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Keywords:

  • Rheumatoid arthritis;
  • Low disease activity;
  • Clinical remission;
  • Minimal disease activity

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Objective

To evaluate published proposed definitions of minimal disease activity (MDA) and remission in patients with early rheumatoid arthritis (RA).

Methods

The cohort comprised disease-modifying antirheumatic drug (DMARD)–naive patients with early seropositive active RA (n = 200) treated with traditional DMARDs in the prebiologic era. MDA definitions included Disease Activity Score in 28 joints (DAS28) ≤2.85, or achieving 5 of 7 World Health Organization (WHO)/International League of Associations for Rheumatology (ILAR) core set measure thresholds as proposed by the Outcome Measures in Rheumatology Clinical Trials. Other MDA definitions included Simplified Disease Activity Index (SDAI) score ≤11 and Clinical Disease Activity Index (CDAI) score ≤10. Remission definitions included American College of Rheumatology (ACR) remission, DAS28 <2.6, DAS28 <2.4, achieving all 7 WHO/ILAR core set measure thresholds, SDAI ≤3.3, and CDAI ≤2.8. Physical function was assessed using the Health Assessment Questionnaire (HAQ) disability index (DI) and radiographic progression was assessed using the Sharp score.

Results

At baseline, no patients were in MDA or remission. Depending on the MDA definition, 20–32%, 27–32%, and 30–48% were in MDA at 6, 12, and 24 months, respectively. Depending on the remission definition, 0.7–15%, 0–24%, and 0–33% were in remission at 6, 12, and 24 months, respectively. For example, at 6 months, lowest (highest) responses for MDA were seen with DAS28 ≤2.85 (SDAI ≤11) and for remission with ACR remission criteria (DAS28 <2.6). Patients who achieved either MDA or remission had lower HAQ DI and radiographic scores compared with patients who achieved neither.

Conclusion

Our study demonstrated that different proportions of patients were classified as MDA or remission depending on the definition used. This has implications in predefining MDA or remission for a clinical trial or to establish goals for optimum management of RA in clinical practice.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Rheumatoid arthritis (RA) is a chronic arthritis associated with disability and decrement in quality of life. New therapeutics have revolutionized the treatment of RA, and the goal of therapy has become to maintain patients in a low disease activity status or remission (1, 2). The Outcome Measures in Rheumatology Clinical Trials (OMERACT) group has recently proposed preliminary definitions of minimal disease activity (MDA), i.e., low disease activity state in RA (3). MDA is defined as a disease state that is “between high disease state and remission” (3). By definition, anyone in remission is also in MDA. In another study, Aletaha et al proposed definitions for MDA and remission (4) based on the Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) (5). We assessed preliminary definitions of MDA and remission in a disease-modifying antirheumatic drug (DMARD)–naive cohort with early, seropositive, active RA.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Patients.

Patients included in this study were a subset of a group of patients with early RA participating in a long-term observational study by the Western Consortium of Practicing Rheumatologists, which is a regional consortium of rheumatology practices in the western US and Mexico. The study was reviewed and approved by the University of California Los Angeles institutional review board.

The consortium and its practices have been detailed in previous publications (6, 7). In brief, patients in this subset had a diagnosis of early RA (median of 5.2 months since symptom onset), had no previous DMARD treatment, were rheumatoid factor (RF) seropositive (median 214 IU/ml), had ≥6 swollen joints and ≥9 tender joints, and had at least 2 sets of scored joint radiographs. Patients with symptom onset >14 months or negative RF were excluded. The consortium rheumatologists assessed patient disease status at study entry (baseline), 6 months, 1 year, and yearly thereafter. Using standard methods, detailed physician assessment included all of the core set outcome measures required to calculate DAS28 score, including complete tender and swollen joint counts and acute-phase reactant measures, as well as 0–10-cm visual analog scales (VAS) for physician global assessment and patient VAS assessments of disease activity, fatigue, stiffness, and pain. The DAS28 was calculated according to the published algorithm using the swollen and tender joint count of 28 joints, patient's global assessment, and erythrocyte sedimentation rate (ESR) in mm/hour (8, 9). At each scheduled physician visit, blood specimens were collected for C-reactive protein level; ESR was determined when clinically indicated in the rheumatologist's office or local laboratory. Patients were asked to complete a detailed self-report mailed questionnaire at study entry and every 6 months thereafter for the duration of the study. In these questionnaires, patients reported changes in demographics, health, medication, pain, and fatigue, and completed the Health Assessment Questionnaire (HAQ) disability index (DI).

