Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory disease requiring early diagnosis and treatment to achieve sustained clinical remission. Achieving a state of remission is associated with favorable outcomes. However, predictive factors for Boolean2.0 remission in RA patients are limited. This retrospective observational study analyzed data from RA patients enrolled in a smart system of disease management group (SSDM) between January 2014 and December 2023. Demographic and clinical characteristics were compared between patients who achieved Boolean2.0 remission and those who did not. Univariate and multivariate logistic regression analyses were performed to identify predictive factors associated with Boolean2.0 remission. Among 5004 patients enrolled for analysis, 541 (10.8%) achieved Boolean2.0 remission. The median (IQR) age at diagnosis of the patients was 51.00 (42.00, 60.00) years, with the majority being female (3978, 79.5%). The median (IQR) disease duration was 26.00 (3.00, 89.00) months. Logistic regression analyses revealed that the likelihood of achieving Boolean2.0 remission was greater in patients who were younger (P = 0.008), had a shorter disease duration (P < 0.001), a lower number of tender joints (P < 0.001), and were prescribed methotrexate (P = 0.012) and leflunomide (P = 0.001). Younger age, shorter disease duration, lower count of tender joints, and treatment with methotrexate and leflunomide were associated with increased likelihood of achieving Boolean2.0 remission. These findings can guide clinicians in identifying high-risk patients and optimizing treatment strategies.
Supplementary Information
The online version contains supplementary material available at 10.1038/s41598-025-97084-2.
Keywords: Rheumatoid arthritis, Boolean2.0 remission, Predictors, Treatment, Disease-modifying antirheumatic drugs
Subject terms: Musculoskeletal system, Rheumatoid arthritis
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by symmetrical polyarthritis, leading to articular cartilage and juxta-articular bone destruction1. Current treatment guidelines recommend the early use of disease-modifying antirheumatic drugs (DMARDs) and treatment should be aimed at reaching a target of sustained remission or low disease activity in patients2. Achieving a state of low disease activity, especially remission, is associated with favorable outcomes3. Clinical remission in RA patients is defined as the absence of signs and symptoms of significant inflammation, which can be variously defined by several instruments including disease activity score using 28 joints (DAS28) based on C-reactive protein (DAS28-CRP) or erythrocyte sedimentation rate (DAS28-ESR)4, clinical disease activity index (CDAI)5, simplified disease activity index (SDAI)6, Boolean remission criteria7, etc.
Boolean remission criteria had been modified in 2022 (Boolean2.0), allowing patients to achieve remission with a higher level (score at 2 on a 0–10 scale) of patients’ global assessment (PtGA)8. As patients may not find it easy to distinguish which of their symptoms are caused by RA and which by chronic widespread pain, scores of PtGA may be higher, thus preventing patients reaching the defined state of remission when using instruments scoring disease activity that include PtGA9. A previous study in the Asia-Pacific region illustrated that conventional synthetic DMARDs (csDMARDs) co-prescribed with glucocorticoids was related to non-remission of RA, while biological/targeted synthetic DMARDs (b/tsDMARDs) prescription was related to RA remission based on Boolean1.0 criteria. Besides, according to DAS28, the favorable related factors were male sex, younger age, whereas treatment with glucocorticoids was negatively related to remission10. The results of a real-world longitudinal study of RA patients showed that age at the disease onset > 60 years, being ACPA negative, and DAS28 at baseline ≤ 5.1 were independent predictors of long-term remission11. Despite this, the study of predictors associated with Boolean2.0 remission based on real-world clinical data is still lacked and the influence of age at RA onset on remission remains underexplored.
A recent study showed that the use of a digital health application (a smart system of disease management group, SSDM) with patient-reported outcomes was associated with an increase in disease control rate12. However, disease remission rates and predictors of remission monitored in the SSDM have not been fully evaluated, especially compared with the Boolean2.0 definition. Therefore, we collected data on RA patients from six centers in the SSDM cohort in this study. Demographic and clinical features were assessed and the predictive factors related to remission according to Boolean2.0 definition were analyzed.
Patients and methods
Study design and participants
A retrospective observational analysis conducted using data from RA patients enrolled in the SSDM between January 2014 and December 2023. The SSDM is a smart disease management system used to prospectively assess the clinical manifestations, disease activities, and outcomes of enrolled patients with systemic and autoimmune rhematic diseases in China12. Inclusion criteria were RA diagnosis and age ≥ 18 years. A total of 10,030 patients with RA were recruited from six tertiary hospitals. Patients without physician’s global assessment (PhGA) scores or with other autoimmune diseases, such as systemic lupus erythematosus, dermatomyositis, or spondyloarthritis, were excluded. To explore the predictors of Boolean2.0 remission, 615 patients attained Boolean2.0 remission when enrolled in the SSDM were also excluded (Supplementary Figure S1). This study complied with the Declaration of Helsinki, and was approved and monitored by the Committee on Scientific Research and Ethics of the Sixth Affiliated Hospital of Sun Yat-sen University (No. 2024ZSLYEC-121).
