Clinical remission andor minimal disease activity in patients receiving adalimumab treatment in a multinational open-label twelve-week study.код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research) Vol. 59, No. 1, January 15, 2008, pp 32– 41 DOI 10.1002/art.23247 © 2008, American College of Rheumatology ORIGINAL ARTICLE Clinical Remission and/or Minimal Disease Activity in Patients Receiving Adalimumab Treatment in a Multinational, Open-Label, Twelve-Week Study GERD R. BURMESTER,1 GIANFRANCO FERRACCIOLI,2 RENÉ-MARC FLIPO,3 INDALECIO MONTEAGUDO-SÁEZ,4 KRISTINA UNNEBRINK,5 SONJA KARY,5 AND HARTMUT KUPPER5 Objective. To evaluate the effect of adalimumab treatment on clinical remission and/or minimal disease activity (MDA) in 6,610 patients with active rheumatoid arthritis (RA) who were enrolled in the Research in Active RA trial, a multinational, open-label, 12-week study with an optional extension period. Methods. Clinical remission was deﬁned as a Disease Activity Score in 28 joints (DAS28) <2.6, Simpliﬁed Disease Activity Index (SDAI) score <3.3, or Clinical Disease Activity Index (CDAI) score <2.8. MDA required absence of tender and swollen joints plus erythrocyte sedimentation rate (ESR) <10 mm/hour; DAS28 score <2.85; or achievement of 5 of 7 core criteria for pain, swollen/tender joints, physical function, physician/patient global assessment, and ESR. Time to and time in remission/MDA and response predictors were analyzed using Kaplan-Meier estimates and Cox proportional hazards regression analysis, respectively. Results. A total of 38%, 24%, and 27% of patients achieved remission deﬁned as DAS28 <2.6, SDAI <3.3, and CDAI <2.8, respectively. MDA was observed in 45% of patients by DAS28 <2.85, in 43% by the core set of criteria, and in 13% by absence of tender/swollen joints plus ESR <10 mm/hour. Median times in continuous remission and MDA were 3.4 and 4.4 months, respectively. Predictors for remission (DAS28 <2.6) and MDA (DAS28 <2.85) were male sex; younger age; concomitant disease-modifying antirheumatic drug use; lower baseline DAS28, CRP concentration, and Health Assessment Questionnaire disease index score; <1 comorbidity; and tumor necrosis factor antagonist naivety. Conclusion. During adalimumab treatment, 25% of patients experienced clinical remission and nearly half achieved MDA. To our knowledge, this analysis represents the largest prospective clinical trial data set to be assessed using Outcome Measures in Rheumatology Clinical Trials MDA criteria. INTRODUCTION Since the introduction of biologic response modiﬁers that inhibit tumor necrosis factor (TNF), the expectations of medical treatment for active rheumatoid arthritis (RA) have changed markedly. Several clinical trials have demonstrated the efﬁcacy of TNF antagonists (adalimumab, etanercept, and inﬂiximab) in signiﬁcantly reducing disClinicalTrials.gov identiﬁer: NCT00448383. Supported by a grant from Abbott GmbH & Co. KG, Ludwigshafen, Germany. Dr. Burmester’s work was supported by Abbott, Schering-Plough, Wyeth, and Roche. 1 Gerd R. Burmester, MD: Charité University Medicine Berlin, Berlin, Germany; 2Gianfranco Ferraccioli, MD: Catholic University of Rome, Rome, Italy; 3René-Marc Flipo, MD: University Hospital, Lille, France; 4Indalecio Monteagudo-Sáez, MD: Hospital General Universitario Gregorio Marañón, Madrid, Spain; 5Kristina Unnebrink, PhD, Sonja Kary, MD, MA, Hartmut Kupper, MD: Abbott GmbH & Co. KG, Ludwigshafen, Germany. 32 ease activity and limiting progression of joint destruction and subsequent disability in patients with RA (1– 4). Appropriate management of RA requires more than the assessment of relative improvement or change in signs and symptoms. Being able to assess the actual state of disease Dr. Burmester has received consultant fees, speaking fees, and honoraria (more than $10,000 each) from Abbott, Schering-Plough, Wyeth, and Roche. Dr. Ferraccioli has received consultancy fees and speaking fees (less than $10,000 each) from Abbott, Wyeth, and Schering-Plough. Dr. Unnebrink holds stock options in Abbott. Dr. Kary is a contractor for Abbott (Germany). Dr. Kupper holds stock options in Abbott. Address correspondence to Gerd R. Burmester, MD, Department of Rheumatology and Clinical Immunology, Charité University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany. E-mail: email@example.com. Submitted for publication March 19, 2007; accepted in revised form June 15, 2007. Clinical Remission and MDA in RA activity is important in making informed treatment