Study assessments included radiographs of the hands, wrists, and forefeet. Standard posteroanterior radiographs including both hands and wrists and anteroposterior radiographs including both forefeet were obtained at entry, 6 months, and yearly thereafter in the rheumatologists' offices or at the radiology facility usually used by the rheumatologists. Two experienced readers (JTS and RHG) scored all available radiographs for erosions (on a scale from 0 to 5) and joint space narrowing (on a scale from 0 to 4); the total score was the sum of the erosion and joint space narrowing scores. After a brief training session in which the readers discussed the scoring scale and reviewed a small group of radiographs to be sure they agreed on the features to be scored, the radiographs were scored independently using the method described by Sharp et al (10, 11) to score 17 joints of each hand and wrist for erosions and 16 for joint space narrowing, and 6 joints of each forefoot for erosions and joint space narrowing. Maximum possible scores for the hands/wrists were 170 for erosion and 128 for joint space narrowing (total score 298), for the feet were 60 for erosion and 48 for joint space narrowing (total score 108), and for both hands/wrists and feet were 230 for erosion and 176 for joint space narrowing (total score 406). Radiographs were read in patient sets and were randomized and blinded for sequence. The independent scores of readers 1 and 2 for each radiograph were averaged, and this average was used for the analysis. Sclerosis or healing of erosions was not scored. For each patient with ≥2 radiographic observations, the slope of the least squares regression line was calculated to estimate the annualized progression rates of erosion score, joint space narrowing score, and total Sharp score, assuming that progression remained relatively constant during the time interval of the observations.

Patients could be treated with ≥1 DMARD at any time after the baseline evaluation. At 2 years of followup, the cumulative patient-years of DMARD use by these 200 patients, individually or in combination, were 187.5 years for methotrexate, 95.7 years for antimalarials, 27 years for sulfasalazine, 2.3 years for etanercept, 1.25 years for infliximab, 13.5 years for intramuscular gold, 2 years for azathioprine, 129.8 years oral prednisone, and 5.5 years for other DMARDs. At some time during the course of the 2 years, ∼28% were receiving double combination DMARD therapy (combinations of either methotrexate, sulfasalazine, or hydroxychloroquine) and 5% were receiving triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine). Nonsteroidal antiinflammatory drugs were used or changed as clinically indicated at the discretion of the physicians.

Preliminary definitions of MDA.

The OMERACT group has proposed preliminary definitions (3) for achieving MDA. For the first definition, patients with no tender joints and no swollen joints and an ESR ≤10 mm/hour are considered to be in MDA. If patients do not meet this criterion, they are still considered to be in MDA if either their DAS28 score is ≤2.85 or they meet 5 of the 7 World Health Organization (WHO)/International League Against Rheumatism (ILAR) core set measure thresholds, i.e., pain ≤2 (0–10 scale), swollen joint count ≤1 (out of 28), tender joint count ≤1 (out of 28), HAQ DI score ≤0.5 (range 0–3), physician global assessment ≤1.5 (0–10 scale), patient global assessment ≤2 (0–10 scale), and ESR ≤20 mm/hour. Aletaha and Smolen have proposed definitions based on the CDAI and SDAI (5). According to the definitions, CDAI scores ≤10 and SDAI scores ≤11 are considered as MDA (Table 1).

