Chinese registry of rheumatoid arthritis (CREDIT) V: sex impacts rheumatoid arthritis in Chinese patients : Chinese Medical Journal

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Original Article

Chinese registry of rheumatoid arthritis (CREDIT) V: sex impacts rheumatoid arthritis in Chinese patients

Jiang, Nan1; Li, Qin2; Li, Hongbin3; Fang, Yongfei4; Wu, Lijun5; Duan, Xinwang6; Xu, Jian7; Zhao, Cheng8; Jiang, Zhenyu9; Wang, Yanhong10; Wang, Qian1; Leng, Xiaomei1; Li, Mengtao1; Tian, Xinping1; Zeng, Xiaofeng1

Editor(s): Guo, Lishao

Author Information
Chinese Medical Journal: September 8, 2022 - Volume - Issue - 10.1097/CM9.0000000000002110
doi: 10.1097/CM9.0000000000002110
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Abstract

Introduction

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases, and is characterized by chronic destructive synovitis and multisystem involvement.[1] Most epidemiological studies have shown a prevalence of RA ranging from 0.5% to 1.0%.[2] RA can occur at any age, although the peak incidence is in the 6th decade.[3] The overall female to male ratio is about 2:1 to 3:1.[4] The impact of sex on the clinical manifestations, disease activities, treatment responses, comorbidities, and outcomes of RA have been reported in several studies.[5-10] However, studies with a large sample size were insufficient, and the results were variable among the investigators.

The Chinese Registry of rhEumatoiD arthrITis (CREDIT), which was established in November 2016, is the first nationwide online multi-center registry for RA in China. Based on data from the CREDIT cohort, the prevalence of remission, the predictors of achieving treatment target, the correlation of disease activity indices, and the major comorbidities of Chinese patients with RA have been described.[11-14] CREDIT provides a platform for investigating the influence of sex on the characteristics of RA.

Methods

Ethical approval

Ethics approval (No. S-478) for the registry was obtained from the Institutional Review Board (IRB) of Peking Union Medical College Hospital (PUMCH), which was accepted by all participating centers as the central IRB. Informed consent was obtained from all the patients during enrollment.

Patient recruitment

Based on the CREDIT online registry, the study was conducted at 274 rheumatology centers in 31 provinces across China. As the leading center, the PUMCH is responsible for the training, communication, and funding of the registry. Chinese RA patients who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria[15,16] were recruited in the registry. We enrolled 11,564 patients who had baseline and at least 3 months of follow-up data. Data were collected between November 2016 and June 2021.

Data collection

All CREDIT centers used the same protocol-directed methods to provide uniform evaluations and record patient data. Investigators received training on diagnosis confirmation, disease activity evaluation, data input, and data quality control. In this study, demographic and clinical indices were collected at enrollment and follow-up visits, including sex, age, disease duration, initial fulfillment of RA classification criteria, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), titer of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies, pain visual analogue scale (VAS), tender joint count (TJC, 28 joint count), swollen joint count (SJC, 28 joint count), patient's and physician's global assessment (PtGA and PhGA), 28-joint disease activity score (DAS28), simplified disease activity index (SDAI), clinical disease activity index (CDAI), and medications for RA, as well as medical history ofinterstitial lung disease (ILD), coronary artery disease (CAD), stroke, malignancy, and fragility fracture. The proportions of patients who achieved treatment target for RA was calculated. The treatment target was defined as remission or low disease activity (LDA), according to the 2014 treat-to target recommendation.[17]

Statistical analysis

The demographic and clinical characteristics of patients of different sexes were compared in all patients with RA and in patients with early RA (defined as disease duration ≤6 months), with Chi-squared test for categorical variables, and Student's t test or Wilcoxon's test for continuous variables according to the distribution. Categorical variables are presented as counts. Continuous variables are presented as means ± standard deviations or medians and quartiles according to the distribution. Statistical significance was set at P < 0.05. All analyses were conducted using the SPSS 22.0 statistical package (SPSS, Chicago, IL, USA).

Results

Baseline characteristics

Among the 11,564 patients, 83.6% were female. The median age was 52.0 years, the median disease duration was 3.0 years, and the median CDAI was 18.3. At baseline, 26.8% of the patients were receiving conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) monotherapy, 32.2% were receiving double or triple csDMARD combination, and 6.8% were receiving biologic DMARDs/targeted synthetic DMARDs plus one csDMARD. The percentage of patients who were prescribed glucocorticoids (GCs) and non-steroidal antiinflammatory drugs (NSAIDs) at baseline were 41.4% and 23.0%, respectively. The patients’ baseline characteristics are shown in Table 1.

