Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study
© Burmester et al.; licensee BioMed Central Ltd. 2014
Received: 4 April 2013
Accepted: 15 January 2014
Published: 27 January 2014
Patients with active rheumatoid arthritis who had failed at least one disease-modifying anti-rheumatic drug (DMARD) were treated with adalimumab (ADA) in the ReAct study with the option to continue treatment for 5 years in ReAlise. The purpose of this study was to evaluate the long-term safety and effectiveness of ADA as prescribed from the first injection in ReAct to the last observation in ReAlise.
Patients received ADA alone or in combination with DMARDs according to usual clinical care practices. Adverse events (AEs) were tabulated by five time windows after the first ADA injection. Effectiveness measures included achievement of low disease activity (LDA), defined as Simplified Disease Activity Index (SDAI) ≤11, or remission, (REM), defined as SDAI ≤3.3.
Of the 6,610 ReAct patients, 3,435 (52%) continued in ReAlise. At baseline in ReAct, mean age was 54 years, mean DAS28 was 6.0 and mean HAQ DI was 1.64. The mean treatment duration was 1,016 days, representing 18,272 patient-years (PYs) of ADA exposure. Overall incidence rates of serious AEs and serious infections were 13.8 and 2.8 events (E)/100 PYs, respectively. Serious AEs occurred most frequently in the first 6 months and deceased thereafter. Standardised mortality ratio was 0.71 (95% CI 0.57 to 0.87) and standardised incidence ratio for malignancies was 0.64 (95% CI 0.53 to 0.76). LDA was achieved by 50% and REM by 21% of patients at last observation.
Results of this large observational study of ADA in routine clinical practice were consistent with controlled trials, with no new safety concerns during a follow-up of more than 5 years. Effectiveness of ADA was maintained during long-term observation.
Patients with rheumatoid arthritis (RA) may not respond to treatment with disease-modifying anti-rheumatic drugs (DMARDs) alone [1–4]. In patients who have failed DMARD therapy for RA, clinical studies have demonstrated the effectiveness of drugs directed against tumour necrosis factor (TNF) as monotherapy or when used in combination with DMARDs [2, 5–10]. Adalimumab (ADA) is a fully human anti-TNF monoclonal antibody for the treatment of moderate to severe RA. Initial clinical trials of ADA in patients with RA demonstrated a good safety profile, with improvements in disease signs and symptoms and functional ability, achievement of clinical remission and inhibition of radiographic disease progression [2, 3, 7].
The Research in Active Rheumatoid Arthritis (ReAct) phase 3b study was initiated in 2002 to assess the safety and effectiveness of ADA in RA patients who had failed treatment with at least one traditional DMARD [11, 12]. ADA was well tolerated and effective, alone or with DMARDs, in 6,610 patients with active RA over a mean treatment duration of 233 days [11, 12]. To evaluate the long-term safety and effectiveness of ADA in clinical practice settings over 5 years in patients who completed ReAct, the REgistry of HUMIRA™ in RA: a Long-Term Investigation of Safety and Efficacy (ReAlise) observational follow-up study was conducted (NCT00234884). The primary objectives of this analysis include examination of adverse events (AEs) and the temporal pattern of their occurrence and maintenance of response through 5 years of ADA treatment (i.e., from the first injection received in ReAct through the last observation in ReAlise).
ReAct was a 12-week, open-label multicentre study with an optional extension phase until ADA became commercially available. Methodology and results have been published . Briefly, ADA was administered to 6,610 patients with active RA (defined as 28-joint Disease Activity Score (DAS28) based on erythrocyte sedimentation rate (ESR) ≥3.2 and an unsatisfactory response to at least one synthetic DMARD). Patients also could have received prior TNF antagonist therapy with infliximab and/or etanercept if treatment was stopped 2 months before inclusion in ReAct. Patients were allowed to continue treatment with DMARDs, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs). Subsequently, patients could enter ReAlise, a multicentre (10 European countries and Australia), 5-year, uncontrolled observational study of ADA in patients with long-standing, severe RA. Patients were treated in accordance with physicians’ usual clinical care practices and local marketing authorisation requirements for commercially available ADA. ReAlise was conducted as a commitment to the European Medicines Agency (EMEA) and in accordance with the Declaration of Helsinki and applicable local regulations; each site’s institutional review board or independent ethics committee approved the protocol (Additional file 1 and Additional file 2 for ReAlise and ReAct, respectively), and all patients provided written informed consent.