decisions (5–9). The general therapeutic goal in RA is to obtain a state of low disease activity, or even clinical remission, thereby preventing further joint destruction with optimal treatment. Historically, several criteria for assessing clinical remission have been developed (10,11). The deﬁnition and therapeutic usefulness of clinical remission or of low disease activity/minimal disease activity (MDA) is complex and recently has been the subject of intense discussion (12–19). One well-established deﬁnition is achievement of a disease activity score ⬍2.6 based on the erythrocyte sedimentation rate (ESR) and Disease Activity Score in 28 joints (DAS28) assessment (5,20,21). Because the DAS28 threshold can be achieved by patients who may be quite symptomatic in the few joints that are swollen, a more restrictive DAS28 score limit of ⬍2.4 has been proposed but not widely accepted (22,23). Furthermore, 2 other criteria for identifying clinical remission, Simpliﬁed Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) cut points of ⱕ3.3 and ⱕ2.8, respectively, are also being investigated and applied in clinical practice (22,24,25). The concept of MDA, which aims for an acceptable state of RA that is near remission and is adequate for many patients, has been developed by the Outcome Measures in Rheumatology Clinical Trials (OMERACT) MDA working group (26). By deﬁnition, the OMERACT MDA criteria include clinical remission as well as a state of low disease activity. In a stepwise process, the proposed OMERACT deﬁnition for identifying MDA ﬁrst considers all patients who have a tender joint count (TJC) of 0 and a swollen joint count (SJC) of 0 plus an ESR ⱕ10 mm/hour; this state of RA is, in fact, clinical remission. In the second step, patients are considered in MDA either when a DAS28 score ⱕ2.85 is achieved or, alternatively, when 5 of the 7 following core criteria are met: pain score ⱕ2 on a 0 –10 visual analog scale (VAS), SJC ⱕ1 in a 28-joint assessment, TJC ⱕ1 in a 28-joint assessment, Health Assessment Questionnaire (HAQ) disability index (DI) score ⱕ0.5 on a 0 –3 scale, physician global assessment of disease activity ⱕ1.5 on a 0 –10 VAS, patient global assessment of disease activity ⱕ2 on a 0 –10 VAS, and ESR ⱕ20 mm/hour. The recently completed Research in Active RA (ReAct) trial provides a large database of 6,610 patients who received adalimumab, a fully human monoclonal antibody against TNF, in an open-label study designed to mimic rheumatologic care in typical clinical practices (27,28). We analyzed the percentage of patients in the ReAct trial who achieved remission or MDA by different scores, the time until remission or MDA after the initiation of adalimumab treatment, and the time in sustained remission or MDA. Also, we investigated possible predictors for achievement and maintenance of clinical remission and MDA. MATERIALS AND METHODS Ethics. The ReAct trial was conducted in accordance with principles of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for 33 Good Clinical Practice, and compliance with all local laws and customs was ensured by the investigators. Written informed consent was obtained from each participant before initiation of any study-related procedures. Patients. The study was conducted in adult patients with RA as deﬁned by the 1987 revised criteria of the American College of Rheumatology (formerly the American Rheumatism Association) (29). Eligible patients had RA for ⱖ3 months; a DAS28 score ⱖ3.2, indicating at least moderate disease activity (20); and treatment failure with at least 1 traditional disease-modifying antirheumatic drug (DMARD). Patients were allowed to continue their current antirheumatic therapy if the treatment regimen was not modiﬁed until week 12. Previous or concurrent treatment with alkylating agents was not allowed. Study design. All patients self-administered a subcutaneous injection of adalimumab 40 mg (Abbott Laboratories, Abbott Park, IL) every other week during this 12week, open-label, multicenter study. After the initial 12-week phase, patients could enter an optional extension until adalimumab became commercially available. Subsequently, patients could also enter an ongoing postmarketing observational study for up to 5 years. Patients who had received adalimumab without combination DMARD use and did not achieve at least a moderate response according to the European League Against Rheumatism response criteria (30) at week 12 could change to weekly injections of adalimumab. Efﬁcacy and