Ocular manifestations in rheumatoid arthritis patients in Bangladesh: A cross-sectional study

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized primarily by persistent synovial inflammation and progressive joint destruction. Beyond musculoskeletal involvement, RA frequently manifests with extra-articular complications that contribute substantially to morbidity, functional impairment, and reduced quality of life.^[1] Among these, ocular involvement represents an important yet often underrecognized aspect of the disease spectrum, with potential to cause significant visual discomfort and, in severe cases, irreversible vision loss.^[2]

RA is a major global public health challenge, with age-standardized prevalence and incidence rates increasing worldwide between 1990 and 2017 – reaching approximately 247 cases and 15 new cases/100,000 population in 2017 – and showing higher rates with advancing age and in females.^[3] In addition, serological markers such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies are well-established indicators of disease severity and prognosis in RA.^[4,5] Several studies have suggested associations between seropositivity, higher inflammatory burden, and extra-articular manifestations, including ocular disease; however, findings remain inconsistent.

Ocular manifestations in RA arise from immune-mediated inflammation, vasculitis, and secondary involvement of exocrine glands, with dry eye disease (DED) being the most common complication.^[6] Inflammatory ocular conditions such as episcleritis, scleritis, and keratitis, although less prevalent, are clinically significant as they may indicate active systemic disease and are potentially sight-threatening if not promptly managed.^[7] Previous studies have reported a wide variation in the prevalence of ocular involvement in RA, ranging from 20% to 70%, likely reflecting differences in disease duration, activity, diagnostic criteria, and study populations.^[2,8]

Bangladesh, like many low- and middle-income countries, bears a substantial and growing burden of RA, yet local data on ocular involvement – particularly their relationship with autoantibody status – remain scarce. By addressing these aspects, this current study seeks to enhance understanding of RA’s ocular burden in a regional context and advocate for routine ophthalmic screening to mitigate complications.

MATERIALS AND METHODS

Ethical approval was obtained from the local institutional ethics committee. Written informed consent was obtained from all participants before enrollment, and the study adhered to the principles of the Declaration of Helsinki.

This descriptive cross-sectional study was conducted from November 2021 to October 2022 in the Departments of Rheumatology and Ophthalmology of a tertiary care center in the Southeastern region of Bangladesh.

Patients diagnosed with RA by a rheumatologist were consecutively enrolled. A total of 141 patients were included in the study. Adult patients (≥18 years) with confirmed RA were included. Patients with other connective tissue diseases, systemic conditions affecting the ocular surface (e.g., diabetes mellitus, Stevens–Johnson syndrome), contact lens users, lid pathologies, prior ocular surgery or trauma, and those receiving medications known to induce dry eye were excluded.

Demographic data (age and sex) and RA-related characteristics were recorded, including disease duration, RF positivity (≥15 IU/mL), anti-CCP positivity (≥5 U/mL), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and disease activity using the disease activity score in 28 joints (DAS-28).^[9] Disease severity was categorized as remission (DAS-28 ≤2.6), low (≤3.2), moderate (>3.2–≤5.1), or high activity (>5.1).^[10]

All patients underwent a comprehensive ophthalmological evaluation by an experienced ophthalmologist. Ocular manifestations assessed included DED, episcleritis, scleritis, and keratitis. DED was diagnosed when either Schirmer’s test or Tear Break-Up Time (TBUT) was abnormal. For the Schirmer’s test, strips were placed at the temporal third of the inferior eyelid for 5 min without anesthesia; a result below 10 mm was considered diagnostic. TBUT was measured by applying fluorescein strips to the inferior fornix and recording the time until the first dark spot appeared after blinking. The final TBUT was the mean of three measurements, with values below 10 s considered diagnostic.^[11] Inflammatory conditions (episcleritis, scleritis, and keratitis) were diagnosed clinically through slit-lamp biomicroscopy, with scleritis further classified as nodular or diffuse as appropriate.

