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Rodgers M, Epstein D, Bojke L, et al. Etanercept, Infliximab and Adalimumab for the Treatment of Psoriatic Arthritis: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Feb. (Health Technology Assessment, No. 15.10.)

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Etanercept, Infliximab and Adalimumab for the Treatment of Psoriatic Arthritis: A Systematic Review and Economic Evaluation.

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3Assessment of clinical effectiveness

Methods for reviewing clinical effectiveness

A systematic review of the evidence for the clinical effectiveness and safety of etanercept, infliximab and adalimumab for the treatment of active and progressive PsA in patients who have an inadequate response to standard treatment (including DMARD therapy) was conducted following the general principles recommended in the guidance of the Centre for Reviews and Dissemination (CRD) guidance75 and the quality of reporting of meta-analyses (QUOROM) statement.76

Search strategy

The following databases were searched for relevant clinical effectiveness and cost-effectiveness research:

  • MEDLINE
  • EMBASE
  • Cochrane Central Register of Controlled Trials (CENTRAL)
  • Science Citation Index (SCI)
  • Conference Proceedings Citation Index – Science (CPCI-S)
  • metaRegister of Current Controlled Trials (mRCT)
  • NHS Economic Evaluation Database (NHS EED)
  • Health Economic Evaluations Database (HEED)
  • EconLit.

Searches of major bibliographic databases were undertaken in three tranches – for RCTs, for economic evaluations and for studies of serious adverse effects. In the RCT and economic evaluation searches, the etanercept and infliximab search was limited by date (1 April 2004 to date), updating the searches undertaken for the 2006 Health Technology Assessment (HTA) report.73 The search for adalimumab had no date limits. The searches for studies of adverse effects of all three drugs were not date limited. Internet resources were also searched for information on adverse effects. At the time of receiving the company submission (August 2009), update searches were conducted to ensure that the review remained up to date and covered all relevant evidence at the time of submission. No language or other restrictions were applied. In addition, reference lists of all included studies and industry submissions made to NICE were hand-searched to identify further relevant studies.

The terms for search strategies were identified through discussion between an information specialist and the research team, by scanning the background literature and browsing the MEDLINE medical subject headings (MeSH). As several databases were searched, some degree of duplication resulted. To manage this issue, the titles and abstracts of bibliographic records were imported into endnote bibliographic management software to remove duplicate records.

Inclusion and exclusion criteria

Two reviewers independently screened all titles and abstracts. Full paper manuscripts of any titles/abstracts that may be relevant were obtained where possible and the relevance of each study was assessed by two reviewers according to the criteria below. Studies were included in the review according to the inclusion criteria, described as follows. Studies that did not meet all of the criteria were excluded and their bibliographic details listed with reasons for exclusion. Any discrepancies were resolved by consensus or consulting a third reviewer if necessary.

Study design

Randomised controlled trials (including any open-label extensions of these RCTs) were included in the evaluation of efficacy. Information on the rate of serious adverse events was sought from regulatory sources [the US Food and Drug Administration (FDA), European Medicines Agency (EMEA)]. If these failed to report the necessary data to calculate event rates then non-randomised studies that provided these data for etanercept, infliximab and adalimumab were included in the review. If multiple non-randomised studies were identified, inclusion was limited to those studies reporting outcomes for a minimum of 500 patients receiving biologic therapy.

Interventions

Etanercept, infliximab and adalimumab were the interventions of interest. Comparators were placebo, another of the three listed agents, or conventional management strategies for active and progressive PsA that have responded inadequately to previous DMARD therapy, excluding TNF inhibitors.

Participants

For the evaluation of the effectiveness of etanercept, infliximab and adalimumab, included studies were of adults with active and progressive PsA with an inadequate response to previous standard therapy (including at least one DMARD). Trials of effectiveness had to specify that the patients had PsA, with the definition and/or the inclusion criteria for PsA stated. For the assessment of adverse effects, studies of patients with other conditions were eligible for inclusion in the review.

Outcomes

The eligible outcomes of effectiveness were measures of the anti-inflammatory response (PsARC, ACR 20/50/70), response of psoriatic skin lesions (PASI), functional measures (HAQ), radiological assessments of disease progression or remission, QoL assessments [e.g. Dermatology Life Quality Index (DLQI)] and overall global assessments.

In terms of the outcomes of adverse events of biologics, we provided an initial overview of previous systematic reviews of biologic safety (see Results of review of clinical effectiveness) before conducting our systematic review of adverse events of these agents. Our systematic review specifically focused on the known serious adverse events of these agents: malignancies, severe infections (i.e. those that require i.v. antibiotic therapy and/or hospitalisation or cause death) and reactivation of latent tuberculosis (TB). If additional serious adverse events have been reported to regulatory bodies then the incidence of these were also assessed. In addition, data relating to serious adverse events in indications other than PsA were also considered in our systematic review, provided it was clinically appropriate to do so.

Data extraction strategy

Data on study and participant characteristics, efficacy outcomes, adverse effects, costs to the health service and cost-effectiveness were extracted. Baseline data were extracted where reported. Data were extracted by one reviewer using a standardised data extraction form and independently checked for accuracy by a second reviewer. The results of data extraction were presented in the structured tables (see Appendix 3, Efficacy data extraction: etanercept/infliximab/adalimumab). Disagreements were resolved through consensus, or consulting a third reviewer if necessary. Attempts were made, where possible, to contact authors for missing data. Data from studies with multiple publications were extracted and reported as a single study. In the rare case of minor discrepancies for the same data between published and unpublished data, data from published sources were used.

Quality assessment strategy

The quality of RCTs and other study designs were assessed using standard checklists.75 Regarding the additional studies reviewed for data on serious adverse events: as all observational studies are prone to confounding and bias to some extent, non-randomised studies including < 500 patients receiving biologics were excluded from the review. The assessment was performed by one reviewer and checked independently by a second. Disagreements were resolved through consensus or by consulting a third reviewer if necessary.

Data analysis

Where sufficient clinically and statistically homogeneous data were available, data were pooled using standard meta-analytic methods. The levels of clinical and methodological heterogeneity were investigated, and statistical heterogeneity was assessed using Q- and I2-statistics. Given the small number of trials available, a fixed-effects model was used to pool outcomes where pooling was appropriate. Sensitivity analyses were undertaken when permitted by sufficient data (e.g. exclusion of concomitant MTX treatment). The potential short- and long-term benefits of etanercept, infliximab and adalimumab on both the psoriasis and arthritis components of PsA were investigated. The rates of serious adverse effects of these biologic agents were synthesised narratively.

As trials conducting head-to-head comparisons of etanercept, infliximab and adalimumab were not available the possibility of conducting some form of indirect comparison was investigated. Indirect comparisons are useful analytic tools when direct evidence on comparisons of interest is absent or sparse.77 Meta-analysis using indirect comparisons enables data from several sources to be combined, while taking into account differences between the different sources, in a similar way to, but distinct from, how a random-effects model takes into account between-trial heterogeneity. As with a mixed-treatment comparison (MTC), Bayesian indirect comparisons need a ‘network of evidence’ to be established between all of the interventions of interest. The three drugs being evaluated all have a common comparator: placebo. It is this common comparator that allows the network between etanercept, infliximab and adalimumab to be established and provide information on the benefits of these agents relative to placebo and each other.

To help inform both the clinical review and the economic modelling four separate outcomes were considered. These outcomes were: PsARC response, HAQ score conditional on PsARC response, ACR 20/50/70 responses and PASI 50/75/90 responses. All outcomes were evaluated at 12 weeks. The evidence synthesis was undertaken using winbugs (version 1.4.2). winbugs is a Bayesian analysis software tool that, through the use of Markov chain Monte Carlo, calculates posterior distributions for the parameters of interest given likelihood functions derived from data and prior probabilities. Full details of the Bayesian indirect comparison methods and the winbugs codes along for the four different analyses are presented in Appendix 5.

Results of review of clinical effectiveness

Quantity and quality of research available

A total of 1320 records were identified from both the clinical effectiveness and adverse event searches (Figure 1). Details of studies excluded at the full publication stage are provided in Appendix 4.

FIGURE 1. Flow chart showing the number of studies identified and included.

FIGURE 1

Flow chart showing the number of studies identified and included.

Randomised controlled trials and extensions in psoriatic arthritis

Of the 701 studies identified from the search for RCTs, a total of 43 publications, representing multiple publications of six RCTs and their extensions met the inclusion criteria for the review of efficacy.51,52,78118 Two placebo-controlled RCTs in patients with PsA were found for each of the three agents: etanercept,52,78,97,99,105,107,110 infliximab7982,8991,95,96,98,106,109,111118 and adalimumab.51,83,88,92,93,100104 Baseline characteristics from all six RCTs are presented in Table 1.