routine safety evaluations were conducted at weeks 2, 6, and 12, and every 8 weeks thereafter. Statistical analysis. Clinical remission was deﬁned as achieving a DAS28 score ⬍2.6, an SDAI score ⱕ3.3, or a CDAI score ⱕ2.8. The SDAI consists of the sum of the number of tender and swollen joints, a global assessment of disease activity by both the patient and the clinician (10-cm VAS), and C-reactive protein (CRP) concentration in mg/dl (22). The CDAI refers to the same clinical variables as the SDAI but omits the CRP component. MDA was evaluated using the preliminary OMERACT deﬁnition as described by Wells and colleagues (26), although we did not perform the analyses in 2 consecutive steps. All patients were entered into the evaluation of actual clinical remission, deﬁned as no tender or swollen joint counts and an ESR ⬍10 mm/hour. Irrespective of the result of this analysis, all patients were also included in the analyses of MDA by either a DAS28 score ⱕ2.85 or 5 of the 7 core set criteria as described earlier. All measures were assessed at week 12 and at the last individual observation for each patient, irrespective of the point in time when the patient discontinued the study. In addition, outcome criteria were assessed at any individual time point during the treatment period. The percentage of patients who fulﬁlled each outcome criterion was calculated using the total number of patients who had the required data available at the deﬁned time points (observed values) as the denominator. In addition, the percentage of patients achieving remission or MDA at any time during 34 treatment was stratiﬁed by baseline patient characteristics and treatment conditions. Analyses of time to remission and time to MDA and of time in remission and time in MDA (in patients who had achieved remission) were limited to the respective DAS28 criteria. Kaplan-Meier survival estimates were used to evaluate the median time from the ﬁrst adalimumab injection to remission and to MDA. If remission or MDA had not been achieved at the time of the last visit, the observation was censored in the Kaplan-Meier analysis. For patients who reached remission, both the time in remission and the time in at least MDA after remission were analyzed using Kaplan-Meier methods. The time in remission and the time in at least MDA were calculated from time of remission to the ﬁrst visit where remission (or MDA) was lost (the “event” in the Kaplan-Meier analysis) or to the last available visit. If remission (or MDA) was ongoing at the time of the last visit, the observation was censored in the Kaplan-Meier analysis. Predictors of achievement and maintenance of remission or MDA were identiﬁed using Cox proportional hazards regression analysis. Again, remission and MDA for this analysis were deﬁned by the DAS28 criterion exclusively. Baseline characteristics entered into the model as possible predictors were DAS28 score (ⱕ5.1, ⬎5.1–7, ⬎7), CRP concentration (⬍20, ⱖ20 mg/liter), physical function (HAQ DI score ⬍1, 1–⬍1.5, 1.5–⬍2, ⱖ2), rheumatoid factor (RF; positive/negative), age (⬍40 years, 40 –ⱕ65 years, ⬎65–ⱕ75 years, ⬎75 years), sex (male/female), smoking history (never/ever), duration of RA (ⱕ1 year, ⬎1–2 years, ⬎2–5 years, ⬎5–10 years, ⬎10 years), number of previously failed DMARDs (1, 2, 3, 4, ⱖ5), history of treatment with etanercept and/or inﬂiximab (yes/no), concomitant use of DMARDs (yes/no), concomitant use of glucocorticoids (yes/no), number of comorbidities (ⱕ1, ⬎1), and time to remission (for sustained remission/MDA only) (31–35). Finally, in a descriptive analysis, the DAS28 values for patients who achieved remission were followed up to the last observation of each patient at study discontinuation. RESULTS A total of 6,610 patients were enrolled in the ReAct trial: 81% were female, 73% were RF positive, 74% were taking at least 1 concomitant DMARD, and 71% were receiving glucocorticoids. Additional baseline characteristics included a mean age of 54 years, mean disease duration of 11 years, mean DAS28 score of 6.0, and mean HAQ DI score of 1.64 (27). During the complete adalimumab treatment period, the mean exposure to adalimumab was 33.3 weeks (maximum of 95.6 weeks), resulting in 4,210 patient-years of adalimumab exposure. At week 12, 93% of enrolled patients continued in the study. The overall withdrawal rate was 20.8%, with 6.8% of patients withdrawing due to lack of effectiveness (27). The number of patients in the ReAct trial gradually decreased as adalimumab was approved for commercial