Table 1 - Baseline characteristics of 11,564 patients with RA based on the CREDIT online registry between November 2016 and June 2021.
Parameters Values
Female 9666 (83.6)
Age (years) 52.0 (43.0, 60.0)
Disease duration (years) 3.0 (1.0, 8.0)
Score of ACR/EULAR criteria 8.0 (7.0, 9.0)
RF positive 7015/8391 (83.6)
RF titer (U/mL) 57.5 (24.2, 112.0)
Anti-CCP positive 6200/8260 (75.1)
Anti-CCP titer (U/mL) 119.0 (20.0, 400.0)
SJC 3 (0, 10)
TJC 4 (1, 11)
ESR (mm/h) 30.0 (15.0, 54.0)
CRP (mg/L) 7.4 (2.5, 22.0)
Pain VAS 4.6 (2.5, 6.4)
PtGA 4.6 (2.6, 6.3)
PhGA 4.4 (2.5, 6.1)
DAS28-ESR 4.7 (3.4, 6.0)
DAS28-CRP 4.1 (2.9, 5.3)
SDAI 20.1 (10.8, 34.5)
CDAI 18.3 (9.8, 31.8)
ILD 246 (2.1)
CAD 187 (1.6)
Stroke 78 (0.7)
Malignancy 106 (0.9)
Fragility fracture 147 (1.3)
Medications
 csDMARDs monotherapy 3096 (26.8)
 csDMARDs combination 3727 (32.2)
 Mono-csDMARD + bDMARDs/tsDMARDs 790 (6.8)
 GC usage 4783 (41.4)
 NSAIDs usage 2656 (23.0)
Data are presented as medians (Q1, Q3) or n (%). ACR: American College of Rheumatology; anti-CCP: Anti-cyclic citrullinated peptide; bDMARDs: Biologic disease-modifying anti-rheumatic drugs; CAD: Coronary artery disease; CDAI: Clinical disease activity index; CREDIT: Chinese Registry of Rheumatoid Arthritis; CRP: C-reactive protein; csDMARDs: Conventional synthetic disease-modifying anti-rheumatic drugs; DAS28-CRP: 28-joint disease activity score using C-reactive protein; DAS28-ESR: DAS28 using erythrocyte sedimentation rate; ESR: Erythrocyte sedimentation rate; EULAR: European League Against Rheumatism; GC: Glucocorticoid; ILD: Interstitial lung disease; NSAIDs: Non-steroidal anti-inflammatory drugs; PhGA: Physician's global assessment; PtGA: Patient's global assessment; RF: Rheumatoid factor; SDAI: Simplified disease activity index; SJC: Swollen joint count; TJC: Tender joint count; tsDMARDs: Targeted synthetic disease-modifying anti-rheumatic drugs; VAS: Visual analogue scale.

Comparison of patients of different sexes

As shown in Table 2, RF, CRP, pain VAS, PtGA, PhGA, disease activity score using CRP (DAS28-CRP), SDAI, and CDAI were all significantly higher in male patients than in female patients. As for comorbidities, the ratios of ILD, CAD, and stroke were higher in male patients, while malignancies were more commonly observed in female patients. A higher proportion of male patients received GCs and NSAIDs, while more female patients received csDMARD monotherapy.