Data collection and definitions of remission
The main variables documented in the SSDM included age, gender, disease duration, inflammatory index and medication use. Clinical data on tender joint count (TJC), swollen joint count (SJC), PtGA, PhGA, Health Assessment Questionnaire Disability Index (HAQ-DI) were collected. Methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, b/tsDMARDs, glucocorticoids, and non-steroidal anti-inflammatory drugs (NSAIDs) administration were also documented. Various criteria for defining RA disease activity including DAS28-CRP, DAS28-ESR4, CDAI5, SDAI6 and Boolean remission criteria7 were calculated, respectively.
Boolean2.0 remission is defined as meeting all the following criteria: TJC ≤ 1, SJC ≤ 1, CRP ≤ 1 mg/mL and PtGA ≤ 2 (on a 0–10 scale)8. Joints need to be evaluated include proximal interphalangeal joints (n = 10), metacarpophalangeal joints (n = 10), wrists (n = 2), elbows (n = 2), shoulders (n = 2), and knees (n = 2).
Statistical analysis
Demographic and clinical characteristics are described as mean ± standard deviation (SD), median with interquartile range (IQR), or proportion (%). Continuous or discrete variables were defined as mean (± SD) or median (IQR) and were compared between the two groups using t-test for normally distributed data and Mann–Whitney U test for data that were not normally distributed. Categorical variables were analyzed using chi-squared test and were presented as percentages. Relationship between Boolean2.0 remission and clinical features was analyzed by univariate and multivariate logistic regression analyses. Statistical significance was set at a two-tailed P < 0.05. Statistical analyses were performed using the IBM SPSS Statistics software (version 26.0) and R software (version 4.2.2).
Results
Demographic and clinical characteristics of enrolled RA patients
In this study, 5004 patients were analyzed, with 541 (10.8%) achieving Boolean2.0 remission. The demographic and clinical characteristics of the enrolled RA patients are summarized in Table 1. The median (IQR) age at RA diagnosis of the patients was 51.00 (42.00, 60.00) years, with the majority being female (3978, 79.5%). The median (IQR) disease duration was 26.00 (3.00, 89.00) months, and the median (IQR) follow-up duration after enrollment in the SSDM group was 1.00 (0, 18.00) months.
Table 1.
Baseline characteristics of enrolled RA patients.
| All patients (n = 5004) | Attained Boolean2.0 remission (n = 541) | Not attained Boolean2.0 remission (n = 4463) | P - value | |
|---|---|---|---|---|
| Age at diagnosis (y) | 51.00 (42.00, 60.00) | 49.00 (41.00, 58.00) | 51.00 (42.00, 61.00) | 0.019 |
| Gender, n (%) | 0.306 | |||
| Female | 3978 (79.5) | 421 (77.8) | 3557 (79.7) | |
| Male | 1026 (20.5) | 120 (22.2) | 906 (20.3) | |
| Disease duration (months) | 26.00 (3.00, 89.00) | 21.00 (2.00, 70.75) | 27.00 (4.00, 91.00) | 0.002 |
| Follow-up duration (months) | 1.00 (0, 18.00) | 19.00 (7.00, 37.00) | 0 (0, 15.00) | < 0.001 |
| RF positive rate, n (%) | 2050 (94.5) | 230 (95.0) | 1820 (94.4) | 0.680 |
| Anti-CCP positive rate, n (%) | 633 (72.7) | 72 (68.6) | 561 (73.2) | 0.314 |
| Stiffness duration (minutes) | 8.00 (0, 30.00) | 3.00 (0, 30.00) | 9.00 (0, 30.00) | < 0.001 |
| No. of tender joints (0–28) | 5.00 (2.00, 12.00) | 4.00 (2.00, 9.00) | 5.00 (2.00, 12.00) | < 0.001 |
| No. of swollen joints (0–28) | 3.00 (2.00, 6.00) | 3.00 (2.00, 6.00) | 3.00 (2.00, 6.00) | 0.923 |
| CRP (mg/L) | 10.08 (3.20, 28.65) | 7.80 (2.93, 21.42) | 10.40 (3.22, 29.80) | < 0.001 |
| ESR (mm/h) | 27.00 (14.00, 50.00) | 25.00 (14.00, 45.00) | 27.16 (14.00, 51.00) | 0.088 |
| IgA (g/L) | 2.77 (1.95, 3.69) | 2.63 (1.76, 3.40) | 2.79 (2.00, 3.78) | 0.102 |
| IgM (g/L) | 1.29 (0.94, 1.73) | 1.35 (0.97, 1.92) | 1.28 (0.93, 1.73) | 0.311 |
| IgG (g/L) | 13.99 (11.50, 17.10) | 14.04 (11.73, 17.30) | 13.97 (11.50, 17.10) | 0.903 |
| CDAI | 15.00 (10.00, 24.00) | 12.00 (8.20, 20.00) | 15.00 (10.00, 24.80) | < 0.001 |
| SDAI | 16.80 (10.92, 27.69) | 13.55 (9.20, 22.84) | 17.13 (11.21, 28.27) | < 0.001 |
| DAS28-CRP | 3.92 (3.05, 4.95) | 3.60 (2.81, 4.53) | 3.96 (3.09, 5.01) | < 0.001 |
| DAS28-ESR | 5.41 (4.29, 6.62) | 5.06 (4.15, 6.12) | 5.45 (4.31, 6.66) | < 0.001 |
| PtGA score | 40.00 (30.00, 50.00) | 31.00 (30.00, 45.00) | 40.00 (30.00, 50.00) | < 0.001 |
| PhGA score | 40.00 (30.00, 50.00) | 32.00 (30.00, 42.00) | 40.00 (30.00, 50.00) | < 0.001 |
| HAQ-DI score | 2.00 (0, 7.00) | 1.00 (0, 5.00) | 3.00 (0, 7.00) | < 0.001 |
Values highlighted in bold represent statistically significant P values (P < 0.05).
