Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by persistent synovitis and multisystem involvement. Early intervention during the “window of opportunity” is critical for preventing irreversible joint damage. Over the past two decades, numerous studies have confirmed the correlation between “timing of intervention” and “treatment efficacy.” However, existing research mostly adopts a binary comparison design of “early stage” versus “late stage,” or treats symptom duration as a continuous variable. Additionally, most studies default to the assumption that “each additional unit of time is accompanied by an equal increase in the degree of disease harm,” overlooking the potential “differences in treatment response mechanisms” across different stages of the disease course. More critically, there remains controversy regarding the specific duration of the RA treatment “window of opportunity.” A 1991 study proposed that the window lasts for 2 years following symptom onset, while more recent studies have suggested it may be limited to the first 3 months or 12 months after symptom onset, based on emerging clinical evidence.1, 2 Meanwhile, data from existing cohorts show that when symptom duration reaches approximately 15–20 weeks, the slope of the “relationship curve between log-HR (logarithmic hazard ratio for remission risk) and symptom duration” begins to decrease significantly.3 This phenomenon suggests that the likelihood of achieving clinical remission decreases markedly beyond this point, indicating that the “treatment window of opportunity” may start to close gradually. Against this backdrop, the Chinese Association of Women in Rheumatology and Immunology has led a national multicenter cross-sectional study. The study aims to systematically compare disease activity, joint involvement characteristics, comorbidity distribution, and initial medication regimens between patients with very early RA (VERA, symptom duration ≤ 3 months)4 and early RA (ERA, symptom duration ≤12 months).2 Furthermore, it intends to analyze differences in clinical characteristics across different stages of RA, thereby providing data to optimize clinical decision-making regarding the “treatment window of opportunity.” This study enrolled participants from 330 centers in China between July and September 2023 (Supporting Information: Table S1). Inclusion criteria for both groups were: fulfillment of 1987 American College of Rheumatology (ACR) classification criteria or 2010 ACR/European Alliance of Associations for Rheumatology RA classification criteria and age ≥18 years. Exclusion criteria included: presence of severe cognitive impairment, or missing key questionnaire data for more than 10%. The collected parameters included: demographic characteristics (sex, age), disease duration, self-rated health status (0–100) (visual analog scale VAS), patient global assessment (0–100 VAS), fatigue score (0–100 VAS), and physician-reported measures: tender joint count-28, swollen joint count-28, physician global assessment (0–100 VAS), and current medications, categorized as, non-steroidal anti-inflammatory drugs, glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological disease-modifying antirheumatic drugs (bDMARDs), and targeted synthetic biological disease-modifying antirheumatic drugs (tsDMARDs). Disease activity was evaluated by the Clinical Disease Activity Index (CDAI). Comorbidity data were initially collected via patient self-report using structured questionnaires (Supporting Information: Supplementary Materials 2, Survey Questionnaire); physicians conducted secondary verification of the reported information to ensure accuracy, safeguarding data reliability and precluding ambiguities in sourcing that might compromise interpretation. The final analytical sample included 3314 ERA patients, 706 comprised the low-activity group (CDAI ≤ 10, combining remission CDAI ≤ 2.8 and low disease activity 2.8 10). The VERA cohort included 852 patients, with 176 in the low-activity group and 676 in the moderate-to-high activity group. Female predominance was more pronounced in the low-activity group (CDAI ≤ 10) than in the moderate-to-high activity group (CDAI > 10) among ERA patients (86.69% vs. 78.90%; OR = 0.56, 95% CI: 0.45–0.71, p 0.05) (Table 1). In both groups, approximately half of the patients were treated with methotrexate. In the ERA group, moderate-to-high activity patients had higher usage of GCs (42.22% vs. 32.72%, OR = 1.50, p < 0.001), iguratimod (35.31% vs. 24.65%, OR = 1.65, p < 0.001), leflunomide (25.27% vs. 17.85%, OR = 1.56, p < 0.001), tumor necrosis factor-α monoclonal antibodies (OR = 1.41, p = 0.037), and abatacept (OR = 4.37, p = 0.009). Low-activity patients had a higher usage of hydroxychloroquine (29.18% vs. 20.90%, OR = 0.64, p < 0.001). In VERA, moderate-to-high activity patients were more likely to use