Elicit: Clinical Outcomes of Adalimumab in Rheumatoid Arthritis

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Clinical Outcomes of Adalimumab in Rheumatoid Arthritis

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May 5, 2026

Clinical outcomes rheumatoid arthritis adalimumab

Adalimumab achieves sustained clinical effectiveness in rheumatoid arthritis, with 50-60% of patients responding within 12 weeks and two-thirds of long-term persisters maintaining low disease activity or remission over 10 years, while combination therapy with methotrexate and earlier treatment initiation yield superior functional and structural outcomes.

Abstract

Adalimumab demonstrates consistent clinical effectiveness across diverse rheumatoid arthritis populations, with ACR20 responses of 50-60% at 12 weeks and rapid onset of action, as 71% of ultimate responses occur by week 2. Among patients who persist on therapy, 67-71% achieve low disease activity or remission, with benefits sustained over 10 years of treatment. Combination therapy with methotrexate substantially outperforms monotherapy, achieving 80% ACR50 responses at 10 years versus 69% with adalimumab alone, and preventing radiographic progression more effectively (modified total Sharp score change of 4.0 versus 8.8 points). Earlier treatment initiation yields superior outcomes, with patients having disease duration ≤2 years achieving normal function (HAQ-DI <0.5) at rates of 61% versus 40% for those with longer disease duration. Adalimumab remains effective following TNF antagonist failure, with 60% ACR20 responses in this population, particularly among patients who experienced loss of initial response to prior biologics. Safety profiles show serious infection rates of 2.4-2.8 events per 100 patient-years and mortality rates below general population expectations (standardized mortality ratio 0.71-0.75), with no unexpected safety signals during exposures extending beyond 5 years.

Methods

We analyzed 10 sources from an initial pool of 200, using 7 screening criteria. Each paper was reviewed for 8 key aspects that mattered most to the research question. More on methods

Records from Elicit search

n = 200

Papers screened using: Adult RA Population, Adalimumab Intervention, Clinical Outcomes Reported, Appropriate Study Design, Adequate Treatment Duration, RA Focus (Not Other Arthritides), Clinical Effectiveness Focus

n = 200

Papers screened out

n = 190

Papers included for extraction

n = 10

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Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: “Clinical outcomes rheumatoid arthritis adalimumab”

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper. We gave the model the extraction instructions shown below for each column.

Extract characteristics of the RA patient population treated with adalimumab, including:

Extract details about adalimumab treatment regimen for RA, including:

Extract all clinical outcome measures assessed for adalimumab treatment in RA patients, including:

Extract quantitative results for clinical outcomes of adalimumab treatment in RA, including:

Extract safety data for adalimumab treatment in RA patients, including:

Extract patient-reported outcomes and quality of life measures for adalimumab treatment in RA, including:

Extract factors that influenced adalimumab effectiveness in RA patients, including:

Extract study design characteristics relevant to interpreting adalimumab outcomes in RA, including:

Results

Characteristics of Included Studies

The review included 10 studies evaluating adalimumab in rheumatoid arthritis patients, with study durations ranging from 12 weeks to 10 years. Full text was available for 6 studies, while 4 were analyzed based on abstracts only.

Study

Full text retrieved?

Study Type

Patient Population

Disease Duration

Baseline Disease Activity

Treatment Regimen

Duration

Setting

V. Strand et al., 2012

Yes

Phase III RCT, double-blind

MTX-naive early RA

Mean 9 months

≥8 swollen joints, ≥10 tender joints

Adalimumab 40mg EOW ± MTX

104 weeks

Clinical trial, 133 sites in North America, Europe, Australia

B. Haraoui et al., 2011

Yes

Multicenter, open-label, prospective single cohort

Active RA, 97.8% prior DMARD experience

Mean >12 years

Mean DAS28 6.1

Adalimumab 40mg EOW + prior DMARDs

12 weeks

Real-world, 69 sites across Canada

S. Bombardieri et al., 2007

No

Open-label trial

Prior TNF antagonist exposure

Not mentioned

Not mentioned

Adalimumab 40mg EOW

12 weeks with optional extension

Clinical trial

D. Pappas et al., 2017

Yes

Observational registry

Biologic-naive adults with RA

Mean 7 years

Mean CDAI 19.9

Not specified

Up to 12 years

Real-world, 170 sites across 40 US states

G. Burmester et al., 2014

Yes

Phase 3b + postmarketing observational (ReAct/ReAlise)

Active RA, failed ≥1 DMARD

Not mentioned

Mean DAS28 6.0

Adalimumab monotherapy or + DMARDs

Mean 1,016 days (5+ years)

Real-world, 10 European countries and Australia

L. B. A. Putte et al., 2003

No

Phase II RCT, double-blind, placebo-controlled

DMARD-refractory, longstanding active RA

Longstanding

Not mentioned

Adalimumab 20/40/80mg weekly monotherapy

12 weeks

Clinical trial

A. E. van der Bijl et al., 2008

Yes

Prospective open-label pilot

Active RA, prior infliximab failure

Mean 12 years

DAS28 ≥3.2

Adalimumab 40mg EOW + existing DMARDs

16 weeks, maintenance to 56 weeks

Clinical trial

E. Keystone et al., 2014

Yes

RCT with open-label extension (PREMIER OLE)

Early RA, disease duration <3 years

<3 years

DAS28 5.6 ± 1.7

Initial: adalimumab 40mg EOW ± MTX; OLE: adalimumab with optional MTX

2 years DB + 8 years OLE

Clinical trial, Australia, Europe, North America

D. Karateev et al., 2012

No

Open-labeled multicenter

Active RA unresponsive to standard therapy

Not mentioned

DAS28-CRP 6.2 ± 0.84

Adalimumab 40mg EOW + DMARDs

24 weeks

Clinical trial, Russia

D. Furst et al., 2015

No

Phase 3 open-label extension (DE020)

DMARD-refractory RA

Mean 11.7 years

Not mentioned

Adalimumab 40mg EOW or monthly

Up to 10 years

Clinical trial continuation

toof

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Studies varied considerably in patient populations. Three studies focused on early RA with disease duration under 3 years, while others enrolled patients with established disease ranging from 7 to over 12 years. Most studies enrolled patients with moderate to severe disease activity at baseline, with mean DAS28 scores ranging from 5.6 to 6.2 where reported. Study populations also differed in prior treatment exposure, with some requiring DMARD failure, others specifically enrolling biologic-naive patients, and some examining patients who had failed prior TNF antagonists.

Clinical Effectiveness

Disease Activity and Response Rates

Clinical effectiveness varied by study duration and population characteristics. In short-term studies (12-24 weeks), ACR20 response rates ranged from 37% at 4 weeks to 88% at 24 weeks. At 12 weeks, ACR20 responses were achieved by 50.7-60% of patients, ACR50 by 27-33%, and ACR70 by 8-13%. In the CanACT study, ACR20 responses were observed in 37% of patients by week 4, increasing to 58.4% by week 12. Similarly rapid onset was noted by van der Putte et al., with 71% of ultimate ACR20 responses achieved by week 2.

