Prevalence of sustained remission in rheumatoid arthritis: impact of criteria sets and disease duration, a Nationwide Study in Sweden

Prevalence of sustained remission in rheumatoid arthritis: impact of criteria sets and disease... Abstract Objectives The aims of this national study in Sweden of patients with RA were to: examine the prevalence of sustained remission (SR), that is, remission lasting for at least 6 months; compare the prevalence of SR in patients with early RA and established RA; study the timing of onset of and time spent in SR; and study possible predictors of SR. Methods Adult patients with RA included in the Swedish Rheumatology Quality registry were studied. The registry was searched for patients fulfilling remission criteria: DAS28-ESR, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and ACR/EULAR remission for at least 6 months. Early RA was defined as symptom duration ⩽6 months at inclusion in the Swedish Rheumatology Quality. Results Of 29 084 patients, 12 193 (41.9%) reached DAS28 SR at some time point during follow-up compared with 6445 (22.2%), 6199 (21.3%) and 5087 (17.5%) for CDAI, SDAI and ACR/EULAR SR, respectively. SR was more common in early RA (P < 0.001). The median time from symptom onset to SR was 1.9, 2.4, 2.4 and 2.5 years according to DAS28, CDAI, SDAI and ACR/EULAR criteria, respectively. Lower age, male sex and milder disease characteristics were associated with SR. Conclusion The majority of patients in this nationwide study never reached SR. Patients with early RA are more likely to reach SR than patients with established RA. rheumatoid arthritis, remission, early RA, disease activity indices, register Rheumatology key messages The majority of patients with RA never reach sustained remission. Prevalence of sustained ACR/EULAR remission of RA is very low. Early diagnosis of RA is associated with sustained remission. Introduction RA is a chronic inflammatory disease associated with articular damage and with increasing disability and socioeconomic consequences [1–4]. During the last decades there have been major changes in the treatment and management of RA, including earlier intervention with DMARDs, combination therapy and introduction of new classes of therapeutic agents such as biologics. The latter include anti-TNF treatment, anti-IL6 receptor blockade, anti-CD20 and inhibition of co-stimulation of T cells. Most recently, small molecules inhibiting the Janus kinase pathway have become a new treatment option. This has changed the prognosis and disease burden for a large proportion of patients [5]. Remission of disease activity has now become the treatment goal but still many patients only respond partially to treatment and it seems that only few experience complete remission [5]. The definition of remission in RA is a challenging problem. Several different remission criteria have been proposed. The ACR/EULAR criteria are Boolean, while the others are based on different disease activity indices with validated cut points for remission [6]. These include the DAS28, the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) [7–9]. Unlike DAS28, which is a rather complex activity measure, SDAI and CDAI are based on addition of core outcome domains. DAS28 has been the most widely used definition of remission in clinical trials. Patients in DAS28 remission possibly represent minimal disease activity rather than true inactive disease state and the ACR/EULAR criteria have been suggested to serve to better define true remission [10]. However, RA is a complex disease and the latter criteria seem almost unreachable for patients with long-standing established disease. Therefore, no universally accepted criteria exist for remission in RA and the treatment guidelines accept low disease activity as a treatment goal in special situations [10]. Furthermore, none of the remission criteria accounts for the time aspect, that is, the duration of remission required to fulfil the definition of remission is not specified. Our group previously showed that remission over time, or sustained remission (SR), is more important than reaching remission only at a certain time point [11]. In view of the existing controversy regarding the utility of the currently suggested remission criteria and the scarcity of large studies of SR, the aims of this national Swedish study of patients with RA were to: examine the prevalence of SR, that is, remission on at least two consecutive occasions for at least 6 months, using four different remission criteria; compare the prevalence of SR in patients with early RA with patients with established RA; study the timing of onset of and time spent in SR; and study baseline predictors of SR in both patients with early and established RA. Methods Patients eligible for the study were adults with a diagnosis of RA according to the clinical judgement of the treating physician, registered in the Swedish Rheumatology Quality (SRQ) registry through December 2012 [12]. The SRQ was originally a national register for follow-up of incident RA that has over time expanded to cover other rheumatic diseases. It was started in 1995 by the Swedish Society for Rheumatology and incorporates such earlier registries as the Early Arthritis Register (including TIRA and BARFOT) and later incorporated biologic registers (ARTIS including SSATG and STURE) [13–17]. Since 2012 it has been a national registry with cooperation of 56 rheumatology units from every region in Sweden [18]. The earlier registries were then conjoined and focus has been on high completeness of all arthritis patients from disease onset. In a report from the National Board of Health and Welfare, the completeness of patients with active RA was estimated to be 75% in 2013 but 83% in 2016 [19]. The first patients were included in the early arthritis registries in 1992 but patients included in the biologic registries from 1999 were often included several years after disease onset and no disease activity data are available prior to inclusion. Ethical approval was obtained from the regional ethical committee in Lund (Dnr 2014/754). Patients are included in the SRQ after giving informed consent. At inclusion into the SRQ, data on symptom onset and date of diagnosis is mandatory, and all previous anti-rheumatic treatments (DMARDs, glucocorticoids, non-steroidals or biologics) are collected by the treating rheumatologist. The registration of the different classification criteria is in the form of checkboxes with a feedback whether patients fulfil the ACR87 and/or the ACR/EULAR 2010 criteria for RA, but this is not mandatory. Operated as part of routine care, at each follow-up visit information on number of swollen (swollen joint count, SJC) and tender joints (tender joint count, TJC), evaluator global assessments of disease activity (EGA, 0–100) and markers of inflammation (CRP/ESR) are registered by the physician. In addition, data on changes in anti-rheumatic treatment and in case of discontinuation the reason for discontinuation is collected. The calculation of patient-related outcomes—HAQ and European Quality of Life-5 Dimensions (EQ-5 D, using the UK Time Trade-Off-based preference set) are based on patients’ answers to questions regarding health and function, which are registered at each follow-up visit and include: patients global assessment (PtGA, 0–100), patients pain (visual analogue scale, 0–100) [12]. In Sweden, the majority of patients starting treatment with biologics are regularly followed up at months 3, 6, 12, 18 and 24, and thereafter once yearly. However, this protocol is not mandatory and therefore the adherence to follow-up protocol may differ between different rheumatology units. Patients are offered DMARD treatment by the treating physician according to traditional standard of care and guidelines. Definition of remission The registry was searched for patients ever fulfilling different remission criteria: DAS28-ESR <2.6, CDAI <2.8, SDAI <3.3, ACR/EULAR Boolean (i.e. TJC ⩽l and SJC ⩽l and CRP ⩽10 mg/l and PtGA ⩽10 on a visual analogue 0–100 scale) and fulfilling the SR criteria, that is, remission on at least two consecutive occasions for at least 6 months [6]. These were categorized as having SR. Remission time is defined as time between first visit in remission and subsequent first visit with higher disease activity (escape). If the time gap between registered visits was longer than 2 years patients were no longer considered in remission; some patients had many years between registered visits and this might influence remission times. Only the first episode with SR per patient was analysed, that is, individual patients only contribute one SR. Follow-up