Background:

Tumour necrosis factor (TNF)-α inhibitors (anti-TNFs) are typically used when the inflammatory rheumatologic diseases ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-AxSpA) have not responded adequately to conventional therapy. Current National Institute for Health and Care Excellence (NICE) guidance recommends treatment with adalimumab, etanercept and golimumab in adults with active (severe) AS only if certain criteria are fulfilled but it does not recommend infliximab for AS. Anti-TNFs for patients with nr-AxSpA have not previously been appraised by NICE.

Objective:

To determine the clinical effectiveness, safety and cost-effectiveness within the NHS of adalimumab, certolizumab pegol, etanercept, golimumab and infliximab, within their licensed indications, for the treatment of severe active AS or severe nr-AxSpA (but with objective signs of inflammation).

Design:

Systematic review and economic model.

Data sources:

Fifteen databases were searched for relevant studies in July 2014.

Review methods:

Clinical effectiveness data from randomised controlled trials (RCTs) were synthesised using Bayesian network meta-analysis methods. Results from other studies were summarised narratively. Only full economic evaluations that compared two or more options and considered both costs and consequences were included in the systematic review of cost-effectiveness studies. The differences in the approaches and assumptions used across the studies, and also those in the manufacturer’s submissions, were examined in order to explain any discrepancies in the findings and to identify key areas of uncertainty. A de novo decision model was developed with a generalised framework for evidence synthesis that pooled change in disease activity (BASDAI and BASDAI 50) and simultaneously synthesised information on function (BASFI) to determine the long-term quality-adjusted life-year and cost burden of the disease in the economic model. The decision model was developed in accordance with the NICE reference case. The model has a lifetime horizon (60 years) and considers costs from the perspective of the NHS and personal social services. Health effects were expressed in terms of quality-adjusted life-years.

Results:

In total, 28 eligible RCTs were identified and 26 were placebo controlled (mostly up to 12 weeks); 17 extended into open-label active treatment-only phases. Most RCTs were judged to have a low risk of bias overall. In both AS and nr-AxSpA populations, anti-TNFs produced clinically important benefits to patients in terms of improving function and reducing disease activity; for AS, the relative risks for ASAS 40 ranged from 2.53 to 3.42. The efficacy estimates were consistently slightly smaller for nr-AxSpA than for AS. Statistical (and clinical) heterogeneity was more apparent in the nr-AxSpA analyses than in the AS analyses; both the reliability of the nr-AxSpA meta-analysis results and their true relevance to patients seen in clinical practice are questionable. In AS, anti-TNFs are approximately equally effective. Effectiveness appears to be maintained over time, with around 50% of patients still responding at 2 years. Evidence for an effect of anti-TNFs delaying disease progression was limited; results from ongoing long-term studies should help to clarify this issue. Sequential treatment with anti-TNFs can be worthwhile but the drug survival response rates and benefits are reduced with second and third anti-TNFs. The de novo model, which addressed many of the issues of earlier evaluations, generated incremental cost-effectiveness ratios ranging from £19,240 to £66,529 depending on anti-TNF and modelling assumptions.

Conclusions:

In both AS and nr-AxSpA populations anti-TNFs are clinically effective, although more so in AS than in nr-AxSpA. Anti-TNFs may be an effective use of NHS resources depending on which assumptions are considered appropriate.

Future work recommendations:

Randomised trials are needed to identify the nr-AxSpA population who will benefit the most from anti-TNFs.

Study registration:

This study is registered as PROSPERO CRD42014010182.

Funding:

The National Institute for Health Research Health Technology Assessment programme.

Article history

The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 13/46/01. The protocol was agreed in June 2014. The assessment report began editorial review in January 2015 and was accepted for publication in April 2015. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors’ report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

Declared competing interests of authors

Lesley Kay has received sponsorship to attend meetings by AbbVie and Merck Sharp & Dohme Limited in 2014. Helena Marzo-Ortega has received grants, sponsorship and/or honoraria from AbbVie, Janssen, Merck Sharp & Dohme Limited, Pfizer and UCB.