2, the rate of anti-TNF-? use is 8–12%, compared with 6% of patients with RA in the UK.10,24 Therefore, uptake of anti-TNF-? use in the UK can be predicted to increase by 25%–100% if the DAS-28 threshold is lowered to 3.2.10,25

However, significant improvements in the level of disease activity (measured using DAS-28) and function (assessed using HAQ scores) can be achieved by the use of combination DMARDs and corticosteroids (i.e. without using biological therapies). This initial approach is strongly recommended in the 2009 NICE Clinical Guideline 79 on RA.2,4 With wider and earlier adoption of this combination DMARD strategy, there should be a reduction in the need for biological therapies, and an overall improvement in outcomes for patients with RA.

The previous 2001 BSR recommendations on the initiation of biological therapies in patients with RA were subsequently adopted virtually unchanged by NICE. We cannot of course guarantee that the same process will be repeated but we anticipate that, with the new evidence presented by the BSR and BHPR guidelines, a reappraisal of the current thresholds in the NICE guidelines will be inevitable. These guidelines serve to illustrate to healthcare professionals the importance of actively treating all patients with RA. Evidence demonstrates that inadequate treatment of patients previously thought to have only moderate disease activity, results in disease progression, joint damage, and reduction in quality of life.

Recommended biological therapies for use after failure of a TNF-? inhibitor

The importance of biological therapies is highlighted by the rapid expansion in the number of NICE technology appraisals, which have been recently published and are ongoing in this clinical area. Two recent and key examples include the recommendations that patients with severe RA who have failed to respond to or are intolerant of anti-TNF-? therapy and rituximab, may now be given a second anti-TNF-? agent, abatacept,26 or tocilizumab.27

Summary

The BSR and BHPR now recommend that biological therapies should be considered in patients with RA who have moderate and severe disease activity and who do not respond adequately to treatment with conventional DMARDs (given alone or in combination). Failure to achieve tight control in this minority of patients will result in long-term permanent damage to joints and functional ability.

