Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by persistent synovial inflammation, progressive joint destruction, and significant functional disability. It affects approximately 0.24% of the global population and remains one of the most common causes of chronic inflammatory arthritis worldwide [1, 2]. RA predominantly affects women and often manifests during the most productive years of adulthood, resulting in substantial personal, societal, and economic burden due to work disability, reduced quality of life, and increased healthcare utilization [3, 4]. The pathological hallmark of RA is chronic synovitis, driven by complex interactions between innate and adaptive immune mechanisms. Persistent activation of immune cells within the synovial membrane leads to synovial hyperplasia, pannus formation, cartilage degradation, and bone erosion, ultimately resulting in irreversible joint damage if inflammation is not adequately controlled [5, 6]. In addition to articular involvement, RA is associated with a wide range of extra-articular manifestations, including cardiovascular disease, pulmonary involvement, anemia, and metabolic disturbances, all of which contribute to increased morbidity and premature mortality [7-9]. Over the past two decades, the management of RA has undergone a major paradigm shift with the advent of conventional disease-modifying antirheumatic drugs (DMARDs), biologic agents, and targeted synthetic therapies. Central to contemporary RA management is the “treat-to-target” strategy, which emphasizes regular assessment of disease activity and timely modification of therapy to achieve predefined goals such as remission or low disease activity [10, 11]. Accurate and sensitive assessment of inflammatory activity is therefore critical to guide therapeutic decisions, prevent structural damage, and optimize long-term outcomes. Disease activity in RA is heterogeneous and dynamic, fluctuating over time and varying widely among individuals. No single clinical feature or laboratory parameter adequately reflects the full spectrum of inflammatory activity in RA. Consequently, composite disease activity indices have been developed to provide a standardized and comprehensive assessment. Widely used indices include the Disease Activity Score in 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), which integrate joint counts, patient- and physician-reported global assessments, and laboratory markers of inflammation [12-14]. Although these indices are invaluable in routine practice, discordance between clinical scores, laboratory parameters, and underlying synovial inflammation is frequently observed. Acute phase reactants (APRs) play a central role in the assessment of systemic inflammation in RA. These proteins are synthesized predominantly by hepatocytes in response to inflammatory cytokines, particularly interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β [15]. Among APRs, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are the most commonly used markers in clinical practice and are incorporated into composite disease activity indices. However, both markers have inherent limitations: ESR is influenced by age, sex, anemia, and plasma protein composition, while CRP may remain normal in a subset of patients with active synovitis, particularly in early disease or during targeted biologic therapy [16-18]. In addition to ESR and CRP, several other APRs have been proposed as potential biomarkers of disease activity in RA. Fibrinogen, a key coagulation factor, contributes to erythrocyte aggregation and increases during systemic inflammation [19]. Ferritin, an intracellular iron storage protein, may be elevated in inflammatory states and reflects macrophage activation and altered iron metabolism [20]. Serum amyloid-associated protein (SAA) is a highly sensitive acute phase protein that rises rapidly during inflammation and has been implicated in chronic inflammatory processes and secondary amyloidosis [21]. Hepcidin, a peptide hormone regulating iron homeostasis, is induced by inflammatory cytokines and plays a central role in anemia of chronic disease, a frequent complication of RA [22]. Haptoglobin, another positive acute phase protein, functions as a hemoglobin-binding protein and has been reported to increase during inflammatory and autoimmune conditions [23]. Despite growing interest in these markers, their relationship with synovial inflammation and their utility in routine disease activity assessment remain incompletely understood. Musculoskeletal ultrasound has emerged as an important adjunct to clinical examination in RA. In particular, power Doppler ultrasound (PDUS) allows sensitive detection of synovial vascularity, which reflects active inflammatory hyperemia within the synovial tissue [24, 25]. PDUS has been shown to detect subclinical synovitis, predict radiographic progression, and identify patients at risk of disease flare, even among those who fulfill clinical remission criteria [26-28]. As such, PDUS provides a valuable imaging-based assessment of true inflammatory activity that may not be fully captured by clinical scores or laboratory markers. However, PDUS is not universally available and is limited by cost, equipment, and operator expertise, particularly in resource-constrained settings. Consequently, identifying laboratory markers that correlate reliably with PDUS-detected synovitis could provide practical surrogate indicators of imaging-based disease activity. Several studies have evaluated the relationship between conventional APRs and ultrasound findings, with variable results, and data on newer APRs remain sparse [29, 30]. Importantly, most existing studies have focused on one or two APRs in isolation, primarily ESR and CRP, with limited comparative evaluation of multiple APRs within the same patient population. Furthermore, data from Indian cohorts are limited, despite potential differences in genetic background, disease phenotype, environmental exposures, and healthcare access that may influence inflammatory profiles and disease expression [31]. Given these gaps in knowledge, a systematic evaluation of a comprehensive panel of acute phase reactants in relation to PDUS-detected synovial inflammation is warranted. Such an approach may help clarify the relative utility of conventional and novel APRs, identify markers that best reflect true inflammatory activity, and improve the interpretation of laboratory results in routine clinical practice. The present study was therefore designed to evaluate the correlation between multiple acute phase reactants—including ESR, CRP, fibrinogen, ferritin, serum amyloid-associated protein, hepcidin, and haptoglobin—and synovial inflammation assessed using a standardized 7-joint power Doppler ultrasound score in patients with rheumatoid arthritis. By integrating laboratory markers with imaging-based assessment, this study aims to provide clinically relevant data from an Indian population and to inform the optimal use of inflammatory biomarkers for assessing disease activity in RA.