Table 1. Various definitions of minimal disease activity (MDA) and remission*
Disease activity measureMDA (reference)Remission (reference)
  • *

    TJC = tender joint count; SJC = swollen joint count; ESR = Westergren erythrocyte sedimentation rate (mm/hour); DAS28 = Disease Activity Score in 28 joints; TJC28 = Tender Joint Count for 28 joints; SJC28 = Swollen Joint Count for 28 joints; GH = patient global assessment; WHO = World Health Organization; HAQ DI = Health Assessment Questionnaire disability index; VAS = visual analog scale; MD global = physician global assessment; CDAI = Clinical Disease Activity Index; SDAI = Simplified Disease Activity Index; CRP = C-reactive protein; ACR = American College of Rheumatology; AM stiffness = morning stiffness in minutes.

TJC = 0; SJC = 0; ESR ≤10All required
DAS28 ESR 4-item = 0.56(√TJC28) + 0.28(√SJC28) + 0.70 ×≤2.85 (3)<2.4 (4)  
 ln(ESR) + 0.014(GH) <2.6 (12)
WHO core set measures thresholds5 of 7 (3)7 of 7 (3)
 TJC28 ≤1; SJC28 ≤2; HAQ DI ≤0.5; ESR ≤20; GH VAS ≤2; MD global VAS ≤1.5; patient pain VAS ≤2  
CDAI = TJC28 + SJC28 + GH (10 cm) + MD global (10 cm)≤10 (5)≤2.8 (5)
SDAI = TJC28 + SJC28 + GH (10 cm) + MD global (10 cm) + CRP≤11 (5)≤3.3 (5)
ACR remission thresholds5 of 6 (13)
 AM stiffness ≤15; fatigue = 0; joint pain = 0; SJC = 0; TJC = 0; ESR <30 for women, <20 for men  

Preliminary definitions of remission.

DAS28 score <2.6 was proposed as a definition of remission by Prevoo et al in 1995 (12). Aletaha and colleagues recently used paper patient profiles and expert opinion of 35 rheumatologists (4) to develop a stricter definition for remission: DAS28 score <2.4. Aletaha and Smolen also proposed CDAI score ≤2.8 and SDAI score ≤3.3 as definitions of being in remission (5). We also assessed a core set–based definition of remission, i.e., achieving 7 of 7 WHO/ILAR core set thresholds, as proposed by the OMERACT group (3). These remission definitions were compared with the American College of Rheumatology (ACR; formerly the American Rheumatism Association) remission definition (13), which involves meeting 5 of the following 6 criteria for at least 2 consecutive months: morning stiffness ≤15 minutes, no fatigue, no joint pain (by history), no swollen joint count, no tender joint count, and ESR <30 mm/hour for women or <20 mm/hour for men. We modified the ACR remission criteria by assessing remission cross-sectionally, i.e., at single points in time, rather than over a consecutive 2-month period (Table 1).

Statistical analysis.

For each definition, the Wilcoxon rank sum test was performed to compare 2 groups (patients classified as MDA versus those not MDA and patients classified as in remission versus those not in remission). Agreement between different definitions of MDA and remission was assessed using the kappa statistic and was interpreted as proposed by Altman (14): 0.20 indicates poor agreement, 0.20–0.40 indicates fair agreement, 0.40–0.60 indicates moderate agreement, 0.60–0.80 indicates good agreement, and 0.80–1.00 indicates excellent agreement. We analyzed the data using SAS software, release 8.02 (SAS Institute, Cary, NC). P values less than 0.05 were considered indicative of statistical significance.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

At baseline, 200 patients had sufficient available data to assess DAS28 score, the 7 core set measures (VAS pain, swollen joint count, tender joint count, HAQ DI score, physician global assessment, patient global assessment, and ESR) (Table 2), morning stiffness, VAS fatigue, and radiographs. The majority of the patients were women (77%) and had moderate patient-reported disability (median HAQ DI score 1.25) and high disease activity (median DAS28 score 5.54). At 6, 12, and 24 months after baseline, 152, 142, and 101 patients, respectively, had complete core set measures, morning stiffness, and VAS fatigue along with Sharp scores of paired radiographic data.

Table 2. Baseline characteristics of the study population (n = 200)*
VariablesMean ± SDMedian (25th, 75th percentile)
  • *

    See Table 1 for definitions.

