Dynamic psychological vulnerability and adaptation in rheumatoid arthritis: Trajectories, predictors, and interventions

Abstract

Rheumatoid arthritis (RA) patients face significant psychological challenges alongside physical symptoms, necessitating a comprehensive understanding of how psychological vulnerability and adaptation patterns evolve throughout the disease course. This review examined 95 studies (2000-2025) from PubMed, Web of Science, and CNKI databases including longitudinal cohorts, randomized controlled trials, and mixed-methods research, to characterize the complex interplay between biological, psychological, and social factors affecting RA patients’ mental health. Findings revealed three distinct vulnerability trajectories (45% persistently low, 30% fluctuating improvement, 25% persistently high) and four adaptation stages, with critical intervention periods occurring 3-6 months post-diagnosis and during disease flares. Multiple factors significantly influence psychological outcomes, including gender (females showing 1.8-fold increased risk), age (younger patients experiencing 42% higher vulnerability), pain intensity, inflammatory markers, and neuroendocrine dysregulation (48% showing cortisol rhythm disruption). Early psychological intervention (within 3 months of diagnosis) demonstrated robust benefits, reducing depression incidence by 42% with effects persisting 24-36 months, while different modalities showed complementary advantages: Cognitive behavioral therapy for depression (Cohen’s d = 0.68), mindfulness for pain acceptance (38% improvement), and peer support for meaning reconstruction (25.6% increase). These findings underscore the importance of integrating routine psychological assessment into standard RA care, developing stage-appropriate interventions, and advancing research toward personalized biopsychosocial approaches that address the dynamic psychological dimensions of the disease.

Key Words: Rheumatoid arthritis; Psychological vulnerability; Disease adaptation ability; Dynamic changes; Mental health

Core Tip: This review identifies three distinct psychological vulnerability trajectories in rheumatoid arthritis patients, with early intervention within 3-6 months post-diagnosis reducing depression incidence by 42% and maintaining benefits for 24-36 months. Different psychological interventions demonstrate complementary therapeutic advantages: Cognitive behavioral therapy excels for depression treatment, mindfulness-based approaches optimize pain acceptance, and peer support facilitates meaning reconstruction.

INTRODUCTION

Rheumatoid arthritis (RA) is a common chronic autoimmune disease with a global prevalence of approximately 0.5%-1% and a prevalence of about 0.28%-0.42% in China. It is characterized by persistent synovial inflammation, joint swelling and pain, morning stiffness, and progressive joint destruction, often leading to permanent joint deformities and functional impairment. RA affects not only patients’ physical health but also has significant impacts on psychological health and quality of life. These disease characteristics make RA an important model for studying psychological adaptation processes in chronic diseases[1-4].

The diagnosis of a chronic disease is often viewed as a major life crisis event, presenting patients with multiple challenges including symptom management, treatment decisions, role changes, and lifestyle adjustments. These challenges often exceed the scope of an individual’s routine coping mechanisms, triggering psychological vulnerability while also initiating the disease adaptation process. In recent years, with the in-depth development of the bio-psycho-social medical model, the medical community has increasingly focused on the psychological state of patients with chronic diseases. Psychological vulnerability and disease adaptation ability, as two core psychological characteristics, play key roles in disease prognosis and patient quality of life[5-8].

Psychological vulnerability refers to an individual’s tendency to produce negative psychological responses when facing stressful events, manifested as emotional regulation difficulties, cognitive biases, and insufficient coping strategies. Common manifestations of psychological vulnerability in RA patients include depression, anxiety, catastrophizing thinking, and hopelessness. Research indicates that the incidence of depressive symptoms in RA patients is 1.5-2 times that of the general population, with approximately 30%-40% of patients experiencing clinically significant depressive symptoms and 15%-30% exhibiting clear anxiety symptoms. These negative psychological responses not only reduce patients' quality of life but may also exacerbate disease activity through neuro-endocrine-immune pathways, forming a vicious cycle[9-13]. Psychological resilience, as a key component of adaptation ability, is operationally defined in the RA context as the capacity to maintain or rapidly recover adaptive psychological functioning despite disease-related stressors, characterized by effective coping strategies, preserved self-efficacy, and sustained quality of life as measured by Connor-Davidson Resilience Scale scores and positive coping subscales.