Long-term studies demonstrated sustained or improved response rates. Among patients who persisted on adalimumab for at least one year in the Corrona registry, 67% achieved low disease activity or remission (CDAI ≤10), with these improvements maintained over 10 years of follow-up. In the PREMIER open-label extension, ACR50 responses at year 10 were 80.0% for adalimumab plus MTX, 69.4% for adalimumab monotherapy, and 74.0% for MTX monotherapy. The DE020 continuation study reported that among the 33.8% of patients who completed 10 years of treatment, 71.2% achieved DAS28-CRP ≤3.2, 42.4% achieved HAQ-DI <0.5, and 37.3% achieved both.

Remission and Low Disease Activity

Remission rates varied by definition and study duration. Using DAS28 <2.6 criteria, remission was achieved by 12-15.3% of patients at 12 weeks, increasing to 25% by 24 weeks. At year 10 in the PREMIER extension, DAS28 remission was achieved by 75.6% in the adalimumab plus MTX group, compared to 61.7% with adalimumab monotherapy and 56.2% with MTX monotherapy. Using SDAI-based criteria, remission rates at 10 years were 29.7% in the DE020 study.

Low disease activity (DAS28 <3.2) was achieved by 28.9% of patients at 12 weeks in the CanACT study, and 37% by 24 weeks in the Russian study. In the ReAct/ReAlise 5-year observational study, 50% of patients achieved low disease activity and 21% achieved remission at final observation. At year 10 in the PREMIER extension, DAS28 low disease activity was achieved by 92.3% of patients receiving adalimumab plus MTX, versus 77.8% with adalimumab and 74.0% with MTX monotherapy.

Functional Outcomes

Functional status improved across studies, measured primarily by HAQ-DI. In the PREMIER trial, patients treated with adalimumab plus MTX demonstrated significant improvements from baseline HAQ-DI scores of 1.5-1.6 to week 104 (p <0.0001 versus MTX monotherapy). The CanACT study showed HAQ-DI improvement of 0.5 units from baseline to week 12. In the Russian study, HAQ functional index decreased from 1.9 ± 0.6 at baseline to 1.04 ± 0.68 at 24 weeks.

Long-term functional benefits were sustained. In the DE020 10-year study, 42.4% of completers achieved HAQ-DI <0.5, while 32% achieved normal function (HAQ-DI ≤0.5) in the ReAct/ReAlise 5-year study. Comprehensive disease control (combining low disease activity and normal function) was achieved by 26.7% of patients in the adalimumab plus MTX group at year 10, compared to 11.8% with adalimumab monotherapy and 13.0% with MTX monotherapy.

Radiographic Progression

Radiographic outcomes were assessed in long-term studies. In the PREMIER 10-year extension, modified total Sharp score change was significantly lower with adalimumab plus MTX (4.0) compared to adalimumab monotherapy (8.8) or MTX monotherapy (11.0). Clinically relevant radiographic progression occurred in only one-third of patients receiving combination therapy, versus over half receiving monotherapy.

Clinical Outcomes in Special Populations

Among patients who had previously failed TNF antagonists, adalimumab demonstrated meaningful clinical benefit. In the ReAct study of 899 patients with prior etanercept and/or infliximab exposure, 60% achieved ACR20 and 33% achieved ACR50 at week 12, with 12% achieving clinical remission (DAS28 <2.6). Among patients who failed infliximab therapy in the van der Bijl study, 46% achieved ACR20 and 28% achieved ACR50 at week 16, with higher response rates observed in patients who experienced loss of response to infliximab (60% ACR20) compared to those with no response (29% ACR20).

Safety Outcomes

Safety data were reported across varying durations of exposure, from 12 weeks to over 5 years. Overall adverse event rates varied from 2.6 events per 100 patient-years in the CanACT study to 317.2 events per 100 patient-years in the DE020 study, though the latter included all events regardless of severity. In the PREMIER extension, 97.3% of patients reported any adverse events, with 72.2% experiencing treatment-emergent adverse events possibly related to adalimumab.

Serious adverse events occurred at rates of 2.6-13.8 events per 100 patient-years. In the ReAct/ReAlise study, serious adverse events were most common in the first six months and decreased thereafter, with an overall incidence of 13.8 events per 100 patient-years. Serious adverse events occurred in 1.8% of patients in the CanACT study and 11.2% of patients in the PREMIER extension.

Serious infections were reported at rates of 2.4-2.8 events per 100 patient-years. The CanACT study reported one death due to myocardial infarction secondary to staphylococcal sepsis attributed to the study drug. In the van der Bijl study of patients who had failed infliximab, one case of pulmonary tuberculosis and one case of cellulitis were reported among serious infections. The PREMIER extension reported 3 cases of active tuberculosis, while tuberculosis risk decreased over time in the ReAct/ReAlise study, with an incidence rate less than 0.1% in patients treated for more than five years. No cases of tuberculosis were reported in the Russian study despite screening all patients.

Malignancy rates showed no overall increase compared to expected rates. In the ReAct/ReAlise study, the standardized incidence ratio for malignancies was 0.64 (95% CI 0.53-0.76). However, the PREMIER extension found increased risk for lymphomas (SIR = 3.75) and squamous cell nonmelanoma skin cancer (SIR = 2.69). Two cases of lymphomas were reported in the van der Bijl study.

Mortality was lower than expected in the general population. The ReAct/ReAlise study reported a standardized mortality ratio of 0.71 (95% CI 0.57-0.87). The PREMIER extension had 23 deaths over 10 years, with a mortality rate of 0.6 events per 100 patient-years and a standardized mortality ratio of 0.75 (95% CI 0.51-1.07).

Discontinuation due to adverse events ranged from 4.4% in the CanACT study to 22.5% in the PREMIER extension. In the van der Bijl study, 14.6% discontinued due to adverse events. In the ReAct/ReAlise study, discontinuations due to adverse events were approximately 2.5% in the first six months and decreased over time.

Patient-Reported Outcomes and Quality of Life

Health-related quality of life measures showed consistent improvements across studies, though the specific instruments varied. The PREMIER trial comprehensively assessed multiple quality of life domains, showing significant improvements in SF-36 Physical Component Summary scores (p <0.0001) and in several domains including physical function, bodily pain, vitality, and role limitations-physical. Health utility measures also improved significantly, with SF-6D scores meeting the minimally clinically important difference of 0.03 (p = 0.0152) and HUI-3 scores exceeding the MCID of 0.03 points (p = 0.0034).

Pain assessments demonstrated substantial improvements. In the PREMIER trial, VAS pain scores improved significantly from baseline to week 104 (p <0.0001). The CanACT study reported pain decreasing from a mean of 66.2 at baseline to 37.3 at week 12. Similarly, patient assessment of disease activity decreased from 65.1 to 37.4 in the CanACT study. In the Corrona registry, pain scores showed significant decreases of 13.5 points in the first year.

Fatigue improved significantly in the PREMIER trial, with FACIT-F scores showing significant improvements (p <0.0001). Patient global assessment also improved significantly (p <0.0001). Work productivity and disability measures, assessed through HAQ-DI, showed significant improvements (p <0.0001).

