ARTHRITIS & RHEUMATISM Vol. 63, No. 12, December 2011, pp 3702–3711 DOI 10.1002/art.30634 © 2011, American College of Rheumatology Joint Damage in Rheumatoid Arthritis Progresses in Remission According to the Disease Activity Score in 28 Joints and Is Driven by Residual Swollen Joints Daniel Aletaha and Josef S. Smolen residual joint swelling (n ⴝ 92, 80.7%) had less radiographic progression over 1 year than those with residual joint swelling (n ⴝ 22, 19.3%) (mean ⴞ SD SHS progression 0.2 ⴞ 2.6 versus 2.2 ⴞ 4.2; P ⴝ 0.11). Likewise, the proportion of patients with a total SHS progression of >0.5/year was significantly lower among those without joint swelling than among those with joint swelling (27.2% versus 50.0%; P ⴝ 0.039). DAS28 remitters without joint swelling showed progression comparable to that in the total group of remitters by the Simplified Disease Activity Index (remission defined as <3.3) and Clinical Disease Activity Index (remission defined as <2.8), namely, 0.2 versus ⴚ0.07 versus 0.16, respectively (P ⴝ 0.66). Conclusion. Radiographic progression with nonbiologic treatment is minimal only when patients in DAS28 remission have no persistent residual joint swelling. Under these conditions, progression is comparable to that in patients with disease in remission according to other disease activity indices. Objective. Remission has been defined as the ultimate target for patients with rheumatoid arthritis. The Disease Activity Score in 28 joints (DAS28) has been criticized for the amount of disease activity that remains in patients despite their achieving DAS28 remission. This study was undertaken to investigate the significance of residual inflammation in remission in relation to radiographic progression. Methods. We pooled 1-year clinical data, kindly provided by the respective sponsors, on 864 patients in methotrexate monotherapy arms of recent pivotal trials. We identified patients who had attained persistent DAS28 remission from month 6 through month 12 (a DAS286–12 of <2.6). Among these patients we then assessed radiographic progression in total Sharp/van der Heijde scores (SHS) from baseline to 12 months between those with residual joint swelling (defined as a swollen joint count from month 6 through month 12 [SJC6–12] of >2) and those without residual joint swelling (defined as an SJC6–12 of <2). Results. One hundred fourteen patients (13.2%) achieved a DAS286–12 of <2.6, of whom those without Rheumatoid arthritis (RA) is an inflammatory joint disease with joint destruction being its most essential hallmark. Joint damage in RA involves both cartilage and bone. While cartilage damage is due to activation of chondrocytes and matrix metalloproteinases (1), bone destruction is a consequence of the activity of osteoclasts (2,3). However, all of these events are driven by the inflammatory response. Indeed, previous studies have revealed that joint damage is related to the level of the acute-phase response and swollen joint counts (SJCs), both at the start of therapy and cumulatively over time, but not to tender joint counts (TJCs) or other clinical variables (4–6). As a consequence, scoring on composite indices of disease activity is also related to the extent of joint damage (5). While physical disability is one of the most important outcomes to prevent in patients with RA, the This is a publication of the Joint and Bone Center for Diagnosis, Research and Therapy of Musculoskeletal Disorders of the Medical University of Vienna. Supported by the European Union Seventh Framework Programme (Coordination Theme 1 [Health], project Masterswitch; HEALTH-F2-2008-223404). Daniel Aletaha, MD, Josef S. Smolen, MD: Medical University of Vienna, Vienna, Austria. Dr. Aletaha has received consulting fees, speaking fees, and/or honoraria from Abbott, Pfizer, MSD, UCB, and Roche (less than $10,000 each). Dr. Smolen has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Bristol-Myers Squibb, Pfizer, MSD, Roche, and UCB (less than $10,000 each). Address correspondence to Daniel Aletaha, MD, Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail: [email protected] Submitted for publication October 14, 2010; accepted in revised form August 16, 2011. 