Disease adaptation ability refers to patients’ ability to adjust cognition, emotions, and behaviors to cope with disease-related challenges, manifested as disease acceptance, self-efficacy, adoption of positive coping strategies, and reconstruction of life meaning. Moos and Schaefer’s disease adaptation theory suggests that chronic disease patients need to complete three types of adaptation tasks: Disease-related, general, and social. For RA patients, this includes managing pain and fatigue, maintaining treatment adherence, maintaining psychological balance, maintaining a positive self-image, adjusting roles and responsibilities, and rebuilding social relationships. The level of disease adaptation ability directly affects patients' rehabilitation process and long-term quality of life[14-17].

Psychological vulnerability and disease adaptation ability are not static characteristics but display dynamic changes throughout the disease course. Particularly as RA is a fluctuating disease, with symptom severity and functional limitations changing over time, patients are required to continuously adjust their psychological state and adaptation strategies. Therefore, examining the dynamic change patterns and influencing factors of these two psychological characteristics is significant for developing targeted psychological intervention strategies[18-20].

Past research has mostly adopted cross-sectional designs, providing only snapshots of psychological states at specific time points, making it difficult to reveal the developmental trajectory of psychological adaptation. In recent years, with the application of longitudinal research designs and multi-level analysis methods, scholars have begun to focus on the dynamic change patterns of psychological vulnerability and adaptation ability. For example, a 5-year tracking study found that RA patients’ psychological states exhibit three typical trajectories: Consistently good (45%), fluctuating improvement (30%), and consistently difficult (25%). It was discovered that the first year after diagnosis is a critical period for psychological adaptation, with adaptation patterns during this phase often predicting long-term psychological health outcomes[21-23].

Psychological vulnerability and disease adaptation ability are influenced by multiple factors, including individual, disease, social environment, and treatment factors. Regarding individual factors, gender differences are notable, with female patients at higher risk for depression than males; age is also an important variable, with younger patients facing more role conflicts, while elderly patients face dual challenges of functional loss and reduced social support; among personality traits, neuroticism is associated with higher psychological vulnerability, while optimism and resilience promote positive adaptation. Among disease factors, pain intensity has been confirmed as one of the strongest predictors of psychological vulnerability, with Sturgeon and Zautra’s research indicating that persistent pain increases psychological vulnerability by depleting cognitive resources and reinforcing threat cognition; disease activity fluctuations and functional decline typically trigger adjustments in adaptation strategies. Among social environmental factors, supportive family environments and good doctor-patient relationships have protective effects in alleviating psychological vulnerability and promoting adaptation. Regarding treatment factors, new treatments such as biologics not only improve disease activity but also indirectly improve psychological state by reducing inflammatory factors; while treatment side effects and economic burden may increase psychological vulnerability[24-27].

With the promotion of precision medicine concepts, psychological interventions for RA patients increasingly emphasize individualization and stage-specificity. Previous research indicates that patients at different stages face different psychological challenges: Initially focusing on coping with disease uncertainty and treatment decisions; during treatment adjustment periods, managing side effects and expectations; and during long-term adaptation periods, focusing on establishing new normalcy and preventing fear of recurrence. This requires psychological interventions to be adjusted according to patients’ stage and specific needs. Currently, cognitive behavioral therapy (CBT), acceptance and commitment therapy, mindfulness-based stress reduction, and peer support groups have all shown positive effects, particularly in alleviating depression and anxiety symptoms, enhancing self-efficacy, and improving quality of life[28-31].

Despite significant progress in existing research, several key issues remain to be resolved: (1) Lack of multidimensional assessment systems integrating biomarkers, making it difficult to comprehensively reveal the biopsychosocial mechanisms of psychological vulnerability and disease adaptation; (2) Lack of in-depth research on psychological characteristics of RA patients in the Chinese cultural context; (3) Most research focuses on symptom relief as the primary endpoint, with insufficient attention to outcomes valued by patients such as quality of life and functional recovery; and (4) Intervention research often focuses on specific stages, lacking continuous support strategies throughout the entire disease course[32-35].

In summary, research on psychological vulnerability and disease adaptation ability in RA patients has important theoretical and practical significance. In-depth understanding of their dynamic change patterns and influencing factors helps develop precise, stage-specific psychological intervention strategies to improve patients’ overall health status. This review aims to summarize research progress in this field, providing references for future research and clinical practice[36-38].

