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Malottki K, Barton P, Tsourapas A, et al. Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Mar. (Health Technology Assessment, No. 15.14.)

3Assessment of clinical effectiveness

Methods for reviewing effectiveness

Search strategy

The following resources were searched for relevant studies:

  • Bibliographic databases: Cochrane Library (CENTRAL) 2009 Issue3, MEDLINE (Ovid) 1,950 to July week 1 2009, MEDLINE In-Process & Other Non-Indexed Citations (Ovid) 13 July 2009, EMBASE (Ovid) 1980–2009 week 28. Searches were based on index and text words that encompassed the condition, RA, and the interventions ADA, IFX, ETN, RTX and ABT.
  • Citations of included studies were examined.
  • Reference lists of identified systematic reviews were checked.
  • Further information was sought from contacts with experts.
  • Research registries of ongoing trials including the National Institute for Health Research (NIHR) Clinical Research Network Portfolio Database, Current Controlled Trials and Clinical Trials.gov using terms for the particular drugs.
  • Manufacturer submissions.

The searches were not limited by date of publication or language.

Search strategies can be found in Appendix 2.

Study selection

All articles identified in the searches were imported into a reference manager database (reference manager v.11, Thomson ResearchSoft). Duplicate entries were allowed to be removed by the inbuilt feature in reference manager and removed when encountered by reviewers. Titles and abstracts were independently checked for relevance based on the population and intervention by two reviewers. If articles were considered relevant by at least one of the reviewers a full paper copy was ordered.

Full papers were assessed for relevance by two independent reviewers using an inclusion/exclusion checklist (see Appendix 6) based on the following criteria:

  • population: a majority of adults with active RA who have had an inadequate response to a TNF inhibitor
  • intervention: ADA, ETN, IFX, RTX, or ABT
  • outcomes: clinical outcomes related to efficacy, safety or tolerability
  • study design: primary study (except case reports) or a systematic review
  • study duration: at least 12 weeks
  • participant numbers: for non-randomised studies – at least 20 patients in one arm.

Disagreements were resolved by discussion with the involvement of a third reviewer when necessary.

Conference abstracts were not sought. If they were identified as relevant in the first stage of study selection, an attempt was made to match them with journal publications. If this was not possible, contact with authors was not attempted owing to time constraints and they were not included in the analysis.

A list of excluded studies and the reason for exclusion were recorded (see Appendix 4).

Included systematic reviews were not themselves systematically reviewed, but were utilised to identify further primary studies.

Additional references identified from systematic reviews or industry submissions were entered into the reference manager database. The same process was applied to additional the references as to the references identified from initial searches.

Data extraction

Data were extracted into a standard form (see Appendix 8) for all included studies by one reviewer. A second reviewer checked the accuracy of the extracted information. Disagreements were resolved by consensus or by referral to a third reviewer if necessary.

Information regarding study design and characteristics of study participants was extracted. Data on the following outcomes were sought from included studies:

  • treatment withdrawal (and reasons for withdrawal)
  • ACR20, ACR50, ACR70
  • disease activity (e.g. DAS28 or DAS)
  • physical function (e.g. HAQ)
  • joint damage/radiological progression (measured by a scoring system)
  • pain
  • extra-articular manifestations of the disease
  • serious AEs (including death)
  • other adverse effects potentially associated with treatments
  • HRQoL.

Data for any outcomes other than those listed above were also extracted if they were considered relevant to this report.

Additional data from industry submissions were extracted by only one reviewer owing to time constraints.

Quality assessment

The quality of included studies was assessed independently by two reviewers. Any disagreements were resolved by discussion and if necessary a third reviewer was consulted.

For randomised trials the following criteria were considered:

  • Randomisation: whether allocation was truly random. Randomisation using a computer or a random number table was considered adequate, whereas the use of alternation, case record numbers, or dates of birth and day of the week was considered inadequate.
  • Allocation concealment: whether allocation concealment was adequate. Any of the following methods was considered adequate: centralised (e.g. allocation by a central office unaware of subject characteristics) or pharmacy-controlled randomisation; pre-numbered or coded identical containers which are administered serially to participants; on-site computer system combined with allocations kept in a locked unreadable computer file that can be accessed only after the characteristics of an enrolled participant have been entered; or sequentially numbered, sealed, opaque envelopes.
  • Blinding: use of blinding and who was blinded (patients, study investigators/outcome assessors, data analysts).
  • Patients withdrawn: what was the percentage of patients withdrawn from the study?
  • Intention-to-treat (ITT) analysis: whether ITT analysis was used.

For non-randomised studies the following criteria were considered:

  • Study design: if the study was controlled or uncontrolled, prospective or retrospective.
  • Inclusion criteria: if inclusion criteria were clearly stated.
  • Consecutive patients: if consecutive patients were included in the study.
  • Patients withdrawn: what was the percentage of patients withdrawn from the study?

The results of quality assessments are reported in relevant sections of the report.

Data analysis/synthesis

Outcomes of interest

Selected outcomes of interest were specified in the review protocol, based upon the final scope issued by NICE for this technology appraisal. These were:

  • treatment withdrawal (and reasons for withdrawal)
  • ACR20, ACR50, ACR70
  • disease activity (e.g. DAS28 or DAS)
  • physical function (e.g. HAQ)
  • joint damage/radiological progression (measured by a valid scoring system)
  • pain
  • extra-articular manifestations of the disease
  • serious AEs (including death)
  • other adverse effects potentially associated with treatment
  • HRQoL.

Handling of data and presentation of results

Comparisons with supportive care

Studies were considered to compare interventions with supportive care if they:

  • had an arm receiving supportive care
  • had a placebo arm.

Owing to the paucity of evidence from controlled studies of TNF inhibitors, evidence from uncontrolled studies (i.e. single-group before-and-after studies) is also considered in this section.

Studies were considered separately for each of the interventions. In addition, TNF inhibitors were discussed together as a class of drugs. Results were presented in figures and discussed in the main text of the report for the following outcomes:

  • withdrawals (for any reason, owing to the lack of efficacy and owing to AEs)
  • ACR20, ACR50 and ACR70
  • European League Against Rheumatism (EULAR) response
  • QoL
  • joint damage
  • serious AEs
  • infections and serious infections

For other outcomes only figures were created, and these can be found in Appendix 10.

Dichotomous measures data are presented as relative risks (RRs) (for RCTs) and percentages (for other study designs). For continuous outcomes, mean differences (for RCTs) and means (for other study designs) were used.

Where available, data were analysed for 3, 6, 9, 12, etc. months' duration of follow-up. They were assumed to be 3-month data if they were collected between 3 and 4 months from the initiation of treatment, 6-month data if they were collected between 5 and 7 months from the initiation of treatment. If more than one estimate was available for a time interval, the value nearest to the assumed follow-up was used.

Pooling of results was not attempted for the assessment of effectiveness of individual technologies because the majority of included studies had no control group and there was substantial methodological and clinical heterogeneity between included studies. Given the relatively small number of patients that can be analysed in subgroup analyses, some pooling of data using a random-effects model was attempted. The results were presented with I2 statistics mainly for demonstrating consistency of findings between studies (see Subgroup analyses).

Comparisons with newly initiated and previously untried conventional disease-modifying antirheumatic drugs

No studies were identified and therefore analyses were not undertaken.

Comparisons with other biologic agents

No studies were identified and therefore analyses were not undertaken.

Comparisons between technologies (head-to-head comparisons)

No studies were identified and therefore direct comparisons were not undertaken.

Indirect comparison (IC) was undertaken when data were available from RCTs. It was conducted using the method by Bucher et al.73 The results of the analyses were presented in tabular format.

Subgroup analyses

The following subgroups were specified in the review protocol:

  • patients having withdrawn from the first TNF inhibitor owing to the lack of response (primary failure), loss of response (secondary failure) or AEs/intolerance
  • subgroups defined by autoantibody status (e.g. presence or absence of RF or anti-CCP antibodies)
  • subgroups defined by different doses of the intervention (within licence)
  • patients with comorbidities for which some treatments may be contraindicated (e.g. heart failure).

No subgroup data concerning the last two categories (varied doses; comorbidities) were identified, and thus no subgroup analysis was performed for these. Subgroup analyses relating to the reasons of withdrawal from the first TNF inhibitor were carried out as two separate comparisons:

  1. withdrawal owing to lack of response versus withdrawal due to loss of response
  2. withdrawal owing to lack of efficacy (which includes both lack of response and loss of response) versus withdrawal due to AEs/intolerance.

In addition to the above, subgroup data in relation to the identity of the first TNF inhibitor which the patients received before discontinuation and the number of prior TNF inhibitor(s) that the patients had tried before switching were reported in some studies. These were considered potentially of clinical relevance and thus subgroup analyses on these were also performed where data were available [commercial-in-confidence information (or data) removed].

Ongoing studies

Ongoing primary studies were identified in the searches. They were not included in the systematic review, but discussed in Ongoing studies.

Assessment of publication bias

All manufacturers of the interventions provided a list of all company-sponsored RCTs and other non-randomised or uncontrolled studies that are relevant for this appraisal. Requests of clarification of trial data that are potentially available but not reported in published papers were also made to the manufacturers of RTX and ABT.

The number of relevant studies for individual technology was too small to allow a formal assessment of publication bias.

Sensitivity analyses

The protocol specified that if evidence permits sensitivity analyses may be carried out taking into account the following factors:

  • quality measures of studies such as blinding and randomisation
  • factors associated with the characteristics of the study population
  • factors associated with study design such as study duration and drug doses
  • exclusion of data supplied as commercial/academic in confidence.

However, sensitivity analyses were not performed as no pooling of study results was undertaken.

Changes to the original protocol

During the study selection process, several potentially relevant studies including mixed proportion of patients with or without prior treatment with a TNF inhibitor were identified. No criterion relating to inclusion or exclusion of these studies was specified in the original protocol. It was agreed by consensus within the project team that studies that included less than 50% of patients with RA who have failed a TNF inhibitor were excluded, unless results from these patients were described separately and the number of these patients was greater than or equal to 20.

This report contains reference to confidential information provided as part of the NICE appraisal process. This information has been removed from the report and the results, discussions and conclusions of the report do not include the confidential information. These sections are clearly marked in the report.

Results: quantity and quality of research available

The searches resulted in the identification of 10,281 records and an additional 17 were identified from industry submissions and 15 from reference lists of included studies.

Nine relevant systematic reviews7482 were identified in addition to the reports conducted for previous NICE appraisals in RA. Examination of these nine reviews did not identify any further primary studies that met all the criteria for inclusion in either the clinical effectiveness or cost-effectiveness sections of this report.

Duplicates had been removed, leaving 7,486 records. Screening of the title and abstract of these articles indicated that 174 were directly relevant to the clinical effectiveness section of this report. Full paper copies of these articles were ordered. Five of them were unobtainable.8387 Inclusion criteria were applied to the remaining 169 articles. Of these, 113 were excluded for not meeting at least one of the inclusion criteria. Three articles were identified as conference abstracts8890 and, as these could not be matched to full publications, they were excluded. Details of excluded studies together with reasons for exclusion can be found in Appendix 4.

A flow diagram presenting the process of identification of relevant studies can be found in Appendix 3.

There were 35 studies described in 45 papers meeting the inclusion criteria. Five of the studies were RCTs, one was a comparative study, one was a non-randomised controlled study and 28 were uncontrolled studies [including one long-term extension (LTE) of an RCT].

A randomised study on RTX [study for understanding rituximab safety and efficacy (SUNRISE)91] that was not yet published in full was identified. Data from this study were requested from the manufacturer; however, the clinical study report was received too late to be included in the analyses.

Table 2 presents mapping of studies to relevant interventions and comparators.

TABLE 2. Mapping of identified studies.

TABLE 2

Mapping of identified studies.

The assessment of effectiveness of the technologies is reported below in six sections, one for each of the technologies and one for TNF inhibitors as a class (see Effectiveness of the technologies compared with supportive care). Studies directly comparing the technologies and ICs are reported in Evidence from comparative studies and Indirect comparisons sections respectively.

Effectiveness of the technologies compared with supportive care

This section describes evidence relating to each of the technologies compared with supportive care, which includes treatments received by the placebo group in placebo-controlled trials and ongoing conventional DMARDs or biologics to which the patients had had inadequate response. Owing to the paucity of evidence from controlled studies for TNF inhibitors, evidence from uncontrolled studies (i.e. single-group before-and-after studies) is also considered in this section.

Adalimumab

Overview of evidence

Five studies in six publications9297 met the inclusion criteria. No RCT was found. Four studies had comparator arms in which the patients were TNF inhibitor naive.9294,96 These arms were excluded here. One of the four studies93 also had a small comparator arm of nine patients, which did not meet the inclusion criteria of this report of greater than or equal to 20 patients for an arm to be included; thus, data from this arm were excluded.

One multicentre study was conducted in 12 countries, 11 of which were European, including the UK. Other studies were conducted in the UK, Sweden and Greece. It was unclear in which country one of the studies was conducted.

Sample sizes were small, ranging from 24 to 41 patients, that are relevant to the review in four studies; in one study there were 899 patients. Patients included all had previous treatment with either one or two TNF inhibitors, most frequently IFX. Reasons for switching TNF inhibitors were lack of efficacy only in one study,93 lack of efficacy or intolerance in two studies96,97 and lack of efficacy or AEs in two studies.92,94 Details on ADA treatment were not reported in one study; in all the other studies ADA was given 40 mg subcutaneously every other week. Study duration ranged from 12 weeks to over 1 year. Further details are outlined in Table 3.

TABLE 3. Adalimumab: characteristics of included studies.

TABLE 3

Adalimumab: characteristics of included studies.

Patient characteristics

Data on patient characteristics can be found in Table 4. Characteristics of the patients included in the five studies varied in some aspects:

TABLE 4. Adalimumab: baseline patient characteristics.

TABLE 4

Adalimumab: baseline patient characteristics.

  • Where reported 81%–92% were female.
  • The mean age of the patients ranged from 50 to 57 years.
  • The mean RA duration ranged from 11.6 to 16.6 years, but was not reported in two studies.
  • The percentage of RF-positive patients was reported only in two studies (63% and 72%).
  • Concomitant DMARDs: where reported 37%–85% patients were on MTX other DMARDs included CyA (4%), leflunonide (3%–13%), HCQ (3%) and AZA (1%).
  • The percentage of patients on concurrent steroids was reported in two studies and ranged from 77% to 100%.
  • Where reported the mean number of previous DMARDs used ranged from 2 to 5.
  • The mean number of previous TNF inhibitors was greater than or equal to 1 in the biggest study, and it was exactly 1 in all the other studies.
  • The HAQ scores ranged from 1.29 to 2.07 in four studies, but were not reported in one study.
  • The mean DAS28 scores were very similar, ranging from 5.5 to 6.3.
  • The mean number of tender and swollen joints at baseline was reported in three studies and ranged from 6 to 15 and from 8 to 11, respectively.
  • Baseline ESR was reported in only one study (41.7 mm/hour) and CRP in only two studies (25.1 mg/dl and 43.9 mg/dl).

Quality assessment

The studies were all uncontrolled; four of them were prospective and one was retrospective.93 Criteria for patient inclusion were clearly stated in four studies; however, in three of these it was unclear whether consecutive patients were included. The highest percentage of patients withdrawn from a study was 26.8%. There were no withdrawals from the retrospective study. In general, the higher withdrawal rates occurred with the longer follow-up durations. Further details on the quality assessment of the studies are given in Table 5.

TABLE 5. Adalimumab: non-RCT quality assessment.

TABLE 5

Adalimumab: non-RCT quality assessment.

Results

Tables 6 and 7 show what outcomes were measured in each study. Outcomes in Table 6 are reported and discussed in the main text of this report and those in Table 7 are reported in Appendix 10 only.

TABLE 6. Adalimumab: outcomes assessed in studies and reported in the main text of the report.

TABLE 6

Adalimumab: outcomes assessed in studies and reported in the main text of the report.

TABLE 7. Adalimumab: outcomes assessed in studies and reported in Appendix 10 only.

TABLE 7

Adalimumab: outcomes assessed in studies and reported in Appendix 10 only.

Withdrawals

Withdrawal rates are presented in Figure 1. At 3 months, the percentage of patients withdrawn was very similar in the two studies that reported this outcome (9.9% and 9.8%). No patients withdrew in a retrospective study during 6 months. Withdrawal rates reported at 1 year were 12.5% and 26.8% in the two studies that reported this outcome. The percentage of patients withdrawn owing to lack of efficacy and owing to AEs at 3 months was reported only in the biggest study and was 2.9% and 5.6%, respectively. The percentage of patients withdrawn owing to lack of efficacy and owing to AEs at 12 months was measured in two studies: 8.3% and 17.1% withdrew because of lack of efficacy and 8.3% and 14.6% withdrew because of AEs.

