Assessment of patients with spondyloarthropathies for treatment with tumour necrosis factor {alpha} blockade

S. Paul1 and A. Keat

Department of Rheumatology, Northwick Park Hospital, Harrow, Middlesex HA1 3UJ, UK.1 Present address: Department of Rheumatology, St Thomas' Hospital, London SE1 7EH, UK

Correspondence to: A. Keat. E-mail: andrew.keat{at}nwlh.nhs.uk


    Introduction
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 Introduction
 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Practical considerations in the...
 References
 
There is no doubt that the arrival and licensing of two tumour necrosis factor (TNF)-blocking drugs—infliximab and etanercept—for the treatment of ankylosing spondylitis (AS) represents the first major advance in the treatment of this condition since the advocacy of exercises and the introduction of phenylbutazone. These agents have also been shown unequivocally to be effective in a proportion of patients with psoriatic arthritis (PsA), comparable to their effect in rheumatoid arthritis (RA), and anecdotal reports also suggest benefits for patients with enteropathic arthritis, persistent reactive arthritis (ReA) and undifferentiated spondyloarthropathy (SpA). But, as with RA, the availability of these agents places a huge responsibility upon rheumatologists, individually and collectively, to negotiate the poorly charted waters of assessment of disease outcomes, known and potential drug toxicity and potentially massive cost. Moreover, all parties to the negotiation are signed up to the provision of such treatment according to criteria that are wise, transparent and fair.

For the SpAs, the opportunities provided by TNF-{alpha} blockade come not a moment too soon but at a difficult time. In recent years huge expertise has developed in the assessment of RA and the development of suitable instruments for that purpose. In contrast, the SpAs have received much less clinical trial attention and clinicians are less well equipped to make objective assessments. Indeed, until the last few years few useful measures were available, especially for the assessment of spinal disease. Fortunately, several groups, notably that at Bath, UK, have developed and validated instruments for measuring such attributes as disease activity, function and pain in AS and more recently an international group of rheumatologists interested in AS have formed the Assessments in Ankylosing Spondylitis (ASAS) working group to attempt to reach consensus over treatment issues which cannot presently be governed by objective criteria such as the presence or absence of joint erosions.

Thus, just in the nick of time, a basis has been laid on which to build a framework within which TNF-{alpha} blockade and other biological therapies can reasonably be used in the treatment of SpAs. Unfortunately, at present much of that framework relies heavily on subjective measures, with very limited objectivity. But the need for guidance is now, as our patients need treatment now. Such guidance as emerges must therefore be seen as provisional and requiring regular revision year on year.


    Rationale for targeting TNF-{alpha} in spondyloarthropathy
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 Introduction
 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Practical considerations in the...
 References
 
Soluble TNF-{alpha} is a homotrimer which is secreted mainly by macrophages and activated T-cells and plays a pivotal role in the inflammatory response via its regulatory and effector actions on lymphocyte activation and release of other cytokines [1]. The therapeutic effect of neutralization of TNF in inflammatory diseases, including RA, Crohn's disease and psoriasis, is now well known [2–4].

TNF-{alpha} mRNA, T cells and macrophages have been found in the sacroiliac joints [5] and entheses [6] of patients with active AS, both sites being characteristically involved in SpA. Elevated levels of TNF-{alpha} have also been found in synovial tissue and serum from patients with SpA [7, 8]. Enhanced synovial fluid TNF-{alpha} expression has also been reported in ReA [9], although in this condition apparently diminished peripheral leucocyte TNF-{alpha} production might predispose to bacterial persistence [10]. Psoriatic skin lesions are rich in TNF-{alpha}, which promotes the production of proinflammatory molecules and leads to apoptosis [11], and cultured peripheral blood monocytes from patients with PsA have been shown to spontaneously secrete higher levels of TNF-{alpha} in vitro compared with healthy controls [12]. The SpAs as a group are associated with chronic inflammatory bowel disorders. TNF-{alpha} is strongly expressed in the bowel of patients with Crohn's disease, in which anti-TNF-{alpha} therapy has been shown to be effective [13]. Elevated levels of TNF-{alpha} have also been reported in aqueous humour and sera of patients with acute uveitis, the serum levels correlating with recurrent uveitis [14].

Whilst these observations do not clarify the precise role of TNF-{alpha} or other cytokines in the pathogenesis of AS or other SpAs, there are clear circumstantial grounds for suspecting its involvement and thus for targeting TNF-{alpha} in these conditions with biological therapies.