use in participating countries. After 1 year, 1,257 patients remained in the study. The baseline characteristics of patients who discontinued the study Burmester et al Figure 1. Clinical remission and minimal disease activity (MDA) at various time points in the Research in Active Rheumatoid Arthritis (ReAct) trial. A, Percentage of patients achieving clinical remission measured by Disease Activity Score in 28 joints (DAS28), Simpliﬁed Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). B, Percentage of patients achieving MDA measured by Outcome Measures in Rheumatology Clinical Trials criteria. Open bars ⫽ week 12; shaded bars ⫽ last observation; solid bars ⫽ any time. TJC ⫽ tender joint count; SJC ⫽ swollen joint count; ESR ⫽ erythrocyte sedimentation rate. before week 52 were very similar to the baseline characteristics of patients who remained in the study after 1 year. Statistically signiﬁcant but clinically irrelevant differences between the ⱖ1-year treatment subset versus the ⬍1-year treatment subset were concomitant DMARD use (77% versus 73%), HAQ DI score (1.7 versus 1.6), mean number of previous DMARDs (3.1 versus 2.7), mean duration of RA (11 years versus 10 years), and mean age (54 years versus 53 years). The median DAS28 score of all enrolled patients at their last visit was 3.6; the ﬁrst quartile DAS28 score at the last visit was 2.6, indicating that one-quarter of all patients discontinued the study nearly in remission. In the extension phase, 414 (6%) of 6,610 patients, most of whom were Clinical Remission and MDA in RA 35 Table 1. Observed percentages of patients in remission or in minimal disease activity measured by various scores at any time during adalimumab treatment* Clinical remission Subgroup All patients (n ⫽ 6,473)‡ Baseline DAS28 score ⱕ5.1 (n ⫽ 1,266) ⬎5.1 (n ⫽ 5,207) ⬎7.0 (n ⫽ 1,275) Baseline C-reactive protein, mg/liter ⬍20 (n ⫽ 3,837) ⱖ20 (n ⫽ 2,562) Baseline HAQ DI score, 0–3 ⬍1 (n ⫽ 1,092) 1–⬍1.5 (n ⫽ 1,334) 1.5–⬍2 (n ⫽ 1,711) ⱖ2 (n ⫽ 2,313) Previous DMARD use, no. ⱕ3 (n ⫽ 4,068) ⬎3 (n ⫽ 2,210) Previous etanercept and/or inﬂiximab use Yes (n ⫽ 878) No (n ⫽ 5,595) Duration of rheumatoid arthritis, years ⱕ5 (n ⫽ 1,973) ⬎5 (n ⫽ 4,466) Rheumatoid factor Positive (n ⫽ 4,714) Negative (n ⫽ 1,748) Age, years ⬍40 (n ⫽ 980) 40–ⱕ65 (n ⫽ 4,046) ⬎65–ⱕ75 (n ⫽ 1,222) ⬎75 (n ⫽ 225) Sex Male (n ⫽ 1,246) Female (n ⫽ 5,227) Comorbidities, no.§ ⱕ1 (n ⫽ 3,991) ⬎1 (n ⫽ 2,482) Concomitant DMARD use, no. 0 (n ⫽ 1,672) ⱖ1 (n ⫽ 4,801) ACR50 response at week 6 Yes (n ⫽ 1,699) No (n ⫽ 4,345) Minimal disease activity DAS28 <2.6 SDAI <3.3 CDAI <2.8 No TJC or SJC and ESR <10 mm/hour DAS28 <2.85 5 of 7 core criteria† 38 24 27 13 45 43 63 32 18 37 21 14 39 24 16 25 11 6 72 39 24 62 38 26 44 29 28 19 29 23 16 10 51 37 46 38 58 47 37 25 42 31 22 14 43 34 24 17 23 16 13 8 65 54 44 32 67 54 41 27 42 31 28 17 31 19 16 10 49 34 48 34 26 40 13 26 15 29 7 14 31 48 27 45 43 36 30 22 33 24 17 12 49 44 48 40 37 42 23 27 26 29 12 17 44 49 42 44 51 39 29 26 34 24 20 17 37 26 21 19 23 13 8 7 58 46 36 28 57 43 35 27 46 36 27 24 30 26 19 12 52 44 48 42 43 31 27 20 30 21 16 9 50 38 48 35 28 42 18 27 20 29 9 15 35 49 34 46 63 29 49 14 54 17 26 9 72 36 74 32 * DAS28 ⫽ Disease Activity Score in 28 joints; SDAI ⫽ Simpliﬁed Disease Activity Index; CDAI ⫽ Clinical Disease Activity Index; TJC ⫽ tender joint count; SJC ⫽ swollen joint count; ESR ⫽ erythrocyte sedimentation rate; HAQ DI ⫽ Health Assessment Questionnaire disability index; DMARD ⫽ disease-modifying antirheumatic drug; ACR50 ⫽ American College of Rheumatology 50% improvement criteria (44). † Fulﬁllment of 5 of the following 7 core criteria: pain score ⱕ2 (0 –10 visual analog scale), swollen joint count ⱕ1 (0 –28 joints), tender joint count ⱕ1 (0 –28 joints), HAQ DI score ⱕ0.5 (0 –3), physician global assessment of disease activity ⱕ1.5 (0 –10), patient global assessment of disease activity ⱕ2 (0 –10 visual analog scale), and ESR ⱕ20 mm/hour. ‡ n ⫽ number of patients with available DAS28 data; other subgroups have slightly different numbers of patients and are not shown but can be provided upon request. § Includes valvular heart disease, congestive heart failure, ischemic heart disease, hypertension, liver disease, peptic ulcer disease, kidney disorder, diabetes mellitus, hyperlipidemia, hypothyroidism, osteoarthritis, osteoporosis, cerebral vascular accident, depression, asthma, emphysema/chronic obstructive pulmonary disease, past tuberculosis, past pneumonia, and drug allergies/reactions. receiving adalimumab