Long-term quality of life data from the ReAct/ReAlise study showed that mean HAQ-DI scores reduced at 6 months and remained stable over 5 years, with 68% of patients achieving clinically relevant reductions in physical disability. The DE020 study reported that higher proportions of patients with shorter disease duration achieved better HAQ-DI scores (60.6% versus 39.5%, p = 0.023).

Factors Influencing Treatment Effectiveness

Disease Duration and Timing of Treatment

Earlier treatment initiation consistently predicted better outcomes. The PREMIER trial specifically enrolled patients with disease duration less than 3 years, demonstrating the efficacy of early intervention. In the DE020 10-year study, patients with shorter baseline disease duration (≤2 years) achieved significantly better outcomes than those with longer disease duration (>2 years), with HAQ-DI <0.5 achieved by 60.6% versus 39.5% (p = 0.023) and combined DAS28-CRP ≤3.2 plus HAQ-DI <0.5 achieved by 58.1% versus 32.5% (p = 0.006). However, effectiveness outcomes were similar regardless of RF status in this population.

Combination Therapy Versus Monotherapy

Combination therapy with methotrexate consistently outperformed monotherapy. In the PREMIER 10-year extension, patients initially randomized to adalimumab plus MTX demonstrated superior outcomes across multiple measures compared to those initiating with monotherapy. At year 10, ACR50 responses were 80.0% for adalimumab plus MTX versus 69.4% for adalimumab monotherapy and 74.0% for MTX monotherapy. DAS28 remission was achieved by 75.6% with combination therapy versus 61.7% and 56.2% with the respective monotherapies. Most notably, radiographic progression was significantly less with combination therapy, with modified total Sharp score changes of 4.0 versus 8.8 and 11.0 for the monotherapy groups.

In the ReAct/ReAlise study, monotherapy and corticosteroid use were associated with slightly higher rates of serious adverse events compared to combination therapy with DMARDs. Most patients in the van der Bijl study received combination therapy with DMARDs, particularly methotrexate, and those receiving methotrexate had higher serum adalimumab concentrations.

Prior Biologic Exposure

Prior biologic exposure influenced treatment responses. In the CanACT study, patients naive to biologic DMARDs demonstrated numerically greater clinical responses compared to those with prior BDMARD experience, though both subgroups showed significant improvements from baseline. The ReAct/ReAlise study found that patients with prior TNF antagonist exposure had slightly lower response rates and higher rates of serious adverse events and infections compared to TNF-naive patients.

However, adalimumab remained effective even after prior TNF antagonist failure. In the ReAct study, 899 patients with prior etanercept and/or infliximab exposure experienced substantial clinical benefit. In the van der Bijl study examining patients who failed infliximab, differential responses were observed based on the reason for discontinuation, with better outcomes in patients who experienced loss of response to infliximab compared to those with no initial response. Notably, baseline HACA (human antichimeric antibody) status did not significantly impact adalimumab effectiveness in this population.

Baseline Disease Severity

Baseline disease severity influenced outcomes in some studies. The Russian study noted differences in effectiveness based on baseline disease activity, though specific details were not provided. The Corrona registry enrolled patients with moderate to severe disease activity at baseline (mean CDAI 19.9), and those achieving low disease activity or remission demonstrated sustained improvements over long-term follow-up.

Synthesis

The included studies demonstrate considerable heterogeneity in design, duration, patient populations, and outcomes, yet several consistent patterns emerge. This heterogeneity can be explained by examining specific contexts and methodological differences rather than declaring conflicting results.

Short-Term Versus Long-Term Effectiveness

Studies reporting outcomes at different time points show distinct but complementary patterns. Short-term studies (12-24 weeks) consistently demonstrate rapid onset of action, with 71% of ultimate ACR20 responses achieved by week 2 in one trial and significant improvements observed by week 4 across multiple studies. These early response rates (ACR20 of 37-60% at 12 weeks) might appear modest compared to long-term outcomes showing 80% ACR50 responses at 10 years.

However, this apparent discrepancy reflects patient selection rather than contradictory findings. Long-term studies inherently examine only patients who persist on therapy—representing 33.8% to 64.1% of initiators at various time points—while short-term studies include all randomized patients regardless of subsequent persistence. The 67% of one-year persisters achieving low disease activity or remission aligns well with the 71.2% of 10-year completers achieving DAS28-CRP ≤3.2, suggesting that patients who continue treatment maintain stable benefit rather than experiencing progressive improvement. Among discontinuers in the Corrona registry, 61.6% were not in low disease activity and 41.9% switched to another biologic within 12 months, confirming that persisters represent a selected population with sustained response.

Combination Therapy Versus Monotherapy Effects

The PREMIER trial provides the most rigorous comparison of combination versus monotherapy, with 10-year data showing superior outcomes for adalimumab plus MTX across clinical, functional, and radiographic measures. Radiographic progression is particularly revealing: the modified total Sharp score increased by only 4.0 points with combination therapy versus 8.8 and 11.0 with monotherapy over 10 years, representing clinically meaningful structural preservation. This combination benefit persisted despite the open-label extension design where MTX could be added to monotherapy arms, yet only one-third showed clinically relevant progression with initial combination therapy versus over half with initial monotherapy.

However, other studies showing effectiveness without explicitly comparing monotherapy versus combination used different populations and designs that preclude direct comparison. The phase II trial by van der Putte et al. specifically evaluated monotherapy in DMARD-refractory patients, achieving 57% ACR20 responses at 12 weeks—lower than the 80% ACR50 seen with combination therapy at 10 years, but in a more treatment-resistant population over a much shorter period. The ReAct/ReAlise observational study, where most patients received combination therapy prescribed according to usual care, found monotherapy associated with higher adverse event rates, but this likely reflects confounding by indication (sicker patients unable to tolerate MTX receiving monotherapy) rather than a pure treatment effect.

Disease Duration and Treatment Timing Effects

Studies in early RA (<3 years disease duration) versus established RA (7-12+ years) reveal dose-response relationships for treatment timing. Within the DE020 study examining the same treatment, patients with ≤2 years disease duration achieved HAQ-DI <0.5 at rates of 60.6% versus 39.5% for those with >2 years (p = 0.023), demonstrating a linear relationship between earlier treatment and better functional outcomes. This pattern holds across studies: the PREMIER early RA trial achieved 92.3% low disease activity with combination therapy, while the CanACT study in patients with mean disease duration >12 years achieved only 28.9% low disease activity.

However, the benefit of early treatment primarily manifests in radiographic outcomes and maximal functional recovery rather than symptomatic control. Studies in established RA still achieved meaningful ACR20-50 responses, but radiographic damage prevention was most pronounced with early combination therapy. This suggests a window for structural preservation that closes with disease progression, while symptomatic benefit remains achievable across disease durations.