Table 2 - Comparison of baseline characteristics of patients of different sexes.
Parameters Male (n = 1898) Female (n = 9666) P values
Age (years) 56.0 (47.0, 65.0) 51.0 (42.0, 59.0) <0.001
Disease duration (years) 2.1 (0.6, 5.8) 3.1 (1.0, 8.7) <0.001
Score of ACR/EULAR criteria 8 (7, 9) 8 (7, 9) 0.411
RF positive 1160/1376 (84.3) 5855/7015 (83.5) 0.450
RF titer (U/mL) 64.4 (25.8, 123.0) 56.0 (24.0, 110.0) <0.001
Anti-CCP positive 1015/1347 (75.4) 5185/6913 (75.0) 0.810
Anti-CCP titer (U/mL) 127.5 (20.0, 488.4) 115.5 (19.9, 399.5) 0.092
SJC 4 (0, 11) 3 (0, 10) 0.236
TJC 4 (1, 12) 4 (1, 11) 0.083
ESR (mm/h) 30.0 (14.0, 60.0) 30.0 (15.0, 53.0) 0.752
CRP (mg/L) 12.0 (3.4, 33.4) 6.7 (2.3, 20.0) <0.001
Pain VAS 4.8 (2.9, 6.4) 4.5 (2.5, 6.3) 0.008
PtGA 4.9 (2.8, 6.3) 4.5 (2.6, 6.3) 0.044
PhGA 4.6 (2.7, 6.3) 4.3 (2.5, 6.1) 0.003
DAS28-ESR 4.8 (3.3, 6.1) 4.7 (3.4, 5.9) 0.287
DAS28-CRP 4.3 (2.0, 5.6) 4.0 (2.9, 5.3) <0.001
SDAI 21.9 (11.5, 37.2) 19.9 (10.7, 33.9) <0.001
CDAI 19.3 (10.0, 33.0) 18.0 (9.8, 31.4) 0.022
ILD 57 (3.0) 189 (1.6) 0.004
CAD 60 (3.2) 127 (1.3) <0.001
Stroke 32 (1.7) 46 (0.5) <0.001
Malignancy 9 (0.5) 97 (1.0) 0.034
Fragility fracture 19 (1.0) 128 (1.3) 0.265
Medications
 csDMARDs monotherapy 449 (23.7) 2647 (27.4) 0.001
 csDMARDs combination 601 (31.7) 3126 (32.3) 0.573
 Mono-csDMARD+ bDMARDs/tsDMARDs 131 (6.9) 659 (6.8) 0.921
 GC usage 841 (44.3) 3942 (40.8) 0.005
 NSAIDs usage 470 (24.8) 2186 (22.6) 0.042
P < 0.05. Data are presented as medians (Q1, Q3) or n (%). ACR: American College of Rheumatology; anti-CCP: Anti-cyclic citrullinated peptide; bDMARDs: Biologic disease-modifying anti-rheumatic drugs; CAD: Coronary artery disease; CDAI: Clinical disease activity index; CRP: C-reactive protein; csDMARDs: Conventional synthetic disease-modifying anti-rheumatic drugs; DAS28-CRP: 28-joint disease activity score using C-reactive protein; DAS28-ESR: DAS28 using erythrocyte sedimentation rate; ESR: Erythrocyte sedimentation rate; EULAR: European League Against Rheumatism; GC: Glucocorticoid; ILD: Interstitial lung disease; NSAIDs: Non-steroidal anti-inflammatory drugs; PhGA: Physician's global assessment; PtGA: Patient's global assessment; RF: Rheumatoid factor; SDAI: Simplified disease activity index; SJC: Swollen joint count; TJC: Tender joint count; tsDMARDs: Targeted synthetic disease-modifying anti-rheumatic drugs; VAS: Visual analogue scale.

The proportions of patients who achieved LDA or remission are shown in Table 3. At baseline, a higher proportion of female patients reached the treatment target according to DAS28-CRP, while more male patients were in remission according to DAS28 using erythrocyte sedimentation rate (DAS28-ESR). However, no such differences were observed when disease activity was assessed using other indices. At 3 months, 6 months, or 12 months, most of the disease activity indices showed no significant difference between males and females.

Table 3 - LDA and remission achievement in patients of different sexes.
LDA or remission achievement Remission achievement