data were available through December 2014. Early RA was defined as symptom duration of <6 months at inclusion in the registry even if the patient already met the 1987 ACR classification criteria; other patients had established RA [20, 21]. Statistical calculations Demographic, disease and patient characteristics at inclusion in the registry were calculated in all patients and after stratification into different groups, that is, early RA and established RA. In order to compensate for lack of disease activity data prior to inclusion in some of the patients we performed a separate analysis using only patients included in the first 2 years from symptom onset. The prevalence of SR was calculated for each remission definition at each year for 10 years after symptom onset, and stratified into early and established RA. Results for SR are given as percentage of patients included in the registry and with a follow-up registered during the current year. Kaplan-Meier analyses were used to estimate the time to SR from symptom onset for each remission definition. In addition, a log rank and an all pairwise multiple comparison procedure (Holm-Sidak method) were used to compare any possible differences. Using the same methods we estimated remission length and compared different remission criteria. Patients were censored at the last follow-up if still in remission. Additional sensitivity analyses were done excluding patients with >12 months between visits once in remission; these were considered to have escaped from remission in the Kaplan-Meier model. Possible baseline predictors of DAS28 SR were chosen based on clinical relevance and availability. These included sex, age at symptom onset, early RA, disease duration, ACPA status, DAS28, EGA, TJC and SJC (28 joint count), and ESR and CRP. Patient-reported outcomes, PtGA, pain, HAQ and EQ-5 D, were also included. After checking for correlations (limit r < 0.6) predictors were studied using Cox regression analysis in three separate models: model A, adjusting for sex and age at symptom onset; model B, multivariate analysis; and model C, univariate. Variables included in the primary analysis included age, sex, DAS28, PtGA, pain, HAQ and ESR. Another model with DAS28 omitted and EGA and TJC included was done because of collinearity. Age was divided into decades before inclusion in the predictor analysis, but all other continuous variables were standardized. The results from models A and C are almost identical, and therefore we present only model A. Baseline is the first registered visit in the SRQ for each patient. For patients with early RA this is usually the first visit to a rheumatologist. All data analyses were done in SPSS 23.0 (IBM, Armonk, North Castle, NY, USA) and SigmaPlot 13.0 (SYSTAT, San Jose, CA, USA). Results Baseline demographics The registry included 40 832 individuals with RA diagnosis, some of which had no visits registered and some with years between registered visits. To be able to calculate SR and remission time, only patients with three or more registered visits and follow-up time of at least 12 months were included in the present study. That left a total of 29 084 patients. Of these, 14 469 patients had available data for calculation of ACR 1987 classifications criteria for RA, with 95% fulfilling the criteria [17]. The mean age at inclusion (range) was 58.8 (18–94) years; 72% were female. In total, 6551 (22.5%) patients with early RA, that is, those included in SRQ within 6 months from symptom onset, were studied. Last follow-up visit was mean (median) 13.9 (10.6) years after symptom onset. Four-variable DAS28-ESR could be calculated after 86.3% of the 286 623 visits and HAQ after 90.7% of visits. ACPA status was available in 5640 patients, with 73.2% of those being ACPA positive. In total 20 590 patients (70.8%) had a registered visit with DAS28 <2.6 at any time point during follow-up. Table 1 shows the demographics and disease activity at inclusion in the registry. For patients with disease onset before 1992 and patients included from the earlier biologic registries, inclusion is not at diagnosis. Time from symptom onset to first registered visit for the whole cohort were mean 7.5 years and median 1.9 (max 78) years, respectively. Because of this skewness, baseline data for patients included within the median time (24 months) from symptom onset and those with early RA are presented separately. Once in SR patients had mean (s.d.) 8.3 (4.9, median 7.0) months between visits. Table 1 Baseline demographics and the frequency of SR Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Stratified after time from symptom onset to inclusion in the registry. All patients, those with disease duration >24 months at inclusion, patients with established RA but included within 24 months from symptom onset and patients with early RA, symptom duration <6 months. aYears from symptom onset at inclusion. b28 joint score. cACPA status was available in 5640 patients. dDAS28 SR. PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D, European Quality of Life-5 Dimensions; SR: sustained remission. Table 1 Baseline demographics and the frequency of SR Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Stratified after time from symptom onset to inclusion in the registry. All patients, those with disease duration >24 months at inclusion, patients with established RA but included within 24 months from symptom onset and patients with early RA, symptom duration <6 months. aYears from symptom onset at inclusion. b28 joint score. cACPA status was available in 5640 patients. dDAS28 SR. PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D, European Quality of Life-5 Dimensions; SR: sustained remission. Comparing patients with established RA included within 24 months from symptom onset with those with early RA (i.e. included within 6 months), patients with early RA were older, more often male, had higher CRP and ESR, higher HAQ, higher joint score and pain score, had lower EQ-5 D, and fewer had ACPA(P < 0.001). Prevalence of SR Of all 29 084 patients, 12 193 (41.9%) reached DAS28 SR at some time point during follow-up. The corresponding proportions of patients reaching CDAI, SDAI and ACR remission were 6445 (22.2%), 6199 (21.3%) and 5087 (17.5%), respectively. One year after symptom onset, 16.4, 6.5, 6.0 and 4.6% were in sustained DAS28, CDAI, SDAI and ACR remission, respectively. The prevalence peaked after 5 years for all criteria (Fig. 1). One year after symptom onset, 21.3% of early RA patients were in DAS28 SR compared with 9.8% of patients with established RA, and this difference remained for at least 10 years (P < 0.001). Fig. 1 shows the percentage of patients in SR in relation to symptom duration in years according to different remission criteria and stratified into early and established RA. Fig. 1 View largeDownload slide The percentage of patients in SR in each year after symptom onset The lines represent different remission criteria. (A) Patients with early RA. (B) Patients with established RA. (C) Patients in DAS28 and ACR SR patients in SR with early vs established RA. The prevalence shown is a percentage of all patients with available follow-up during each year. SR: sustained remission; CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Fig. 1 View largeDownload slide The percentage of patients in SR in each year after symptom onset The lines represent different remission criteria. (A) Patients with early RA. (B) Patients with established RA. (C) Patients in DAS28 and ACR SR patients in SR with early vs established RA. The prevalence shown is a percentage of all patients with available follow-up during each year. SR: sustained remission; CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Time to SR The fact that some patients have long-standing disease at inclusion in the SRQ may impact the timing of remission in our study. Therefore, we focused these calculations on patients with inclusion no more than 2 years from symptom onset, i.e. ∼50% of the RA population. The mean [median (s.d.)] time from symptom onset to DAS28 SR in these patients was 3.3 [1.9 (3.3)] years. The corresponding figures were 3.7 [2.4 (3.4)], 3.7 [2.4 (3.4)] and 3.8 [2.5 (3.5)] years for SDAI, CDAI and ACR SR, respectively. Using life table analysis of median time to SR, time to DAS28 SR was significantly shorter than to CDAI, SDAI and ACR SR. Time to CDAI/SDAI SR was significantly shorter than to ACR SR (log-rank test P < 0.001 for all comparisons except SDAI vs CDAI, P = 0.026). The mean [median (s.d.)] time to DAS28 SR was 2.9 [1.4 (3.3)] years in early RA compared with 3.6 [2.3 (3.3)] years in established RA (P < 0.001). Fifty percent