The validity of RF testing was established in 2170 patients and ACPA testing was established in 871 patients.
anti-CCP, anti-cyclic citrullinated peptides; CDAI, clinical disease activity index; CRP, C-reactive protein; DAS28-CRP, disease activity score 28 based on C-reactive protein; DAS28-ESR, disease activity score 28 based on erythrocyte sedimentation rate; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; PhGA, physicians’ global assessment; PtGA, patients’ global assessment; RA, rheumatoid arthritis; RF, rheumatoid factor; SDAI, simplified disease activity index.
The patients who achieved Boolean2.0 remission (49.00 [41.00, 58.00] years) were younger than those who did not (51.00 [42.00, 61.00] years) at RA diagnosis. The median (IQR) disease duration was shorter in the remission group (21.00 [2.00, 70.75] months) compared to the non-remission group (27.00 [4.00, 91.00] months), and the median follow-up duration was significantly longer in the remission group (19.00 [7.00, 37.00] months vs. 0 [0, 15.00] months). The duration of morning stiffness was significantly shorter in the group of patients achieving Boolean2.0 remission (P < 0.001). The patients who did not achieve remission had a higher median number of tender joints (5.00 [2.00, 12.00]) than that in the remission group (4.00 [2.00, 9.00]) at the baseline, while the number of swollen joints were comparable.
Patients who achieved Boolean2.0 remission exhibited lower levels of C-reactive protein at the baseline. Furthermore, disease activity scores of RA patients achieving Boolean2.0 remission, including CDAI, SDAI, DAS28-CRP and DAS28-ESR, as well as scores reflecting patient and physician assessments, including PtGA, PhGA, HAQ-DI, were significantly lower at the baseline (all P < 0.001).
Treatment comparison of RA patients categorized by Boolean2.0 remission
Treatment strategies of enrolled RA patients are illustrated in Table 2. Methotrexate (2259, 45.1%) and leflunomide (2202, 44.0%) were the most common csDMARDs administered, following by hydroxychloroquine (1027, 20.5%). The frequency of JAKi (134, 2.7%) and TNFi (161, 3.2%) were relatively low for our RA patients when enrolled in the SSDM. Besides, glucocorticoids (800, 16.0%) and NSAIDs (1009, 20.2%) were also administered to patients as adjunctive therapy. Among patients who achieved Boolean2.0 remission, a higher percentage were prescribed with methotrexate (292 [54.0%] vs. 1967 [44.1%]), and leflunomide (267 [49.4%] vs. 1935 [43.4%]). Conversely, a lower percentage of patients were treated with JAKi (5 [0.9%] vs. 129 [2.9%]) or glucocorticoids (62 [11.5%] vs. 738 [16.5%]).
Table 2.
Baseline treatment strategies of enrolled RA patients.
| All patients (n = 5004) | Attained Boolean2.0 remission (n = 541) | Not attained Boolean2.0 remission (n = 4463) | P - value | |
|---|---|---|---|---|
| Medications | ||||
| csDMARDs | ||||
| Methotrexate | 2259 (45.1) | 292 (54.0) | 1967 (44.1) | < 0.001 |
| Leflunomide | 2202 (44.0) | 267 (49.4) | 1935 (43.4) | 0.008 |
| Hydroxychloroquine | 1027 (20.5) | 126 (23.3) | 901 (20.2) | 0.092 |
| Sulfasalazine | 44 (0.9) | 5 (0.9) | 39 (0.9) | 0.809 |
| b/tsDMARDs | ||||
| JAKi | 134 (2.7) | 5 (0.9) | 129 (2.9) | 0.007 |
| TNFi | 161 (3.2) | 16 (3.0) | 145 (3.2) | 0.717 |
| Others | ||||
| Glucocorticoids | 800 (16.0) | 62 (11.5) | 738 (16.5) | 0.002 |
| NSAIDs | 1009 (20.2) | 125 (23.1) | 884 (19.8) | 0.071 |
| Therapeutic regimen | ||||
| csDMARDs monotherapy | 2457 (49.1) | 253 (46.8) | 2204 (49.4) | 0.250 |
| Combination therapy with 2 csDMARDs | 1225 (24.5) | 185 (34.2) | 1040 (23.3) | < 0.001 |
| Combination therapy with ≥ 3 csDMARDs | 82 (1.6) | 10 (1.8) | 72 (1.6) | 0.684 |
| Combination therapy with TNFi and csDMARDs | 134 (2.7) | 11 (2.0) | 123 (2.8) | 0.325 |
| Combination therapy with JAKi and csDMARDs | 109 (2.2) | 3 (0.6) | 106 (2.4) | 0.006 |
Values highlighted in bold represent statistically significant P values (P < 0.05).
b/tsDMARDs, biological/targeted synthetic disease-modifying anti-rheumatic drugs; csDMARDs, conventional synthetic disease-modifying anti-rheumatic drugs; JAKi, Janus kinase inhibitors; NSAIDs, non-steroidal anti-inflammatory drugs; TNFi, tumor necrosis factor inhibitors.