Study Design and Setting This cross-sectional observational study was conducted at a tertiary care rheumatology centre in India between September 2018 and March 2020. The study was designed to evaluate the relationship between acute phase reactants (APRs), composite disease activity indices, and power Doppler ultrasound (PDUS)-detected synovial inflammation in patients with rheumatoid arthritis (RA). The cross-sectional design was chosen to enable simultaneous assessment of clinical, laboratory, and imaging parameters within a real-world clinical setting. The study protocol was approved by the Institutional Ethics Committee, and the study was conducted in accordance with the principles outlined in the Declaration of Helsinki. Written informed consent was obtained from all participants prior to enrolment. Study Participants A total of 90 adult patients diagnosed with RA were consecutively recruited from the outpatient rheumatology clinic during the study period. All patients fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA [32]. Eligible participants were aged 18 years or older and included patients across a broad spectrum of disease duration and disease activity states. Patients were excluded if they had coexisting conditions that could confound inflammatory markers or ultrasound findings, including active infection, pregnancy, malignancy, chronic liver or kidney disease, uncontrolled diabetes mellitus, or other systemic autoimmune or inflammatory diseases. Patients who had received recent biological therapy or high-dose corticosteroids were also excluded to minimize treatment-related modulation of inflammatory markers. Clinical Assessment All patients underwent a standardized clinical evaluation performed by a trained rheumatologist. Disease activity was assessed using a 28-joint count, including tender joint count (TJC) and swollen joint count (SJC), in accordance with established guidelines [33]. Patient global assessment (PGA) and physician global assessment (EGA) were recorded using a 10-cm visual analogue scale (VAS), where higher scores indicated greater disease activity. Composite disease activity indices were calculated for each patient, including the Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and Disease Activity Score using 28 joints (DAS28). CDAI and SDAI were calculated using standard formulas incorporating joint counts and global assessments, with SDAI additionally including CRP values [34, 35]. DAS28 scores were calculated using CRP values, consistent with contemporary practice. Disease activity was categorized into remission, low, moderate, or high activity based on established cut-off values for each index [36]. Power Doppler Ultrasound Assessment Musculoskeletal ultrasound assessment was performed using a standardized 7-joint PDUS protocol based on the EULAR-OMERACT recommendations [37, 38]. The following joints of the dominant side were examined: wrist, second metacarpophalangeal (MCP-2), third metacarpophalangeal (MCP-3), second proximal interphalangeal (PIP-2), third proximal interphalangeal (PIP-3), second metatarsophalangeal (MTP-2), and fifth metatarsophalangeal (MTP-5) joints. Ultrasound examinations were conducted using a high-frequency linear transducer by a trained rheumatologist with experience in musculoskeletal ultrasound, who was blinded to clinical and laboratory data at the time of assessment. Synovial Doppler activity was graded on a semi-quantitative scale ranging from 0 to 3 for each joint, where grade 0 indicated no Doppler signal and grade 3 indicated marked synovial hyperemia occupying more than 50% of the synovial area [6]. The individual joint scores were summed to obtain a total PDUS score ranging from 0 to 21, with higher scores indicating greater synovial inflammatory activity. Laboratory Assessment Overnight fasting venous blood samples were collected from all participants on the same day as clinical and ultrasound assessments. Serum was separated by centrifugation and stored at −80 °C until analysis to preserve sample integrity. Routine laboratory investigations included complete blood count, liver and kidney function tests, fasting blood glucose, rheumatoid factor, and anti-citrullinated peptide antibody. The following acute phase reactants were measured: erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ferritin, fibrinogen, hepcidin, haptoglobin, and serum amyloid-associated protein (SAA). ESR was measured using the Westergren method. Serum CRP and ferritin levels were quantified using automated nephelometry. Plasma fibrinogen was measured using a commercial coagulation assay on an automated analyzer. Serum hepcidin, haptoglobin, and SAA were measured using standardized sandwich enzyme-linked immunosorbent assay (ELISA) kits according to the manufacturers’ instructions. Statistical Analysis Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software. Continuous variables were expressed as mean ± standard deviation or median with interquartile range, depending on data distribution. Categorical variables were expressed as frequencies and percentages. Correlations between PDUS scores and acute phase reactants, as well as between PDUS scores and composite disease activity indices, were assessed using Spearman’s rank correlation coefficient, given the non-parametric distribution of several variables [39]. A two-tailed p-value of <0.05 was considered statistically significant.