Prior Biologic Exposure Effects

The effectiveness of adalimumab following TNF antagonist failure initially appears contradictory to immunological expectations of class effects. Yet examining specific failure mechanisms resolves this apparent paradox. Patients who experienced loss of initial response to infliximab achieved 60% ACR20 responses to adalimumab, while those with no initial response achieved only 29%, suggesting that secondary failure (often due to anti-drug antibodies) predicts switching success better than primary failure (possibly reflecting true class non-response). The finding that baseline HACA status did not impact adalimumab effectiveness supports this mechanistic explanation—antibodies to infliximab do not cross-react with adalimumab’s fully human structure.

Furthermore, the ReAct/ReAlise study’s finding that prior TNF exposure conferred slightly lower response rates and higher infection risks aligns with cumulative immunosuppression effects rather than pure treatment resistance. The 60% ACR20 and 33% ACR50 responses in the TNF-experienced ReAct population remain clinically meaningful, particularly given that alternative treatments for this difficult-to-treat population are limited.

Methodological Quality and Real-World Effectiveness

The convergence of findings from randomized controlled trials and real-world observational studies strengthens confidence in effectiveness estimates. The CanACT real-world Canadian study achieved 58.4% ACR20 at 12 weeks, closely matching the 57.1% ACR20 seen with adalimumab 40mg in the phase II RCT at the same timepoint, despite the real-world study including patients with longer disease duration and prior DMARD failures. Similarly, the Corrona registry’s finding that 67% of persisters achieved low disease activity aligns well with the 71.2% achieving DAS28-CRP ≤3.2 in the controlled DE020 extension.

However, safety event rates show greater heterogeneity between controlled and observational settings, ranging from 2.6 events per 100 patient-years in the CanACT real-world study to 317.2 in the DE020 trial. This likely reflects different event ascertainment and reporting protocols rather than true variation—the PREMIER extension reported that 97.3% of patients experienced any adverse events, a rate consistent with comprehensive prospective capture of all events including mild ones, while real-world studies may only capture events prompting medical attention. Serious adverse events and infections showed more consistent rates (2.4-2.8 per 100 patient-years for serious infections), suggesting these more objective outcomes are reliably detected across settings.

References

S. Bombardieri, Aa Ruiz, P. Fardellone, P. Geusens, Frank McKenna, and 5 more\ (2007).Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice. Rheumatology

D. Pappas, J. Kremer, J. Griffith, G. Reed, Bob A. Salim, and 2 more\ (2017).Long-Term Effectiveness of Adalimumab in Patients with Rheumatoid Arthritis: An Observational Analysis from the Corrona Rheumatoid Arthritis Registry. Rheumatology and Therapy

G. Burmester, M. Matucci-Cerinic, X. Mariette, F. Navarro-Blasco, S. Kary, and 2 more\ (2014).Safety and effectiveness of adalimumab in patients with rheumatoid arthritis over 5 years of therapy in a phase 3b and subsequent postmarketing observational study. Arthritis Research & Therapy

V. Strand, A. Rentz, M. Cifaldi, N. Chen, Sanjoy Roy, and 1 more\ (2012).Health-related Quality of Life Outcomes of Adalimumab for Patients with Early Rheumatoid Arthritis: Results from a Randomized Multicenter Study. Journal of Rheumatology

B. Haraoui, A. Cividino, J. Stewart, B. Guérette, E. Keystone\ (2011).Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study. BMC Musculoskeletal Disorders

L. B. A. Putte, R. Rau, F. Breedveld, J. Kalden, M. Malaise, and 8 more\ (2003).Efficacy and safety of the fully human anti-tumour necrosis factor α monoclonal antibody adalimumab (D2E7) in DMARD refractory patients with rheumatoid arthritis: a 12 week, phase II study. Annals of the Rheumatic Diseases

A. E. van der Bijl, F. Breedveld, C. Antoni, J. Kalden, S. Kary, and 4 more\ (2008).An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clinical Rheumatology

E. Keystone, F. Breedveld, D. M. van der Heijde, R. Landewé, S. Florentinus, and 4 more\ (2014).Longterm Effect of Delaying Combination Therapy with Tumor Necrosis Factor Inhibitor in Patients with Aggressive Early Rheumatoid Arthritis: 10-year Efficacy and Safety of Adalimumab from the Randomized Controlled PREMIER Trial with Open-label Extension. Journal of Rheumatology

D. Karateev, E. Nasonov, E. Luchikhina, V. Mazurov, I. Salikhov, and 2 more\ (2012).[The efficiency and safety of adalimumab treatment in patients with active rheumatoid arthritis unresponsive to standard therapy: Russian national study results]. Терапевтический архив

D. Furst, A. Kavanaugh, S. Florentinus, H. Kupper, M. Karunaratne, and 1 more\ (2015).Final 10-year effectiveness and safety results from study DE020: adalimumab treatment in patients with rheumatoid arthritis and an inadequate response to standard therapy. Rheumatology

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Safety and effectiveness of adalimumab in a clinical setting that reflects Canadian standard of care for the treatment of rheumatoid arthritis (RA): Results from the CanACT study

B. Haraoui, A. Cividino, J. Stewart, B. Guérette, E. Keystone

BMC Musculoskeletal Disorders·

2011·

13 citations

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Patient Population

- Disease duration at baseline: Mean disease duration > 12 years - Disease severity/activity at baseline: Mean DAS28 score of 6.1 - Prior DMARD experience and failures: 97.8% previously treated with 1 or more DMARDs; unsatisfactory responses or intolerance - Rheumatoid factor (RF) status: Positive RF as one of the eligibility criteria - Demographics: 18 years of age or older - Functional status at baseline: Mean HAQ-DI score of 1.5 - Specific inclusion criteria: Active RA with at least 5 swollen joints; positive RF, joint erosions, or HAQ-DI score of at least 1

Adalimumab Treatment

- Dosage and frequency: 40 mg every other week - Route of administration: Subcutaneous - Treatment duration and follow-up period: 12 weeks with assessments every 4 weeks - Combination therapy: Used with pre-study DMARD treatment regimens, corticosteroids, and NSAIDs - Concomitant medications: DMARDs, corticosteroids, NSAIDs - Dose adjustments or treatment modifications: Not mentioned - Setting: Real-world, reflecting Canadian clinical practice

Clinical Outcome Measures

- Disease activity measures: DAS28 - ACR response criteria: ACR20, ACR50, ACR70 - Remission definitions: DAS28 < 2.6, DAS28 < 3.2 - Functional measures: HAQ-DI - Joint assessments: Tender joint count, Swollen joint count - Laboratory markers: ESR - Radiographic progression measures: Not mentioned - Time points: Weeks 4, 8, 12