Data were analyzed using IBM Statistical Package for the Social Sciences Statistics (version 25). Continuous variables were expressed as mean ± standard deviation or median with interquartile range (IQR), while categorical variables were presented as frequencies and percentages. To assess associations between categorical variables, such as age groups (<40, 40–59, ≥60 years) and the prevalence of ocular conditions (dry eye, episcleritis, scleritis, and keratitis), Chi-square tests of independence were applied. Due to several contingency tables containing cells with expected frequencies <5 (ranging from 33.3% to 50.0%), P-values were calculated using the Monte Carlo simulation of Fisher’s exact test where appropriate. For sex-stratified comparisons and serological associations (RF and anti-CCP positivity), Chi-square tests or Fisher’s exact tests were used as appropriate. P < 0.05 was considered statistically significant.

RESULTS

A total of 141 patients with RA were included in the study. The age of the participants ranged from 18 to 85 years, with a mean age of 48.4 ± 11.6 years. The majority of patients were aged 40–59 years (63.8%), followed by those aged <40 years (19.2%) and ≥60 years (17.0%). Females constituted 83.0% of the cohort (n = 117), resulting in a female-to-male ratio of 4.9:1. The mean duration of RA was 7.6 ± 6.6 years, with a median duration of 7.0 years (IQR: 2.0–12.0). Musculoskeletal deformities were present in 31 (22.0%) of patients, predominantly involving the hands or fingers 29 (20.6%), followed by foot or toe deformities 18 (12.8%). RF positivity was detected in 63.8% (n = 90) of patients, whereas anti-CCP antibodies were present in 51.8% (n = 73). The median ESR was 50 mm in the first hour (h) (IQR: 32.0–70.0), and the median CRP level was 12.0 mg/dL (IQR: 5.9–24.0). Disease activity assessment using DAS-28 (ESR-based) showed a mean score of 4.3 ± 1.5 and a median score of 4.5 (IQR: 3.4–5.6). Most patients had active disease, with 41.1% exhibiting moderate disease activity and 39.7% having high disease activity. Only 15.6% were in remission. Regarding treatment patterns, methotrexate was the most commonly used disease-modifying antirheumatic drug (DMARD), prescribed to 135 (95.7%) patients. Other commonly used DMARDs included hydroxychloroquine (26.2%), sulfasalazine (26.2%), and the Janus kinase inhibitor tofacitinib (22.7%) [Table 1].

Overall, ocular involvement was detected in 92 of 141 patients, yielding a prevalence of 65.2%. Among patients with ocular involvement, DED was the most frequent manifestation, observed in 78.3% (72/92). Episcleritis was present in 13.0% (12/92), scleritis in 6.5% (6/92), and keratitis in 2.2% (2/92). When calculated for the entire study population, DED affected 51.1% (72/141) of patients [Table 2].

Age-stratified analysis demonstrated a statistically significant association between DED and age group (P < 0.001). The prevalence of dry eye was highest among patients aged <40 years (92.6%), compared with 41.1% in those aged 40–59 years and 41.7% in those aged ≥60 years. In contrast, no significant association was observed between age and episcleritis (P = 0.185), scleritis (P = 0.249), or keratitis (P = 0.337). DED was more frequent among females (52.1%; 61/117) than males (45.8%; 11/24), although this difference was not statistically significant (P = 0.574). Episcleritis was observed in 7.7% of females and 12.5% of males (P = 0.430). The prevalence of scleritis was similar in both sexes (4.3% in females vs. 4.2% in males; P = 1.000). Keratitis was uncommon in both groups and did not differ significantly by sex (P = 0.312) [Table 3].

Among RF-positive patients, DED was observed in 46.7%, whereas 49.3% of anti-CCP-positive patients had DED. Episcleritis, scleritis, and keratitis occurred in smaller proportions in both seropositive groups. No statistically significant association was identified between RF positivity or anti-CCP positivity and any ocular manifestation (all P > 0.05) [Table 4].

DISCUSSION

The findings from this study provide a comprehensive look at the demographic profile, disease characteristics, and ocular manifestations of patients with RA.