Patient Characteristics A total of 90 patients with rheumatoid arthritis (RA) were included in the study. The mean age of the cohort was 50.6±13.0 years, with a clear female predominance. Most patients were seropositive for rheumatoid factor and/or anti-citrullinated peptide antibodies. Table 1: Baseline demographic and serological characteristics Parameter RA (n=90) Controls (n=50) Age (years), mean±SD 50.6±13.0 41.0±14.4 Female, n (%) 66 (73.3) 23 (46.0) RF and/or Anti-CCP positive, n (%) 82 (91.1) — Clinical Disease Activity Clinical evaluation showed predominantly low to moderate disease activity based on composite indices. The distribution of disease activity categories is summarized below. Table 2: Composite disease activity indices (summary) Index Summary value Low/Remission (%) Moderate-High (%) CDAI Mean 12.8±8.8 41.1 58.9 SDAI Mean 14.2±9.6 40.0 60.0 DAS28-CRP Mean 3.4±1.2 35.6 64.4 Power Doppler Ultrasound Findings The median PDUS score was 4 (range 0-21), indicating mild-to-moderate synovial Doppler activity across the cohort. PDUS scores demonstrated strong positive correlations with CDAI, SDAI, and DAS28-CRP, supporting concordance between imaging-detected synovitis and clinical disease activity. Table 3: Correlation of PDUS score with disease activity indices Index Spearman r p-value CDAI 0.74 <0.001 SDAI 0.76 <0.001 DAS28-CRP 0.78 <0.001 Correlation of PDUS with Acute Phase Reactants Significant positive correlations were observed between PDUS scores and conventional acute phase reactants, particularly CRP, ESR, and fibrinogen, with the strongest association noted for CRP. No statistically significant correlations were observed for ferritin, hepcidin, haptoglobin, or SAA. Table 4: Correlation of PDUS with acute phase reactants Marker Spearman r p-value CRP 0.49 <0.001 ESR 0.33 <0.001 Fibrinogen 0.38 <0.001 Ferritin NS >0.05 Hepcidin NS >0.05 Haptoglobin NS >0.05 SAA NS >0.05 Figures Fig 1: Disease activity categories based on DAS28-CRP. Fig 2: Correlation between PDUS score and DAS28-CRP.

The present study provides a comprehensive evaluation of the relationship between power Doppler ultrasound (PDUS)-detected synovial inflammation, composite clinical disease activity indices, and a panel of conventional and novel acute phase reactants (APRs) in patients with rheumatoid arthritis (RA). By integrating clinical assessment, laboratory biomarkers, and imaging findings within the same cohort, this study offers important insights into the heterogeneity of inflammatory burden in RA and the relative utility of different markers in reflecting true synovial disease activity. A key finding of this study is the strong concordance between PDUS scores and composite disease activity indices, including CDAI, SDAI, and DAS28-CRP. PDUS demonstrated robust positive correlations with all three indices, supporting its validity as an objective imaging tool for assessing active synovitis. These findings are consistent with previous studies demonstrating that PDUS is sensitive to synovial vascularity and correlates closely with clinical measures of disease activity [40, 41]. Importantly, PDUS has been shown to detect subclinical synovitis even in patients classified as being in clinical remission, underscoring its value in identifying residual inflammatory activity that may not be captured by routine clinical examination alone [42]. Among laboratory parameters, conventional acute phase reactants—particularly C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen—demonstrated significant positive correlations with PDUS scores. CRP showed the strongest association with PDUS, indicating that higher synovial vascular activity corresponds to greater systemic inflammatory burden. This observation aligns with prior evidence suggesting that CRP is a more responsive and specific marker of inflammation in RA compared with ESR, which is influenced by several non-inflammatory factors such as age, sex, and hemoglobin levels [43, 44]. The strong association between CRP and PDUS supports its continued use as the most reliable laboratory surrogate of active synovitis in routine clinical practice. Fibrinogen also showed a significant, though comparatively weaker, correlation with PDUS scores. Fibrinogen is a key acute phase protein with roles in both coagulation and inflammation and contributes to erythrocyte aggregation, partly explaining its association with ESR [45]. Its elevation in RA reflects systemic inflammatory activation and may additionally contribute to the prothrombotic state observed in chronic inflammatory diseases. However, the weaker correlation with PDUS compared with CRP suggests that fibrinogen may reflect broader systemic inflammation rather than localized synovial activity. ESR demonstrated a statistically significant but modest correlation with PDUS scores. While ESR remains widely used in clinical practice and is incorporated into DAS28-ESR, its limitations are well recognized. Previous studies have shown that ESR may remain normal in a substantial proportion of patients with active RA, particularly in early disease or in those receiving targeted therapies [44, 46]. The present findings reinforce the concept that ESR should be interpreted cautiously and preferably in conjunction with CRP and clinical findings rather than as a standalone marker of disease activity. In contrast, novel or less commonly used