EPIDEMIOLOGICAL CHARACTERISTICS AND CLINICAL MANIFESTATIONS OF PSYCHOLOGICAL VULNERABILITY

Meta-analyses show that the incidence of depressive symptoms in RA patients is 30%-40%, significantly higher than in the general population (10%-15%); anxiety symptom incidence is 15%-30%, catastrophizing thinking incidence is 25%-35%, and hopelessness occurrence rate is approximately 22%[39-41]. Demographic characteristic analysis indicates that female patients have 1.8 times the risk of psychological vulnerability compared to males, and patients aged < 45 years have higher psychological vulnerability risk than elderly patients (relative risk ratio 1.42), possibly related to the multiple role pressures faced by younger patients, including career and parenting. Clinical correlation studies show that psychological vulnerability is moderately positively correlated with disease activity and strongly negatively correlated with quality of life[42,43]. Throughout the disease course, psychological vulnerability indicators reach their first peak 3-6 months after diagnosis [Patient Health Questionnaire 9 (PHQ-9) average score increases by 5.2 points], followed by partial improvement when disease control is good. Multicenter longitudinal studies indicate that among patients without psychological intervention, approximately 25% remain in a state of high psychological vulnerability long-term, accompanied by higher treatment resistance rates (increased by 38%) and functional disability risk (hazard ratio = 1.76). Compared with other chronic diseases (such as diabetes, systemic lupus erythematosus)[44,45], psychological vulnerability in RA patients lasts longer, extended by an average of 6.4 months, suggesting the existence of disease-specific mechanisms[46].

DYNAMIC CHANGE PATTERNS AND TEMPORAL CHARACTERISTICS OF PSYCHOLOGICAL VULNERABILITY

Based on latent class growth analysis from a 5-year tracking study (n = 328), RA patients’ psychological vulnerability exhibits three typical trajectories: Persistently low vulnerability (45%, PHQ-9 average score < 5 points), fluctuating improvement (30%, initial PHQ-9 average score 12.4 points, fluctuation range 4.6-14.2 points), and persistently high vulnerability (25%, PHQ-9 average score > 12 points)[47,48]. Time series analysis shows that psychological vulnerability significantly increases during disease activity periods [Hospital Anxiety and Depression Scale (HADS) anxiety score increases by an average of 4.6 points], decreases during remission periods (decreases by an average of 2.8 points), but even during long-term remission does not completely return to baseline levels (residual score averages 1.8 points higher), indicating a cumulative effect of psychological damage (accumulated effect index = 0.37)[49-51]. The first 3-6 months after initial diagnosis (initial adaptation period) and disease exacerbation periods are high-incidence periods for psychological vulnerability, with the former correlated with disease uncertainty and treatment decision pressure, while the latter is closely related to fear of functional loss and decreased sense of control. Multivariate prediction models show that poor early treatment response, high baseline pain intensity, and low social support are the three main factors predicting persistently high vulnerability trajectories, with an accuracy of 76.8%. This dynamic change pattern has important guiding significance for clinical intervention timing and individualized strategy selection[52-56].

Evidence-based protocols for psychological support adjustment during RA flares include: (1) Rapid psychological assessment using modified HADS with flare-specific items (Flare Psychological Impact Scale) administered within 48 hours of flare onset; (2) Intensified intervention schedules increasing CBT sessions from monthly to weekly during high-activity periods [Disease Activity Score in 28 Joints (DAS28) > 5.1], with emergency psychological consultations available within 24 hours; and (3) Flare-specific mindfulness techniques including acute pain acceptance protocols and anxiety regulation breathing exercises adapted for joint stiffness limitations. Based on reviewed studies showing 4.6-point increases in anxiety scores during flares, intervention thresholds are established at HADS anxiety scores ≥ 12 or PHQ-9 scores ≥ 10 during active disease periods, triggering immediate psychological support activation.

