European Journal of Cardiovascular Medicine

Rheumatoid arthritis (RA) is the most prevalent form of inflammatory arthritis, affecting 0.5–1% of the population. It is a chronic, systemic autoimmune condition characterized by symmetrical, deforming polyarthritis involving both small and large joints, and is associated with systemic manifestations such as vasculitis and nodules. The pathogenesis of RA involves both adaptive and innate immune responses, leading to synovial inflammation and cartilage destruction.¹

Renal involvement in RA can arise from the disease itself or as a consequence of medications used in treatment, including both biological and non-biological disease-modifying anti-rheumatic drugs (DMARDs) and non-steroidal anti-inflammatory drugs (NSAIDs) Renal pathology in RA patients often reveals secondary amyloidosis, membranous nephropathy, and, less commonly, rapidly progressive glomerulonephritis.²

Microalbuminuria serves as a non-invasive early marker of glomerular injury and is defined as urinary albumin excretion of 30–300 mg/day. It represents a leakage of small amounts of albumin due to increased glomerular permeability and indicates subclinical renal damage.³ While not specific to RA, microalbuminuria has been observed in other rheumatic diseases such as systemic lupus erythematosus and systemic sclerosis, where it is associated with a poorer prognosis.⁴

In RA, microalbuminuria may reflect glomerular damage from the disease itself or drug-induced nephrotoxicity. Its presence has been linked to elevated urinary albumin index in RA patients, especially those on DMARD therapy. However, despite being a well-established predictor of cardiovascular and renal morbidity in conditions like diabetes and hypertension, its clinical significance in RA remains underexplored.⁵

This study aimed to evaluate subclinical renal dysfunction in RA patients using microalbuminuria and correlate it with disease activity indicators such as Disease Activity Score (DAS28), Rheumatoid Factor (RF), anti-CCP antibodies, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and the count of tender and swollen joints. Early microalbuminuria detection in RA may enable timely intervention and serves as a marker for predicting renal dysfunction versus controls.

Study: This hospital-based observational study was conducted from March 2023 to August 2024 in the Department of General Medicine, Mahatma Gandhi Medical College & Hospital. The study included all diagnosed rheumatoid arthritis (RA) patients attending OPD/IPD who met inclusion criteria. A total of 75 RA patients aged over 18 years, satisfying the 2010 ACR-EULAR criteria, were enrolled as the case group. An equal number of age- and sex-matched non-RA individuals were selected as controls based on exclusion criteria.

Inclusion Criteria:  Patients’ who give consent for the study.

Exclusion Criteria: Patients were excluded if they had cardiovascular diseases (e.g., hypertension, myocardial infarction, or heart failure), renal dysfunction, diabetes mellitus, urinary tract infections, were pregnant, or bedridden for over two weeks. Additionally, individuals who did not provide consent were excluded from the study.

Methodology:

This prospective observational study was conducted over 18 months at Mahatma Gandhi Medical College & Hospital. All diagnosed RA patients visiting OPD/IPD were included. Investigations included CBC, FBS/PPBS, blood urea, serum creatinine, ESR, CRP, rheumatoid factor, anti-CCP, HbA1c, and urine microalbumin. DAS-28 scoring was used to assess disease activity, incorporating 28 tender/swollen joints, ESR, and VAS. DAS28 scores were interpreted as: remission (≤2.6), low (2.6–3.2), moderate (3.2–5.1), and high disease activity (>5.1). Standard lab equipment and validated methods were used for all tests.

Statistical Analysis:

Data were coded in Microsoft Excel and analyzed using IBM SPSS Version 25. Descriptive statistics included means, percentages, and standard deviations. Normality was assessed using the Kolmogorov-Smirnov test. The unpaired t-test was applied for quantitative comparisons, while the chi-square test was used for qualitative variables. A p-value of ≤0.05 was considered statistically significant.

Table No. 1: Age Group-wise Comparison of the Study

In the case group, most participants were aged 45–65 years, with 36% aged 45–55 and 33.3% aged 55–65. In the control group, age distribution was similar, with 33.3% aged 45–55, 34.7% aged 55–65, and 32% over 65 years, showing comparable age patterns.

Table 2: Microalbuminuria-Wise Comparison of the Study

In the case group, 56% showed positive microalbumin and 44% were negative, whereas in the control group, 96% were negative and only 4% were positive. The mean microalbumin level was 35.26 in the case group and 12.89 in the control group. This difference was statistically significant, indicating greater renal involvement in the case group.

