What is meant by active disease in the NICE recommendation on use of combination therapy in early RA?

Sir, The National Institute for Health and Clinical Excellence (NICE) RA management guidelines have been well received by the rheumatology community [1]. They recommend that newly diagnosed active RA patients should be offered a combination of DMARDs (including MTX, at least one other DMARD, plus short-term glucocorticoids) as first-line treatment as soon as possible [1] This has led to some discussion, particularly as the recently published European League Against Rheumatism (EULAR) guidelines suggest that MTX monotherapy should be the first-line treatment for RA [2]. The NICE recommendation only applies to active RA, and not to all early inflammatory arthritis. Where there is a current dearth of evidence is how best to treat early milder forms of RA, or palindromic disease that might evolve into RA. For these patients, DMARD monotherapy may be appropriate [2]. The recommendation specifies active disease because it is based on the studies in which patients had to have active disease to be included. However, the recommendation does not define what is meant by active disease, because each of the studies that were used to formulate this recommendation had their own definition of active disease in their inclusion criteria. It would be helpful to have some evidence-based direction on what is meant by active disease to inform clinical practice in implementing the NICE recommendation. The studies used by the NICE Rheumatoid Arthritis Management Guideline Development Group (NICE RA GDG) to formulate the recommendation on combination therapy were obtained. For each independent study, the inclusion criteria for what was active disease were ascertained. Studies that did not have specific criteria for the initiation of combination therapy were excluded. Where studies used tender joint counts and swollen joint counts, these were used to calculate the median tender and swollen joint counts for all the studies combined. The median number of tender and swollen joints and ESR value were then used to calculate an overall DAS-28, where a visual analogue score of 50/100 was assumed. After removing duplications, there were 16 independent studies remaining. The patient inclusion criteria for all these studies were based on the fulfilment of the ACR 1987 revised criteria for RA [3]. The 16 studies had a variety of ways of defining active disease (Table 1). Eleven studies specified swollen joint counts (1–11). These were ≥2 in one study (11), ≥3 in four (1, 2, 5, 7) and ≥6 in six studies (3, 4, 6, 8–10). Tender joint counts were specified as ≥6 in six studies (1, 5, 6, 7, 9, 10), ≥8 in one (8), ≥9 in two studies (3, 4) and ≥10 in one study (2). Nine studies specified an ESR that was ≥28 mm/h in seven studies (1–3, 5–7, 10), ≥30 in one study (4) and ≥30 in women and ≥20 in men in one study (8). Five studies specified a level of CRP that was ≥19 mg/dl in one (2) and ≥20 in four studies (4, 6, 9, 12). Six studies specified duration of morning stiffness, which was ≥29 min in one (2), and ≥45 min in five studies (1, 3, 5, 7, 8). Three studies specified a DAS-44 > 2.4 (10, 14, 15) and one >3.0 (16). DAS-28 of >5.1 was specified in one study (13). Criteria used for defining active disease For 12 of the 16 studies, the total swollen and tender joint counts were not reported. It is assumed where it is not reported that it is TJC/68, SJC/66. The four studies specifying out of how many joints use TJC/68, SJC/66. Study 3 adds that they must be at three or more different sites. All studies treat CRP or ESR as interchangeable and one criterion. The criteria listed are not exhaustive. The following used all the criteria listed: 1 (4/4), 2 (3/3), 6 (3/3), 8 (4/4), 9 (3/3), 11 (1/1) and 12 (1/1). The following studies used a fraction of the listed criteria: 3 (2/3), 4 (3/4), 5 (3/4) and 7 (3/4). SJC: swollen joint count; TJC: tender joint count. Criteria used for defining active disease For 12 of the 16 studies, the total swollen and tender joint counts were not reported. It is assumed where it is not reported that it is TJC/68, SJC/66. The four studies specifying out of how many joints use TJC/68, SJC/66. Study 3 adds that they must be at three or more different sites. All studies treat CRP or ESR as interchangeable and one criterion. The criteria listed are not exhaustive. The following used all the criteria listed: 1 (4/4), 2 (3/3), 6 (3/3), 8 (4/4), 9 (3/3), 11 (1/1) and 12 (1/1). The following studies used a fraction of the listed criteria: 3 (2/3), 4 (3/4), 5 (3/4) and 7 (3/4). SJC: swollen joint count; TJC: tender joint count. In summary, the most common definitions of active disease included an ESR ≥ 28 mm/h, CRP ≥ 20 mg/dl, morning stiffness ≥45 min, and swollen and tender joint counts ≥6 each. If the six tender and six swollen joints were in a distribution that is recognized by the DAS-28 (with the main exclusion being feet and ankles), and if the patient had an ESR of 28 mm/h with a visual analogue score of 50/100, this would translate into a DAS-28 of 5.1. This is convenient, because it is identical to the EULAR criteria for severely active disease [3]. In Derby, we have agreed to use the criteria of either a DAS-28 ≥5.1 (or alternatively, six tender and six swollen joints in patients presenting with joint inflammation outside the DAS-28 distribution, particularly foot joint synovitis, who have a DAS-28 < 5.1) to define active disease. In our practice, only patients with RA satisfying the 1987 ARA criteria who have active disease according to this definition go onto combination therapy from the start of their management, because this is consistent with the evidence base that was used to generate the NICE recommendation on combination therapies. Use of the updated ACR/EULAR 2010 classification criteria has not been validated for these purposes, but would probably lower the threshold for using combination therapies [4]. A recent study of combination therapy in early RA used this criterion [5]. This provides an evidence base to help colleagues decide on how to define active RA in clinical practice and which patients are suitable to go onto combination DMARD therapy. More data need to be generated on whether other prediction models should dictate who has poor prognosis disease and should go onto combination therapy from the start of their disease. Disclosure statement: K.