of patients that reached any SR criteria have done so within 2.25 years; the corresponding time for patients with early RA to reach DAS28 SR was 1.25 years (Fig. 2). Fig. 2 View largeDownload slide Graph showing the timing of reaching SR The bars represent the percentage of patients that reach SR at each time point during the first 15 years after symptom onset. (A) Patients in DAS28 SR categorized into early RA (grey) and established RA (dark grey). (B) All patients in ACR SR (white) and SDAI SR (grey). CDAI SR is not shown since the histogram is almost identical to SDAI SR. SR: sustained remission; CDAI: clinical disease activity index; SDAI: simple disease activity index. Fig. 2 View largeDownload slide Graph showing the timing of reaching SR The bars represent the percentage of patients that reach SR at each time point during the first 15 years after symptom onset. (A) Patients in DAS28 SR categorized into early RA (grey) and established RA (dark grey). (B) All patients in ACR SR (white) and SDAI SR (grey). CDAI SR is not shown since the histogram is almost identical to SDAI SR. SR: sustained remission; CDAI: clinical disease activity index; SDAI: simple disease activity index. Time in SR We estimated the time in remission for every patient ever reaching SR. Estimated median time (range) in remission was 7.2 (range 0.5–18.3), 4.0 (0.5–17.1), 4.0 (0.5–17.1) and 3.5 (0.5–17.0) years for DAS28, CDAI, SDAI and ACR remission, respectively (Fig. 3). CDAI and SDAI remission times are almost identical, but patients stay longer in DAS28 remission (P < 0.001) and less time in ACR remission (P < 0.001). At the last registered follow-up visit, half of the patients fulfilling the ACR SR criteria were still in remission. The corresponding figures were 54% for CDAI or SDAI and 72% for DAS28 (Fig. 3). At 5 years, 62.7% were still in DAS28 SR. When the time between visits was limited to 12 months, only 25% were still in remission after 5 years and the estimated median time in remission was 2.3 years (range 0.5–16.8). Fig. 3 View largeDownload slide Kaplan-Meier curve showing the estimated time in remission according to the different remission criteria Time in sustained remission is defined as time from first visit in remission to subsequent visit with higher disease activity (escape). Patients still in remission at last visit are censored. CDAI and SDAI remission times are almost identical. CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Fig. 3 View largeDownload slide Kaplan-Meier curve showing the estimated time in remission according to the different remission criteria Time in sustained remission is defined as time from first visit in remission to subsequent visit with higher disease activity (escape). Patients still in remission at last visit are censored. CDAI and SDAI remission times are almost identical. CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Predictors of DAS28 SR The primary analysis included all 29 084 patients and the separate analysis included 6551 patients with early RA (Table 2). After adjusting for sex and age, ACPA positivity and variables associated with disease activity—DAS28, PtGA, pain, HAQ, ESR, EGA and TJC—were negatively associated with SR. Early RA was positively associated with SR as was EQ-5 D, but SJC did not predict SR. Univariate ordinal regression analysis was almost identical (data not shown) and the same variables predicted SR in early RA. In the multivariate model (model B) DAS28 did not predict SR and EGA became positively associated with SR, but age, ACPA positivity, PtGA, pain, HAQ, ESR and TJC count were negatively associated with SR. Early RA predicted SR but analysing patients with early RA separately influenced neither the predictive variables nor the direction of association. For the full list of predictors, see Table 2. Table 2 Predictors of SR at baseline Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Two separate models are presented for all patients and for patients with early RA separately. Model A: adjusted for sex and age; model B: multivariate analysis. Variables included in the primary analysis: age, sex, DAS28, PtGA, pain, HAQ and ESR. Another model with DAS28 omitted and EGA and TJC included was done because of collinearity. ACPA status was available in 5640 patients and a separate model was done with ACPA included. The table shows the results of the first model including DAS28 and HAQ. Continuous variables were standardized before inclusion in the predictor analysis. aSJC was left out of the multivariate analysis since it has a high correlation with TJC. bEQ-5 D was left out of the multivariate analysis because of high collinearity (r > 0.6) with multiple variables. HR: hazard ratio; PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D: European Quality of Life-5 Dimensions; SR: sustained remission. Table 2 Predictors of SR at baseline Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Two separate models are presented for all patients and for patients with early RA separately. Model A: adjusted for sex and age; model B: multivariate analysis. Variables included in the primary analysis: age, sex, DAS28, PtGA, pain, HAQ and ESR. Another model with DAS28 omitted and EGA and TJC included was done because of collinearity. ACPA status was available in 5640 patients and a separate model was done with ACPA included. The table shows the results of the first model including DAS28 and HAQ. Continuous variables were standardized before inclusion in the predictor analysis. aSJC was left out of the multivariate analysis since it has a high correlation with TJC. bEQ-5 D was left out of the multivariate analysis because of high collinearity (r > 0.6) with multiple variables. HR: hazard ratio; PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D: European Quality of Life-5 Dimensions; SR: sustained remission. Discussion A key finding in this nationwide, observational register study of RA patients was that fewer than half of all patients diagnosed with RA in Sweden since 1992 receiving standard of care therapy reached DAS28 SR at any time point. Around one in five patients reached SDAI, CDAI or ACR/EULAR SR. From the second year after symptom onset, ∼30% fulfilled DAS28 SR criteria, slightly more patients with early RA. When more stringent criteria were applied, 25% fulfilled CDAI and SDAI and ∼10% the ACR/EULAR Boolean criteria for SR over the first 10 years. Patients with early RA, included within 6 months from disease onset, do better and 50% of those reach DAS28 SR at some time point during follow-up. The majority of patients that reach DAS28 SR do so within 2 years from symptom onset, even though in some cases it takes up to 15 years. Early diagnosis of RA is positively associated with SR, as is the absence of ACPA. Milder disease characteristics in terms of TJC, ESR and HAQ, but a higher EGA, predicts SR. As expected, the ACR/EULAR criteria were the strictest, followed by SDAI, CDAI and DAS28. DAS28 definition of remission (DAS28 <2.6) has consistently been shown to be the least stringent of the four used in this study, with at least twice as many patients in remission compared with the ACR/EULAR Boolean definition [22–25]. Similar proportions fulfilling different remission criteria were published previously although without focus on the sustainability of remission [22–24, 26–30]. Our group previously reported the frequency of SR in a population of patients treated with anti-TNF in southern Sweden (SSATG cohort). Among these patients with established RA and mean disease duration of 12 years before anti-TNF treatment only 15.8% reached sustained DAS28 remission and 10.1% did so in the first year of treatment [27]. The frequency of SR reported in the literature varies, as does the definition of SR. In a group of patients treated with MTX and adalimumab in an open-label study, 38.1% reached SR [31]. In a report from the Corrona registry in the USA, 7.9 and 7.6% of patients starting anti-TNF treatment reached DAS28 and CDAI SR, respectively, during a 1 year follow-up, but 3.5 and 7.6% of non-biologic users reached DAS28 and CDAI SR, respectively [32]. In another cohort patients in Canada, 21.5, 9.9, 4.5 and 6.8% achieved DAS28, CDAI, SDAI and ACR/EULAR SR, respectively, during treatment with biologics [33]. In stricter settings, as in clinical trials, remission rates are higher. In an etanercept tapering study, 63% of patients treated with etanercept and MTX were in DAS28 SR for at least 15 weeks after 23 months of treatment [34]. The prevalence of SR peaked after 5 years in our study. Even though some patients reached SR more than a decade after symptom onset, the majority of patients reached