TABLE 1. Summary of trial population characteristics.

TABLE 1

Summary of trial population characteristics.

Additional adverse event studies

In total, 742 records were identified from the separate search for larger studies reporting adverse event rates for biologic agents in any indication. Of these records, 32 publications reported treatment with etanercept, infliximab or adalimumab in 500 or more patients, and reported either adverse event rates directly or provided sufficient information to calculate these rates (Figure 1).89,97,99,119148

Assessment of effectiveness

Efficacy of etanercept

Both trials evaluating etanercept for PsA were double-blind and placebo-controlled, and both were rated as ‘good’ on the quality assessment rating (Table 2).52,78,97,99,105,107,110 Both trials were available as industry trial reports and journal publications.

TABLE 2. Results of quality assessment for trials of etanercept.

TABLE 2

Results of quality assessment for trials of etanercept.

The baseline characteristics of the trial population are summarised in Table 1. Both trials were of adults (aged 18–70 years), with active PsA (defined in both trials as at least three swollen joints and at least three tender or painful joints, although only the more recent trial52,97,99,105,107,110 specified stable plaque psoriasis). Patients in both trials had demonstrated an inadequate response to NSAIDs. Over 70% of the patients in the larger trial52,97,99,105,107,110 had previously used at least one DMARD. Over 80% of patients in the Mease et al.52,97,99,105,107,110 trial had polyarticular disease, indicating that, overall, the disease was severe. Patients were not required to have active psoriasis at baseline, but 77% of etanercept patients and 73% of placebo patients did have. The proportion of patients with spine involvement and arthritis mutilans at baseline was reported only for the larger trial, where such patients made up only a small proportion of the trial population. These details were not available for the smaller of the two trials, so the severity of disease across that population is unknown. However, given the similarity between the trials for other measures of disease activity (TJC, SJC, HAQ at baseline, plus baseline and previous medication), significant differences between the populations in terms of overall disease severity are unlikely. Patients taking stable doses of MTX or corticosteroids were permitted to continue with that dose and randomisation was stratified for MTX use at baseline. Overall, the baseline characteristics demonstrate that the trial populations are similar and are likely to be representative of a population with PsA requiring DMARD or biologic therapy. It should be noted, however, that the populations in these trials of etanercept are not representative of the patients for whom etanercept is recommended for use: these patients, according to the BSR, would have demonstrated a lack of response to at least two DMARDs.149

In both trials, etanercept was administered by subcutaneous (s.c.) injection twice weekly at a dose of 25 mg. Treatment with active drug or placebo was administered for 12 weeks in the smaller trial78 and for 24 weeks in the larger trial.52,97,99,105,107,110 In both trials the controlled phase was followed by a follow-up period during which etanercept was administered in an open-label fashion to all patients.

Outcome data derived under RCT conditions are available from both trials for PsARC, ACR 20/50/70 and HAQ at week 12. The primary outcome variable in the Mease 2000 trial78 was PsARC, whereas in the Mease et al. 52,97,99,105,107,110 trial it was ACR 20. Data on PASI at week 12 are available from the small78 trial only. RCT outcome data for PsARC, ACR 20/50/70, HAQ, PASI and radiographic assessment of progression at week 24 are available from the larger trial52,97,99,105,107,110 (n = 205). In addition, a subgroup analyses by concomitant MTX use provided additional PsARC, ACR 20/50/70 data at weeks 12 and 24. As subgroup analyses in already fairly small trials, the findings generated must be interpreted with some caution. They are useful, however, to explore the influence concomitant MTX has on the main treatment effect. All outcome data are summarised in Table 3, with pooled 12-week data shown in Table 4.

TABLE 3. Etanercept efficacy outcomes: RCT data.

TABLE 3

Etanercept efficacy outcomes: RCT data.

TABLE 4. Meta-analysis of etanercept efficacy data: outcomes at 12 weeks.

TABLE 4

Meta-analysis of etanercept efficacy data: outcomes at 12 weeks.

Uncontrolled data on all outcomes are also available at 36 weeks or 12 months (uncontrolled follow-up data). These data are summarised in Table 4.

Efficacy after 12 weeks' treatment

The individual trial results (Table 3) and pooled estimates of effect (Table 4) demonstrate a statistically significant benefit of etanercept for all joint disease and HAQ score outcomes. There was no statistical heterogeneity for any outcome.

Across the two trials at 12 weeks almost 85% of patients treated with etanercept achieved a PsARC response, which is the only joint disease outcome measure that has been specifically defined for PsA. In addition, around 65% of patients treated with etanercept achieved an ACR 20 response, demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. Around 45% of patients treated with etanercept achieved an ACR 50 response, and around 12% achieved an ACR 70 response, demonstrating a good level of efficacy. The subgroup analyses conducted on the Mease et al. 52,97,99,105,107,110 data revealed that the effect of etanercept was not dependent on patients' concomitant use, or not, of MTX. The PASI results from Mease et al.78 indicate some beneficial effect on psoriasis at 12 weeks; however, the data were too sparse (38 patients in total) to establish statistical significance. The statistically significant reduction in HAQ score with etanercept compared with placebo indicates a beneficial effect of etanercept on functional status.

Efficacy after 24 weeks' treatment

At 24 weeks, the treatment effect for all joint disease outcome measures was statistically significantly greater with etanercept than with placebo, although these data were available only for one trial (see Table 3). As at 12 weeks, the subgroup analyses conducted on the Mease et al. 52,97,99,105,107,110 data revealed that the effect of etanercept was not dependent upon patients' concomitant use, or not, of MTX. The size of treatment effect did not appear greater at 24 weeks than at 12 weeks.

At 24 weeks, the TSS annualised rate of progression was statistically significantly lower in patients treated with etanercept than in patients receiving placebo. This treatment difference did not vary with or without concomitant MTX use. However, this duration of follow-up is to be considered short and barely adequate for this outcome.

At 24 weeks, the treatment effect on psoriasis favoured etanercept with relative risks (RRs) for PASI 75 of 7.05 [95% confidence interval (CI) 1.68 to 29.56], PASI 50 of 2.65 (95% CI 1.46 to 4.80) and PASI 90 of 1.88 (95% CI 0.36 to 9.90). The result for PASI 75 and PASI 50 was statistically significant despite there being only 66 patients on etanercept evaluable for psoriasis.52,97,99,105,107,110

Longer-term follow-up

The results for long-term follow-up are summarised in Table 5. The data are uncontrolled and therefore cannot be taken as reliable. In general, they do indicate that the improvements in patients' joint and skin symptoms and HAQ score achieved during the controlled phase of the trials are maintained in the medium term. At 1 year, the mean annualised rate of progression TSS for all patients was −0.03 [standard deviation (SD 0.87)] indicating that on average no clinically significant progression of joint erosion had occurred. Limited 2-year data indicated little change in mean TSS, although data on patient numbers or variability were not reported.

TABLE 5. Etanercept efficacy outcomes: uncontrolled follow-up data.

TABLE 5

Etanercept efficacy outcomes: uncontrolled follow-up data.

Summary of the efficacy of etanercept in the treatment of psoriatic arthritis
  • There is evidence from double-blind placebo-controlled trials of a good level efficacy for etanercept in the treatment of PsA. Conclusions to be drawn from these data are limited by the small sample size and the short duration of one of the trials.
  • There is evidence from two RCTs that etanercept treatment improves patients' functional status as assessed using the HAQ score.
  • There is limited evidence from the two RCTs that etanercept treatment has a beneficial effect on the psoriasis component of the disease.
  • Uncontrolled follow-up of patients indicate that treatment benefit is maintained for at least 50 weeks; however, these data may not be reliable.
  • There are radiographic data from controlled trials for etanercept in PsA that demonstrate a beneficial effect on progression of joint disease at 24 weeks. This is a very short time over which to identify a statistically significant effect of therapy and indicates a rapid onset of action of etanercept. Data from uncontrolled follow-up indicate that, on average, disease progression may be halted for at least 1 year; however, these data may not be reliable.

Efficacy of infliximab

The literature search identified two RCTs of infliximab for the treatment of PsA.7982,8991,95,96,98,106, 109,111118 Both were rated as ‘good’ by the quality assessment (Table 6). The trials were reported in published papers and abstracts, and the industry trial report was made available.

TABLE 6. Results of quality assessment for trials of infliximab.

TABLE 6

Results of quality assessment for trials of infliximab.