3702 JOINT DAMAGE PROGRESSION IN DAS28 REMISSION interest in joint damage relates to the fact that permanent RA-related disability is greatly due to joint destruction (7–9). Clinical remission will not only reverse disability that is related to activity, but will also halt progression of joint destruction, especially if sustained over time (10,11). Therefore, remission will also prevent the accrual of irreversible disability. Only recently has remission become an achievable goal (12,13), and only few trials have employed remission as a primary end point (14,15). While there are several definitions of remission (16,17), remission as defined by the Disease Activity Score in 28 joints (DAS28) (18) is most frequently reported in clinical trials (14,19). However, DAS28 remission has been under scrutiny over recent years, since a large proportion of patients with DAS28 remission have significant residual SJCs (20–23). While stringent remission criteria, such as those of the Simplified Disease Activity Index (SDAI) (24) or Clinical Disease Activity Index (CDAI), allow for the presence of a maximum of 2 swollen joints in the state defined as remission, DAS28 remission allows for the presence of even more than a dozen swollen joints (20,21). This residual joint activity in DAS28 remitters has now also been confirmed by sonographic joint assessment (23). Moreover, DAS28 remission rates exceed rates of patients meeting the American College of Rheumatology 70% improvement criteria (ACR70 response rates) (25) in many trials and even ACR50 response rates in some trials (14). This indicates a limited stringency of the state of remission when defined by the DAS28. Nonetheless, a DAS28 of ⬍2.6 clearly constitutes a desirable state spanning from no disease activity to relatively low disease activity. This range between no residual activity and little residual activity is of particular interest, as it is unclear how much residual disease activity is tolerable to prevent radiographic damage and, consequently, the associated functional disability. In the present study we evaluated whether DAS28 remission is a sufficiently stringent goal regarding the major shortterm outcome of RA, namely, progression of joint damage. PATIENTS AND METHODS Data sources. We were kindly provided with random 80–90% patient-level data by the sponsors of the following trials: the ASPIRE (Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset) trial of infliximab plus methotrexate (MTX) versus MTX alone in MTX-naive patients with early RA of ⱕ3 years (26); the PREMIER trial of adalimumab versus MTX 3703 versus the combination of adalimumab and MTX in patients with early, aggressive RA who did not have previous MTX treatment (27); the ERA (Early RA) trial of etanercept versus MTX (28); the TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) study, which compared etanercept monotherapy, etanercept plus MTX, and MTX monotherapy (29); and trials of leflunomide (LEF) compared with sulfasalazine or MTX (30–33). All patients had active RA at entry into these studies and were required to have 6–10 swollen joints and at least 6–12 tender joints. With the exception of the ASPIRE trial, elevations in acute-phase reactants were also required for enrollment (C-reactive protein [CRP] level ⱖ1.5–2.0 mg/dl or erythrocyte sedimentation rate [ESR] ⱖ28 mm/hour). Sharp or modified Sharp/van der Heijde scores (SHS) (34) were available for radiographic analysis in all trials. Patient demographics have been presented in the respective reports. Data preparation. We analyzed patient data from all MTX monotherapy trial arms (ASPIRE, ERA, PREMIER, TEMPO, and LEF trials), which were the active comparators in all of these trials. Patients treated with MTX monotherapy were selected because we used radiographic progression as the outcome of interest, which would be retarded or halted on treatment with tumor necrosis factor (TNF) inhibitors plus MTX even at states of disease activity higher than remission (35–37). For completeness, we also evaluated and present the results on this combination group. We identified and pooled patients with complete clinical data at baseline and at 6, 9, and 12 months, as well as complete radiographic data at baseline and at 12 months (n ⫽ 864). If needed, data obtained within 4 weeks after the above-mentioned time points were allowed as substitutes for the 6-, 9-, and 12-month time points. Outcome measures. We evaluated the baseline characteristics for this cohort, including SJCs and TJCs on a 28-joint scale, patient’s and evaluator’s global assessments of