acute phase reactants—including ferritin, hepcidin, haptoglobin, and serum amyloid-associated protein (SAA)—did not demonstrate significant correlations with PDUS scores in this study. Although some of these markers were elevated in RA patients compared with controls, their lack of association with imaging-detected synovitis suggests limited utility in reflecting current inflammatory activity at the joint level. Ferritin, for instance, is influenced by iron stores, metabolic factors, and macrophage activation and may represent chronic inflammatory or metabolic status rather than active synovitis [47]. Similarly, hepcidin is primarily a regulator of iron homeostasis and is closely linked to anemia of chronic disease, a common extra-articular manifestation of RA, rather than a direct marker of synovial inflammation [48]. SAA is known to be a highly sensitive acute phase protein that rises rapidly in inflammatory states and has been implicated in secondary amyloidosis in chronic inflammatory diseases. However, several studies have reported that SAA levels may not correlate consistently with clinical disease activity indices or imaging findings in treated RA populations [49]. The lack of correlation observed in the present study supports the notion that SAA may be more useful as a marker of persistent systemic inflammation or long-term complications rather than as a routine disease activity marker. The findings of this study have important clinical implications, particularly in the context of treat-to-target strategies. While PDUS offers a sensitive and objective assessment of synovial inflammation, its routine use is limited by availability, cost, and operator dependency, especially in resource-constrained settings. In such contexts, identifying laboratory markers that reliably reflect PDUS-detected synovitis is of considerable value. The strong association observed between CRP and PDUS supports the continued reliance on CRP as the most informative laboratory marker for monitoring inflammatory activity in RA when imaging is not readily accessible. Another important observation from this study is the predominance of low to moderate disease activity in the cohort, despite the presence of measurable synovial Doppler activity in a substantial proportion of patients. This highlights the well-recognized phenomenon of discordance between clinical remission or low disease activity states and ongoing subclinical inflammation. Previous longitudinal studies have demonstrated that persistent PDUS activity, even in clinically quiescent disease, is associated with higher risk of flare and radiographic progression [50, 51]. Although the present study is cross-sectional and does not evaluate longitudinal outcomes, the observed associations reinforce the importance of imaging-based assessment in comprehensive disease evaluation. The strengths of this study include the simultaneous evaluation of multiple APRs, standardized PDUS assessment using EULAR-OMERACT recommendations, and correlation with validated composite disease activity indices. Additionally, the study contributes valuable data from an Indian population, where such integrative assessments remain limited. However, certain limitations should be acknowledged. The cross-sectional design precludes assessment of temporal changes and responsiveness of biomarkers to treatment. The study was conducted at a single tertiary care center, which may limit generalizability. Furthermore, the absence of longitudinal follow-up prevents evaluation of the predictive value of PDUS and APRs for disease progression or flare. In conclusion, this study demonstrates that PDUS is strongly correlated with clinical disease activity indices and conventional acute phase reactants, particularly CRP, ESR, and fibrinogen. Among these, CRP emerges as the most reliable laboratory correlate of imaging-detected synovitis. Novel acute phase reactants, despite being elevated in RA, showed limited utility in reflecting synovial inflammatory activity. These findings support a pragmatic approach to disease monitoring in RA, emphasizing the combined use of clinical assessment, CRP-based indices, and PDUS where available, to achieve optimal disease control and long-term outcomes.

Power Doppler ultrasound (PDUS)-detected synovial activity in rheumatoid arthritis correlated significantly with conventional acute phase reactants, particularly C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen. Among these, CRP showed the strongest association with PDUS scores, suggesting that it best reflects imaging-defined inflammatory burden. These findings support the continued clinical value of conventional inflammatory markers in routine monitoring and indicate that CRP, ESR, and fibrinogen may serve as practical surrogate indicators of active synovitis when PDUS is unavailable or not feasible. In contrast, newer acute phase reactants such as ferritin, hepcidin, haptoglobin, and serum amyloid-associated protein demonstrated limited correlation with PDUS activity, indicating restricted utility for assessing current synovial inflammation in this setting. Overall, integrating clinical indices with CRP-based assessment, and using PDUS where available, may improve accurate evaluation of inflammatory activity and help guide treat-to-target management in rheumatoid arthritis.

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