Therapeutic regimens were further explored, which were divided into 5 categories, including csDMARD monotherapy, combination therapy with two csDMARDs, three or more csDMARDs combination, TNFi combination with csDMARDs, and JAKi combination with csDMARDs. A higher percentage of patients achieved Boolean2.0 remission received combination therapy with two csDMARDs (185 [34.2%] vs. 1040 [23.3%]) whereas a lower percentage administered with JAKi and csDMARDs combination (3 [0.6%] vs. 106 [2.4%]) when compared with patients not achieved remission.
Predictors of Boolean2.0 remission in enrolled RA patients
To explore the predictors of Boolean2.0 remission, logistic analyses were further carried out. The results of univariate logistic analysis were illustrated in Fig. 1. Younger age at RA diagnosis, shorter disease duration, lower number of tender joints were positively related to remission. As for treatment strategies, treatment with methotrexate and leflunomide were related to remission, while glucocorticoids and JAKi were related to non-remission (all P < 0.05).
Fig. 1.
Univariate logistic analysis to analyze the predictive factors of achieving Boolean2.0 remission in RA patients. Values highlighted in bold represent statistically significant P values (P < 0.05). NSAIDs, non-steroidal anti-inflammatory drugs; JAKi, janus kinase inhibitors; OR, odds ratio; SJC, swollen joint count; TNFi, tumor necrosis factor inhibitors; TJC, tender joint count.
Multivariate analysis was further performed to analyze the predictive factors of achieving Boolean2.0 remission in RA patients (Fig. 2). The likelihood of being in remission was higher in patients with younger age, shorter disease duration, lower number of tender joints, methotrexate and leflunomide prescription (all P < 0.05).
Fig. 2.
Multivariate logistic analysis to analyze the predictive factors of achieving Boolean2.0 remission in RA patients. Values highlighted in bold represent statistically significant P values (P < 0.05). OR, odds ratio; TJC, tender joint count.
Subgroup analysis between different groups based on age
As age was one of risk factors for Boolean2.0 remission, we further explored the clinical characteristics in different age groups. The cut-off point of age (61.5 years) at diagnosis was determined with ROC curves (high Youden index).
In total of 720 patients were 61.5 years or older when diagnosed with RA, among whom 77 (10.7%) patients achieved Boolean2.0 remission (Table 3). In the group of patients with 61.5 years or older, the median follow-up duration was significantly longer in the remission group (19.00 [9.00, 30.50] months vs. 1.00 [0, 20.00] months). The patients who did not achieve remission had a significantly higher median number of tender joints (9.00 [4.00, 18.00]) than that in the remission group (5.00 [3.00, 13.00]) at the baseline. Patients who achieved Boolean2.0 remission exhibited lower levels of inflammatory index, including C-reactive protein and erythrocyte sedimentation rate at the baseline. Furthermore, disease activity scores of RA patients achieving Boolean2.0 remission, including CDAI, SDAI, DAS28-CRP and DAS28-ESR, as well as scores reflecting patient and physician assessments, including PtGA, PhGA, HAQ-DI, were significantly lower at the baseline (all P < 0.001). In terms of treatment regimen, methotrexate (306, 42.5%) and leflunomide (334, 46.4%) were the most common administered DMARDs, and compared to patients not in remission, patients in remission had relatively higher rates of methotrexate and leflunomide usage. Furthermore, a higher percentage of patients achieved Boolean2.0 remission were prescribed with two csDMARDs combination therapy compared to non-remission patients (30 [39.0%] vs. 155 [24.1%]).
Table 3.
Clinical characteristics of enrolled RA patients ≥ 61.5 years.
