Rheumatology Advance Access published online on January 25, 2007
Rheumatology, doi:10.1093/rheumatology/kel430
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Characteristics and treatment responses of patients satisfying the BSR guidelines for anti-TNF in ankylosing spondylitis
Department of Rheumatology, Debyshire Royal Infirmary, Derby, UK.
Correspondence to:
C. Deighton, Department of Rheumatology, Derbyshire Royal Infirmary, London Road, Derby DE1 2QY, UK. E-mail: chris.deighton{at}derbyhospitals.nhs.uk
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Abstract |
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Objective. We present the results of the response to anti-tumour necrosis factor (anti-TNF) of 30 ankylosing spondylitis (AS) patients where we have complied with the BSR guidelines.
Method. All patients had pre-assessments of Bath AS Disease Activity Index (BASDAIs) at two points a month apart prior to commencing anti-TNF. They then had 2 week and 2 month assessments followed by 3 monthly thereafter. BASDAI, visual analogue scales, blood count and erythrocyte sedimentation rate (ESR) were performed on each occasion.
Results. All patients had stable active disease at the pre-assessments with a mean BASDAI of 6.8. Twenty-nine patients showed a rapid and dramatic response with a mean BASDAI at 2 months assessment of 3.2 (P < 0.001). This was maintained for up to 20 months of follow up. Haemoglobin rose significantly (mean of 13.0 g/dl to 13.8) and the ESR dropped from 49 mm/h to 23 (both P < 0.001). Fifteen patients (51.7%) were able to stop their non-steroidal anti-inflammatory drugs (NSAIDs) and a further eight reduced them.
Conclusion. Patients who fulfil the BSR guidelines for anti-TNF in AS have sustained active inflammatory disease prior to going onto etanercept or infliximab. Despite this, they show rapid, dramatic sustained responses to treatment, and over half are able to stop their NSAIDs. Any health economic analyses of anti-TNF in UK clinical practice need to take these observations into account.
KEY WORDS: Ankylosing spondyltitis, Biological therapy, Guidelines
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Introduction |
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Ankylosing spondylitis (AS) varies widely in prognosis and outcome. Most patients experience a chronic disease punctuated by exacerbations (flares) and quiescent periods [1]. Brophy and Calin described 214 AS patients who experienced one to five localized flares per year [2]. Eighty-five patients (39.7%) also experienced more generalized flares. Flares lasted a few days to a few weeks, and no long-term effects on the AS followed a flare. In contrast, a report from Truro showed that over a 5 yr follow-up period approximately one-third of patients have Bath AS Disease Activity Index (BASDAI) scores
4 on each occasion, reflecting ongoing active disease [3]. In RA, concern has been expressed over discrepancies in results of anti-tumour necrosis factor (anti-TNF) therapy results in randomized clinical trials (RCTs) and observational studies [4]. It has been suggested that RCTs capture patients during flares of their disease, and this will lead to over estimates of the cost-effectiveness of anti-TNF therapies. The corollary of this is that if AS is a disease largely punctuated by intermittent flares, then anti-TNF may simply return the patient to their baseline of low-level inflammatory activity. If this was the case it would be difficult to build a strong case for anti-TNF being economically viable in most health care systems.
In the UK, rheumatology departments often have restricted access to anti-TNF therapies for AS. Many funding authorities suggest they are waiting for the National Institute of Clinical Excellence to provide guidance before they will commit funds for treatment. In Derby we are fortunate to have secured funding for anti-TNF treatment for AS and we obtained early named-patient use of these drugs for some patients prior to their licensing. We follow the BSR guidelines for eligibility [5]. We also made a decision, prior to their launch, to mirror the BSR RA anti-TNF guidelines [6] and perform pre-assessments at two points a month apart to ensure that patients had ongoing active disease. Fortunately, we had anticipated the recommendation of the AS guidelines that stated that the BASDAI [7] and spinal pain visual analogue scale (VAS) should be at least 4 cm on two occasions at least 4 weeks apart [5]. These recommendations are very similar to the updated international Assessment in AS (ASAS) consensus statement recommendations for the use of anti-TNF in AS [8]. Here we present the results of our experience with anti-TNF in our AS clinical practice.