References

  1. 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.
  2. National Collaborating Centre for Chronic Conditions. Rheumatoid arthritis: National clinical guideline for management and treatment in adults. London: RCP, 2009. Available at: www.nice.org.uk/CG79 nhs accred
  3. Pugner K, Scott D, Holmes J, Hieke K. The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum 2000; 29 (5): 305–320.
  4. National Institute for Health and Care Excellence. Rheumatoid arthritis: the management of rheumatoid arthritis in adults. Clinical Guideline 79. London: NICE, 2009. Available at: www.nice.org.uk/Guidance/CG79 nhs accred
  5. Emery P, McInnes I, van Vollenhoven R, Kraan M. Clinical identification and treatment of a rapidly progressing disease state in patients with rheumatoid arthritis. Rheumatology 2008; 47 (4): 392–398.
  6. National Institute for Health and Care Excellence. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. Technology Appraisal 130. London: NICE, 2007. Available at: www.nice.org.uk/guidance/TA130 nhs accred
  7. 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/guidance/TA186 nhs accred
  8. Van der Heijde D, van’t Hof M, van Riel P, van de Putte L. Development of a disease activity score based on judgment in clinical practice by rheumatologists. J Rheumatol 1993; 20 (3): 579–581.
  9. Prevoo M, van’t Hof M, Kuper H. 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): 44–88.
  10. Deighton C, Hyrich K, Ding T et al. BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. Rheumatology 2010; 49 (6): 1197–1199.
  11. Jerram S, Butt S, Gadsby K, Deighton C. Discrepancies between the EULAR response criteria and the NICE guidelines for continuation of anti-TNF therapy in RA: a cause for concern? Rheumatology 2008; 47 (2): 180–182.
  12. British Society for Rheumatology. Guidelines for prescribing TNF-? blockers in adults with rheumatoid arthritis. London: BSR, 2001.
  13. British National Formulary. BNF 60. London: British Medical Association and Royal Pharmaceutical Society, 2010.
  14. Van der Heijde D, van’t Hod M, van Riel P et al. Validity of single variables and composite indices for measuring disease activity in rheumatoid arthritis. Ann Rheum Dis 1992; 51 (2): 177–181.
  15. Welsing P, Landewe R, van Riel P et al. The relationship between disease activity and radiologic progression in patients with rheumatoid arthritis: a longitudinal analysis. Arthritis Rheum 2004; 50 (7): 2082–2093.
  16. Smith N, Gadsby K, Butt S et al. Is pre-assessment for anti-TNF therapy in RA necessary in the UK? Analysis of DAS28 in six centres. Rheumatology 2007; 46 (10): 1557–1559.
  17. Symmonds D, Tricker K, Roberts C et al. The British Rheumatoid Outcome Study Group (BROSG) randomized controlled trial to compare the effectiveness and cost-effectiveness of aggressive versus symptomatic therapy in established rheumatoid arthritis. Health Technol Assess 2005; 9 (34): iii-iv, ix-x: 1–78.
  18. Conaghan P, Hensor E, Kennan A, Emery P. Year Consortium. Persistent moderate DAS is not a benign state: loss of function occurs in early RA despite step-up DMARD therapy. Rheumatology 2009; 48 (Suppl. 1): i137.
  19. Dixey J, Jayakumar K, Koduri G et al. Disease activity and five year outcome of early rheumatoid arthritis in a biologic drug free inception cohort. Rheumatology 2009; 48 (Suppl.II): i136.
  20. Kiely P, Jayakumar K, Norton S et al. Relation between year 1 DAS28 status and 2 year disease activity, function and employment in DMARD treated RA patients in an Early Rheumatoid Arthritis Network (ERAN). Rheumatology 2009; 48 (Suppl. II): i187.
  21. Aletaha D, Funovits J, Keystone E, Smolen J. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum 2007; 56 (10): 3226–3235.
  22. Hetland M, Lindegaard H, Hansen A et al. Do changes in prescription practice in patients with rheumatoid arthritis treated with biological agents affect treatment response and adherence to therapy? Results from the nationwide Danish DANBIO Registry. Ann Rheum Dis 2008; 67 (7): 1023–1026.
  23. Hyrich K, Deighton C, Watson K et al. Benefit of anti-TNF therapy in rheumatoid arthritis patients with moderate disease activity. Rheumatology 2009; 48 (10): 1323–1327.
  24. Jonsson B, Kobelt G, Smolen J. The burden of rheumatoid arthritis and access to treatment: uptake of new therapies. Eur J Health Econ 2008; 8 (2): 61–86.
  25. Emery P, Van Vollenhoven R, Ostergaard M et al. Guidelines for initiation of anti-tumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe. Ann Rheum Dis 2009; 68 (4): 456–459.
  26. 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 nhs accred
  27. 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 G

A checklist to aid the implementation of the BSR and BHPR rheumatoid arthritis guideline on eligibility criteria for first biological therapy can be found here

View the Guidelines summary of the BSR and BHPR guideline on the management of rheumatoid arthritis at: eguidelines.co.uk/link/123

  • The updated BSR and BHPR recommendations are likely to lead to higher costs because of an increase in the use of biological drugs
  • These drugs are not included in tariff charges but are chargeable to commissioners
  • Local agreements need to be made between commissioners and specialists on the criteria for the use of biological agents
  • Some of these drugs are covered by NICE Technology Appraisal 195, which commissioners have a legal duty to fund unlike NICE guidance or BSR or BHPR guidance
  • For commissioners, the cost of the increased use of biologicals will need to be balanced against other clinical priorities and the likely benefits to long-term health and possibly reduced costs associated with rheumatoid arthritis-related disability.
BSR=British Society Rheumatology; BPHR=British Health Professionals in Rheumatology; RA=rheumatoid arthritis; DAS-28=disease activity score; DMARD=disease-modifying anti-rheumatic drug