| All patients (n = 720) | Attained Boolean2.0 remission (n = 77) | Not attained Boolean2.0 remission (n = 643) | P - value | |
|---|---|---|---|---|
| Age at diagnosis (y) | 67.00 (64.00, 71.00) | 68.00 (64.50, 71.00) | 67.00 (64.00, 71.00) | 0.614 |
| Gender, n (%) | 0.499 | |||
| Female | 501 (69.6) | 51 (66.2) | 450 (70.0) | |
| Male | 219 (30.4) | 26 (33.8) | 193 (30.0) | |
| Disease duration (months) | 8.50 (1.00, 36.00) | 6.00 (1.00, 29.00) | 9.00 (1.00, 36.00) | 0.214 |
| Follow-up duration (months) | 3.00 (0.00, 23.00) | 19.00 (9.00, 30.50) | 1.00 (0.00, 20.00) | < 0.001 |
| RF positive rate, n (%) | 340 (94.7) | 33 (100.0) | 307 (94.2) | 0.237 |
| Anti-CCP positive rate, n (%) | 86 (72.9) | 13 (76.5) | 73 (72.3) | 1.000 |
| Stiffness duration (minutes) | 11.00 (0.00, 30.75) | 5.00 (0.00, 32.50) | 13.00 (0.00, 31.00) | 0.375 |
| No. of tender joints (0–28) | 9.00 (4.00, 18.00) | 5.00 (3.00, 13.00) | 9.00 (4.00, 18.00) | 0.003 |
| No. of swollen joints (0–28) | 4.00 (2.00, 9.75) | 3.50 (2.00, 9.00) | 4.00 (2.00, 10.00) | 0.954 |
| CRP (mg/L) | 16.48 (5.00, 46.78) | 10.40 (3.08, 26.29) | 17.04 (5.70, 50.04) | 0.003 |
| ESR (mm/h) | 39.00 (21.00, 63.00) | 36.00 (15.00, 54.50) | 39.00 (22.00, 64.00) | 0.038 |
| CDAI | 19.05 (11.03, 33.00) | 13.00 (8.95, 28.50) | 20.00 (12.00, 34.00) | 0.002 |
| SDAI | 22.43 (13.08, 37.59) | 14.24 (9.58, 32.28) | 23.16 (13.64, 38.23) | 0.001 |
| DAS28-CRP | 4.51 (3.44, 5.74) | 3.77 (2.99, 5.30) | 4.61 (3.54, 5.76) | 0.001 |
| DAS28-ESR | 6.16 ± 1.71 | 5.56 ± 1.88 | 6.24 ± 1.68 | 0.001 |
| PtGA score | 40.00 (30.00, 50.00) | 30.00 (29.50, 45.00) | 40.00 (30.00, 50.00) | < 0.001 |
| PhGA score | 40.00 (30.00, 50.00) | 30.00 (30.00, 41.00) | 40.00 (30.00, 50.00) | < 0.001 |
| HAQ-DI score | 5.00 (2.00, 9.00) | 4.00 (0.00, 7.00) | 5.00 (2.00, 10.00) | 0.004 |
| Medications | ||||
| csDMARDs | ||||
| Methotrexate | 306 (42.5) | 42 (54.5) | 264 (41.1) | 0.024 |
| Leflunomide | 334 (46.4) | 44 (57.1) | 290 (45.1) | 0.045 |
| Hydroxychloroquine | 135 (18.8) | 14 (18.2) | 121 (18.8) | 0.892 |
| Sulfasalazine | 8 (1.1) | 1 (1.3) | 7 (1.1) | 0.597 |
| b/tsDMARDs | ||||
| JAKi | 5 (0.7) | 0 (0) | 5 (0.8) | 1.000 |
| TNFi | 12 (1.7) | 2 (2.6) | 10 (1.6) | 0.373 |
| Others | ||||
| Glucocorticoids | 106 (14.7) | 13 (16.9) | 93 (14.5) | 0.571 |
| NSAIDs | 190 (26.4) | 16 (20.8) | 174 (27.1) | 0.237 |
| Treatment regimen | ||||
| csDMARDs monotherapy | 344 (47.8) | 32 (41.6) | 312 (48.5) | 0.248 |
| Combination therapy with 2 csDMARDs | 185 (25.7) | 30 (39.0) | 155 (24.1) | 0.005 |
| Combination therapy with ≥ 3 csDMARDs | 6 (0.8) | 0 (0) | 6 (0.9) | 1.000 |
| Combination therapy with TNFi and csDMARDs | 10 (1.4) | 1 (1.3) | 9 (1.4) | 1.000 |
| Combination therapy with JAKi and csDMARDs | 5 (0.7) | 0 (0) | 5 (0.8) | 1.000 |
Values highlighted in bold represent statistically significant P values (P < 0.05).
The validity of RF testing was established in 359 patients and ACPA testing was established in 118 patients.
anti-CCP, anti-cyclic citrullinated peptides; b/tsDMARDs, biological/targeted synthetic disease-modifying anti-rheumatic drugs; CDAI, clinical disease activity index; CRP, C-reactive protein; csDMARDs, conventional synthetic disease-modifying anti-rheumatic drugs; DAS28-CRP, disease activity score 28 based on C-reactive protein; DAS28-ESR, disease activity score 28 based on erythrocyte sedimentation rate; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; JAKi, Janus kinase inhibitors; NSAIDs, non-steroidal anti-inflammatory drugs; PhGA, physician’s global assessment; PtGA, patients’ global assessment; RF, rheumatoid factor; SDAI, simplified disease activity index; TNFi, tumor necrosis factor inhibitors.
