Rheumatology Research Unit, First Floor, Old Nurses Home, Leeds General Infirmary, Great George Street, Leeds LS1 3EX and 1University of Leeds, Rehabilitation Research Unit, School of Medicine, 36 Clarendon Road, Leeds, LS2 9NZ, UK.
Correspondence to: P. Emery. E-mail: p.emery{at}leeds.ac.uk
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Abstract |
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Methods. A total of 308 consecutive patients referred to a tertiary centre for biological therapy between January 1999 and February 2001 were studied prospectively. They were considered by their own consultant to have failed standard therapy. Prior to biologics, conventional therapy was escalated to include combination and parenteral methotrexate treatment. Patients were assessed at 12-weekly intervals for 1 yr and therapy was changed if response was not satisfactory. The subsequently released BSR/NICE biologic eligibility criteria were applied retrospectively. Response (disease activity, disability and quality of life) to escalated therapy in those patients who did or did not satisfy current eligibility criteria were compared.
Results. In total, 159 satisfied BSR/NICE criteria and would have been eligible for immediate treatment with biologics [DAS28 > 5.1, failed methotrexate (20 mg/week or lower dose owing to toxicity) and one other DMARD]; however, 93 of these responded to escalated conventional therapy and did not require biologics [significant improvement (P < 0.01) in disease activity, disability and quality of life]. However, mild disease activity (DAS28 < 3.2) was only achieved in 7% of these patients at 12 months.
Conclusions. Although over half the patients who satisfied standard criteria for biologics responded satisfactorily to escalated therapy, only a minority achieved mild disease activity. The savings achieved by treating with conventional therapies need to be weighed against the risk of persistent disease activity.
KEY WORDS: Rheumatoid arthritis, Anti-cytokine therapy.
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Introduction |
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Subsequent publication of the BSR/NICE guidelines allowed the retrospective application of the criteria to patients treated using the more rigid protocol. This provided a unique opportunity to assess the impact of escalating conventional therapy in patients who had satisfied the BSR/NICE criteria at referral and who would have immediately qualified for treatment with biologics. In addition, factors that predict response or resistance to increased conventional therapy in such patients were analysed.
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Subjects and methods |
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Baseline assessment
At the first visit, a detailed history of previous DMARD therapy was taken. Where possible the maximum dose of methotrexate taken previously and/or reason for discontinuation was ascertained. The following data were also collected: age, sex, disease duration, age at disease onset, presence of rheumatoid factor (RF), positive family history of RA and previous joint replacements. Disease activity [tender and swollen joint counts, erythrocyte sedimentation rate (ESR), patient visual analogue score for general health (VASGH) and C-reactive protein (CRP)], disability (Health Assessment Questionnaire, HAQ) [8] and quality of life (RAQol questionnaire) [9] were assessed. A composite score of disease activity (DAS28) was calculated (Fig. 2) [10].
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Assessment of response
Patients were reviewed at 12-weekly intervals. Patients were assessed by one of two research registrars (SB or MB), but treatment change decisions were made by one consultant (PE). Therapy was changed to the next stage in the protocol if the patient felt that there was no improvement and the physician assessment indicated clinically unacceptable disease activity. Patients were not assessed within 4 weeks of intramuscular or intra-articular steroids. At each visit disease activity (tender and swollen joint counts, ESR, VASGH, CRP), disability (HAQ) and quality of life (RAQol) were assessed. DAS28 and EULAR response [11] were calculated (Fig. 2).
Retrospective application of BSR/NICE criteria
Using the baseline dataset the BSR criteria were applied to assess which patients would have been eligible for biologics at their first visit.
Prediction of response to escalated conventional therapy
The baseline dataset was analysed to assess if any factors could predict which patients would require biologics (i.e. had not responded satisfactorily to escalated conventional therapy) within 1 yr.
Statistics
Baseline data and therapy received are presented descriptively. To account for cases where follow-up data were missing, an intention-to-treat analysis was carried out using the last value carried forward. Response to escalated therapy was analysed using the paired t-test (owing to the large number of tests undertaken, the significance level was reduced to < 0.01). Binary logistic regression was used to identify baseline factors that predict use of biologics within 1 yr.
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Results |
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Retrospective application of BSR/NICE criteria
As the disease activity score was calculated retrospectively, a baseline disease activity score could not be calculated in all cases owing to missing data. A score was available for 89% of patients (274). The mean DAS28 was 5.97 (S.D. 1.32); 213 patients had severe disease activity (DAS28 > 5.1). A total of 217 (71%) patients had previously failed methotrexate at 20 mg/week or had failed a lower dose owing to toxicity, and methotrexate was contraindicated in nine patients. Seventy one (21%) had failed methotrexate at <20 mg/week owing to inefficacy which does not satisfy BSR guidelines. Fourteen cases were excluded: 10 owing to missing data, one had never received methotrexate and three had only failed one previous DMARD.