Patients aged ≥18 years were eligible for ReAlise if they were in good health (per physician’s discretion) with a recent stable medical history, receiving ongoing ADA treatment, completed ≥3 months of the ReAct study, and were prescribed ADA. Patients could enroll in ReAlise within 12 months of completing ReAct. Patients continued taking concomitant medications, including DMARDs and corticosteroids, per usual care. Assessments were made at weeks 2, 6 and 12, and every 8 weeks thereafter in ReAct, every 3 months during the patients’ first year in ReAlise and every 6 months thereafter until the last observation in ReAlise.
This analysis includes clinical assessments of safety and effectiveness made at 0.5, 1, 3 and 5 years and the last visit after the first ADA injection in ReAct. AEs were collected throughout ReAct and ReAlise and for 3 months after the last visit in ReAlise. There was no systematic collection of AEs during the interval between the last assessment in ReAct and enrolment in ReAlise. AEs were tabulated using five time windows (≤0.5, 0.5 to 1, >1 to 3, >3 to 5 and >5 years) beginning after the first injection of ADA in ReAct. Standardised mortality rates (SMRs) and standardised incidence rates (SIRs) for malignancies were calculated for all patients, for all completed treatment periods.
Clinical effectiveness was assessed by the following measures: American College of Rheumatology improvements of 20% (ACR20), 50% (ACR50) and 70% (ACR70) ; European League Against Rheumatism (EULAR) categorical responses of moderate and good ; DAS28 (ESR) including individual components: swollen and tender joint counts (SJC, TJC), patient global assessment (PtGA), and ESR; low disease activity (LDA) and remission (REM) were assessed using the Simplified Disease Activity Index (SDAI) scores of ≤11 or ≤3.3, respectively . Physical functioning was measured using the Health Assessment Questionnaire Disability Index (HAQ DI). Data were analysed for mean HAQ DI scores, the percentage of patients with minimal important difference ≥0.22 and the percentage of patients with normal function, defined as HAQ DI ≤0.5.
Data were integrated from ReAct and ReAlise to evaluate long-term ADA treatment. Safety and effectiveness analyses were performed on the intention-to-treat (ITT) population and included all patients who had at least one ADA injection in ReAct. AEs were reported as events (E) and E per 100 patient-years (PYs) for all treated patients. For SMRs, study results were compared against age- and sex-matched data from the World Health Organization for each country in which the study was conducted . SIRs for malignancies were determined by comparing study results with the National Cancer Institute (NCI) Surveillance, Epidemiology and End Results (SEER) database for all malignancies and lymphoma .
To examine the effect of different therapies on the incidence of AEs, subgroup analyses were conducted for patients receiving ADA monotherapy (defined as no concomitant DMARD irrespective of combination with corticosteroids or NSAIDs) versus combination therapy of ADA with at least one DMARD. Patients also were stratified by use of corticosteroids and prior use of TNF antagonists (infliximab or etanercept) versus those who had not used these medications.
Mean (standard deviation (SD)) values were reported for clinical effectiveness measures with continuous data (for example, DAS28) using observed values. Categorical data (for example, ACR, EULAR responses) were summarised with absolute and relative frequencies using observed values.