Among 4282 patients younger than 61.5 years, 464 (10.8%) patients attained Boolean2.0 remission (Table 4). The median (IQR) age at RA diagnosis was 48.00 (39.00, 54.00) years, with the majority being female (3447, 81.2%). Compared to non-remission patients, the median disease duration (25.00 [2.00, 82.00] months vs. 36.00 [6.00, 120.00] months) and stiffness duration (2.50 [0.00, 30.00] minutes vs. 9.00 [0.00, 30.00] minutes) were shorter whereas follow-up duration was significantly longer (18.50 [7.00, 38.00] months vs. 0.00 [0, 15.00] months) in the remission group. Patients who achieved Boolean2.0 remission exhibited lower number of tender joints and lower levels of C-reactive protein at the baseline. Furthermore, disease activity scores of RA patients achieving Boolean2.0 remission, including CDAI, SDAI, DAS28-CRP and DAS28-ESR, as well as scores reflecting patient and physician assessments, including PtGA, PhGA, HAQ-DI, were significantly lower at the baseline (all P < 0.001). With respect to medications, patients in remission group had relatively higher rates of methotrexate, leflunomide and NSAIDs, and lower rates of JAKi and glucocorticoids usage. Further exploration about treatment regimen showed that a higher percentage of patients achieved Boolean2.0 remission received combination therapy with two csDMARDs than that in non-remission groups (165 [35.6%] vs. 960 [25.1%]).
Table 4.
Clinical characteristics of enrolled RA patients < 61.5 years.
| All patients (n = 4284) | Attained Boolean2.0 remission (n = 464) | Not attained Boolean2.0 remission (n = 3820) | P - value | |
|---|---|---|---|---|
| Age at diagnosis (y) | 48.00 (39.00, 54.00) | 47.00 (40.00, 54.00) | 48.00 (38.00, 54.00) | 0.880 |
| Gender, n (%) | 0.407 | |||
| Female | 3447 (81.2) | 370 (79.7) | 3107 (81.3) | |
| Male | 807 (18.8) | 94 (20.3) | 713 (18.7) | |
| Disease duration (months) | 34.00 (5.00, 117.00) | 25.00 (2.00, 82.00) | 36.00 (6.00, 120.00) | < 0.001 |
| Follow-up duration (months) | 1.00 (0.00, 18.00) | 18.50 (7.00, 38.00) | 0.00 (0.00, 15.00) | < 0.001 |
| RF positive rate, n (%) | 1710 (94.4) | 197 (94.3) | 1513 (94.4) | 0.912 |
| Anti-CCP positive rate, n (%) | 547 (72.6) | 59 (67.0) | 488 (73.4) | 0.210 |
| Stiffness duration (minutes) | 8.00 (0.00, 30.00) | 2.50 (0.00, 30.00) | 9.00 (0.00, 30.00) | < 0.001 |
| No. of tender joints (0–28) | 5.00 (2.00, 10.00) | 4.00 (2.00, 8.00) | 5.00 (2.00, 10.00) | 0.008 |
| No. of swollen joints (0–28) | 3.00 (2.00, 6.00) | 3.00 (1.75, 6.00) | 3.00 (2.00, 6.00) | 0.927 |
| CRP (mg/L) | 9.49 (3.13, 26.35) | 7.73 (2.83, 20.60) | 9.69 (3.16, 26.97) | < 0.001 |
| ESR (mm/h) | 26.00 (13.00, 47.00) | 25.00 (14.00, 43.00) | 26.00 (13.00, 48.00) | 0.401 |
| CDAI | 14.00 (10.00, 22.20) | 12.00 (8.13, 20.00) | 14.50 (10.00, 23.00) | < 0.001 |
| SDAI | 16.12 (10.65, 25.66) | 13.54 (9.20, 22.47) | 16.37 (10.99, 26.26) | < 0.001 |
| DAS28-CRP | 3.85 (3.00, 4.81) | 3.54 (2.79, 4.44) | 3.88 (3.03, 4.85) | < 0.001 |
| DAS28-ESR | 5.26 (4.20, 6.45) | 5.00 (4.17, 6.06) | 5.29 (4.21, 6.50) | 0.003 |
| PtGA score | 40.00 (30.00, 50.00) | 33.00 (30.00, 45.00) | 40.00 (30.00, 50.00) | < 0.001 |
| PhGA score | 40.00 (30.00, 50.00) | 33.00 (30.00, 43.50) | 40.00 (30.00, 50.00) | < 0.001 |
| HAQ-DI score | 2.00 (0.00, 6.00) | 1.00 (0.00, 4.00) | 2.00 (0.00, 6.00) | < 0.001 |
| Medications | ||||
| csDMARDs | ||||
| Methotrexate | 1953 (45.6) | 250 (53.9) | 1703 (44.6) | < 0.001 |
| Leflunomide | 1868 (43.6) | 223 (48.1) | 1645 (43.1) | 0.040 |
| Hydroxychloroquine | 892 (20.8) | 112 (24.1) | 780 (20.4) | 0.062 |
| Sulfasalazine | 36 (0.8) | 4 (0.9) | 32 (0.8) | 1.000 |
| b/tsDMARDs | ||||
| JAKi | 129 (3.0) | 5 (1.1) | 124 (3.2) | 0.010 |
| TNFi | 149 (3.5) | 14 (3.0) | 135 (3.5) | 0.566 |
| Others | ||||
| Glucocorticoids | 694 (16.2) | 49 (10.6) | 645 (16.9) | < 0.001 |
| NSAIDs | 819 (19.1) | 109 (23.5) | 710 (18.6) | 0.011 |
| Treatment regimen | ||||
| csDMARDs monotherapy | 2113 (49.3) | 221 (47.6) | 1892 (49.5) | 0.440 |
| Combination therapy with 2 csDMARDs | 1125 (26.3) | 165 (35.6) | 960 (25.1) | < 0.001 |
| Combination therapy with ≥ 3 csDMARDs | 76 (1.8) | 10 (2.2) | 66 (1.7) | 0.510 |
| Combination therapy with TNFi and csDMARDs | 124 (2.9) | 10 (2.2) | 114 (3.0) | 0.314 |
| Combination therapy with JAKi and csDMARDs | 104 (2.4) | 3 (0.6) | 101 (2.6) | 0.008 |
Values highlighted in bold represent statistically significant P values (P < 0.05).