Both were double-blind, placebo-controlled trials of adult patients with active PsA, randomising a total of 304 patients. All patients had been diagnosed with PsA for at least 6 months, with a negative RF and active disease including 5+ swollen/tender joints. All patients must have had an inadequate response to at least one DMARD.7982,8991,95,96,98,106,109,111118 One trial required patients to have active plaque psoriasis with at least one qualifying target lesion (≥ 2-cm diameter).82,90,91,95,98,106,112,116 The earlier of the two trials did not require patients to have active psoriasis at baseline, but 42% of infliximab patients and 33% of placebo patients did have (defined as PASI score of at least 2.5).7981,89,96,109,111,113115,117,118 The proportion of patients with spine involvement, arthritis mutilans and erosions at baseline was not reported for either trial, so the severity of disease across the populations is unknown. The baseline characteristics of the trial populations are summarised in Table 1. These demonstrate that the trial populations are broadly similar, are likely to be representative of a population with quite severe PsA requiring further DMARD or biologic therapy, and that the treatment and placebo groups were well balanced. Relative to the patients for whom infliximab treatment is recommended in practice, these trial populations may be less severely affected, with only around one-half in the Infliximab Multinational Psoriatic Arthritis Controlled Trial (IMPACT)7981,89,96,109,111,113115,117,118 and possibly even fewer in IMPACT 2,82,90,90,95,98,106,112,116 having failed to respond to two or more DMARDs (failure to respond to DMARDs as defined by the BSR).149

In the RCT phase of the IMPACT trial,7981,89,96,109,111,113115,117,118 infliximab (5 mg/kg) or placebo was infused at weeks 0, 2, 6 and 14, with follow-up at week 16. Further infusions of infliximab were administered to all patients in an open-label fashion at 8-week intervals, with further follow-up at week 50. Patients in the IMPACT 2 trial82,90,91,95,98,106,112,116 were randomised to receive infusions of placebo or infliximab, 5 mg/kg, at weeks 0, 2, 6, 14 and 22, with assessments at weeks 14 and 24. Further infusions of infliximab were administered to all patients in an open-label fashion (timing dependent upon whether they were originally randomised to infliximab, or crossed over from placebo either at week 16 or 24) with further follow-up at week 54.

The primary outcome variable in these trials was ACR 20 at 14 or 16 weeks. The two trials also reported 14-week and/or 16-week outcome data for ACR 50, ACR 70, PsARC, HAQ, PASI 50, PASI 75 and PASI 90 (RCT data). IMPACT 282,90,91,95,98,106,112,116 also maintained randomisation and reported these outcomes at week 24. Both studies reported longer-term open-label follow-up of patients after 50 and 54 weeks (IMPACT7981,89,96,109,111,113115,117,118 and IMPACT 2,82,90,91,95,98,105,112,115 respectively). All data are summarised in Table 7, with pooled data presented in Table 8.

TABLE 7. Infliximab efficacy outcomes: RCT data.

TABLE 7

Infliximab efficacy outcomes: RCT data.

TABLE 8. Meta-analysis of infliximab efficacy data: outcomes at 14 weeks.

TABLE 8

Meta-analysis of infliximab efficacy data: outcomes at 14 weeks.

Efficacy after 14–16 weeks' treatment

At 14 weeks, both trials reported a significant improvement in the PsA-specific PsARC measure for patients receiving infliximab, relative to those receiving placebo (pooled RR 3.44, 95% CI 2.53 to 4.69 – Table 8). There was evidence of statistical heterogeneity (I2 = 68%) between the two study estimates, due to the different placebo response rates (13.5% vs 27%). PsARC response on infliximab was around 77% in both trials.

The pooled RR for ACR 20 at 14 weeks was 5.47 (95% CI 3.43 to 8.71), with an overall response of 61% in infliximab-treated patients, demonstrating a clear degree of efficacy of infliximab in terms of arthritis-related symptoms. As very few patients receiving placebo achieved an ACR 50 or ACR 70 response, the pooled RRs clearly favoured infliximab in terms of these outcomes, although the limited number of observations mean that there is considerable uncertainty around these pooled estimates, as reflected by their CIs (see Table 8). Despite the potentially large relative effects, it should also be noted that only the minority of infliximab-treated patients achieved an ACR 50 or ACR 70 response at 14 weeks (36% and 17%, respectively). Data from the IMPACT trial7981,89,96,109,111,113115,117,118 indicated no significant difference in ACR 20 response at 16 weeks between patients with and without concomitant MTX, although the number of patients in each of these groups was small.

As with the ACR outcomes, few patients receiving placebo demonstrated skin improvements over 14–16 weeks in terms of a PASI response; the pooled RR for PASI 50 was 10.58 (95% CI 5.47 to 20.48), demonstrating a clear degree of efficacy of infliximab in terms of skin-related symptoms. PASI 75 and PASI 90 response measures favoured infliximab even more strongly, although it should be noted that PASI outcomes were recorded only for those patients with a score of at least 2.5 at baseline. Forty-two per cent of patients receiving infliximab achieved the highest level of skin response (PASI 90), although again there is considerable uncertainty around the estimates (see Table 7).

The statistically significant pooled percentage change from baseline in HAQ score with infliximab compared with placebo [mean difference −60.37 (−75.28 to −45.46)] indicates a beneficial effect of infliximab on functional status.

Efficacy after 24 weeks

The IMPACT 2 trial82,90,91,95,98,106,112,116 maintained randomisation for 24 weeks. The data for all measures of joint disease, psoriasis and HAQ are similar to those observed at the earlier 14-week follow-up, suggesting that the benefits of infliximab are maintained up to 24 weeks of treatment (see Table 7). Change from baseline in modified van der Heijde–Sharp score significantly differed between infliximab and placebo groups, indicating that infliximab may inhibit progression of joint damage at 24 weeks (see Table 7).

Longer-term follow-up

The data for longer-term follow-up (50 or 54 weeks) from the two IMPACT trials are summarised in Table 9. These data are uncontrolled and may therefore be unreliable. Also, the duration of treatment varied between participants, as some will have crossed over from placebo treatment. However, the data broadly indicate that the levels of efficacy achieved with infliximab in terms of joint disease, psoriasis and HAQ after 14–24 weeks' treatment might be maintained in the medium term.

TABLE 9. Infliximab efficacy outcomes: uncontrolled follow-up data.

TABLE 9

Infliximab efficacy outcomes: uncontrolled follow-up data.

In terms of radiographic assessment, there was no significant change from baseline in the total modified van der Heijde–Sharp score for those infliximab-treated patients followed up at 50 or 54 weeks in the two studies, suggesting infliximab may inhibit progression of joint damage. However, as with other post-24-week outcomes, there was no placebo group for comparison.

Summary of the efficacy of infliximab in the treatment of PsA
  • There is evidence from two double-blind placebo controlled trials of a good level of efficacy for infliximab in the treatment of PsA, with beneficial effects on joint disease, psoriasis and functional status as assessed by HAQ.
  • Conclusions to be drawn from these data are limited by the short duration of the controlled trials; controlled data to evaluate long-term effects are not available.
  • Uncontrolled follow-up of patients indicate that short-term benefit is maintained for at least 50 weeks; however, these data may not be reliable.
  • Radiographic data from uncontrolled follow-up of infliximab trials suggest that the drug may delay the progression of joint disease in PsA, although these data are not of high quality.

Efficacy of adalimumab

Both trials evaluating adalimumab for PsA were double blind and placebo controlled, and both were rated as ‘good’ on the quality assessment rating (Table 10).51,83,88,92,93,100104

TABLE 10. Results of quality assessment for trials of adalimumab.

TABLE 10

Results of quality assessment for trials of adalimumab.

Both trials were of adults (aged 18–70 years), with active PsA (defined in both trials as three or more swollen joints and three or more tender or painful joints, with active psoriatic skin lesions or a documented history of psoriasis). Patients in the larger trial had demonstrated an inadequate response to NSAIDs and received no concomitant DMARDs other than MTX.51,88,92,93,100104 All patients in the smaller trial received concomitant DMARDs or had a history of DMARD therapy with inadequate response.83

The baseline characteristics of the trial populations are summarised in Table 1. In both trials, around one-half of the randomised patients received concomitant MTX. Other DMARDs and NSAIDs were used concomitantly by patients in the smaller trial,83 but not by those in the larger trial.51,88,92,93,100104 The mean number of prior DMARDs used was similar between the trials, although as seen in trials of the other biologics, the trials clearly included patients who had not yet demonstrated a lack of response to at least two DMARDs. The proportion of patients with polyarticular disease between the two trials indicated that overall the disease was moderate to severe. The proportion of patients with spine involvement, and arthritis mutilans at baseline made up only a small proportion of the trial population. The similarity of the trials on other measures of disease activity (TJC, SJC and HAQ at baseline) suggests that significant differences between the populations in terms of overall disease severity are unlikely. Overall, the baseline characteristics demonstrate that the trial populations are similar and are likely to be representative of a population with PsA requiring DMARD or biologic therapy.