FIGURE 1. Adalimumab: withdrawals from studies by reason.

FIGURE 1

Adalimumab: withdrawals from studies by reason. LCI, lower confidence interval; UCI, upper confidence interval.

One study92 reported withdrawal data based on all 70 patients, including 44 patients who received a prior TNF inhibitor as well as TNF inhibitor-naive patients; the withdrawal data were not included in this report.

ACR20 response

The ACR20 response was assessed in four studies (Figure 2). Two studies assessed it at 3 months and the response was achieved by around half of the patients (46% and 60%). In the other two studies, the percentage of patients who achieved ACR20 response was 70% at 6 months and 75% at 12 months.

FIGURE 2. Adalimumab: ACR (20, 50, 70) responses.

FIGURE 2

Adalimumab: ACR (20, 50, 70) responses. LCI, lower confidence interval; UCI, upper confidence interval.

ACR50 response

The ACR50 response was measured in three studies (Figure 2): 26.8%–33% of patients achieved ACR50 response at 3 months. When measured at 12 months in the other study, half of the patients achieved this response.

ACR70 response

The ACR70 response was measured in three studies (Figure 2). ACR70 response at 3 months was similar in two studies that measured this outcome (13% and 12%). ACR70 response at 12 months was reported in one study, with 33% of the patients achieving this response.

A similar pattern was seen for ACR20, ACR50 and ACR70, with a relatively higher percentage of patients achieving a response with longer duration of treatment.

DAS28

One study measured DAS28 at 3 and 6 months and another study at 12 months; the mean scores were 4.5, 4.2 and 3.2, respectively. See Figure 3 for details. The mean changes from baseline to 3 months and to 6 months [note: in the Bennett et al. study92 it was measured after mean treatment duration of 8.5 (range 1–19) months], were reported in four studies including the biggest study. They all showed that treatment with ADA significantly improved DAS28 scores (mean changes ranged from −1.30 to −1.90). See Figure 4 for details.

FIGURE 3. Adalimumab: DAS28 scores.

FIGURE 3

Adalimumab: DAS28 scores. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

FIGURE 4. Adalimumab: mean changes in DAS28 scores.

FIGURE 4

Adalimumab: mean changes in DAS28 scores. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

EULAR response

Two studies reported EULAR response at 3 months; most of the patients had a good/moderate response (76% and 78%) and 17%–23% had a good response. The Bennett et al. study92 measured EULAR response after a mean treatment duration of 8.5 months (range 1–19 months); the response rate was 65%, of whom 46% had a moderate response and 19% had a good response. See Figure 5 for details.

FIGURE 5. Adalimumab: EULAR response.

FIGURE 5

Adalimumab: EULAR response. (a) Nikas et al. only reported ‘EULAR response’ without providing further detail. LCI, lower confidence interval; UCI, upper confidence interval.

Health Assessment Questionnaire

Mean change in HAQ score was reported in three studies. Figure 6 shows that the mean HAQ score measured at 3 months in two studies, including the biggest study, and at mean 8.5 months (range 1–19 months) in the Bennett et al. study92 in all cases showed a significant decrease, ranging from −0.21 to −0.48, with the largest improvement observed in the biggest study.

FIGURE 6. Adalimumab: mean change in HAQ scores.

FIGURE 6

Adalimumab: mean change in HAQ scores. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

Joint damage

None of the studies reported this outcome measure.

Quality of life

None of the studies reported this outcome measure.

Serious adverse events

One study (the largest) reported that 18% of the patients experienced serious AEs and 13% withdrew because of AEs; none of these was lupus related or a demyelinating disorder.96,97

Any infections/serious infections

The largest study reported that the serious infection rate was 10.0/100 patient-years. The prevalence of TB infection was 0.4/100 patient-years in this study. In another study97 one patient developed pulmonary TB at 11 months. In the latter study, serious infection with cellulitis was also reported in one patient. One patient in a 12-month study by Nikas et al.94 had to stop the study because of herpes zoster infection; it was not reported at which time point the treatment was stopped.

Injection site reaction/infusion reaction

The largest study stated that none of the patients experienced a serious anaphylactic response during the study period of 3 months. In a 12-month study,94 one patient had to stop the study because of an immediate hypersensitivity reaction; it was not reported at which time point it was stopped.

Summary

Five uncontrolled studies were identified for the assessment of effectiveness of ADA in comparison with standard care. Follow-up duration ranged from 3 months to over 1 year. All patients included in the studies were generally similar. The main results are summarised in Table 8.

TABLE 8. Adalimumab: summary of main results.

TABLE 8

Adalimumab: summary of main results.

Etanercept

Overview of evidence

No RCT was found. Seven uncontrolled observational studies98104 were identified that assessed efficacy of ETN.

In the studies by Buch et al.99 and Bingham et al.104 lack of efficacy was the primary reason for switching to ETN. In studies by Haraoui et al.,98 Cohen et al.100 and Buch et al.101 patients discontinued IFX owing to a lack of efficacy or safety. In Iannone et al.,102 patients had to have responded to prior IFX treatment but later switched to ETN due to side effects. The patient population in this study was therefore different from the other studies. In Laas et al.,103 patients discontinued IFX owing to a lack of efficacy, safety or non-medical reasons. The group of patients who discontinued IFX owing to non-medical reasons (46%, 23/49) had responded well to IFX, but switched to ETN for practical reasons such as convenience (e.g. no need for hospital visit to receive infusion). Two studies99,101 were carried out at the same centre (Leeds Teaching Hospitals) in the UK. These studies were described separately in this section although it is possible that patients included in Buch et al. 200599 were a subgroup of the cohort included in Buch et al. 2007.101 The other studies were carried out in France,100 Italy,102 Finland103 and the USA.98 One study104 was a multicentre study that enrolled patients from both the USA and Canada. The length of follow-up varied from 12 weeks to more than 9 months. Further details are provided in Table 9.

TABLE 9. Etanercept: characteristics of included studies.

TABLE 9

Etanercept: characteristics of included studies.

Patient characteristics

Full details of patients' characteristics are reported in Table 10. The number of patients included in the studies varied from 24 to 201. Patient characteristics differed across the seven studies:

TABLE 10. Etanercept: baseline patient characteristics.

TABLE 10

Etanercept: baseline patient characteristics.

  • Where reported, the percentage of female patients ranged from 60% to 88%.
  • Where reported, the mean age ranged from 49 to 57 years.
  • Where reported, the mean disease duration ranged from 8.3 to 12.2 years.
  • Where reported, the percentage of RF-positive patients ranged from 44% to 75%.
  • Where reported concomitant DMARDs were: 88–99% MTX, other DMARDs included HCQ (9%) and sulfasalazine (5%).
  • Where reported, 40%–88% of patients were receiving corticosteroids.
  • Where reported, the mean/median number of previously used conventional DMARDs varied from 4.1 to 7.0.
  • All the studies included patients previously treated with IFX.
  • Where reported the mean baseline HAQ ranged from 0.90 to 2.16.
  • The mean baseline DAS28 score ranged from 5.6 to 6.6.
  • One study102 reported baseline DAS44 (mean value was 2.7).
  • Where reported, the mean number of tender and swollen joints was variable (tender: 10.0–17.8 and swollen: 8.6–14.3).
  • Baseline ESR was reported only in two studies (21 mm/hour and 30 mm/hour).
  • Where reported, CRP ranged from 0.6 (median) to 6.2 (mean) mg/dl.

The baseline values listed in Table 10 for Iannone et al.102 were measured 8 weeks before patients switched from IFX to ETN (while they were still responding to IFX) and thus the values may not be comparable with those from the other studies.

Quality assessment

All the seven studies were uncontrolled studies. Five were prospective98,99,101,103,104 and two were retrospective.100,102 Full details of the quality assessment are reported in Table 11. With the exception of Laas et al.,103 studies stated clearly their inclusion criteria. Only Buch et al. 200599 and Buch et al. 2007101 clearly stated that consecutive patients were included in the studies; this information was unclear in Bingham et al.104 and Haraoui et al.100 Only one study104 reported the percentage of patients lost to follow-up (0.5%).

TABLE 11. Etanercept: non-RCT quality assessment.

TABLE 11

Etanercept: non-RCT quality assessment.

Results

Table 12 and Table 13 show what outcomes were measured in each study. Outcomes in Table 12 are reported and discussed in the main text and in Table 13 are reported in Appendix 10 only.

TABLE 12. Etanercept: outcomes assessed in studies and reported in the main text of the report.

TABLE 12

Etanercept: outcomes assessed in studies and reported in the main text of the report.

TABLE 13. Etanercept: outcomes assessed in studies and reported in Appendix 10 only.

TABLE 13

Etanercept: outcomes assessed in studies and reported in Appendix 10 only.

Withdrawals

Five out of seven studies reported withdrawals and the reasons for withdrawing from treatment. The percentages and reasons for withdrawing from the study after commencing ETN are shown in Figure 7. The percentage of patients who withdrew for any reason ranged from as low as 6.5% (at 3 months) to as high as 58.3% (at 12 months). The percentage of patients who withdrew because of AEs and lack of efficacy ranged from 0% to 16.3% and from 0% to 29.2%, respectively.

FIGURE 7. Etanercept: withdrawals in the studies by reason.

FIGURE 7

Etanercept: withdrawals in the studies by reason. LCI, lower confidence interval; UCI, upper confidence interval.

ACR20 response

The ACR20 response was assessed in four studies (Figure 8). The percentage of patients treated with ETN after IFX failure that achieved ACR20 response after 3 months ranged from 37.5% to 72.0%.

FIGURE 8. ACR20: responses in patients receiving etanercept.

FIGURE 8

ACR20: responses in patients receiving etanercept. LCI, lower confidence interval; UCI, upper confidence interval.

ACR50 response

The ACR50 response was assessed in five studies, but results from Iannone et al.102 are not presented here, as explained above (Figure 9). The proportion of patients achieving a ACR50 response after 3 months ranged from 18.4% to 64.0%.

FIGURE 9. ACR50: responses in patients receiving etanercept.

FIGURE 9

ACR50: responses in patients receiving etanercept. LCI, lower confidence interval; UCI, upper confidence interval.

ACR70 response

The ACR70 response was assessed in five studies, but results from Iannone et al.102 are not presented here, as explained above (Figure 10). The proportion of patients achieving a ACR70 response after 3 months ranged from 4.2% to 20.0%.

FIGURE 10. ACR70: responses in patients receiving etanercept.

FIGURE 10

ACR70: responses in patients receiving etanercept. LCI, lower confidence interval; UCI, upper confidence interval.

DAS

Figure 11 presents the mean changes from baseline in DAS. Four studies100,101,103,104 reported using DAS28. The mean decrease in DAS28 ranged from 1.47 to 1.80 at 3 months. One study102 reported no statistically significant decrease in DAS28 score from baseline at 12 months [mean change = −0.47, 95% confidence interval (CI) −1.06 to 0.12]. One study102 reported DAS calculated based on 44 joints (DAS44). Iannone et al.102 found no statistically significant differences in DAS44 scores when results for 16 and 24 weeks were compared with the baseline value.

FIGURE 11. Etanercept: mean changes from baseline in DAS.

FIGURE 11

Etanercept: mean changes from baseline in DAS. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

EULAR response

Three studies reported EULAR responses. Figure 12 shows the proportion of patients treated with ETN who achieved a good and good-to-moderate EULAR response after IFX failure. The percentage of patients who achieved a good score EULAR ranged from 12.5% to 45.8% at 3 months. The percentage of patients who achieved a good-to-moderate EULAR response ranged from 58.2% to 61.1% at 3 months.

FIGURE 12. Etanercept: EULAR.

FIGURE 12

Etanercept: EULAR. LCI, lower confidence interval; UCI, upper confidence interval.

Health Assessment Questionnaire

Three studies reported mean changes from baseline in HAQ score (Figure 13). In Haraoui et al.,98 the change in HAQ score was −0.45. However, it was not reported whether this change was statistically significant. For Iannone et al.,102 the value of HAQ remained largely unchanged at 16 weeks (0.90) and 24 weeks (0.75) compared with the baseline value (0.75). In Bingham et al.,104 there was a mean decrease in HAQ score of 0.35 at 3 months; this corresponds to a 22% decrease from baseline. This change was statistically significant.

FIGURE 13. Etanercept: mean change from baseline in HAQ.

FIGURE 13

Etanercept: mean change from baseline in HAQ. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

One study98 reported the percentage of patients who achieved minimal clinically important difference (MCID) in physical function (Figure 14). MCID was defined as a change of at least 0.22 in HAQ score. The percentage of patients who achieved MCID was 52%. Forty per cent of patients experienced an improvement in physical function of at least twice the value considered to represent MCID.

FIGURE 14. Etanercept: MCID physical function.

FIGURE 14

Etanercept: MCID physical function. LCI, lower confidence interval; UCI, upper confidence interval.

Quality of life

None of the studies assessed QoL.

Joint damage

None of the studies assessed joint damage.

Serious adverse events

Two studies reported serious AEs (Figure 15). Haraoui et al.98 reported that no serious AEs occurred during the study. Bingham et al.104 found that 5% of the patients experienced a serious AE during the study period.

FIGURE 15. Etanercept: reported serious AEs.

FIGURE 15

Etanercept: reported serious AEs. LCI, lower confidence interval; UCI, upper confidence interval.

Infection and serious infection

Three studies reported infection and serious infection (Figure 16). One study104 reported that two patients (1%) experienced serious infections. The percentage of patients treated with ETN who reported any infection ranged from 4.1% to 8.3%.

FIGURE 16. Etanercept: reported infection or serious infection.

FIGURE 16

Etanercept: reported infection or serious infection. LCI, lower confidence interval; UCI, upper confidence interval.

Injection/infusion reaction

No study reported injection or infusion reaction.

Summary

For the assessment of effectiveness of ETN, seven uncontrolled studies were identified. Follow-up duration ranged from 12 weeks to over 9 months. Patients included in the studies were generally similar. The main results are summarised in Table 14.

TABLE 14. Etanercept: summary of main results.

TABLE 14

Etanercept: summary of main results.

Infliximab

Overview of evidence

Three studies were identified that assessed IFX in comparison with standard care: one uncontrolled prospective study107 and two uncontrolled retrospective studies.105,106 (Note: the study by Yazici et al.107 had a control group consisting of patients who were given their first biologic drug. This control group was not relevant to this report and, therefore, the study was utilised as uncontrolled.)

All included patients had tried one TNF inhibitor (ETN) before. Reasons for discontinuation included lack of efficacy, toxicity drug shortage, patient concerns about safety and thrombocytopenia.

All studies were conducted in the USA. Duration of follow-up was unclear in all the three studies.

Further details are provided in Table 15.

TABLE 15. Infliximab: characteristics of included studies.

TABLE 15

Infliximab: characteristics of included studies.

Patient characteristics

All three studies were rather small, with the number of patients treated with IFX ranging from 20 to 24. They provided very little information about the baseline characteristics of included patients. However, based on the available information there might have been some baseline differences between study populations (Table 16).

TABLE 16. Infliximab: baseline patient characteristics.

TABLE 16

Infliximab: baseline patient characteristics.

  • In two studies the percentage of female participants ranged from 60% to 90%; Yazici et al.107 did not provide any information.
  • In two studies the mean age was 48 years and 61 years; it was not reported in Ang et al.105
  • In two studies disease duration was 9.3 years and 13.4 years; it was not reported in Ang et al.105
  • In two studies 34%–65% of patients were RF positive; no information was provided in Yazici et al.107
  • In Ang et al.105 62% of patients were receiving MTX and 31% LEF; in Hansen et al.106 all patients were receiving LEF and some of them also other DMARDs (AZA, sulfasalazine, MTX and prednisone); Yazici et al.107 did not report concomitant DMARDs.
  • Only one study (Hansen et al.106) reported that 75% of patients were receiving concomitant prednisone.
  • Two studies reported the number of previous DMARDs – it ranged from 0 to over 5; it was not reported in Hansen et al.106
  • Patients had tried one previous TNF inhibitor (ETN) in all three studies.
  • None of the studies reported the baseline HAQ or DAS score.
  • Only one study106 reported that patients had a mean of 14 tender and 14 swollen joints at baseline.
  • Only one study106 reported the baseline ESR (mean 13 mm/hour) and CRP (mean 23.8 mg/dl).

Quality assessment

Of the three identified studies, two were uncontrolled retrospective analyses. One study was uncontrolled and prospective. None of the studies reported inclusion criteria clearly. It was unclear if consecutive patients were included in Yazici et al.107 and this item was not applicable to retrospective studies. A total of 28.6% were withdrawn from Yazici et al.107 and this percentage was unclear in the remaining two studies. Details of the quality assessment are reported in Table 17.

