New Research Finds 13 Risk Factors for RA-Interstitial Lung Disease

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A new study found the prevalence of interstitial lung disease in rheumatoid arthritis (RA) is approximately 18.7% and identified 13 risk factors for RA-interstitial lung disease.¹

“Coinciding with a considerable rise in mortality of RA- [interstitial lung disease], the global prevalence is expected to rise and varies widely,” wrote investigators, led by Hong-Fei Wang, from the First School of Clinical Medicine at Zhejiang Chinese Medicine University in China.

Despite RA patients with interstitial lung disease having a 3 times greater mortality risk than RA patients without interstitial lung disease, the prevalence and risk factors for RA-associated interstitial lung disease were unknown.² Therefore, investigators aimed to close this knowledge gap.¹

The team conducted a systematic review and meta-analysis, leveraging 56 relevant observational studies from EMBASE, Web of Science, PubMed, and Cochrane Library (1972 – 2022) with 11,851 patients. Studies were a mix of cross-sectional (n = 32), case-control (n = 12), and cohort (n = 12), carried out in Europe (n = 13), Asia (n = 22), Africa (n = 2), and America (n = 17).

The prevalence of RA-associated interstitial lung disease in the sample ranged from 2.96% to 71.60%, with a pooled prevalence of 18.7% (95% confidence interval [CI], 15.8 – 21.6). Subgroup analyses showed the RA- interstitial lung disease prevalence was 17.8% in Asia, 14.3% in Europe, and 7.6% in North America.

“Given the multi-ethnic populations in each region, it is likely that this variation is related to the local ethnic composition,” investigators wrote. “Previous studies found that Indian ethnicity was more susceptible to developing Ra- [interstitial lung disease] and African Americans developed [interstitial lung disease] earlier than non-African Americans, indicating the impact of genetic factors.”

Wang and colleagues also assessed several potential risk factors, such as sex, age, ethnicity, education level, air pollution exposure, smoking history, body mass index, age of RA onset, comorbidities, RA duration, anti-cyclic citrullinated peptide antibody, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, surfactant protein D, Krebs von den Lungen-6 glycoprotein, DAS28, erosion rheumatoid nodules, functional compacity, the Multidimensional Health Assessment Questionnaire, the clinical disease activity index, lactate dehydrogenase, tumor markers, methotrexate, leflunomide, biological agents usage, and steroid usage.

Out of those factors, investigators identified 13 risk factors for RA-associated interstitial lung disease:

1. Male sex (odds ratio [OR], 95% CI, 1.70 – 2.16; P < .05)
2. Older age (WMDs, 6.89, 95% CI 3.10 – 10.67; P < .05)
3. Smoking history (OR, 1.91; 95% CI, 1.48 –2.47; P < .05).
4. Pulmonary comorbidities predicted (hazard ratio [HR], 2.08; 95% CI 1.89 – 2.30; P < .05)
5. Longer RA duration (OR, 1.03; 95% CI, 1.01 – 1.05; P < .05)
6. Older age of RA onset (WMDs, 4.46; 95% CI, 0.63 – 8.29; P < .05)
7. Positive rheumatoid factor (HR, 1.15; 95% CI, 0.75 – 1.77; OR, 2.11; 95% CI, 1.65 – 2.68; P < .05)
8. Positive anti-cyclic citrullinated peptide antibody (OR, 2.11; 95% CI, 1.65 – 2.68; P < .05)
9. Greater erythrocyte sedimentation rate (OR, 1.008; 95% CI, 1.002 – 1.014; P < .05)
10. Moderate and high DAS28 (≥3.2) (OR, 1.87; 95% CI, 1.36 – 2.58; P < .05)
11. Rheumatoid nodules (OR, 1.87; 95% CI, 1.18 – 2.98; P < .05)
12. Leflunomide use (OR, 1.42; 95% CI 1.08 – 1.87; P < .05)
13. Steroid use (HR, 1.70; 95% CI, 1.13 – 2.55); P < .05)

Investigators also found biological agents were a protective factor of RA-associated interstitial lung disease (HR, 0.77; 95% CI, 0.69 – 0.87).

The team acknowledged several limitations, including the diagnostic criteria variation, the inability to prove causality due to examining observational studies, and some risk factors barely populated the body of research.

Ultimately, the study shows the onset of RA-interstitial lung disease is connected to environmental exposures, as well as sociodemographic and clinical characterization factors.

“Despite the identification of several risk factor[s], it’s still possible for [interstitial lung disease] to develop without them,” investigators wrote. “Therefore, a comprehensive search of evidence for risk factors for RA- [interstitial lung disease] surveillance of the progression of RA-[interstitial lung disease] is essential for the prompt application of therapeutic strategies to improve prognosis.”

References

1. ^{Wang HF, Wang YY, Li ZY, He PJ, Liu S, Li QS. The prevalence and risk factors of rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis. Ann Med. 2024;56(1):2332406. doi:10.1080/07853890.2024.2332406}

2. ^{Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010;62(6):1583-1591. doi:10.1002/art.27405}