In both trials adalimumab was administered by subcutaneous injection every other week at a dose of 40 mg. Treatment with active drug or placebo was administered for 12 weeks in the smaller trial (Genovese et al.)83 and for 24 weeks in the larger trial (Adalimumab Effectiveness in Psoriatic Arthritis Trial – ADEPT).51,88,92,93,100104 In both trials the controlled phase was followed by a follow-up period, during which adalimumab was administered in an open-label fashion to all patients.

Outcome data derived under RCT conditions are available from both trials for PsARC, ACR 20, ACR 50 and ACR 70 and HAQ at week 12. The larger of the two trials also reported these outcomes at 24 weeks. In addition, this trial reported PASI 50/70/90 outcomes at 12 and 24 weeks, as well as data on progression of joint disease at 24 weeks expressed in terms of the mean TSS.51,88,92,93,100104 All randomised outcome data are summarised in Table 11, with pooled data presented in Table 12.

TABLE 11. Adalimumab efficacy outcomes: RCT data.

TABLE 11

Adalimumab efficacy outcomes: RCT data.

TABLE 12. Meta-analysis of adalimumab efficacy data: outcomes at 12 weeks.

TABLE 12

Meta-analysis of adalimumab efficacy data: outcomes at 12 weeks.

ADEPT51,88,92,93,100104 reported longer-term open-label follow-up of patients at 48, 104, and 144 weeks. These data are summarised in Table 13.

TABLE 13. Adalimumab efficacy outcomes: uncontrolled follow-up data.

TABLE 13

Adalimumab efficacy outcomes: uncontrolled follow-up data.

Efficacy after 12 weeks' treatment

At 12 weeks, both trials reported a significant improvement in the PsA-specific PsARC measure for adalimumab relative to placebo (pooled RR 2.24; 95% CI 1.74 to 2.88), with an overall response rate of around 59% for adalimumab. The pooled RR for ACR 20 at 12 weeks was 3.65 (95% CI 2.57 to 5.17), demonstrating a clear degree of efficacy of adalimumab in terms of arthritis-related symptoms. There was no statistically significant heterogeneity between any of the pooled outcomes. The pooled RRs for ACR 50 and ACR 70 also clearly favoured adalimumab, although as with other estimates of these outcomes their related CIs were wide (Table 12). Again, the large relative differences on these higher-response thresholds reflect some response with biologic therapy versus virtually none with placebo (e.g. 18% vs 0.5% for ACR 70). Data from the larger trial indicated little evidence of any differential ACR response at 12 weeks between patients with and without concomitant MTX.51,88,92,93,100104

Only one trial reported 12-week PASI response measures: in patients with psoriasis of at least 3% BSA at baseline.51,88,92,93,100104 Response was significantly greater for adalimumab than placebo at all three PASI thresholds (PASI 50/75/90 – see Table 11). As with the ACR outcomes, there was little evidence of any differential PASI response between patients receiving and not receiving concomitant MTX, although the number of patients in each subgroup was small.

The statistically significant pooled absolute mean change from baseline in HAQ score with adalimumab compared with placebo (mean difference −0.27; 95% CI −0.36 to −0.18) indicates a beneficial effect of adalimumab on functional status.

Efficacy after 24 weeks' treatment

The ADEPT trial51,88,92,93,100104 maintained randomisation for 24 weeks. The data for all measures of joint disease, psoriasis and HAQ were all similar to those observed at the earlier 14-week follow-up, suggesting that the benefits of adalimumab are maintained for up to 24 weeks of treatment (see Table 12).

In addition, this trial51,88,92,93,100104 reported a statistically significant difference in mean change in TSS score from baseline (−0.2 vs 0.1, p < 0.001), favouring adalimumab over placebo in terms of delayed progression of joint disease. However, this duration of follow-up is to be considered short and barely adequate for this outcome.

The smaller of the two trials allowed patients to enter an open-label follow-up period from weeks 12–24.83 The pattern of reported joint disease outcomes appears similar to those reported at the end of the 12-week randomised period; however, estimates based on these non-randomised data cannot be considered reliable.

Longer-term follow-up

The larger adalimumab trial followed patients in an open-label fashion, measuring several outcomes at 48 weeks and at 2 years (Table 13).51,88,92,93,100104 Both ACR response rates and mean HAQ scores at weeks 48 and 104 appeared to have remained stable relative to the randomised observations of these outcomes at weeks 12 and 24. Similarly, rates of PASI response reported at 48 weeks appeared largely consistent with the earlier randomised observations. Disease progression as measured by TSS was reported at weeks 48 and 144, with higher mean values than observed at 24 weeks, although the open-label observational nature of these open-label data makes it difficult to reliably determine any clear changes in TSS over time.

Summary of the efficacy of adalimumab in the treatment of psoriatic arthritis
  • There is evidence from two double-blind placebo-controlled trials of a good level efficacy for adalimumab in the treatment of PsA, with beneficial effects on joint disease and functional status as assessed by HAQ.
  • There is limited evidence from a single RCT that adalimumab treatment has a beneficial effect on the psoriasis component of the disease in patients with PsA, as measured by PASI.
  • Conclusions to be drawn from these data are limited by the short duration the controlled trials; large-scale controlled data to evaluate long-term effects are not available.
  • Uncontrolled follow-up of patients indicate that treatment benefits in terms of joint disease and HAQ measures may be maintained at up to 2 years; however, these data may not be reliable.
  • Radiographic data from a single controlled trial for adalimumab in PsA demonstrate a beneficial effect on progression of joint disease at 24 weeks. This is a very short time over which to identify a statistically significant effect of therapy and indicates a rapid onset of action of adalimumab. Data from uncontrolled follow-up are inadequate to determine whether any potential delay in disease progression persists at 1–2 years' follow-up.

Efficacy of all three biologics

As described above (see Data analysis), the Bayesian indirect comparison enables a comparison to be made across all three biologics despite the lack of head-to-head trial data. The three agents were included in the analysis, with placebo being the common comparator. All of the trials identified in the systematic review were used in the analysis, although not all trials provided data for all of the outcomes analysed. Full details of the methods used are given in Appendix 5.

Psoriatic Arthritis Response Criteria response

The results of the evidence synthesis for PsARC response are in the form of probability of response (Table 14). The mean probability of a PsARC response was estimated to be 71% for etanercept, 79% for infliximab and 59% for adalimumab, compared with 25% for placebo. While the credible intervals for all three biologics overlap each other, none overlap placebo.

TABLE 14. Probability of PsARC response to biologics.

TABLE 14

Probability of PsARC response to biologics.

Changes in Health Assessment Questionnaire

The results of the evidence synthesis of HAQ conditional on response are presented as absolute changes in HAQ. These are calculated separately for the patients achieving a PsARC response (Table 15) and those who did not achieve a PsARC response (Table 16).

TABLE 15. Change in HAQ in patients who responded to treatment.

TABLE 15

Change in HAQ in patients who responded to treatment.

TABLE 16. Change in HAQ in patients who did not respond to treatment.

TABLE 16

Change in HAQ in patients who did not respond to treatment.

Statistically significant reductions in mean HAQ score were achieved with all four treatments compared, i.e. the credible intervals did not include zero. However, patients who responded to placebo achieved an improvement in the HAQ score of −0.244, which is below the minimum clinically significant threshold for PsA of −0.3.150 Patients who responded to etanercept and infliximab achieved similar mean changes in HAQ (−0.630 and −0.657, respectively), whereas responders to adalimumab achieved a lower mean change in the HAQ score of −0.477, although credible intervals overlap those of the other two treatments.

For all three biologics the changes in HAQ for those patients who did not respond to treatment were below the minimum clinically significant threshold. Placebo non-responders were used as a baseline in the synthesis.

Psoriasis Area and Severity Index

The results of the evidence synthesis for a PASI response are in the form of probability of response (Table 17). The mean probability of a PASI 75 response was estimated to be 18% for etanercept, 77% for infliximab and 48% for adalimumab, compared with 4% for placebo. The credible intervals for infliximab and etanercept do not overlap each other and none for the biologics overlap placebo.

TABLE 17. Probability of PASI response to biologic agents.

TABLE 17

Probability of PASI response to biologic agents.