Table 3: Comparative Analysis Of CRP, ESR, And DAS28 In Relation To Microalbuminuria.

The study showed statistically significant differences in inflammatory markers and disease activity. Mean DAS28 was 4.62 in the case group. ESR and CRP were higher in cases than controls. Positive microalbumin cases had higher CRP (30.56), ESR (52.76), DAS28 (4.98), and RA factor (63.33) compared to negative microalbumin cases, indicating a strong association between microalbuminuria and disease severity in rheumatoid arthritis patients.

Figure 1: Anti-CCP-Based Comparison of Study Groups

Abnormal ANTI-CCP case was 86.6% in case group. Comparison of ANTI-CCP was showed statistically significant results.

Figure 2: Anti-CCP Levels in RA Cases with Microalbuminuria

The graph shows the distribution of Anti-CCP levels in relation to microalbumin status. Among 75 patients, 73.3% had abnormal Anti-CCP levels, with the majority (70.7%) being microalbumin positive. Only 2.7% of patients with abnormal Anti-CCP were microalbumin negative. All normal Anti-CCP results (26.7%) were observed in microalbumin-positive patients. This indicates a strong association between abnormal Anti-CCP levels and the presence of microalbuminuria in rheumatoid arthritis patients.

The present study observed a marginal difference in the mean age between case (59.45 ± 11.41 years) and control (61.17 ± 10.80 years) groups, which was statistically insignificant (p=0.34). This suggests a comparable age distribution, minimizing confounding influence of age in interpreting disease associations. The age group distribution indicated that the majority of cases were between 45-65 years, aligning with the known peak incidence of autoimmune inflammatory disorders like rheumatoid arthritis (RA) within the 4th to 6th decade of life. Previous epidemiological studies have affirmed that RA typically presents after 40 years, with its prevalence increasing up to the age of 65, stabilizing thereafter.⁶ Notably, the youngest age group (35–45 years) contributed a small fraction (5.3%) among cases, absent in controls, potentially indicating early disease onset in a minority. However, this was not statistically significant (p=0.19). An age-matched control design remains a strength here as it facilitates reliable interpretation of clinical and serological comparisons without substantial age bias.⁷

Microalbuminuria was significantly more frequent in the case group (56%) than in controls (4%) (p=0.001). This indicates a potential role of renal involvement or systemic endothelial dysfunction in the disease group. The strong statistical association suggests microalbuminuria as a surrogate marker for disease activity or severity. Inflammatory cytokines such as TNF-α and IL-6, prevalent in autoimmune diseases like RA, can damage glomerular endothelium, leading to increased albumin leakage.⁸  Moreover, RA-related vasculitis and the use of nephrotoxic drugs may contribute to microalbuminuria. Its presence has also been correlated with cardiovascular risk in RA, marking it as an important prognostic factor.^,9 In the study, the mean microalbumin level in the case group was significantly elevated (35.26 ± 15.89 mg/L) compared to the control group (12.89 ± 4.59 mg/L), with a p-value <0.001. This reinforces the prevalence of subclinical renal involvement in RA, often mediated by immune complex deposition, glomerulonephritis, or drug-induced nephropathy.^,10

Mean CRP was 16.51 in case group and 5.37 in control group, p < 0.001. This aligns with CRP being an acute-phase reactant directly reflecting systemic inflammation in autoimmune diseases like RA.¹¹

Mean DAS28 in the case group was 4.62 ± 1.21, indicating moderate to high disease activity. No DAS28 score was available in the control group. The DAS28 score is a validated composite index used globally to assess RA activity and treatment response.¹² The ESR was significantly higher in RA patients (34.28 ± 8.23 mm/hr) compared to controls (14.94 ± 5.06 mm/hr), p < 0.001. ESR is a longstanding inflammatory marker used in conjunction with CRP to monitor disease activity.¹³

Mean CRP levels were markedly elevated in the case group (16.51) compared to controls (5.37) with statistical significance (p=0.001). Furthermore, within the case group, those with positive microalbumin had a significantly higher CRP (30.56 vs 20.58; p=0.001), indicating a strong inflammatory profile.