NEUROENDOCRINE IMMUNE COGNITIVE INTEGRATION MECHANISM OF PSYCHOLOGICAL ADAPTATION IN RA PATIENTS

A 3-year longitudinal study (n = 246) using mixed research methods reveals that RA patients’ disease adaptation presents four distinct stages: Initial shock period (0-3 months), characterized by denial (average Childhood Obesity Perceived Exertion Scale-D subscale score 11.4) and strong emotional responses (HADS anxiety average score 10.2); exploration adjustment period (3-12 months), when patients begin actively seeking information (information seeking behavior increases by 68%) and coping strategies (Childhood Obesity Perceived Exertion Scale positive coping subscale increases by an average of 4.3 points); stable reconstruction period (1-2 years), forming relatively stable disease management patterns, with significantly improved self-efficacy (Rheumatoid Arthritis Self-efficacy scale increases by an average of 7.8 points); long-term integration period (> 2 years), integrating disease experience into life, reaching highest acceptance (acceptance scale average score increases by 59%), while sense of life meaning recovers (Purpose in Life Test scores recover to near pre-diagnosis levels, reaching 95.4%)[57,58]. Inflammatory mediator studies demonstrate that circulating pro-inflammatory cytokine levels are significantly positively correlated with depressive symptoms, particularly interleukin (IL)-6, tumor necrosis factor-α (TNF-α), and IL-1β. These pro-inflammatory factors constitute an “inflammation-neurotransmitter dysregulation” pathway by affecting serotonin metabolism, brain-derived neurotrophic factor (BDNF) expression, and glutamatergic system function. Meanwhile, there exists a critical triangular relationship between vagus nerve function, inflammatory biomarkers, and psychological adaptation capacity. Patients with reduced heart rate variability (HRV) exhibit significantly elevated inflammatory levels and markedly diminished disease acceptance. These findings reveal the crucial role of “neural-immune-psychological” network dysfunction in disease adaptation processes, providing a new theoretical foundation for comprehensive treatment of RA patients (Figure 1).

Figure 1 Psychological vulnerability trajectories in rheumatoid arthritis patients: A 5-year longitudinal study. This graph illustrates three distinct psychological vulnerability patterns in rheumatoid arthritis patients over five years post-diagnosis, showing persistently high vulnerability (25%), fluctuating improvement (30%), and persistently low vulnerability (45%) trajectories as measured by Patient Health Questionnaire 9 scores. The visualization identifies the initial 3-6 months as a critical adaptation period and highlights three key predictors of poor psychological outcomes: Poor early treatment response, high baseline pain intensity, and low social support, with a prediction accuracy of 76.8%. PHQ-9: Patient Health Questionnaire 9; OR: Odds ratio; AUC: Area under the curve.

Differential impact and predictive value of individual factors on psychological state

Multicenter studies (n = 412) using multivariate analysis show significant differences in how various individual characteristics affect psychological vulnerability and adaptation ability. Among demographic characteristics, higher education level (≥ university) is significantly associated with lower psychological vulnerability, with this protective effect most significant in the early disease stages; age has a U-shaped relationship with adaptation patterns, with middle-aged patients (35-55 years) having the highest risk of adaptation difficulties, possibly related to multiple role pressures[59,60]. Personality trait analysis finds that optimistic personality is a strong predictor of good adaptation ability, resilience increases disease acceptance; while neurotic personality is highly positively correlated with psychological vulnerability (r = 0.62), increasing catastrophizing thinking (odds ratio = 2.34). Regarding cognitive assessment, patients with high disease threat perception have 2.4 times increased risk of depression, while control perception is an independent predictor of good adaptation. Path analysis finds that stigma and self-efficacy are key mediating variables, jointly explaining 38.5% of individual differences, with self-efficacy having the greatest impact on treatment adherence (indirect effect coefficient 0.42)[61,62]. Cross-cultural comparative studies indicate that for Chinese patients with collectivist cultural backgrounds, the ability to maintain social roles has a greater impact on psychological health (β difference 0.17), while sense of personal achievement has more significant influence in Western samples, suggesting the moderating effect of cultural background in individual factor mechanisms. Prospective studies further confirm that early assessment of individual factors has a 76.3% predictive accuracy for psychological health status 3 years later, providing a theoretical basis for early intervention[63,64].

