Rheumatology Advance Access originally published online on July 1, 2008
Rheumatology 2008 47(10):1441-1443; doi:10.1093/rheumatology/ken242
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EDITORIALS |
The British Society for Rheumatology Biologics Register: 6 years on
1ARC Epidemiology Unit, University of Manchester, Manchester and 2Centre for Rheumatology Research, Division of Medicine, UCL, London, UK
Correspondence to: K.L. Hyrich, ARC Epidemiology Unit, Stopford Building, University of Manchester, Oxford Road, Manchester M13 9PT, UK. E-mail: kimme.hyrich{at}manchester.ac.uk
The introduction of anti-TNF and other biological therapies for the management of patients with RA has significantly improved the outcome for patients with severe disease. However, despite demonstrated safety compared with placebo in early clinical trials, there were still many uncertainties about their long-term safety, particularly with respect to serious infection and malignancy. There was also concern about rare and unexpected adverse events. In contrast, the possibility existed that by reducing levels of inflammation it might be possible to reduce the risk of atherosclerosis. Against this background, the British Society for Rheumatology (BSR) proposed to develop a large prospective epidemiological study, to monitor patients with RA receiving these drugs in the UK.
History and structure of the BSR Biologics Register
The BSR Biologics Register (BSRBR) was launched in October 2001. The primary aim of this study was to investigate the long-term outcome of patients with RA treated with biologic agents with particular reference to safety. The study was organized under the auspices of the BSR and based at the Arthritis Research Campaign (ARC) Epidemiology Unit at The University of Manchester. Funding for this study comes from the pharmaceutical companies that market anti-TNF agents and other biologics in the UK to the BSR. To date these companies have included Wyeth, Schering-Plough, Abbott Laboratories and Amgen. Each company has a separate contract with the BSR, which in turn has awarded the ARC Epidemiology Unit a research grant for the running of the study. The BSR in effect acts as a ‘blind trust’ ensuring that the ARC Epidemiology Unit has academic freedom in running the study. The pharmaceutical companies have the right to look at potential publications and comment on them, but may only delay the despatch of written articles by up to 30 days; they cannot veto them. This arrangement has the strong support of the National Institute for Health and Clinical Excellence (NICE).
The project is overseen by a Steering Committee appointed by the BSR. In addition, a Data Monitoring and Ethics Committee has been established to review safety data regularly and comment on the need for any ad hoc analyses in the case of possible signal detection. An example is the possible association between anti-TNF therapies and new-onset psoriasis. The register runs in parallel with other European registries, in particular, registers established in Germany and Sweden, which are funded by similar routes and are collecting the same core data. Representatives from these registers meet on an annual basis to discuss progress of the registers as well as issues related to the collection and analysis of safety data.
Sample size and patient recruitment
The original sample size calculation for the BSRBR was based on the ability to detect a two-fold increase in lymphoma. This equated to 20 000 person-years in both a treated and untreated cohort. For ease, this was equated to a sample size of 4000 patients with a follow-up of 5 yrs each, for each of the three currently available NICE-approved anti-TNF drugs (etanercept, infliximab and adalimumab) and a similarly sized DMARD-treated control group. Patients on biologics have been recruited from 251 hospitals across the UK. The majority have very active disease [28-joint disease activity score (DAS28) >5.1] which has been resistant to at least two DMARDS, in accordance with the current national guidelines on the use of these agents [1]. In 2005, the target of 4000 etanercept-treated patients was reached and recruitment to this cohort was closed. The last of 4000 infliximab-treated patients was recruited in early 2007. The anti-TNF arm of the BSRBR is now only recruiting patients starting adalimumab as their first anti-TNF drug, with an estimate of completing recruitment in the summer of 2008.
The recruitment of a comparable control cohort is an important element of the BSRBR. It is well recognized that RA is associated with an increased risk of infections, lymphoproliferative malignancy and cardiovascular disease, even prior to the advent of anti-TNF therapies [2–4]. Understanding what additional risks (or benefits) these drugs may place on patients must therefore, take into account the background risk for all of these events. Control patients for this study are selected from 25 different rheumatology centres across the UK. Inclusion criteria include a diagnosis of RA, active disease with a DAS28 of at least 4.2, and treatment with a DMARD. Ironically as a result of the success of anti-TNF prescribed across the UK, the numbers of patients with severe disease not receiving anti-TNF therapies is decreasing, leading to a slower recruitment to the control arm. The control cohort has now recruited over 3300 patients and it is anticipated that the recruitment of this group will also be completed in 2008. Not unexpectedly these control patients have somewhat less severe disease. The patients enrolled in the anti-TNF cohort of the BSRBR have severe long-standing disease, with at least 50% of the patients having failed at least four previous DMARDs. The mean disease duration at the start of anti-TNF therapy is 13 yrs, the mean DAS28 is 6.6 (S.D. 1.0) and the mean HAQ is 2.1 (S.D. 0.6). This compares with a mean disease duration of only 10 yrs in the control cohort, who have a mean DAS28 of 5.1 (S.D. 1.4) and a mean HAQ of 1.5 (S.D. 0.8).