Clinical Effectiveness Results

- Percentage of patients achieving each outcome measure: - Clinical remission (DAS28 < 2.6): 15.3% at Week 12 - Low-disease activity (DAS28 < 3.2): 28.9% at Week 12 - ACR20: 37% at Week 4, 58.4% at Week 12 - ACR50: 10.6% at Week 4, 30.6% at Week 12 - ACR70: 2.4% at Week 4, 12.7% at Week 12 - Mean changes from baseline with statistical significance: - DAS28: Significant improvements as early as Week 4 - Tender joints: Decreased from 14.9 to 6.8 - Swollen joints: Decreased from 13.2 to 6.4 - HAQ-DI score: Improved by an average of 0.5 units - ESR: Decreased from 30.3 mm/h to 20.0 mm/h (P < 0.001) - Response rates at different time points: - Week 4: ACR20 (37%), ACR50 (10.6%), ACR70 (2.4%) - Week 12: ACR20 (58.4%), ACR50 (30.6%), ACR70 (12.7%) - Remission rates: - Clinical remission (DAS28 < 2.6): 15.3% at Week 12 - Low disease activity achievement rates: - Low-disease activity (DAS28 < 3.2): 28.9% at Week 12 - Radiographic progression results: - Not mentioned - Time to response: - Significant improvements as early as Week 4 - Sustained response data: - Continued improvements through Week 12 - Comparative effectiveness vs other treatments: - Patients naïve to BDMARD therapy showed greater clinical responses compared to those with prior BDMARD experience

Safety Outcomes

- Overall adverse event rate: 2.6 events per 100 patient-years - Serious adverse events: 1.8% of patients - Serious infections: 2.4 events per 100 patient-years - Malignancies: One case of basal cell carcinoma (not related to adalimumab) - Deaths: One patient died due to myocardial infarction secondary to staphylococcal sepsis (attributed to study drug) - Discontinuation rate due to adverse events: 4.4% - Specific safety concerns: No cases of tuberculosis reported

Quality of Life

- HAQ-DI score improved by an average of 0.5 units from 1.5 (0.6) at baseline to 1.0 (0.7) at Week 12. - Patient's assessment of pain decreased from a mean (SD) of 66.2 (22.3) to 37.3 (27.5). - Patient's assessment of disease activity decreased from 65.1 (22.7) to 37.4 (27.2). - No information on SF-36 scores, SF-6D, HUI-3, EQ-5D, FACIT-F, work productivity/disability measures, or sleep quality.

Outcome Moderators

- Prior biologic exposure: Patients naïve to BDMARD therapy showed greater clinical responses compared to those with prior BDMARD exposure. - Concomitant medication effects: DMARDs were allowed to continue throughout the study, indicating combination therapy. - Baseline disease severity: Mean DAS28 score was 6.1, but no specific subgroup analysis based on baseline severity is mentioned. - Impact of disease duration: Not mentioned. - Effect of RF status: Not mentioned. - Differences between monotherapy vs combination therapy: Combination therapy with DMARDs was allowed. - Age or gender differences: Not mentioned. - Subgroup analyses: Only prior biologic exposure is discussed.

Study Design

- Study type: Multicenter, open-label, prospective, single cohort study - Study duration and follow-up period: 12 weeks with follow-up visits every 4 weeks - Sample size and completion rates: 879 patients enrolled, 772 (87.9%) completed - Control groups or comparators: None - Blinding status: Open-label - Geographic location/healthcare setting: Conducted at 69 sites across Canada - Enrollment period/dates: Not specified - Primary vs secondary analysis designation: Primary objective is safety; secondary objectives include clinical effectiveness and other outcomes

BackgroundThis multicenter, open-label, prospective, single cohort study evaluated the effectiveness and safety of adalimumab in a clinical setting reflecting the Canadian standard of care for the treatment of patients with rheumatoid arthritis (RA).MethodsPatients ≥ 18 years of age with a history of active RA ≥ 3 months and fulfilling Canadian requirements for biological therapy received adalimumab 40 mg subcutaneously every other week for 12 weeks. Pre-study DMARD treatment regimens, corticosteroids, or NSAIDs were allowed throughout the study. The primary effectiveness outcome measure was the mean change in 28-joint disease activity score (DAS28) from baseline to Week 12. Secondary measures included the proportion of patients achieving joint remission (DAS28 < 2.6) and low-disease activity (DAS28 < 3.2) at Week 12, and European League Against Rheumatism (EULAR: moderate and good) and American College of Rheumatology (ACR: ACR20, 50, and 70) responses, as well as responses in ACR core components at Weeks 4, 8, and 12. Subgroup analysis included a comparison of patients naïve to biological DMARD (BDMARD) therapy versus BDMARD-experienced patients. Safety was assessed in terms of adverse and serious adverse events.ResultsA total of 879 patients (mean disease duration > 12 years) were enrolled; 772 (87.9%) completed the 12-week period. Adalimumab treatment was associated with rapid and sustained improvements in the signs and symptoms of RA. Significant improvements in mean DAS28 score were observed as early as Week 4. After 12 weeks of adalimumab treatment, 15.3% and 28.9% of patients achieved clinical remission and low-disease activity, respectively. Similarly, significant improvements in ACR core components were observed as early as Week 4, with continued improvements occurring through 12 weeks. Patients naïve to BDMARD therapy demonstrated numerically greater clinical responses when compared with patients who had experienced prior BDMARD therapy, although both subgroups were associated with significant improvements from baseline. The rates and types of adverse events, as well as the results of laboratory measures, demonstrated that adalimumab was generally safe and well-tolerated.ConclusionsThis study demonstrated that, under conditions reflective of the normal clinical practice in Canada, adalimumab is an effective and safe treatment for patients with RA.Trial registrationNCT00649545.

Background

Rheumatoid arthritis (RA) is the most common inflammatory form of arthritis, affecting approximately 1% of Canadian adults [1]. The long-term prognosis of RA is poor. After 10 years, approximately 50% of patients will have work disability. Moreover, after 20 years, up to 80% of patients will have evidence of physical disability or joint abnormalities [2]. RA is also associated with premature death. Indeed, the median life expectancy of an RA population is reduced by 3 to 18 years when compared with a non-RA population [3].

Tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine, plays a critical role in mediation of the inflammatory synovitis, cartilage matrix degradation, and bony erosions in RA [4]. TNF-α has been shown to be highly expressed in inflamed synovial tissue of patients with RA, particularly at the cartilage-pannus junction [5][6][7]. Adalimumab is a fully human recombinant immunoglobulin G1 (IgG1) monoclonal antibody directed against TNF-α [8,9]. Structurally and functionally analogous to naturally occurring human IgG1, adalimumab has a terminal half-life of approximately 2 weeks. Adalimumab has a high affinity for TNF-α and does not bind to other cytokines such as lymphotoxin. Adalimumab exerts its therapeutic effects by blocking the interaction of TNF-α with the p55 and p75 TNF-α cell surface receptors [8].

Adalimumab has been extensively studied for the treatment of RA. The clinical efficacy and safety parameters of recommended doses of adalimumab were determined from the results of 4 pivotal trials (DE011, ARMADA, STAR and DE019) [10][11][12][13]. Data from these studies have shown that adalimumab significantly reduced the signs and symptoms of RA. The administration of adalimumab was also associated with significant improvements in physical function and quality of life-related outcomes. The beneficial effects of adalimumab were observed whether it was administered as monotherapy or used in combination with traditional disease-modifying antirheumatic drugs (DMARDs). Moreover, data from the DE019 study [11] indicated that adalimumab reduced the radiologic progression of RA when administered to patients who partially responded to methotrexate (MTX) therapy. Interestingly, the results from the DE013 (PREMIER) study [14] confirmed that the administration of adalimumab in combination with MTX is more effective than monotherapy with either adalimumab or MTX alone in inhibiting the progression of structural joint damage in patients with early RA. Results obtained from open-labelextension studies suggest that the long-term administration of adalimumab is associated with continued efficacy and is generally safe and well-tolerated [15][16][17].