TABLE 17. Infliximab: non-RCT quality assessment.

TABLE 17

Infliximab: non-RCT quality assessment.

Results

Table 18 indicates which of the outcomes reported in the main text of the report were assessed in individual studies and Table 19 provides similar information for outcomes described in Appendix 10 only.

TABLE 18. Infliximab: outcomes assessed in studies and reported in the main text of the report.

TABLE 18

Infliximab: outcomes assessed in studies and reported in the main text of the report.

TABLE 19. Infliximab: outcomes assessed in studies and reported in Appendix 10 only.

TABLE 19

Infliximab: outcomes assessed in studies and reported in Appendix 10 only.

Ang et al.105 reported results in a way that made it impossible to utilise them in this report (correlations between response to IFX and ETN).

Withdrawals

Withdrawal for any reason was assessed only in Yazici et al.,107 withdrawal because of lack of efficacy only in Hansen et al.106 and withdrawal because of AEs was not assessed in any of the studies. Details are reported in Figure 17. Yazici et al.107 reported that 28.6% of patients were withdrawn from the study for any reason (follow-up unclear). Ten per cent of patients were withdrawn from Hansen et al.106 owing to lack of efficacy (follow-up unclear).

FIGURE 17. Infliximab: withdrawals.

FIGURE 17

Infliximab: withdrawals. LCI, lower confidence interval; NR, not reported; UCI, upper confidence interval.

ACR20 response

None of the studies assessed ACR20 response.

ACR50 response

None of the studies assessed ACR50 response.

ACR70 response

None of the studies assessed ACR70 response.

DAS28

The only information on DAS28 change came from Yazici et al.107 and the authors claimed that at 12 months patients ‘improved significantly’.

EULAR response

The EULAR response was not assessed in any of the studies.

Health Assessment Questionnaire

The only information on HAQ change came from Yazici et al.107 and the authors claimed that at 12 months patients ‘improved significantly’.

Quality of life

Quality of life was not assessed in any of the studies.

Joint damage

Joint damage was not assessed in any of the studies.

Serious adverse events

Serious AEs were not assessed in any of the studies.

Infections/serious infections

Details of infections are reported in Figure 18. Fifteen percent of patients in Hansen et al.106 experienced an infection (follow-up was unclear). No other studies reported infections. Serious infections were not reported in any of the studies.

FIGURE 18. Infliximab: infections.

FIGURE 18

Infliximab: infections. LCI, lower confidence interval; NR, not reported; UCI, upper confidence interval.

Injection/infusion reaction

There were no infusion reactions in Hansen et al.106 Other studies did not report this outcome.

Infliximab in comparison with an ongoing biologic agent

One RCT [open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept (OPPOSITE133)] was identified that compared IFX with ongoing ETN. Although the study met the inclusion criteria of the systematic review, this comparison was not considered relevant to this report and, therefore, the study was not analysed.

It was a multicentre randomised trial and included 27 patients who had active RA and had an ‘incomplete response to etanercept’. Patients were randomised either to discontinue ETN and receive IFX (13 patients) or to continue ETN treatment (14 patients). The follow-up duration was 30 weeks. Data were collected on outcomes including ACR response, HAQ, radiological progression, serum biomarker levels and safety.

Summary

Three studies compared IFX with standard care: two uncontrolled retrospectiv105,106 and one uncontrolled prospective Yazici et al. studies.107 They included small numbers of patients ranging from 20 to 24. Follow-up was unclear in all of them. There was little information about baseline characteristics; however, it seems that there may be some, if small, differences between studies. The main results of included studies are summarised in Table 20.

TABLE 20. Infliximab: summary of main results.

TABLE 20

Infliximab: summary of main results.

Tumour necrosis factor inhibitors as a class

Overview of evidence

This section reports on studies that evaluated the use of TNF inhibitors as a class after the failure of the first one. No RCT was found. One controlled121123 and six uncontrolled observational studies108113 were identified. In Finckh et al.136,137 lack of efficacy was the primary reason for switching TNF inhibitors. In Hyrich et al.,121123 Gomez-Reino et al.108 and Blom et al.113 patients switched to another TNF inhibitor because of a lack of efficacy or AEs. In Hjardem et al.,110 Duftner et al.111 and Karlsson et al.112 patients switched TNF inhibitorsowing to lack of efficacy or AEs or for other reasons. The reason for changing from one TNF inhibitor to another was unclear in Solau-Gervais et al.109 Hyrich et al.121123 used data from the BSRBR. The other studies were carried out in Switzerland, Spain, France, Denmark, Austria, Sweden and the Netherlands. The length of follow-up ranged from 3 months to up to 4 years. Further details are provided in Table 21.

TABLE 21. Tumour necrosis factor inhibitors as class: characteristics of included studies.

TABLE 21

Tumour necrosis factor inhibitors as class: characteristics of included studies.

Patient characteristics

Full details of patients' characteristics are reported in Table 22. The number of patients included in the studies ranged from 70 to 818. Patient characteristics were generally similar across the eight studies:

TABLE 22. Tumour necrosis factor inhibitors as a class: baseline patient characteristics.

TABLE 22

Tumour necrosis factor inhibitors as a class: baseline patient characteristics.

  • The percentage of female patients ranged from 67% to 89%.
  • Where reported, the mean age ranged from 51 years to 58 years.
  • Where reported, the mean disease duration ranged from 8.0 years to 14.7 years.
  • Where reported, the percentage of RF-positive patients ranged from 51.5% to 81%.
  • Where reported, 61%–75% patients were on MTX; 55%–68% of patients were receiving corticosteroids.
  • Where reported, the mean number of previously used conventional DMARDs varied from 4.0 to 4.7.
  • Where reported, studies included patients who previously tried IFX, ETN and ADA.
  • Where reported, the mean baseline HAQ ranged from 1.4 to 1.9.
  • Where reported, the mean DAS28 score ranged from 4.1 to 6.5.
  • The mean number of tender and swollen joints was reported only in one study (tender 9.3 and swollen 8.4).
  • The mean baseline ESR was reported in one study and was 36 mm/hour.
  • The baseline CRP was reported in one study and was 2.8 mg/dl.

Quality assessment

One study was controlled.121123 Two studies108,109 were uncontrolled and prospective. Four studies were uncontrolled and retrospective.110113 Finckh et al.136,138 was a non-randomised comparative study (TNF inhibitors vs RTX). This section presents data only for TNF inhibitors. Full details of the quality assessment are reported in Table 23. Most studies stated clearly their inclusion criteria. The inclusion criteria were unclear in two studies.108,110 It was unclear in most studies whether consecutive patients were included in the study. Nearly one-third (140/477) of patients who met the study inclusion criteria were excluded from Karlsson et al.112 because of dropouts/missing response data at 3 months. The exclusion of these patients may partly account for the higher rates of EULAR responses observed in this study compared with other studies (see Figure 25). The percentage of patients withdrawn was clearly reported in two studies.

TABLE 23. Tumour necrosis factor inhibitors as class: non-RCT quality assessment.

TABLE 23

Tumour necrosis factor inhibitors as class: non-RCT quality assessment.

FIGURE 25. TNF inhibitors as a class: EULAR response rates.

FIGURE 25

TNF inhibitors as a class: EULAR response rates. LCI, lower confidence interval; UCI, upper confidence interval.

Results

Tables 24 and 25 state which outcomes were measured in each study and whether they are reported in the main text or Appendix 10 of this report.

TABLE 24. Tumour necrosis factor inhibitors as class: outcomes assessed in studies and reported in the main text of the report.

TABLE 24

Tumour necrosis factor inhibitors as class: outcomes assessed in studies and reported in the main text of the report.

TABLE 25. Tumour necrosis factor inhibitors as class: outcomes assessed in studies and reported in the Appendix 10 only.

TABLE 25

Tumour necrosis factor inhibitors as class: outcomes assessed in studies and reported in the Appendix 10 only.

Withdrawals

Two studies reported withdrawals together with reasons for withdrawing treatment (Figure 19). The percentage of patients who withdrew for any reason ranged from 7.6% (at 3 months) to 38.6% (at 12 months). The percentage of patients who withdrew because of AEs ranged from 6.1% (at 3 months) to 10.2% (at 6 months). At 12 months, the percentage of patients who withdrew because of AEs ranged from 6.0% to 14.7%. The percentage of patients who withdrew because of lack of efficacy ranged from 1.5% (at 3 months) to 22.6% (at 12 months).

FIGURE 19. Tumour necrosis factor inhibitor as a class: withdrawals from the studies by reason.

FIGURE 19

Tumour necrosis factor inhibitor as a class: withdrawals from the studies by reason. LCI, lower confidence interval; UCI, upper confidence interval.

One study reported 1-year drug survival108 (probability of staying on treatment at 12 months) of 0.79 (95% CI 0.74 to 0.83). Two studies reported median drug survival.110,111 Hjardem et al.110 and Duftner et al.111 reported that the median drug survival was 37 weeks and 8.0 months (range 0–43.7 months), respectively.

ACR20 response

The ACR20 response was assessed in one study (Figure 20). Karlsson et al.112 reported that at 3 months ACR20 response rate was 49.0% (95% CI 43.5% to 54.4%).

FIGURE 20. TNF inhibitors as a class: ACR20 response.

FIGURE 20

TNF inhibitors as a class: ACR20 response. LCI, lower confidence interval; UCI, upper confidence interval.

ACR50 response

The ACR50 response was assessed in one study (Figure 21). Karlsson et al.112 reported that at 3 months ACR50 response rate was 25.8% (95% CI 21.2% to 30.8%).

FIGURE 21. TNF inhibitors as a class: ACR 50 response.

FIGURE 21

TNF inhibitors as a class: ACR 50 response. LCI, lower confidence interval; UCI, upper confidence interval.

ACR70 response

The ACR70 response was assessed in one study (Figure 22). Karlsson et al.112 reported that at 3 months ACR70 response rate was 7.1% (95% CI 4.6% to 10.4%).

FIGURE 22. TNF inhibitor as a class: ACR70 response.

FIGURE 22

TNF inhibitor as a class: ACR70 response. LCI, lower confidence interval; UCI, upper confidence interval.

DAS28

Three studies reported mean changes from baseline in the DAS28 score (Figure 23). The mean decrease in DAS28 ranged from 0.86 to 1.00 at 3 months and from 0.88 to 0.92 at 6 months. Two studies112,113 reported low disease activity (DAS28 less than 3.2) (Figure 24). At 3 months the percentage of patients with low disease activity ranged from 14.2% to 29.1%. One study reported DAS28 remission (DAS28 less than 2.6) (Figure 24). Karlsson et al.112 reported that 15.4% (95% CI 11.7% to 19.7%) of patients were in remission.

FIGURE 23. TNF inhibitors as a class: mean changes from baseline in DAS28.

FIGURE 23

TNF inhibitors as a class: mean changes from baseline in DAS28. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

FIGURE 24. TNF inhibitors as a class: low disease activity (DAS28 < 3.2) and remission (DAS28 < 2.6).

FIGURE 24

TNF inhibitors as a class: low disease activity (DAS28 < 3.2) and remission (DAS28 < 2.6). LCI, lower confidence interval; UCI, upper confidence interval.

EULAR response

Three studies110,112,113 reported the percentage of patients who achieved good and good-to-moderate EULAR responses (Figure 25). The percentage of patients who achieved good EULAR response ranged from 8.6% to 22.8% at 3 months and was 9.1% at 6 months. The percentage of patients who achieved good-to-moderate EULAR response ranged from 31.5% to 64.7% at 3 months. Only one study reported good-to-moderate EULAR response at 6 months (32.5%).

Health Assessment Questionnaire

Only one study reported mean changes from baseline in HAQ score (Figure 26). Hyrich et al.121123 compared patients who discontinued TNF inhibitor within the first 12 months and did not start a subsequent TNF inhibitor or other biologic drug during the next 12 months (‘stoppers’) with patients who stopped their first TNF inhibitor within the first 12 months of therapy because of the lack of efficacy, but started a second TNF inhibitor during the subsequent 12 months (‘switchers’). The mean change in HAQ score was adjusted for differences in age, gender, disease duration, HAQ score at first failure, DAS28 at start of first TNF inhibitor and DAS28 score at first failure. ‘Switchers’ (adjusted mean change = −0.11, 95% CI −0.18 to −0.04) had significantly greater improvement in HAQ score than ‘stoppers’ (Figure 26).

FIGURE 26. TNF inhibitors as a class: adjusted mean change from baseline in HAQ score.

FIGURE 26

TNF inhibitors as a class: adjusted mean change from baseline in HAQ score. Adjusted for age, gender, disease duration, HAQ score at first failure, DAS28 at start of first TNF inhibitor and DAS28 score at first failure. LCI, lower confidence interval; (more...)

Quality of life

None of the studies reported QoL.

Joint damage

None of the studies reported joint damage.

Serious adverse events

Only one study reported serious AEs (Figure 27). Hjardem et al.110 reported that 6.0% (95% CI 3.3% to 9.8%) of the patients experienced a serious AE during the study period.

FIGURE 27. TNF inhibitors as a class: serious adverse events.

FIGURE 27

TNF inhibitors as a class: serious adverse events. LCI, lower confidence interval; UCI, upper confidence interval.

Infection and serious infection

Two studies reported infection and serious infection (Figure 28). At 3 months the percentage of patients who experienced infection ranged from 27.2% to 28.1%. One study111 reported that 13.9% (95% CI 9.1% to 19.9%) of the patients experienced serious infections at 3 months.

FIGURE 28. TNF inhibitors as a class: infections and serious infections.

FIGURE 28

TNF inhibitors as a class: infections and serious infections. LCI, lower confidence interval; UCI, upper confidence interval.

Injection/infusion reaction

None of the studies reported injection or infusion reactions.

Summary

For the assessment of effectiveness of TNF inhibitors as a class after failure of the first TNF inhibitor, one non-randomised comparative and seven uncontrolled studies were identified. Follow-up duration ranged from 3 months to 4 years. Patients included in the studies were generally similar. The main results are summarised in Table 26.

TABLE 26. TNF inhibitors as a class: summary of main results.

TABLE 26

TNF inhibitors as a class: summary of main results.

Rituximab

Overview of evidence

Seven studies were identified that assessed RTX: one RCT [randomised evaluation of long-term efficacy of rituximab in rheumatoid arthritis (REFLEX)124126] and six uncontrolled studies.114118,137,139 One of these (Finckh et al.136,137) contained a comparative arm with an alternative TNF inhibitor; the comparative data are described in the section Evidence from comparative studies. One study116 included data from patients of whom nearly half were previously TNF inhibitor naive. Only data reported separately for those who had a previous TNF inhibitor were included in this report. In another study,118 at 6 months, 17 patients (including five who were TNF inhibitor naive at original baseline) started a second course of TNF inhibitor; data for this group of patients were excluded from the report.

Data from one cohort analysis of the REFLEX RCT extension139 and one pooled analysis of all RTX development studies from the MS are also described. The REFLEX extension139 was a long-term follow-up analysis of repeated treatment data of the original RCT: it included patients who had responded to an initial course of RTX during the RCT and received open-label treatment with the same RTX regimen for up to three repeat treatment courses. (Note: responding patients in the initial REFLEX RCT124126 after reaching the primary end point at week 24 requiring further courses of RTX treatment entered the open-extension study.) Patients from the placebo arm of the RCT were also included and received their first course of RTX within the extension study. A total of 480 patients from the RCT (308 from the RTX arm and 172 from the placebo arm) entered the extension phase.

The manufacturer's pooled analysis combined data from patients of the REFLEX RCT,124126 together with data from its open-label extension study, and from other studies in manufacturer's RTX development programme. (Note: data were pooled for patients who only received the expected licensed dose of RTX two × 1,000 mg plus MTX regimen for first and subsequent courses and who received prior TNF inhibitor therapy.) It is unclear how many patients from the REFLEX trial124126 were included in the pooled analysis.

The Keystone et al. uncontrolled study116 also reported data for up to two treatment courses; these data are presented with those from the REFLEX extension139 and the RTX pooled analysis.

The REFLEX trial was a multicentre RCT conducted in 114 counties in the USA, Europe, Canada and Israel. Of the six uncontrolled studies, one was conducted in Switzerland, one in the UK, one in Sweden, one in the Netherlands and one in France. For the studies included in the Keystone et al. analysis,116 and for those included in the manufacturer's pooled analysis, except the REFLEX trial,139 it is unclear in which country the studies were conducted.

Further details are provided in Table 27.

TABLE 27. Rituximab: characteristics of included studies.

TABLE 27

Rituximab: characteristics of included studies.