SR within 3 years, independent of which criteria were used. In a study from the Nijmegen early RA cohort the median time to sustained DAS remission was 9 months compared with 1.5 years in the present study [35]. Half of all patient reach DAS28 SR at some point, but most patients relapse within a few years. This reflects the fluctuating nature of the disease and implies that even in remission the patient must be followed according to the Treat to Target concept [5]. Prince et al. [32] reported that only about half of patients in remission were still in remission at follow-up 12 months later, regardless of the remission criteria used. In the Nijmegen cohort the median time in SR was 19 months [35]. In our previous study median remission time was just over 5 years, with a group of patients in remission lasting many years [36]. In the present study, many patients were still in remission at the last follow-up. Early RA, e.g. having a first registered visit within 6 months from symptom onset, was the strongest predictor of SR in our study. This is in line with a recent meta-analyses showing the importance of early treatment initiation [37]. A good physical function measure, e.g. low HAQ score, was identified as another predictor of SR. This was seen in both patients with established disease and those with early RA with little or no irreversible structural joint damage. These findings confirm our previous results including a cohort of patients starting their first anti-TNF treatment [11]. In accordance with several previous studies, male sex and lower HAQ predict good clinical response, occasional remission and SR [29, 33, 38–42]. However, we found ACPA to be negatively associated with SR. Similarly, in the IMPROVED study, drug-free remission was less often sustained in ACPA-positive patients [43]. In addition, ACPA positivity predicted relapse in drug-free remission and was association with radiographic progression in patients with early arthritis [44, 45]. In agreement with others, a younger age and lower ESR at inclusion in the registry was a predictor of SR [36, 46]. Patient-related outcomes, e.g. lower pain and lower PtGA and TJC, were predictors of SR, but only when all patients were included in the analysis. On the contrary, among early RA patients a more objective measure such as low DAS28, but not the patient-reported outcomes, predicted SR. This might reflect the higher importance of inflammation in the early course of the disease. A surprising finding in the present study was that higher EGA score predicted SR. One possible explanation could be that our assessment of disease as more active globally results in more intensive treatment and consequently a better outcome, for example, SR. This study has several strengths. It is based on nationwide data from almost 30 000 patients with RA, which allows us to estimate the prevalence of SR over a long period of time. All data were collected prospectively in daily routine care and thus include large numbers of patients that would have been excluded from intervention trials [47]. The registry lacks early follow-up data, especially at baseline for some patient groups, that is, those included from the earlier biologic registries, but that does not necessarily influence the prevalence numbers since these are based on every patient available at each time point. On the other hand, this could well influence time to remission calculations, which we have tried to compensate by selecting only patients included in the registry within 2 years from symptom onset. We did so for two reasons. Patients with long-standing disease are probably not as likely to reach remission since long-standing disease increases the risk for joint damage and residual disease, and secondly because late inclusion in the registry may miss previous remission periods. Many more patients experience non-SR than SR and the risk for escape after the first visit in remission is high. After the second visit in remission, patients are more likely to stay in remission. In our previous study on anti-TNF-treated patients, only 15.8% reached SR but 91.3, 74.8 and 60.0% remained in SR at 12, 24 and 48 months, respectively [36]. In Sweden, we usually decrease the visit frequency once the patient has reached remission but these results indicate that visit frequency should only be changed when remission is sustained over time [48]. Another weakness of our study is that the visit frequency may impact both the frequency of SR and the calculations of time in remission. Patients are instructed to report any signs of flare in disease but less formal contacts are not always registered in the SRQ. The time in remission was considerably shorter when patients were considered to have escaped from remission after 12 months without a visit, as opposed to 24 months. Since the visit frequency is lower once in remission and some rheumatology units schedule visits beyond 12 months once in SR, the 12-month time frame excludes these patients. On the other hand, there is a risk for overestimation of the true remission time when 24 months are allowed to pass between visits. In addition, the completeness or coverage of RA is a weakness of the present study. In 2016, the completeness of data in the SRQ was estimated as 83% of all patients with RA in Sweden, which is equal or higher than in registries for other chronic diseases such as cardiac failure [19]. These figures are in line with data from the Danish national registry (DANBIO) where the national completeness was 85% in 2013 [49]. Completeness of the data on diagnosis, disease onset, DAS and HAQ reported was between 83 and 93% in DANBIO. The national completeness of a chronic disease like RA is not easy to estimate, partly since there is no clear date for onset of disease, unlike for the acute diseases such as a stroke, and partly because there is risk for overestimation when deciding the true national prevalence. The specificity and sensitivity of the RA capture mechanism used by the National Patient Register is somewhat limited, based on registered diagnosis and prescriptions of DMARDs in specialist care. Using the ACR 1987 criteria as reference, a false-positive rate of around 6–15% has been estimated [50]. Patients with RA are typically diagnosed and treated by rheumatologists rather than by general practitioners in Sweden; the opposite would lead to underestimation of the prevalence. Importantly, the coverage of each of the SRQ sub-cohorts was good, for instance SSATG covered over 90% of all RA patients on biologics [51, 52]. In conclusion, the majority of RA patients in SRQ never reach DAS28 SR at any point after inclusion and even fewer reach CDAI, SDAI or ACR/EULAR SR. The prevalence of SR increases during the first disease years and peaks at 5 years. The pattern was similar for all remission criteria. In general, milder disease characteristics at baseline, including absence of ACPA, are associated with SR, as well as male sex and lower age. Acknowledgement The authors thank Pontus Geborek for skilful help with data management and statistical calculations. 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For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Prevalence of sustained remission in rheumatoid arthritis: impact of criteria sets and disease duration, a Nationwide Study in Sweden

Rheumatology , Volume Advance Article – Mar 12, 2018

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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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Abstract