While randomized, controlled trials (RCTs) are fundamental in assessing efficacy and tolerability of therapies, often there are discrepancies between treatments in controlled circumstances and those of usual clinical practice. In addition, practice may vary between countries and regions. The CanACT study was designed to assess the effectiveness and tolerability of subcutaneous (sc) adalimumab 40 mg administered every other week (eow) to patients with RA in a setting that reflects Canadian routine clinical care.

Patients

Eligible patients were 18 years of age or older and had a history of RA, diagnosed according to the 1987 revised criteria of the American College of Rheumatology (ACR) [18] for at least 3 months. To be eligible for study entry, patients had to have active disease, which was defined by the presence of at least 5 swollen joints (of 66 joints evaluated) and 1 of the following: positive rheumatoid factor (RF), 1 or more joint erosions present on x-ray, or a disability index of the health assessment questionnaire (HAQ-DI) score of at least 1. In addition, patients had to have a history of unsatisfactory responses or intolerance to prior antirheumatic therapies, as required by local Canadian provincial guidelines for the initiation of biological DMARDs (BDMARDs). Concomitant prednisone dosages had to be < 10 mg/ day. All patients were screened for latent tuberculosis and treated, when indicated, according to the Canadian Rheumatology Association (CRA) recommendations.

Patients were excluded from the study if they had failed more than 1 BDMARD, had received prior anti-CD4 therapy, had a positive HIV status, or had a history of active tuberculosis or other infections suggestive of significant or profound immunosuppression. Patients with a history of cancer within the past 10 years other than successfully treated nonmetastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix were excluded, as were those with a history of malignant lymphoma or leukemia, those with a history of neurologic symptoms suggestive of central nervous system demyelinating disease (eg, multiple sclerosis), and those with a history of or current acute inflammatory joint disease or an origin other than RA (eg, systemic lupus erythematosus).

Protocol

This study was a multicenter, open-label, prospective, single cohort study of adalimumab with concomitant antirheumatic medications. The primary objective was to assess the safety of adalimumab 40 mg administered eow to patients with moderate to severe, active RA who failed prior DMARD therapy. The secondary objectives of the study were to assess the clinical effectiveness of adalimumab and its impact on quality of life, productivity, and specific direct medical and indirect resource utilization in these same patients.

Performed at 69 sites across Canada, this study was conducted in accordance with ICH Good Clinical Practice and ethical principles as defined in the Declaration of Helsinki (1989 revision) and all applicable local regulations. All patients gave their written, informed consent. The study protocol, informed consent form, and patient information were reviewed and approved for community sites by an independent Ethics Committee/ Institutional Review Board (IRB Services, Aurora, Ontario) or by respective University Institutional review boards.

After screening and baseline evaluations, patients returned for assessments every 4 weeks until the Week 12 visit. Patients who completed the minimum 12-week treatment period before adalimumab became commercially available were eligible to enter a 12-week continuation phase. Results are presented for the first 12 weeks of therapy only.

All patients received adalimumab at a dose of 40 mg sc eow. All patients were instructed in self-injection techniques. DMARD treatment regimens as well as prednisone or equivalent (< 10 mg/day) and nonsteroidal anti-inflammatory drugs (NSAIDs) were allowed to continue at the prestudy dose throughout the course of the study. Other biological therapies and cyclosporine were excluded during the study. Patients previously treated with approved biologics (eg, etanercept, infliximab, anakinra) were allowed to enter the study only if the respective treatment was discontinued at least 2 months prior to baseline. Cyclosporine had to be discontinued at baseline. Intra-articular injections of corticosteroids were allowed at any time during the course of the study if deemed absolutely necessary to mimic real practice. Injected joints were excluded from further evaluation.

The primary effectiveness outcome measure in this study was the mean change in the 28-joint disease activity score (DAS28) [19] from baseline to Week 12. Secondary effectiveness assessments included the proportion of patients achieving clinical remission (defined as DAS28 < 2.6) and low-disease activity (defined as DAS28 < 3.2) at Week 12, as well as the proportion achieving European League Against Rheumatism (EULAR: moderate and good) and American College of Rheumatology (ACR: ACR20, 50, and 70) responses at Weeks 4, 8, and 12. Other secondary outcome measures were the mean changes in ACR core components [tender joint count, swollen joint count, erythrocyte sedimentation rate (ESR), physician's global assessment of disease activity, patient's global assessment of disease activity, patient's assessment of pain, and physical function as assessed by the HAQ-DI [20]]. Patients who failed to achieve at least an ACR20 response at Week 12 were analyzed for mean changes and mean percent changes in ACR core components from baseline to Week 12.

Safety was assessed on the basis of adverse events reported by patients, physical examination findings, and laboratory evaluations. All adverse events were coded according to the MedDRA dictionary of terms (version 9.0). All non-serious adverse events were collected from the time of the first dose of study drug until 5 half-lives (70 days) after discontinuation of study drug. Serious adverse events were collected from the time the patient signed the study-specific informed consent until 5 halflives after discontinuation of study drug. All serious adverse events, including those that occurred during the 70-day post-therapy period, were followed until resolution or stabilization of the event was documented. Adverse events are reported during the first 12 weeks plus the 70-day post-therapy period.

Statistical Analysis

All patients who received at least 1 dose of adalimumab and returned for 1 or more follow up visits were included in the effectiveness analysis. This included patients who were protocol violators. Observed data analyses were used to describe the effectiveness of adalimumab at Weeks 4, 8 and 12. There were no replacements of missing data conducted prior to the Week 12 visit. Subgroup analysis included a comparison of patients who were naïve to BDMARD therapy versus patients who had experienced prior BDMARD therapy. All patients who received at least 1 dose of adalimumab were included in the safety analysis.

The statistical significance of the change in DAS28 from baseline to Week 12 of treatment was assessed with the paired Student's t-test. Linear regression analysis was used to estimate and test the statistical significance of the rate of change in the DAS28 over time. The proportions of patients achieving ACR20, ACR50, and ACR70 therapeutic responses at Weeks 4, 8, and 12 were calculated using the number of patients returning for follow-up at these visits as the denominator. The statistical significance of any change in the continuousscale secondary effectiveness measures, specifically physician and patient global assessment of disease activity, patient assessment of pain, and HAQ-DI scores, was also assessed with the paired Student's t-test. The rate of change in these variables over time during the 12 weeks of the study was estimated and tested for statistical significance using repeated measures linear regression analysis.

To assess the potential effect of bias due to differential attrition, the baseline characteristics of the patients who reached Week 12 were compared with those of patients who did not complete the first 12 weeks of the study.

The incidence of adverse events was reported as the proportion of patients with at least 1 event and the number of events per 100 patient-years.