    Current anti TNF-{alpha} agents: infliximab, etanercept and adalimumab
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 Introduction
 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Practical considerations in the...
 References
 
Infliximab is a chimeric monoclonal IgG antibody with human constant and murine variable regions. It has a molecular weight of 149 kilodaltons and acts by capturing soluble TNF-{alpha}, thereby preventing its binding to the TNF-{alpha} receptor. Each molecule of infliximab is capable of binding to two TNF-{alpha} molecules. Infliximab also promotes cell lysis by binding to cell membrane-bound TNF in vitro. Its elimination half-life is more than 8 days and it is given as an intravenous infusion.

Etanercept is a 150-kilodalton recombinant fusion protein which acts as a decoy receptor for soluble TNF-{alpha}. Its elimination half-life is more than 4 days and, unlike infliximab, it also demonstrates high affinity for TNF-ß. It is given by subcutaneous injection.

Adalimumab is a fully human monoclonal antibody to TNF-{alpha} that is given by subcutaneous injection. To date there have been no published articles regarding its efficacy in SpA.

The amount of long-term data from anti-TNF-{alpha} experience in RA and other inflammatory diseases is steadily growing. About 300 patients world-wide with SpA have received treatment with infliximab and etanercept and therefore only limited safety data are available. The toxicity profile in SpA appears similar to that seen in RA.


    Outcomes of treatment of SpA and their assessment
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 Introduction
 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
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Ideally, effective treatment of AS and other SpAs should produce symptomatic benefit in terms of pain, stiffness and fatigue, biological benefit in the reduction or prevention of joint damage and ankylosis, and societal benefit in the form of reduced need for surgery, the maintenance of employment and reduced mortality. Current evidence for the use of TNF-{alpha} blockade treatment in SpA relates only to symptomatic benefit. It is possible that other benefits of treatment will eventually be shown, and indeed it is urgent that such evidence is accumulated. For the present, however, the assessment of outcomes of treatment must deal essentially with symptoms. This is especially problematic in AS as symptoms have been difficult to quantify objectively and laboratory measures, such as the ESR and CRP, correlate poorly with inflammatory activity as reflected by symptoms [15].

Numerous measures have been and are used for assessing patients with AS. Some, such as modified Schober's measurements, chest expansion and tragus-to-wall distance, provide reasonably reproducible, if insensitive, measures of disease progression; others, such as the ESR and CRP, may reflect activity in peripheral joints but seem not to correlate with spinal inflammation. Moreover, it has been difficult to derive reproducible and widely accepted measures of disease activity, pain and function that relate specifically to spondylitis per se. Outcome measures for the treatment of AS have been considered by the ASAS working group and some important consensus has been achieved. A core set of 10 domains—function, spinal pain, spinal mobility, patient global assessment, stiffness, peripheral joints and entheses, acute-phase reactants, radiographs of the spine, radiographs of the hips, and fatigue—has been identified with suitable instruments for the assessment of each [16]. These have been endorsed by the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) and The International League Against Rheumatism. Some of the measures have been included in composite scores which are convenient to use and have been validated in AS.

Hence, treatment studies have used a variety of measures based especially on the ASAS instruments and composite scores. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) includes measures of spinal stiffness and fatigue but not of specific spinal pain (Fig. 1) [17].



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FIG. 1. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Add scores (taking mean of stiffness questions 5 and 6) to make a score out of 50. Then multiply by 2 and divide by 10 to make the total BASDAI out of 10.

 
Thus, some studies have added a separate measure of spinal pain using either a 10-cm VAS or a five-point Likert scale. Function can be assessed using either the Bath Ankylosing Spondylitis Functional Index (BASFI) [18] or the Dougados functional index [19]. Changes in mobility can be reflected either in single measures of spinal range of movement or in composite scores, such as the Bath Ankylosing Spondylitis Metrology Index (BASMI) [20]. Reduction in inflammation and pain with substantial improvements in well-being are not necessarily reflected in changes in mobility, and the same is true for radiographic measures, important though these ultimately must be. Other studies have relied on criteria agreed by the ASAS group for significant improvement in AS with symptom-modifying and disease-controlling treatments [21]. These require improvement of 20% or more (Fig. 2) in three of the four domains (physical function, pain, patient global assessment and inflammation) without deterioration in the fourth.



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FIG. 2. Assessments in Ankylosing Spondylitis Working Group criteria for 20% response.

 
Although current evidence [22, 23] suggests that TNF-{alpha} blockade treatment might actually suppress ankylosis—and therefore be truly disease-modifying—the data are not yet clear, so that criteria for introducing TNF-{alpha} blockade must rely on symptom control for the present.