American College of Rheumatology model

The results of the evidence synthesis for a ACR response are in the form of probability of response (Table 18). The ACR 20 is generally accepted to be the minimal clinically important difference that indicates some response to a particular intervention in terms of arthritis-related symptoms. The mean probability of an ACR 20 response was estimated to be 61% for etanercept, 68% for infliximab and 56% for adalimumab, compared with 14% for placebo. The credible intervals for all three biologics overlap each other, but none overlap those for placebo.

TABLE 18. Probability of ACR response to biologics.

TABLE 18

Probability of ACR response to biologics.

Summary of evidence synthesis results

Across all outcomes – PsARC, ACR and PASI – infliximab is associated with the highest probability of response. The response in joint disease (PsARC and ACR) is greater with etanercept than with adalimumab, whereas the response in skin disease (PASI) is greater with adalimumab than with etanercept, although these differences are not statistically significant. In those patients who achieve a PsARC response to treatment the highest mean reductions in HAQ are seen with infliximab and etanercept.

Comparison of evidence synthesis results

Each of the three company submissions combined evidence derived using Bayesian evidence synthesis methods. A brief comparison of these methods and the methods used by the assessment team are presented in Table 19 and discussed below.

TABLE 19. Comparison of industry and Assessment Group evidence syntheses.

TABLE 19

Comparison of industry and Assessment Group evidence syntheses.

Two of the company submissions – Abbott151 and Schering-Plough152 – conducted evidence syntheses to derive estimates that would allow the relative efficacy of the drugs to be compared (Table 19). (Since the production of this report, Schering-Plough has merged with Merck.) Wyeth153 chose not to conduct this synthesis themselves but to use the results of a previously published single technology appraisal (STA) relating to Abbott's adalimumab.74

Full details of the evidence synthesis model used by Wyeth153 were not provided in the Wyeth submission.153 Further, the methodology of the evidence synthesis from which these results were obtained was not presented in the original report.151 The synthesis was conducted by Abbott151 on the request from the Evidence Review Group (ERG) and only the results were presented in the ERG report. For this reason no summary/critique of the methods can be presented. The following section gives a comparative overview of the evidence synthesis results obtained by Schering-Plough,152 Abbott151 and by the Assessment Group in this report.

Psoriatic Arthritis Response Criteria response For PsARC response, all of the evidence synthesis models used a fixed-effects meta-analysis to synthesise the evidence. Both the Assessment Group and Schering-Plough152 identified and included six RCTs in their synthesis. Abbott,151 with slightly broader inclusion criteria, identified and included 10 RCTs. Abbott151 included RCTs in which the drug golimumab was administrated to the comparator arm of the RCT and, although no results were presented for this comparator, the other estimates do ‘borrow strength’ from these data. Although including the same six RCTs, both the Assessment Group and Schering-Plough152 estimated PsARC response using slightly different data. The Assessment Group used the closest follow-up outcome to 12 weeks, whereas Schering-Plough152 used the latest available end points (Table 20). This meant that, with the exception of the adalimumab data, the data inputs were principally the same. Abbott151 took a more complex bivariate approach, which enabled them to model the joint distribution of ACR/PsARC response at 12 weeks. Taking a bivariate approach allows the correlation between outcomes, if present, to be accounted for. However, if the correlation is zero then any bivariate joint modelling will arrive at the same estimates as two independent models. Given the lack of transparency of the Abbott151 evidence synthesis, it was not possible to unpick and decipher the subtleties of their model. The Assessment Group, following clinical advice, have used PsARC at 12 weeks to determine response to treatment. This follows clinical practice.

TABLE 20. Key assumptions in the synthesis models.

TABLE 20

Key assumptions in the synthesis models.

As can be seen from the results presented for the probability of response to the biologics under appraisal (and placebo) (Table 21), all of the mean estimates obtained were very similar, despite the different modelling assumptions and evidence used. There does appear to be some difference in the level of uncertainty, as presented by the confidence/credible intervals, but generally the means were close and the ranking consistent. The Abbott151 evidence synthesis model was extremely difficult to interpret; however, the analysis enabled the estimation of the joint probability of an ACR response and a PsARC response at 12 weeks. The 24-week results of the PsARC and ACR were then estimated individually, conditional on the 12-week response. Schering-Plough152 based their evidence synthesis on a previous HTA report,73 which linked two meta-analyses, one estimating PsARC the other HAQ conditional on PsARC.

TABLE 21. Psoriatic Arthritis Response Criteria model results.

TABLE 21

Psoriatic Arthritis Response Criteria model results.

Health Assessment Questionnaire conditional on a Psoriatic Arthritis Response Criteria response The economic models developed by both the Schering-Plough152 and the Assessment Group required an estimate of the expected change in HAQ in the first 3 months for treatment responders and non-responders, as measured by PsARC. HAQ conditional on a PsARC response was modelled by both the Assessment Group and Schering-Plough.152 The two modelling approaches were based on fixed-effects meta-analysis. The Schering-Plough152 approach uses two linked meta-analyses, which estimated the probability of response and then the mean reduction in HAQ score conditional on that response. The Assessment Group estimated the probability of PsARC response in one meta-analysis and then used this result to inform a second HAQ model. Both synthesis models used the same clinical trials to inform the HAQ–PsARC estimates. However, Schering-Plough152 used the latest available end points for HAQ, in contrast with the Assessment Group, who elected to use the 12- to 16-week HAQ data to reflect short-term benefits. Long-term benefits are considered explicitly in the economic model.

The results obtained (Table 22) were generally similar, with the drugs maintaining the same ranking. The differences may reflect the slightly differing modelling approaches or the difference in data used. The Assessment Group included only the five trials that reported HAQ outcomes for responders and non-responders. To enable them to include all six trials, Schering-Plough152 assumed that for the one trial where the data were not stratified by responder/non-responder78 the HAQ change for the PsARC non-responder was equivalent to the average HAQ change in the non-responders, as seen in other trials, and that the HAQ change for the PsARC responders could be inferred to match the reported mean HAQ change. The Assessment Group opted not to make this assumption, as it was not clear that it was appropriate or that it would have a significant impact on the results obtained. The Assessment Group took the decision to use only data that reported in a manner that facilitated modelling. The Schering-Plough152 report clearly states that six trials were considered; however, the detailed appendix and model code both appear to consider a seventh trial of the biologic golimumab. Although they state that this was used only to inform relationships between variables, the coding and appendix do not make this clear.

TABLE 22. Health Assessment Questionnaire conditional on response: different treatment effects (common baseline).

TABLE 22

Health Assessment Questionnaire conditional on response: different treatment effects (common baseline).

Abbott151 did not model HAQ conditional on response, although HAQ for the economic modelling section of their report they did state that relationships between ACR response rate and HAQ improvement, and PASI response and PASI improvement were developed in order to obtain estimates of HAQ and PASI improvement for responders and non-responders for each treatment.

This analysis estimated the expected change in HAQ in the first 3 months, conditional on treatment response. PsARC is not a baseline variable and therefore conditioning the analysis on PsARC response may be potentially biased. The analysis assumes there are no confounding factors (unrelated to treatment received) that change during the trial and affect both PsARC response and, independently, the change in HAQ.

Psoriasis Area and Severity Index 50/75/90 response The PASI outcomes were synthesised by Abbott,151 Schering-Plough152 and the Assessment Group. Schering-Plough152 elected to use absolute PASI change as their main outcome, on the basis that this was the most appropriate outcome for the economic modelling. As a result, the estimates obtained are not comparable with the Assessment Group or Abbott151 results, both of which elected to use probability of achieving each PASI outcome (50/75/90) as their main outcome. This was achieved using two different modelling approaches. The Assessment Group elected to use an ordered multivariate logit model, whereas Abbott151 chose to use a bivariate probit model. The logit and probit models are similar; both allow the different thresholds of PASI (50/75/90) to be modelled simultaneously, the ordered nature of the data to be maintained and an estimate of patients' percentage reduction in PASI score from baseline to be obtained. The results estimated and presented in Table 23 are similar. As previously stated, the Abbott model151 was complex and (as felt by the assessment team) difficult to fully understand. As such it is not clear if data from all 10 included trials were used in the Abbott PASI model.151 The data inputs for the Assessment Group model are reported in Appendix 5. Owing to a lack of reporting in some trials, the Assessment Group model included data from five trials, one of which provided data on only two of the outcomes (PASI 50/75).

TABLE 23. Psoriasis Area and Severity Index common effects model.

TABLE 23

Psoriasis Area and Severity Index common effects model.