Abstract Objectives The aims of this national study in Sweden of patients with RA were to: examine the prevalence of sustained remission (SR), that is, remission lasting for at least 6 months; compare the prevalence of SR in patients with early RA and established RA; study the timing of onset of and time spent in SR; and study possible predictors of SR. Methods Adult patients with RA included in the Swedish Rheumatology Quality registry were studied. The registry was searched for patients fulfilling remission criteria: DAS28-ESR, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and ACR/EULAR remission for at least 6 months. Early RA was defined as symptom duration ⩽6 months at inclusion in the Swedish Rheumatology Quality. Results Of 29 084 patients, 12 193 (41.9%) reached DAS28 SR at some time point during follow-up compared with 6445 (22.2%), 6199 (21.3%) and 5087 (17.5%) for CDAI, SDAI and ACR/EULAR SR, respectively. SR was more common in early RA (P < 0.001). The median time from symptom onset to SR was 1.9, 2.4, 2.4 and 2.5 years according to DAS28, CDAI, SDAI and ACR/EULAR criteria, respectively. Lower age, male sex and milder disease characteristics were associated with SR. Conclusion The majority of patients in this nationwide study never reached SR. Patients with early RA are more likely to reach SR than patients with established RA. rheumatoid arthritis, remission, early RA, disease activity indices, register Rheumatology key messages The majority of patients with RA never reach sustained remission. Prevalence of sustained ACR/EULAR remission of RA is very low. Early diagnosis of RA is associated with sustained remission. Introduction RA is a chronic inflammatory disease associated with articular damage and with increasing disability and socioeconomic consequences [1–4]. During the last decades there have been major changes in the treatment and management of RA, including earlier intervention with DMARDs, combination therapy and introduction of new classes of therapeutic agents such as biologics. The latter include anti-TNF treatment, anti-IL6 receptor blockade, anti-CD20 and inhibition of co-stimulation of T cells. Most recently, small molecules inhibiting the Janus kinase pathway have become a new treatment option. This has changed the prognosis and disease burden for a large proportion of patients [5]. Remission of disease activity has now become the treatment goal but still many patients only respond partially to treatment and it seems that only few experience complete remission [5]. The definition of remission in RA is a challenging problem. Several different remission criteria have been proposed. The ACR/EULAR criteria are Boolean, while the others are based on different disease activity indices with validated cut points for remission [6]. These include the DAS28, the Simplified Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI) [7–9]. Unlike DAS28, which is a rather complex activity measure, SDAI and CDAI are based on addition of core outcome domains. DAS28 has been the most widely used definition of remission in clinical trials. Patients in DAS28 remission possibly represent minimal disease activity rather than true inactive disease state and the ACR/EULAR criteria have been suggested to serve to better define true remission [10]. However, RA is a complex disease and the latter criteria seem almost unreachable for patients with long-standing established disease. Therefore, no universally accepted criteria exist for remission in RA and the treatment guidelines accept low disease activity as a treatment goal in special situations [10]. Furthermore, none of the remission criteria accounts for the time aspect, that is, the duration of remission required to fulfil the definition of remission is not specified. Our group previously showed that remission over time, or sustained remission (SR), is more important than reaching remission only at a certain time point [11]. In view of the existing controversy regarding the utility of the currently suggested remission criteria and the scarcity of large studies of SR, the aims of this national Swedish study of patients with RA were to: examine the prevalence of SR, that is, remission on at least two consecutive occasions for at least 6 months, using four different remission criteria; compare the prevalence of SR in patients with early RA with patients with established RA; study the timing of onset of and time spent in SR; and study baseline predictors of SR in both patients with early and established RA. Methods Patients eligible for the study were adults with a diagnosis of RA according to the clinical judgement of the treating physician, registered in the Swedish Rheumatology Quality (SRQ) registry through December 2012 [12]. The SRQ was originally a national register for follow-up of incident RA that has over time expanded to cover other rheumatic diseases. It was started in 1995 by the Swedish Society for Rheumatology and incorporates such earlier registries as the Early Arthritis Register (including TIRA and BARFOT) and later incorporated biologic registers (ARTIS including SSATG and STURE) [13–17]. Since 2012 it has been a national registry with cooperation of 56 rheumatology units from every region in Sweden [18]. The earlier registries were then conjoined and focus has been on high completeness of all arthritis patients from disease onset. In a report from the National Board of Health and Welfare, the completeness of patients with active RA was estimated to be 75% in 2013 but 83% in 2016 [19]. The first patients were included in the early arthritis registries in 1992 but patients included in the biologic registries from 1999 were often included several years after disease onset and no disease activity data are available prior to inclusion. Ethical approval was obtained from the regional ethical committee in Lund (Dnr 2014/754). Patients are included in the SRQ after giving informed consent. At inclusion into the SRQ, data on symptom onset and date of diagnosis is mandatory, and all previous anti-rheumatic treatments (DMARDs, glucocorticoids, non-steroidals or biologics) are collected by the treating rheumatologist. The registration of the different classification criteria is in the form of checkboxes with a feedback whether patients fulfil the ACR87 and/or the ACR/EULAR 2010 criteria for RA, but this is not mandatory. Operated as part of routine care, at each follow-up visit information on number of swollen (swollen joint count, SJC) and tender joints (tender joint count, TJC), evaluator global assessments of disease activity (EGA, 0–100) and markers of inflammation (CRP/ESR) are registered by the physician. In addition, data on changes in anti-rheumatic treatment and in case of discontinuation the reason for discontinuation is collected. The calculation of patient-related outcomes—HAQ and European Quality of Life-5 Dimensions (EQ-5 D, using the UK Time Trade-Off-based preference set) are based on patients’ answers to questions regarding health and function, which are registered at each follow-up visit and include: patients global assessment (PtGA, 0–100), patients pain (visual analogue scale, 0–100) [12]. In Sweden, the majority of patients starting treatment with biologics are regularly followed up at months 3, 6, 12, 18 and 24, and thereafter once yearly. However, this protocol is not mandatory and therefore the adherence to follow-up protocol may differ between different rheumatology units. Patients are offered DMARD treatment by the treating physician according to traditional standard of care and guidelines. Definition of remission The registry was searched for patients ever fulfilling different remission criteria: DAS28-ESR <2.6, CDAI <2.8, SDAI <3.3, ACR/EULAR Boolean (i.e. TJC ⩽l and SJC ⩽l and CRP ⩽10 mg/l and PtGA ⩽10 on a visual analogue 0–100 scale) and fulfilling the SR criteria, that is, remission on at least two consecutive occasions for at least 6 months [6]. These were categorized as having SR. Remission time is defined as time between first visit in remission and subsequent first visit with higher disease activity (escape). If the time gap between registered visits was longer than 2 years patients were no longer considered in remission; some patients had many years between registered visits and this might influence remission times. Only the first episode with SR per patient was analysed, that is, individual patients only contribute one SR. Follow-up data were available through December 2014. Early RA was defined as symptom duration of <6 months at inclusion in the registry even if the patient already met the 1987 ACR classification criteria; other patients had established RA [20, 21]. Statistical calculations Demographic, disease and patient characteristics at inclusion in the registry were calculated in all patients and after stratification into different groups, that is, early RA and established RA. In order to compensate for lack of disease activity data prior to inclusion in some of the patients we performed a separate analysis using only patients included in the first 2 years from symptom onset. The prevalence of SR was calculated for each remission definition at each year for 10 years after symptom onset, and stratified into early and established RA. Results for SR are given as percentage of patients included in the registry and with a follow-up registered during the current year. Kaplan-Meier analyses were used to estimate the time to SR from symptom onset for each remission definition. In addition, a log rank and an all pairwise multiple comparison procedure (Holm-Sidak method) were used to compare any possible differences. Using the same methods we estimated remission length and compared different remission criteria. Patients were censored at the last follow-up