leflunomide (20.27% vs. 11.93%, OR = 1.87, p = 0.009), while no significant differences were observed in GCs or iguratimod usage (p = 0.341 and p = 0.303, respectively) (Table 1). The data indicate that females constitute a higher proportion of the low-activity group in both cohorts. This aligns with established epidemiological patterns in RA; a Chinese study showed females have a 5.75-fold higher RA prevalence than males (0.46% vs. 0.08%),5 and international data report a 2-4:1 female-to-male ratio. This sex distribution likely reflects differences in healthcare-seeking behavior: females tend to seek early medical care more promptly (due to greater sensitivity to symptoms like joint pain/morning stiffness), whereas males often delay. As such, our sample is representative of “early RA in specialist settings” (rather than the general population) and retains clinical relevance. Previous studies have primarily focused on the relationship between disease onset age and joint damage; our data further show that diabetes is one of the common comorbidities for moderate-to-high disease activity in both VERA and ERA patients. Hypertension and obesity were particularly significant in the ERA group. Our findings align with prior reports that highlight the pro-inflammatory effects of metabolic syndrome in RA patients, but we extend these findings to the very early stages of the disease. This suggests that metabolic dysregulation may contribute to the initiation of RA. Moreover, the cumulative effect of comorbidities, like obesity and hypertension may influence RA disease activity, with these effects becoming more pronounced in ERA patients due to longer disease duration. These results underscore the importance of screening for metabolic syndrome, especially diabetes, during the early phases of RA to optimize disease management. The cross-sectional design limits causal inference between metabolic comorbidities and disease activity, and fails to track comorbidity evolution from VERA to ERA. Future prospective longitudinal studies with extended follow-up periods, using generalized estimating equations, are needed to validate these stage-specific patterns. In conclusion, by moving beyond a simple early-late dichotomy, our findings reveal that the VERA (≤3 months) and ERA (≤12 months) phases are characterized by distinct, stage-specific clinical profiles, including features, comorbidities, and medication choices. These stage-specific profiles may provide insight for stratified management strategies within the critical window of opportunity, paving the way for more precise and timely interventions in RA. Yin Su conceived and designed the study and is responsible for the overall content as the guarantor. Liyun Zhang, Yuehong Huo, Rui Wu, Lijun Wu, Ling Lei, Linyu Geng, Chunyu Tan, Xiaomei Li, Ru Li, and Yin Su participated in data collection. Haojie Xu performed the statistical analysis and wrote the manuscript. All authors contributed to data analysis, manuscript revision, and read and approved the submitted version. The study was supported by grants from the National Natural Science Foundation of China (92374101, 82230121) and Beijing Science and Technology Planning Project (Z191100006619111) to Prof. Yin Su. This work was conducted under the framework of the Women's Rheumatoid Arthritis Research Collaborative Group established by the Chinese Association of Women in Rheumatology and Immunology. We sincerely appreciate the experts who participated in the compilation and discussion of the survey report. They are listed by their affiliated hospitals as follows: Liling Xu and Yuan Jia (Department of Rheumatology and Immunology, Peking University People's Hospital); Wen Zhang and Wenjie Zheng (Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences Lie Dai (Department of Rheumatology and Immunology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University); Quan Jiang (Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences); Jin Lin (Department of Rheumatology, The First Affiliated Hospital, Zhejiang University School of Medicine); Rong Mu (Department of Rheumatology and Immunology, Peking University Third Hospital); and Miaojia Zhang (Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University). The authors declare no conflicts of interest. The study was approved by the Institutional Review Board of Peking University People's Hospital (Approval Number: 2023PHB048-001), with written informed consent obtained from all participants. During the preparation of this work, the authors used ChatGPT 4o to polish the language of this Article. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. All applicants are asked to sign a data access agreement. Please send any requests to the principal investigator of this study. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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