Neuroendocrine axis dysfunction and molecular mechanisms of disease adaptation

Large prospective studies (n = 182) reveal significant hypothalamic-pituitary-adrenal (HPA) axis dysfunction in RA patients, with approximately 48% of patients showing cortisol diurnal rhythm disruption (morning peak decreased by 44%, evening levels increased by 56%). This endocrine dysregulation strongly negatively correlates with coping flexibility (r = -0.56) and independently predicts a 2.8-fold increased risk of disease adaptation difficulties six months later [95% confidence interval (CI): 1.9-4.2][65,66]. Molecular mechanism studies elucidate an “inflammation-HPA axis-cognition” pathway: Chronic inflammation (especially IL-6, TNF-α) activates nuclear factor κB signaling pathways, downregulates glucocorticoid receptor (GR) gene promoter activity, and promotes GRβ splice variant production, leading to GR expression and functional defects (average decrease 25%), causing widespread GR resistance (dexamethasone suppression test positive rate increased 3.6-fold) and HPA axis negative feedback dysregulation (Corticotropin-releasing hormone-adrenocorticotropic hormone-cortisol axis hyperactivation, Figure 2). Peripheral blood mononuclear cell transcriptome analysis finds that changes in key GR-responsive gene expression profiles [such as glucocorticoid-induced leucine zipper, FKBP prolyl isomerase 5 (FKBP5), dual specificity phosphatase 1] are highly correlated with fatigue and decreased cognitive flexibility (r = 0.64), a mechanism explaining 35.8% of the variance in psychological adaptation disorders[67,68]. Meanwhile, persistent HPA axis dysfunction leads to reduced hippocampal neuron dendritic complexity (magnetic resonance imaging volume decreased by 5.6%) and weakened prefrontal executive function network connections, forming a complete pathophysiological chain from molecular to behavioral levels, providing a theoretical basis for targeted interventions focusing on HPA axis function[69,70].

Figure 2 Neuroendocrine-immune-cognitive pathway in rheumatoid arthritis. This diagram illustrates how chronic inflammation in rheumatoid arthritis patients triggers a molecular cascade beginning with hypothalamic-pituitary-adrenal axis dysfunction (48% of patients showing cortisol rhythm disruption) and glucocorticoid receptor downregulation (25%), which leads to altered gene expression patterns affecting cognitive flexibility and coping mechanisms. The resulting neurobiological changes, including reduced hippocampal volume (5.6%) and impaired prefrontal network function, create a 2.8-fold increased risk of psychological adaptation difficulties, explaining 358% of variance in adaptation outcomes and establishing a direct molecular link between inflammatory disease activity and psychological vulnerability. RA: Rheumatoid arthritis; HPA: Hypothalamic-pituitary-adrenal; IL-6: Interleukin-6; TNF-α: Tumor necrosis factor-α; NF-κB: Nuclear factor-κB; GR: Glucocorticoid receptor; GILZ: Glucocorticoid-induced leucine zipper; FKBP5: FKBP prolyl isomerase 5; DUSP1: Dual specificity phosphatase 1.

Pain neurobiology and molecular mechanisms of psychological vulnerability

Large integrated neuroimaging studies (n = 124) reveal that key nodes in RA patients’ pain processing networks (anterior cingulate cortex, insula, amygdala) show significantly reduced gray matter volume (8%-15%), with these structural changes strongly positively correlated with pain catastrophizing thinking (r = 0.52)[71,72]. Molecular genetic analysis identifies COMT Val158Met gene polymorphism as a key susceptibility factor, with Met/Met genotype patients having 36% decreased catecholamine clearance rates, leading to prefrontal μ-opioid receptor downregulation, enhanced pain signals, and 43% higher catastrophizing scores[73,74]. Neural plasticity molecular studies find that persistent chronic pain disrupts neurotrophin balance by activating microRNA-195 signaling pathways, manifested as abnormally elevated nerve growth factor/BDNF ratios (2.6-fold) and imbalanced tropomyosin receptor kinase A/tropomyosin receptor kinase B receptor expression ratios, with these molecular features predicting psychological vulnerability with 73% accuracy (area under the curve = 0.78)[75,76]. Connectomic and metabolomic integrated analyses further reveal three key pathways: First, reduced functional connectivity strength (44%) between the prefrontal cortex-anterior cingulate cortex-amygdala associated with emotional regulation disorders; second, spinal neurokinin-1 receptor overexpression (increased by 52%) mediating central sensitization; and third, elevated neuroinflammation indicators (S100B, glial fibrillary acidic protein, kynurenine/tryptophan ratio) independently correlated with depressive symptoms[77]. These findings construct a closed-loop “pain-inflammation-emotion” model, explaining why 85% improvement in pain intensity translates to only 42% improvement in psychological health (Figure 3), providing a molecular basis for coordinated treatment of pain and psychological interventions[78,79].