Parameters Male Female P values Male Female P values
Baseline (n = 11,564) n = 1898 n = 9666 n = 1898 n = 9666
 DAS28-ESR 437 (23.0) 2129 (22.0) 0.349 302 (15.9) 1276 (13.2) 0.002
 DAS28-CRP 536 (28.2) 3066 (31.7) 0.003 364 (19.2) 1918 (19.8) 0.508
 CDAI 486 (25.6) 2570 (26.6) 0.378 131 (6.9) 659 (6.8) 0.921
 SDAI 457 (24.1) 2498 (25.8) 0.107 130 (6.8) 684 (7.1) 0.732
3 months (n = 8032) n = 1355 n = 6677 n = 1355 n = 6677
 DAS28-ESR 608 (44.9) 2730 (40.9) 0.007 395 (29.2) 1787 (26.8) 0.076
 DAS28-CRP 697 (51.4) 3541 (53.0) 0.296 496 (36.6) 2473 (37.0) 0.781
 CDAI 680 (50.2) 3158 (47.3) 0.053 203 (15.0) 928 (13.9) 0.304
 SDAI 649 (47.9) 3172 (47.5) 0.811 201 (14.8) 960 (14.4) 0.672
6 months (n = 4821) n = 742 n = 4079 n = 742 n = 4079
 DAS28- ESR 364 (49.1) 1852 (45.4) 0.072 262 (35.3) 1259 (30.9) 0.018
 DAS28-CRP 402 (54.2) 2352 (57.7) 0.083 293 (39.5) 1736 (42.6) 0.125
 CDAI 394 (53.1) 2146 (52.6) 0.811 136 (18.3) 729 (17.9) 0.795
 SDAI 385 (51.9) 2143 (52.5) 0.749 135 (18.2) 702 (17.2) 0.527
1 year (n = 2848) n = 423 n = 2425 n = 423 n = 2425
 DAS28-ESR 205 (48.5) 1152 (47.5) 0.752 143 (33.8) 798 (32.9) 0.737
 DAS28-CRP 239 (56.5) 1469 (60.6) 0.119 174 (41.1) 1084 (44.7) 0.185
 CDAI 239 (56.5) 1623 (45.7) 0.095 78 (18.4) 468 (19.3) 0.689
 SDAI 230 (54.4) 1385 (57.1) 0.832 70 (16.5) 486 (20.0) 0.097
P < 0.05. Data are presented as medians (Q1, Q3) or n (%). CDAI: Clinical disease activity index; CRP: C-reactive protein; DAS28-CRP: 28-joint disease activity score using C-reactive protein; DSA28-ESR: DAS28 using erythrocyte sedimentation rate; ESR: Erythrocyte sedimentation rate; LDA: Low disease activity; SDAI: Simplified disease activity index.

Comparison of patients with early RA

The characteristics of patients with early RA were analyzed separately. As shown in Table 4, age, SJC, TJC, ESR, CRP, pain VAS, PtGA, PhGA, DAS28-ESR, DAS28-CRP, SDAI, and CDAI were all significantly higher in men than in women. CAD and stroke were more commonly observed in male patients than in female patients. The ratios of ILD, malignancy, and fragility fractures were similar in the 2 sexes. More male patients with early RA received GC treatment, while more female patients received csDMARD monotherapy.

Table 4 - Comparison of baseline characteristics of patients with early RA.
Parameters Male (n = 402) Female (n = 1368) P values
Age (years) 56.0 (47.0, 64.0) 49.0 (39.0, 57.0) <0.001
Disease duration (years) 0.24 (0.14, 0.36) 0.24 (0.13, 0.37) 0.523
Score of ACR/EULAR criteria 7 (7, 9) 7 (7, 9) 0.159
RF positive 264/303 (87.1) 860/1026 (83.8) 0.175
RF titer (U/mL) 63.5 (26.6, 129.0) 58 (24.9, 113.7) 0.069
Anti-CCP positive 231/302 (76.5) 813/1011 (80.4) 0.144
Anti-CCP titer (U/mL) 170.5 (20.6, 543.4) 179.0 (30.0, 458.0) 0.947
SJC 4 (1, 13) 4 (1, 10) 0.044
TJC 6 (2, 14) 5 (1, 11) 0.014
ESR (mm/h) 36.0 (17.0, 62.0) 30.0 (16.0, 54.0) 0.013
CRP (mg/L) 17.0 (5.1, 45.0) 6.5 (2.4, 21.9) <0.001
Pain VAS 5.1 (3.2, 6.6) 4.7 (2.8, 6.2) 0.001
PtGA 5.1 (3.1, 6.5) 4.7 (2.9, 6.2) 0.004
PhGA 5.1 (3.3, 6.4) 4.4 (2.7, 6.0) <0.001
DAS28-ESR 5.1 (3.8, 6.4) 4.8 (3.5, 6.0) 0.002
DAS28-CRP 4.6 (3.5, 5.9) 4.1 (3.0, 5.3) <0.001
SDAI 26.1 (14.3, 41.5) 20.8 (12.0, 34.6) <0.001
CDAI 22.4 (12.7, 37.7) 19.0 (11.0, 32.0) 0.002
ILD 6 (1.5) 30 (2.2) 0.431
CAD 12 (3.0) 16 (1.2) 0.014
Stroke 7 (1.7) 3 (0.2) 0.002
Malignancy 4 (1.0) 11 (0.8) 0.757
Fragility fracture 4 (1.0) 15 (1.1) 1.000
Medications
 csDMARDs monotherapy 101 (25.1) 443 (32.4) 0.006
 csDMARDs combination 118 (29.4) 416 (30.4) 0.711
 Mono-csDMARDs + bDMARDs/tsDMARDs 31 (7.7) 88 (6.4) 0.428
 GC usage 165 (41.0) 479 (35.0) 0.029
 NSAIDs usage 123 (30.6) 391 (28.6) 0.453
P < 0.05. Data are presented as medians (Q1, Q3) or n (%). ACR: American College of Rheumatology; anti-CCP: Anti-cyclic citrullinated peptide; bDMARDs: Biologic disease-modifying anti-rheumatic drugs; CAD: Coronary artery disease; CDAI: Clinical disease activity index; CRP: C-reactive protein; csDMARDs: Conventional synthetic disease-modifying anti-rheumatic drugs; DAS28-CRP: 28-joint disease activity score using C-reactive protein; DAS28-ESR: DAS28 using erythrocyte sedimentation rate; ESR: Erythrocyte sedimentation rate; EULAR: European League Against Rheumatism; GC: Glucocorticoid; ILD: Interstitial lung disease; NSAIDs: Non-steroidal anti-inflammatory drugs; PhGA: Physician's global assessment; PtGA: Patient's global assessment; RA: Rheumatoid arthritis; RF: Rheumatoid factor; SDAI: Simplified disease activity index; SJC: Swollen joint count; TJC: Tender joint count; tsDMARDs: Targeted synthetic disease-modifying anti-rheumatic drugs; VAS: Visual analogue scale.