Patient Disposition

A total of 879 patients were enrolled from 69 sites across Canada. Of these, 772 (87.8%) completed the 12week study. The primary reasons for study discontinuation of the remaining 107 patients were as follows: lost to follow-up (n = 48, 5.5%), adverse events (n = 39, 4.4%), lack of efficacy (n = 15, 1.7%), withdrawal of consent (n = 4, 0.5%), and protocol violation (n = 1, 0.1%).

Demographic and Baseline Characteristics

Demographic and disease characteristics at baseline were typical of a patient population with long-standing and moderate to severe RA (Table 1 ): the mean disease duration since diagnosis was 12.5 years, while the mean tender and swollen joint counts were 14.9 and 13.2, respectively, the mean HAQ-DI score was 1.5, and the mean DAS28 was 6.1.

A total of 860 (97.8%) of the patients previously received treatment with 1 or more DMARDs at the time of enrollment; these agents could be continued throughout the course of the study. Of the patients enrolled, 42.2% were treated with adalimumab in combination No differences were detected between the baseline demographic and disease characteristics of patients who reached the Week 12 visit and those who discontinued before the Week 12 visit (data not shown), with the exception of the proportion of patients that received adalimumab without a DMARD (29.9% vs. 13.3%, P = 0.001).

Effectiveness

Mean DAS28 decreased from 6.1 (95% confidence interval [CI]: 6.0, 6.2) at baseline to 4.2 (95% CI: 4.1, 4.3) at Week 12 (P < 0.001; Figure 1A ), with a significant decrease occurring as early as Week 4. From a linear regression analysis, mean change in DAS28 (SD) was -0.157 (0.006) per week (P < 0.001). Following 12 weeks of treatment with adalimumab, 15.3% and 28.9% of patients achieved clinical remission (defined as a DAS28 value < 2.6) and low-disease activity (defined as a DAS28 value < 3.2), respectively.

Moderate and good clinical responses, as defined by the European League Against Rheumatism (EULAR) criteria [21], were observed at Week 4 for 50.1% and 11.7% of patients, respectively (data not shown). Patients with a good EULAR response increased steadily over time, with 25.9% of patients achieving a good response at 12 weeks. Similar trends were observed for ACR response criteria. Following 4 weeks of treatment, the proportions of patients achieving ACR20, ACR50, and ACR70 improvements were 37%, 10.6%, and 2.4%, respectively (Figure 2A ). These proportions increased to 58.4%, 30.6%, and 12.7% following 12 weeks of adalimumab therapy.

Patients experienced improvements in each of the ACR core components during 12 weeks of adalimumab treatment, with significant improvements occurring as early as Week 4 (Table 2 ). By Week 12, the mean (SD) number of tender joints decreased from 14.9 (7.1) to 6.8 (6.8), and the mean (SD) number of swollen joints was reduced from 13.2 (5.2) to 6.4 (5.2). As measured on a 0-100 mm Visual Analog Scale (VAS), patient's assessment of pain decreased from a mean (SD) of 66.2 (22. 3) to 37.3 (27.5), patient's assessment of disease activity decreased from 65.1 (22.7) to 37.4 (27.2), and physician's assessment of disease activity decreased from 63.6 (17.6) to 29.0 (22.7) . The mean (SD) HAQ-DI score improved by an average of 0.5 units from 1.5 (0.6) at baseline to 1.0 (0.7) at Week 12. In addition, significant reductions in ESR were observed as early as Week 4, resulting in near normal levels. At Week 12, the ESR decreased from a mean (SD) of 30.3 (23.8) mm/h at baseline to 20.0 (18.6) mm/h (P < 0.001). Repeated measures linear regression analysis demonstrated a significant change over time in each of the ACR core components (P < 0.001, data not shown). A subset analysis of patients who failed to achieve at least an ACR20 response at Week 12 (n = 321/772, 41.6%) demonstrated reductions in ACR core component values at Week 12 (Table 3 ). Furthermore, ACR20 non-responders demonstrated > 20% improvements from baseline in tender and swollen joint counts and in physician's global assessment of disease activity.

Mean (95% CI) DAS28

A. When patients were classified according to prior experience with a BDMARD, a clear trend in clinical responses was observed: patients naïve to BDMARD therapy typically demonstrated greater clinical effectiveness when compared with patients who had experienced prior BDMARD therapy, despite comparable baseline disease characteristics (data not shown). For example, BDMARDnaïve patients exhibited lower DAS28 scores at Week 12 than patients who had experienced prior BDMARD therapy (4.0 versus 4.6 for BDMARD-naive and prior BDMARD subgroups, respectively; Figure 1B ). Similarly, patients naive to BDMARD therapy demonstrated numerically higher rates of ACR20, 50, and 70 responses at Week 12 when compared with patients who had experienced prior BDMARD therapy (Figure 2B ).

Safety

A total of 551 non-serious adverse events were reported by 371(43.4%) patients during the safety assessment period, translating into an overall rate equivalent of 2.6 events/patient-year. The majority of the adverse events were mild to moderate in intensity. Adverse events that occurred in more than 1% of the study population are summarized in Table 4 . Injection site reaction was the most common adverse event, reported by 9.9% of the patients. The most common injection site reaction was injection site erythema, which was reported by 3.5% of the patients; injection site reactions described as pruritus or rash were reported by 1.4% and 2.8% of patients, respectively. Of the treatment-emergent adverse events considered by the investigator to be related to study drug, injection site reaction and headache were the most frequently reported (≥ 5% of patients). One patient reported 2 breast cysts following 37 days of treatment with adalimumab, which, although severe, were deemed to be non-serious and unrelated to study drug.

A total of 19 serious adverse events were reported by 16 (1.8%) patients. The most frequently reported events were cardiac disorders (n = 2, 0.2%) and gastrointestinal disorders (n = 2, 0.2%). Specifically, these included 1 case of congestive heart failure (CHF), 1 case of mitral Response rate (%) A.

B.

Figure 2 Response in American College of Rheumatology (ACR) Criteria Following Adalimumab Treatment. Percentages of patients who met the AC R criteria for 20%, 50%, and 70% improvement (ACR20, ACR50, and ACR70, respectively) with adalimumab 40 mg administered subcutaneously every other week with concomitant standard antirheumatic therapy. A.) All randomized patients. B) Subgroup analysis of randomized patients on the basis of experience with biological DMARD (BDMARD) therapy. valve incompetence, 1 case of myocardial infarction, 1 case of pulmonary edema, 1 case pancreatitis, and 1 case of gastroesophageal reflux disease. One patient died within the safety assessment period. The cause of death was myocardial infarction secondary to staphylococcal sepsis, attributed to study drug. In all, 9 (1.0%) patients reported 10 incidences of serious infections within the safety assessment period. In addition to the Staphylococcus aureus septicemia that occurred in the patient who died, other incidences of serious infection included 3 cases of pneumonia, 2 cases of surgical wound infections, 1 case of postoperative infection, 1 case of foot cellulitis, 1 case of possible septic arthritis, and 1 case of pyelonephritis. The rate of serious infections was estimated to be 2.4 events/100 patient-years.