monotherapy, underwent dose escalation to adalimumab 40 mg weekly. For these patients, the ﬁrst quartile DAS28 score 16 weeks after dose increase was 3.4, indicating that only some of these patients experienced remission/MDA after dose increase. Clinical remission and MDA at various time points. At week 12, a total of 1,187 (20%) of 6,051 patients were in remission as measured by a DAS28 score ⬍2.6, and 1,494 (25%) of 6,051 were in a state of MDA as measured by a DAS28 score ⱕ2.85. Compared with week 12, higher per- 36 Burmester et al Figure 2. Inverted Kaplan-Meier curves of time to ﬁrst occurrence of clinical remission (Disease Activity Score in 28 joints [DAS28] ⬍2.6; median 10.4 months) and of minimal disease activity (MDA; DAS28 score ⱕ2.85; median 8.2 months). * Number of patients still under observation excluding those who already achieved remission. ⫹ Number of patients still under observation excluding those who already achieved MDA. Solid line ⫽ time to MDA; broken line ⫽ time to remission. centages of patients achieved both deﬁnitions of response at the last observation (25% and 31%, respectively) and at any time during adalimumab treatment (38% and 45%, respectively) (Figure 1). With respect to clinical remission by the SDAI score ⱕ3.3 and CDAI score ⱕ2.8 deﬁnitions, 11% of patients met the threshold for each measure of remission at week 12. Similar to the DAS28 results, the percentages of patients meeting the SDAI and CDAI remission criteria increased at the last observation and at any time during the study (Figure 1A). MDA was observed in 43% of patients according to the core set of criteria at any time during adalimumab treatment, compared with 24% and 30% at week 12 and the last observation, respectively. Absence of tender/swollen joints plus ESR ⱕ10 mm/hour resulted in the lowest percentage of patients achieving MDA at all time points (5% of all patients at week 12, 7% of all patients at the last observation, and 13% at any time) (Figure 1B). In addition, the remission and MDA data as achieved at any time during the study were stratiﬁed by baseline patient and treatment characteristics (Table 1). Irrespective of the assessment method, patients with lower baseline DAS28 score, HAQ DI score, CRP concentration, age, and number of previous DMARDs and who were TNF antagonist naive and RF negative were more likely to achieve remission/ MDA. These univariate analyses were then scrutinized using the Cox proportional hazards regression model. Time to clinical remission or time to MDA and predictors for response. For all patients enrolled, the KaplanMeier estimates were 10.4 months (95% conﬁdence interval [95% CI] 10.1–11.7) for median time to remission and 8.2 months (95% CI 7.2– 8.3) for MDA (Figure 2). In the 38% and 45% of all patients who achieved remission or MDA during adalimumab therapy, the median time to response was 2.8 months for both measures (mean 3.7 months and 3.4 months, respectively). We identiﬁed the following predictors for clinical remission response by Cox regression: lower baseline HAQ DI score, lower baseline DAS28 score, younger age, male sex, concomitant DMARD treatment, lower CRP concentration, ⱕ1 comorbidity, and no previous TNF antagonist treatment (Table 2). The predictors for MDA were identical with the addition of a weak positive impact of never smoking and fewer previous DMARDs (data not shown). Time in clinical remission or time in MDA and predictors of maintenance. Overall, of the patients who achieved remission (DAS28 score ⬍2.6) during adalimumab treatment, 47% discontinued the study in a state of remission and 55% discontinued the study in MDA after a period of continuous remission or MDA. The Kaplan-Meier estimate for median time in continuous remission was 3.4 months (95% CI 3.2–3.7) (Figure 3). Similarly, the median time that patients remained in at least continuous MDA following remission was 4.4 months (95% CI 4.1–5.1). Twenty-ﬁve percent of patients remained in remission for at least 8.7 months (95% CI 7.3– 12.5). The analysis of predictors for sustained remission, measured as hazard ratios for loss of remission, revealed that the following factors were associated with a longer duration of remission: male sex, no previous TNF antagonist treatment, younger age, and short time to clinical remission (Table 3). Additional factors predicting a longer time in at least MDA after clinical remission (measured as time to loss of MDA) were smoking (never), ⱕ1 comorbidity, and low baseline HAQ DI score and