Treatment target achievement and remission achievement in patients with early RA are shown in Table 5. At baseline, the proportions of treatment target achievement were higher in female patients than in male patients, and the differences were significant according to DAS28-CRP, CDAI, and SDAI. The proportions of remission were similar between men and women at baseline; only, a higher proportion of female patients was observed in DAS28-CRP. At 3 months, 6 months, and 12 months, the proportions of treatment target achievement and remission were still higher in female patients according to most of the indices, but most of the differences were not statistically significant.

Table 5 - LDA and remission achievement in patients with early RA.
LDA or remission achievement Remission achievement


Parameters Male Female P values Male Female P values
Baseline ( n = 1770) n = 402 n = 1368 n = 402 n = 1368
 DAS28-ESR 72 (17.9) 274 (20.0) 0.354 38 (9.5) 144 (10.5) 0.576
 DAS28-CRP 83 (20.6) 393 (28.7) 0.001 52 (12.9) 238 (17.4) 0.038
 CDAI 73 (18.2) 320 (23.4) 0.029 24 (6.0) 80 (5.8) 1.000
 SDAI 66 (16.4) 312 (22.8) 0.007 21 (5.2) 83 (6.1) 0.550
3 months ( n = 1323) n = 309 n = 1014 n = 309 n = 1014
 DAS28-ESR 142 (46.0) 469 (46.3) 0.948 87 (28.2) 312 (30.8) 0.396
 DAS28-CRP 163 (52.8) 583 (57.5) 0.150 114 (36.9) 430 (42.4) 0.086
 CDAI 160 (51.8) 520 (51.3) 0.897 40 (12.9) 186 (18.3) 0.031
 SDAI 155 (50.2) 523 (51.6) 0.697 41 (13.3) 190 (18.7) 0.032
6 months ( n = 754) n = 154 n = 600 n = 154 n = 600
 DAS28-ESR 76 (49.4) 298 (49.7) 1.000 55 (35.7) 219 (36.5) 0.925
 DAS28-CRP 70 (45.5) 383 (63.8) <0.001 57 (37.0) 280 (46.7) 0.037
 CDAI 77 (50.0) 330 (55.0) 0.278 30 (19.5) 134 (22.3) 0.511
 SDAI 74 (48.1) 335 (55.8) 0.086 28 (18.2) 133 (22.2) 0.322
1 year ( n = 398) n = 77 n = 321 n = 77 n = 321
 DAS28-ESR 37 (48.1) 173 (53.9) 0.376 25 (32.5) 121 (37.7) 0.431
 DAS28-CRP 38 (49.4) 207 (64.5) 0.019 30 (39.0) 166 (51.7) 0.057
 CDAI 42 (54.5) 197 (61.4) 0.301 15 (19.5) 62 (19.3) 1.000
 SDAI 39 (50.6) 199 (62.0) 0.072 14 (18.2) 65 (20.2) 0.752
P < 0.05. Data are presented as n (%). CDAI: Clinical disease activity index; CRP: C-reactive protein; DAS28-CRP: 28-joint disease activity score using C-reactive protein; DAS28-ESR: DAS28 using erythrocyte sedimentation rate; ESR: Erythrocyte sedimentation rate; LDA: Low disease activity; RA: Rheumatoid arthritis; SDAI: Simplified disease activity index.