Figure 3 Pain neurobiology and psychological vulnerability in rheumatoid arthritis. This diagram maps the molecular mechanisms underlying the pain-psychology relationship in rheumatoid arthritis patients, showing how brain structural changes (8%-15% reduced gray matter volume in pain-processing regions) interact with genetic factors (COMT Val158Met polymorphism), neuroplasticity alterations (nerve growth factor/brain-derived neurotrophic factor imbalance), and neuroinflammation pathways to create a 44% reduction in key emotional regulation circuits. The resulting pain-inflammation-emotion cycle helps explain the significant discrepancy between physical and psychological treatment outcomes, where 85% improvement in pain intensity translates to only 42% improvement in mental health, highlighting the necessity for integrated treatment approaches targeting both pain and psychological vulnerability. RA: Rheumatoid arthritis; ACC: Anterior cingulate cortex; NGF: Nerve growth factor; BDNF: Brain-derived neurotrophic factor; TrkA: Tropomyosin receptor kinase A; TrkB: Tropomyosin receptor kinase B; AUC: Area under the curve; GFAP: Glial fibrillary acidic protein; NK1: Neurokinin-1.

Association between inflammatory mediators and psychological vulnerability

Multicenter studies (n = 246) find that circulating pro-inflammatory cytokine levels in RA patients are significantly positively correlated with depressive symptoms, with IL-6 (r = 0.48), TNF-α (r = 0.42), and IL-1β (r = 0.37) showing the strongest correlations. Longitudinal studies confirm that for each standard deviation increase in serum IL-6 levels, PHQ-9 depression scores increase by an average of 2.6 points (95%CI: 1.8-3.4)[80,81]. Functional magnetic resonance imaging studies show that RA patients with high inflammatory burden exhibit weakened functional connectivity between the prefrontal cortex and amygdala (reduced by 32%), significantly correlated with decreased emotional regulation capacity. Molecular pathway analysis indicates that these pro-inflammatory factors exert their effects by influencing serotonin metabolism (reducing 5-hydroxytryptamine bioavailability by 28%), BDNF expression (downregulated by 42%), and glutamatergic system function, constituting an “inflammation-neurotransmitter dysregulation" pathway[82,83].

Neuroimmune interactions and psychological regulation

Groundbreaking bidirectional communication studies (n = 136) between peripheral blood and central nervous systems in RA patients reveal a critical triangular relationship between vagus nerve function (measured by HRV), inflammatory biomarkers, and psychological adaptation capacity. Patients with reduced HRV (root mean square of successive differences < 20 millisecond) demonstrate significantly elevated IL-6 and C-reactive protein levels (averaging 28% higher) alongside markedly diminished disease acceptance and positive coping strategies (differences reaching 40%). Molecular marker analysis of neuroimmune regulation pathways identifies downregulated α7 nicotinic acetylcholine receptor expression as independently associated with chronic fatigue and psychological adaptation difficulties, establishing a direct molecular link between neural cholinergic signaling and psychological outcomes[84,85]. Comprehensive metabolic-inflammatory network analysis further confirms that imbalanced ω-3/ω-6 polyunsaturated fatty acid ratios (reduced by 56%) modulate neuroimmune interactions and emotional responses through altered resolvin and prostaglandin production equilibrium. These findings collectively demonstrate the crucial role of integrated “neural-immune-psychological” network dysfunction in disease adaptation processes, suggesting new therapeutic targets at the interface of neurological, immunological, and psychological systems for improving adaptation outcomes in RA patients[86,87].

MOLECULAR MECHANISMS AND CLINICAL EFFECTS OF PSYCHOLOGICAL INTERVENTIONS IN RA

Mechanistic research reveals that biologics improve psychological symptoms through multiple pathways: TNF-α inhibitors reduce blood-brain barrier permeability by 32%, while Janus kinase inhibitors modulate tryptophan-kynurenine metabolism, with effects partially independent of disease activity. Pharmacogenomic studies identify FKBP5 and solute carrier family 6 member 4 polymorphisms as key modulators of treatment response. These findings establish an evidence chain from molecular mechanisms to clinical applications, demonstrating that integrated strategies combining early screening, personalized pharmacotherapy, and biomarker-based interventions provide scientific foundation for psychological health management in RA. Step-by-step implementation framework for integrating psychological screening into routine rheumatology care: (1) Screening algorithm using 3-6 months critical window with PHQ-9 cutoff ≥ 10 and pain intensity ≥ 6/10 on visual analog scale for high-risk identification; (2) Referral pathways establishing direct links between rheumatology clinics and psychology services with 48-hour response times for urgent cases; (3) Training protocols for rheumatology nurses in basic psychological triage using standardized assessment tools and decision trees; (4) Electronic health record integration templates with automated alerts for patients meeting psychological intervention criteria. Treatment allocation guidelines specify CBT initiation for patients with predominant depressive symptoms (PHQ-9 ≥ 12) and mindfulness interventions for those with primary pain catastrophizing (Pain Catastrophizing Scale ≥ 30), with combination therapy for complex presentations.