DAS28 score, whereas age had no signiﬁcant impact on time in MDA after remission (data not shown). Finally, the DAS28 values of those patients who experienced clinical remission (DAS28 score ⬍2.6) at any time during adalimumab treatment were evaluated until patients discontinued the study. This patient subset entered the study with a mean and median DAS28 score of 5.6. The mean and median DAS28 scores at the last observation were 2.5 and 2.3, respectively, indicating that more than 50% of this subset discontinued the study in a state of clinical remission. At 8, 16, 24, and 32 weeks after the ﬁrst assessment of clinical remission, the observed mean and Clinical Remission and MDA in RA 37 Table 2. Predictors of time to clinical remission (DAS28 score <2.6)* Possible confounder Baseline DAS28 ⬎7 vs ⱕ5.1 ⬎5.1–ⱕ7 vs ⱕ5.1 Baseline C-reactive protein, mg/liter ⱖ20 vs ⬍20 Baseline HAQ DI score, 0–3 ⱖ2 vs ⬍1 1.5–⬍2 vs ⬍1 1–⬍1.5 vs ⬍1 Previous DMARD use, no. ⱖ5 vs 1 4 vs 1 3 vs 1 2 vs 1 Previous etanercept and/or inﬂiximab use Yes vs no Duration of rheumatoid arthritis, years ⬎10 vs ⱕ1 ⬎5–10 vs ⱕ1 ⬎2–5 vs ⱕ1 ⬎1–2 vs ⱕ1 Rheumatoid factor Positive vs negative Age, years ⬎75 vs ⬍40 ⬎65–ⱕ75 vs ⬍40 40–ⱕ65 vs ⬍40 Sex Male vs female Comorbidities, no.‡ ⬎1 vs ⱕ1 Concomitant DMARD use, no. ⱖ1 vs 0 Concomitant glucocorticoids (maximum dosage 10 mg/day) Yes vs no Smoking history Ever vs never Hazard ratio 95% CI P 0.265 0.504 0.225–0.311 0.459–0.553 ⬍0.0001† ⬍0.0001 ⬍0.0001 0.838 0.769–0.913 0.603 0.739 0.870 0.533–0.683 0.659–0.829 0.778–0.974 0.879 1.056 1.034 1.100 0.754–1.025 0.921–1.212 0.916–1.168 0.983–1.231 0.825 0.709–0.960 0.884 0.901 0.846 1.056 0.720–1.085 0.732–1.109 0.687–1.041 0.837–1.332 0.942 0.861–1.031 0.611 0.676 0.779 0.461–0.810 0.584–0.783 0.701–0.865 0.1943 ⬍0.0001† 0.0006 ⬍0.0001 ⬍0.0001 1.284 1.160–1.422 ⬍0.0001 0.853 0.780–0.932 0.0005 1.340 1.209–1.484 ⬍0.0001 1.047 0.959–1.144 0.3034 1.076 0.987–1.174 0.0973 ⬍0.0001 ⬍0.0001† ⬍0.0001 ⬍0.0001 0.0157 0.0443† 0.1004 0.4354 0.5872 0.0967 0.0126 0.0725† 0.2377 0.3248 0.1144 0.6462 * 95% CI ⫽ 95% conﬁdence interval; see Table 1 for additional deﬁnitions. † Overall P value for all subcategories. ‡ Includes valvular heart disease, congestive heart failure, ischemic heart disease, hypertension, liver disease, peptic ulcer disease, kidney disorder, diabetes mellitus, hyperlipidemia, hypothyroidism, osteoarthritis, osteoporosis, cerebral vascular accident, depression, asthma, emphysema/chronic obstructive pulmonary disease, past tuberculosis, past pneumonia, and drug allergies/reactions. median DAS28 scores in 2,049, 1,639, 1,235, and 862 patients, respectively, were 2.5 and 2.4 at each time point. DISCUSSION The database from the ReAct trial presented an excellent opportunity to investigate the effectiveness of adalimumab on achievement of clinical remission and MDA in patients with severe RA (mean baseline DAS28 score 6.0) (26,27). Limitations of the study, including an open-label design and a relatively short study duration, are balanced by a large data set that was obtained in a study designed to reﬂect usual clinical practice. In the current analyses, we focused on the clinical aspects of remission or MDA dur- ing adalimumab therapy and did not attempt to validate the various assessment methods. A separate evaluation of the various methodologic approaches will be published separately. Regardless of the assessment method, the percentage of patients who met the remission or MDA requirements increased after week 12. Dose escalation was rare during the study and had no impact on the overall rate of remission/MDA. In general, clinical remission rates using the SDAI and CDAI deﬁnitions were similar to each other but were more restrictive than the DAS28 deﬁnition. We also applied the new OMERACT concept of MDA, which encompasses a restrictive parameter (absence of tender/swollen joints plus normal ESR) that is indicative of remission, 38 Burmester et al Figure 3. Kaplan-Meier curves for time in continuous remission (Disease Activity Score in 28 joints [DAS28] ⬍2.6; median 3.4 months) or in minimal disease activity (MDA; DAS28 score ⱕ2.85; median 4.4 months). * Number of patients still under observation excluding those who already experienced loss of remission. ⫹ Number of patients still under observation excluding those who already experienced loss of MDA. Solid line ⫽ time in MDA after remission; broken line ⫽ time in remission. as well as 2 other deﬁnitions for an acceptable state of low disease activity in