Age, years51.38 ± 12.9150.85 (42.12, 61.72)
Disease duration, months5.94 ± 3.295.28 (3.40, 8.13)
Patient global assessment (0–10)4.30 ± 2.334.62 (2.15, 6.27)
Physician global assessment (0–10)5.19 ± 2.085.30 (3.40, 6.70)
Patient pain assessment (0–10)5.13 ± 2.425.28 (3.30, 6.93)
ESR, mm/hour42.67 ± 24.6638.00 (26.00, 55.00)
HAQ (0–3)1.20 ± 0.711.25 (0.63, 1.63)
Tender joint count (0–28)13.97 ± 7.6313.00 (8.50, 20.00)
Swollen joint count (0–28)13.33 ± 7.1312.00 (8.00, 19.00)
DAS28/ESR 4 item5.48 ± 1.025.54 (4.78, 6.24)
SDAI (0–86)41.09 ± 16.4938.75 (28.65, 51.95)
CDAI (0–76)38.27 ± 15.3636.01 (26.65, 48.51)
Total Sharp score6.36 ± 8.663.67 (1.25, 8.25)
Erosion score2.15 ± 3.960.75 (0.17, 2.50)
Joint space narrowing score4.21 ± 6.222.00 (0.67, 5.75)

Minimal disease activity and remission.

The proportions of patients in MDA as defined by no tender joints and no swollen joints and an ESR ≤10 mm/hour were as follows: 3%, 2%, and 3% at 6, 12, and 24 months, respectively (Table 3). For patients who did not achieve MDA as described above, the 2 other definitions (DAS28 score ≤2.85 and 5 of 7 WHO/ILAR core set criteria thresholds) were assessed. For the 5 of 7 WHO/ILAR core set criteria definition (including patients who also achieved MDA by no tender joints and no swollen joints and an ESR ≤10 mm/hour), 23%, 27%, and 30% of patients achieved MDA at 6, 12, and 24 months, respectively (Table 3, Figure 1). The proportions of patients achieving MDA as defined by DAS28 score ≤2.85 (including patients who achieved MDA by no tender joints and no swollen joints and an ESR ≤10 mm/hour) were very similar: 20%, 27%, and 35% at 6, 12, and 24 months, respectively. The proportions of patients in MDA at 6, 12, and 24 months using the definition SDAI score ≤11 were 32%, 32%, and 45%, respectively, and using the definition CDAI score ≤10 were 30%, 32%, and 48%, respectively.

Table 3. Proportion of patients in minimal disease activity (MDA) state at 0, 6, 12, and 24 months*
DefinitionBaseline (n = 200)6 months (n = 152)12 months (n = 142)24 months (n = 101)
MDANo MDAMDANo MDAMDANo MDAMDANo MDA
  • *

    Values are the number or number (percentage). ILAR = International League of Associations for Rheumatology; see Table 1 for additional definitions.

SJC = 0, TJC = 0, and ESR ≤10 (definition 1)02004 (3)1483 (2)1393 (3)98
5 of 7 WHO/ILAR core sets020035 (23)11738 (27)10430 (30)71
DAS28 ≤2.85020031 (20)12138 (27)10435 (35)66
SDAI ≤11020048 (32)10446 (32)9645 (45)56
CDAI ≤10020046 (30)10646 (32)9648 (48)53
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Figure 1. Proportions of patients (n = 152) with minimal disease activity (MDA) or remission at month 6, using various definitions of MDA and remission. SJC = swollen joint count; TJC = tender joint count; ESR = erythrocyte sedimentation rate; DAS = Disease Activity Score; WHO = World Health Organization; ILAR = International League of Associations for Rheumatology; CDAI = Clinical Disease Activity Index; SDAI = Simplified Disease Activity Index; ACR = American College of Rheumatology.