disease activity on a 0–100-mm visual analog scale, ESR in mm/hour, CRP level in mg/dl, Health Assessment Questionnaire (HAQ) score (38), and total SHS. Based on the individual instruments for the assessment of disease activity we calculated values for 3 composite indices: the DAS28 (0.56 ⫻ ⻫[TJC28] ⫹ 0.28 ⫻ ⻫[SJC28] ⫹ 0.70 ⫻ ln[ESR] ⫹ 0.014 ⫻ global health) (18); the SDAI (SJC ⫹ TJC ⫹ patient’s global assessment ⫹ evaluator’s global assessment ⫹ CRP level) (24); and the CDAI (SJC ⫹ TJC ⫹ patient’s global assessment ⫹ evaluator’s global assessment) (5,24). Customarily, we used the patient’s global assessment as the global health measurement for the DAS28 (in mm); patient’s global assessment and evaluator’s global assessment in the SDAI and CDAI were measured in cm (with 1 decimal). The CRP level in the SDAI was measured in mg/dl. Radiographs were scored according to the total Sharp score or total SHS. The definition of remission was ⬍2.6 for the DAS28, ⱕ2.8 for the CDAI, and ⱕ3.3 for the SDAI. Main analyses. We identified patients who attained persistent DAS28 remission, defined as an average DAS28 at the 6-, 9-, and 12-month visits of ⬍2.6 (a DAS286–12 of ⬍2.6); the period of 6 months and the average score (instead of requiring a DAS28 ⬍2.6 at all visits) were used to allow for slight fluctuations of disease activity (compensation of higher levels with lower levels of disease activity) and to achieve patient numbers that would provide sufficient power for our 3704 ALETAHA AND SMOLEN Table 1. Baseline characteristics of the patient population (n ⫽ 864) Age, years Disease duration, years Women Rheumatoid factor positive Swollen joint count, 0–28 Tender joint count, 0–28 Patient’s global assessment of disease activity, 0–100 mm Evaluator’s global assessment of disease activity, 0–100 mm C-reactive protein, mg/dl Erythrocyte sedimentation rate, mm/hour Disease Activity Score in 28 joints Simplified Disease Activity Index Clinical Disease Activity Index Health Assessment Questionnaire score, 0–3 Sharp/van der Heijde score analysis. Conversely, DAS28 nonremission was defined as a DAS286–12 of ⱖ2.6. For each patient, we calculated mean SJC for the 6–12-month period and then divided the patients into 2 groups, those with residual joint swelling (defined as an SJC6–12 of ⱖ2) and those without (defined as an SJC6–12 of ⬍2). This cut point was chosen because ⬃75% of surveyed rheumatologists would not tolerate more than 2 swollen joints as being compatible with remission (39), which was recently also confirmed by another survey performed in the course of developing the new ACR/European League Against Rheumatism remission definition (40,41). As will be shown in the Results, the mean SJC was 0.4 in patients with SJC6–12 ⬍2. In patients with persistent DAS28 remission (DAS286–12 ⬍2.6), we used the chi-square statistic to compare the proportions of patients with (SJC6–12 ⱖ2) and without (SJC6–12 ⬍2) residual joint swelling who experienced radiographic progression, defining progression as an increase in total SHS of ⬎0.5 from baseline to 12 months (42). We also compared the radiographic progression (total SHS) from baseline to 12 months between the 2 patient populations by evaluating the median (quartiles) of radiographic progression using the Wilcoxon test (2 groups) and the Kruskal-Wallis test (⬎2 groups). We used probability plots to depict the progression in the different groups. We subsequently performed the same comparative analysis of the effect of residual joint swelling in the subgroup of patients whose disease was not in remission (“DAS28 nonremitters,” i.e., patients with a DAS286–12 of ⱖ2.6). For some of the trials, radiographic data were available also at 6 months, which allowed us to match the clinical and the radiographic time periods using both average DAS28 and average SJC, as well as radiographic progression from month 6 to month 12. We also wished to compare the results obtained in DAS28 remitters without residual joint swelling to results obtained in patients with disease in remission by the SDAI or CDAI. By definition, the latter groups would fulfill the criterion of SJC6–12 ⬍2, as the SDAI/CDAI definitions do not allow for more than 2 swollen joints in a state of remission. Persistent SDAI/CDAI remissions were defined in a manner analogous to the DAS28, as SDAI6–12 and CDAI6–12. While the patients studied here primarily were treated