Background/Purpose: Systemic sclerosis (SSc) is an intractable connective tissue disease that causes skin and organ fibrosis, and its prognosis is affected by pulmonary hypertension (PH). Attention has been paid to borderline mPAP that does not lead to PH diagnosis at 21 ≤ mean pulmonary arterial pressure < 25 mmHg with a right heart catheter (RHC). In recent years, a mouse model of PH has been established by administering IL-33, which leads to pulmonary artery narrowing. In this model, PH was prevented by suppressing IL-5. Previous reports have demonstrated elevated serum YKL-40 levels in SSc and SSc-PH in Japanese patients with progressive pulmonary capillary lesions. The chitinase-like protein, YKL-40, has been implicated in inflammation, tissue remodeling, and angiogenesis in malignant tumors. We examined the relationship among YKL-40, VEGF, and IL-5 levels, which play an important role in SSc patients with borderline mPAP and PH.

Methods: We conducted a retrospective analysis of 64 SSc patients who were referred to our institution for treatment between August 2014 and April 2017. Group 1 included 47 patients without PH, group 2 included 6 patients with borderline mPAP, and group 3 included 11 patients with PH. Exclusion criteria were arthritis, infection, and malignant tumor complications. We measured serum YKL-40, VEGF, and IL-5 levels using ELISA and examined the correlation between YKL-40 age percentile, which was age-corrected for serum YKL-40 levels. The diagnosis of PH was made using an RHC.

Results: Age, sex (male:female), disease duration, and disease type (diffuse cutaneous SSc: limited cutaneous SSc) were as follows: group 1, 63.5 ± 12.8 years, 7: 40, 10. 2 ± 10.0 years, and 7: 40; in group 2, 66.0 ± 8.5 years, 1: 5, 13.7 ± 12.5 years, and 1:5; and in group 3; 60.7 ± 9.2 years, 1:10, 11.9 ± 11.2 years, 4: 7, respectively. The YKL-40 age percentile, VEGF (pg/mL), and IL-5 (pg/mL) results were as follows: in group 1, 44.2 ± 26.8, 307.8 ± 167.4, and 1.2 ± 0.3; in group 2, 93.3 ± 7.2, 401.0 ± 128.4, and 1.8 ± 0.6; and in group 3, 90.2 ± 11.2, 584.1 ± 387.3, and 1.3 ± 0.4, respectively. YKL-40 level was significantly elevated in groups 2 and 3, VEGF level was higher in group 3 that in group 1, and IL-5 level was higher in group 2 than in group 1. Moreover, a positive correlation was found between YKL-40 and IL-5 levels, with a correlation coefficient of r = 0.3.

Conclusion: YKL-40, a biomarker that reflects vascular lesions of SSc at an early stage, may be a useful biomarker for the early diagnosis of borderline mPAP as it was significantly elevated in groups 2 and 3. We found that IL-5 level was elevated in the borderline mPAP complex, indicating that it may be involved in the progression at an early stage of pulmonary artery injury. As VEGF was elevated in the PH complex, it may also contribute to the progression of the vascular injury. From these results, early therapeutic intervention may improve the survival prognosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/relationship-between-ykl-40-vegf-and-il-5-in-borderline-mpap-and-pulmonary-hypertension-in-systemic-sclerosis/