Study design and patient follow-up
All patients (anti-TNF treated and DMARD controls) have 6-monthly questionnaires completed by the rheumatologist or rheumatology nurse specialist for the first 3 yrs of the study and then annual questionnaires for a further 2 yrs. In addition, patients completed a diary recording all hospitalizations and other adverse events 6-monthly for 3 yrs. All patients are also flagged with the Office for National Statistics, which provides ongoing information on all patients who die or develop a malignancy within the UK. Despite this intensive programme, the follow-up rates have been excellent, with 90% of available consultant follow-up returned to the arc EU. Patient response rates have also been very good, with 75% of all diaries returned. Regular feedback to patients and health care professionals via newsletters has helped to maintain the momentum of this study.
What have we learned so far?
The BSRBR has now been recruiting patients for 6 yrs and is still relatively ‘young’ in terms of long-term safety monitoring. As is the case with many long-term prospective studies, many years must pass until sufficient data are available for meaningful analyses. However, there have now been many important publications that have arisen from this study, which are summarized in this editorial. These have largely focused on two main areas: real-world effectiveness and safety.
Anti-TNF treatment effectiveness
Effectiveness of anti-TNF therapy
Although the BSRBR was established primarily as a safety study, the routine collection of disease activity data has also allowed us to analyse anti-TNF treatment effectiveness, particularly in the first 6 months of treatment, during which few patients may have discontinued therapy. The mean improvement in DAS28 after 6 months of therapy was in the range of 2, with 68% of patients classified as EULAR (European league Against Rheumatism) moderate or good responders [5]. There was a clear advantage of adding etanercept to background MTX on EULAR response at 6 months [adjusted odds ratio (OR) of response 2.0; 95% CI 1.5, 2.7]. However, it was difficult, based on clinical factors alone, to predict which patients would respond to anti-TNF therapy [6]. The strongest predictors, in addition to combining therapy with MTX, were HAQ score, concurrent use of NSAIDs and current cigarette smoking (an association strongest in the infliximab-treated patients).
Anti-TNF switching
Inevitably, not all patients will respond and a further proportion will experience adverse events leading to drug discontinuation. Approximately 22% of the patients have now switched to a second anti-TNF agent (2/3 for inefficacy and 1/3 for an adverse event on their first anti-TNF drug). An analysis of the first 800 switchers demonstrated that patients are likely to discontinue a second anti-TNF agent for similar reasons for discontinuing their first [7]. Patients who had already stopped one drug for inefficacy were 2–3 times as likely to stop their second for inefficacy compared with the overall risk of stopping a first anti-TNF for inefficacy. Similar results were found for those stopping their first anti-TNF therapy following an adverse event. However, patients who had not previously experienced an adverse event were no more likely to stop a second anti-TNF drug for an adverse event than those starting their first anti-TNF drug and patients who switched for an adverse event were as likely to respond to the second drug.
Drug safety
We are now starting to explore the safety of these drugs among patients with RA, with publications having focused on three main areas: serious infection, myocardial infarction (MI) and pregnancy. In the background, we have shown a substantial level of comorbidity in both the anti-TNF-treated and DMARD-treated control RA cohorts [8] at the time of recruitment, stressing the burden of illness in this population. These comorbidities included hypertension (22%), asthma (10%), COPD (5%), diabetes (5%) and depression (19%), with rates comparable between the two cohorts.
Serious infections
Overall, compared with our control group, we found no overall increase in risk of serious infections in patients actively receiving anti-TNF agents (defined as the time from first dose until first missed dose), although there was an increased risk of serious skin and soft tissue infections among the anti-TNF-treated patients [9]. However, an analysis limited to the first 90 days of treatment revealed an increased risk during this early period of follow-up (adjusted incident rate ratio 4.6; 95% CI 1.8, 11.9) [10]. We have also demonstrated a higher than expected incidence of bacterial intracellular infections, including tuberculosis (TB), Salmonella, Listeria and Legionella. Importantly, some cases of TB were reported after anti-TNF therapy had been stopped, indicating that vigilance should be maintained for this infection, even after an anti-TNF drug is discontinued. Reports of other bacterial intracellular infections have resulted in warnings to patients and health care professionals regarding the consumption of unpasteurized and undercooked foods.
Myocardial infarction
The rates of myocardial infarction (MI) in the two cohorts were similar after adjusting for baseline cardiovascular risk. However, we found an early signal that risk of future MI may be reduced by up to 60% among patients receiving anti-TNF therapies classified as EULAR responders at 6 months, which supports the underlying role of inflammation in cardiovascular disease [11].
Pregnancies
A review of 32 pregnancies in women receiving anti-TNF therapies (23 actively receiving at the time of conception) did not reveal any reports of congenital malformations and found the miscarriage rate to be in keeping with that of the general population [12].
Malignancy
One issue that we have not yet explored in detail is malignancy. The sample size of this study was powered to detect an increased risk of lymphoma. To date, we have not reached this sample size and therefore, are not yet in a robust enough position to address this question. There has been a signal, however, that the risk of a new malignancy may be increased in patients who have a history of cancer prior to anti-TNF therapy [13]. Further follow-up of this cohort will allow us to explore this and other questions about cancer risk in more detail.
BSRBR—the future
The register has already taught us a significant amount about the safety and effectiveness of anti-TNF drugs. It has also revealed the intricacies and intensity of work at all levels required for the successful running and analyses of such an extensive national register. The project's success ultimately lies with the consultant rheumatologists, rheumatology nurse specialists and the patients who provide the high-quality data to the register. The BSRBR will continue to be a source of valuable information for rheumatology health care professionals and patients both locally and internationally for many years to come. Active follow-up of patients enrolled in this study will continue until at least 2013. In addition, rituximab is now about to join the register and other newer biologic agents may follow in due course as they receive appropriate approval, to understand not only the risk of these new agents, but also the risks (and benefits) of consecutive biologic agents in patients with severe RA.
Acknowledgements
The authors acknowledge the enthusiastic collaboration of all consultant rheumatologists and their specialist nurses in the UK in providing the data used in this report. We also acknowledge the significant contribution of Prof. Alan Silman in the conception and establishment of the BSRBR. The substantial contribution of Andy Tracey, Katie McGrother and Dr Mark Lunt in database design and manipulation is recognized. We also acknowledge the support from Dr Ian Griffiths, Chairman of the BSRBR Management Committee, Prof. Gabriel Panayi, Prof. David G. I. Scott and Dr Andrew Bamji, Presidents of the BSR during the period of data collection, for their active role in enabling the Register to undertake its tasks and to Samantha Peters (CEO of the BSR), Mervyn Hogg and the BSR staff for considerable administrative support.
Disclosure statement: The authors have declared no conflicts of interest.
References
- Ledingham J, Deighton C. Update on the British Society for Rheumatology guidelines for prescribing TNFalpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatology (2005) 44:157–63.
[Free Full Text] - Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum (2002) 46:2287–93.[CrossRef][Web of Science][Medline]
- Watson DJ, Rhodes T, Guess HA. All-cause mortality and vascular events among patients with rheumatoid arthritis, osteoarthritis, or no arthritis in the UK General Practice Research Database. J Rheumatol (2003) 30:1196–202.
[Abstract/Free Full Text] - Thomas E, Brewster DH, Black RJ, Macfarlane GJ. Risk of malignancy among patients with rheumatic conditions. Int J Cancer (2000) 88:497–502.[CrossRef][Web of Science][Medline]
- Hyrich KL, Symmons DP, Watson KD, Silman AJ. Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum (2006) 54:1786–94.[CrossRef][Web of Science][Medline]
- Hyrich KL, Watson KD, Silman AJ, Symmons DP. Predictors of response to anti-TNF-alpha therapy among patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. Rheumatology (2006) 45:1558–65.
[Abstract/Free Full Text] - Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ. Outcomes after switching from one anti-tumor necrosis factor alpha agent to a second anti-tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large UK national cohort study. Arthritis Rheum (2007) 56:13–20.[CrossRef][Web of Science][Medline]
- Hyrich K, Symmons D, Watson K, Silman A. Baseline comorbidity levels in biologic and standard DMARD treated patients with rheumatoid arthritis: results from a national patient register. Ann Rheum Dis (2006) 65:895–8.
[Abstract/Free Full Text] - Dixon WG, Watson K, Lunt M, Hyrich KL, Silman AJ, Symmons DP. Rates of serious infection, including site-specific and bacterial intracellular infection, in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum (2006) 54:2368–76.[CrossRef][Web of Science][Medline]
- Dixon WG, Symmons DP, Lunt M, Watson KD, Hyrich KL, Silman AJ. Serious infection following anti-tumor necrosis factor alpha therapy in patients with rheumatoid arthritis: lessons from interpreting data from observational studies. Arthritis Rheum (2007) 56:2896–904.[CrossRef][Web of Science][Medline]
- Dixon WG, Watson KD, Lunt M, Hyrich KL, Silman AJ, Symmons DP. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum (2007) 56:2905–12.[CrossRef][Web of Science][Medline]
- Hyrich KL, Symmons DP, Watson KD, Silman AJ. Pregnancy outcome in women who were exposed to anti-tumor necrosis factor agents: results from a national population register. Arthritis Rheum (2006) 54:2701–2.[CrossRef][Web of Science][Medline]
- Watson KD, Dixon WG, Hyrich KL, Lunt M, Symmons DPM, Silman AJ. Influence of anti-TNF therapy and previous malignancy on cancer incidence in patients with rheumatoid arthritis (RA): results from the BSR biologics register (BSRBR). Rheumatology (2006) 45:I10.
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  K. L. Hyrich, C. Deighton, K. D. Watson, BSRBR Control Centre Consortium, D. P. M. Symmons, M. Lunt, and on behalf of the British Society for Rheumatology Benefit of anti-TNF therapy in rheumatoid arthritis patients with moderate disease activity Rheumatology, October 1, 2009; 48(10): 1323 - 1327. [Abstract] [Full Text] [PDF]
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