Department of Rheumatology, 1 GKT School of Medicine, Weston Education Centre, Kings College, 10 Cutcombe Road, London SE5 9RS, 2 Kings College Hospital, Denmark Hill, London SE5 9RS and 3 University Hospital Lewisham, Lewisham High Street, London SE13 6LH, UK.
Correspondence to: G. H. Kingsley, Department of Rheumatology, GKT School of Medicine, Weston Education Centre, Kings College, Cutcombe Road, London SE5, UK. E-mails: gabrielle.kingsley{at}kcl.ac.uk and janice.jimenez{at}kcl.ac.uk
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Abstract |
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Methods. We studied 504 patients in a cross-sectional study, 156 in a longitudinal study and 94 starting new DMARDs or biologics. Patients were classified as trial active (met entry criteria), in remission or intermediately active (between the two). We also evaluated the effect of amendments to criteria.
Results. Cross-sectionally only 38% patients were trial active, but longitudinally 68% were trial active at least once. Thus, many clinic patients do have disease activity below the level required for trial entry, but over time most reach eligibility levels. More (62%) of the cohort starting new treatment were trial active, suggesting that recruitment criteria relate to clinical decisions. Criteria omitting morning stiffness and a disease activity score (DAS28) 5.4 replicated the classification given by current criteria.
Conclusions. Trial results can be generalized to routine practice because most clinic patients are trial active when their therapy is changed and most become trial active over time. As DAS-based criteria are simpler and relate directly to response measures, their use should be considered in future.
KEY WORDS: Rheumatoid arthritis, Clinical assessment, Clinical trial methodologies
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Introduction |
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Since RCTs remain the best way to assess drug efficacy, it is crucial to optimize trial entry criteria ensuring generalizability yet facilitating recruitment. A common definition of patients who are active enough to enter trials (trial active) is that they should meet three out of four of the following: 6 tender joints,
6 swollen joints, erythrocyte sedimentation rate (ESR)
28 mm/h and
45 min early morning stiffness (EMS). The justification for these empirically adopted criteria is much less sound than the disease activity score (DAS) and ACR response criteria that are fully validated, internally consistent and, unlike the rheumatoid arthritis (RA) trial entry criteria, use the same components.
Sokka and Pincus [4, 5] have particularly criticised the disease activity aspect of current trial entry criteria. They showed that many routine clinic patients had insufficiently active disease to be eligible for RCTs of new disease-modifying anti-rheumatic drugs (DMARDs) and biologics and concluded these trials were therefore unsuitable as guides to practice. However, they did not look at variability of disease activity over time.
We investigated two facets of trial entry. First, we analysed whether the level of disease activity in trial patients was representative of that seen in routine clinic attendees at a single time point, over time and in patients changing therapy. Second, we examined whether simpler trial entry criteria, more consistent with DAS and response measures, could be developed by analysing the effect of different criteria on the proportion of patients eligible for trial entry.
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Patients and methods |
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Group A, a cross-sectional cohort of 504 consecutive attendees assessed once, had a male/female (M/F) ratio of 109/395, mean age 56 yr (range 1889 yr) and mean disease duration of 10 yr (range 153 yr). Three hundred and thirty-six (73%) were taking DMARDs including methotrexate in 237 (47%), sulphasalazine in 40 (8%), anti-tumour necrosis factor (TNF) in 14 (3%) and oral or recent i.m. steroids in 117 (23%).
Group B, a longitudinal cohort of 156 patients assessed four times or more by a single rheumatologist (EC), had (at the first visit) a M/F ratio of 38/118, mean age 59 yr (range 2487 yr) and mean disease duration of 10 yr (range 146 yr). One hundred and twenty-seven (81%) were on DMARDs including methotrexate in 82 (52%), sulphasalazine in 9 (6%), anti-TNF in 5 (3%) and oral/recent i.m. steroids in 34 (22%).
Group C, a cross-sectional cohort of 94 consecutive patients starting new DMARDs or biologics, had a M/F ratio of 18/76, mean age 58 yr (range 1888 yr) and mean disease duration of 12 yr (range 140 yr). Forty-two (45%) were starting methotrexate, 11 (12%) sulphasalazine, 8 (9%) anti-TNF and 33 other drugs; 25 (27%) were taking oral or had recent i.m. steroids.
Assessment and classification of patients and analysis of data
We recorded 28 joint counts for tender and swollen joints, EMS and ESR at all visits. Patients were classified as in remission, intermediately active (between remission and trial active) or trial active at each visit. We defined remission (using a variant of the ARA Remission Criteria which omits fatigue [7]) as EMS 15 min, ESR<30 mm/h (females) or <20 mm/h (males), no joint swelling, no joint tenderness and no joint pain. We defined trial active disease using accepted criteria (three out of four of tender joints
6, swollen joints
6, ESR
28 mm/h and EMS
45 min). We calculated DAS28 using the standard formula (with ESR).