In total, data were sufficient to test criteria satisfaction in 272 cases: 159 (59%) patients retrospectively satisfied BSR criteria and would have immediately qualified for anti-TNF therapy (Fig. 3).
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Response to escalated conventional therapy
In the 93 patients who had satisfied BSR/NICE criteria for biologics and received only conventional therapy for 1 yr, there was significant (P < 0.01) reduction in disease activity (DAS28 and CRP), disability and quality of life at every time point up to 1 yr (except CRP at 12 weeks).
At baseline, the mean DAS28 was 6.43 (S.D. 0.83) and, by definition, 100% of patients had severe disease (DAS28 > 5.1); this was reduced to 73% at 6 months and 65% at 12 months. A moderate or good EULAR response (Fig. 2) was achieved in 32 and 55% of patients at 6 and 12 months, respectively. However, a mild disease activity score (DAS28 < 3.2) was achieved in only 7% of patients at 12 months.
Comparison of response to conventional therapy between patients who did or did not satisfy BSR/NICE criteria at baseline
Sixty-eight patients did not satisfy BSR criteria at baseline and did not receive biologics. The mean DAS28 in this group was lower at 5.1 (S.D. 1.59). In this group there was a decrease in most measured variables during 1 yr on conventional therapies, but only the reduction in RAQol at 12 and 24 weeks reached statistical significance.
At baseline, 44% of patients had severe disease (DAS28 > 5.1); this increased at 6 and 12 months (46 and 51%, respectively). A moderate or good EULAR response (Fig. 2) was achieved in 21% at both 6 and 12 months. A mild disease activity score (DAS28 < 3.2) was achieved in 10% of patients at 12 months.
Predicting response to escalated conventional therapy
Using logistic regression analysis, the following factors were individually found to influence need for biologics: younger age (P < 0.001), younger age at onset of disease (P < 0.001) (but not disease duration), a higher number of previous DMARDs (P = 0.003) (probably reflecting presentation at a later stage of the protocol) and higher RAQol score (P = 0.008) (Table 1). When these factors were entered together, the model was not significant (Cox & Snell R2 = 0.084). No relationship was observed between satisfaction of the BSR criteria and requirement of biologics by 1 yr. This was confirmed using Pearson's 2-test (P = 0.780). The baseline DAS28 did not influence non-response to conventional therapy and need for biologics.
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Discussion |
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Satisfaction of the BSR/NICE criteria for biologics did not predict non-response to conventional therapy and need for biologics. Patients with a high baseline DAS28 were not more likely to receive biologics. This was calculated retrospectively and it appears that disease activity did not play a large role in clinical decision-making in terms of selection for biologics. Patients who had satisfied BSR/NICE criteria at baseline appeared to respond better to escalation of conventional therapy than those who had not. This may be due to the higher level of disease activity present at baseline facilitating a greater capacity to respond.
Younger patients and those with a worse quality of life score were more likely to receive biologics, which may reflect bias in the subjective assessment of patients by physicians (the subsequent availability of the BSR/NICE guidelines should now prevent this). No other factors could be identified that would aid the early identification of potential non-responders.
The simplistic interpretation of this result is that not all patients fulfilling BSR/NICE guidelines require anti-TNF therapy. Our data show that there is the potential for further response to escalated conventional treatments. The aim of the guidelines is to restrict biologics to those patients who have no alternatives, but this study suggests that patients should be required to have failed escalated therapy in order to qualify. However, 68% of patients who retrospectively had qualified for anti-TNF but received conventional therapy failed to achieve an adequate response (good or moderate EULAR response) at 6 months, although this reduced to 45% by 12 months. This compares with 23% of patients failing to achieve such a response with etanercept or infliximab by 6 months in our unit. Thus this approach cannot be deemed to be optimal and the financial savings need to be balanced against the negative effect of continued disease activity in these patients. Accurate assessment of the level of damage that occurred in these patients and models for assessing the cost-effectiveness of this approach need to be developed. Further analysis will include a comparison of the response in this cohort to conventional therapy with that in a matched cohort receiving anti-TNF
. Although, the patients in this analysis represent those at the severe end of the spectrum who may not be a typical population, the data provide a starting point for a debate of these issues.
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Acknowledgments |
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Prof. Emery has undertaken clinical trials and contract work for Shering-Plough and Wyeth.
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References |
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