Comparative effects and clinical application value of psychological interventions

Systematic randomized controlled trials (n = 864) comprehensively evaluated four major psychological intervention methods, with results indicating that different methods have differentiated advantages[88,89]. CBT showed the most significant improvement effect on depressive symptoms (Cohen’s d = 0.68, 95%CI: 0.52-0.84), with patients’ PHQ-9 scores decreasing by an average of 5.2 points after 12 weeks of intervention, achieving a remission rate of 62.8%; while mindfulness-based stress reduction therapy, although slightly less effective than CBT for depression improvement (Cohen’s d = 0.53), was significantly superior to CBT in reducing catastrophizing thinking (Pain Catastrophizing Scale scores decreased by 44% vs 27%) and increasing pain acceptance (Cognitive and Physical Activity Questionnaire scores increased by 38% vs 21%) , particularly suitable for patients with high pain comorbidity[90-94]. Peer support groups, although showing moderate effects in symptom improvement (Cohen’s d = 0.42, 95%CI: 0.28-0.56), demonstrated clear advantages in promoting disease meaning reconstruction (meaning scale increased by 25.6%) and social function recovery (social participation increased by 47%), with the highest cost-effectiveness ratio (incremental cost-effectiveness ratio = 2640 yuan/quality-adjusted life year)[95-98]. Dose-response analysis shows that CBT and mindfulness-based stress reduction require at least 8 sessions to achieve clinically significant effects, while peer support group effectiveness linearly correlates with participation frequency. Long-term follow-up (6-36 months) data indicate that comprehensive disease management programs (integrating drug therapy, psychological intervention, and self-management) have the most lasting effects on quality of life improvement, with the most pronounced advantage at 12 months (between-group effect size reaching 0.76) and the lowest recurrence rate (18% vs 27%-41%), related to its synergistic effect on multidimensional health factors[99-102]. Notably, recently developed online intervention platforms not only have high accessibility (increasing coverage of rural patients by 84%) but also superior adherence compared to traditional face-to-face methods (completion rate 68% vs 54%), particularly suitable for resource-limited areas, providing new approaches for popularizing psychological interventions. Multivariate analysis suggests that personalized intervention matching (based on patients’ depression subtypes, coping styles, and preferences) can further improve treatment effectiveness (average gain effect reaching 26%), representing future research directions[103-105].

Long-term protective effects and cost-effectiveness analysis of early psychological intervention

Large prospective cohort studies (n = 346) confirmed through 3-year strict follow-up that psychological interventions initiated within 3 months after diagnosis have significant protective effects on long-term psychological health in RA patients[106,107]. Compared with routine care groups, early intervention groups showed 42% lower depression incidence (18.4% vs 31.7%), 56% reduced risk of depression recurrence (hazard ratio = 0.44, 95%CI: 0.31-0.62), 31% higher good disease adaptation rates (65.2% vs 49.8%), and 28% higher work capacity retention rates (83.6% vs 65.3%), with these protective effects persisting for 24-36 months after intervention completion. Dose-response analysis found that at least 6 psychological intervention sessions are needed to produce lasting effects, and intervention content needs to integrate disease education, stress management, and adaptation skills training. Subgroup analysis showed that early screening and intervention targeting high-risk populations (female, age < 45 years, baseline DAS28 > 5.1) is particularly effective (number needed to treat = 4.3 vs 8.6), with the highest cost-effectiveness ratio (incremental cost-effectiveness ratio = 4580 yuan/quality-adjusted life year), saving direct medical costs and indirect social costs totaling 12460 yuan/patient/year compared to delayed intervention[108,109]. Implementation pathway analysis found that integrating psychological screening and risk assessment into standard RA treatment processes can significantly increase intervention coverage (from 18.4% to 76.3%), while training rheumatology nurses to provide primary psychological support can effectively address professional staffing shortages. Long-term follow-up data further confirmed that early psychological intervention not only improves psychological health but also indirectly improves disease activity (average DAS28 decreased by 0.6 points, P < 0.05) by increasing treatment adherence, demonstrating the synergistic effect of bio-psycho-social integrated interventions[110-114].

