The impact of escalating conventional therapy in rheumatoid arthritis patients referred for anti-tumour necrosis factor-{alpha} therapy

S. J. Bingham, M. H. Buch, A. Tennant1 and P. Emery

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


    Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Objective. To assess the impact of escalating conventional therapy in patients with RA who satisfy BSR/NICE criteria for biologics.

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.


    Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Rheumatoid arthritis (RA) is a severe progressive autoimmune condition that can lead to disability, impaired quality of life and in some cases reduced life expectancy [1]. Traditional therapy regimes involved sequential treatment with slow-acting disease-modifying anti-rheumatic drugs (DMARDs) such as sulphasalazine and methotrexate. Several studies have demonstrated the additional benefit of more aggressive therapy with DMARD combinations in resistant cases [2] and such strategies are becoming standard practice. In the last 2 yr a new generation of therapies have been licensed for RA in the form of the tumour necrosis factor-{alpha} (TNF{alpha}) blocking agents etanercept (Enbrel®) and infliximab (Remicade®). The drugs are highly effective in reducing disease activity [3, 4], but are expensive (over £10 000 per patient per year) and there have been uncertainties regarding long-term toxicity [5]. Consequently, these agents have been reserved for patients who have persistent active disease and have failed conventional DMARDs. In April 2001, the British Society for Rheumatology (BSR) [6] published guidelines for selection of appropriate patients with RA for anti-TNF{alpha} (Fig. 1), which have now been adopted by The National Institute of Clinical Excellence (NICE) [7].



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FIG. 1. BSR/NICE eligibility criteria for biologics [6, 7].

 
From 1999, patients in North, West and East Yorkshire have been referred to a regional centre for assessment for anti-TNF{alpha} treatment. This was prior to the publication of the BSR guidelines so a local protocol was adopted to identify objectively absolute non-responders to conventional therapy. This protocol escalated conventional therapy to include combination therapy, parenteral methotrexate and a newly available DMARD leflunomide (Arava®). Patients with persistent unacceptable disease activity were commenced on anti-TNF{alpha}.

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.


    Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Subjects
Patients were referred from North, West and East Yorkshire to a central assessment clinic at Leeds General Infirmary. The referring consultant had deemed each patient to have failed conventional therapy and to be a potential candidate for biologics. Since 1999, more than 500 patients have been assessed. A total of 308 consecutive patients who were initially assessed before February 2001 have been included in this analysis. Patients first seen after February 2001 were not included as the 1-yr follow-up period would have overlapped with the publication of the BSR/NICE guidelines.

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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FIG. 2. DAS28 calculation and EULAR response criteria.

 
Therapy
Following local ethical approval (from the Research Ethics Committee of Leeds General Infirmary), patients were treated according to a local protocol of intensified conventional therapy. This escalated therapy from monotherapy with sulphasalazine at 3 g/day or methotrexate at 20 mg/week, to combination therapy with methotrexate (20 mg/week) ± sulphasalazine (3 g/day) ± hydroxychloroquine (200 mg/day), to parenteral methotrexate (20 mg/week) and then to leflunomide (20 mg/day) prior to consideration of biologics. The stage at which they entered the protocol depended on previous treatment received prior to referral. For example, patients who had previously received methotrexate and sulphasalazine monotherapy without benefit were given triple therapy; patients who had previously failed high-dose oral methotrexate without benefit were given parenteral methotrexate. A small minority of patients received other conventional therapy (such as cyclosporin A or intramuscular gold) if they had completed the protocol but it was felt that they were unsuitable for biologics owing to low disease activity, contra-indication (sepsis or previous malignancy) or patient preference. These patients were included in the analysis of response to conventional therapy. The therapy received by all patients was documented and the number receiving biologics within 1 yr was noted.

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.


    Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The mean age of the 308 patients entered into the study was 53 yr (range 15–82), 69% were female, the mean disease duration was 11 yr (range 0.5–47), the mean age at disease onset was 42 yr (range 3–79), 69% were rheumatoid factor (RF) positive, 34% had a positive family history and 20% had had a previous joint replacement. The mean number of previously failed DMARDs was 5 (range 1–12). Active disease was present at baseline; the mean tender joint count was 13 (of 28 joints assessed), mean swollen joint count was 10 (of 28 joints assessed), mean ESR was 42 mm/h, mean VASGH was 61 mm and mean CRP was 45 g/dl. These patients had a significant amount of disability [mean HAQ 2.0 (range 0–3)] and impaired quality of life [mean RAQol 21 (maximum 30)].{triangleup}

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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FIG. 3. Satisfaction of BSR eligibility criteria and therapy received (numbers of patients).

 
Therapy received
Of the whole group (272 patients) at 1 yr, escalation of conventional therapy provided satisfactory (to patient and physician) disease control in 161 (59%), whereas biologics were required by 111 (41%). In the 159 patients satisfying the BSR/NICE criteria the proportion of patients who achieved adequate control with conventional therapy was exactly the same at 93 (59%), whilst those requiring biologics was 66 (41%). In the 113 patients who did not satisfy BSR/NICE criteria at baseline, biologics were required in 45 (40%) and escalated conventional therapy produced satisfactory improvement in 68 (60%). That is, the proportions requiring biologics were identical irrespective of whether the criteria were fulfilled or not.

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 {chi}2-test (P = 0.780). The baseline DAS28 did not influence non-response to conventional therapy and need for biologics.


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TABLE 1. Logistic regression analysis of ability of baseline variables to predict need for biologics by 1 yr (factors analysed individually)a

 

    Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
This analysis was conducted to assess if patients with ‘resistant’ active RA who qualify for anti-TNF{alpha} therapy according to standard national guidelines could still respond to escalation of conventional therapies. The guidelines have not been validated and they are not meant to provide individual treatment decisions, but they have been devised to define a population who can have access to new and expensive treatments. Our study showed that over half the patients who satisfied the guidelines did respond to escalated conventional therapy in a manner satisfactory to the patient and their doctor for at least 1 yr. Ninety-three patients who would have qualified for biologics according to BSR/NICE criteria were maintained on conventional therapy for 1 yr; this equates to a drug budget saving of £930 000 per year in this region alone.

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{alpha} 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{alpha}. 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.


    Acknowledgments
 
We are grateful to the following consultant rheumatologists who referred patients for assessment for biologics: Dr Ahmed, Dr Al-Ansari, Dr Baguley, Prof. Bird, Dr Clague, Dr Cooper, Dr Devlin, Dr Doherty, Dr Gough, Dr Harvey, Dr Heliwell, Dr Horden, Dr Humberstone, Dr Huston, Dr Isaacs, Dr Isdale, Dr Iveson, Dr James, Dr Martin, Dr Melsom, Dr Miles, Dr Pease, Dr Peskett, Dr Platt, Dr Reece, Dr Sattar, Dr Tait, Dr Tomlinson and Dr Veale.

Prof. Emery has undertaken clinical trials and contract work for Shering-Plough and Wyeth.


    References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Submitted 24 April 2003; Accepted 24 September 2003