with MTX, we Mean ⫾ SD or percent Median (range) 53 ⫾ 13 2.4 ⫾ 3.4 75 71 13.9 ⫾ 6.4 16.0 ⫾ 6.9 62 ⫾ 21 63 ⫾ 17 3.6 ⫾ 3.9 47 ⫾ 26 6.6 ⫾ 1.1 46 ⫾ 15 42 ⫾ 14 1.49 ⫾ 0.65 21 ⫾ 31 54 (18–82) 1 (0–18) – – 13 (0–28) 15 (0–28) 65 (3–100) 62 (10–100) 2 (0–26) 42 (2–150) 7 (3–9) 45 (5–91) 41 (4–74) 2 (0–3) 10 (3–331) also repeated this main analysis (comparing average progression between DAS28 remitters with and without residual joint swelling) in the 2 other treatment groups, pooled TNF inhibitor monotherapy or TNF inhibitor plus MTX. Sensitivity analyses. Since the main results of the TNF inhibitor monotherapy group were similar to those in the MTX monotherapy group, we pooled these groups for all subgroup/ sensitivity analyses as described below to achieve sufficient power. In the main analysis we defined sustained remission as an average DAS28 of ⬍2.6. As this theoretically allows disease activity to be above the cut point of 2.6 on at least some occasions, we performed an additional analysis in which we required disease to be in remission at all 3 visits (at 6, 9, and 12 months). Since we based the choice of cut point for presence or absence of joint swelling (SJC6–12 ⬍2 or ⱖ2) on a survey, we evaluated additional cut points to ensure that the observed results were not completely inherent to that definition. In this sensitivity analysis, we simply repeated the main analysis in DAS28 remitters first defining residual joint swelling by a cut point of 1 (⬍1 and ⱖ1) and then by a cut point of 3, instead of the cut point of 2 that we used in the rest of the study. We finally evaluated whether the observed differences in radiographic progression related more to differences in progression of erosions or differences in progression of joint space narrowing. All analyses were performed using SPSS software, version 16.0 and the SAS package, version 9.1.3. P values less than 0.05 were considered significant. RESULTS Differences in values of disease activity core set variables among patients in DAS28 remission with and without residual joint swelling. Table 1 presents the baseline characteristics of the 864 MTX-treated patients that we studied. Of these, 114 (13.2%) achieved a state of DAS28 remission (DAS286–12 ⬍2.6; mean ⫾ SD 2.0 ⫾ 0.4), among whom 22 (19.3%) showed residual joint swelling (SJC6–12 ⱖ2); the median SJC6–12 in this JOINT DAMAGE PROGRESSION IN DAS28 REMISSION 3705 Table 2. Average values of core set variables during months 6–12 among patients in persistent DAS28 remission (mean DAS28 ⬍2.6 during months 6–12)* Core variable SJC ⬍2 (n ⫽ 92) SJC ⱖ2 (n ⫽ 22) P SJC, 0–28 TJC, 0–28 PGA, 0–100 mm EGA, 0–100 mm CRP, mg/dl ESR, mm/hour DAS28 SDAI CDAI HAQ score, 0–3 0.4 ⫾ 0.5 0.7 ⫾ 1.1 9.8 ⫾ 11.4 7.8 ⫾ 8.1 0.62 ⫾ 0.59 12.0 ⫾ 8.1 2.0 ⫾ 0.5 3.5 ⫾ 2.4 2.9 ⫾ 2.4 0.21 ⫾ 0.36 3.6 ⫾ 1.32 0.8 ⫾ 1.0 13.4 ⫾ 10.3 13.1 ⫾ 8.7 0.51 ⫾ 0.41 6.4 ⫾ 3.6 2.1 ⫾ 0.3 7.5 ⫾ 2.5 7.0 ⫾ 2.4 0.21 ⫾ 0.29 ⬍0.0001 0.74 0.16 0.008 0.42 ⬍0.002 0.27 ⬍0.0001 ⬍0.0001 0.992 * Values are the mean ⫾ SD. DAS28 ⫽ Disease Activity Score in 28 joints; SJC ⫽ swollen joint count; TJC ⫽ tender joint count; PGA ⫽ patient’s global assessment of disease activity; EGA ⫽ evaluator’s global assessment of disease activity; CRP ⫽ C-reactive protein; ESR ⫽ erythrocyte sedimentation rate; SDAI ⫽ Simplified Disease Activity Index; CDAI ⫽ Clinical Disease Activity Index; HAQ ⫽ Health Assessment Questionnaire. Structural progression as a function of DAS28 remission status and joint swelling. Table 3 shows that the proportion of patients without progression of joint damage (change in score ⬍0.5) was significantly higher in DAS28 remitters without residual joint swelling than in those with residual swelling. In accordance with these data, the medians tended to be lower in the former group than in the latter (P ⫽ 0.1); comparing the means by t-test also revealed a significant difference among the groups (data not shown). Taken together, these results imply that DAS28 remission alone, even over a period of 6 months, is not sufficient to halt radiographic progression; patients need to be further evaluated for the level of residual joint swelling, which is a key driver of progression, even if the DAS28 is ⬍2.6. The importance of joint swelling is further supported by the investigation of patients who did not achieve DAS28 remission. Among these patients with a mean DAS286–12 of ⱖ2.6, those without joint