Number and quality of studies

The review of the clinical evidence identified 40 studies: three trials of the efficacy of the interventions of interest (two for etanercept and one for infliximab), 23 studies of the adverse effects of the interventions and 14 trials of the efficacy of the DMARDs.

The trials of the efficacy of the interventions were all double-blind and placebo-controlled trials and were rated 'Good' by the quality assessment. A total of 265 patients were included in the etanercept trials and 104 in the infliximab trial.

Efficacy of the interventions

Across the two trials, at 12 weeks, around 65% of patients treated with etanercept achieved an American College of Rheumatology (ACR) 20 {pooled relative risk (RR) 4.19 [95% confidence interval (CI) 2.74 to 6.42]}, demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. In addition, around 45% of patients treated with etanercept achieved an ACR 50 [pooled RR 10.84 (95% CI 4.47 to 26.28)] and around 12% achieved an ACR 70 [pooled RR 16.28 (95% CI 2.20 to 120.54)], demonstrating a good level of efficacy. The subgroup analyses conducted in one trial revealed that the effect of etanercept was not dependent upon patients' concomitant use of methotrexate. In addition, almost 85% of patients treated with etanercept achieved a Psoriatic Arthritis Response Criteria (PsARC) [pooled RR 2.60 (95% CI 1.96 to 3.45)], which is the only joint disease outcome measure that has been specifically defined for psoriatic arthritis. The Psoriatic Area and Severity Index (PASI) results indicate some beneficial effect on psoriasis at 12 weeks; however, the data are sparse. The statistically significant reduction (improvement) in Health Assessment Questionnaire (HAQ) score with etanercept compared with placebo indicates a beneficial effect of etanercept on function. Similar results were seen at 24 weeks, except that the results for PASI 75 and PASI 50 now achieved statistical significance and data for Total Sharp Score (TSS) annualised rate of progression were available; this was statistically significantly lower in etanercept-treated patients than in placebo-treated patients. Uncontrolled follow-up of patients indicated that treatment benefit may be maintained for at least 50 weeks.

At 16 weeks, 65% of patients treated with infliximab achieved an ACR 20 [RR 6.80 (95% CI 2.89 to 16.01)], demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. This level of efficacy was not dependent upon patients' concomitant use of methotrexate. Almost half the patients treated with infliximab achieved an ACR 50 [RR 49.00 (95% CI 3.06 to 785.06)] and over one-quarter achieved an ACR 70 [RR 31.00 (95% CI 1.90 to 504.86)] compared with none of the placebo group, demonstrating a good level of efficacy. In addition, 75% of patients treated with infliximab achieved a PsARC [RR 3.55 (95% CI 2.05 to 6.13)]. The beneficial treatment effect on psoriasis was also statistically significant with a mean difference in percentage change from baseline in PASI of -5 (95% CI -6.8 to -3.3), as was the percentage improvement from baseline in HAQ score with infliximab compared with placebo [mean difference 51.4 (95% CI 48.08 to 54.72)], indicating a beneficial effect of infliximab on functional status.

Uncontrolled data from all measures of joint disease, psoriasis and HAQ collected at up to 50 weeks of follow-up reflect those at 16 weeks. There were no radiographic assessments, so the potential or otherwise of infliximab to delay the progression of joint disease could not be assessed.

Adverse effects

Injection site reactions appear to be the most common adverse effects of etanercept. Overall, etanercept appeared to be well tolerated in short-and long-term use, although much of the long-term data are not from patients with psoriastic arthritis. As identified in earlier reviews, the main areas of concern relate to uncommon but serious adverse events the significance of which is not readily discernible from the published reports of clinical trials.

Overall, infusion reactions, the development of antibodies and infections appear to be the most common adverse effects of infliximab, although it is unclear whether they occur more frequently than on placebo. In the long term, the possible risk of serious adverse effects requires caution and further monitoring and investigation.

Importantly, both biologics are new drugs with which there is only very limited experience and long-term monitoring. Therefore, review and further investigations of their safety are warranted.

DMARDs

The available drug treatments for psoriatic arthritis, with the exception of sulfasalazine and possibly leflunomide, have not been investigated thoroughly. The available limited data indicate some degree of efficacy for all DMARDs, but the evidence for intramuscular gold and azathroprine is particularly weak and may not be reliable.