Baseline demographics and disease activity
At baseline in ReAct
At baseline in ReAlise
Age, y, mean (SD)
Female, n (%)
Duration of RA, y, mean (SD)
Rheumatoid factor positive, n (%)
DMARD use at baseline, n (%)
SJC (28), mean (SD)
TJC (28), mean (SD)
PtGA, mm VAS, mean (SD)
DAS28 (ESR), mean (SD)
HAQ DI, mean (SD)
CRP, mg/L, mean (SD)
From the first dose of ADA in ReAct, the mean (SD) and median treatment durations were 1,016 (895) and 546 days, respectively (range, 14 to 2,681 days) or 2.9 (2.5) and 1.5 years, representing 18,272 PYs of exposure. The mean (SD) and median intervals between completion of ReAct and enrolment in ReAlise were 5.5 (3.4) and 4.8 months, respectively.
Overview of serious adverse events and adverse events of interest (E (E/100 PYs)) during more than 5 years of ADA treatment
Time windows after the first injection of ADA in ReAct
>0.5 to 1 Y
>1 to 3 Y
>3 to 5 Y
N = 6,610
N = 5,922
N = 4,283
N = 2,623
N = 2,000
Adverse event (AE)
Overall N = 6,610 (18,272 PYs)
Serious hepatic events*
SIR was 0.64 (95% confidence interval (CI) 0.53 to 0.76) for all malignancies (118 observeda/185.48 expected), excluding NMSC, and 1.99 (95% CI 1.11 to 3.28) for lymphomas (15 observed/7.55 expected). SIR for melanoma was 1.29 (95% CI 0.59 to 2.54; 8 observed/6.20 expected). Overall SMR was 0.71 (95% CI 0.57 to 0.87); there were fewer observed deaths during ADA exposure (90) than expected (127). The SMR was 0.60 (95% CI 0.38 to 0.89) for men and 0.76 (95% CI 0.59 to 0.96) for women. For both men and women, fewer deaths were observed (23 and 67, respectively) than were expected (39 and 88, respectively).
Subgroup safety analyses
The incidences of SAEs were slightly higher among patients who received ADA monotherapy (no DMARDs) and those who received corticosteroids (17.4 and 14.9 E/100 PYs, respectively) than for those who received at least one concomitant DMARD and those who did not receive corticosteroids (12.8 and 11.5 E/100 PYs, respectively). The rates of serious infections were generally similar. For patients who had received prior TNF antagonists, the overall incidence of serious infections was higher (4.2 E/100 PYs) than that for patients who had not received prior TNF antagonists (2.7 E/100 PYs). All other AEs of interest, including malignancies and lymphomas, were reported at similar rates for patients with and without a history of exposure to TNF antagonists at study entry. Similar to the overall population, SAEs and AEs of interest occurred more frequently during the initial 6 months of therapy and decreased thereafter in all subgroups (see Tables S1-S6 in Additional file 3 for data).
DAS28 (ESR) composite and individual component values, and SDAI and HAQ DI scores at 0.5, 1, 3 and 5 years of ADA exposure and last observation
PtGA, mm VAS
HAQ DI score
For patients who had received prior TNF antagonists (infliximab or etanercept), both the ACR and EULAR responses were slightly lower than those patients who had not received prior TNF antagonists (Figure S1 in Additional file 4 and Figure S2 in Additional file 5). At last observation the ACR20, ACR50, and ACR70 responses were achieved by 68%, 47%, and 29% in those without prior TNF antagonists and 55%, 32%, and 17% in the patients who had received prior TNF antagonists. The percentages of patients achieving the stringent ACR/EULAR index-based definitions of LDA and REM based on SDAI were also slightly less for the patients who had previous TNF antagonists (Figure S3 in Additional file 6). Additionally, the proportion of patients with normal function (HAQ DI ≤0.5) was 34% at last observation for those without prior TNF antagonists and 19% in the patients who had received prior TNF antagonists.
The combined data from ReAct and ReAlise include more than 6,600 RA patients and provide one of the largest well-monitored evaluations of the long-term safety and effectiveness of a single TNF antagonist in routine clinical practice settings. Other reports involving thousands of RA patients come from country registries that record and compare use of multiple TNF antagonists [18–22]. The observational study design allows for inclusion of patients receiving routine care for RA and is not restricted to patients who meet the stricter entry criteria of randomised controlled trials, including fewer comorbidities. Patients enrolled in ReAct and ReAlise reflect typical RA patients treated with TNF antagonists, who have long-standing RA with moderate to severe baseline disease activity despite treatment with DMARDs. Some patients also had previously received infliximab and/or etanercept.