The impact of changing trial entry criteria was assessed using two types of modification. First, using Cohort A (504 consecutive cases), we examined simplified versions of the existing criteria (and other single/composite measures), which replicated the level of disease activity defined by the current trial entry criteria. Second, using Cohort C (94 cases starting new treatment), we selected criteria replicating the level of disease activity in this cohort of patients considered by clinicians in routine practice to need a new DMARD. For each definition, the numbers of patients defined as trial active and, where appropriate, the sensitivity and specificity compared with current criteria, were calculated.
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Results |
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One hundred and eighty-nine (38%) patients in Cohort A had trial active disease, 299 (59%) were intermediately active and 16 (3%) were in remission. Longitudinal Cohort B patients at their first visit were similar: 50 (32%) had trial active disease, 98 (63%) were intermediately active and 8 (5%) were in remission. In contrast, almost twice as many (58; 62%) Cohort C patients had trial active disease; however, a significant number still did not meet trial entry criteria with 36 (38%) intermediately active and none in remission. Whilst this could reflect a difference in the level of activity required for trial entry compared with that precipitating a change of drug in practice, it could also be that some patients were changing therapy for other reasons such as toxicity.
Disease activity during longitudinal follow-up of Cohort B (Table 1)
Only 43 patients (28%) stayed in their initial disease activity group and 10 (6%) spent periods in all three groups. At most visits, patients were intermediately active with only 28 (18%) in remission at any time point. Importantly, 68% (106) Cohort B patients, irrespective of initial activity classification, met trial entry criteria on at least one occasion.
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Simplification by using a composite measure (Table 2)
DAS is commonly used to assess activity and response in routine practice and RCTs but not for trial recruitment. DAS28 levels from 5.1 (common cut-off for high disease activity) to 5.5 were studied. DAS28 5.4 best replicated current entry criteria, defining an identical proportion (38%) of patients as active; however, 68 (13%) patients changed classification, suggesting that the population identified is different. This could not be explained by the inclusion of EMS in current criteria since current criteria minus EMS still classified 1315% of cases differently to DAS.
Modification of existing trial entry criteria: replicating clinicians routine practice
Fifty-eight patients (62%) in Cohort C were classified as trial active by current criteria whereas criteria designed to replicate routine practice should classify most as active. Low-stringency criteria (three out of four of one tender joint, one swollen joint, ESR 20 mm/h and EMS
15 min) classified 90 (96%) cases as active. On substituting
3 tender and
3 swollen joints into these, 80 (85%) cases were defined as active; on substituting
4 tender and
4 swollen joints, this declined further to 72 (77%). In all instances EMS had minimal impact.
Using DAS-based criteria, DAS28 3.1 (lowest level conventionally defined as active), classified 92 (98%) of these patients as active; increasing the level of DAS reduced the number of trial active patients.
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Discussion |
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The second aspect we investigated was whether alternative trial entry criteria are simpler, less restrictive and more consistent with standard disease activity and response measures. This is potentially possible as trials have employed entry criteria with varying numbers of tender or swollen joints [9], levels of ESR [10] and durations of morning stiffness [11], and have combined domains differently [12]. We recommend abandoning early morning stiffness in the definition of trial active RA because it has little impact on classification and it is not one of the outcome assessments currently used in RCTs or clinical practice. The other assessmentsswollen joint counts, tender joint counts and ESRappear essential. However, they could be incorporated into one measure, namely DAS, that is widely used as a composite outcome measure. Using DAS is rational because it was derived using routine clinic patients with early RA changing DMARDs [13]. Furthermore using the same measure to assess suitability for entry and trial outcome is simple and logical. Using a single summary assessment, like the physicians global assessment, which has the attraction of simplicity, was tried by McConkey and colleagues but was not pursued due to variations between individual clinicians and centres [14]. We conclude there is a strong case for rationalizing the definition of trial active RA by focusing on tender and swollen joint counts and ESR; these could be combined into one summary measure, the DAS.
There is continual debate on optimal outcome measures for RCTs [15] including radical suggestions like time on treatment [16] or changes in HAQ scores [17]. Similar debate is needed around trial entry criteria. Different criteria may be needed in trials undertaken for different purposes. Trials with entry criteria that identify patients with a high level of disease activity may be appropriate for establishing the efficacy of new drugs. However, criteria identifying a lower level of disease activity may be more relevant in defining how best to further improve moderately active disease with adjunctive therapy.
Finally, we appreciate that no single group can provide a definitive answer on optimal entry criteria for clinical effectiveness trials. Rather than providing definitive recommendations, our intention has been to highlight the need for further work to achieve a new international consensus. This will need to involve a wide range of clinicians with an interest in the field.
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Acknowledgments |
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We would also like to acknowledge the help of clinical colleagues at Kings College Hospital, University Hospital Lewisham and Queen Mary's Hospital Sidcup in allowing their patients to be recruited for this study.
The authors have declared no conflicts of interest.
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References |
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