Patient characteristics

Data on patient baseline characteristics can be found in Table 28. Patient characteristics were not reported for the manufacturer's pooled analysis and were not reported separately for the patients who had previously received a TNF inhibitor in the Keystone et al. analysis.116

TABLE 28. Rituximab: baseline patient characteristics.

TABLE 28

Rituximab: baseline patient characteristics.

The number of patients included in the REFLEX RCT124126 was 517 and ranged from 20 to 155 in the six uncontrolled studies. Where reported, characteristics of the patients included in the studies varied in some aspects, but were generally similar:

  • The percentage of female patients ranged from 77% to 86%.
  • The mean age ranged from 52 to 58 years in four studies and the median age in two studies was 54–55 years.
  • The mean disease duration ranged from 10 to 15 years in four studies and the median age in two studies was 12–16 years.
  • The percentage of RF-positive patients ranged from 79% to 90% and was lowest in the REFELX study; one study and both analyses from the MS did not report this.
  • Concomitant DMARDs were reported in five studies: 30%–100% patients were on MTX; all the patients in the REFLEX RCT124126 were on concomitant DMARDs.
  • The proportion of patients who were receiving concurrent steroids ranged from 55% to 100%; one study did not report this.
  • The mean number of previously used conventional DMARDs reported in three studies ranged from 2.5 to 4.2 and median reported in the other two ranged from 3 to 4.
  • Where reported, the mean number of previous TNF inhibitors was 1 or greater than 1 and the median number reported in two uncontrolled studies was 2.
  • The mean baseline HAQ was reported only in the REFELX study was 1.9 and the median baseline HAQ reported in two uncontrolled studies ranged from 1.6 to 2.6.
  • Where reported, the mean DAS28 score ranged from 5.0 to 6.9 and it was the highest in the REFELX study.
  • The mean number of tender joints was 34 and swollen joints was 23 in the REFLEX trial; 124126 the median number was 26 and 13 respectively in Jois et al.;115 other studies did not report the baseline number of tender and swollen joints.
  • The baseline mean ESR was 48 mm/hour in REFLEX124126 and the median value 37 mm/hour and 56 mm/hour in other two studies.
  • The mean CRP was 3.7 mg/dl in the REFELEX trial and 3.2 mg/dl in another study; median CRP was 1.9 and 2.9 in the other two studies.

Quality assessment

Randomised controlled trial

The only RCT (REFLEX124126) was of good quality. Full details of the quality assessment are reported in Table 29. Randomisation was appropriate and allocation concealment was not described in the paper. Patients and outcome assessors were blinded. It was not clear if data analysts were aware to which group patients were assigned. Withdrawal rate from the RTX group and the placebo group was 18% and 46%, respectively, at week 24, and 63% and 89%, respectively, at week 48. ITT analysis was not used, as 21 patients were excluded from analysis owing to protocol violations.

TABLE 29. Rituximab: RCT quality assessment.

TABLE 29

Rituximab: RCT quality assessment.

Non-randomised controlled trials

All the non-RCTs were uncontrolled; four of these were prospective and two were retrospective. Full details of the quality assessment are reported in Table 30. All stated clearly their inclusion criteria; however, only in one study was it clear that consecutive patients were included. The percentage of patients withdrawn reported in one study was 25% (at 6 months), the percentage was unclear in two studies and was not applicable in two retrospective studies as only patients with follow-up assessment were included.

TABLE 30. Rituximab: non-RCT quality assessment.

TABLE 30

Rituximab: non-RCT quality assessment.

REFLEX extension and rituximab pooled analyses

Although some inclusion criteria were stated, in both analyses information on the study characteristics, patient characteristics and methodological appropriateness was insufficient, in particular in the pooled analysis. Details of the quality assessment are reported in Table 30.

Results

Tables 31 and 32 present what outcomes were measured in the studies. Outcomes in Table 31 are reported and described in the main text of this report and those in Table 32 are reported in Appendix 10 only. Outcome data from the RTX arm in the RCT are also included in the section on uncontrolled studies for comparison purposes. As data from the REFLEX extension cohort139 and the RTX pooled analyses were analysed according to RTX treatment courses, the results of these analyses are described separately from the results of the uncontrolled studies.

TABLE 31. Rituximab: outcomes assessed in studies and reported in the main text of the report.

TABLE 31

Rituximab: outcomes assessed in studies and reported in the main text of the report.

TABLE 32. Rituximab: outcomes assessed in studies and reported in the Appendix 10 only.

TABLE 32

Rituximab: outcomes assessed in studies and reported in the Appendix 10 only.

Withdrawals

Randomised controlled trial Withdrawal rates are presented in Figure 29. At week 24, there were significantly fewer withdrawals for any reason in the RTX arm than in the placebo arm of the REFLEX RCT124126 (RR = 0.39, 95% CI 0.29 to 0.51). Risk of withdrawal because of AEs tended to be higher in the RTX than in the placebo group; however, the difference was not statistically significant (RR = 2.71, 95% CI 0.58 to 12.65).

FIGURE 29. Rituximab: withdrawals in the REFLEX RCT at 24 weeks by reason.

FIGURE 29

Rituximab: withdrawals in the REFLEX RCT at 24 weeks by reason.

Non-randomised controlled trials Withdrawal rate for any reason at 6 months was reported in only one uncontrolled study115 and it was 10%. For comparison, 17.9% of patients in the RTX arm in the REFLEX RCT124126 withdrew at 6 months for any reason and 2.6% withdrew because of AEs (Figure 30). In one study114 the total number of patients withdrawn by reason was not reported, but it was stated that one patient discontinued RTX treatment after a second infusion (week 4) because of severe headache and stomach pain. Two patients who had a medical history of chronic myocardial ischaemia died of myocardial infarction, one within the first month and the other at 13 months.

FIGURE 30. Rituximab: withdrawals in uncontrolled studies by reason.

FIGURE 30

Rituximab: withdrawals in uncontrolled studies by reason. LCI, lower confidence interval; UCI, upper confidence interval.

ACR20

Randomised controlled trial In the REFLEX trial,124126 the percentage of patients who achieved ACR20 response at week 24 in the RTX group was nearly three times that in the placebo group and the difference was statistically significant (RR = 2.85, 95% CI 2.08 to 3.91). At week 48, the response rate based on observed data (of a smaller number of patients) favoured the RTX group, but the difference was not significant (RR = 1.53, 9% CI 0.84 to 2.76); when analysed based on non-responder imputation data, the response rate in the RTX group was nearly five times of that in the placebo group and the difference was significant (RR = 4.92, 95% CI 2.40 to 10.09). Details can be found in Figure 31.

FIGURE 31. Rituximab: ACR20 response in the REFLEX study (observed data and non-responder imputation data are from MS).

FIGURE 31

Rituximab: ACR20 response in the REFLEX study (observed data and non-responder imputation data are from MS).

Non-randomised controlled trials In the Keystone et al.116 pooled analysis, 24 weeks after the first course of RTX, 65.2% patients had an ACR20 response, while in the RTX arm of the REFLEX trial124126 the figure was 51% (Figure 32). None of the other uncontrolled studies reported ACR20 responses.

FIGURE 32. Rituximab: ACR20 response in cohorts 24 weeks after first course of RTX.

FIGURE 32

Rituximab: ACR20 response in cohorts 24 weeks after first course of RTX. LCI, lower confidence interval; UCI, upper confidence interval.

ACR50

Randomised controlled trial At week 24 in the REFLEX trial,124126 the percentage of ACR50 responders in the RTX group was nearly five and a half times that of the placebo group and the difference was statistically significant (RR = 5.40, 95% CI 2.87 to 10.16). The effect persisted at week 48, analysed based on either observed data (RR = 4.11, 95% CI 1.06 to 15.85) or non-responder imputation data, and based on non-responder imputation data the response rate in the RTX group was over 13 times that of the placebo group (RR = 13.23, 95% CI 3.23 to 54.20). Details are presented in Figure 33.

FIGURE 33. Rituximab: ACR50 response in the REFLEX study (the observed data and non-responder imputation data were from MS).

FIGURE 33

Rituximab: ACR50 response in the REFLEX study (the observed data and non-responder imputation data were from MS).

Non-randomised controlled trials In the Keystone et al.116 pooled analysis, 24 weeks after the first course of RTX, ACR50 response was observed in 32.9% patients, while in the RTX arm of the REFLEX trial124126 it was 26.8% (Figure 34). None of the other uncontrolled studies reported ACR50 response.

FIGURE 34. Rituximab: ACR50 response in uncontrolled studies 24 weeks after the first course of RTX.

FIGURE 34

Rituximab: ACR50 response in uncontrolled studies 24 weeks after the first course of RTX. LCI, lower confidence interval; UCI, upper confidence interval.

ACR70

Randomised controlled trial At week 24 the percentage of patients achieving ACR70 response in the RTX group in the REFLEX trial124126 was over 12 times of that of the placebo group and the difference was statistically significant (RR = 12.14, 95% CI 2.96 to 49.86). At week 48 the beneficial effect of RTX was not significant based on observed data for a much smaller patient group (RR = 3.37, 95% CI 0.47 to 24.2), but was significant based on non-responder imputation data (RR = 10.86, 95% CI 1.45 to 81.24). See Figure 35 for details.

FIGURE 35. Rituximab: ACR70 response in the REFLEX study (those based on observed data and non-responder imputation data were from manufacturer's submission).

FIGURE 35

Rituximab: ACR70 response in the REFLEX study (those based on observed data and non-responder imputation data were from manufacturer's submission).

Non-randomised controlled trials In the Keystone et al. pooled analysis the percentage of ACR70 responders 24 weeks after the first course of RTX was 12.3%; it was similar to that reported in the RTX arm of the REFLEX trial124126 (12.1%) (Figure 36). No other uncontrolled study reported ACR70 responses.

FIGURE 36. Rituximab: ACR70 response in uncontrolled studies 24 weeks after the first course of RTX.

FIGURE 36

Rituximab: ACR70 response in uncontrolled studies 24 weeks after the first course of RTX.

EULAR response

Randomised controlled trial EULAR responses are presented in Figures 37 and 38. In the REFLEX trial,124126 at week 12 the percentage of patients achieving good or moderate response in the RTX group was over twice that of the placebo group, as was the percentage achieving a good response; the effects were statistically significant (RR = 2.02, 95% CI 1.64 to 2.49 and RR = 2.23, 95% CI 1.12 to 4.41, respectively). At week 24 the percentage of patients achieving a EULAR good or moderate response in the RTX group was nearly three times that of the placebo group and the effect was significant (RR = 2.96, 95% CI 2.25 to 3.89); the rate of achieving a good response was also higher in the RTX group and the difference was statistically significant (RR = 7.59, 95% CI 2.77 to 20.77).

FIGURE 37. Rituximab: EULAR response at week 12 in the REFLEX study (data from the manufacturer's submission).

FIGURE 37

Rituximab: EULAR response at week 12 in the REFLEX study (data from the manufacturer's submission).

FIGURE 38. Rituximab: EULAR response at week 24 in the REFLEX study.

FIGURE 38

Rituximab: EULAR response at week 24 in the REFLEX study.

Non-randomised controlled trials None of the uncontrolled studies reported EULAR response at 3 months, whereas three reported it at 6 months. At 3 months in the RTX arm of the REFLEX RCT,124126 68.5% of patients had moderate or good response, with 11.1% having achieved a good response; at 6 months the rates remained similar (64.8% and 15.1%, respectively). At 6 months the percentage of good or moderate EULAR responders in four uncontrolled studies including the RTX arm of the REFLEX trial124126 ranged from 64.8% to 82%, and the good response rate ranged from 15.1% to 36%. The REFLEX trial124126 had the lowest percentage of responders in both categories. One study also reported EULAR low disease activity and remission at 6 months (13.3% and 5.7%, respectively). See Figure 39 for details.

FIGURE 39. Rituximab: EULAR response in uncontrolled studies (3-month data for the REFLEX trial from MS).

FIGURE 39

Rituximab: EULAR response in uncontrolled studies (3-month data for the REFLEX trial from MS). LCI, lower confidence interval; UCI, upper confidence interval.

DAS28

Randomised controlled trial In the REFLEX trial,124126 at week 24, the RTX arm had a significantly smaller mean DAS28 score and significantly greater reduction in the mean DAS28 score from baseline than the placebo arm (−1.40, 95% CI −1.67 to −1.13, and − 1.50, 95% CI −1.74 to −1.26, respectively). At week 24, the proportion of patients with DAS28 improvement in the RTX group was over five times that in the placebo group and the difference was statistically significant. See Figures 4042 for details.

FIGURE 40. Rituximab: DAS28 score at week 24 in the REFLEX trial (last observation carried forward, data from MS).

FIGURE 40

Rituximab: DAS28 score at week 24 in the REFLEX trial (last observation carried forward, data from MS). SD, standard deviation.

FIGURE 41. Rituximab: DAS28 score change from baseline at week 24 in the REFLEX trial (last observation carried forward, data from MS).

FIGURE 41

Rituximab: DAS28 score change from baseline at week 24 in the REFLEX trial (last observation carried forward, data from MS). SD, standard deviation.

FIGURE 42. Rituximab: percentage of patients with DAS28 improvement from baseline at week 24 in the REFLEX trial (last observation carried forward, data from the MS).

FIGURE 42

Rituximab: percentage of patients with DAS28 improvement from baseline at week 24 in the REFLEX trial (last observation carried forward, data from the MS).

Non-randomised controlled trials DAS28 score at 3 months was available in only one uncontrolled study (median DAS28 = 5.60). DAS28 score at 6 months was measured in three studies. The mean score was 5.0 in one study and it was the same as that of the RTX arm of the REFLEX trial.124126 Two studies provided a median score and it was 5.50 and 3.97. See Figure 43 for details. (Note: for the Jois et al.115 and Assous et al.117 studies scores were reported as medians.)

FIGURE 43. Rituximab: mean DAS28 in uncontrolled studies.

FIGURE 43

Rituximab: mean DAS28 in uncontrolled studies. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

In Finckh et al.136 the change in mean DAS28 score from baseline at 6 months was reported only for a subgroup of 50 patients. It was similar to that reported for the RTX arm of the REFLEX trial124126 and both showed significant improvement (−1.90, 95% CI −2.08 to −1.72, and −1.61, 95% CI −1.98 to −1.24, respectively). See Figure 44 for details.

FIGURE 44. Rituximab: DAS28 scores change from baseline in uncontrolled studies (data for REFLEX from MS).

FIGURE 44

Rituximab: DAS28 scores change from baseline in uncontrolled studies (data for REFLEX from MS). LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

Health Assessment Questionnaire

Randomised controlled trial In the REFLEX trial,124126 the RTX group had significantly more reduction in mean HAQ score from baseline at week 24 compared with the placebo group (mean difference = −0.30, 95% CI −0.40 to −0.20; Figure 45).

FIGURE 45. Rituximab: mean change in HAQ scores from baseline at week 24 in REFLEX trial.

FIGURE 45

Rituximab: mean change in HAQ scores from baseline at week 24 in REFLEX trial. SD, standard deviation.

The percentage of patients who showed HAQ improvement, defined as a decrease in score from baseline of greater than 0.25, in the RTX group of the REFLEX trial124126 was nearly twice that of the placebo group at week 12, and over two and a half times as high at week 24; both effects were statistically significant (RR = 1.63, 95% CI 1.29 to 2.07, and RR = 2.55, 95% CI 1.89 to 3.43, respectively). See Figure 46 for details.

FIGURE 46. Rituximab: percentage of patients with a decrease in HAQ score > 0.25 from baseline in the REFLEX study (data from MS).

FIGURE 46

Rituximab: percentage of patients with a decrease in HAQ score > 0.25 from baseline in the REFLEX study (data from MS).

At week 24, the observed percentage of patients with minimal clinically meaningful improvement in HAQ, defined as a decrease in HAQ score of 0.22, in the RTX group of the REFLEX trial,124126 was over 1.6 times that of the placebo groups and the difference was significant; whereas observed at week 48 there was no significant difference (Figure 47).

FIGURE 47. Rituximab: percentage of patients with a clinically meaningful improvement in HAQ, 24 and 48 weeks after the first course of RTX (observed data from MS).

FIGURE 47

Rituximab: percentage of patients with a clinically meaningful improvement in HAQ, 24 and 48 weeks after the first course of RTX (observed data from MS).

When analysed based on non-responder imputation data, the percentage of patients with minimal clinically meaningful improvement in HAQ at week 24 and week 48 in the RTX group was over two and a half and over three and a half times that of the placebo group (58% vs 23% and 23% vs 6%, respectively) and both differences were statistically significant (Figure 48).

FIGURE 48. Rituximab: percentage of patients with a clinically meaningful improvement in HAQ, 24 and 48 weeks after the first course of RTX (non-responder imputation data from MS).

