SSc is a severe and fatal systemic autoimmune disease that affects multiple organs and systems, including the lung, heart, kidney, skin, and microvascular system[14, 15]. The clinical manifestations of SSc are highly heterogeneous, and there are still no clinical indicators that can accurately predict prognosis and guide treatment decision. Therefore, it is of great clinical significance to explore novel, effective and non-invasive biomarkers that can be used efficiently for the clinical management of SSc patients[16–18].A single prognostic index can not fully describe the whole picture of the disease. Therefore, this study collects the common clinical data in our hospital in the past 10 years and establish a nomogram model of SSc organ damage, so as to provide a basis for clinicians to make treatment plans.
According to Cox analysis and lasso analysis, we determined 5 indexes, including course of disease, mRSS, DUs, OPN, elevated myoglobin. We established a nomogram model and verify that the model is a valuable tool for predicting organ damage in patients with SSc and has good clinical application value. Our results show that patients with longer course of disease, vascular lesions such as DUs, high mRSS scores and muscle involvement, have a higher risk of organ damage.
Our study found that the average OPN of patients with diffuse SSc was 47.5ng/ml, and patients with organ damage had a higher OPN, OPN ≥ 25ng/ml was an independent risk factor for organ damage in SSc. Survival analysis also demonstrated that patients with OPN ≥ 25ng/ml had a higher incidence of organ damage. In idiopathic pulmonary fibrosis, OPN is involved in inflammatory response, ECM deposition and epithelial-mesenchymal transition[19].OPN is associated with poor prognosis of pulmonary fibrosis[20].OPN is produced by a variety of cell types, including B cells, T cells, natural killer cells, macrophages, neutrophils, dendritic cells(DCs), bone cells, epithelial cells, and neuronal cells. Binding of OPN to integrin or CD44 is involved in immune response and fibrosis [21].In terms of immune response, the interaction between OPN and CD44 in Th cells enhances the differentiation of Th1 and Th17 cells. OPN promotes Th1-mediated inflammation and increases IL-17 production by Th17 cells[22].In DCs, OPN inhibited the expression of IL-27 and enhanced the response of Th17 cells[23]. OPN mediates the chemotaxis of macrophages, DCs, mast cells and T cells, stimulates B cells to produce antibodies, regulates the production of nitric oxide, and promotes an effective type 1 immune response[24, 25]. The interaction between OPN and its receptors leads to a decrease in B-cell activity and a significant decrease in IL-6 production[26].In terms of fibrosis, Spp1 + macrophages can proliferate in liver, kidney, heart, lung and other organs, and play a vital role in the progression of organ fibrosis[27–29]. OPN acts on neighboring macrophages in an autocrine or paracrine manner, causing macrophages to polarize into a fibrosis-promoting phenotype (M2), thereby promoting the progression of pulmonary fibrosis[30].These pathophysiological functions are consistent with the pathological process of SSc. OPN is elevated in serum of patients with SSc and is associated with lung, kidney and bone marrow fibrosis[31]. MiR-27a-3p negatively regulates the expression of OPN and ERK signal pathway, which plays an anti-fibrotic role in SSc skin and lung tissue[32]. OPN may be a target for delaying the progression of skin and lung fibrosis in SSc[32].
Our study also found that patients with diffuse SSc had a median mRSS of 15, and mRSS ≥ 16 was an independent risk factor for organ damage. mRSS progression is associated with lung disease progression, overall disease progression, and all-cause mortality[33]. Although mRSS is non-invasive and cost-effective, it also has many disadvantages, including the subjectivity of skin palpation, difficulty in scoring marginal skin sclerosis, and confounding effects caused by tissue inflammation or edema[34, 35]. Therefore, some scholars suggest that standardized training for skin scoring may improve the accuracy[36].
The level of IL-6 in serum of patients with SSc is increased[37], and long-term use of topirazumab can delay the progression of skin and organ damage[38]. However, in our study, IL-6 was elevated in SSc patients with organ damage, but it was not an independent risk factor for organ damage. In the early stage of SSc, mast cells, T, B lymphocytes and macrophages infiltrate the diseased tissue and produce cytokines such as IL-6 and TGF- β, which mediate the transdifferentiation of myofibroblasts and eventually lead to organ fibrosis. In this process, IL-6 is in the upstream of the disease[39].Therefore, we speculated that IL-6 may have a better predictive effect in patients with short disease course and inflammation as the main manifestation, while the disease course of our patient was relatively long, and the pathological change of the disease was mainly chronic fibrosis, serum IL-6 could not well predict the damage of the disease organs.
There are also some limitations in this study. First of all, the data used in this study were all from single-center cases, and multi-center verification was not performed. Secondly, this study was a retrospective analysis with a long follow-up time,so the medical records of patients, especially the description of physical signs, may not be very comprehensive. Thirdly, more indicators can be considered for combined forecasting in the future, which may improve the accuracy of the forecasting model.