Evidence synthesis

A Bayesian evidence synthesis was undertaken to complete the clinical evaluation and to estimate relevant parameters for the economic model. The need to populate the economic model indicated a focus on response rates to therapy in terms of PsARC and changes in HAQ conditional on whether the patient responds to therapy. The synthesis relates to etanercept, infliximab and placebo as these are the comparators in the economic model. The probability of responding to infliximab treatment was estimated to be 0.7705, and for etanercept this probability is also estimated as 0.7705. The RR of infliximab versus etanercept of 1.0 (95% CI 0.82 to 1.18) also highlighted that, as far as response rates are concerned, the evidence synthesis suggested the two treatments are very similar. The evidence synthesis showed that responders to either treatment experienced a statistically significant improvement in HAQ scores. Incremental to the natural progression baseline change in HAQ of 0.0166 (95% CI 0.002 to 0.031), responders to etanercept treatment experienced an additional change in HAQ of -0.72 (95% CI -0.83 to -0.61), and responders to infliximab treatment of -0.67 (95% CI -0.84 to -0.49). Both of these HAQ changes are significantly different from the incremental HAQ change experienced by placebo responders, of -0.28 (95% CI -0.39 to -0.18), but do not differ substantially between the two active treatments.

Cost-effectiveness

Cost-effectiveness models were submitted by Wyeth and Schering-Plough. Wyeth's model estimated the incremental cost per quality-adjusted life-year (QALY) gained for etanercept (compared with a composite comparator) to range from £28,189 for a 10-year time horizon to £66,580 for a 6-month time horizon. Schering-Plough presented two models. The 'Active Joint' model estimated an incremental cost per QALY gained for infliximab of £36,786 (5-year time horizon). The 'Chronic Active Joint' model estimated an incremental cost-effectiveness ratio (ICER) of £33,877 (30-year time horizon).

Given some potential limitations of the manufacturers' models and their failure to compare the two biological therapies directly and with palliative care, a new model was developed (the York Model). Results were estimated over a range of time horizons and based on a number of alternative assumptions. Infliximab is consistently dominated by etanercept because of its higher acquisition and administration costs without superior effectiveness. The incremental cost per QALY gained of etanercept compared with palliative care ranges from £14,818 (females, 40-year time horizon) to £49,374 (males, 1-year time horizon) if it is assumed that, when patients eventually fail on biological therapy, their disability (in terms of HAQ score) deteriorates by the same amount as it improved when they initially respond to treatment (rebound equal to gain). The ICERs of etanercept range from £25,443 (females, 40-year time horizon) to £49,441 (males, 1-year time horizon) if it is assumed that, when patients fail on therapy, their disability level returns to what it would have been had they never responded (rebound equal to natural history).

Sensitivity analyses

Probabilistic sensitivity analysis showed that etanercept and palliative care have the highest probabilities of being cost-effective. At lower levels of the threshold value of cost-effectiveness, palliative care has the higher probability of being cost-effective. As the threshold increases, so does the probability that etanercept is optimal. Scenario analysis was undertaken to assess the sensitivity of the results to other assumptions in the model. The most important analysis indicates that the ICER of etanercept increases markedly if it is assumed that etanercept only improves symptoms and does not retard disease progression. We also examined an alternative specification of the prior distribution in the evidence synthesis used to reflect between-trial variation in the placebo response rate, but no substantive change in the results was observed.

Limitations of the calculations (assumptions made)

A number of parameters in the model are based on very limited evidence. This applies, in particular, to the long-term withdrawal rate (based on a non-randomised observational study and assumed to be the same for the two biological therapies), the natural history HAQ progression (based on an unpublished cohort study of 24 PsA patients reported in the Wyeth submission) and the HAQ progression in patients responding to therapy (assumed to be zero based on some evidence for the open-label continuation studies after etanercept and infliximab).

Other important issues regarding implications

The model considered the cost-effectiveness of etanercept and infliximab compared with each other and with palliative care. This is equivalent to assuming that the biological therapies would be used 'end of line' once DMARD therapies have been tried and failed. The York Model was not able to incorporate the possible quality of life impact of the biological therapies on patients' skin. This assumption also had to be made in the two manufacturers' models. The York Model uses HAQ score as the measure of disability, which drives both quality of life and costs in the model. This is consistent with both the Wyeth models in PsA and many cost-effectiveness models of biological therapies in RA, but the use of radiological measures of disease progression may be more appropriate should data become available.

Notes on the generalisability of the findings

The efficacy data used in the clinical evaluation, evidence synthesis and the economic models were very limited, being derived from just three trials and 369 patients, with only 134 patients treated with etanercept and 52 treated with infliximab. Furthermore, these trial populations were not precisely representative of those for whom etanercept and infliximab are licensed: neither population was made up exclusively of patients who had failed to respond to at least two DMARDs. Other parameters within the economic models were also based on very limited evidence.