FIGURE 48

Rituximab: percentage of patients with a clinically meaningful improvement in HAQ, 24 and 48 weeks after the first course of RTX (non-responder imputation data from MS).

Non-randomised controlled trials Two uncontrolled studies reported HAQ score. The median HAQ score in one study115 was 2.13 (range 0.63–2.88) at 3 months and decreased to 1.86 (range 1–3) at 6 months; however, in both cases, the reduction compared with baseline was not significant. In the Keystone et al. study,116 the percentage of patients with a decrease in the mean HAQ score of greater than or equal to 0.22 from baseline at week 24 (after one course of RTX treatment) was 71.8%, which is very similar to the observed rate reported in the RTX arm of the REFLEX trial124126 (70.5%) (Figure 49).

FIGURE 49. Rituximab: percentage of patients with clinically meaningful improvement in HAQ score from baseline at week 24.

FIGURE 49

Rituximab: percentage of patients with clinically meaningful improvement in HAQ score from baseline at week 24. LCI, lower confidence interval; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

Joint damage

Randomised controlled trial The RTX group of the REFLEX trial124126 had significantly less changes in Sharp-Genant total score from baseline than the placebo group at both week 56 (mean difference = −1.12, 95% CI −2.13 to −0.11) and week 104 (mean difference = −1.67, 95% CI −2.67 to −0.67). At week 56 the percentage of patients with no worsening of Sharp-Genant total score from baseline in the RTX group was nearly one and a half times that in the placebo group and the difference was statistically significant. Sharp-Genant total score measured at week 104 favoured the RTX group but the difference was not statistically significant (mean difference = −3.53, 95% CI −9.21 to 2.15). See Appendix 10 for details.

There was significantly less change from baseline in the erosion score in the RTX group than in the placebo group at week 56 (mean difference = −0.75, 95% CI −1.43 to −0.07), and at week 104 the significant difference became larger (mean difference = −1.08, 95% CI −1.73 to −0.43). The erosion score at week 104 favoured the RTX arm, but the difference was not statistically significant (mean difference = −2.48, 95% CI–5.55 to 0.59). The percentage of patients with no erosive progression from baseline at week 104 in the RTX group was nearly one and a half times that of the placebo group and the difference was statistically significant (RR = 1.38, 95% CI 1.14 to 1.66).

Joint space narrowing score change from baseline was smaller in the RTX group than in the placebo group both at week 56 and week at 104; the difference was not statistically significant at week 56 but became significant at week 104, though at week 104 the joint space narrowing score was not significantly lower in the RTX group than in the placebo group.

Non-randomised controlled trials None of the uncontrolled studies reported joint damage.

Quality of life

Randomised controlled trial Mean Short Form questionnaire-36 items (SF-36) mental and physical health scores measured at week 24 in the REFLEX trial124126 were both significantly higher in the RTX group than in the placebo group (Figure 50). The RTX group increased mean SF-36 physical health score by 5.16 and mean SF-36 mental health score by 3.07 higher than in the placebo group, and the differences were statistically significant (Figure 51).

FIGURE 50. Rituximab: mean SF-36 items scores at week 24 in the REFLEX trial (last observation carried forward, data from MS).

FIGURE 50

Rituximab: mean SF-36 items scores at week 24 in the REFLEX trial (last observation carried forward, data from MS). SD, standard deviation.

FIGURE 51. Rituximab: change in SF-36 items scores from baseline to week 24 in REFLEX trial.

FIGURE 51

Rituximab: change in SF-36 items scores from baseline to week 24 in REFLEX trial. SD, standard deviation.

Non-randomised controlled trials None of the uncontrolled studies reported QoL.

Serious adverse events

Randomised controlled trial In the REFLEX trial,124126 the percentage of patients with serious AEs was lower in the RTX group than in the placebo group; the difference was not statistically significant (RR = 0.74, 95% CI 0.42 to 1.31). See Figure 52 for details.

FIGURE 52. Rituximab: serious AEs at week 24 in the REFLEX trial.

FIGURE 52

Rituximab: serious AEs at week 24 in the REFLEX trial.

Non-randomised controlled trials In one 12-month study,114 one patient (2%) had severe headache and stomach pain 1 day after RTX infusion and this led to a discontinuation of treatment. A 6-month study,115 stated that no major side effects were found during the study. During a 6-month period the Thurlings et al.118 study reported five serious AEs (16.7%): two severe infusion reactions, one arterial embolism, one pulmonary embolism and one toxic hepatitis. The other studies did not report information on serious AEs.

Any infection/serious infection

Randomised controlled trial In the REFLEX trial124126 both the percentage of patients with any infections and the percentage of patients with serious infections were greater in the RTX group than in the placebo group; however, none of the differences was statistically significant (RR = 1.08, 95% CI 0.87 to 1.35 and RR = 1.58, 95% CI 0.41 to 6.05, respectively). See Figure 53 for details.

FIGURE 53. Rituximab: any infection and serious infection at week 24 in the REFLEX trial.

FIGURE 53

Rituximab: any infection and serious infection at week 24 in the REFLEX trial.

Non-randomised controlled trials In the Bokarewa et al. study114 3 months after the treatment with RTX, pneumonia requiring hospitalisation was reported in one patient (2.0%). In Thurlings et al.118 the incidence of infection per patient-year was 0.9: 48 infections requiring antibiotic, antimycotic, or antiviral treatment and one serious infection requiring i.v. antibiotics occurred among 30 patients over 2 years of follow-up. One serious infection requiring i.v. antibiotics was observed in this study.

Injection site reaction/infusion reaction

Randomised controlled trial In the REFLEX trial,124126 the percentage of patients with acute infusion reactions did not differ significantly between groups (RR = 1.24, 95% CI 0.90 to 1.83, for the first course and RR = 0.74, 95% CI 0.43 to 1.24, for the second course). See Figure 54 for details.

FIGURE 54. Rituximab: percentage of patients who had acute infusion reactions after the first and second infusion.

FIGURE 54

Rituximab: percentage of patients who had acute infusion reactions after the first and second infusion.

Non-randomised controlled trials One study (Finckh et al.,137 subgroup of 50 patients) reported three mild-to-moderate infusion reactions. Another study118 reported two severe infusion reactions. The other studies did not report information on infusion site reactions.

Data reported by treatment course

Pooled analysis (data from Keystone et al.)

In the Keystone et al. study,116 based on evaluable data, the percentage of patients achieving ACR responses increased from course 1 to course 2 of RTX measured 24 weeks after each course (Figure 55). A similar pattern was seen for the percentage of patients with EULAR response 24 weeks after course 1 and course 2 (Figure 56).

FIGURE 55. Percentage of patients achieving ACR responses 24 weeks after course 1 and course 2 – based on evaluable patients who had prior TNF inhibitor.

FIGURE 55

Percentage of patients achieving ACR responses 24 weeks after course 1 and course 2 – based on evaluable patients who had prior TNF inhibitor. LCI, lower confidence interval; UCI, upper confidence interval.

FIGURE 56. Percentage of patients with EULAR responses 24 weeks after course 1 and course 2 – based on evaluable patients who had prior TNF inhibitor.

FIGURE 56

Percentage of patients with EULAR responses 24 weeks after course 1 and course 2 – based on evaluable patients who had prior TNF inhibitor. LCI, lower confidence interval; UCI, upper confidence interval.

The percentage of patients who achieved meaningful improvement in HAQ, i.e. had a decrease of HAQ scores at least 0.22 from baseline, were similar 24 weeks after course 1 and course 2 of RTX treatment (Figure 57).

FIGURE 57. Percentage of patients with a decrease in HAQ score of ≥ 0.22 at week 24 after course 1 and course 2 – based on evaluable patients who had prior TNF inhibitor.

FIGURE 57

Percentage of patients with a decrease in HAQ score of ≥ 0.22 at week 24 after course 1 and course 2 – based on evaluable patients who had prior TNF inhibitor. LCI, lower confidence interval; UCI, upper confidence interval.

Data from manufacturer's submission

Data analysis based on the MS can be found together with all additional analyses in Appendix 10.

Summary

For the assessment of effectiveness of RTX in comparison with standard care, one RCT and six uncontrolled studies were identified. Follow-up duration ranged from 3 months to 24 months. Patients included in the studies were generally similar. The main results of the seven studies are summarised in Table 33.

TABLE 33. Rituximab: summary of main results.

TABLE 33

Rituximab: summary of main results.

Abatacept

Overview of evidence

Three studies were identified that assessed ABT: one RCT [abatacept trial in treatment of anti-TNF inadequate responders (ATTAIN127132)], an extension of this RCT (ATTAIN LTE119) and an uncontrolled study [abatacept researched in rheumatoid arthritis patients with an inadequate anti-TNF response to validate effectiveness (ARRIVE)120].

Patients were included in the ATTAIN LTE119 after completing 6 months of the RCT. It was reported that in total 74.4% of the placebo group and 86.4% of the ABT group were included in the extension.

Patients in the studies were non-responders to at least one TNF inhibitor. In the ATTAIN RCT127132 and LTE119 lack of efficacy was the primary reason for switching biologic agents. In ARRIVE120 patients discontinued the previous TNF inhibitor because of lack of efficacy, safety concerns or intolerability.

All studies were carried out in North America and Europe. ARRIVE120 additionally included Mexican patients. No information was provided if these studies included UK patients. Follow-up was 6 months for the ATTAIN RCT127132 and ARRIVE study.120 In the ATTAIN LTE119 patients were followed up for up to 5 years; however, there was no published data beyond 2 years. Further details are provided in Table 34.

TABLE 34. Abatacept: characteristics of included studies.

TABLE 34

Abatacept: characteristics of included studies.

Patient characteristics

Full details of patient characteristics are reported in Table 35.

TABLE 35. Abatacept: baseline patient characteristics.

TABLE 35

Abatacept: baseline patient characteristics.

The number of patients included in the studies was 391 in the ATTAIN RCT,127132 317 in its LTE119 and 1,046 in the ARRIVE study.120 Patient characteristics were generally similar across studies and study arms:

  • The percentage of female patients ranged from 78% to 81%.
  • The mean age ranged from 53.0 to 54.4 years.
  • The mean disease duration ranged from 11.6 to 11.9 years.
  • In two studies the percentage of RF-positive patients ranged from 61.3% to 73.2%; it was not reported in the ATTAIN LTE.119
  • Concomitant DMARDs were reported in detail in ATTAIN127132 and ARRIVE:120 69.8%–77.7% patients were on MTX; other DMARDs included HCQ (8.9%–15.0%), LEF (8.7%–2.8%) and sulfasalazine (8.0%–8.8%). In the ARRIVE study,120 AZA (4.1%) and gold (0.5%) were also used.
  • In two studies 58.4%–68.3% of patients were receiving corticosteroids; this information was not reported in detail in the ATTAIN LTE.120
  • The number of previously used conventional DMARDs was not reported in any of the studies.
  • The number of previous TNF inhibitors ranged from one to two in the ATTAIN127132 and ATTAIN LTE119 studies and from one to three in the ARRIVE study.120
  • The mean baseline HAQ ranged from 1.7 to 1.8.
  • The mean DAS28 score ranged from 6.2 to 6.5.
  • The mean number of tender and swollen joints ranged from 17.8 to 31.8 and from 13.6 to 22.3, respectively.
  • Baseline ESR was not reported in any of the studies.
  • CRP ranged from 2.1 mg/dl to 4.4 mg/dl.

Quality assessment

Randomised controlled trial The only RCT (ATTAIN127132) was of high quality. Full details of the quality assessment are reported in Table 36. Randomisation and allocation concealment were appropriate. Patients and investigators/outcome assessors were blinded. It was not clear if data analysts knew to which group patients were assigned. A total of 13.6% of patients were withdrawn from the ABT group and 25.6% from the placebo group. ITT analysis was not used, as only data from patients who received at least one dose of the study drug were analysed. Two patients were excluded from analysis because of protocol violations, possibly post hoc. The potential impact on the results is likely to be small.

TABLE 36. Abatacept: RCT quality assessment.

TABLE 36

Abatacept: RCT quality assessment.

Non-randomised controlled trials Both non-randomised studies were uncontrolled and prospective. Full details of the quality assessment are reported in Table 37. Both studies stated clearly their inclusion criteria; however, it was not clear if consecutive patients were included in ARRIVE.120 The percentage of patients withdrawn from the study was 18% in the ARRIVE study120 at 6 months and 30% in the ATTAIN LTE119 at 2 years.

TABLE 37. Abatacept: non-RCT quality assessment.

TABLE 37

Abatacept: non-RCT quality assessment.

Results

The RCT and non-randomised studies were analysed separately. Data from the ABT arm of the ATTAIN RCT are included in all figures referring to uncontrolled studies for comparison.

Table 38 indicates which of the outcomes reported in the main text of the report were assessed in individual studies and Table 39 provides similar information for outcomes described in Appendix 10 only.

TABLE 38. Abatacept: outcomes assessed in studies and reported in the main text of the report.

TABLE 38

Abatacept: outcomes assessed in studies and reported in the main text of the report.

TABLE 39. Abatacept: outcomes assessed in studies and reported in Appendix 10 only.

TABLE 39

Abatacept: outcomes assessed in studies and reported in Appendix 10 only.

Withdrawals

Randomised controlled trial There were significantly fewer withdrawals for any reason in the ABT arm than in the placebo arm of the ATTAIN RCT127132 (RR = 0.53, 95% CI 0.35 to 0.81). There were also significantly fewer withdrawals in the ABT group because of lack of efficacy (RR = 0.27, 95% CI 0.15 to 0.49). The risk of withdrawal because of AEs was similar in both groups (RR = 0.93, 95% CI 0.32 to 2.71). Details of the analysis are presented in Figure 58.

FIGURE 58. Abatacept: withdrawals by reason in the ATTAIN RCT at 6 months.

FIGURE 58

Abatacept: withdrawals by reason in the ATTAIN RCT at 6 months.

Non-randomised control trials At 6 months 17.8% patients withdrew from the ARRIVE study.120 This percentage was slightly higher than in the ABT-treated arm of the RCT. At 2 years, 30% of patients had withdrawn from the ATTAIN LTE.119 In both studies, more patients withdrew because of lack of efficacy than because of AEs. A similar relationship was observed in the ABT arm of the RCT. Full details are presented in Figure 59.

FIGURE 59. Abatacept: withdrawals in uncontrolled studies by reason.

FIGURE 59

Abatacept: withdrawals in uncontrolled studies by reason. LCI, lower confidence interval; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

ACR20 response

Randomised control trial ATTAIN127132 reported ACR20 response at 3 and 6 months. At both follow-up times the risk of an ACR20 response was over two and a half times higher in the ABT group than in the placebo group and the difference was statistically significant (for 3 months, RR = 2.53, 95% CI 1.72 to 3.73; for 6 months, RR = 2.56, 95% CI 1.77 to 3.69). Details can be found in Figure 60.

FIGURE 60. Abatacept: ACR20 response in the ATTAIN RCT at 3 and 6 months.

FIGURE 60

Abatacept: ACR20 response in the ATTAIN RCT at 3 and 6 months.

Non-randomised control trials Of the uncontrolled studies, only the ATTAIN LTE119 reported ACR20 response. Results are reported by subgroup based on whether patients were originally randomised to ABT or placebo in the randomised phase (see Figure 61). After 6 months of ABT treatment, 57.3% patients in the group initially randomised to ABT and 63.6% in the group initially randomised to placebo achieved an ACR20 response. This was slightly more than in the ABT arm of the RCT (50.0%). After 6 months, there was a further increase in the percentage of ACR20 responders at 12 months in those initially randomised to ABT followed by a decrease up to 5 years (30.3%). Among those initially randomised to placebo, there was a decrease in the percentage of responders from 12 months onwards, and at 54 months 30.3% of patients were ACR20 responders.

FIGURE 61. Abatacept: ACR20 response in non-RCTs.

FIGURE 61

Abatacept: ACR20 response in non-RCTs. LCI, lower confidence interval; n/a, not available; PL, placebo; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

If only patients for whom data were available at different time points were analysed, the increase in percentage of ACR20 responders continued to 3 years (82.1%) and then decreased to 65.6% at 5 years for patients initially randomised to ABT. In the same analysis, among patients initially randomised to placebo there was an increase in the percentage of ACR20 responders up to 42 months (82.0%), and at 54 months 78.9% were ACR20 responders.

ACR50 response

Randomised controlled trial At 6 months the percentage of ACR50 responders was over five times higher in the ABT group than in the placebo group of the ATTAIN trial127132 and the difference was statistically significant (RR = 5.36, 95% CI 2.19 to 13.10). Details are presented in Figure 62.