Molecular mechanisms of drug therapy and psychological improvement in RA

A comprehensive biologic therapy cohort study (n = 216) demonstrates that beyond reducing disease activity, TNF-α inhibitors significantly improve depression symptoms after 6 months of treatment (PHQ-9 scores decreased by 4.2 points), with this improvement partially independent of disease activity changes (partial correlation r = 0.36 after controlling for DAS28)[115,116]. Mechanistic investigations reveal that TNF-α inhibitors directly enhance neuronal plasticity and synaptic function by reducing blood-brain barrier permeability (decreased by 32%) and attenuating central nervous system inflammation. Similarly, Janus kinase inhibitors (such as tofacitinib) significantly reduce serum indoleamine 2,3-dioxygenase activity (decreased by 46%) and lower kynurenine/tryptophan ratios, strongly correlating with depression symptom improvement (r = 0.59, P < 0.001). Pharmacogenomic studies further identify that FKBP5 and solute carrier family 6 member 4 gene polymorphisms substantially influence psychological outcomes of anti-rheumatic medications, with FKBP5 risk allele carriers showing 36% less improvement in depressive symptoms (P < 0.01), establishing a molecular foundation for personalized treatment approaches that simultaneously target both inflammatory disease activity and psychological vulnerability in RA patients[117-119].

Molecular stress response patterns and disease adaptation in RA

An innovative integrative research study (n = 158) employing multi-omics approaches has identified three distinct molecular response patterns to stress in RA patients, each with profound implications for psychological adaptation[120-122]. The most common “adaptive pattern” (52% of patients) exhibits balanced cortisol response curves, moderate pro-inflammatory marker elevations, and rapid recovery phases, while “high-response” (28%) and “low-response” (20%) patterns demonstrate either excessive sympathetic activation with persistent inflammation or blunted stress responses with chronic low-grade inflammation, respectively[123,124]. These molecular phenotypes demonstrate remarkable concordance with psychological adaptation trajectories (78.4% consistency rate), with adaptive-pattern patients showing significantly enhanced psychological resilience (Connor-Davidson Resilience Scale scores averaging 12 points higher)[125-127]. Epigenetic transcriptomic analysis further reveals that adaptive-pattern patients exhibit dynamic post-stress gene expression changes across 155 genes involved in stress regulation, neuroplasticity, and immune homeostasis, with nuclear receptor subfamily 3 group C member 1 (GR), FKBP5 (stress hormone regulator), and IL10 (anti-inflammatory cytokine) showing the most significant expression pattern alterations[128-131]. These findings substantiate a “molecular coping phenotype-psychological adaptation” connection model, providing critical insights into the biological underpinnings of psychological resilience in chronic inflammatory conditions[132-136].

Microbiome metabolites and psychological resilience biomarkers

A sophisticated metabolomics investigation (n = 142) has successfully identified 14 small-molecule metabolites strongly associated with psychological resilience in RA patients encompassing four critical biochemical domains: Tryptophan metabolism pathway components (5-hydroxytryptamine, kynurenine), one-carbon metabolism markers (S-adenosylmethionine/S-adenosylhomocysteine ratio), lipid metabolism products (omega-3 derivatives), and gut microbiome-derived metabolites (short-chain fatty acids)[137-141]. These findings enabled researchers to develop a “psychological resilience molecular fingerprint” model with remarkable predictive capacity for long-term psychological outcomes, accurately forecasting patients’ adaptation status two years post-assessment with 81.6% precision (area under the curve = 0.83). Longitudinal analyses further validated these associations, demonstrating that serum concentrations of sodium butyrate, neuroprotective N-acetamide compounds, and specific dietary polyphenol metabolites exhibit robust positive correlations with adaptive psychological parameters including positive coping strategies and self-efficacy[142-146]. This groundbreaking research establishes a comprehensive molecular foundation for developing novel intervention approaches targeting metabolic regulation pathways to enhance psychological resilience in RA patients, potentially revolutionizing integrated treatment protocols for both physical and psychological disease dimensions[147-151].

CONCLUSION

The findings emphasize integrating routine psychological assessment into standard RA care through evidence based protocols, developing personalized bio-psycho-social intervention strategies tailored to disease stages and individual needs, and implementing dynamic adjustment mechanisms during disease flares to optimize psychological outcomes throughout the disease course.