Discussion

In the current study, we compared the clinical characteristics at baseline and proportion of patients who achieved LDA or remission at follow-up between male and female patients with RA. The results showed that male patients had higher disease activity at baseline, while more female patients with early RA were in remission or in a LDA state at baseline. At 3 months, 6 months, and 12 months, the proportions of remission and treatment target achievement were similar between the 2 sexes.

As previously reported, RA is a disease that frequently occurs in women.[18] Our data showed an approximately 4-fold increase in the frequency of RA in women vs. men, which was consistent with the results reported by other investigators,[6,10,19] especially in a large Japanese cohort, which was constituted by the same ethnic group as our cohort.[20]

The RF was reported to be equally prevalent among sexes in Quantitative Standard Monitoring of Patients with RA registry,[21] which was conducted in 6004 RA patients in 25 countries. In our study, we found that RF titer was significantly higher in male patients. The results were consistent with data from familial RA patients in the North American Rheumatoid Arthritis Consortium cohort.[22] In our patients with early RA, the RF titer was also higher in men, although the difference was not significant (P = 0.069). As RF is a well-accepted unfavorable prognostic factor, the results might indicate a worse prognosis in male patients with RA.

Sex impacts on RA presentation and progression were diversely reported in previous studies [Table 6]. In 1998, Weyand et al[23] reported a more aggressive disease appearance in men than in women, among 165 patients. Subsequently, the influence of sex on disease activity, radiographic progression, and patient-report outcome in patients with RA has been reported in numerous studies. Some studies have shown that men were unlikely to achieve point remission,[19] or had worse bone erosion.[6] More studies indicated that women had higher disease activity, worse patient-report outcome, or more rapid disease progression.[6,20,21,24] However, there were conflicting results among these reports, or even in the same report, when different disease parameters were studied. In addition, some investigators reported finding no significant difference between sexes in clinical, laboratory, or radiological findings.[5,25,26] According to the existing literature, there is no conclusion regarding the influence of sex on disease activity of RA. The diversity of results among the investigators was possibly due to multiple reasons, including different ethnic groups, different disease stages of patients, and different disease indices used. Moreover, menopause status was reported to be an important factor influencing disease activity. Post-meno-pausal women were revealed to have more active disease than men and pre-menopausal women.[23,25]

Table 6 - Previous reports of sex impacts on RA.
Author Country Number of patients (female%) Conclusions
Weyand et al [23] USA 165 (66.7) Men were correlated with a higher risk of bony erosions and an accelerated course of RA
Voulgari et al [5] Greece 38 (71.2) There was no significant difference between sexes in clinical, laboratory, and radiological findings
Gossec et al [25] France 266 (50.0) No difference in clinical or radiological indicators was observed
Jawaheer et al [6] USA 292 (77.1) Men and women had similar disease activity and joint damage at baseline. Men had significantly worse erosion. Responses to treatment over time were better in male patients
Rintelen et al [10] Australia 557 (77.6) Female patients had significantly higher SDAI and CDAI level than males
Kuiper et al [26] Holland 332 (63.0) DAS was equivalent between sexes at study entry, but was significantly higher in females at follow-ups
Tengstrand et al [24] Sweden 8 (63.7) Women had higher DAS28 and HAQ scores at study entry and at 2-year follow-up. Men had a higher frequency of remission
Iikuni et al [20] Japan 823 (83.5) Women overall have higher RA disease activity and are prone to greater and faster progression of disability
Jawaheer et al [19] USA 10,299 (76.6) Women had more severe disease at baseline. Men were more likely to achieve sustained remission in early RA, but were unlikely to achieve point remission in established RA
Sokka et al [21] 25 countries 600 (79.2) Women had higher pain VAS, PtGA, DAS28, and HAQ scores
CDAI: Clinical disease activity index; DAS28:28-joint disease activity score; HAQ: Health Assessment Questionnaire; PtGA: Patient's global assessment; RA: Rheumatoid arthritis; SDAI: Simple disease activity index; VAS: Visual analogue scale.