The ASAS group have recently published proposals for criteria for introducing and stopping anti-TNF-{alpha} treatment [24] and the British Society for Rheumatology will shortly bring forward proposals for the use of these drugs in the UK. Inevitably, in the present circumstances such criteria must depend on data which are largely subjective.

The assessment of peripheral arthritis presents different problems. As in RA, objective measures such as swollen and tender joint counts and erosion scores can be made. However, oligoarticular disease makes use of the DAS 28 or ACR criteria for RA inappropriate. The Psoriasis Area and Severity Index (PASI) is a well-established instrument for the assessment of psoriasis and its response to treatment [25].


    Efficacy of anti-TNF-{alpha} therapy ankylosing spondylitis
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 Introduction
 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Practical considerations in the...
 References
 
Infliximab
Two randomized, double-blind, placebo-controlled trials have confirmed the findings of initial open-label pilot studies [26, 27] that infliximab is effective in AS.

In a German study [28], 70 patients with severe active AS (defined in the study as a BASDAI score of at least 4/10) in patients meeting the modified New York criteria for AS (Table 1), most of whom were HLA-B27-positive, were randomized to receive infusions of infliximab at a dose of 5 mg/kg at 0, 2 and 6 weeks. Patients were followed up for 12 weeks. Fifty-three per cent of the infliximab group had at least 50% reduction in BASDAI at 3 months compared with 9% of controls. The treatment effect was rapid, being seen in 41% of the infliximab group by the second week. Significant improvement in all aspects of the Short Form-36 (SF-36), apart from the mental health component, was also demonstrated in the infliximab group. When the results were analysed using the multidomain ASAS multiple domain scoring system group, a 20% ASAS response was seen as early as week 2 in the majority of patients. Infliximab treatment resulted in more patients discontinuing NSAIDs (56% vs 9%). There was some evidence that patients with CRP levels greater than 10 mg/l at baseline benefited more than those with low or normal levels. At 3 months the placebo group crossed over to receive infliximab using the same induction regime and continued with infliximab every 6 weeks. Seventy-eight per cent of patients were still receiving treatment with infliximab after 1 yr. At week 54, approximately 50% of patients in both groups had sustained a 50% reduction in BASDAI scores [30].


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TABLE 1. The modified New York criteria for AS [29]

 
Similar findings were obtained in a Belgian study in patients with SpA [31]. In their patients functional impairment fell in the treated group but actually increased in the placebo group. Appendicular symptoms were significantly reduced. Continued benefit with retreatment every 14 weeks, albeit with 10 mg/kg of infliximab, has been reported [32]. The same group have demonstrated that significant improvement was sustained over a year with infliximab retreatment at 14 weeks at a dose of 5 mg/kg [33].

Fifty patients with severe axial AS [34] were treated in a French open-label study. Of the 38 who had baseline spinal X-rays, nine had advanced ossification. A cumulative ASAS 20% response was achieved in 94% of patients within 4 weeks of starting treatment. Inflammatory markers demonstrated maximal improvement within 4 weeks also. Global pain score reduction by at least 20% was achieved in all responders; no correlation was seen between the extent of spinal fusion on X-ray and the maximal global pain score improvement.

Treatment with infliximab results in changes in scintigraphic appearances [35] and improvement or complete regression of inflammatory spinal lesions has also been demonstrated on magnetic resonance imaging (MRI) within a few weeks of infliximab loading [22, 26] mirroring improvement of symptoms. However, changes in ankylosed lesions may not be detected on MRI after infliximab treatment [36]. It is clear that X-rays lack the sensitivity to demonstrate effective suppression of spondylitis within a reasonable time frame. These rapid changes seen on MRI may form the basis of a much-needed objective outcome assessment, particularly where the cost of continued long-term treatment outweighs that of repeated MRI scanning. A novel scoring system has been proposed based on MRI changes following 3 infusions of infliximab, but awaits further validation [37].

In patients with AS, loss of bone density occurs early in the course of disease and vertebral fracture is not uncommon [38–40]. A short-duration study suggested that TNF-{alpha} blockade leads to increased bone mineral density [41], though whether this translates into reduced fracture risk or reduced morbidity remains unknown.

Histological analysis of synovial tissue from AS patients treated with infliximab shows a reduction in thickness and inflammatory cell infiltrate [42].

Most studies have used infliximab as monotherapy without methotrexate and it appears that combination therapy in the treatment of AS is unnecessary. Doses have ranged from 3 to 10 mg/kg body weight [36, 32] but most studies have used 5 mg/kg administered with a loading dose at 0, 2 and 6 weeks. In a Canadian study [36], the 3 mg/kg dose needed to be increased in three patients to 5 mg/kg after 14 weeks (one patient eventually requiring 6 mg/kg every 4 weeks) with resultant improvement. Methotrexate was started in two patients after inadequate responses at 3 mg/kg, but it is not yet clear whether combination therapy confers advantages over either drug alone. Infliximab is currently licensed in the UK at induction and maintenance doses of 5 mg/kg in AS.