ADA was well tolerated, and no new or unexpected safety concerns were identified during more than 5 years of therapy, representing nearly 20,000 PYs. The pattern and rates of AEs were comparable with those observed in double-blind studies of ADA with or without methotrexate [2, 3, 7]. SAEs, including serious infections and TB, were reported more frequently during the first year, after which the incidences decreased and remained stable. This finding is expected because of positive selection bias of the patients who tolerate the drug and less frequent visits in ReAlise, and generally aligns with data from ADA clinical trials and registries [4, 7, 18, 23–25]. A recent review of safety data from ADA clinical studies across indications found a stable rate of serious infections throughout ADA exposure, which may be attributed to differences in populations and methodology . Beyond the positive selection bias of the patients who tolerate the drug, the other possible explanations for the decrease in infection risk with ongoing TNF antagonist therapy may include decreased use of corticosteroids and better control of the RA disease process that reduces disease-associated alterations in natural immunity [18, 19]. The overall incidence rates of SAEs and serious infections with ADA (13.8 and 2.8 E/100 PYs) were found to be within the range of those previously reported in long-term clinical trials of other TNF antagonists and biological DMARDs. Rates of serious infections for infliximab and etanercept after a median follow-up of 3.9 years in the British registry were 4.6 and 3.8 E/100 PYs, respectively . Five-year data on abatacept and tocilizumab report serious infection rates of 3.0 and 5.7 E/100 PYs, respectively [27, 28]. SAEs of interest other than serious infections occurred at a low frequency and decreased over time with ADA. Similarly, the risk of TB decreased over time, with an incidence rate <0.1% in the patients treated more than 5 years. Still, five cases occurred in patients treated for more than 3 years, underscoring the need for continued attention to the risk of infection. There was no overall increased risk of malignancies; however, use of a US database (NCI) as a comparator for SIRs in this largely European population may limit interpretation of results. The observed risk of lymphomas was consistent with that for RA patients. The risk of lymphoma, both Hodgkin’s and non-Hodgkin’s, is increased by approximately two-fold in patients with RA, and this increase has been associated with the chronic inflammation of RA [23, 29, 30]. Use of disease-modifying treatment that controls chronic inflammation may reduce the elevated risk associated with uncontrolled RA. Recent long-term studies have failed to identify an effect of TNF antagonists on the incidence of cancer, including lymphoma (with exception of NMSC), and also determined that the relative risk of cancer did not increase with time since first starting a TNF antagonist or with cumulative duration of TNF antagonist therapy [31–33]. Lastly, mortality rates were lower in patients receiving ADA therapy in ReAct and ReAlise than observed in a matched population without RA, and there was no increase in the overall mortality rate over the course of the studies. The decreased rates of cancer and mortality must be interpreted with caution because patients with previous cancers may have been excluded from receiving a TNF antagonist.
Patients were allowed to continue concomitant DMARD therapy and/or corticosteroids with ADA in ReAct and ReAlise. Generally, the incidences of SAEs were similar among subgroups based on concomitant therapy, with a slightly higher rate among patients who received ADA monotherapy (no DMARDs) and those who received corticosteroids (17.4 and 14.9 E/100 PYs, respectively). Patients who had received etanercept and/or infliximab before enrolling in ReAct showed a higher rate of SAEs and infections than patients without prior history of TNF antagonist therapy, but no differences in the rates of malignancies or lymphoma were observed. Statistical analyses of these subgroups were not performed in this observational study; however, no statistical differences have been identified in controlled clinical studies that evaluated AEs in subgroups based on prior or concomitant treatment [2, 3, 12].