FIGURE 62. Abatacept: ACR50 response in the ATTAIN RCT at 6 months.

FIGURE 62

Abatacept: ACR50 response in the ATTAIN RCT at 6 months.

Non-randomised contolled trials Of the uncontrolled studies, only the ATTAIN LTE119 reported ACR50 response. Results are reported by subgroup based on whether patients were originally randomised to ABT or placebo in the randomised phase (see Figure 63). This outcome was achieved at 6 months by 22.9% patients in the arm initially randomised to ABT and 37.4% in the arm initially randomised to placebo. For comparison, this outcome was achieved by 20.2% of patients in the ABT arm of the RCT. In the arm initially randomised to ABT, the percentage of ACR50 responders increased up to 18 months (33.9%) and then decreased to 20.6% at 5 years. In the arm initially randomised to placebo, there was a decrease after 6 months to 21.2% achieving ACR50 response at 48 months.

FIGURE 63. Abatacept: ACR50 response in non-RCTs.

FIGURE 63

Abatacept: ACR50 response in non-RCTs. LCI, lower confidence interval; n/a, not available; PL, placebo; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

In the analysis based on the observed data, only the percentage of ACR50 responders among those initially randomised to ABT increased up to 3 years (51.1%) and then it was 46.1% at 4 years and 51.1% at 5 years. Among those initially randomised to placebo there was an almost constant increase up to 48 months (53.8%).

ACR 70 response

Randomised controlled trial In the ATTAIN RCT,127132 the percentage of patients achieving ACR70 response at 6 months was almost seven times higher in the ABT group than in the placebo group (RR = 6.70, 95% CI 1.62 to 27.8). This difference was statistically significant; however, it needs to be highlighted that the CIs were very wide (see Figure 64).

FIGURE 64. Abatacept: ACR70 response in the ATTAIN RCT at 6 months.

FIGURE 64

Abatacept: ACR70 response in the ATTAIN RCT at 6 months.

Non-randomised controlled trials Of the uncontrolled studies, only the ATTAIN LTE119 reported ACR70 response. After 6 months of treatment the percentage of ACR70 responders was 11.5% among patients initially treated with ABT and 13.1% among patients initially treated with placebo. For comparison, it was 10.1% in the ATTAIN RCT.127132 In the arm initially randomised to ABT, there was a further increase to 17.0% at 12 months followed by a decrease to 9.6% at 5 years. In the arm initially randomised to placebo, there was an increase up to 15.2% at 30 months followed by a decrease to 7.1% at 54 months. Analysis based on observed data only provided more favourable results, with the highest percentage of ACR70 responders being 23.4% at 36 months in the arm initially randomised to ABT and 25.9% at 30 months in the arm initially randomised to placebo. See Figure 65 for details.

FIGURE 65. Abatacept: ACR70 response in non-RCTs.

FIGURE 65

Abatacept: ACR70 response in non-RCTs. LCI, lower confidence interval; n/a, not available; PL, placebo; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

DAS28

Randomised controlled trial The mean change from baseline in DAS28 was −1.98 in the ABT group and −0.71 in the placebo group. The difference between these values was −1.27 (95% CI −1.62 to −0.93, p < 0.001). These data were provided in the industry submission only. No further information was provided and therefore analyses could not be undertaken.

As indicated in Figure 66, over twice as many patients achieved a clinically meaningful DAS28 improvement (defined as greater than or equal to 1.2) in the ABT arm as in the control arm (RR = 2.15, 95% CI 1.54 to 2.99).

FIGURE 66. Abatacept: patients with clinically meaningful (≥ 1.2) DAS28 improvement in the ATTAIN RCT at 6 months.

FIGURE 66

Abatacept: patients with clinically meaningful (≥ 1.2) DAS28 improvement in the ATTAIN RCT at 6 months.

The ATTAIN study127132 also reported percentages of patients who, based on DAS28, achieved a low score (DAS28 less than or equal to 3.2) or remission (DAS28 less than 2.6). At 6 months, patients in the ABT arm were over five times more likely to have a DAS28 less than or equal to 3.2 than those in the placebo arm and the difference was statistically significant (RR = 5.67, 95% CI 2.08 to 15.44). They were also over 13 times more likely to have a DAS28 less than 2.6 than the placebo group and the difference was statistically significant (RR = 13.40, 95% CI 1.84 to 97.69); however, the CIs were wide. See Figure 67 for details.

FIGURE 67. Abatacept: patients with final DAS28 of ≤ 3.2 and of < 2.6 in the ATTAIN RCT at 6 months.

FIGURE 67

Abatacept: patients with final DAS28 of ≤ 3.2 and of < 2.6 in the ATTAIN RCT at 6 months.

Non-randomised controlled trials Change in the DAS28 score was assessed in both uncontrolled studies. Details are presented in Figure 68. After 6 months of treatment, there was a mean change of −1.99 in the arm initially randomised to ABT and of −2.14 in the arm initially randomised to placebo in the ATTAIN LTE,119 and of −2.00 in the ARRIVE study.120 This was similar in the RCT.127132 In the ATTAIN LTE,119 DAS28 further decreased with time and the mean change was −2.90 at 5 years in the arm initially randomised to ABT and −2.96 at 54 months in the arm initially randomised to placebo.

FIGURE 68. Abatacept: DAS28 change from baseline in uncontrolled studies.

FIGURE 68

Abatacept: DAS28 change from baseline in uncontrolled studies. LCI, lower confidence interval; n/a, not available; PL, placebo; SD, standard deviation; UCI, upper confidence interval.

ARRIVE120 measured clinically meaningful DAS28 improvement. It was defined as a decrease of greater than or equal to 1.2 or a score of less than or equal to 3.2. At 6 months, 56.1% of patients in ARRIVE120 achieved this outcome. This was slightly more than in the ABT group of the RCT127132 (although in ATTAIN127132 this was defined as a decrease of greater than or equal to 1.2 only). See Figure 69 for details.

FIGURE 69. Abatacept: clinically meaningful DAS28 improvement in non-randomised studies at 6 months.

FIGURE 69

Abatacept: clinically meaningful DAS28 improvement in non-randomised studies at 6 months.

Both uncontrolled studies reported percentages of patients who, based on DAS28, achieved a low score (DAS28 less than or equal to 3.2) or remission (DAS28 less than 2.6). Full details are reported in Figure 70.

FIGURE 70. Abatacept: patients with final DAS28 values ≤ 3.2 and < 2.6 in uncontrolled studies.

FIGURE 70

Abatacept: patients with final DAS28 values ≤ 3.2 and < 2.6 in uncontrolled studies. LCI, lower confidence interval; n/a, not available; PL, placebo; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

At 6 months a DAS28 score of less than or equal to 3.2 was achieved by 10.6% of patients initially randomised to ABT in the ATTAIN LTE,119 by 22.2% of patients initially randomised to placebo in the ATTAIN LTE119 and by 22.4% of patients in ARRIVE.120 For comparison, this was 17.1% of patients in the ABT arm of ATTAIN.127132 The percentage of patients initially randomised to ABT in ATTAIN LTE119 who achieved a DAS28 of less than or equal to 3.2 increased up to 18 months (28%) and then decreased up to 5 years (15.1%). In the arm initially randomised to placebo, the percentage of patients with low DAS28 decreased up to 54 months (7.1%).

A DAS28 of less than 2.6 was achieved at 6 months by 10.6% and 17.2% in the ATTAIN LTE119 (initial ABT and placebo, respectively) and by 13.0% in ARRIVE.120 For comparison, 10.1% of the ABT arm of the RCT achieved this outcome. In the ATTAIN LTE119 arm initially randomised to ABT, the highest percentage of patients with DAS28 less than 2.6 was recorded at 18 months (17.0%), following which it decreased to 9.6% at 5 years. In the arm initially randomised to placebo, the highest percentage of patients with DAS28 less than 2.6 was recorded after 6 months of treatment, and at 54 months it was 6.1%.

EULAR response

EULAR response was not assessed in any of the studies.

Health Assessment Questionnaire

Randomised controlled trial At 6 months, the HAQ change from baseline in the ATTAIN RCT127132 was −0.45 in the ABT group and −0.11 in the placebo group and the difference between the two groups was reported to be statistically significant (p < 0.001). No data on uncertainty of individual assessments were provided in the study and therefore further analyses could not be undertaken.

This study also assessed clinically meaningful HAQ improvement, defined as a decrease in HAQ score of at least 0.3 (details are reported in Figure 71). Clinically meaningful HAQ improvement was over two times more frequent in the ABT group than in the placebo group and the difference was statistically significant (RR = 2.01, 95% CI 1.44 to 2.81).

FIGURE 71. Abatacept: clinically meaningful improvement (≥ 0.3) in HAQ score.

FIGURE 71

Abatacept: clinically meaningful improvement (≥ 0.3) in HAQ score.

Non-randomised control trials Change in HAQ score was assessed in both uncontrolled studies (however, in the case of for ARRIVE120 only data for a subgroup of 43 US patients receiving monotherapy were reported; ABT monotherapy is licensed in the USA but not in Europe). Figure 72 presents the mean changes from baseline in HAQ score. The mean change from baseline at 6 months was −0.51 in the arm of ATTAIN127132 initially randomised to ABT, −0.40 in the arm of ATTAIN127132 initially randomised to placebo and −0.38 in the monotherapy subgroup of ARRIVE.120 The results for the ABT arm of the RCT were similar. In the arm initially randomised to ABT in the ATTAIN LTE,119 the change decreased up to 3 years (−0.65) and then started slowly increasing (to −0.58 at 4 years and to −0.56 at 5 years). In the group initially randomised to placebo, there was a decrease up to 54 months of treatment (−0.71).

FIGURE 72. Abatacept: mean changes from baseline in HAQ score.

FIGURE 72

Abatacept: mean changes from baseline in HAQ score. LCI, lower confidence interval; PL, placebo; SD, standard deviation; UCI, upper confidence interval.

Both uncontrolled studies reported the number of patients who achieved a clinically meaningful improvement in HAQ (details are provided in Figure 73). The ATTAIN LTE119 defined this outcome as an improvement of at least 0.3 in the HAQ score, while in ARRIVE120 it was an improvement of at least 0.22. After 6 months of treatment with ABT, the percentage of patients who achieved this outcome was 52.8% in the ATTAIN LTE119 arm that comprised patients initially randomised to ABT, 49.5% in the ATTAIN LTE119 arm comprising patients initially randomised to placebo and 46.7% in the ARRIVE study.120 For comparison, it was 46.9% in the ABT arm of the RCT. Analysis of the data from the ATTAIN LTE119 using a non-responder imputation showed a decrease in the percentage of patients who achieved a clinically meaningful HAQ over time, with 24.8% of patients initially randomised to ABT achieving clinically meaningful HAQ improvement at 5 years and 27.3% of patients initially randomised to placebo achieving clinically meaningful HAQ improvement at 54 months. When the analysis in both groups included only patients in whom HAQ improvement was measured at different time points, there was a slight increase in the percentage over time, with a decrease in the last outcome measurement.

FIGURE 73. Abatacept: clinically meaningful improvement in HAQ score (≥ 0.3 in ATTAIN studies and ≥ 0.22 in ARRIVE) LCI, lower confidence interval; PL, placebo; UCI, upper confidence interval.

FIGURE 73

Abatacept: clinically meaningful improvement in HAQ score (≥ 0.3 in ATTAIN studies and ≥ 0.22 in ARRIVE) LCI, lower confidence interval; PL, placebo; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

Quality of life

Randomised controlled trial The ATTAIN RCT127132 assessed patients' QoL using the SF-36 scale. Patients in the ABT arm improved significantly more in both the physical component (mean difference = 5.50, 95% CI 3.74 to 7.26) and the mental component (mean difference = 3.70, 95% CI 1.45 to 5.95). Details are presented in Figure 74.

FIGURE 74. Abatacept: SF-36 items changes from baseline in components in the ATTAIN RCT at 6 months.

FIGURE 74

Abatacept: SF-36 items changes from baseline in components in the ATTAIN RCT at 6 months. SD, standard deviation.

For all individual SF-36 items there was a significantly higher improvement in the ABT arm than in the placebo arm. Details for each item are presented in Figure 75.

FIGURE 75. Abatacept: SF-36 items changes from baseline in items at 6 months in the ATTAIN RCT.

FIGURE 75

Abatacept: SF-36 items changes from baseline in items at 6 months in the ATTAIN RCT. SD, standard deviation.

Non-randomised controlled trials Of the uncontrolled studies, change in SF-36 was assessed only in the ARRIVE study120 (however, it was reported only for a subgroup of 43 patients receiving monotherapy; ABT monotherapy is licensed in the USA but not in Europe). For the physical component of the SF-36 scale, there was improvement of 4.80 for the monotherapy subgroup of ARRIVE.120 For the mental component, the improvement was 7.34. For comparison, in the ABT arm of ATTAIN127132 it was 6.50 and 5.40, respectively. Further details are provided in Figure 76. Data for individual items were not reported in ARRIVE.120

FIGURE 76. Abatacept: SF-36 items changes from baseline in components.

FIGURE 76

Abatacept: SF-36 items changes from baseline in components. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

Joint damage

Joint damage was not assessed in any of the studies.

Serious adverse events

Randomised controlled trial In ATTAIN,127132 there was no significant difference at 6 months between ABT and placebo in the risk of experiencing a serious AE (RR = 0.93, 95% CI 0.51 to 1.68). Details are presented in Figure 77.

FIGURE 77. Abatacept: serious AEs in the ATTAIN RCT at 6 months.

FIGURE 77

Abatacept: serious AEs in the ATTAIN RCT at 6 months.

Non-randomised controlled trials Serious AEs were assessed in both uncontrolled studies. At 6 months the percentage of patients who had experienced a serious AE was 10.4% in ARRIVE.120 It was similar in the ABT arm of the ATTAIN RCT127132 (10.5%). At 2 years, 32.5% of patients in the ATTAIN LTE119 had experienced a serious AE. Full details are presented in Figure 78.

FIGURE 78. Abatacept: serious adverse events in non-randomised studies.

FIGURE 78

Abatacept: serious adverse events in non-randomised studies. LCI, lower confidence interval; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

Infections/serious infections

Randomised controlled trial At 6 months there was no statistically significant difference between ABT and placebo in the risk of infection (RR = 1.16, 95% CI 0.87 to 1.56) or serious infection (RR = 1.03, 95% CI 0.26 to 4.06). Details are presented in Figure 79.

FIGURE 79. Abatacept: infections in the ATTAIN RCT at 6 months.

FIGURE 79

Abatacept: infections in the ATTAIN RCT at 6 months.

Non-randomised controlled trials Both uncontrolled studies reported infections. The percentages of patients who experienced any infection were similar at 6 months in the ABT arm of ATTAIN127132 and in the ARRIVE study120 (37.6% and 38.9%, respectively). Of these 2.3% and 2.4% were serious. At 2 years 73.8% of patients in the ATTAIN LTE119 experienced an infection of any kind and 7.9% a serious infection. Details are reported in Figure 80.

FIGURE 80. Abatacept: infections in non-randomised studies.

FIGURE 80

Abatacept: infections in non-randomised studies.

Injection/infusion reaction

Randomised controlled trial At 6 months there was no statistically significant difference between ABT and placebo in the risk of infusion reaction (RR = 1.68, 95% CI 0.56 to 5.04). Details are reported in Figure 81.

FIGURE 81. Abatacept: infusion reactions.

FIGURE 81

Abatacept: infusion reactions. LCI, lower confidence interval; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

Non-randomised controlled trials Of the uncontrolled studies, infusion reactions were reported only in ARRIVE.120 At 6 months, 5.4% patients had experienced infusion reactions. For comparison, this figure was 5.0% in the ABT arm of ATTAIN.127132 Details are provided in Figure 82.

FIGURE 82. Abatacept: infusion reactions.

FIGURE 82

Abatacept: infusion reactions. LCI, lower confidence interval; UCI, upper confidence interval. Bold type indicates that the study was an RCT.

Abatacept in combination with other biologic drugs

Two RCTs [Weinblatt et al.134 and abatacept study of safety in use with other rheumatoid arthritis therapies (ASSURE)135] were identified that assessed ABT in combination with previously tried biologic drugs. Although both studies met the inclusion criteria of the systematic review, combination therapy was not considered relevant to this report and, therefore, they were not analysed.

The study by Weinblatt et al.134 was a multicentre placebo-controlled randomised trial and included 121 patients who had active RA despite treatment with ETN. Patients were randomised to receive ETN and ABT or ETN and placebo and were followed up for 1 year. Afterwards they could enter a LTE (data provided for 2 years of the extension study). Data were collected on outcomes including ACR response, HAQ, SF-36 and safety.