The observed mean age of 48.4 ± 11.6 years and the concentration of 63.8% of patients within the 40–59 years age bracket underscore RA as a disease primarily affecting the middle-aged population. The wide age range (18–85 years) indicates that RA can affect adults across a broad age spectrum, emphasizing the need for vigilance for systemic and ocular complications at all ages. Similar findings have also been reported in recent studies.^[5] Our result deviates from global patterns. Disability-adjusted life years and prevalence rates grew as patients aged and were more pronounced in women. Specifically, the highest impact occurred among women aged 70–74 and men aged 75–79.^[3] From a public health perspective, the prevalence of the disease during these peak productive years suggests a significant socioeconomic burden, as functional impairment in this age group often translates to long-term work disability and diminished quality of life. Regarding sex distribution, our study demonstrated a profound female preponderance (117/141, 83.0%), resulting in a female-to-male ratio of 4.9:1. This ratio is notably higher than the global average of 2.9:1.^[3] The higher ratio in our study could be influenced by sociodemographic factors, such as differences in healthcare-seeking behavior or occupational exposures between genders in this specific region.

In the present study, the mean duration of RA patients was 7.6 ± 6.6 years with a median (IQR) of 7.0 (2.0–12.0) years. Charanya et al. (2014) found that most of the patient with 1–5 years duration while another recent study found that most of the patients’ disease duration was 5–10 years, with a mean duration of 9.5 ± 5.32 years.^[5,12] The median disease duration of 7 years reflects a cohort with longstanding RA, which is clinically important as extra-articular manifestations, including ocular involvement, are more frequent with increasing disease duration.^[4] A substantial proportion of patients was seropositive, with RF positivity in 90 (63.8%) and anti-CCP positivity in 73 (51.8%) of cases. Higher rates of RF positivity have been reported.^[5] In contrast, lower frequencies (40%) of RF positivity were documented in an earlier study.^[13] In addition, the presence of anti-CCP antibodies specific to RA was found to be statistically significantly correlated with ocular symptoms in a previous study.^[4] The observed variability in seropositivity rates across studies may be attributed to differences in disease duration, population characteristics, diagnostic criteria, and laboratory techniques. Inflammatory markers were notably elevated, as reflected by median ESR (50 mm in 1^st h) and CRP values (12.0 mg/dL), suggesting persistent systemic inflammation. In a previous study, similar findings were observed.^[2] The median DAS-28 score of 4.3 ± 1.5 indicates that most patients had active disease. Indeed, more than 80% of patients fell into the moderate or high disease activity categories, highlighting suboptimal disease control in a large proportion of cases. DAS-28 was not significantly associated with any of the ocular surface abnormalities.^[2,5,14]

The present study demonstrates that ocular involvement is a common extra-articular manifestation of RA, with more than half of the patients (92/141, 65.2%) exhibiting at least one ocular abnormality. This prevalence is comparable to earlier reports, which have documented ocular involvement in approximately 20–70% of RA patients, depending on disease duration, activity, and diagnostic criteria used.^{[2,4,8,12,15]}

Among the affected patients, DED was the most frequent ocular manifestation, occurring in 78.3% (72/92) of those with ocular involvement. When calculated across the entire cohort, dry eye affected 51.1% (72/141) of all RA patients. This predominance is consistent with the known association between RA and secondary Sjögren’s syndrome, lacrimal gland dysfunction, and chronic ocular surface inflammation.^[6,7] Similar studies have reported dry eye prevalence ranging from 30% to 85% in RA populations, supporting the robustness of our findings.^[2,4,15] Inflammatory ocular conditions were less common in the present study. Episcleritis was identified in 13.0% (12/92), scleritis in 6.5% (6/92), and keratitis in only 2.2% (2/92) of patients with ocular involvement. The lower prevalence of more severe inflammatory conditions may reflect earlier diagnosis, improved systemic disease control, or referral bias in tertiary care settings. Although less prevalent, these conditions are clinically important due to their association with active systemic disease and potential for vision-threatening complications.