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At baseline, as expected, no patients were in MDA or remission. At months 6, 12, and 24, 15%, 24%, and 33% were in remission using DAS28 score <2.6, respectively (Table 4). In comparison, 13%, 19%, and 25% were in remission using DAS28 score <2.4 and 3%, 4%, and 6% were in remission using the 7 of 7 core set criterion at 6, 12, and 24 months, respectively. For ACR remission criteria, 0.7%, 0%, and 0% were in remission at 6, 12, and 24 months, respectively. The proportions of patients in remission at 6, 12, and 24 months for SDAI score ≤3.3 were 11%, 11%, and 15%, respectively, and for CDAI score ≤2.8 were 12%, 11%, and 17%, respectively.

Table 4. Proportion of patients in remission at baseline, 6, 12, and 24 months*
DefinitionBaseline (n = 200)6 months (n = 152)12 months (n = 142)24 months (n = 101)
RemissionNo remissionRemissionNo remissionRemissionNo remissionRemissionNo remission
  • *

    Values are the number or number (percentage). ILAR = International League of Associations for Rheumatology; see Table 1 for additional definitions.

DAS28 <2.6020023 (15)12934 (24)10833 (33)68
DAS28 <2.4020020 (13)13227 (19)11525 (25)76
7 of 7 WHO/ILAR core sets02005 (3)1475 (4)1376 (6)95
ACR remission (5 of 6 items)02001 (0.7)15101420101
SDAI ≤3.3020017 (11)13515 (11)12715 (15)86
CDAI ≤2.8020018 (12)13416 (11)12617 (17)84

We assessed agreement at the 6-month, 12-month, and 24-month time points among the different definitions. The agreement between different definitions of MDA was good to excellent (range 0.67–0.97) (Table 5). However, agreement among the definitions of remission ranged from poor to excellent (range 0.07–0.97) (Table 6). For example, the ACR remission definition had poor agreement with DAS28 score <2.4, DAS28 score <2.6, CDAI score ≤2.8, and SDAI score ≤3.3, and only a fair agreement with the 7 of 7 WHO/ILAR core sets.

Table 5. Agreement between the different definitions of low disease activity at 6 months*
 5 of 7 WHO/ILAR core setsDAS28 ≤2.85SDAI ≤11CDAI ≤10
  • *

    ILAR = International League of Associations for Rheumatology; see Table 1 for additional definitions.

5 of 7 WHO/ILAR core sets10.69 (good)0.69 (good)0.68 (good)
DAS28 ≤2.85 10.68 (good)0.67 (good)
SDAI 11  10.97 (excellent)
Table 6. Agreement between the different definitions of remission at 6 months*
 DAS28 <2.6DAS28 <2.47 of 7 WHO/ILAR core setsACR remissionSDAI ≤3.3CDAI ≤2.8
  • *

    Degree of agreement indicated by kappa values: <0.2 = poor agreement; 0.2–0.4 = fair agreement; >0.4–0.6 = moderate agreement; >0.6–0.8 = good agreement; >0.8–1.0 = excellent agreement. Parentheses indicate the range of values at the 6-month, 12-month, and 24-month assessments. ILAR = International League of Associations for Rheumatology; see Table 1 for additional definitions.

DAS28 <2.610.92 (excellent)0.32 (fair)0.07 (poor)0.48 (moderate)0.52 (moderate)
DAS28 <2.4 10.20 (fair)0.08 (poor)0.48 (moderate)0.46 (moderate)
7 of 7 WHO/ILAR core sets  10.33 (fair)0.23 (fair)0.31 (fair)
ACR remission (5 of 6 items)   10.10 (poor)0.09 (poor)
SDAI ≤3.3    10.97 (excellent)

Using the various proposed definitions, the HAQ DI status and radiographic scores of patients who achieved MDA (or remission) compared with patients who did not are presented in Tables 7 and 8. Patients classified as being in MDA (or remission) had lower median HAQ DI and radiographic scores compared with patients who were not in MDA or remission, except for a few outlier comparisons when only ≤2 patients achieved MDA or remission.

Table 7. Effects of minimal disease activity (MDA) state on HAQ score status and radiographic score*
Definition6 months (n = 152)12 months (n = 142)24 months (n = 101)
MDANo MDAMDANo MDAMDANo MDA
  • *

    Values are the median (25th, 75th percentile) unless otherwise indicated. ILAR = International League of Associations for Rheumatology; see Table 1 for additional definitions.