if still in remission. Additional sensitivity analyses were done excluding patients with >12 months between visits once in remission; these were considered to have escaped from remission in the Kaplan-Meier model. Possible baseline predictors of DAS28 SR were chosen based on clinical relevance and availability. These included sex, age at symptom onset, early RA, disease duration, ACPA status, DAS28, EGA, TJC and SJC (28 joint count), and ESR and CRP. Patient-reported outcomes, PtGA, pain, HAQ and EQ-5 D, were also included. After checking for correlations (limit r < 0.6) predictors were studied using Cox regression analysis in three separate models: model A, adjusting for sex and age at symptom onset; model B, multivariate analysis; and model C, univariate. Variables included in the primary analysis included age, sex, DAS28, PtGA, pain, HAQ and ESR. Another model with DAS28 omitted and EGA and TJC included was done because of collinearity. Age was divided into decades before inclusion in the predictor analysis, but all other continuous variables were standardized. The results from models A and C are almost identical, and therefore we present only model A. Baseline is the first registered visit in the SRQ for each patient. For patients with early RA this is usually the first visit to a rheumatologist. All data analyses were done in SPSS 23.0 (IBM, Armonk, North Castle, NY, USA) and SigmaPlot 13.0 (SYSTAT, San Jose, CA, USA). Results Baseline demographics The registry included 40 832 individuals with RA diagnosis, some of which had no visits registered and some with years between registered visits. To be able to calculate SR and remission time, only patients with three or more registered visits and follow-up time of at least 12 months were included in the present study. That left a total of 29 084 patients. Of these, 14 469 patients had available data for calculation of ACR 1987 classifications criteria for RA, with 95% fulfilling the criteria [17]. The mean age at inclusion (range) was 58.8 (18–94) years; 72% were female. In total, 6551 (22.5%) patients with early RA, that is, those included in SRQ within 6 months from symptom onset, were studied. Last follow-up visit was mean (median) 13.9 (10.6) years after symptom onset. Four-variable DAS28-ESR could be calculated after 86.3% of the 286 623 visits and HAQ after 90.7% of visits. ACPA status was available in 5640 patients, with 73.2% of those being ACPA positive. In total 20 590 patients (70.8%) had a registered visit with DAS28 <2.6 at any time point during follow-up. Table 1 shows the demographics and disease activity at inclusion in the registry. For patients with disease onset before 1992 and patients included from the earlier biologic registries, inclusion is not at diagnosis. Time from symptom onset to first registered visit for the whole cohort were mean 7.5 years and median 1.9 (max 78) years, respectively. Because of this skewness, baseline data for patients included within the median time (24 months) from symptom onset and those with early RA are presented separately. Once in SR patients had mean (s.d.) 8.3 (4.9, median 7.0) months between visits. Table 1 Baseline demographics and the frequency of SR Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Stratified after time from symptom onset to inclusion in the registry. All patients, those with disease duration >24 months at inclusion, patients with established RA but included within 24 months from symptom onset and patients with early RA, symptom duration <6 months. aYears from symptom onset at inclusion. b28 joint score. cACPA status was available in 5640 patients. dDAS28 SR. PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D, European Quality of Life-5 Dimensions; SR: sustained remission. Table 1 Baseline demographics and the frequency of SR Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Symptom duration at inclusion All patients Disease duration >24 months at inclusion Disease duration 6–24 months at inclusion Early RA (<6 months) at inclusion N (%) 29 084 14 379 (49.5) 8147 (28.0) 6551 (22.5) Age, n (s.d.), years 58.1 (14.1) 58.8 (12.9) 56.4 (15.2) 58.3 (14.9) Years,a mean (median) 7.5 (1.9) 14.6 (11.8) 0.9 (0.4) 0.3 (0.1) Female sex, n (%) 21 025 (72.3) 10 808 (75.2) 5765 (70.8) 4452 (68.0) CRP, mean (s.d.), mg/l 22.7 (29.8) 20.2 (26.6) 21.7 (29.1) 29.0 (35.8) ESR, mean (s.d.), mm 30.1 (23.5) 28.0 (22.6) 29.2 (23.4) 35.1 (24.8) DAS28-ESR, mean (s.d.) 4.8 (1.5) 4.5 (1.6) 4.7 (1.5) 5.2 (1.3) HAQ, 1–3, mean (s.d.) 1.04 (0.7) 1.09 (0.7) 0.93 (0.6) 1.05 (0.6) Pain, 0–100, mean (s.d.) 49.2 (26.3) 49.4 (26.5) 46.5 (26.1) 51.9 (25.8) PtGA, 0–100, mean (s.d.) 49.3 (26.3) 49.9 (26.4) 46.4 (26.3) 51.6 (25.9) EGA, 0–100, mean (s.d.) 47.4 (22.3) 44.7 (23.4) 46.9 (21.4) 53.67 (19.6) TJC,bn (s.d.) 6.6 (6.2) 6.0 (6.1) 6.7 (6.0) 7.9 (6.2) SJC,bn (s.d.) 7.1 (5.8) 6.3 (5.7) 7.1 (5.6) 8.8 (5.8) ACPA (+),cn (%) 3614 (73.5) 1107 (77.0) 1348 (74.3) 1159 (68.9) EQ-5 D, mean (s.d.) 0.57 (0.3) 0.59 (0.3) 0.59 (0.31) 0.50 (0.3) DAS28 SR,dn (%) 12193 (41.9) 5274 (36.7) 3701 (45.4) 3218 (49.1) Stratified after time from symptom onset to inclusion in the registry. All patients, those with disease duration >24 months at inclusion, patients with established RA but included within 24 months from symptom onset and patients with early RA, symptom duration <6 months. aYears from symptom onset at inclusion. b28 joint score. cACPA status was available in 5640 patients. dDAS28 SR. PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D, European Quality of Life-5 Dimensions; SR: sustained remission. Comparing patients with established RA included within 24 months from symptom onset with those with early RA (i.e. included within 6 months), patients with early RA were older, more often male, had higher CRP and ESR, higher HAQ, higher joint score and pain score, had lower EQ-5 D, and fewer had ACPA(P < 0.001). Prevalence of SR Of all 29 084 patients, 12 193 (41.9%) reached DAS28 SR at some time point during follow-up. The corresponding proportions of patients reaching CDAI, SDAI and ACR remission were 6445 (22.2%), 6199 (21.3%) and 5087 (17.5%), respectively. One year after symptom onset, 16.4, 6.5, 6.0 and 4.6% were in sustained DAS28, CDAI, SDAI and ACR remission, respectively. The prevalence peaked after 5 years for all criteria (Fig. 1). One year after symptom onset, 21.3% of early RA patients were in DAS28 SR compared with 9.8% of patients with established RA, and this difference remained for at least 10 years (P < 0.001). Fig. 1 shows the percentage of patients in SR in relation to symptom duration in years according to different remission criteria and stratified into early and established RA. Fig. 1 View largeDownload slide The percentage of patients in SR in each year after symptom onset The lines represent different remission criteria. (A) Patients with early RA. (B) Patients with established RA. (C) Patients in DAS28 and ACR SR patients in SR with early vs established RA. The prevalence shown is a percentage of all patients with available follow-up during each year. SR: sustained remission; CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Fig. 1 View largeDownload slide The percentage of patients in SR in each year after symptom onset The lines represent different remission criteria. (A) Patients with early RA. (B) Patients with established RA. (C) Patients in DAS28 and ACR SR patients in SR with early vs established RA. The prevalence shown is a percentage of all patients with available follow-up during each year. SR: sustained remission; CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Time to SR The fact that some patients have long-standing disease at inclusion in the SRQ may impact the timing of remission in our study. Therefore, we focused these calculations on patients with inclusion no more than 2 years from symptom onset, i.e. ∼50% of the RA population. The mean [median (s.d.)] time from symptom onset to DAS28 SR in these patients was 3.3 [1.9 (3.3)] years. The corresponding figures were 3.7 [2.4 (3.4)], 3.7 [2.4 (3.4)] and 3.8 [2.5 (3.5)] years for SDAI, CDAI and ACR SR, respectively. Using life table analysis of median time to SR, time to DAS28 SR was significantly shorter than to CDAI, SDAI and ACR SR. Time to CDAI/SDAI SR was significantly shorter than to ACR SR (log-rank test P < 0.001 for all comparisons except SDAI vs CDAI, P = 0.026). The mean [median (s.d.)] time to DAS28 SR was 2.9 [1.4 (3.3)] years in early RA compared with 3.6 [2.3 (3.3)] years in established RA (P < 0.001). Fifty percent of patients that reached any SR criteria have done so within 2.25 years; the corresponding time for patients with early RA to reach DAS28 SR