In our large-scale registry of Chinese patients, the acute phase reactants, the PtGA/PhGAs, and the disease activity assessed by the composite indices were all higher in men than in women at baseline, both in patients with early RA and established RA. Fewer male patients were in remission or in a LDA state compared to females. The higher percentage of GC usage in men at baseline also demonstrated more active disease in male patients, as GC is the most frequently used medication for inflammation control and symptom relief. In our study, csDMARD monotherapy was more commonly used in male patients. We infer that this result was also because male patients had more active disease given that physicians tend to prescribe csDMARD monotherapies for patients with less severe disease. Taken together, these results indicated that male patients had higher disease activity. Furthermore, since patients with early RA were less affected by treatment or other factors and had comparable disease duration, the higher disease activity observed in male patients can reflect the original state of the disease to a large extent.

At follow-up visits in our cohort, the differences in disease activity between men and women were diminished. Although there were still some differences in the proportions of remission and LDA, statistical significance was only observed in a minority of the indices. These alterations can be interpreted as the impact of the treatment. After effective treatment for RA, the disease activity was lowered in men, so that the disparity of their baseline disease activity with women was diminished to some extent. There were some conflicting results between data of all patients and patients with early RA, especially in remission or LDA achievement defined by DAS28. We considered that the early RA data, which was much less influenced by treatment and other factors, were more reliable for this issue. Moreover, in clinical practice, CDAI is considered to be a more suitable and reliable disease activity index than DAS28; therefore, we believe that remission or LDA achievement defined by CDAI was more important in our real-world cohort. More long-term follow-up data are needed to demonstrate the differences in prognosis between men and women.

ILD is an important complication of RA and usually occurs in patients with long disease duration and inadequately controlled RA.[27] In our study, the prevalence of ILD was higher in male patients, which was consistent with the results of other investigators.[28,29] In early RA, given that the disease duration was too short to develop ILD, the ratios of ILD were low and showed no significant difference between sexes. It is widely accepted that the risks of cardiovascular disease and cerebrovascular disease are increased in patients with RA. In the general population, men are known to be at a higher risk of cardiovascular and cerebrovascular diseases than women. In patients with RA, the relative risk of cardiovascular disease was found to be equally increased for men and women in a meta-analysis including 13 studies.[30] Therefore, the higher percentages of CAD and stroke in males observed in our registry were quite reasonable.

The present study has some limitations. First, the CREDIT cohort has only been established for 5 years, and a number of patients were recently recruited. Thus, the long-term follow-up data regarding the outcomes of RA were insufficient. Second, radiological information and health assessment questionnaire were not collected in this study, so the differences in joint damage and patient-report outcomes between men and women could not be well assessed. Third, fibromyalgia and osteoporosis, 2 important comorbidities of RA, were not recorded. The above unresolved questions remain to be answered in future studies with the development of the CREDIT cohort.

In conclusion, we conducted a large-scale study on the influence of sex on clinical characteristics of Chinese patients with RA. At baseline, male patients were found to have more active RA and a lower proportion of treatment target achievement than female patients. During the 1 year of follow-up, the differences in the percentages of LDA and remission between men and women were diminished to some extent. Male patients had more CAD and stroke than female patients. The results of our study suggest that the more active RA in men should call our attention and be intensively managed, and physicians should pay attention to the prevention and management of cardiovascular diseases in male patients with RA.

Acknowledgments

We acknowledge the contributions from all CREDIT centers all over China and HealthCloud Co., Ltd. as the system provider.

Funding

The work was supported by grants from the Chinese National Key Technology R&D Program, Ministry of Science and Technology (Nos. 2017YFC0907601, 2017YFC0907602, and 2017YFC0907603); the Beijing Municipal Science and Technology Commission (Nos. Z201100005520022, 23, and 25–27); and the CAMS Innovation Fund for Medical Sciences (CIFMS) (No. 2021-I2M-1-005).

Conflicts of interest

None.

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Keywords:

Rheumatoid arthritis; Sex; Disease activity; Treatment target; Comorbidities

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