  • P < 0.01 for MDA versus no MDA at months 6, 12, or 24.

  • P < 0.05 for MDA versus no MDA at months 6, 12, or 24.

SJC = 0, TJC = 0, and ESR ≤10 (definition 1), no. (%)4 (3)1483 (2)1393 (3)98
 HAQ0.25 (0.0, 0.8)0.75 (0.3, 1.2)0.13 (0.0, 1.1)0.50 (0.0, 1.1)0.25 (0.0, 0.5)0.56 (0.1, 1.1)
 Total Sharp score1.75 (0.8, 2.8)5.50 (2.0, 10.5)8.00 (0.0, 16.0)6.50 (3.5, 13.5)15.50 (6.0, 18.3)8.63 (4.0, 17.5)
5 of 7 WHO/ILAR core sets, no. (%)35 (23)11738 (27)10430 (30)71
 HAQ0.00 (0.0, 0.3)0.88 (0.5, 1.4)0.06 (0.0, 0.4)0.81 (0.1, 1.4)0.00 (0.0, 0.1)1.00 (0.4, 1.5)
 Total Sharp score2.75 (0.8, 5.5)6.50 (2.0, 14.3)4.25 (2.3, 10.5)7.63 (3.5, 15.0)5.50 (3.0, 12.5)12.00 (5.0, 18.8)
DAS28 ≤2.85, no. (%)31 (20)12138 (27)10435 (35)66
 HAQ0.00 (0.0, 0.5)0.88 (0.4, 1.4)0.13 (0.0, 0.8)0.75 (0.1, 1.3)0.13 (0.0, 0.5)0.94 (0.4, 1.4)
 Total Sharp score2.75 (0.5, 7.0)6.00 (2.5, 12.0)4.25 (2.0, 9.5)7.63 (3.5, 15.0)5.00 (1.5, 13.5)12.38 (5.5, 18.8)
SDAI ≤11, no. (%)48 (32)10446 (32)9645 (45)56
 HAQ0.25 (0.0, 0.8)0.88 (0.5, 1.4)0.13 (0.0, 0.4)0.88 (0.1, 1.4)0.13 (0.0, 0.5)1.00 (0.4, 1.5)
 Total Sharp score3.50 (1.3, 7.8)6.88 (2.0, 11.5)4.25 (2.0, 7.0)9.00 (4.0, 15.5)5.63 (2.0, 13.5)12.50 (5.5, 18.5)
CDAI ≤10, no. (%)46 (30)10646 (32)9648 (48)53
 HAQ0.25 (0.0, 0.8)0.88 (0.5, 1.4)0.13 (0.0, 0.4)0.81 (0.1, 1.4)0.13 (0.0, 0.7)1.00 (0.4, 1.5)
 Total Sharp score3.25 (1.0, 7.5)6.88 (2.3, 11.5)4.38 (2.0, 7.0)9.00 (3.5, 15.0)6.00 (3.0, 15.5)12.38 (5.5, 18.1)
Table 8. Effects of remission state on HAQ score status and radiographic score*
Definition6 months (n = 152)12 months (n = 142)24 months (n = 101)
RemissionNo remissionRemissionNo remissionRemissionNo remission
  • *

    Values are the median (25th, 75th percentile) unless otherwise indicated. ILAR = International League of Associations for Rheumatology; see Table 1 for additional definitions.

  • P < 0.01 for remission versus no remission at months 6, 12, or 24.

  • P < 0.05 for remission versus no remission at months 6, 12, or 24.