American College of Rheumatology 20/50/70 response Schering-Plough152 did not synthesise for this outcome. Both the Assessment Group and Abbott151 did, but again elected to use two differing modelling approaches, ordered logit and bivariate probit. The comparative results are presented in Table 24. The results are again similar, with the ranking of the drugs being maintained.

TABLE 24. American College of Rheumatology model common effects.

TABLE 24

American College of Rheumatology model common effects.

Abbott's model151 produced estimates of 24-week ACR response conditional on the 12-weeks ACR response rate. The 12-week response rate was modelled as a joint distribution of 12-week PsARC and ACR response rates. The code and explanation of this modelling was not clear and therefore it was not possible to fully interpret all of the modelling conducted. As the Abbott economic model151 included both PsARC and ACR there was a need for them to estimate the correlation between these two outcomes. The correlation was estimated using the available evidence. However, it was unclear as to the number of trials informing the Abbott ACR synthesis151 and the correlation estimate. The Assessment Group have presented an ordered logit model, using data from all six trials. The estimates obtained were not used in the Assessment Group economic model, so it was not necessary to make any assumptions on the correlation between PsARC and ACR outcomes.

The annotated winbugs code, assumptions and data have been presented for all models used by the Assessment Group. Although it can be difficult to justify some of the differences in modelling assumptions taken by the various groups, the Assessment Group have tried to reflect clinical reality, minimise generalising assumptions and allow the results obtained to reflect the evidence obtained as part of the clinical review.

Review of adverse events

Overview of existing systematic reviews of adverse events

Several existing systematic reviews have investigated the safety of biologic agents. This section provides an overview of those reviews that were sufficiently rigorous to meet the Database of Abstracts of Reviews of Effects (DARE) inclusion criteria.75 The searches (see Appendix 1) resulted in 16 potentially relevant reviews; 10 were excluded because of a failure to meet the DARE criteria or to report relevant data on adverse events of biologics. Six systematic reviews (Table 25) were therefore included in this overview.

TABLE 25. Published systematic reviews of adverse events of biologics.

TABLE 25

Published systematic reviews of adverse events of biologics.

All of the six systematic reviews were published between 2006 and 2009. Three reviews158160 included patients with RA and three reviews161163 included patients with PsA or psoriasis. Almost all reviews evaluated the safety of more than two biologics. The sample size of included reviews varied from 982 to 7931. Almost all systematic reviews included RCTs to assess the safety of biologics, whereas only one review160 included both RCTs and observational studies. The search strategies were generally adequate to identify both published and unpublished studies, thereby minimising the potential of publication bias.164,165 However, in the majority of these reviews158161,163 it was unclear whether any language restrictions on study inclusion were made, which may have introduced the possibility of language bias.166

There were variations in methods of pooling the adverse event data in these reviews. Five reviews158,159,161163 used meta-analyses to synthesise the evidence of adverse event data of biologics, whereas one review used a narrative synthesis.160 For those using meta-analyses, the included studies were combined using either a fixed-effects or random-effects model; one review by Bongartz et al.159 also used the individual patient data (IPD) to pool the results. Where there were no direct head-to-head studies comparing one biologic with another, an indirect comparison was undertaken using placebo as the common comparator in two reviews.158,162 Statistical heterogeneity167,168 was adequately assessed in most reviews. In addition, three reviews assessed the adverse events for more than two biologics combined,158,161,162 whereas the other reviews evaluated them for each biologic respectively.159,160,163

A range of adverse events of biologics were evaluated in these reviews. Three reviews160,162,163 evaluated both common and serious adverse events of biologics, whereas two reviews exclusively focused on serious adverse events such as malignancy.158,159 Two reviews161,162 used withdrawal rate due to toxicity/adverse events of biologics as the review outcome.

There were considerable variations in the effect estimations between the reviews. Brimhall et al.163 reported that there were no significant increased incidences of one or more adverse events or serious adverse events for patients receiving etanercept; they also reported that there was no significant increase in the incidence of serious adverse events for patients receiving infliximab compared with those receiving placebo, although patients who received infliximab experienced a significant increased incidence of one or more adverse events. It should be noted that this systematic review was limited to short-term safety data of over 10–30 weeks of the biologic treatment. The review by Gartlehner et al.,160 which principally evaluated the common adverse events of biologics, showed similar results based on the data from 18 experimental and observational studies for patients with RA. This review reported that biologics appeared to have a good tolerability profile; injection site reactions or infusion reactions were the most commonly reported adverse events for biologics of etanercept, infliximab and adalimumab. However, a lack of sound long-term safety data prevented this review from drawing a firm conclusion about the comparative safety between these three biologics for patients with RA.

Both the review by Ravindran et al.161 and the review by Saad et al.162 used the withdrawal rate due to toxicity/adverse events as the outcome measure to assess the safety of biologics. These are two reviews that exclusively include patients with PsA. The review by Ravindran et al.161 reported that biologic treatment for patients with PsA was associated with a non-significant increase of withdrawal rate due to toxicity compared with placebo, when pooling the data from five RCTs of etanercept, infliximab and adalimumab. Similar results were found in the review by Saad et al.162 on the basis of the pooled results of five RCTs (including the same four RCTs as Ravindran et al.161), which also reported a non-significant difference between biologics and placebo in the proportion of patients with PsA experiencing withdrawals due to adverse events or serious adverse events. It should be noted that this outcome measure is associated with a methodological limitation: it is difficult to discern withdrawals due to adverse events from those due to poor efficacy, and those that result from a combination of both. In addition, the lack of long-term adverse event data in these two reviews makes it difficult to assess rare but potentially serious adverse events (e.g. malignancy or serious TB infection) of biologics for patients with PsA.

Two reviews assessed the serious adverse events of malignancy and/or serious infections due to use of biologics for patients with RA.158,159 Bongartz et al.158 reported that malignancies were significantly more common in patients treated with biologics compared with placebo: the pooled odds ratio (OR) for malignancy in patients receiving infliximab and adalimumab compared with placebo was 3.3 (95% CI 1.2 to 9.1) and for serious infection was 2.0 (95% CI 1.3 to 3.1). Malignancies were also significantly more common in patients receiving higher doses of biologics than in patients receiving lower doses of biologics. However, some inconsistent findings were reported in the review by Bongartz et al.,159 which exclusively assessed the serious adverse event of malignancy for etanercept. This review reported that the pooled increased hazard ratio (HR) for malignancies based on IPD was not statistically significant (HR 1.84, 95% CI 0.79 to 4.28) in patients using etanercept compared with placebo or mixed control patients being treated with one DMARD. Similar non-significant results were also generated from the random-effects models. It is noteworthy that the pooled estimate of malignancy due to use of biologics in both of the reviews was limited to short-term follow-up; there is a necessity to evaluate the risk of malignancy of biologics on long-term follow-up durations.

Based on these reviews of adverse events of biologics, in general there is a concern that biologics may be associated with an increased risk of infection and malignancy. Due to some inconsistencies in the results and variations in methods of synthesising the data, no firm conclusions could be drawn from these reviews about the evidence of adverse events of biologics, especially for these serious adverse events. The lack of long-term adverse event data in the majority of reviews could compromise any comparative safety estimation between biologics. Furthermore, a probable exacerbation of latent TB is also considered to be potentially associated with use of biologics.146,169171 However, no reviews have addressed this outcome. In particular, adalimumab is a new drug for which there is only limited experience on long-term monitoring; further investigation on its safety is warranted.

In light of the outstanding uncertainties around the findings of previous reviews of biologic safety, our systematic review (see the following section) specifically focused on the serious potential adverse events of these biologics: malignancies, severe infections (i.e. those that require i.v. antibiotic therapy and/or hospitalisation or cause death) and reactivation of latent TB. Apart from RCTs, our systematic review also included observational studies in order to evaluate the long-term adverse events of biologics.

Review of primary studies

Two main sources of information on adverse events were incorporated into the review: RCTs evaluating etanercept, infliximab and adalimumab in PsA, and controlled and uncontrolled studies or registry data in which at least 500 patients with any indication received one or other of these agents.

As the identified non-randomised studies were highly heterogeneous, and because some studies using the same registry at different time points (thereby being likely to contain an overlap in patient data), the range of rates have summarised in a narrative synthesis, and no attempt has been made to pool values across studies. Reported percentage rates of adverse events are presented for randomised trials and single-arm studies. For non-randomised controlled studies in which the length of follow-up differed between groups, results are presented as the number of events per 100 patient-years where reported.