Whilst the manufacturer's dose and frequency schedules are a good starting point, further work may refine both issues. Kruithof and colleagues [33] used intervals of 14 weeks but recurrence of symptoms (though not full relapse) was seen after 10 weeks in some patients. In another study [43] symptoms recurred as early as a median of 7 weeks (range 1–17 weeks) after the third infusion, indicating that infusions at 6-weekly intervals are necessary to sustain improvement. In an open-label pilot study [34], the median delay between relapse and the last infusion of infliximab was 14 weeks (range 0–19), although a significant proportion of responders were relapse-free 6 months after the loading regimen. Infliximab is licensed in the UK for use every 6–8 weeks after a loading regimen in the treatment of AS [44]. Clearly, there is a need to re-evaluate doses and interdose intervals in individual patients once stable benefit is achieved.

Etanercept
Overall there have been more studies of infliximab than of etanercept in the treatment of AS, but etanercept has also been the subject of controlled trials and is now licensed in the UK for the treatment of AS [45]. In a placebo-controlled trial of etanercept 25 mg subcutaneously twice weekly for 4 months [46], significant improvement in measures of morning stiffness, spinal pain, patient global assessment of disease activity, function and joint swelling were observed in the etanercept-treated arm. Eighty per cent of etanercept-treated patients vs 30% of placebo patients demonstrated a 20% or greater improvement in three of five primary outcome measures.

In a larger multicentre, randomized, placebo-controlled trial of 25 mg of etanercept twice weekly over 24 weeks in 277 patients with active AS 59% of etanercept-treated and 28% of placebo-treated patients achieved an ASAS 20 response at 3 months. The difference between groups was seen within 2 weeks [47].

In a German placebo-controlled trial of etanercept [48], a 50% reduction in BASDAI (BASDAI 50) was used as the primary outcome measure; 57% of the etanercept-treated arm compared with 6% of the placebo arm achieved BASDAI 50 after 12 weeks. After cessation of therapy almost all patients relapsed at a mean of 6 weeks.


    Efficacy of anti-TNF-{alpha} therapy in PsA
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 Introduction
 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
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Etanercept 25 mg twice weekly was shown to be effective for both skin and joint lesions and well-tolerated in a study of 60 patients with PsA and psoriasis [49]. Skin and joint scores improved significantly in the 3-month study.

Use of infliximab in PsA was examined in the IMPACT (Infliximab Multinational Psoriatic Arthritis Controlled Trial) [50]. One hundred and two patients with active PsA received infliximab at a dose of 5 mg/kg given at 0, 2, 6 and 14 weeks, followed by a 50-week open-label extension of 5 mg/kg infliximab every 8 weeks. Co-medication with DMARDs, NSAIDs and corticosteroids was allowed. Fourteen patients discontinued infliximab, seven because of adverse reactions and six because of lack of efficacy. Eight per cent of the placebo group achieved an ACR 20 response compared with 69% of the infliximab group at week 16. At week 50, sustained improvement was seen in the infliximab–infliximab group, mirrored by improvement in the placebo–infliximab group. Skin lesions also improved.


    Efficacy of anti-TNF-{alpha} therapy in undifferentiated SpA (uSpA), ReA, enteropathic arthropathy and uveitis
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 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
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Preliminary results of infliximab treatment in uSpA suggest a rapid response. In a study of six patients with severe, persistent uSpA given infliximab at a dose of 3 or 5 mg/kg, axial and appendicular symptoms and laboratory parameters improved rapidly [51]. Currently, there are no validated outcome measures for uSpA, so the authors used AS outcome tools. There appeared to be no serious side-effects in this short study.

Anecdotal reports of treatment of two patients with Yersinia enterocolitica ReA treated with infliximab [52] suggest good short-term benefit, though both patients required continued conventional or biological therapy.

In two small series of patients with Crohn's disease-related arthropathy, a rapid and dramatic response in gastrointestinal and joint symptoms and CRP levels was seen with infliximab 5 mg/kg [53] and etanercept 25 mg twice weekly [54]. Reduction in rheumatic disease activity may be seen despite flares or persistence of bowel disease, suggesting different modes of action of TNF-{alpha} blocking drugs in these two circumstances.