CRP is a widely accepted biomarker of systemic inflammation and is directly related to disease activity in RA. The observed correlation with microalbumin reinforces the interplay between systemic inflammation and vascular permeability or renal endothelial injuri.¹⁴

Among cases, ESR and DAS scores were significantly elevated in patients with positive microalbuminuria. ESR was 52.76 vs 25.67 (p=0.001) and DAS was 4.98 vs 3.19 (p=0.001), reflecting active disease status. These findings reaffirm the utility of microalbuminuria as an adjunctive indicator of inflammation and disease activity in autoimmune rheumatic disease.

The DAS28 score remains a validated tool to quantify disease burden in RA and is influenced by tender/swollen joint counts, ESR, and patient’s global assessment. The relationship between high DAS and renal markers highlights the systemic nature of the disease and potential early renal involvement.

RA factor was positive in 56% of cases and absent in controls. Anti-CCP antibodies, abnormal in 86.6% of cases, were strongly associated with positive microalbuminuria (73.3%). Both markers showed statistical significance (p=0.001 and 0.01 respectively), reiterating their diagnostic value.

Anti-CCP antibodies offer high specificity for RA and often precede clinical symptoms. Their relationship with microalbuminuria points to early subclinical systemic involvement, possibly predicting more aggressive disease or extra-articular manifestations.^15,16

The study demonstrated a significantly higher prevalence of microalbuminuria among RA patients compared to controls, and its strong association with markers of disease activity (ESR, CRP, DAS28, RA factor, and anti-CCP). This underscores the clinical value of screening for microalbuminuria in RA patients as an early indicator of renal involvement and systemic inflammation. Incorporating such markers into routine assessment could help identify patients at higher risk for complications, enabling timely interventions and improved management outcomes.

1. Alawneh KM, Khassawneh BY, Ayesh MH, Smadi M. Rheumatoid arthritis in Jordan: a cross sectional study of disease severity and associated comorbidities. Ther Clin Risk Manag. 2014;10:363-6
2. Liu Y, Wen HY, Wang LH, Wang C. Focal segmental glomerulosclerosis lagged behind the onset of rheumatoid arthritis by 7 years: A case report and literature review. Medicine (Baltimore). 2017;96(1):e5789
3. American Diabetes Association. Nephropathy in diabetes (Position Statement). J Diabetes Care 2004;27(S1):79-83
4. Cirillo M. Evaluation of glomerular filtration rate and of albuminuria/proteinuria. J Nephrol 2010;23(02):125–132
5. Bhatt G, Mathur DS, Saxena GN, Bhanadari S. Microalbuminuria in rheumatoid arthritis: a correlation with disease activity. J Assoc Physicians India 2002; 50:82
6. Scott DL, Wolfe F, Huizinga TWJ. Rheumatoid arthritis. Lancet. 2010;376(9746):1094–108
7. Uhlig T, Haavardsholm EA, Aga AB, Olsen IC, Lillegraven S, Hammer HB. Incidence and predictors of RA in the general population. Ann Rheum Dis. 2009;68(3):423–9
8. Wasserman AM. Renal involvement in rheumatoid arthritis. Clin Rheumatol. 2002;21(3):183–8
9. Nidavani RB, Mahalakshmi AM, Patil JS. Microalbuminuria in RA patients: implications for cardiovascular risk. Mod Rheumatol. 2006;16(4):223–8
10. Vupputuri S, Sandler DP. Lifestyle risk factors and chronic kidney disease. Ann Epidemiol. 2003;13(10):712–720
11. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–2038.
12. Wells G, Becker JC, Teng J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and its component scores. Arthritis Res Ther. 2009;11(3):R73
13. Zeggar MN, Laouar M, Touil-Boukoffa C. Clinical value of ESR and CRP in RA patients. Rheumatol Int. 2011;31(3):403–409
14. Gonzalez-Gay MA. CRP and endothelial dysfunction in RA. Clin Exp Rheumatol. 2008;26(4):648–53
15. Sokolove J, Bromberg R, Deane KD, Lahey LJ, Derber LA, Chandra PE et al. Autoantibody epitope spreading in the preclinical phase of RA. Arthritis Rheumatol. 2012;64(5):1272–81
16. van Boekel MA,  Vossenaar ER, van den Hoogen FH, van Venrooij WJ. Autoantibody systems in RA: specificity, sensitivity, and diagnostic value. Arthritis Res. 2002;4(2):87–93