Etanercept

Randomised controlled trials in psoriatic arthritis Two placebo-controlled RCTs evaluated etanercept in patients with PsA. The first, which followed 60 patients for 12 weeks, reported more infections in the etanercept group than the placebo group for respiratory tract infection (27% vs 13%, respectively), pharyngitis (17% vs 10%), rhinitis (17% vs 13%) and sinusitis (10% vs 7%). Influenza was more commonly reported in the placebo group (0% vs 20%).78 However, given the small numbers of patients in each group, these differences could be attributable to the play of chance. No deaths or withdrawals due to adverse events were reported for either group. Data on cancer and TB were not clearly reported.

A second, larger placebo-controlled RCT by the same authors, followed 205 patients over 24 weeks.52,97,99,105,107,110 One patient in the placebo group died following surgical complications, and one patient from each group withdrew from the study. There were no reported cancers. Similar rates were observed between the etanercept and placebo groups for upper respiratory tract infection (URTI) (21% vs 23%), sinusitis (6% vs 8%) and urinary tract infection (6% vs 6%), although again, this efficacy study was not powered to detect a difference between groups in terms of adverse events. TB was not reported.

Non-randomised studies/large randomised controlled trials in other conditions Thirteen non-randomised studies, in which more than 500 patients received biologic agents, reported adverse event data for etanercept. The majority of treated patients had RA, although outcomes for PsA, juvenile idiopathic arthritis, ankylosing spondylitis and patients with other chronic inflammatory conditions were also reported (Table 26). Average length of follow-up ranged from 48 weeks to 7 years.

TABLE 26. Adverse events reported for etanercept.

TABLE 26

Adverse events reported for etanercept.

The total reported rate of infections ranged from 9.6% to 54.4% (reported by five studies), with serious infections (requiring hospitalisation) ranging from 2.6% to 16.2% (nine studies). Only three studies clearly reported cancer, with rates ranging from 1% to 5.7%. Seven out of eleven studies reporting rates of TB in patients receiving etanercept found no cases. The remaining four studies reported rates ranging from 0.03% to 1.4%. Four studies reported rates of withdrawal due to adverse events, ranging from 4.6% to 13.6%. Where reported, mortality ranged from 0% to 3.1% (five studies).

Two of these studies compared adverse event rates in patients receiving etanercept against control.99,122 One cohort study122 reported significantly more infections in patients with RA receiving etanercept than control patients (22.6 vs 6.8 infections per 100 patient-years, p < 0.01; 6.4 vs 2.3 serious infections per 100 patient-years, p < 0.01). However, a second study, an analysis of collated trial data on the use of etanercept reported no significant difference in overall infection rates between etanercept and control (placebo or MTX) across a range of conditions (54.4% vs 41.4%, p > 0.05).99

Infliximab

Randomised controlled trials in psoriatic arthritis Two placebo-controlled RCTs evaluated infliximab in patients with PsA.7982,8991,95,96,98,106,109,111118 One RCT followed 104 patients over 16 weeks, reporting more respiratory tract infections in placebo-treated patients than in infliximab-treated patients (9.8% vs 1.9% respectively), though reported rates of bronchitis (7.8% vs 5.8%) and rhinitis (3.9% vs 5.7%) were similar between groups.7981,89,96,109,111,113115,117,118 However, the very small numbers of events reported preclude any meaningful interpretation of these differences. No deaths or withdrawals were reported for either group.

The second RCT followed 200 patients over 24 weeks and reported similar rates between infliximab and placebo groups for URTI (10% vs 14%), pharyngitis (5% vs 4%) and sinusitis (5% vs 4%), although as with other RCTs, the study was not powered to detect differences in adverse events.82,90,91,95,98,106,112,116 One patient in the placebo group developed basal cell carcinoma of the skin, although no deaths or withdrawals due to adverse events were reported.

Non-randomised studies/large randomised controlled trials in other conditions Eighteen non-randomised studies and two RCTs in indications other than PsA reported adverse event data for infliximab. Outcomes were reported for patients with PsA, juvenile idiopathic arthritis and ankylosing spondylitis, although the vast majority of patients had RA (Table 27). Average length of follow-up ranged from 22 weeks to 6 years.

TABLE 27. Adverse events reported for infliximab.

TABLE 27

Adverse events reported for infliximab.

The total reported rate of infections ranged from 8.7% to 26.6% (reported by four studies). Where detailed separately, the most common infections were URTIs, ranging from 10.8% to 38.5% (three studies). Serious infections (requiring hospitalisation) ranged from 0.8% to 13.8% (12 studies). Eight studies reported total cancers, with rates ranging from 0.16% to 5.1%. Sixteen studies reported rates of TB in patients receiving infliximab, 11 of which reported rates less than 0.5%, with the overall range being 0% to 4.6%. Where reported, mortality ranged from 0.06% to 2% (seven studies). Four studies reported rates of withdrawal due to adverse events, ranging from 5.3% to 12.8%.

Four of the studies compared adverse event rates for patients receiving infliximab against some form of control group.119,122,139,143 Two of these were RCTs of infliximab versus placebo plus MTX in RA,139,143 of which one found no difference in serious infections between groups at 22 weeks (3.3% vs 1.7%, p > 0.05),139 and one reported significantly more serious infections associated with infliximab at around 54 weeks (5.3% vs 2.1%, p < 0.05).143 Two cohort studies compared adverse event rates between infliximab and control patients: one reported significantly higher rates of overall infections (28.3 per 100 patient-years vs 6.8 per 100 patient-years, p < 0.01) and serious infections (6.2 per 100 patient-years vs 2.3 per 100 patient-years) among patients with RA receiving infliximab,122 the second reported no significant differences in serious infections (1.6 per 100 patient-years vs 1.1 per 100 patient-years) or cancer (0.4 per 100 patient-years vs 0.5 per 100 patient-years) or mortality (0.3 per 100 patient-years vs 0.2 per 100 patient-years).119

Adalimumab

Randomised controlled trials in psoriatic arthritis The smaller of the two RCTs evaluating adalimumab (102 patients over 12 weeks) reported more overall infections in placebo-treated than adalimumab-treated patients (32.7% vs 17.6%, respectively), with the infection classified as ‘serious’ for a single patient in each group. Reported rates of URTI were 8.2% and 13.7%, respectively.83 As with other RCTs, small numbers of events reported limit meaningful interpretation of these differences. No deaths were reported for either group, and the small proportions of withdrawals were comparable.

The larger trial, which randomised 315 patients over 24 weeks, reported similar rates between adalimumab and placebo groups for URTI (12.6% vs 14.8%, respectively) and nasopharyngitis (9.9% vs 9.4%).51,88,92,93,100104 Serious infections were reported in three patients; two receiving adalimumab and one receiving placebo. No deaths were reported.

Non-randomised studies/large randomised controlled trials in other conditions Eight non-randomised studies and two RCTs in indications other than PsA reported adverse event data for adalimumab. Outcomes were reported for patients with PsA, juvenile idiopathic arthritis and ankylosing spondylitis, although, as for the other agents, most patients had RA (Table 28). Average length of study follow-up ranged from 12 weeks to 5 years.

TABLE 28. Adverse events reported for adalimumab.

TABLE 28

Adverse events reported for adalimumab.

The total reported rate of infections ranged from 9.1% to 45.3% (three studies), with serious infections ranging from 0.4% to 7.3% (nine studies). Four studies reported total cancer, with rates ranging from 0.1% to 1.1%. Eight studies reported rates of TB in patients receiving infliximab, ranging from 0% to 0.4%. Four studies reported rates of withdrawal due to adverse events, ranging from 5.8% to 10.7%. Where reported, mortality ranged from 0.2% to 0.9% (three studies).

Two of these studies were RCTs of adalimumab in conditions other than PsA.133,140 One RCT of adalimumab alone or in combination with MTX against MTX alone in patients with RA, reported no difference between adalimumab monotherapy and MTX monotherapy in terms of overall infections (110 per 100 patient-years vs 119 per 100 patient-years), serious infections (0.7 per 100 patient-years vs 1.6 per 100 patient-years), or cancer (0.9 per 100 patient-years in each group). However, significantly more serious infections were observed for combined adalimumab/MTX therapy than for adalimumab monotherapy (2.9 per 100 patient-years vs 0.7 per 100 patient-years, p < 0.05).140 The second RCT reported that, after 56 weeks of treatment in patients with Crohn's disease, no significant differences were found between adalimumab and placebo in terms of overall (45.3% vs 36.8%) or serious infection rates (2.7% vs 3.4%).133

Studies reporting more than one agent

No RCTs exist that provide a head-to-head comparison between any of the three agents of interest, and substantial clinical heterogeneity precludes any meaningful comparison of rates between the different uncontrolled studies summarised above. However, limited information on the relative rates of certain adverse events between agents was reported by 10 of these uncontrolled studies (Table 29).