DAS28 <2.6, no. (%)23 (15)12934 (24)10833 (33)68
 HAQ0.00 (0.0, 0.3)0.88 (0.3, 1.3)0.13 (0.0, 0.6)0.75 (0.1, 1.3)0.13 (0.0, 0.5)0.88 (0.3, 1.4)
 Total Sharp score2.13 (0.5, 7.0)5.50 (2.3, 11.8)4.00 (1.8, 5.5)7.63 (4.0, 15.5)5.00 (2.0, 11.3)12.38 (5.4, 19.1)
DAS28 <2.4, no. (%)20 (13)13227 (19)11525 (25)76
 HAQ0.00 (0.0, 0.4)0.88 (0.3, 1.3)0.13 (0.0, 0.6)0.63 (0.1, 1.3)0.13 (0.0, 0.4)0.81 (0.3, 1.3)
 Total Sharp score2.13 (0.5, 6.8)5.50 (2.0, 11.5)4.13 (1.8, 7.5)7.50 (3.5, 15.0)5.13 (3.5, 13.5)12.00 (4.5, 18.8)
7 of 7 WHO/ILAR core sets, no. (%)5 (3)1475 (4)1376 (6)95
 HAQ0.00 (0.0, 0.3)0.75 (0.3, 1.3)0.00 (0.0, 0.0)0.50 (0.1, 1.1)0.00 (0.0, 0.1)0.63 (0.1, 1.3)
 Total Sharp score2.88 (1.6, 5.5)5.50 (2.0, 10.5)2.00 (1.3, 4.5)6.75 (3.5, 13.8)2.75 (1.3, 6.0)11.00 (4.5, 17.8)
ACR remission, no. (%)1 (0.7)1510 (0)1420 (0)101
 HAQ0.00 (0.0, 0.0)0.75 (0.3, 1.1) 0.50 (0.0, 1.1) 0.50 (0.1, 1.1)
 Total Sharp score8.00 (8.0, 8.0)5.25 (2.0, 10.5) 6.50 (3.5, 13.5) 8.75 (4.5, 17.5)
SDAI ≤3.3, no. (%)17 (11)13515 (11)12715 (15)86
 HAQ0.25 (0.0, 0.8)0.75 (0.3, 1.3)0.13 (0.0, 0.6)0.50 (0.1, 1.3)0.00 (0.0, 0.4)0.63 (0.1, 1.3)
 Total Sharp score2.75 (0.5, 8.0)5.50 (2.0, 10.5)4.00 (1.3, 5.5)7.13 (3.5, 13.8)6.00 (1.5, 11.0)10.04 (4.5, 18.6)
CDA1 ≤2.8, no. (%)18 (12)13416 (11)12617 (17)84
 HAQ0.25 (0.0, 0.8)0.75 (0.3, 1.3)0.19 (0.0, 0.5)0.56 (0.1, 1.3)0.00 (0.0, 0.3)0.69 (0.2, 0.3)
 Total Sharp score2.63 (0.5, 7.5)5.50 (2.0, 10.5)4.25 (1.6, 10.8)7.00 (3.5, 13.5)5.00 (1.3, 11.0)11.63 (4.5, 18.8)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

This study evaluated several published proposed definitions of MDA states and remission in a cohort of patients with early, seropositive RA. With the advent of new therapies, the goal of current RA treatment is to achieve MDA and remission (15–17). As pointed out by the OMERACT group, with the recent advances in RA therapy, “the proportion of patients achieving a satisfactory state of MDA is becoming an important measure with which to compare different treatment strategies” (3). Our cohort comprised patients with early, seropositive RA, defined as active disease by ≥6 swollen joints and ≥9 tender joints, who were treated with traditional DMARDs before the biologic era.

Although the clinical concepts of treatment-induced remission, spontaneous remission (persisting without treatment), and MDA state (very good, but not quite remission) in RA are easily understood and increasingly realistic goals of modern treatment regimens (16, 18), this study clearly illustrates the lack of consensus in attempts to quantitatively define these concepts. In our observational cohort, the proportions of patients who were classified as being in remission or MDA varied widely among the published proposed definitions (Figure 1).