was 1.25 years (Fig. 2). Fig. 2 View largeDownload slide Graph showing the timing of reaching SR The bars represent the percentage of patients that reach SR at each time point during the first 15 years after symptom onset. (A) Patients in DAS28 SR categorized into early RA (grey) and established RA (dark grey). (B) All patients in ACR SR (white) and SDAI SR (grey). CDAI SR is not shown since the histogram is almost identical to SDAI SR. SR: sustained remission; CDAI: clinical disease activity index; SDAI: simple disease activity index. Fig. 2 View largeDownload slide Graph showing the timing of reaching SR The bars represent the percentage of patients that reach SR at each time point during the first 15 years after symptom onset. (A) Patients in DAS28 SR categorized into early RA (grey) and established RA (dark grey). (B) All patients in ACR SR (white) and SDAI SR (grey). CDAI SR is not shown since the histogram is almost identical to SDAI SR. SR: sustained remission; CDAI: clinical disease activity index; SDAI: simple disease activity index. Time in SR We estimated the time in remission for every patient ever reaching SR. Estimated median time (range) in remission was 7.2 (range 0.5–18.3), 4.0 (0.5–17.1), 4.0 (0.5–17.1) and 3.5 (0.5–17.0) years for DAS28, CDAI, SDAI and ACR remission, respectively (Fig. 3). CDAI and SDAI remission times are almost identical, but patients stay longer in DAS28 remission (P < 0.001) and less time in ACR remission (P < 0.001). At the last registered follow-up visit, half of the patients fulfilling the ACR SR criteria were still in remission. The corresponding figures were 54% for CDAI or SDAI and 72% for DAS28 (Fig. 3). At 5 years, 62.7% were still in DAS28 SR. When the time between visits was limited to 12 months, only 25% were still in remission after 5 years and the estimated median time in remission was 2.3 years (range 0.5–16.8). Fig. 3 View largeDownload slide Kaplan-Meier curve showing the estimated time in remission according to the different remission criteria Time in sustained remission is defined as time from first visit in remission to subsequent visit with higher disease activity (escape). Patients still in remission at last visit are censored. CDAI and SDAI remission times are almost identical. CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Fig. 3 View largeDownload slide Kaplan-Meier curve showing the estimated time in remission according to the different remission criteria Time in sustained remission is defined as time from first visit in remission to subsequent visit with higher disease activity (escape). Patients still in remission at last visit are censored. CDAI and SDAI remission times are almost identical. CDAI: Clinical Disease Activity Index; SDAI: Simple Disease Activity Index. Predictors of DAS28 SR The primary analysis included all 29 084 patients and the separate analysis included 6551 patients with early RA (Table 2). After adjusting for sex and age, ACPA positivity and variables associated with disease activity—DAS28, PtGA, pain, HAQ, ESR, EGA and TJC—were negatively associated with SR. Early RA was positively associated with SR as was EQ-5 D, but SJC did not predict SR. Univariate ordinal regression analysis was almost identical (data not shown) and the same variables predicted SR in early RA. In the multivariate model (model B) DAS28 did not predict SR and EGA became positively associated with SR, but age, ACPA positivity, PtGA, pain, HAQ, ESR and TJC count were negatively associated with SR. Early RA predicted SR but analysing patients with early RA separately influenced neither the predictive variables nor the direction of association. For the full list of predictors, see Table 2. Table 2 Predictors of SR at baseline Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Two separate models are presented for all patients and for patients with early RA separately. Model A: adjusted for sex and age; model B: multivariate analysis. Variables included in the primary analysis: age, sex, DAS28, PtGA, pain, HAQ and ESR. Another model with DAS28 omitted and EGA and TJC included was done because of collinearity. ACPA status was available in 5640 patients and a separate model was done with ACPA included. The table shows the results of the first model including DAS28 and HAQ. Continuous variables were standardized before inclusion in the predictor analysis. aSJC was left out of the multivariate analysis since it has a high correlation with TJC. bEQ-5 D was left out of the multivariate analysis because of high collinearity (r > 0.6) with multiple variables. HR: hazard ratio; PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D: European Quality of Life-5 Dimensions; SR: sustained remission. Table 2 Predictors of SR at baseline Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Model A Model B All patients HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.83 (0.82–0.84) <0.001 Male sex 1.51 (1.44, 1.57) <0.001 Early RA 3.18 (3.04, 3.32) <0.001 3.45 (3.29, 3.62) <0.001 DAS28-ESR 0.80 (0.78, 0.81) <0.001 0.98 (0.95, 1.01) 0.190 PtGA (0–100) 0.78 (0.77, 0.80) <0.001 0.95 (0.92, 0.99) 0.005 Pain (0–100) 0.79 (0.78, 0.81) <0.001 0.99 (0.96, 1.80) <0.001 HAQ (0–3) 0.68 (0.67, 0.70) <0.001 0.72 (0.70, 0.74) <0.001 ESR (mm) 0.79 (0.78, 0.81) <0.001 0.84 (0.82, 0.87) <0.001 ACPA (+) 0.86 (0.79, 0.94) 0.001 0.86 (0.78, 0.94) 0.001 EGA (0–100) 0.93 (0.91, 0.94) <0.001 1.16 (1.13, 1.19) <0.001 TJC (0–28) 0.87 (0.86, 0.89) <0.001 0.93 (0.90, 0.95) <0.001 SJC (0–28) 1.00 (0.98, 1.01) 0.595 a EQ-5 D 1.24 (1.16, 1.33) <0.001 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Early RA HR (95% CI) P-value HR (95% CI) P-value Age (decades) 0.94 (0.92, 0.97) <0.001 Male sex 1.50 (1.38, 1.62) <0.001 DAS28-ESR 0.75 (0.72, 0.78) <0.001 0.87 (0.82, 0.92) <0.001 PtGA (0–100) 0.85 (0.82, 0.88) <0.001 1.00 (0.94, 1.06) 0.996 Pain (0–100) 0.85 (0.82, 0.88) <0.001 0.99 (0.93, 1.05) 0.638 HAQ (0–3) 0.80 (0.77, 0.83) <0.001 0.89 (0.85, 0.94) <0.001 ESR (mm) 0.78 (0.75, 0.81) <0.001 0.87 (0.83, 0.92) <0.001 ACPA (+) 0.88 (0.77, 1.02) 0.09 0.81 (0.70, 0.95) 0.010 EGA (0–100) 0.93 (0.90, 0.97) <0.001 1.19 (1.13, 1.25) <0.001 TJC (0–28) 0.82 (0.79, 0.85) <0.001 0.84 (0.80, 0.88) <0.001 SJC (0–28) 0.98 (0.94, 1.01) 0.154 a EQ-5 D 1.16 (1.03, 1.31) 0.017 b Two separate models are presented for all patients and for patients with early RA separately. Model A: adjusted for sex and age; model B: multivariate analysis. Variables included in the primary analysis: age, sex, DAS28, PtGA, pain, HAQ and ESR. Another model with DAS28 omitted and EGA and TJC included was done because of collinearity. ACPA status was available in 5640 patients and a separate model was done with ACPA included. The table shows the results of the first model including DAS28 and HAQ. Continuous variables were standardized before inclusion in the predictor analysis. aSJC was left out of the multivariate analysis since it has a high correlation with TJC. bEQ-5 D was left out of the multivariate analysis because of high collinearity (r > 0.6) with multiple variables. HR: hazard ratio; PtGA: patient global assessment; EGA: evaluator global assessment; TJC: tender joint count; SJC: swollen joint count; EQ-5 D: European Quality of Life-5 Dimensions; SR: sustained remission. Discussion A key finding in this nationwide, observational register study of RA patients was that fewer than half of all patients diagnosed with RA in Sweden since 1992 receiving standard of care therapy reached DAS28 SR at any time point. Around one in five patients reached SDAI, CDAI or ACR/EULAR SR. From the second year after symptom onset, ∼30% fulfilled DAS28 SR criteria, slightly more patients with early RA. When more stringent criteria were applied, 25% fulfilled CDAI and SDAI and ∼10% the ACR/EULAR Boolean criteria for SR over the first 10 years. Patients with early RA, included within 6 months from disease onset, do better and 50% of those reach DAS28 SR at some time point during follow-up. The majority of patients that reach DAS28 SR do so within 2 years from symptom onset, even though in some cases it takes up to 15 years. Early diagnosis of RA is positively associated with SR, as is the absence of ACPA. Milder disease characteristics in terms of TJC, ESR and HAQ, but a higher EGA, predicts SR. As expected, the ACR/EULAR criteria were the strictest, followed by SDAI, CDAI and DAS28. DAS28 definition of remission (DAS28 <2.6) has consistently been shown to be the least stringent of the four used in this study, with at least twice as many patients in remission compared with the ACR/EULAR Boolean definition [22–25]. Similar proportions fulfilling different remission criteria were published