which future joint damage can be prevented (26). The core set of MDA criteria tended to produce response proﬁles similar to the DAS28 score ⱕ2.85 requirement, whereas the strictest MDA deﬁnition yielded fewer responders than the DAS28 deﬁnition of clinical remission. Wells and colleagues (36) evaluated MDA outcomes in 2 abatacept studies. In their study of TNF antagonist–naive patients with RA, a lower percentage of patients in MDA were reported at week 12 compared with our study; however, this comparison is limited by differences in study design (36). Overall, results from the ReAct trial were consistent with previous placebo-controlled, randomized clinical trials of adalimumab as a treatment for RA (37–39). The remission rates documented for clinical studies of etanercept (40 – 42) and inﬂiximab (4) are similar to or somewhat lower than those observed in the ReAct trial; however, differences in study design limit our ability to directly compare the results of our study with results from randomized controlled studies. The 1-year remission rate associated with biologic treatment was 16% in the German biologics register (pooled data of 4 biologics, with 15% of patients receiving adalimumab) (34). No data on remission during adalimumab treatment have been published by the British biologic register, but the remission rates for etanercept and inﬂiximab were lower than in clinical studies (32,33). The baseline characteristics of patients in the ReAct trial were similar to the patients in the German register (34), whereas patients in the British register had notably higher disease activity and worse physical function (32,33). In general, a comparison between the studies is limited by both different response assessments and different statistical methods used to assess predictors. However, the results of our univariate subgroup analyses are similar overall to previously reported ﬁndings for both biologic registry and clinical trial data (31–35,43). Irrespective of the assessment method, patients with moderate RA activity achieved higher rates of remission/MDA compared with patients with more severe RA. Moreover, the percentage of patients meeting the most restrictive MDA deﬁnition was substantially higher in patients who were less disabled at baseline. In addition, patients who achieved a rapid response to adalimumab treatment achieved higher rates of clinical remission/MDA compared with nonresponders. Although the median time to remission or MDA was ⬃3 months in patients who experienced remission/MDA, other results, including the relatively low rate of remission/MDA observed in the analyses of week 12 data, indicate that many patients experienced remission or MDA later in the course of adalimumab treatment. Among other factors, younger age, male sex, less severe RA, and concomitant DMARD therapy increased the likelihood of achieving clinical remission or MDA, whereas the number of previous DMARDs, the duration of RA, concomitant glucocorticoid therapy, and smoking history had no inﬂuence. Overall, these ﬁndings were consistent with the results published in the British register (33). However, we did not assess the impact of nonsteroidal antiinﬂammatory drug use in our analysis. Remission is, in general, difﬁcult to maintain in patients with RA, particularly in patients with long-established and severe RA (19). The mean adalimumab treatment duration of approximately 8 months in the ReAct trial restricts the evaluation of maintenance of remission/MDA, but this period is comparable with published data (34,42). In the German register, 7.7% of patients treated with antiTNF with a DAS28 score ⬍2.6 achieved this value after 6 months of treatment (34). In the Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes, 18% of patients with a DAS28 score ⬍2.6 sustained this level of response after 6 months of treatment with etanercept and methotrexate (42). In the ReAct trial, approximately 50% of patients who achieved remission experienced sustained remission for a median of 3.4 months, and 25% experienced sustained remission for 7.5 months. We analyzed the time in MDA after remission because MDA is consid- Clinical Remission and MDA in RA 39 Table 3. Predictors of time to loss of clinical remission (DAS28 score >2.6)* Possible confounder Hazard ratio 95% CI P Time to remission (per month) Baseline DAS28 score ⬎7.0 vs ⱕ5.1 ⬎5.1–ⱕ7 vs ⱕ5.1 Baseline C-reactive protein, mg/liter ⱖ20 vs ⬍20 Baseline HAQ DI score, 0–3 ⱖ2 vs ⬍1 1.5–⬍2 vs ⬍1 1–⬍1.5 vs ⬍1 Previous DMARD use, no. ⱖ5 vs 1 4 vs 1 3 vs 1 2 vs 1 Previous etanercept and/or inﬂiximab use Yes vs no Duration of rheumatoid arthritis, years ⬎10 vs ⱕ1 ⬎5–10 vs ⱕ1 ⬎2–5 vs ⱕ1 ⬎1–2 vs ⱕ1 Rheumatoid factor Positive vs negative Age, years ⬎75 vs ⬍40 65–ⱕ75 vs ⬍40 40–ⱕ65 vs ⬍40 Sex Male vs female Comorbidities, no.