The validity of RF testing was established in 1811 patients and ACPA testing was established in 753 patients.
anti-CCP, anti-cyclic citrullinated peptides; b/tsDMARDs, biological/targeted synthetic disease-modifying anti-rheumatic drugs; CDAI, clinical disease activity index; CRP, C-reactive protein; csDMARDs, conventional synthetic disease-modifying anti-rheumatic drugs; DAS28-CRP, disease activity score 28 based on C-reactive protein; DAS28-ESR, disease activity score 28 based on erythrocyte sedimentation rate; ESR, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire Disability Index; JAKi, Janus kinase inhibitors; NSAIDs, non-steroidal anti-inflammatory drugs; PhGA, physician’s global assessment; PtGA, patients’ global assessment; RF, rheumatoid factor; SDAI, simplified disease activity index; TNFi, tumor necrosis factor inhibitors.
Discussion
In this relatively large-scale multicenter study in China, data of demographic and clinical characteristics were collected from the SSDM. The frequency of Boolean2.0 remission was relatively low in our cohort of RA patients. The likelihood of being in remission was higher in patients with younger age, shorter disease duration, lower number of tender joints, methotrexate and leflunomide prescription. Additionally, longer follow-up duration in the SSDM and combination therapy with two csDMARDs at the baseline might be beneficial to achieve Boolean2.0 remission.
Recent research has shown that age could significantly impact the likelihood of achieving remission in patients with RA. A systematic review found that older age at the onset of RA is inversely associated with disease remission13, which was consistent with the results of our study, suggesting that younger age at RA diagnosis was one of predictors to Boolean2.0 remission. Greater awareness of the disease and higher adherence might also contribute to disease remission. In a retrospective national study, patients over 53 years old treated with TNFi had a reduced likelihood of achieving remission compared to younger patients14. Furthermore, data from large cohorts such as the BRASS and KORONA studies highlighted that younger age was consistently identified as an independent predictor of sustained remission in RA15.
In this study, it was found that a shorter duration of disease corresponded to higher likelihood of achieving the Boolean2.0 remission. This correlation was observed not only in the overall population but also within a subgroup of patients aged 61.5 years or younger. Multivariate analyses from the BRASS and KORONA studies revealed that those with shorter disease duration were more likely to experience sustained remission15. A Swedish nationwide study further supported this finding, indicating that early RA, defined as symptoms lasting six months or less, was associated with a higher frequency of sustained remission16. Conversely, the tofacitinib ORAL Start trial demonstrated lower remission rates in both the methotrexate monotherapy and combination therapy groups, which might be attributable to the inclusion of patients with a relatively longer disease duration, averaging three years17. Furthermore, a systematic review examining the prevalence and predictors of sustained remission or low disease activity following the discontinuation of TNFi therapy in RA patients found that successful discontinuation was less probable among patients who had had RA for a longer period18.
A previous study recruited early RA patients who were naive to DMARDs and had a symptom duration of less than two years. These patients were then treated according to an aggressive treat-to-target protocol. Multivariate logistic regression analysis revealed that a higher tender joint score, as measured by the Ritchie Articular Index, at the onset of RA significantly decreased the likelihood of achieving sustained remission according to various definitions, including the DAS based on the Ritchie Articular Index, Boolean1.0, and the SDAI remission criteria19. Furthermore, this study also found that joint tenderness is associated with increased ultrasound power Doppler activity, indicating inflammation, which suggested that joints tenderness in early RA might reflect underlying inflammation that was not always clinically detectable19. In our study, the number of tender joints was inversely associated with Boolean2.0 remission, indicating that higher inflammation reflected by joints tenderness in early RA was unfavorable for remission.
Early control of inflammation in RA generally results in better outcomes. In our study, administrated with methotrexate and leflunomide were associated with Boolean2.0 remission. Optimal usage of DMARDs and tight control strategies could enable disease remission become achievable, which may be approval of ‘window of opportunity’ hypothesis20. Methotrexate is still today the anchor drug and the first-line treatment after RA diagnosis. However, studies showed that methotrexate alone often resulted in lower remission rates compared to combination therapy with b/tsDMARDs21. The OPERA trial indicated a significant difference in remission rates between methotrexate monotherapy (49%) and combination therapy with adalimumab (74%), while a similar percentage of patients in the two groups achieved low disease activity (80% vs. 76%, P = 0.65)22. However, the frequency of b/tsDMARDs was comparatively low in our study, necessitating additional data and further research. Leflunomide exerts its therapeutic effect by inhibiting dihydroorotate dehydrogenase, an essential enzyme in the synthesis of pyrimidines. This inhibition reduces the availability of pyrimidines, impairing DNA synthesis and ultimately suppressing the immune response involved in RA. This mechanism helps in reducing inflammation and achieving disease remission23. Leflunomide prescription was related to Boolean2.0 remission in our study. A study compared leflunomide with low-dose rituximab in RA patients who were refractory to initial DMARDs. The results showed that leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks24. Patients who took leflunomide had significant improvements in disease activity scores, indicating its potential in achieving remission when methotrexate alone is insufficient24.