swelling experienced only little progression of joint destruction group was 3.7, with 25% of patients exceeding 4 swollen joints to a maximum of 6. Patients in DAS28 remission without residual joint swelling had significantly lower disease activity levels by SDAI and CDAI than did those with swelling (mean ⫾ SD SDAI 3.5 ⫾ 2.4 versus 7.5 ⫾ 2.5, mean ⫾ SD CDAI 2.9 ⫾ 2.4 versus 7.0 ⫾ 2.4; P ⬍ 0.0001 for both). These higher levels were not solely due to the differences in SJC, but were also a consequence of higher levels of evaluator’s global assessment and, by trend, of patient’s global assessment (Table 2). Interestingly, TJCs were similar between these 2 groups, and ESR was even significantly lower in patients with higher joint counts (P ⬍ 0.002); in other words, because the ESR is highly weighted in the DAS28, and SJC and patient’s global assessment have only low weights (43), a lower level of ESR (even within the normal range) allowed for much higher levels of SJC and patient’s global assessment, while a disease activity state reflected by a DAS28 ⬍2.6 was still maintained. HAQ scores at 1 year were similar in both groups. Table 3. Average increase in total SHS and percent of those with progression of joint damage (change in SHS ⬎0.5) over year 1 in the methotrexate-treated patient groups of the analyzed trials* Patients with progression, % Patients in DAS28 remission SJC ⬍2 SJC ⱖ2 Patients not in DAS28 remission SJC ⬍2 SJC ⱖ2 P† 27 50 0.039 40 56 ⬍0.001 Total SHS increase, mean ⫾ SD Total SHS increase, median (IQR) 0.2 ⫾ 2.6 2.2 ⫾ 4.2 0 (0, 0.5) 0.6 (⫺0.3, 4.5) 1.1 ⫾ 4.2 2.8 ⫾ 11.5 0 (1.0, 1.5) 0.9 (0, 4.0) P‡ 0.110 ⬍0.001 * SHS ⫽ Sharp/van der Heijde score; IQR ⫽ interquartile range; DAS28 ⫽ Disease Activity Score in 28 joints; SJC ⫽ swollen joint count. † By chi-square test. ‡ By Wilcoxon test. 3706 ALETAHA AND SMOLEN Figure 1. Structural progression as a function of Disease Activity Score in 28 joints (DAS28) remission (REM) status and residual joint swelling. DAS28 remission is defined as a mean DAS28 at the 6-, 9-, and 12-month visits of ⬍2.6 (DAS28 nonremission [NONREM] is defined as a mean DAS28 of ⱖ2.6), while the presence or absence of residual joint swelling is defined as a mean swollen joint count over the same period of ⱖ2 or ⬍2, respectively. Analyses were performed in the patient group treated with methotrexate. The graph shows individual data points for the 4 groups, using probability plots of radiographic progression according to residual swelling. P ⫽ 0.11 for comparison of groups with disease in remission; P ⫽ 0.0003 for comparison of groups with disease not in remission, by Wilcoxon test. when compared to nonremitters with joint swelling (Table 3). Similarly, the proportion of patients with radiographic progression was significantly higher in those with than in those without residual joint swelling. In fact, as can be appreciated from Table 3 and Figure 1, progression was similar in individuals with residual joint swelling regardless of whether patients were in DAS28 remission or not (median progression 0.63 versus 0.91, respectively). Importantly, among patients without residual joint swelling there was no difference in radiographic progression between those who attained DAS28 remission and those who did not. This further supports the notion that the reduction in SJC rather than the DAS28 remission state is important in interfering with progression of joint damage. When we evaluated radiographic progression between 6 months and 12 months (instead of between 0 months and 12 months), we found a similar result. DAS28 remitters over the same period (mean DAS286–12 ⬍2.6, as used in the main analysis) without residual joint swelling (SJC6–12 ⬍2) also had a lower rate of progression compared to those with residual joint swelling (15.2% versus 38.9%; P ⫽ 0.022) and a lower average/median progression (mean ⫾ SD 0 ⫾ 0.8 versus 0.7 ⫾ 2.5) (median 0.0 versus 0.3) (P ⫽ 0.042 by Wilcoxon test). Comparative analyses using other scores. Remission was then defined by the SDAI and CDAI criteria. Fifty-two patients (6.0%) had SDAI remission (SDAI ⱕ3.3; mean ⫾ SD 1.8 ⫾ 0.8), with a mean ⫾ SD SJC of 0.3 ⫾ 0.4 for the 6–12-month period; 60 patients (6.9%) had CDAI remission (CDAI ⱕ2.8; mean ⫾ SD 1.4 ⫾ 0.8), with a mean ⫾ SD SJC of 0.4 ⫾ 0.5. The mean ⫾ SD SJCs in these patient groups were therefore very JOINT DAMAGE PROGRESSION IN DAS28 REMISSION 3707 Figure 2. Comparative analyses using other scores. Radiographic progression in different groups is presented in a manner analogous to that in Figure 1. There is no difference in progression between patients in remission (REM) according to the Disease Activity Score in 28 joints (DAS28), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) if patients with DAS28 remission are limited to those without residual joint swelling. P ⫽ 0.66 across all 3 groups, by Kruskal-Wallis test. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley. com/journal/10.1002/(ISSN)1529-0131. similar to that seen in the subgroup of patients with DAS28 remission and SJC ⬍2 (0.4 ⫾ 0.5) (Table 2). In contrast to the DAS28-based definition of remission, no patient in SDAI or CDAI remission can possibly have more than 2 swollen joints, simply by the nature of the respective formula and cut points. Consequently, the average number of swollen joints of all patients in DAS28 remission (mean ⫾ SD SJC6–12 1.0 ⫾ 1.0) was significantly higher than that of all patients in either SDAI or CDAI remission (P ⬍ 0.0001 for both comparisons), as was the mean TJC, patient’s global assessment, and evaluator’s global assessment (P ⬍ 0.0001 for each) (detailed data not shown). Similarly, while HAQ scores were low among patients in DAS28 remission (mean ⫾ SD 0.21 ⫾ 0.35), they were considerably lower among patients in SDAI remission (0.09 ⫾ 0.18) (P ⫽ 0.0023) and CDAI remission (0.12 ⫾ 0.26) (P ⫽ 0.057). Given that the majority of the analyzed patients had early disease and therefore mostly fully reversible impairment of physical function, this implies that physical function essentially normalizes in SDAI and CDAI remission, while there is a slight residual disability in DAS28 remission, potentially reflecting the higher joint counts and global assessments as shown above. Finally, among patients in SDAI and CDAI remission, joint damage progressed by a mean ⫾ SD of only ⫺0.07 ⫾ 0.56 and 0.16 ⫾ 0.49, respectively— degrees almost identical to that seen in the subgroup of DAS28 remitters who had no residual joint swelling (P ⫽ 0.66) (Figure 2 and Table 4), and the proportion of 3708 ALETAHA AND SMOLEN Table 4. Analysis using other treatment groups, cut points, and radiographic time points, and using the radiographic subscales* Analysis type, swelling status (n) Main analysis (base case)§ No swelling (92) Swelling (22) Anti-TNF¶ No swelling (59) Swelling (16) Anti-TNF ⫹ MTX# No swelling (201) Swelling (31) Increased stringency of remission** No swelling (81) Swelling (17) SJC cut point ⫽ 1†† No swelling (114) Swelling (75) SJC cut point ⫽ 3‡‡ No swelling (165) Swelling (24) Erosion score§§ No swelling (151) Swelling (38) JSN score¶¶ No swelling (151) Swelling (38) Patients with progression (change in SHS ⬎0.5), % P† Total SHS increase, mean ⫾ SD Total SHS increase, median (IQR) P‡ 27 50 0.039 0.2 ⫾ 2.6 2.2 ⫾ 4.2 0 (0, 0.5) 0.6 (⫺0.3, 4.5) 0.110 27 63 0.008 ⫺1.4 ⫾ 7.3 0.5 ⫾ 0.9 0 (⫺1.0, 0.5) 0.5 (0.0, 1.0) 0.009 31 29 0.796 ⫺0.1 ⫾ 3.1 ⫺0.5 ⫾ 2.4 0 (⫺1.0, 0.6) 0 (⫺1.4, 0.6) 0.600 25 53 0.020 0.0 ⫾ 2.7 0.6 ⫾ 2.5 0 (⫺0.3, 0.3) 0.5 (0, 1.0) 0.103 28 40 0.087 ⫺0.6 ⫾ 5.6 0.8 ⫾ 3.1 0 (0, 0.5) 0 (⫺0.3, 1.0) 0.185 30 50 0.055 ⫺0.3 ⫾ 5.0 1.4 ⫾ 2.8 0 (⫺0.3, 0.5) 0.4 (0, 1.9) 0.028 27 50 0.007 ⫺0.1 ⫾ 3.2 1.1 ⫾ 3.0 0 (0, 0.5) 0.4 (0, 1.0) 0.007 9 29 0.001 ⫺0.3 ⫾ 2.1 0.3 ⫾ 1.7 0 (0, 0) 0 (0, 0.5) 0.104 * One or more items of the main analysis are modified in each analysis. IQR ⫽ interquartile range. † By chi-square test. ‡ By Wilcoxon test. § Methotrexate (MTX) subgroup; total Sharp/van der Heijde score (SHS); remission defined as a Disease Activity Score in 28 joints (DAS28) from month 6 through month 12 of ⬍2.6; swollen joint count (SJC) cut point ⫽ 2; total of 864 patients; 114 patients (13%) in DAS28 remission. ¶ Anti–tumor necrosis factor (anti-TNF) subgroup; total of 407 patients; 75 patients (18%) in DAS28 remission. # Anti-TNF plus MTX subgroup; total of 740 patients; 232 patients (31%) in DAS28 remission. ** Pooled MTX only/anti-TNF only; all visits in DAS28 remission; total of 1,271 patients; 98 patients (8%) in DAS28 remission. †† Pooled MTX only/anti-TNF only; SJC cut point ⫽ 1; total of 1,271 patients; 189 patients (15%) in DAS28 remission. ‡‡ Pooled MTX only/anti-TNF only; SJC cut point ⫽ 3; total of 1,271 patients; 189 patients (15%) in DAS28 remission. §§ Pooled MTX