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Methods |
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All patients were eligible to go onto anti-TNF according to the BSR guidelines [5], i.e. they satisfied the modified New York criteria for AS [9], had a persistently elevated BASDAI and spinal VAS as defined above, and had failed on at least two non-steroidal anti-inflammatory drugs (NSAIDs). Each patient had the following measurements performed at 2 months and 1 month prior to further baseline measures being taken: BASDAI, VAS of general health and well-being and spinal pain VAS. Blood was taken for full blood count, and erythrocyte sedimentation rate (ESR) on each occasion. After initiation of anti-TNF, the same assessments and blood tests were performed at 2 weeks, 2 months, 3 months and 3 monthly thereafter (in keeping with the BSR guidelines [5]). The clinical and blood test results were then analysed using SPSS 13.0, and paired t-tests performed to compare the clinical or blood test parameter at pre-assessment, baseline and consecutive assessments thereafter. In Derby, the policy has been to give patients the choice of intravenous or subcutaneous forms of anti-TNF therapy. Adalimumab did not have a licence at the time of performing this analysis. At the 2-month assessment we also asked patients if they had managed to decrease or stop their NSAIDs and analgesics.
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Results |
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The first 30 patients to go onto anti-TNF were included in this study; 20 were male. The mean age of the group was 51 yrs with a range of 33–70 yrs. Mean symptomatic disease duration was 22 yrs with a range of 2–43 yrs. Seven of the patients had significant peripheral inflammatory arthritis affecting hips or knees. One patient had both knees replaced, and one both hips. The pre-assessment variables at 2 months and 1 month prior to baseline, and at baseline, are shown in Table 1. There was no significant change in any of the variables at any of these time points. At initiation of treatment, 21 patients were treated with etanercept and nine with infliximab. Etanercept was administered subcutaneously as either 25 mg twice weekly or 50 mg once weekly. Infliximab was administered at 5 mg/kg every 6–8 weeks after induction. Subsequently, five of the infliximab patients transferred from infliximab to etanercept for the convenience of self-administration (four patients) and for adverse events (one patient with drug-induced lupus). All five patients who transferred form infliximab to etanercept continued to do well, with response maintained. One patient dropped from 5 mg/kg of infliximab to 3 mg/kg before moving over to 25 mg twice weekly of etanercept, and subsequently 25 mg once weekly because he has been doing so well.
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Only one patient of the 30 failed to make a satisfactory response to etanercept, which was discontinued at 12 weeks. One patient of the 29 was showing only partial response at 8 weeks (BASDAI reduction of 0.43), but had shown more than the required drop of 2.0 when reassessed at 12 weeks (in keeping with the BSR guidelines [5]), with a fall of 3.6. The remaining 29 patients had responded significantly to treatment (BASDAI fall >2.0) when assessed at 2 months. Analysis of the 29 responders showed that the average BASDAI fell from 6.8 at baseline to 3.2 at 2 months, mean difference 3.6 (CI 2.6–4.7, t = 7.34, P < 0.001) (Fig. 1). Spinal pain fell from 6.5 to 3.5, mean difference 3.0 (CI 1.7–4.3, t = 4.7, P < 0.001). VAS of general health and well-being fell from 7.0 to 3.6, mean difference 3.4 (CI 2.1–4.8, t = 5.5, P < 0.001). All measures had shown a significant drop at 2 weeks, which was maintained at 2 months and thereafter, up to 20 months at the time of writing (see Fig. 1 for BASDAI as an example).
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Mean haemoglobin was 13.0 g/dl at baseline, which increased to 13.8 at 2-month assessment (CI of difference 0.3–1.2, t = –3.7, P = 0.001). Mean ESR fell from 49 mm/h to 23, a mean fall of 26 (CI 17–36, P < 0.001). All of these reductions were maintained at up to 20 months at the time of writing (see Fig. 1 for details). Additionally, 25 out of the 29 responding patients had reduced significantly or stopped their NSAID and analgesics at the time of their 2-month assessment. For NSAIDs, 15 patients stopped (51.7%) and eight reduced, with five of them requiring at least a daily dose and three using the drugs when necessary. Six patients (20.7%) did not change their NSAID dosage. For analgesics, 14 patients stopped (48.3%), 13 reduced their dose, with 11 of these going to a when necessary regimen, and two remained on the same dose (6.9%).