TABLE 29. Studies reporting adverse events for more than one biologic agent.

TABLE 29

Studies reporting adverse events for more than one biologic agent.

Patients with RA predominated and the average length of study follow-up (where reported) ranged from 1 to 5 years. One prospective cohort study reported a total rate of infections of 21.3% (6.1% serious) and 26.6% (5.8% serious) for etanercept and infliximab, respectively.122 Three more studies reported rates of serious infections for all three agents: etanercept (5.8%, 11.2%, 4.5%), infliximab (8.9%, 13.8%, 8.1%) and adalimumab (5.1%, 7.3%, 6.6%).129,136,147

Rates of TB were reported in seven studies of patients receiving etanercept (0%–1.4%) and infliximab (0%–4.6%), four of which also included patients receiving adalimumab (0%–0.3%).

One large prospective cohort study of reported that 0.76% of patients treated with biologic agents developed cancer during follow-up.148 None of the studies provided adequate data on rates of withdrawal, and no studies provided separate mortality data for each agent.

Summary of serious adverse events across all three agents

Table 30 summarises the rates of serous adverse events, where reported, among the included non-randomised studies and large RCTs. This indicates that the rates of serious adverse events cover a broadly similar range across the three different biologic agents. However, it should be noted that all of these estimates are derived from a highly heterogeneous group of studies in terms of participants (e.g. inflammatory condition, disease severity), study design (e.g. length of follow-up) and treatment regimens (e.g. dose and frequency). Consequently, reliable estimates of the relative rate of serious adverse events for each drug cannot be made.

TABLE 30. Range of serious adverse event and withdrawal rates across non-randomised studies/large RCTs.

TABLE 30

Range of serious adverse event and withdrawal rates across non-randomised studies/large RCTs.

Withdrawal rates due to adverse events were typically < 10% for all drugs, with the highest reported single estimate being 13.8% for one etanercept study. This would suggest that the majority of patients can tolerate biologic treatment in the medium term, although again these estimates are derived from a highly heterogeneous group of studies, therefore poorer tolerability in specific patient groups cannot be ruled out.

Discussion of clinical evaluation

Efficacy

Study design and quality

All six included studies were randomised, double-blind controlled trials. Based on the quality assessment using the pre-specified criteria, all the included trials were rated as ‘good’ quality. Concealment allocation and blinding were adequate in almost all included trials. All of the trials appeared to deal with withdrawals appropriately by using intention-to-treat (ITT) analyses. The completeness of follow-up was fairly good in all trials, with losses to follow-up of < 20%, thereby minimising attrition bias.172 All the trials reported the use of a power calculation to determine the sample size. Five of them had an open-label extension after the randomisation period. However, it should be noted that the maximum randomised follow-up period across these trials was only 24 weeks.

Though there were some differences relating to patients' characteristics at baseline across the trials, participants were generally similar in terms of disease activity and severity, and were likely to represent a population with moderate to severe PsA requiring further treatment. This was reflected by the lack of evidence for statistical heterogeneity in most efficacy analyses in this review. However, although the majority of patients in the trials had previously received at least one DMARD, no trial specified the failure to respond to at least two DMARDs (patients whom the current BSR guidelines consider eligible for biologic treatment) as a recruitment criterion. Therefore, trial participants were not precisely representative of patients receiving these agents in practice, and were likely to have had less severe disease, having often received biologic therapy after failing a single DMARD.

There were inconsistencies in the choice of primary outcome between included studies. Most studies used the ACR 20 as the primary outcome measure, while one trial used the PsARC as the primary outcome. However, it should be noted that ACR 20 is not frequently used in routine clinical practice to measure response to a biologic treatment.

Outcomes relating to joint disease

There were limited efficacy data from RCTs for the three biological agents. For each agent, there were two RCTs with around 200 or fewer patients receiving active treatment. However, all six trials were of good quality and provided clear indication of a response to treatment at 12–16 weeks, with continued efficacy at 24 weeks for each biologic agent.

Point estimates of effect sizes were generally moderate to large, implying that these treatment effects could be clinically significant. Moreover, although a very small number of studies were pooled for each estimate, the CIs indicate reasonable precision of these estimates. However, pooling the long-term efficacy data from trials was impossible due to lack of data.

In general, there was no significant heterogeneity in the treatment effect for almost all of the efficacy outcomes, with the PsARC in infliximab being the only exception. The radiographic data from RCTs of etanercept and adalimumab in PsA demonstrated a beneficial effect on joint disease progression at 24 weeks. Follow-up this early is often considered insufficient to detect radiological changes, although if the 24-week effect is reliable it would indicate a rapid onset of action in terms of joint disease for these agents. The open-label extensions of these RCTs also provided data on radiographic assessment at long-term follow-up, indicating that the effect on joint disease progression may persist over time. However, the reliability of these longer-term data was compromised by the lack of a control group.

Functional status (Health Assessment Questionnaire)

All three agents appeared to have beneficial effects on functional status as measured by HAQ. The estimates with relatively high precision indicated that all of the biologic therapies significantly improved the functional status of patients with PsA at around 3 months' follow-up. The clinical significance of these effects was not entirely clear, for example, adalimumab was associated with a significant absolute mean reduction of HAQ score from baseline of −0.27 (95% CI −0.36 to −0.18). However, only changes > −0.3 have been considered as clinically meaningful improvement in PsA.150

In this systematic review, the benefit of the biologic treatment compared with placebo on joint disease outcomes was consistent with the previous systematic review, which investigated the efficacy of etanercept and infliximab in the treatment of PsA.73 In general, both of the systematic reviews used the same rigorous methodology and revealed similar magnitudes of the treatment effect of etanercept and infliximab. The current review also assessed effects of the recently licensed biologic agent ‘adalimumab’ and demonstrated its beneficial treatment effects compared with placebo.

Outcomes relating to skin disease (psoriasis component)

Skin outcomes (i.e. PASI response) were less commonly reported than joint response measures. Where reported, these results were generally statistically significant, although CIs were wide – possibly due to the small sample size of patients evaluable for psoriasis in the trials. Overall, biologic treatment appears to have a broadly beneficial effect on skin disease in patients with PsA. Evidence of response from trials in patients with psoriasis lay outside the scope of this evaluation.173,174

Relative efficacy of the biologics

As data for the direct head-to-head comparison between these biologic agents were not available from trials, the relative efficacy of these biologic agents in the treatment of PsA was evaluated using Bayesian indirect comparison methodology.

The results of this evidence synthesis highlighted the superior efficacy of biologics over placebo across the outcomes evaluated. Infliximab appears to be the most effective among the three biologics. Patients treated with infliximab had a higher probability of responding to treatment regarding both the skin and arthritis aspects of disease. Additionally, we have estimated that infliximab allows improvements in the functional and psychological impact of the disease, measured by HAQ. However, patients who responded to etanercept achieved similar mean changes in HAQ (−0.6275 for infliximab and −0.6235 for etanercept) with placebo non-responders being used as a baseline in the synthesis. For all three biologics the changes in HAQ for those patients who did not respond to treatment were below the suggested minimum clinically significant threshold,150 and only those for infliximab achieved statistical significance. A comparison of the indirect comparison undertaken by the Assessment Group with those of the manufacturers shows similar mean estimates of treatment effect despite the rather different methods used.

Safety

Study design and quality

For the evaluation of adverse events of these biological agents, this review included a range of study types including RCTs, trial open-label extensions and observational studies. The quality of studies therefore varied across these different study designs; in particular, observational studies were subject to confounding, thereby threatening the internal validity of their findings. In addition, the definition of serious adverse events was also unclear in most studies.

Outcomes relating to serious adverse events

Previous systematic reviews have focused on short-term follow-up and reported conflicting findings on the risk of serious infections and cancer associated with biologic treatment. Our current systematic review contributes an evaluation of potential serious adverse events of biologic treatment in the longer term, incorporating the risk of activation of latent TB. Although the estimates of the rates of these adverse events varied widely, the findings from our review did raise a concern that treatment with etanercept, infliximab and adalimumab might be associated with an increased risk of serious infection, malignancy and activation of latent TB. The adverse event analyses demonstrated that etanercept, infliximab and adalimumab were associated with a broadly similar range of incidences of these events. However, there was considerable uncertainty around these estimates, in part due to the high degree methodological and clinical diversity between the included studies. In addition, the adverse event data were derived primarily from patients with RA or other indications, so the generalisability of these findings to patients with PsA remains unclear. Overall, the limited evidence prevents firm conclusions about the comparative safety of the three biologic agents being drawn from our systematic review.

© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK109497

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