There is limited experience in the treatment of HLA-B27-associated uveitis. A single intravenous dose of 10 mg/kg of infliximab given as the only anti-inflammatory drug induced rapid improvement in the majority of patients treated, although some relapsed [55]. There have been uncontrolled observations of uveitis relapsing during anti-TNF-{alpha} therapy [26].

There is a clear need for further controlled data on the use of anti-TNF-{alpha} agents in patients with uSpA, ReA, bowel-related SpA and uveitis.


    Practical considerations in the initiation of anti-TNF agents in SpA
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 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Practical considerations in the...
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Practical guidance in the use of TNF-{alpha} blockers in SpA is emerging, though it will be some time before there is real clarity and consensus. The ASAS group has published preliminary recommendations regarding the initiation of disease-controlling agents, in particular anti-TNF treatment [56], and the Spondyloarthritis Research Consortium of Canada (SPARCC) has also evaluated the evidence for the use of anti-TNF agents in SpA, according grades of recommendation [57]. Some answers to important questions can be drawn from both of these organizations and current practice in the UK.

Who should prescribe?
Decisions to use TNF blockade treatment in this context should be made by a senior clinician (in the UK, a consultant) with specialist experience in inflammatory back pain and the use of anti-TNF-{alpha} agents. Treatment should be managed and monitored by a suitably expert individual or team according to locally or nationally agreed protocols.

Which patients should be treated?
Diagnoses should conform to robust, internationally recognized diagnostic criteria, such as the modified New York criteria for AS [29] (Table 1) wherever possible. Failure of predefined conventional treatment, such as two or more NSAIDs in the case of AS, is necessary. Specific proposals for the treatment of peripheral arthritis and entheseal involvement in AS have also been made (see below).

Which patients should not be treated?
Criteria for withholding and withdrawal of TNF blockade have been clearly delineated for RA; it is likely that these are equally applicable to SpA.

What regimes and for how long?
Presently there are no better guides to the treatment regimes than the manufacturer's recommendations. Decisions as to the continuation and cessation of treatment must fall broadly in line with use in RA, except that there are no grounds for including the presence or absence of a disease-modifying effect in the assessment presently. The studies to date indicate that the optimum effect is likely to be reached by 12 weeks, so that a decision to stop or continue, on efficacy grounds, should be made at this time.

How do we know if the treatment has been adequately effective?
For some patients with peripheral joint disease, criteria designed for use in RA may be appropriate. Criteria for use in patients with oligoarticular arthritis need to be devised. In the assessment of spinal disease activity in AS the main choice is between the BASDAI 50 (Fig. 1), which is simple and quick and requires no specific additional metrology skills, and the ASAS 20 (Fig. 2), which is also simple but requires a little more specialist input. It remains unclear whether either measure has genuine advantage over the other. It is also unclear whether there is clear advantage in including measures of function, mobility or quality of life (QoL) in monitoring TNF blockade treatment in AS. At a time when all the means of assessment of treatment in AS are essentially subjective indicators of symptom reduction, suitable measures of QoL, such as the SF-36 [58] and Ankylosing Spondylitis Quality of Life measure (ASQoL) [59] might yet have a place in determining whether the treatment is worthwhile.

Where now?
The British Society for Rheumatology will shortly publish considered guidelines for the use of these agents in AS and psoriatic arthritis. It is clear that such guidance must be less clearly evidence-based than would be ideal and use more subjective and fewer objective criteria than would be ideal; yet they will have to be pragmatic and robust if they are to enable doctors to take wise, transparent, fair and defensible decisions. Inevitably, the guidance emerging now will have to be revised regularly rather than being seen as set in stone, and those prescribing these agents will all have to be prudent, alert and patient. Ultimately, we must hope that if a disease-modifying effect is demonstrated in SpA, objective criteria such as MRI scanning can be included to provide a clearer basis for the continued provision of this expensive and still uncertain form of treatment. Meanwhile, there is an urgent need to answer critical outstanding questions through continuing research. Chief amongst these are questions concerning optimum doses and regimens, effects on ankylosis, the value of combination therapies, overall cost–benefit analysis, predictors of response and long-term safety. Of these, the most critical must be the effect on ankylosis.

AK has received honoraria from Wyeth for speaking at sponsored meetings, and the department is in receipt of a grant from Schering Plough. SP has declared no conflicts of interest.


    References
 Top
 Introduction
 Rationale for targeting TNF...
 Current anti TNF-{alpha} agents:...
 Outcomes of treatment of...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Efficacy of anti-TNF-{alpha}...
 Practical considerations in the...
 References
 

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Submitted 8 April 2004; Accepted 6 July 2004