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Conclusions |
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A number of RCTs of anti-TNF in AS have demonstrated their efficacy (reviewed in [10, 11]). Our experience has confirmed that in clinical practice, anti-TNF therapy is very effective in rapidly decreasing disease activity in patients with ongoing active AS, and maintains that response for up to 20 months, which is the limit of our current follow-up. Our results are similar to those of previous studies. Baraliakos et al. [12] followed up 26 AS patients over 2 yrs on etanercept. Their baseline mean BASDAI was 6.3 and this was maintained around a mean value of 2.6 over the 2 years. Other long-term follow-up studies of etanercept in AS have shown similar sustained responses [13]. In order to fulfil the current BSR guidelines, the patients who went onto anti-TNF therapy demonstrated ongoing active disease over a 2-month period. This contrasts with other patients with AS who might have stable disease with just the occasional short-lasting flare. The patients that we found to be eligible had a mean BASDAI of 6.8 at baseline, considerably higher than the 4.0 that the guidelines recommend [5]. Despite this high baseline, our patients showed a rapid, dramatic and sustained response to anti-TNF therapy.
Other factors supporting the patients’ ongoing active disease include the rise in haemoglobin and the fall in ESR following intiation of anti-TNF therapy. Although the mean haemoglobin started at a borderline mean low-level of 13.0 g/dl and no patients had indices suggesting iron deficiency, the progressive rise in haemoglobin may reflect a positive effect of anti-TNF on a mild anaemia of chronic disease. This has been well documented in RA [14]. Another potential explanation for the rise in haemoglobin is the ability to stop or cut down NSAIDs, which may have led to some chronic low-grade gastrointestinal blood loss. The ESR is governed by a number of factors, including haemoglobin level, but the rapid and sustained reduction is in keeping with effective reductions in acute phase proteins.
This was an observational study, not an RCT, and the BASDAI and VASs are wholly patient-rated. Patients may have reported greater benefit than was truly the case for fear of being classified a non-responder and having their treatment stopped. However, objective measures of disease activity such as their haemoglobin and ESRs also improved, suggesting a benefit that goes above and beyond patient symptoms.
In our limited experience we found that swapping from infliximab to etanercept resulted in ongoing efficacy for patients. The main reason for swopping in our patients was ease of self-administration. Delauney et al. [14] reported 13 spondyloarthropathy patients who swopped from infliximab to etanercept due to inadequate response or adverse events, and after 10 months, 9 of the 13 had responded with no intolerance. This is in keeping with the RA literature where a growing body of evidence supports efficacy when switching from one anti-TNF to another, whatever the reason [15–17].
In conclusion, in our experience the BSR AS anti-TNF therapy guidelines select patients with ongoing active disease. We have validated subjective patient assessments that this therapeutic intervention leads to rapid and sustained benefit, and objective haemoglobin and ESR improvements that support this. The majority of patients were able to cut down or stop their NSAIDs and analgesics. We feel that these factors need to be considered in any health economic analyses of the impact of anti-TNF on AS patients fulfiling the BSR guidelines for going onto these treatments.
Conflict of interest. The Department of Rheumatology at Derbyshire Royal Infirmary has received sponsorship from Wyeth, Abbott and Schering Plough Pharmaceuticals for support of clinical meetings, and unrestricted grants from Wyeth and Schering Plough to support an anti-TNF audit clerk and research nurse. Kate Gadsby sits on an advisory board for Schering Plough, and has received honoraria for talks at symposia sponsored by Wyeth and Abbott. Dr Deighton has previously sat on an advisory board for Schering Plough and received honoraria for talks at symposia sponsored by Wyeth and Abbott.
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