ASSURE135 was a multicentre placebo-controlled randomised trial and included 167 patients who had active RA in spite of receiving therapy with biologic agents (ETN, IFX, ADA and anakinra), ‘warranting additional therapy at the discretion of the investigator’. (Note: it also included 1,274 patients who received background DMARDs and were probably biologic naive.) Patients continued their treatment and in addition to that were randomised to receive ABT or placebo. They were followed up for 1 year. The study assessed outcomes including HAQ Disability Index, pain, patient and physician global assessment and safety.

Summary

Three studies assessed ABT in comparison with standard care: one RCT (ATTAIN127132) and two uncontrolled studies (ATTAIN LTE119 and ARRIVE120). Follow-up ranged from 6 months to 5 years. All studies included patients with similar baseline characteristics. The main results of the included studies are summarised in Table 40.

TABLE 40. Abatacept: summary of main results.

TABLE 40

Abatacept: summary of main results.

Effectiveness of the technologies compared with newly initiated and previously untried conventional disease-modifying antirheumatic drug

No study addressing the comparison was found.

Effectiveness of the technologies compared with other biologic agents

No study addressing this comparison was found.

Comparison of effectiveness between technologies (head-to-head comparisons)

Evidence from comparative studies

Overview of evidence

One prospective cohort study was identified to compare RTX with TNF inhibitors as a class.136,137

Included patients had tried at least one TNF inhibitor (ADA, ETN or IFX) before and discontinued treatment owing to inadequate response. The study was conducted in Switzerland and the median duration of follow-up was 11 months. Full details of this study are provided in Table 41.

TABLE 41. Comparative study: characteristics of the included study.

TABLE 41

Comparative study: characteristics of the included study.

Patient characteristics

Full details baseline characteristics are reported in Table 42. The study included 318 patients and:

TABLE 42. Comparative study: baseline patient characteristics.

TABLE 42

Comparative study: baseline patient characteristics.

  • The proportion of women was 77.5%.
  • The mean age was 55 years.
  • The mean disease duration was 11.3 years.
  • The proportion of RF-positive patients was 82.4%.
  • Concomitant DMARDs used were MTX (63.9%), LEF (18%) and other (4.5%).
  • The proportion of patients receiving steroids was 56.5%.
  • The number of previous DMARDs was not reported.
  • The number of previous TNF inhibitors ranged from one to over two.
  • The mean baseline HAQ score was 1.5.
  • The mean baseline DAS28 score was 4.5.
  • No information was provided on CRP and ESR.

Quality assessment

Full details of quality assessment are reported in Table 43. The study was a prospective cohort. It had clearly defined inclusion criteria. It was; however, unclear if consecutive patients were included in the study and what percentage of patients were withdrawn.

TABLE 43. Comparative study: non-RCT quality assessment.

TABLE 43

Comparative study: non-RCT quality assessment.

Results

Table 44 indicates which of the outcomes reported in the main text of the report were assessed in the Finckh et al. study.136,137 No outcomes apart from the ones reported in Table 44 were assessed.

TABLE 44. Comparative study: outcomes assessed in the study and reported in the main text of the report.

TABLE 44

Comparative study: outcomes assessed in the study and reported in the main text of the report.

Withdrawals

Withdrawals were not assessed in this study.

ACR20/50/70 response

ACR response was not assessed in this study.

DAS28

There was a trend favouring TNF inhibitors over RTX for change from baseline in DAS28; however, this difference was not statistically significant (mean difference = −0.35, 95% CI −0.71 to 0.01). The follow-up for this outcome was unclear. See Figure 83 for details.

FIGURE 83. Tumour necrosis factor inhibitors versus rituximab: DAS28 change from baseline.

FIGURE 83

Tumour necrosis factor inhibitors versus rituximab: DAS28 change from baseline. SD, standard deviation.

EULAR response

EULAR response was not reported in this study.

Health Assessment Questionnaire

Health Assessment Questionnaire score was reported only for baseline in this study.

Quality of life

Quality of life was not reported in this study.

Joint damage

Joint damage was not reported in this study.

Serious adverse events

Serious AEs were not reported in this study.

Infections/serious infections

Infections were not reported in this study.

Injection/infusion reaction

Data for injection/infusion reactions were reported only for a subgroup of 116 patients.136 Dermatological complications (mainly injection site reactions) occurred in one RTX patient and nine TNF inhibitor patients. Infusion reactions were reported in three RTX and none of the TNF inhibitor patients. Data from both categories were analysed together to compare AEs associated with drug administration (Figure 84). There was no statistically significant difference between groups (RR = 1.70, 95% CI 0.56 to 5.22).

FIGURE 84. Tumour necrosis factor inhibitors versus rituximab: injection/infusion site reactions.

FIGURE 84

Tumour necrosis factor inhibitors versus rituximab: injection/infusion site reactions.

Summary

One prospective cohort study136,137 compared TNF inhibitors as a class with RTX. The median follow-up was 11 months; however, it was not clearly stated when outcomes were assessed. The main results of the study are summarised in Table 45.

TABLE 45. Comparative study: summary of main results.

TABLE 45

Comparative study: summary of main results.

Indirect comparisons

Two placebo-controlled RCTs were identified that were considered amenable for an IC of effectiveness of two of the drugs of interest. These trials were REFLEX124126 and ATTAIN127132 which investigated RTX and ABT, respectively, in similar populations with similar follow-up and outcome measures.

Indirect comparison was conducted (RTX vs ABT) using the method of Bucher et al.73 The following binary outcomes were examined: ACR20, ACR50 and ACR70 responses and ‘withdrawal for any reason’. The results are summarised in Table 46.

TABLE 46. Indirect comparison: ACR response.

TABLE 46

Indirect comparison: ACR response.

No IC approached statistical significance; however, the IC point estimates slightly favoured RTX for ACR20, ACR70 and withdrawal for any reason.

Indirect comparison for change in HAQ score from baseline to 6 months of treatment was of potential interest. However, data reporting was incomplete in REFLEX124126 and the uncertainty in the reported estimates could not be computed reliably. The change in HAQ score was almost the same in the two trials (see Table 47) so that it is unlikely that an IC would indicate a difference between the treatments for this outcome measure.

TABLE 47. Indirect comparison: change from baseline in HAQ score.

TABLE 47

Indirect comparison: change from baseline in HAQ score.

Subgroup analyses

This section summarises results from subgroup analyses. Data from RCTs and observational studies were reported separately. Planned subgroup analyses from placebo-controlled RCTs provide the least biased information with regard to whether effectiveness (i.e. the effects of treatment over and above what could be expected without the treatment) varies significantly between the subgroups of interest. Subgroup analyses performed post hoc were highlighted and need to be interpreted with caution.

Owing to the relatively small number of data from RCTs, results from non-randomised, uncontrolled studies were also included but were reported separately from RCT data. Because of the lack of control groups in these studies, any observed differences in the observed response (i.e. not corrected for what would happen without treatment) between the subgroups can be due to differences in baseline characteristics before switching, (and the natural course of the disease that follows) as well as genuine differences in the effectiveness between the subgroups.

In accordance with the study selection criteria for non-randomised studies, subgroup analyses were included only if the number of patients was greater than or equal to 20 in at least one of the subgroups being compared. For studies in which some patients were excluded owing to missing data, ‘non-responder imputations’ were performed and presented for binary outcomes assuming patients with missing data did not achieve the favourable outcomes such as ACR20. ‘Observed data’ analyses based on actually observed/reported data were presented only when the statistical significance of the results and/or the direction of effect differ from non-responder imputation analyses. For continuous outcomes, results were presented as reported in the original papers and no imputation of missing data was carried out. Where data were available from more than one study for a given outcome/time point, pooled estimates using the random-effects model were presented. Given the potential differences in the populations and methods between studies, the main aim is to illustrate the existence or absence of heterogeneity between studies using the I2 statistic.

Reasons for withdrawal of the previous tumour necrosis factor inhibitor

Lack of response (primary failure) versus loss of response (secondary failure)

Randomised controlled trials

No evidence from RCTs was reported.

Non-randomised controlled trials

Subgroup data were available for switching to ADA, ETN, an unspecified TNF inhibitor and ABT. No subgroup data were identified for switching to IFX and RTX.

Adalimumab Two uncontrolled studies reported data separately for patients who switched because of lack of response and those who had initial treatment response but later switched because of loss of response.96,97 Results comparing these two subgroups of patients are summarised in Tables 48 and 49.

TABLE 48. Switching to ADA owing to lack of response versus owing to loss of response in observational studies – binary outcomes.

TABLE 48

Switching to ADA owing to lack of response versus owing to loss of response in observational studies – binary outcomes.

TABLE 49. Switching to ADA owing to lack of response versus owing to loss of response in observational studies – continuous outcomes.

TABLE 49

Switching to ADA owing to lack of response versus owing to loss of response in observational studies – continuous outcomes.

Overall there was no significant difference in treatment withdrawal between the two subgroups. Patients who switched to ADA because of loss of response had significantly higher response rates for ACR20 and ACR50.

Etanercept Two uncontrolled studies reported subgroup data.101,104 The results are summarised in Tables 50 and 51. Overall the results were similar between the subgroups and no significant difference was observed.

TABLE 50. Switching to ETN owing to lack of response versus owing to loss of response in observational studies – binary outcomes.

TABLE 50

Switching to ETN owing to lack of response versus owing to loss of response in observational studies – binary outcomes.

TABLE 51. Switching to ETN owing to lack of response versus owing to loss of response in observational studies – continuous outcomes.

TABLE 51

Switching to ETN owing to lack of response versus owing to loss of response in observational studies – continuous outcomes.

Infliximab No studies of switching to IFX provided subgroup data.

Tumour necrosis factor inhibitors as a class One observational study reported data separately for patients who switched because of lack of response and those who had initial treatment response but later switched because of loss of response.113 Outcomes for the second TNF inhibitor were reported as an aggregated group and were not reported separately for individual TNF inhibitors. The results from the study are shown in Tables 52 and 53.

TABLE 52. Switching to TNF inhibitors owing to lack of response versus owing to loss of response in observational studies – binary outcomes.

TABLE 52

Switching to TNF inhibitors owing to lack of response versus owing to loss of response in observational studies – binary outcomes.

TABLE 53. Switching to TNF inhibitors owing to lack of response versus owing to loss of response in observational studies – continuous outcomes.

TABLE 53

Switching to TNF inhibitors owing to lack of response versus owing to loss of response in observational studies – continuous outcomes.

There were no significant differences between the subgroups in withdrawal and treatment response, except for the analysis with non-responder imputation for good/moderate EULAR response at 3 months. A significantly higher proportion of patients who switched owing to lack of response achieved a good/moderate EULAR response compared with those who switched owing to loss of response. Data were missing for nearly half of the patients in the ‘switching owing to loss of response’ for several outcomes, which may compromise the reliability of the results.

Rituximab No studies of switching to RTX provided subgroup data.

Abatacept Subgroup data from the LTE of the ATTAIN trial (ATTAIN LTE119) were reported in the MS. As patients had to complete 6 months of treatment in the ATTAIN trial127132 in order to enter ATTAIN LTE,119 the included patients were no longer representative of the randomised cohort. The results are shown in Table 54. A significant difference between the subgroups was found only in an observed data analysis of HAQ improvement greater than or equal to 0.3 at 6 months. Significantly more patients who switched owing to loss of response achieved this criterion than those who switched owing to lack of response.

TABLE 54. Switching to ABT owing to lack of response versus owing to loss of response in the ATTAIN LTE – binary outcomes.

TABLE 54

Switching to ABT owing to lack of response versus owing to loss of response in the ATTAIN LTE – binary outcomes.

Summary
  • No conclusion can be made with regard to whether the effectiveness of the five technologies varies according to lack of response or loss of response to the prior TNF inhibitor because of the lack of RCT evidence.
  • Evidence from two uncontrolled studies96,97 of switching to ADA showed significant differences in favour of patients who switched because of loss of response for ACR20 and ACR50.
  • Evidence from two uncontrolled studies101,104 of switching to ETN indicated that there was no significant difference in treatment withdrawal and response between the subgroups.
  • Evidence from a Dutch study (DREAM113) of switching to an unspecified alternative TNF inhibitor did not find a significant difference between the subgroups.
  • Evidence from the ATTAIN LTE119 of switching to ABT did not find a significant difference between the subgroups except in an analysis based on observed data in which more patients who switched due to loss of response achieved HAQ improvement greater than or equal to 0.3 at 6 months than due to lack of response.
  • No evidence from observational studies was identified for switching to IFX and RTX.
  • Discussion: there is lack of RCT evidence. It has been speculated that patients who withdrew from a TNF inhibitor owing to lack of response may not respond as well to another TNF inhibitor as those who withdrew owing to loss of response. This was observed in studies of switching to ADA, but not in studies of switching to ETN or an unspecified alternative TNF inhibitor. Of note, a similar trend (higher response rates for patients who withdrew owing to loss of response) was seen in the ATTAIN LTE119 for switching to ABT, which is not a TNF inhibitor. These observational studies were insufficiently powered to identify clinically important differences and thus the findings require further confirmation.

Switching due to lack of efficacy (lack or loss of response) versus switching due to intolerance (adverse events)

Randomised controlled trials

RCT evidence was available only for RTX. Data were provided in the MS as commercial-in-confidence information.

Rituximab Commercial-in-confidence information (or data) removed.

Non-randomised controlled trials

Subgroup data were available for switching to ADA, ETN and an alternative, unspecified, TNF inhibitor.

Adalimumab Subgroup data were reported in two uncontrolled studies96,97 and were summarised in Tables 55 and 56. The results, mainly driven by the Research in Active Rheumatoid Arthritis (ReAct) study,96 showed significant differences for EULAR response and change in DAS28 in favour of patients who switched because of intolerance/AEs.

TABLE 55. Switching to ADA owing to lack of efficacy versus owing to intolerance/AEs in observational studies – binary outcomes.

TABLE 55

Switching to ADA owing to lack of efficacy versus owing to intolerance/AEs in observational studies – binary outcomes.

TABLE 56. Switching to ADA owing to lack of efficacy versus owing to intolerance/AEs in observational studies – continuous outcomes.

TABLE 56

Switching to ADA owing to lack of efficacy versus owing to intolerance/AEs in observational studies – continuous outcomes.

Etanercept Subgroup data were available from one uncontrolled study.103 The results are presented in Table 57. No significant difference between subgroups was found.

TABLE 57. Switching to ETN owing to lack of efficacy versus owing to intolerance/AEs in an observational study – continuous outcome.

TABLE 57

Switching to ETN owing to lack of efficacy versus owing to intolerance/AEs in an observational study – continuous outcome.

Tumour necrosis factor inhibitors as a class Subgroup data were available from three observational studies.110,112,113 The results are shown in Tables 58 and 59. Patients who withdrew from the previous TNF inhibitors because of intolerance/AEs were more likely to withdraw because of intolerance/AEs again compared with those who withdrew from the previous TNF inhibitors because of lack of efficacy. On the other hand, patients who withdrew from the previous TNF inhibitors because of intolerance/AEs were more likely to achieve various ACR, EULAR and other DAS28-based response criteria.

TABLE 58. Switching to an alternative TNF inhibitor owing to lack of efficacy versus owing to intolerance/AEs in observational studies – binary outcomes.

TABLE 58

Switching to an alternative TNF inhibitor owing to lack of efficacy versus owing to intolerance/AEs in observational studies – binary outcomes.

TABLE 59. Switching to an alternative TNF inhibitor owing to lack of efficacy versus owing to intolerance/AE in observational study – continuous outcome.

TABLE 59

Switching to an alternative TNF inhibitor owing to lack of efficacy versus owing to intolerance/AE in observational study – continuous outcome.

Summary
  • Evidence [commercial-in-confidence information (or data) removed]. No subgroup data from RCT were identified for the other technologies.
  • Evidence from observational studies was available for switching to ADA, ETN and an alternative, unspecified, TNF inhibitor. Evidence was not available for switching to IFX and ABT.
  • Evidence from two observational studies of switching to ADA showed significant differences for EULAR response and change in DAS28 in favour of patients who switched because of intolerance/AEs.
  • No significant difference between subgroups was found in a small, uncontrolled study of switching to ETN.
  • Evidence from three observational studies110,112,113 of switching to an unspecified, alternative TNF inhibitor suggested that patients who withdrew from the previous TNF inhibitor because of intolerance/AE were more likely to withdraw because of intolerance/AEs and more likely to achieve ACR, EULAR and DAS28-related response criteria than patients who withdrew from the previous TNF inhibitor because of lack of efficacy.
  • Discussion: it is suggested that the effectiveness of a TNF inhibitor may differ between patients who have withdrawn from the previous TNF inhibitor because of lack of efficacy and those who have withdrawn because of AEs, but the effectiveness of other technologies with different mechanism of action may not. There is a lack of RCT evidence to confirm the former. RCT evidence suggests that [commercial-in-confidence information (or data) removed]. RCT evidence for ABT is also lacking. Data from observational studies appear to agree with what is expected in terms of treatment withdrawal and treatment response.