only/anti-TNF only; erosion score used instead of total SHS; total of 1,271 patients; 189 patients (15%) in DAS28 remission. ¶¶ Pooled MTX only/anti-TNF only; joint space narrowing (JSN) score used instead of total SHS; total of 1,271 patients; 189 patients (15%) in DAS28 remission. patients with progression did not differ significantly among these 3 groups (32.7% versus 35.0% versus 27.2%, SDAI remitters, CDAI remitters, and DAS28 remitters without swelling, respectively; P ⫽ 0.56 by chi-square test). Analysis of patients treated with TNF inhibitors. TNF inhibitors in combination with MTX have a considerable impact on radiographic progression, a major reason for the selection of the MTX-treated patients as the analysis group for identifications of associations. Indeed, in the group receiving MTX in combination with a TNF inhibitor (n ⫽ 740), there was virtually no difference from the results obtained in the MTX monotherapy group (base case), since progression was totally halted in both DAS28 remission groups (Table 4). In contrast, analysis of the smaller subgroup of patients treated with TNF blocker monotherapy (n ⫽ 407) showed associations with progression similar to those seen with MTX monotherapy (Table 4), revealing a significant difference in the proportion of patients with progression (27% versus 63%; P ⬍ 0.01) and in average progression between patients with and those without joint swelling in DAS28 remission (mean ⫾ SD 0.5 ⫾ 0.9 versus ⫺1.4 ⫾ 7.3, respectively) (median 0.5 versus 0, respectively) (P ⬍ 0.01 by Wilcoxon test); this is consistent with previous observations that monotherapy with TNF inhibitors has less effect on structural damage than does therapy combining TNF blockers with MTX (27–29). Additional analyses. Effects of stringent definition of sustained remission. In our main analysis, we used the average DAS28 from 6–12 months to assess remission. JOINT DAMAGE PROGRESSION IN DAS28 REMISSION When using an “all-in-remission” definition (i.e., all visits with DAS28 ⬍2.6), a significantly higher proportion of patients with residual joint swelling still had progression as opposed to those without residual joint swelling (52.9% versus 24.7%; P ⫽ 0.02) (Table 4). Modifying the cut point for “absence of joint swelling.” An additional sensitivity analysis showed that a similar association of residual joint swelling with radiographic joint progression in DAS28 remitters could be seen if a cut point of 1 or 3 was used (instead of the cut point of 2) for defining presence or absence of residual swelling. In both analyses, the results of the main analysis were generally confirmed (Table 4). Erosion and joint space narrowing subscales of radiographic scores. Finally, we performed a separate analysis of joint space narrowing and erosions to learn if the residual swelling would affect one feature of joint damage more than the other. As shown in Table 4, the lower progression in DAS28 remitters without joint swelling was generally confirmed for both features, erosions and joint space narrowing. DISCUSSION In the present study we showed that ⬃1 in 5 RA patients who achieved sustained DAS28 remission with MTX treatment had average residual SJCs of ⱖ2, some even up to an average number of 6 swollen joints. The hypothesis that the DAS28 does not provide sufficiently stringent remission criteria was further substantiated by the fact that among patients in DAS28 remission who had residual joint swelling, joint damage progressed significantly despite a state of DAS28 remission over 6 months. Regardless of the definition of nonswelling, radiographic progression in DAS28 remission was minimized only if patients were in the nonswelling group. This was also the case for patients in remission by the SDAI and CDAI, who by definition had joint counts of ⱕ2. The same observations were made in patients remaining in DAS28 remission from month 6 to month 12, whether radiographic progression was assessed for the whole first year or only for the 6–12-month period. This indicates that not only the initial period of higher disease activity, but also the period during which the residual swelling occurred, was important. Not only do these data support the well-known notion that joint swelling is a crucial feature of RA and a highly important prognostic factor for radiographic progression (4,6), but they also suggest that the presence of joint swelling even trumps the prognostic value of achieving remission, at least by the most commonly used index, the DAS28. Interestingly, while disability as assessed by the 3709 HAQ decreased to ⬃0.1 among patients in SDAI/CDAI remission, it was—although still low—significantly higher in DAS28 remission, i.e., ⬃0.2. A similar observation has also been made for the EuroQol 5-domain instrument (44) value, which differed significantly from the general population among RA patients in DAS28 remission, while values were normalized among those in CDAI remission (45). Therapy with TNF blockers plus MTX led to similar inhibition of joint damage whether patients in DAS28 remission did or did not have residual joint swelling; this is consistent with earlier observations on the reduction of the dependence of joint damage on the inflammatory response (dissociation) upon therapy with TNF inhibitor plus MTX (35,37). Importantly, in the small group of patients treated with TNF inhibitor monotherapy, there was still an observable difference, which suggests that such dissociation does not take place upon TNF inhibition without the use of MTX. Several limitations of our study need to be borne in mind when interpreting the data. First, this was a post hoc analysis in which the outcomes assessed did not constitute primary end points, although the data came from patients enrolled in randomized controlled trials who were starting MTX therapy. Second, the MTX trial arms from several studies were pooled. However, this was necessary to obtain a critical number of patients in DAS28, SDAI, and CDAI remission; moreover, it may not necessarily be disadvantageous to evaluate patients coming from trials with slightly different inclusion criteria and different populations, as the heterogeneity adds to the generalizability of the results. Further, the sensitivity analyses using more or less stringent cut points for joint counts further supported our findings, although some of these analyses showed differences only by trend due to low numbers and consequently low power. Undoubtedly, it is of utmost importance to achieve a good clinical state, ideally remission, in patients with RA, and it has been shown that this is more effective for reducing progression of joint damage and restoring physical function than just achieving improvement, even by an ACR70 response (46). Indeed, clinical remission should ideally be accompanied by structural and functional remission (i.e., no progression of joint damage and maximal reduction of physical disability). However, in our study, we have shown not only that a large proportion of patients in DAS28 remission have a significant number of residual swollen joints, but also that this is in particular a determinant of progression of joint damage. In accordance with observations that DAS28 remission rates often exceed the proportions of patients attaining ACR70 and even ACR50 responses 3710 ALETAHA AND SMOLEN (14,27,47,48), these data indicate that more stringent criteria are needed for the definition of remission, and these have in fact been published very recently (40,41). Importantly, in this definition the present SDAI and CDAI cutoffs for remission have been maintained. The conclusion from our study is that DAS28 remission is strict with regard to serologic markers of inflammation but less strict with regard to clinical markers of inflammation, the latter of which seem to carry greater significance regarding structural progression. Our study confirms that patients in DAS28 remission but with residual joint swelling do not experience slowing or arrest of structural progression. 7. 8. 9. 10. 11. ACKNOWLEDGMENTS We thank Abbott, Amgen, Centocor, and Wyeth, which was acquired by Pfizer in October 2009, for kindly providing the data from their clinical trials. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Aletaha 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 conception and design. Aletaha, Smolen. Acquisition of data. Aletaha, Smolen. Analysis and interpretation of data. Aletaha, Smolen. 12. 13. 14. 15. 16. REFERENCES 1. Gay S, Gay RE, Koopman WJ. Molecular and cellular mechanisms of joint destruction in rheumatoid arthritis: two cellular mechanisms explain joint destruction? Ann Rheum Dis 1993;52 Suppl 1:S39–47. 2. Gravallese EM, Harada Y, Wang JT, Gorn AH, Thornhill TS, Goldring SR. 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