Circulating Dickkopf-1 as a Potential Biomarker Associated with the Prognosis of Patients with Rheumatoid Arthritis-Associated Interstitial Lung Disease
Interstitial lung disease (ILD) is a significant extra-articular manifestation in patients with connective tissue diseases (CTDs), including rheumatoid arthritis (RA). It contributes substantially to the disease burden and excess mortality in these patients. It has been well-established that RA-associated ILD (RA-ILD) patients face a threefold higher risk of death compared to RA patients without ILD. However, diagnosing ILD remains challenging, as approximately 30% of ILD patients cannot be definitively diagnosed based on clinical findings and high-resolution computed tomography (HRCT) features alone. This diagnostic uncertainty complicates management strategies. In this context, noninvasive blood biomarkers with diagnostic and prognostic utility could provide valuable information for identifying vulnerable patients, particularly in clinical settings with limited medical resources.
Dickkopf-1 (DKK1) is a protein that has been found to be elevated in lung tissue specimens from donors and patients with idiopathic pulmonary fibrosis (IPF). DKK1 has been shown to modulate Wnt-induced epithelial cell proliferation in a dose-dependent manner, suggesting its potential clinical relevance in both ILD and RA. This study aimed to investigate the role of circulating DKK1 as a biomarker in RA-ILD patients and its association with disease prognosis.
The study was conducted at the General Hospital of Ningxia Medical University and was approved by the institution’s Ethics Committee. Written informed consent was obtained from all participants prior to their inclusion. A total of 102 RA patients were recruited, including 35 RA-ILD patients and 67 RA patients without ILD. The diagnosis of RA was based on the criteria of the American College of Rheumatology, while ILD was classified according to the 2013 idiopathic interstitial pneumonia (IIP) classification. Patients were enrolled from December 2010 to January 2019, and their clinical, laboratory, radiographic, and outcome data were collected from medical records. Survival status was determined through medical records and/or telephone interviews.
Serum DKK1 concentrations were measured using commercially available enzyme-linked immunosorbent assay (ELISA) kits from Elsbscience Inc. (Wuhan, China). The ELISA procedure was performed according to the manufacturer’s instructions, with undiluted serum samples used for detection. Statistical analysis was conducted using PRISM (version 5; GraphPad Software, La Jolla, CA, USA) and SPSS for Windows (version 18.0; SPSS Inc., Chicago, IL, USA). Group comparisons were performed using one-way analysis of variance or the Kruskal-Wallis test, while the t-test was used for comparisons between two groups. Receiver operating characteristic (ROC) curves were employed to determine the optimal cut-off values and validity of variables. Multivariate logistic regression analysis was also performed to evaluate risk factors for mortality.
Among the 35 RA-ILD patients, the mean age was 60.4 ± 1.6 years (range: 50.0–80.0 years), with 18 females (51.4%) and 17 males (48.6%). The average disease duration was 10.1 ± 1.6 years (range: 0.4–40.0 years) at the time of sample collection. The majority of the patients were of Chinese Han ethnicity (95%). Notably, 22 patients (55.0%) were current smokers. The average 28-joint disease activity score (DAS28) was 5.9 ± 1.1 (range: 4.0–7.7), with an average swollen joint count of 6 (range: 3–12) and an arthralgic count of 8 (range: 4–12). At the time of ILD diagnosis, patients were treated with conventional synthetic and biologic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 7, 20%), glucocorticoids (n = 4, 11.4%), methotrexate (MTX) (n = 7, 20.0%), and disease-modifying antirheumatic drugs (DMARDs) (n = 17, 48.6%). RA-ILD patients were significantly more likely to be current or former smokers, regardless of gender or RA duration.
The study found that circulating DKK1 protein levels were significantly higher in RA-ILD patients (mean ± SEM: 0.90 ± 0.17 ng/ml) compared to RA patients without ILD (mean ± SEM: 0.34 ± 0.03 ng/ml, P < 0.0001) and healthy subjects (mean ± SEM: 0.28 ± 0.03 ng/ml, P < 0.0001). This suggests that DKK1 may play a role in the pathogenesis of RA-ILD and could serve as a potential biomarker for the disease.
Further analysis revealed a positive correlation between DKK1 protein levels and C-reactive protein (CRP) (r = 0.4837, P = 0.0032). The mean CRP level in the RA-ILD group (45.5 ± 7.90 mg/L) was significantly higher than that in the RA control group (20.89 ± 4.03 mg/L, P = 0.0086) over a 9-year follow-up period. This indicates that elevated DKK1 levels are associated with increased systemic inflammation in RA-ILD patients.
To evaluate the clinical utility of DKK1 as a biomarker, the study analyzed its sensitivity and specificity for identifying RA-ILD patients. The area under the curve (AUC) for DKK1 was 0.726 (SE: 0.053; range: 0.622–0.830; threshold: 0.78), indicating its potential diagnostic value. Multivariate logistic regression analysis identified DKK1 protein (OR: 15.764; 95% CI: 1.086–228.843; P = 0.043) and CRP (OR: 1.072; 95% CI: 1.000–1.150; P = 0.049) as significant risk factors for mortality in RA-ILD patients.
A follow-up study was conducted to assess the prognostic value of DKK1 in RA-ILD. Of the 35 RA-ILD patients initially enrolled, 8 were lost to follow-up, leaving 27 patients for analysis. Among these, 15 patients (55.6%) were positive for DKK1 based on the ROC threshold. The median survival time was significantly shorter in the DKK1-positive group (2.7 years; range: 1.1–10.3 years) compared to the DKK1-negative group (5.1 years; range: 1.3–12.0 years; P = 0.041). This suggests that elevated DKK1 levels are associated with worse survival outcomes in RA-ILD patients. Notably, the causes of death were available for only a small portion of the 27 RA-ILD patients, but among the known deaths, 5 were pulmonary in nature, indicating that RA-ILD played a significant role in their mortality.
The study concludes that circulating DKK1 protein may serve as a valuable serological biomarker for predicting disease progression and prognosis in RA-ILD patients. However, the study has several limitations, including the small sample size of RA-ILD patients, incomplete follow-up data (e.g., lack of pulmonary function tests or bronchoalveolar lavage fluid [BALF] testing), and the fact that most RA-ILD patients did not undergo surgical lung biopsy to confirm the pathological type. These limitations may explain discrepancies between this study and others in the field. Therefore, further research involving larger and more diverse patient populations is needed to confirm these findings.
In summary, this study highlights the potential of circulating DKK1 as a biomarker for RA-ILD, with implications for both diagnosis and prognosis. Elevated DKK1 levels were associated with increased systemic inflammation, worse survival outcomes, and a higher risk of mortality in RA-ILD patients. These findings warrant further investigation in clinical settings to validate the utility of DKK1 as a predictive biomarker for RA-ILD.
doi.org/10.1097/CM9.0000000000001267
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