One patient was diagnosed with basal cell carcinoma 97 days after starting study drug. This event was considered to be serious but of moderate severity and not related to adalimumab according to the judgment of the treating physician.

Adalimumab therapy was associated with slight decreases in white blood cell count, neutrophils, Swollen joint count (0-66 scale) 12.9 ± 5.

Discussion

The relationship between observational studies and RCTs is widely considered to be complementary, not alternative [22]. Open-label observational studies offer greater understanding of the effectiveness of medications in real-world clinical practice, which cannot be provided by RCTs. In addition, the inclusion of patients and treatments reflecting varying clinical practices, rather than the narrow range included in RCTs, offers a better environment to study the safety profile of drugs and to determine their tolerability profile.

CanACT is the largest observational study designed to evaluate the effectiveness and safety of adalimumab in a setting reflective of the Canadian clinical practice for the treatment of RA. In this study, patients who failed prior DMARD therapy received sc adalimumab eow; patients were allowed to continue antirheumatic treatment (eg, DMARDs, low-dose corticosteroids, NSAIDs, analgesics, etc.), with the exception of BDMARDs and cyclosporine. Patients had experienced many years of active disease prior to enrollment [mean (SD) = 12.5 (9.7) years], a result that is reflective of access to care in Canada and consistent with data from many European and American BDMARD registries [23]. The results of this 12-week study support the effectiveness and tolerability of adalimumab under conditions of routine clinical care.

As demonstrated through the examined effectiveness measures, responses to adalimumab therapy were rapid. Significant reductions from baseline were observed as early as 4 weeks from the start of therapy. At this time point, more than a third (37.6%) of the patients already were classified as ACR20 responders. Significant changes in DAS28 also were observed at this visit. Interestingly, improvements in DAS28 were numerically greater during the four weeks that followed the initiation of adalimumab than between any of the subsequent visits. At Week 12, more than 15% of patients achieved clinical remission as defined by DAS28 < 2.6, and nearly double (28.9%) achieved a low-disease state (DAS28 < 3.2). Further, clinically important ameliorations in physical functions were observed in the first few weeks that followed the initiation of adalimumab therapy. These changes from baseline were maintained over time. Even patients who failed to satisfy ACR20 response criteria experienced significant improvements in most of the ACR core component measures with the exception of patient's global and pain evaluations.

The effectiveness of adalimumab against active RA that is unresponsive or only partially responsive to standard antirheumatic therapy demonstrated in this realworld trial confirms the results of other placebo-controlled studies in which adalimumab was administered either as monotherapy [13], in combination with MTX [11,12,14,15], or concomitantly with standard antirheumatic therapy [10]. Further, these results support earlier findings that adalimumab is efficacious even for patients who have failed or become intolerant to other TNF-αantagonist therapies [24]. The data presented in the present analysis suggest that patients who are naïve to BDMARD therapy tend to achieve better disease status over a short period of time than patients with prior exposure to BDMARDs. While these results strongly support the use of adalimumab as a first line biological agent, adalimumab remains a viable option as a second line biological agent.

Adalimumab was well-tolerated in the CanACT study population with 87.8% completing the 12-week study. Only 39 of the 879 (4.4%) enrolled patients discontinued because of an adverse event. Most of the adverse events reported in this study were nonserious and considered to be either mild or moderate in intensity. Injection site reaction, which is frequently associated with subcutaneously administered agents, was the most commonly reported adverse event.

Nine patients in the study reported serious infections, resulting in an estimated rate of 2.4 events/100 patientyears. Similar rates have been observed during studies in which patients were treated with adalimumab plus MTX [11,14,15], or with standard antirheumatic therapy [10]. Patients treated with TNF-α antagonists are considered to be at increased risk of developing serious infections. However, the rate of serious infections reported in the present study was less than both the rate in the adalimumab clinical trial safety database (4.7/100 patientyears) and the rate in the general RA population as reported in the literature (3.1-9.6/100 patient-years) [25], a finding that may reflect the short duration of the study. There were no reported cases of tuberculosis during the study.

Congestive heart failure (CHF) was reported as a study-drug-related serious adverse event in 1 patient in the present study. This is in keeping with results from other clinical trials involving adalimumab [25,26], in which CHF has been described in patients both with and without a history of the disease. Proportionally, more patients with a history than without a history of CHF have reported this as an adverse event (7% vs. 0.3%). However, it be noted that patients with a history of CHF were usually excluded from clinical trials. No cases of lupus or lupus-like syndrome occurred in patients in the present study, which is in accord with observations from previous clinical trials that demonstrated that these conditions are rarely associated with adalimumab [25,26].

The aforementioned results demonstrate that the safety profile of adalimumab is similar to that previously reported in controlled trials. In studies in which adalimumab was administered concomitantly with MTX [10][11][12]14,15], this combination was found to be safe and well-tolerated.

Conclusions

In conclusion, the results of the present study demonstrate that adalimumab 40 mg given sc eow was effective in producing clinically important and statistically significant reductions in the signs and symptoms of disease. In addition, adalimumab therapy was associated with significant improvements in the physical functioning of patients with RA. The safety profile of adalimumab observed in this patient group was comparable with that of previous studies with this agent. Taken together, the current study supports the use of adalimumab 40 mg sc eow in the management of patients with RA who have not responded satisfactorily or who have proved intolerant to antirheumatic DMARD therapies.

annex

Author details 1 Department of Rheumatology, CHUM-Hôpital Notre Dame, Montreal, Quebec, Canada. 2 Department of Medicine, Division of Rheumatology, McMaster University, Hamilton, Ontario, Canada. 3 Department of Medicine, Penticton Regional Hospital, British Columbia, Canada. 4 Rheumatology, Global Medical Affairs, Abbott, Rungis, France. 5 The Rebecca MacDonald Centre for Arthritis and Autoimmune Disease, Mount Sinai Hospital, Toronto, Ontario, Canada.

Authors' contributions BH, AC, JS, and EK. were study investigators for the CanACT trial, and participated in its design and coordination. BG. participated in data interpretation. All authors read and approved the final manuscript.

Competing interests

B.H. has received consulting fees or other remuneration from Abbott, Amgen, Bristol-Myers Squibb, Merck, Pfizer, Roche, and UCB. A.C. has performed clinical trial work for Abbott, UCB, Pfizer, Roche, Amgen, and Bristol-Myers Squibb. J.S. declares no competing interests. E.K. has received research grants or consulting fees/other remuneration from, or served on speakers bureaus on behalf of, Abbott, Amgen, AstraZeneca, Biotest, Bristol-Myers Squibb, Centocor, F Hoffmann-LaRoche, Genentech, Genzyme, Merck, Novartis, Nycomed, Pfizer, and UCB. B.G. is a full-time employee of Abbott and may hold stock or stock options.

Pre-publication history

The pre-publication history for this paper can be accessed here:

Acknowledgements

Acknowledgements and FundingAbbott sponsored the study and was responsible for its design (NCT0006545).Benjamin Wolfe, PhD, of Abbott, provided medical writing support, and JSS Medical Research conducted the statistical analyses on behalf of Abbott.

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