In our study, the analysis of both the entire population and subgroups showed that a higher percentage of patients who achieved Boolean2.0 remission were prescribed a combination therapy of two csDMARDs compared to those who did not achieve remission. A systematic review of studies found that intensive treatment strategies, which included methotrexate combined with other DMARDs tended to increase the frequency of remission and yield better outcomes, both in early and established RA25. A study found that low-dose, short-term prednisone therapy markedly improved disease severity in newly diagnosed RA patients. About 54.2% of patients achieved remission following this treatment, and early exposure to glucocorticoids was associated with better outcomes26. The CAPRA-2 trial demonstrated that adding low-dose prednisone to existing DMARDs regimens resulted in better disease control compared to placebo over a 12-week period in patients with established RA27. However, the results of a large-scale multinational study in the Asia-Pacific region illustrated that less glucocorticoids usage were related to higher remission rates10. In our study, administration with glucocorticoids was inversely associated with Boolean2.0 remission, which may be due to higher inflammatory state and disease activity in patients prescribed with glucocorticoids at the baseline. Indeed, several issues, including the benefit-to-risk ratio of low-dose glucocorticoids and the optimal duration of glucocorticoid use as bridging therapy, remain on the research agenda.
A recent study showed that the use of the SSDM with patient-reported outcomes was associated with an increase in disease control rate12. Besides, patient-initiated care supported by smartphone self-monitoring was noninferior to usual care in terms of the decrease of DAS28-ESR and led to a 38% reduction in rheumatologist consultations in RA patients with stable low disease activity28. In this study, the duration of follow-up after enrollment in the SSDM was significantly longer for the remission group, both in the overall population and within the subgroup analyses. This suggests that smartphone applications like SSDM may have the potential to be integrated into daily clinical practice, thereby reducing the management burden on rheumatologists and aiding in the control of RA disease activity.
However, this study has limitations. Firstly, radiographic and ultrasound data were not available, thus imaging-based assessments of joint damage were unable to be performed in this study. Secondly, the population analyzed was limited to patients from specific regions of China, and the findings may not be generalizable to RA populations in other countries, necessitating further investigation to validate the results. Thirdly, the impact of adjustments to therapeutic strategies during follow-up should be explored in future studies.
Conclusion
In conclusion, this study identified predictors of Boolean2.0 remission in RA patients, including younger age, shorter disease duration, lower count of tender joints, and the prescription of methotrexate and leflunomide. These factors could aid clinicians in identifying patients at greater risk and in implementing more aggressive treatment strategies to enhance the likelihood of achieving remission. Implementing these findings in clinical practice may reduce the risk of long-term complications and mitigate the economic impact of the disease.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Abbreviations
- Anti-CCP
Anti-cyclic citrullinated peptides
- CDAI
Clinical disease activity index
- CRP
C-reactive protein
- DAS28-CRP
Disease activity score using 28 joints based on C-reactive protein
- ESR
Erythrocyte sedimentation rate
- HAQ-DI
Health Assessment Questionnaire Disability Index
- JAKi
Janus kinase inhibitors
- NSAIDs
Non-steroidal anti-inflammatory drugs
- PhGA
Physician’s global assessment
- PtGA
Patient’s global assessment
- RA
Rheumatoid arthritis
- RAPID3
Routine assessment of patient index data 3
- RF
Rheumatoid factor
- SDAI
Simplified disease activity index
- SSDM
A smart system of disease management group
- TNFi
Tumor necrosis factor inhibitors
Author contributions
J-L H, P-J X and Y-Q Z designed the study, reviewed the manuscript, analyzed and interpreted the patient data regarding rheumatoid arthritis. Y-Q Z and K-Q D performed data collection and analysis and were major contributors in writing the manuscript. W B, Y-F W, H W, X-X F, J X and P-J X contributed to the data collection. All authors revised and approved the final manuscript.
Funding
This study was supported by Basic and Applied Basic Research Foundation of Guangdong Province, China (2021A1515220041).
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Declarations
Competing interests
The authors declare no competing interests.
Ethics approval and informed consent
This study was approved and monitored by the Committee on Scientific Research and Ethics of the Sixth Affiliated Hospital of Sun Yat-sen University (No. 2024ZSLYEC-121). Informed consent was obtained from all the patients enrolled in this study.
Footnotes
Publisher’s note
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Contributor Information
Peijun Xu, Email: xupj@mail.sysu.edu.cn.
Jianlin Huang, Email: hjianl@mail.sysu.edu.cn.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.