Age-stratified analysis revealed a highly significant association between DED and age (P < 0.001). Interestingly, the prevalence of dry eye was disproportionately higher in the <40-year age group (92.6%) compared with 41.1% in patients aged 40–59 years and 41.7% in those aged ≥60 years. This finding contrasts with the recent population-based data, where dry eye prevalence typically increases with advancing age.^[16] One possible explanation is that younger RA patients in this cohort may have had more aggressive systemic disease, higher inflammatory activity, or earlier autoimmune involvement of exocrine glands. In addition, increased digital device use and environmental exposure among younger individuals may exacerbate ocular surface symptoms, amplifying clinically detectable dry eye. In contrast, no statistically significant age-related associations were observed for episcleritis (P = 0.185), scleritis (P = 0.249), or keratitis (P = 0.337). The relatively small number of inflammatory ocular cases in each age subgroup may have limited the statistical power to detect meaningful differences. Nevertheless, these findings suggest that inflammatory ocular manifestations may be more closely related to systemic disease activity rather than chronological age alone.

Sex-based analysis demonstrated that dry eye was more common in females (52.1%; 61/117) than in males (45.8%; 11/24), although the difference was not statistically significant (P = 0.574). This trend aligns with the higher overall prevalence of RA and autoimmune disorders among females and the known influence of hormonal factors on tear film stability. Episcleritis was observed in 12.5% of males and 7.7% of females (P = 0.430), whereas scleritis showed nearly identical frequencies between sexes (4.2% in males vs. 4.3% in females; P = 1.000). Keratitis was rare in both groups but slightly higher in males (4.2% vs. 0.9% in females; P = 0.312). Overall, the absence of statistically significant sex differences suggests that ocular manifestations in RA are not strongly sex-dependent once the disease is established.

Dry eye was the most frequent manifestation among both RF-positive (46.7% of 90 patients) and anti-CCP-positive (49.3% of 73 patients) individuals. However, no statistically significant associations were identified between RF or anti-CCP positivity and any ocular manifestation (dry eye: P = 0.220 and 0.737; episcleritis: P = 0.120 and 0.553; scleritis: P = 1.000 for both; keratitis: P = 0.535 and 0.497, respectively). These findings indicate that ocular surface and inflammatory eye disease in RA can occur independently of these common autoantibodies in our cohort. These results contrast with several published reports that have demonstrated a stronger link between autoantibody status and ocular involvement in RA.^[4,17] The lack of significant association between serological markers and ocular involvement likely stems from several factors. The small sample of patients with inflammatory conditions such as episcleritis, scleritis, and keratitis limited the statistical power to detect links with RF or anti-CCP status. Furthermore, the cohort was dominated by dry eye, a multifactorial condition significantly associated with age in this study (P < 0.001) rather than autoantibody presence. Finally, modern RA management and tighter systemic control may attenuate the historical correlation between high seropositivity and severe extra-articular complications, suggesting that serological status is no longer a direct predictor of ocular disease in the current treatment era.

Clinically, these findings reinforce the importance of routine ophthalmologic screening in all RA patients, regardless of serological profile. Ocular manifestations, particularly DED, can significantly impair quality of life, and early detection is essential to prevent complications. Management should adopt a multidisciplinary approach integrating rheumatologic control of systemic disease with targeted ocular therapies (e.g., lubricants and anti-inflammatory agents) and psychosocial support, given the known correlations between DED severity and anxiety, depression, and sleep disturbances in autoimmune populations.

Limitations of the study include its cross-sectional design, which precludes assessment of causality or temporal relationships, single-center recruitment (potentially limiting generalizability), and the relatively small numbers of rarer inflammatory manifestations, which may reduce statistical power for subgroup analyses. Future prospective multicenter studies with larger samples, detailed autoantibody titers, and longitudinal follow-up would help clarify the complex interplay between serology, disease activity, and ocular outcomes in RA.

CONCLUSION

Ocular involvement is common in RA, with dry eye as the most prevalent manifestation. No significant association was observed between RF or anti-CCP positivity and specific ocular manifestations, suggesting that ocular involvement may not be solely dependent on serological status. RA patients should undergo routine ophthalmologic screening, even if asymptomatic and irrespective of RF/anti-CCP status, to enable early detection and management of ocular disease. Close collaboration between rheumatology and ophthalmology services is recommended.