Autoantibody status

Randomised controlled trial

RCT data for subgroups stratified by autoantibody status were available only from the REFLEX trial124126 of RTX.

Rituximab

Subgroup data stratified by RF status from the REFLEX trial124126 were reported in the MS. Randomisation in this trial was stratified by RF status (RF +, defined as a value of RF greater than or equal to 20 IU/ml at screening; or RF−, defined as RF less than 20 IU/ml at screening) and region (US or non-US). The results for ACR20 at 6 months are shown in Figure 87 (RR) and Figure 88 [risk difference (RD)] and for all the ACR response criteria are shown in Table 60. Although the proportion of patients achieving ACR criteria was generally lower in RF− patients than in RF + patients, there was no significant difference in treatment effect between the subgroups.

FIGURE 87. Subgroup analysis (switching to rituximab) by RF status: ACR20 at 6 months (relative risk).

FIGURE 87

Subgroup analysis (switching to rituximab) by RF status: ACR20 at 6 months (relative risk).

FIGURE 88. Subgroup analysis (switching to rituximab) by RF status: ACR20 at 6 months (risk difference).

FIGURE 88

Subgroup analysis (switching to rituximab) by RF status: ACR20 at 6 months (risk difference).

TABLE 60. Subgroup analyses (switching to RTX) by RF status in the REFLEX trial: ACR20, ACR50 and ACR70 at 6 months.

TABLE 60

Subgroup analyses (switching to RTX) by RF status in the REFLEX trial: ACR20, ACR50 and ACR70 at 6 months.

Further subgroup data stratified by baseline RF and anti-CCP status from the REFLEX trial124126 were also reported in the MS and are summarised in Table 61. Although test for interaction was significant for RD in ACR50, suggesting a greater treatment effect in patients who were either RF or anti-CCP positive than in those with both RF and anti-CCP negative, the number of patients in the latter subgroup was too small to allow firm conclusion to be drawn. This subgroup analysis was performed post hoc and needs to be interpreted with caution.

TABLE 61. Subgroup analyses (switching to RTX) by baseline RF and anti-CCP status in the REFLEX trial: ACR20, ACR50 and ACR70 at 6 months.

TABLE 61

Subgroup analyses (switching to RTX) by baseline RF and anti-CCP status in the REFLEX trial: ACR20, ACR50 and ACR70 at 6 months.

Non-randomised controlled trials

No subgroup data from observational studies was identified.

Summary

  • Evidence from the REFLEX trial124126 did not suggest a significant difference in the effectiveness of RTX according to the presence or absence of RF, although the trial may be underpowered for ruling out a clinically relevant difference between subgroups. There is lack of evidence for other technologies.
  • Discussion: in the REFLEX trial,124126 the proportion of patients achieving ACR criteria was generally lower in RF− patients than in RF + patients irrespective of treatment group. The treatment effects in terms of RDs between RTX and placebo group were generally larger in RF + patients than in RF− patients, but this does not hold true when RR is used as the measure of effect. Differences between subgroups were not statistically significant according to test for interaction, but the test may be underpowered due to the sample size. Post hoc analysis according to RF and anti-CCP status needs to be interpreted with caution.

Number of tumour necrosis factor inhibitors previously tried

Randomised controlled trials

Randomised controlled trial data stratified by the number of TNF inhibitors the patients had tried before switching were available from the REFLEX trial124126 of RTX and the ATTAIN trial127132 of ABT.

Rituximab

Subgroup data from the REFLEX trial124126 stratified by the number of prior TNF inhibitors (one prior TNF inhibitor vs two or more prior TNF inhibitors) were reported in the MS and are presented in Table 62. The results show that RTX was more effective than placebo in both subgroups and there is no significant difference in treatment effects between the subgroups.

TABLE 62. Subgroup analyses (switching to RTX) by number of prior TNF inhibitors in the REFLEX trial: ACR20, ACR50 and ACR70 at 6 months.

TABLE 62

Subgroup analyses (switching to RTX) by number of prior TNF inhibitors in the REFLEX trial: ACR20, ACR50 and ACR70 at 6 months.

Abatacept

Subgroup data from the ATTAIN trial127132 stratified by prior TNF inhibitor (ETN, IFX or both) were reported in the MS. For this subgroup analysis, data from patients who had received either ETN or IFX were combined and then were compared with data from patients who had received both ETN and IFX before switching to ABT. The trial was conducted before ADA became widely available and thus few patients had tried more than two TNF inhibitors.

The results are shown in Table 63. Irrespective of the number of prior TNF inhibitor(s), a higher proportion of patients in the ABT group than in the placebo group achieved ACR20 and a HAQ improvement of greater than or equal to 0.3. The difference was larger and statistically significant in the subgroup of patients who had one prior TNF inhibitor, and was smaller and not statistically significant in the subgroup of patients who had two prior TNF inhibitors. The results of tests for interaction do not suggest differential treatment effects between the subgroups, although the tests may be underpowered as the number of patients in the subgroup of two prior TNF inhibitors is relatively small.

TABLE 63. Subgroup analyses (switching to ABT) by number of prior TNF inhibitors in the ATTAIN trial: ACR20 and HAQ improvement of ≥ 0.3 at 6 months.

TABLE 63

Subgroup analyses (switching to ABT) by number of prior TNF inhibitors in the ATTAIN trial: ACR20 and HAQ improvement of ≥ 0.3 at 6 months.

Non-randomised controlled trials

Subgroup data stratified by the number of prior TNF inhibitors (or prior biologics) were available for switching to an unspecified TNF inhibitor and to ABT.

Tumour necrosis factor inhibitors as a class

Subgroup data (one prior TNF inhibitor vs two prior TNF inhibitors) were reported in Karlsson et al.112 and the results are presented in Table 64. A higher proportion of patients who previously tried one TNF inhibitor achieved various ACR and EULAR response criteria than those who previously tried two TNF inhibitors, although the differences were not statistically significant except for the difference in achieving good EULAR response (25% vs 8%).

TABLE 64. Switching to an alternative TNF inhibitor by number of TNF inhibitors previously tried (observational studies) – binary outcomes.

TABLE 64

Switching to an alternative TNF inhibitor by number of TNF inhibitors previously tried (observational studies) – binary outcomes.

In addition to the above, Duftner et al.111 reported a 12-month discontinuation rate of 53.5%, 66.7% (18/27) and 28.6% for the first, second and third biologics (ADA, ETN, IFX and anakinra) in Austrian RA patients. This study included a mixed patient population of those with RA (63%, 109/173) and other rheumatic diseases (37%). The exact number of patients from whom the above RA-specific discontinuation rates were derived was not clearly stated except for the second biologic.

Abatacept

Subgroup data stratified by the number of prior TNF inhibitors (one, two or three) were reported by Schiff et al. (ARRIVE study).120 The results are presented in Figures 89 and 90. The results indicate that the proportion of patients achieving DAS28-related response criteria decreases as the number of prior TNF inhibitor(s) that the patients have tried increases (χ2 test for linear trend, p = 0.009 for DAS28 less than or equal to 3.2 and p = 0.005 for DAS28 less than 2.6). The change in DAS28 from baseline at 6 months was the same for patients who had previously tried one or two TNF inhibitors, but was significantly lower for patients who had previously tried three TNF inhibitors (−2.1 vs −1.7, test for interaction, p = 0.001).

FIGURE 89. Switching to abatacept: DAS28 responses at 6 months stratified by the number of prior TNF inhibitors in the ARRIVE study.

FIGURE 89

Switching to abatacept: DAS28 responses at 6 months stratified by the number of prior TNF inhibitors in the ARRIVE study. LCI, lower confidence interval; UCI, upper confidence interval.

FIGURE 90. Switching to abatacept: DAS28 change from baseline at 6 months stratified by the number of prior TNF inhibitors in the ARRIVE study.

FIGURE 90

Switching to abatacept: DAS28 change from baseline at 6 months stratified by the number of prior TNF inhibitors in the ARRIVE study. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

Summary

  • Evidence from the REFLEX trial124126 did not show a significant difference in the effectiveness of RTX (measured as RRs of achieving ACR responses over placebo) between the subgroup of patients who had tried one TNF inhibitor and those who had tried more than one TNF inhibitor. However, the trial may be underpowered for ruling out a clinically relevant difference between the subgroups. The response rates tend to be higher among patients who had tried one TNF inhibitor than among with those who had tried more than one TNF inhibitor irrespective of treatments (i.e. RTX or placebo) received.
  • Evidence from the ATTAIN trial127132 did not show a significant difference in the effectiveness of ABT (measured as RRs of achieving ACR20 response and HAQ improvement over placebo) between the subgroup of patients who had tried one TNF inhibitor and those who had tried more than one TNF inhibitor. The number of patients in the latter subgroup was small and the difference between ABT and placebo did not reach statistical significance. The trial is likely to be underpowered for ruling out a clinically relevant difference between the subgroups.
  • No evidence from RCTs and observational studies was available for the individual TNF inhibitors.
  • In an observational study112 of switching to an unspecified, alternative TNF inhibitor, higher response rates to ACR and EULAR response criteria were reported in patients who tried one TNF inhibitor than in those who tried two TNF inhibitors.
  • One observational study120 of switching to ABT showed that the proportion of patients achieving DAS28-related response criteria decreases as the number of prior TNF inhibitors increases.
  • Discussion: many of the studies included in this review included patients who had previously tried more than one TNF inhibitor. Determining whether the effectiveness of the technologies varies depending on the number of TNF inhibitors previously tried is useful to inform the applicability of findings from these studies to the main population of interest for this appraisal, i.e. patients who had previously had inadequate response to one TNF inhibitor. Results from the REFLEX124126 and ATTAIN127132 trials suggested that the effectiveness of RTX and ABT (measured as RRs of achieving various improvement criteria over placebo) does not differ significantly between patients who have tried one TNF inhibitor compared and those who have tried more than one. The subgroup analyses; however, were limited by the relatively small number of patients, and thus the possibility of differential treatment effect, particularly in terms of RD, cannot be ruled out. Findings from observational studies for switching to an alternative TNF inhibitor and to ABT agree with an inverse relationship between treatment response and number of prior TNF inhibitors. To what extent the effectiveness of the technologies (in particular the TNF inhibitors) varies by the number of prior TNF inhibitors remains unclear owing to the small volume or complete lack of evidence from RCTs.

Prior tumour necrosis factor inhibitor

Randomised controlled trials

RCT data stratified by the TNF inhibitor from which the patients had switched were available only from the ATTAIN trial127132 of ABT.

Abatacept

Subgroup data stratified by prior TNF inhibitor (ETN vs IFX) from the ATTAIN trial127132 were reported in the MS and are presented in Table 65. The results of the subgroup analyses show that ABT is more effective than placebo in both patients who have previously had inadequate response to ETN and those who have previously had inadequate response to IFX. Tests for interaction do not suggest differential treatment effects between subgroups, although the tests may be underpowered.

TABLE 65. Subgroup analyses (switching to ABT) by prior TNF inhibitor (ETN or IFX) in the ATTAIN trial: ACR20 and HAQ improvement of ≥ 0.3 at 6 months.

TABLE 65

Subgroup analyses (switching to ABT) by prior TNF inhibitor (ETN or IFX) in the ATTAIN trial: ACR20 and HAQ improvement of ≥ 0.3 at 6 months.

Non-randomised controlled trials

Adalimumab

Subgroup data stratified by patients who switched from either ETN or IFX to ADA were available from one study (ReAct).96 The results are shown in Tables 66 and 67. No significant difference between the subgroups was found.

TABLE 66. Switching to ADA by prior TNF inhibitor in observational studies – binary outcomes.

TABLE 66

Switching to ADA by prior TNF inhibitor in observational studies – binary outcomes.

TABLE 67. Switching to ADA by prior TNF inhibitor in observational studies – continuous outcomes.

TABLE 67

Switching to ADA by prior TNF inhibitor in observational studies – continuous outcomes.

In addition to the above, Gomez-Reino et al.108 reported 12-month retention on treatment of 0.75 (95% CI 0.31 to 0.93) for patients who switched from ETN to ADA (n = 33) and 0.69 (95% CI 0.43 to 0.85) for patients who switched from IFX to ADA (n = 14). No statistical comparisons were made.

Abatacept

Subgroup data stratified by the TNF inhibitor from which the patients switched were reported by Schiff et al. (ARRIVE study).120 The results are presented in Figures 91 and 92. At 6 months, there was no significant difference in the proportion of patients who achieved DAS28 less than or equal to 3.2 (χ2 test, p = 0.67) and DAS28 less than 2.6 (χ2 test, p = 0.34). The mean changes from baseline in DAS28 were also similar between the groups (test for interaction, p = 0.21).

FIGURE 91. Switching to abatacept: DAS28 responses at 6 months stratified by prior TNF inhibitor in the ARRIVE study.

FIGURE 91

Switching to abatacept: DAS28 responses at 6 months stratified by prior TNF inhibitor in the ARRIVE study. LCI, lower confidence interval; UCI, upper confidence interval.

FIGURE 92. Switching to abatacept: DAS28 change from baseline at 6 months stratified by prior TNF inhibitor in the ARRIVE study.

FIGURE 92

Switching to abatacept: DAS28 change from baseline at 6 months stratified by prior TNF inhibitor in the ARRIVE study. LCI, lower confidence interval; SD, standard deviation; UCI, upper confidence interval.

Summary

  • Evidence from the ATTAIN trial127132 suggested that the effectiveness of ABT did not vary significantly according to the TNF inhibitor (ETN or IFX) from which the patients had switched, although the subgroup analysis may be underpowered. No RCT evidence was identified for the other technologies.
  • Evidence from observational studies of switching to ADA96 and to ABT120 suggested that treatment response does not vary significantly according to the TNF inhibitor that the patients had previously tried.
  • Assuming no interaction between the technologies that have been used sequentially, the results of this subgroup analysis provide an indication of whether patients previously treated with different TNF inhibitors represented distinctly different populations when they switch. Limited data do not suggest this is the case although the evidence is very limited in view of possible combinations of treatment sequence.

Ongoing studies

Electronic searches

Electronic searches for ongoing studies identified only two relevant studies. One of these is looking at extended treatment with RTX in patients who have had an inadequate response (due to toxicity or inadequate efficacy) to previous or current treatment with ETN, IFX or ADA are being entered into an open-label study of two doses RTX and subsequently randomised to a third dose or placebo (if still having B cells). The study acronym is EXTRRA and it is being conducted in the UK. It has a target sample size of 60. The study appears to have been completed in 2010 but has not yet been published. Parts of this study are relevant to the decision problem in this report.

The second study is a ‘multicentre clinical observation real-life study’ of RTX in patients with active RA whose current treatment with TNF inhibitors in combination with MTX is insufficient. The study acronym is RIRA, and it has a target sample size of 20. It appears to have been undertaken in Austria and to have been completed. This study does not as yet appear to have been published.

Manufacturer's submissions

Mentions of ongoing studies in the MSs were as follows:

  • Adalimumab: no explicit statements are provided in the MS about ongoing studies on ADA. Data from large registries are included.
  • Etanercept: no explicit statements are provided in the MS about ongoing studies on ETN. Data from registries and LTEs are included.
  • Infliximab: the MS provides details on an ongoing multicentre open-label RCT (RE-START; C0168Z05) which aims to assess the efficacy and safety of IFX in patients with active RA who inadequately respond to ETN or ADA. The primary outcome is EULAR response at week 10. Other outcomes will include ACR, tender/swollen joints, HAQ and HRQoL using the SF-36 instrument. Evaluations will be made up to 26 weeks. The study is being conducted in North America, the EU and Israel. The sample size is indicated as ~ 200.
  • Rituximab: the MS lists eight ongoing studies (REFLEX open-label extension, SERENE, IMAGE, MIRROR, SUNRISE, SIERRA, DANCER open-label extension, WA16291 and its open-label extension) and various data are presented from these studies in the submission.
  • Abatacept: no explicit statements are provided in the MS about ongoing studies on ABT. Data from registries and LTEs are included.
© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation
Adalimumab, Etanercept, Infliximab, Rituximab and Abatacept for the Treatment of Rheumatoid Arthritis After the Failure of a Tumour Necrosis Factor Inhibitor: A Systematic Review and Economic Evaluation.
Health Technology Assessment, No. 15.14.
Malottki K, Barton P, Tsourapas A, et al.
Southampton (UK): NIHR Journals Library; 2011 Mar.

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