‡ ⬎1 vs ⱕ1 Concomitant DMARD use, no. ⱖ1 vs 0 Concomitant glucocorticoid use (maximum dosage 10 mg/day) Yes vs no Smoking history Ever vs never 1.024 1.003–1.046 1.177 1.122 0.939–1.476 0.984–1.278 0.946 0.842–1.064 1.213 1.134 1.018 1.019–1.444 0.966–1.331 0.868–1.195 1.008 0.995 0.929 0.869 0.820–1.241 0.824–1.202 0.785–1.100 0.743–1.017 1.336 1.097–1.629 1.211 1.302 1.188 1.225 0.907–1.643 0.964–1.757 0.879–1.607 0.879–1.709 1.096 0.967–1.243 1.581 1.301 1.280 1.084–2.306 1.056–1.603 1.100–1.489 0.711 0.614–0.824 ⬍ 0.0001 1.065 0.942–1.205 0.3136 0.975 0.844–1.126 0.7280 1.114 0.982–1.263 0.0924 1.104 0.980–1.243 0.1030 0.0243 0.1813† 0.1576 0.0857 0.3544 0.0950† 0.0302 0.1252 0.8250 0.3691† 0.9364 0.9604 0.3949 0.0794 0.0041 0.4865† 0.1884 0.0855 0.2627 0.2312 0.1525 0.0063† 0.0174 0.0136 0.0014 * 95% CI ⫽ 95% conﬁdence interval; see Table 1 for additional deﬁnitions. † Overall P value for all subcategories. ‡ Includes valvular heart disease, congestive heart failure, ischemic heart disease, hypertension, liver disease, peptic ulcer disease, kidney disorder, diabetes mellitus, hyperlipidemia, hypothyroidism, osteoarthritis, osteoporosis, cerebral vascular accident, depression, asthma, emphysema/chronic obstructive pulmonary disease, past tuberculosis, past pneumonia, and drug allergies/reactions. ered an acceptable state from both a patient and physician perspective. Half of the patients maintained at least MDA for a median of 4.4 months. However, approximately onequarter of the patients discontinued in a state of remission or MDA and could not be evaluated for long-term outcomes. The maintenance of remission was strongly dependent on male sex and, to a lesser degree, on a short time to remission, the absence of previous TNF antagonist therapy, and younger age. By comparison, sustained MDA was dependent not on age but on smoking history (never). Consistent with previous reports, we found a strong relationship between male sex and achievement and maintenance of remission (32,43). To our knowledge, this analysis represents the largest, prospective clinical trial data set to be characterized using the OMERACT criteria for MDA. Because remission is difﬁcult to maintain, the MDA data demonstrating the beneﬁt of adalimumab treatment should be of value to rheumatologists treating patients with RA. Depending on the assessment method, clinical remission was achieved in approximately one-quarter to more than one-third of patients with active RA during adalimumab therapy in the ReAct trial. Nearly half of the patients experienced MDA as deﬁned by OMERACT methods. Initiation of adalimumab treatment in combination with DMARDs in patients who are less disabled and have developed few comorbidities substantially increases the likelihood of remission/MDA. Overall, more than half of 40 Burmester et al the patients who had experienced remission at any time during the study remained in remission at study end. Throughout the complete course of adalimumab therapy, at least MDA was sustained for a median of 4.4 months in patients who achieved remission. 9. 10. ACKNOWLEDGMENTS Abbott thanks the physicians and staff members of all study centers for having participated in ReAct. We thank Dr. Uemit Oezer for medical support, Dr. David Webber and Ina Reinhardt for study management, and Dana L. Randall, MS, PharmD, for editorial assistance. AUTHOR CONTRIBUTIONS Dr. Burmester had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design. Burmester, Unnebrink, Kupper. Acquisition of data. Burmester, Monteagudo-Sáez, Unnebrink. Analysis and interpretation of data. Burmester, Ferraccioli, Flipo, Monteagudo-Sáez, Unnebrink, Kary, Kupper. Manuscript preparation. Burmester, Flipo, Monteagudo-Sáez, Unnebrink, Kary, Kupper. Statistical analysis. Flipo, Unnebrink. ROLE OF THE STUDY SPONSOR Abbott GmbH & Co. KG collaborated with Drs. Burmester, Ferraccioli, Flipo, and Monteagudo-Sáez to design and conduct the study. All authors analyzed the data, reviewed the manuscript critically for important intellectual content, approved the ﬁnal draft, and agreed to its submission. . REFERENCES 1. Navarro-Sarabia F, Ariza-Ariza R, Hernandez-Cruz B, Villanueva I. 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