The effectiveness of ADA in reducing disease activity and inflammation was maintained over more than 5 years of treatment, as evidenced by the percentages of patients achieving ACR20, 50 and 70 responses and at least moderate EULAR responses. The initial 12-week improvements observed in ReAct included ACR20 in 69% and moderate and good EULAR responses in 83% and 33%, respectively . For patients who continued in ReAlise, these response rates were 66%, 80% and 42%, respectively, at last observation. LDA and REM rates also were maintained at last observation, with half of the patients achieving LDA, and one in five achieving REM. Clinically relevant functional improvement was reported for approximately two-thirds of patients, and one-third of patients reported normal function at last observation.
Approximately 70% of patients who received prior TNF antagonists discontinued that therapy because of loss or lack of response before enrolling in ReAct/ReAlise. At week 12 of ReAct, substantial clinical benefit was achieved with ADA in patients previously treated with infliximab and/or etanercept , and response rates were maintained through 3 years of ADA . In agreement with our data, clinical studies that have evaluated the effectiveness of switching TNF antagonists have generally found that treatment with a second TNF antagonist can offer comparable or slightly lower response rates than those observed in TNF antagonist-naive patients [20, 35, 36]. However, as the number of TNF antagonists increase to three or more, response rates decrease. In a study of more than 2,000 RA patients, discontinuation rates were similar for infliximab, etanercept and ADA, and factors predictive of discontinuation were increased disease severity and comorbidities . Delaying administration of TNF antagonists in patients who fail to achieve an adequate response with methotrexate has been associated with poorer clinical, functional and radiographic outcomes [4, 37]. The findings from ReAct/ReAlise indicate that switching from failed therapy with a traditional DMARD or TNF antagonist to ADA (with or without concomitant DMARD) is a reasonable strategy.
Limitations of long-term observational studies include inherent bias. Patients who experience effective or tolerable therapy are likely to continue treatment. In ReAct/ReAlise, the most common reasons for patients discontinuing the study were loss of efficacy and AEs. To address potential bias, assessment of effectiveness over 5 years included results for all efficacy parameters at last observation. Results at last observation were consistent with results at the end of 12-week treatment in ReAct .
In a clinical practice setting, ADA was well tolerated, and no new safety concerns were identified during nearly 20,000 PYs of exposure. The incidence of SAEs and serious infections decreased with ongoing ADA treatment over 5 years. The incidences of deaths and malignancies were lower than expected for the general population, and the incidence of lymphoma was within expected rates for patients with RA. Clinical response to ADA, as measured by reduced disease activity and functional improvements, was maintained through more than 5 years of observation in patients with long-standing, severe RA. Safety and effectiveness observed in more than 6,600 RA patients over 5 years were consistent with results of randomised clinical trials of ADA [2, 3, 7].
aFrom a total of 129 cases (114 cases of malignancy (excluding lymphomas, and NMSC) plus 15 cases of lymphoma), 11 were excluded (9 cases of carcinoma in situ and 2 of metastases for which the primary cancer was already counted), in keeping with the SEER database criteria for comparison.
American College of Rheumatology
28-joint Disease Activity Score based on ESR
disease-modifying anti-rheumatic drug
European Medicines Agency
erythrocyte sedimentation rate
European League Against Rheumatism
- HAQ DI:
Health Assessment Questionnaire Disability Index
low disease activity
National Cancer Institute
non-melanoma skin cancer
non-steroidal anti-inflammatory drug
patient global assessment
serious adverse event
Simplified Disease Activity Index
Surveillance, Epidemiology and End Results
standardised incidence ratio
swollen joint count
standardised mortality ratio
tender joint count
tumour necrosis factor.
The authors wish to thank Dr. Ümit Özer, a former contractor working for AbbVie, for her dedicated work as study-designated physician in both studies ReAct and ReAlise. Writing and editorial assistance, funded by AbbVie Inc., was provided by Michelle McDermott, Pharm.D., Marsha Hall, and Barbara Brooks of Scientific Connexions, Newtown, PA, USA and by Jessica L. Suboticki, PhD, an employee of AbbVie.
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