previously although without focus on the sustainability of remission [22–24, 26–30]. Our group previously reported the frequency of SR in a population of patients treated with anti-TNF in southern Sweden (SSATG cohort). Among these patients with established RA and mean disease duration of 12 years before anti-TNF treatment only 15.8% reached sustained DAS28 remission and 10.1% did so in the first year of treatment [27]. The frequency of SR reported in the literature varies, as does the definition of SR. In a group of patients treated with MTX and adalimumab in an open-label study, 38.1% reached SR [31]. In a report from the Corrona registry in the USA, 7.9 and 7.6% of patients starting anti-TNF treatment reached DAS28 and CDAI SR, respectively, during a 1 year follow-up, but 3.5 and 7.6% of non-biologic users reached DAS28 and CDAI SR, respectively [32]. In another cohort patients in Canada, 21.5, 9.9, 4.5 and 6.8% achieved DAS28, CDAI, SDAI and ACR/EULAR SR, respectively, during treatment with biologics [33]. In stricter settings, as in clinical trials, remission rates are higher. In an etanercept tapering study, 63% of patients treated with etanercept and MTX were in DAS28 SR for at least 15 weeks after 23 months of treatment [34]. The prevalence of SR peaked after 5 years in our study. Even though some patients reached SR more than a decade after symptom onset, the majority of patients reached SR within 3 years, independent of which criteria were used. In a study from the Nijmegen early RA cohort the median time to sustained DAS remission was 9 months compared with 1.5 years in the present study [35]. Half of all patient reach DAS28 SR at some point, but most patients relapse within a few years. This reflects the fluctuating nature of the disease and implies that even in remission the patient must be followed according to the Treat to Target concept [5]. Prince et al. [32] reported that only about half of patients in remission were still in remission at follow-up 12 months later, regardless of the remission criteria used. In the Nijmegen cohort the median time in SR was 19 months [35]. In our previous study median remission time was just over 5 years, with a group of patients in remission lasting many years [36]. In the present study, many patients were still in remission at the last follow-up. Early RA, e.g. having a first registered visit within 6 months from symptom onset, was the strongest predictor of SR in our study. This is in line with a recent meta-analyses showing the importance of early treatment initiation [37]. A good physical function measure, e.g. low HAQ score, was identified as another predictor of SR. This was seen in both patients with established disease and those with early RA with little or no irreversible structural joint damage. These findings confirm our previous results including a cohort of patients starting their first anti-TNF treatment [11]. In accordance with several previous studies, male sex and lower HAQ predict good clinical response, occasional remission and SR [29, 33, 38–42]. However, we found ACPA to be negatively associated with SR. Similarly, in the IMPROVED study, drug-free remission was less often sustained in ACPA-positive patients [43]. In addition, ACPA positivity predicted relapse in drug-free remission and was association with radiographic progression in patients with early arthritis [44, 45]. In agreement with others, a younger age and lower ESR at inclusion in the registry was a predictor of SR [36, 46]. Patient-related outcomes, e.g. lower pain and lower PtGA and TJC, were predictors of SR, but only when all patients were included in the analysis. On the contrary, among early RA patients a more objective measure such as low DAS28, but not the patient-reported outcomes, predicted SR. This might reflect the higher importance of inflammation in the early course of the disease. A surprising finding in the present study was that higher EGA score predicted SR. One possible explanation could be that our assessment of disease as more active globally results in more intensive treatment and consequently a better outcome, for example, SR. This study has several strengths. It is based on nationwide data from almost 30 000 patients with RA, which allows us to estimate the prevalence of SR over a long period of time. All data were collected prospectively in daily routine care and thus include large numbers of patients that would have been excluded from intervention trials [47]. The registry lacks early follow-up data, especially at baseline for some patient groups, that is, those included from the earlier biologic registries, but that does not necessarily influence the prevalence numbers since these are based on every patient available at each time point. On the other hand, this could well influence time to remission calculations, which we have tried to compensate by selecting only patients included in the registry within 2 years from symptom onset. We did so for two reasons. Patients with long-standing disease are probably not as likely to reach remission since long-standing disease increases the risk for joint damage and residual disease, and secondly because late inclusion in the registry may miss previous remission periods. Many more patients experience non-SR than SR and the risk for escape after the first visit in remission is high. After the second visit in remission, patients are more likely to stay in remission. In our previous study on anti-TNF-treated patients, only 15.8% reached SR but 91.3, 74.8 and 60.0% remained in SR at 12, 24 and 48 months, respectively [36]. In Sweden, we usually decrease the visit frequency once the patient has reached remission but these results indicate that visit frequency should only be changed when remission is sustained over time [48]. Another weakness of our study is that the visit frequency may impact both the frequency of SR and the calculations of time in remission. Patients are instructed to report any signs of flare in disease but less formal contacts are not always registered in the SRQ. The time in remission was considerably shorter when patients were considered to have escaped from remission after 12 months without a visit, as opposed to 24 months. Since the visit frequency is lower once in remission and some rheumatology units schedule visits beyond 12 months once in SR, the 12-month time frame excludes these patients. On the other hand, there is a risk for overestimation of the true remission time when 24 months are allowed to pass between visits. In addition, the completeness or coverage of RA is a weakness of the present study. In 2016, the completeness of data in the SRQ was estimated as 83% of all patients with RA in Sweden, which is equal or higher than in registries for other chronic diseases such as cardiac failure [19]. These figures are in line with data from the Danish national registry (DANBIO) where the national completeness was 85% in 2013 [49]. Completeness of the data on diagnosis, disease onset, DAS and HAQ reported was between 83 and 93% in DANBIO. The national completeness of a chronic disease like RA is not easy to estimate, partly since there is no clear date for onset of disease, unlike for the acute diseases such as a stroke, and partly because there is risk for overestimation when deciding the true national prevalence. The specificity and sensitivity of the RA capture mechanism used by the National Patient Register is somewhat limited, based on registered diagnosis and prescriptions of DMARDs in specialist care. Using the ACR 1987 criteria as reference, a false-positive rate of around 6–15% has been estimated [50]. Patients with RA are typically diagnosed and treated by rheumatologists rather than by general practitioners in Sweden; the opposite would lead to underestimation of the prevalence. Importantly, the coverage of each of the SRQ sub-cohorts was good, for instance SSATG covered over 90% of all RA patients on biologics [51, 52]. In conclusion, the majority of RA patients in SRQ never reach DAS28 SR at any point after inclusion and even fewer reach CDAI, SDAI or ACR/EULAR SR. The prevalence of SR increases during the first disease years and peaks at 5 years. The pattern was similar for all remission criteria. In general, milder disease characteristics at baseline, including absence of ACPA, are associated with SR, as well as male sex and lower age. Acknowledgement The authors thank Pontus Geborek for skilful help with data management and statistical calculations. 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RheumatologyOxford University Press

Published: Mar 12, 2018

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