Depending on the MDA definition used, 20–32% of patients were in MDA at 6 months, 27–32% were in MDA at 12 months, and 30–48% were in MDA at 24 months. For the MDA definitions, the lowest response rates were seen with DAS28 score ≤2.85 (20% at 6 months and 27% at 12 months) and 5 of 7 WHO/ILAR criteria (30% at 24 months), and the highest response rates were seen with SDAI score ≤11 (32% at 6 and 12 months) and CDAI score ≤10 (48% at 24 months). Similarly, for the remission definitions, the lowest responses rates were seen with the ACR remission criteria (0.7%, 0%, and 0% at 6, 12, and 24 months, respectively) and the highest response rates were seen with DAS28 score <2.6 (15%, 24%, and 33% at 6, 12, and 24 months, respectively).

The higher proportions of patients achieving MDA at month 24 may be due to selection bias because patients with more active disease might have dropped out of the consortium. Considering the various definitions for remission, the proportions of patients meeting criteria with DAS28 score <2.4, DAS28 score <2.6, SDAI score ≤3.3, or CDAI score ≤2.8 were between 11% and 15% at 6 months, 11% and 24% at 12 months, and 15% and 33% at 24 months. There is currently an effort to revise the definitions of remission. Patients who achieve remission as defined by DAS28 score <2.6 may still have substantial disease activity (19), and as stated by Aletaha and colleagues, “even the new, more stringent DAS28 cutoff value of 2.4 allows for the presence of up to 12 swollen joints in our patients” (4). In contrast, the definitions of remission using the SDAI and CDAI only permit 2 swollen or 2 tender joints or 1 tender and 1 swollen joint. The ACR remission criteria and 7 of 7 WHO/ILAR criteria were stricter: 0.7% and 3% at 6 months, 0% and 4% at 12 months, and 0% and 6% at 24 months, respectively, achieved these criteria for remission. As the definition of remission undergoes refinement, our data suggest that OMERACT's first definition of achieving MDA (no tender joints or swollen joints and an ESR ≤10 mm/hour) may be better used as a definition of remission (only 2–3% achieved remission at different time points). Supporting the MDA and remission definitions, patients who achieved either MDA or remission by most definitions had lower HAQ DI and radiographic scores at months 6, 12, and 24 compared with patients who did not achieve MDA or remission (except for the ACR remission criteria and 7 of 7 WHO/ILAR criteria, which were attained by only a few patients).

Our study has several strengths. First, the patients enrolled in the cohort were DMARD naive at entry and had active disease as defined by ≥6 swollen and 9 tender joint counts. No patient was in MDA or remission at baseline, providing face validity to the definitions. Second, after entering the cohort almost all patients were started on traditional DMARDs by their rheumatologists. The proportions of patients achieving MDA and remission using different definitions provide a benchmark for comparison with future cohorts. However, our study has limitations. Because missing data were not imputed, fewer baseline patients were able to be evaluated at 6, 12, and 24 months. This restricted our ability to assess MDA and remission in all 200 patients during each time point. However, this should not invalidate our conclusions, because our goal was to evaluate the preliminary definitions of MDA and remission. Biologic agents had not been approved when these patients were studied (1993–1997); the proportions of patients achieving MDA or remission may be larger now. In addition, our findings may not be generalizable to other RA patient populations, e.g., patients with seronegative RA, less active RA, or longer disease duration.

In conclusion, we assessed the definitions of MDA and remission in a cohort of patients with early, active, seropositive RA. If these criteria are used as secondary outcomes in clinical trials, it is essential that the selected definition of MDA or remission is fully described because the proportion of patients so classified varies widely depending on the definition selected. Much more work will be needed to reach consensus on single uniform definitions of MDA and remission. Agreement on easily measured uniform definitions is particularly desirable at this time because it may provide an attainable goal for optimal management of RA in clinical practice. Use of these uniform definitions of MDA and remission in clinical trials may help to determine the most beneficial regimens for management of the various stages of RA.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES

Dr. Khanna 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. Khanna, Furst, Paulus.

Acquisition of data. Gold, Sharp, Park, Paulus.

Analysis and interpretation of data. Khanna, Furst, Ranganath, Park, Paulus.

Manuscript preparation. Khanna, Furst, Ranganath, Sharp, Keystone, Paulus.

Statistical analysis. Khanna, Oh.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES