Keh669 939.947

BSR guidelines for prescribing TNF-a blockersin adults with ankylosing spondylitis. Report of aworking party of the British Societyfor Rheumatology A. Keat, N. Barkham1, A. Bhalla2, K. Gaffney3, H. Marzo-Ortega1,S. Paul4, F. Rogers5, M. Somerville3, R. Sturrock6 and P. Wordsworth7on behalf of the BSR Standards, Guidelines and Audit Working Group Two TNF-blocking drugs are now licensed for the treatment of the prevalence of AS ranges from 0.05 [3] to 0.23% [4] in adults, ankylosing spondylitis (AS) and there is clear evidence of men being affected 3–4 times more frequently than women, and symptomatic efficacy. It is recognized that the instruments for in Rochester, Minnesota, an annual incidence rate of 7.3 per analysing aspects of AS and the outcomes of treatment are 100 000 person years has been calculated [5]. The prevalence of imperfect, though they are validated and adequate for the purpose.
AS and HLA-B27 within different ethnic populations has been This document provides guidance to enable consultant rheumatologists in the UK to balance the demonstrated merits In a community with a population of 500 000 adults, of TNF blockade treatment against the known and unknown approximately 500–1000 cases may be expected. Currently some patients with AS do not seek hospital care. Some ofthese have mild symptoms. Others have ceased to attendhospital The availability of new and effective treatment may well AS is an inflammatory condition primarily affecting the spine.
influence the number of AS sufferers who seek hospital Onset is most common in the third decade of life, though the disease may remain symptomatic and progressive throughout life.
It is part of the family of spondyloarthropathies, which also includes psoriatic arthritis, reactive arthritis and enteropathicarthritis. Undifferentiated forms of spondyloarthopathy, often Individuals with AS suffer pain and disability comparable to that presenting as mono- or oligoarthritis, are also recognized, as of patients with rheumatoid arthritis [7]. Because the onset of AS are juvenile forms of spondyloarthopathy, in which the spine is not is typically earlier than that of rheumatoid arthritis, the impact affected but may become so later. Thus, many individuals with AS of these social and economic factors is felt at a younger age.
also suffer from involvement of the hips, peripheral joints and Up to 50% of patients with adult-onset AS and a higher peripheral entheses as well as periodic eye inflammation, proportion of those with juvenile onset develop hip arthritis, inflammatory bowel disease and psoriasis. The treatment of axial and many of these will undergo hip replacement surgery [8]; and peripheral elements of this disease therefore requires distinct a minority of patients will also require surgery to other criteria and guidance that is specific for the particular feature.
joints, especially the knees. Because of heterotopic ossification Symptoms may persist throughout adult life, though some as well as younger age at the time of surgery, revision of patients experience a diminution of symptoms or even remission hip replacements is more often necessary than when this procedure of active disease after a period of years. The consequences of is performed for other indications. A minority of patients also active spinal disease, including spinal stiffness or rigidity and undergo spinal surgery because of severe deformity or spinal increased risk of spinal fracture, are irreversible.
fracture. Osteoporosis occurs early in disease and contributes tothe increased susceptibility to spinal fracture later in life [9, 10].
Life expectancy for people with AS is reduced; the standard- Prevalence and incidence of ankylosing spondylitis ized mortality ratio is 1.5 [11, 12]. The excess mortality is Susceptibility to AS is influenced by genetic factors, particularly mainly accounted for by cardiac valvular disease, amyloidosis HLA-B27 [1, 2]. Thus, the population prevalence of HLA-B27 and fractures. As a consequence, people with AS bear higher influences the population prevalence of AS. In Caucasians, personal insurance costs than the healthy population.
Northwick Park Hospital, Harrow, 1Leeds General Infirmary, Leeds, 2RNHRD, Bath, 3Norfolk and Norwich Hospital, Norwich, 4St Thomas’ Hospital,London, 5National Ankylosing Spondylitis Society, Mayfield, 6University of Glasgow and Glasgow Royal Infirmary, Glasgow and 7University of Oxfordand Nuffield Orthopaedic Centre, Oxford, UK.
Submitted 20 August 2004; revised version accepted 29 March 2005.
Published on the British Society for Rheumatology website in July 2004.
Correspondence to: A. Keat, Arthritis Centre, Northwick Park Hospital, Harrow, Middlesex, AAI 30J, UK. E-mail: andrew.keat@nwlh.nhs.uk Published by Oxford University Press on behalf of the British Society for Rheumatology 2005.
about appearance (51%), worry about the future (50%) andmedication side-effects (41%).
Studies using the SF-36 (SF-36 Health Survey: Medical The impact of AS on employment status is significant [7].
Outcomes Trust Inc.) showed that quality of life for AS sufferers In a Dutch study, overall participation in the labour force was poor, especially in the physical component, figures being was 54.2% for the AS cohort, a significant reduction of 11% worse than some published data for rheumatoid arthritis compared with the general population of the same working and even for some cancers [19]. This is also reflected in poor age [13]. More than three-quarters of patients with AS who had AS-specific quality of life assessment, ASQoL [20].
stopped working were officially recognized as work-disabled.
Approximately one-third of individuals with AS give up work prematurely on health grounds, and an additional 15% suffer constraints within work, including reduction in hoursworked and a change of job, as a result of the disease. Work Traditionally, treatment of AS has been directed to relieving disability is associated with being older, longer duration of pain and stiffness in an attempt to preserve mobility and maintain function. Regular physiotherapy and the use of physical impairment, pain, fatigue, stiffness, anxious and non-steroidal anti-inflammatory agents (NSAIDs) form the depressed mood, and lower self-esteem [14].
mainstay of treatment. NSAIDs have a quick symptomaticeffect, providing in most cases rapid improvement within 48 hafter intake and leading to rapid relapse after their discontinua- tion [21]. This is true to the extent that it has been suggested that, for patients with back pain, the probability of suffering AS carries a significant economic burden, arising from the from AS is as low as 3% if there is a failure to respond to direct costs of medical care and disability care, and from the NSAIDs [22]. There is, however, no clear indication that their indirect costs associated with loss of earnings and reduced long-term use alters the structural progression of the disease.
This, together with the known risk of side-effects (mainly A prospective longitudinal study of 241 patients with AS [15] gastrointestinal), has translated into these drugs being used in the majority of patients for clinical relapses rather than as diagnostic tests, ambulatory care visits, assistive devices, travel, a continuous therapy. The advent of the new cyclooxygenase paid household help and other treatments) and annual indirect 2 (COX-2)-specific inhibitors, thought to be as efficacious as costs (work days missed or, for retirees, days of limited activity).
conventional NSAIDs [23], may challenge this view.
Patients had a mean duration of disease of 20 yr. All patientswere assessed for 1 yr, with a subset of 111 patients followedup for 5 yr. Functional disability was measured using the Instruments for the diagnosis and assessment of AS Health Assessment Questionnaire disability index, modified The diagnosis of AS is made according to the modified 25-question self-report instrument that asks respondents to The most widely used measure of the inflammatory activity of assess functional difficulty in 10 areas (dressing, arising, eating, AS is the Bath Ankylosing Spondylitis Disease Activity Index walking, hygiene, reaching, gripping, errands and chores, (BASDAI) [25]. This simple instrument is patient-completed, bending, and driving). The range for each question is from sensitive to change over 3 weeks, and has been validated. Some 0 (no difficulty) to 3 (unable to do) and the scores are averaged studies have used the two BASDAI spinal stiffness scores as measures of spinal inflammation. Several investigators have In the 1-yr follow up, annual total costs averaged US$6720, included a visual analogue score (VAS) of spinal pain within the direct costs contributing 26% of total costs. These figures last week as a measure of active disease, as the BASDAI does were similar in the 5-yr cohort. In contrast, studies of the not specify this as a single criterion. Since measures of the acute- direct and indirect costs of rheumatoid arthritis have suggested phase response are not indicative of the activity of spinal disease, that indirect costs are comparable to or lower than direct these have not been included in this guideline.
costs [16, 17]. The larger contribution of indirect costs in Response to treatment has been gauged primarily by two AS may reflect the younger age of patients, who may experience measures in clinical trials. The reduction in the BASDAI work disability for a longer proportion of their working years.
has been shown to be simple and sensitive. Fifty per cent Functional disability was the most important indicator of reduction in the BASDAI (BASDAI 50) has been suggested as high total costs and direct costs among these patients. In the an appropriate treatment outcome by the Assessments in 1-yr study, the risks of having high total costs (>$10 000/yr) Ankylosing Spondylitis (ASAS) Working Group. They have increased by a factor of 3 with each 1-point increase in the also recommended that significant clinical benefit is indicated HAQ-S score. Results were similar in the 5-yr follow up cohort, by reduction of the BASDAI by 50% or a fall of 2 units [26].
where the likelihood of high costs (>$50 000 over 5 yr) was Earlier deliberations of the ASAS working group concluded that increased by >6 with each 1-point increase in HAQ-S. The a response to treatment should be assessed according to a authors concluded that interventions that reduce functional composite score, including VAS scales reflecting pain, inflam- disability would be anticipated to be the most effective means mation, well-being and function [27]. Improvement in three modalities by 20% or more, without deterioration in the fourthmodality, constitutes an ASAS 20 response. Improvements of50 and 70% in three modalities constitute ASAS 50 and 70responses, respectively. Current clinical studies indicate compar- able performance of the ASAS combined score and the BASDAI Quality of life has been shown to be adversely affected by AS 50 or a fall of !2 units in assessing response to treatment.
[18]. The most prevalent quality of life issues related to stiffness Expert opinion has been recommended by the ASAS group (90%), pain (83%), fatigue (62%), poor sleep (54%), concerns as part of the assessment of appropriateness of TNF blockade BSR guidelines for prescribing TNF- blocks in adults with AS treatment [27]. Because of lack of transparency and consistency, this has been considered unsuitable for inclusion within arigorous and transparent guideline.
There are currently no longitudinal data on the preventionof ankylosis after treatment with biologicals. It is postulatedthat aggressive and persistent suppression of disease activityshould lead to prevention of structural damage. MRI is a sensitive imaging technique that allows visualization with Two TNF-blocking agents are presently licensed in the UK for good anatomical detail of both the axial and peripheral skeleton.
the treatment of AS: infliximab and etanercept. Others are It is able to detect active inflammation, as shown by bone likely to become available. All trials with etanercept and the oedema, as well as chronic change. A number of studies have majority of trials with infliximab have used treatment regimens used MRI to assess disease activity and response to treatment as set out in the manufacturers’ recommendations. These advise with biologicals [37–39]. Preliminary data suggest that regression that treatment with infliximab should be administered by slow of bone marrow oedema is a sensitive sign of improvement of intravenous infusion with a loading regimen of 5 mg/kg given spinal inflammation in AS; however, all these studies reported at weeks 0, 2 and 6, and maintenance treatment at the same only on small numbers of patients over a period of time no dose given at 6- to 8-weekly intervals. Etanercept is recom- longer than 6 months. Follow-up data are sparse, and although mended to be given by subcutaneous injection at a dose of 25 mg preliminary results suggest a possible role for MRI as a prognostic predictor, this needs to be confirmed in larger andlonger-term studies.
Clinical efficacy of TNF blockade treatment in AS Spinal diseaseSeveral major studies, summarized in Table 1, attest to the efficacy of infliximab and etanercept (in conjunction with disease and spondyloarthropathy were treated with infliximab NSAIDs) compared with placebo in the symptomatic treatment for resistant bowel inflammation. Gastrointestinal symptoms improved and the CRP level fell. In all patients, there was By 6–12 weeks, 70–94% of patients achieved the ASAS 20% improvement criteria (ASAS 20) with infliximab [28–31], as did 59–78% of those treated with etanercept [32, 33]. Similarfindings were reported by Gorman and colleagues [34], though Uveitis. A retrospective study analysed the effectiveness of response criteria differed slightly from those recommended by etanercept (in 14 patients) or infliximab (two patients) on the ASAS group. Davis et al. [33] demonstrated that around immunosuppressive resistant eye inflammation when given 40% of patients achieved a 50% reduction (ASAS 50) and either for the inflammatory eye disease or associated joint around 25% achieved a 70% reduction (ASAS 70) within disease [42]. Eight patients had rheumatoid arthritis, three 12 weeks of etanercept treatment, with 17% classified as having juvenile rheumatoid arthritis, one ankylosing spondylitis and achieved ASAS partial remission after 24 weeks. Similarly, one spondyloarthropathy. In three patients, there was no Braun et al. [28] demonstrated that around 45% of patients associated systemic disease. In all 12 patients with active achieved an ASAS 50 response and around 20% achieved an articular symptoms and inflammation, there was an improve- ASAS partial remission at 12 weeks after three doses of ment, but only six out of 16 patients with ocular inflammation experienced improvement. Five patients developed inflammatory Reduction of the BASDAI by 50% was achieved by 55% of eye disease for the first time whilst taking anti-TNF therapy.
patients treated with infliximab [28] and 57% of those receiving It was concluded that TNF inhibitors may benefit certain etanercept [32] within 6 weeks of treatment. Studies have subgroups of patients with inflammatory eye disease, but more also demonstrated a significant reduction in the BASDAI perspective studies were considered necessary.
compared with baseline values within 2 weeks of treatment withinfliximab [29, 35].
Currently, there are no trial data to indicate the need for, or effects of etanercept on psoriasis and psoriatic arthritis. These benefit from, combining either agent with a second-line drug, are cited in the BSR guideline for anti-TNF therapy in psoriatic or to indicate the optimum duration of treatment. Response to TNF blockade treatment occurs principally at 6–9 weeks.
Cessation of treatment with either agent usually results inrecrudescence of symptoms.
Two studies have examined the effects of anti-TNF treatmenton BMD in patients with a spondyloarthropathy. One study used infliximab, and either 5 or 3 mg/kg [44] demonstrated a These guidelines refer specifically to spinal disease. Further significant increase in bone density at the lumbar spine, total consideration will be given to the treatment of peripheral hip and greater trochanter over a 6-month period. There was an increase in the bone formation marker osteocalcin betweenbaseline and week 6 without any corresponding change in abone resorption marker. The second study examined 10 patientswith spondyloarthropathy compared with 10 controls with shorter disease duration [45]. Patients were treated with These guidelines refer specifically to spinal disease. Further etanercept 25 mg subcutaneously twice weekly. BMD at the consideration will be given to the treatment of peripheral lumbar spine and total hip increased in the anti-TNF group compared with the control group treated with NSAIDs and BSR guidelines for prescribing TNF- blocks in adults with AS sulphasalazine, though only the total hip bone density change There were no deaths or cases of demyelination reported.
reached statistical significance compared with baseline.
Antinuclear antibodies developed in 42 out of 276 patients (15%)in which these data were recorded. No cases of SLE werereported.
In an open-label study of patients meeting the New Yorkcriteria for AS, infliximab 5 mg/kg was infused at 0, 2 and 6 weeks [46]. Eight of the 21 patients had MRI imagingboth before and after infusion to assess inflammatory change.
These guidelines have been drawn up by a working party One patient with a contraindication to MRI was examined whose membership and affiliations are recorded in Appendix 1.
with ultrasound. MRI demonstrated an improvement in seven They have been developed for use by consultant rheumatologists of the eight patients in the imaging cohort; improvement in within the UK in the treatment of adults with AS. Guidelines for the use of etanercept in children (under 19 yr of age) In the second study, of 10 patients with spondyloarthropathy with juvenile idiopathic arthritis have also been drawn up treated with etanercept 25 mg twice weekly for 6 months, (NICE Technology Appraisal Guidance 35, March 2002).
MRI scans of the sacroiliac joints, the lumbar spine and These specialists have experience in the management of patients affected peripheral joints were performed at baseline and with ankylosing spondylitis and familiarity with the use of 6 months [38]. A total of 99 entheseal lesions were detected before treatment, of which 86% had regressed or improved at These guidelines have been developed in the knowledge of existing guidelines for the use of TNF-blocking drugs in patients MRI imaging of the spine in patients with ankylosing spondylitis before and after therapy with infliximab has also should be read in conjunction with BSR guidelines relating to been assessed using a novel scoring system [47]. Lesions, scored the treatment of psoriatic arthritis, and the prevention and by two radiologists, improved by 40% in the infliximab group management of opportunistic infections, including tuberculosis.
compared with 6% in the placebo group, determined using These recommendations are based on available clinical evidence. In addition to clinical trial data, the guideline group sequences, improvement of lesions was seen in 60% of the was cognizant of expert opinions expressed in published papers infliximab group compared with a deterioration in 21% of the [including those listed as 51–53]. It is recognized that, as further placebo group. The chronic lesion score improved by 7% in the evidence becomes available, these guidelines will need to be infliximab group and worsened by 30% in the placebo group. It was concluded that this technique, using STIR (short TI The use of TNF-blocking drugs in this population must be inversion recovery) and gadolinium enhancement sequences and seen in the context of other available therapies. It is anticipated a scoring system, is useful in assessing acute spinal inflammation; that these agents will be indicated for some but not all patients, MRI activity scores in the spine are parallel but do not precisely and that for most patients existing modalities of treatment will still be appropriate, either alone or in combination withTNF-blocking drugs.
Effective patient education is an important contributor to the effective use of these guidelines.
(see Appendix 2) and have been appraised according to the arthropathy resistant to conventional treatment at baseline,week 2 and week 12 of a conventional infliximab treat- chemically. There was a decrease in synovial layer thicknessand a reduction in the number of CD55þ synoviocytes atweek 12. Vascularity was diminished in the sublining area at week 2, with reduced endothelial expression of VCAM, but Eligibility for treatment with TNF-blocking drugs not ICAM, PECAM and E-selectin. At week 12, the numbers Treatment with TNF blocking agents may be appropriate if: of neutrophils and CD68þ macrophages were reduced, but theoverall  The patient’s disease satisfies the modified New York criteria In another study [49] of patients with ankylosing spondylitis, infliximab treatment down-regulated both interferon and Radiological criterion: Sacroiliitis at least grade 2 bilaterally TNF- secretion by T cells, but did not alter cytokine Clinical criteria: Low back pain and stiffness for morethan 3 months that improves with exercise but is not relieved Table 2 summarizes treatment withdrawals and adverse events (a) Limitation of motion of the lumbar spine in both the in clinical trials of anti-TNF- in AS undertaken to assess treatment efficacy and/or safety as the primary outcome (b) Limitation of chest expansion relative to normal values variables. In publications in which the same cohorts of patients are reported, we considered this information when preparingthe table. Of 394 AS patients studied, nine (2.3%) discon- A definite diagnosis of ankylosing spondylitis requires the tinued treatment due to lack of efficacy. Twenty-eight patients radiological criterion and at least one clinical criterion.
(7.1%) were withdrawn because of adverse events. These (All reasonable measures should be taken to ensure that included three major infections (two cases of tuberculosis, symptoms are due predominantly to AS and that alternative causes, including spinal fracture, disc disease and fibromyalgia, patients and five systemic infliximab-related infusion reactions.
BSR guidelines for prescribing TNF- blocks in adults with AS  Ankylosing spondylitis is active. Active spinal disease should be However, the working group recommends that such a register is set up for these patients; the BSR is currently pursuing this.
In the meantime, the BSR currently recommends that data collection, including updated dosage, outcome and toxicity (b) And spinal pain VAS (last week) at least 4 cm.
information, is conducted at a local level. Adverse incidents/ (c) Both on two occasions at least 4 weeks apart without any serious side-effects arising whilst on anti-TNF therapy should be notified immediately via the yellow card system.
 Failure of conventional treatment with two or more NSAIDs, each taken sequentially at maximum tolerated/recommendeddosage for 4 weeks.
These guidelines will be reviewed annually.
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36. Maksymowych WP, Jhangri GS, Lambert RG et al. Infliximab tion cohort analysis of efficacy and safety. J Rheumatol 2002; Appendix 1. Members and affiliations of the working group 37. Kruithof E, Van den Bosch F, Baeten D et al. Repeated infusions of Dr Andrew Keat, Chairman (Consultant Rheumatologist, infliximab, a chimeric anti-TNFa monoclonal antibody, in patients with active spondyloarthropathy: one year follow up. Ann Rheum Dr Nick Barkham (Specialist Registrar in Rheumatology, Leeds 38. Marzo-Ortega H, McGonagle D, O’Connor P, Emery P. Efficacy of Dr Ashok Bhalla (Consultant Rheumatologist RNHRD, Bath) etanercept in the treatment of the entheseal pathology in resistant Dr Karl Gaffney (Consultant Rheumatologist, Northfolk & spondylarthropathy: a clinical and magnetic resonance imaging study [comment]. Arthritis Rheum 2001;44:2112–7.
Dr Helena Marzo-Ortega (Specialist Registrar in Rheumatology, 39. Brandt J, Haibel H, Sieper J, Reddig J, Braun J. Infliximab treatment of severe ankylosing spondylitis: one year follow-up.
Arthritis Rheumatism 2001;44:2936–7.
40. Brandt J, Haibel H, Reddig J, Sieper J, Braun J. Successful short Mr Fergus Rogers (Director, National Ankylosing Spondylitis term treatment of severe undifferentiated spondyloarthropathy with the anti-tumour necrosis factor alpha monoclonal antibody Margaret Somerville (Clinical Research Manager, Department infliximab. J Rheumatol 2002;29:118–22.
of Rheumatology, Northfolk & Norwich Hospital) BSR guidelines for prescribing TNF- blocks in adults with AS therapies (either educational or promotional) or for activities not University of Glasgow, Consultant Rheumatologist, Glasgow The following replies were received.
Professor Paul Wordsworth (Professor of Rheumatology, University of Oxford, Consultant Rheumatologist, Nuffield  The units in which the following working party members work have received funding from one or more of the manufacturers oftherapies for ankylosing spondylitis: K. Gaffney, N. Barkham,H. Marzo-Ortega, R. Sturrock, M. Somerville, A. Keat.
 The following working party members have received funding Appendix 2. Process of review and appraisal of this draft biological therapies to attend scientific meetings in the past Formal comments have been sought by the presentation of a 24 months: N. Barkham, A. Keat, M. Somerville, F. Rogers, draft document at the Annual Meeting of BSR in April 2004 and  BSR has established a register which is funded by the manufacturers of biological therapies for rheumatoid arthritis; training for rheumatologists in data collection has also been  The following working party members have received honoraria British Society for Paediatric and Adolescent Rheumatology: from the manufacturers of therapies for ankylosing spondylitis: BSR Psoriatic Arthritis and TNF blockade Working Group:  The following working party members have received funding for taking part in clinical trials of the new biological therapies: BSR Rheumatoid Arthritis and TNF Blockade Working  No working party members declared a direct financial stake, such as personal shareholding, in companies manufacturing thenew biological therapies.
Appendix 3. Declaration of interest statement The Working Party was set up independently of any input or Appendix 4. Other guidelines and documents which should funding from the manufacturers of the biological therapies forankylosing spondylitis.
be read in conjunction with this document Members of the Working Party were asked to clarify their  Update of BSR guidelines for prescribing TNF- blockers relationships with the manufacturers of the biological therapies.
in adults with rheumatoid arthritis, including update on Members were asked to declare if they, as individuals, had been sponsored to attend scientific or other meetings in the past  Guideline for anti-TNF- therapy in psoriatic arthritis 2004 [43].
24 months or if they had a direct financial stake in the manu-  Guideline for the use of etanercept in juvenile idiopathic facturing companies. They were also asked if their units had arthritis (NICE Technology Appraisal Guidance 35, March received funding from the manufacturers to take part in clinical trials of the new biological therapies. Organizations were asked  BPRG protocol for prescribing biological therapies in children to declare if they had received sponsorship from manufacturers and young people with juvenile idiopathic arthritis 2000 of the new biological therapies for activities related to the new

Source: http://karlgaffney.co.uk/pubs/939.pdf