The value of serum biomarkers in the management of interstitial lung disease in patients with connective tissue disease: a protocol for an observational study

Introduction

Connective tissue disease (CTD) is a type of autoimmune disease characterized by connective tissue inflammation, immune abnormalities, and fibrosis (1). CTD can involve multiple organs and systems, and the lungs are common sites of CTD complications (2). Interstitial lung disease (ILD) is the most common pulmonary manifestation in CTD, and is characterized by varying degrees of fibrosis and inflammation-mediated lung parenchymal damage (3,4). ILD occurs in most types of CTD, including rheumatoid arthritis (RA), idiopathic inflammatory myopathies (IIM), systemic lupus erythematosus (SLE), primary Sjögren’s syndrome (pSS), systemic sclerosis (SSc), and mixed connective tissue disease (MCTD) (5). Accurate and timely diagnosis, stratification, and prognostic estimation are prerequisites for the management of CTD-ILD.

Currently, the gold standard for diagnosing ILD is lung biopsy or high-resolution computed tomography (HRCT) (6). Biopsy is an invasive procedure with a high risk of complications, including prolonged air leak, pneumothorax, bleeding, infection, and worsening oxygenation. These complications may even progress to respiratory failure or perioperative death in some patients (7). In addition, the accuracy of biopsy may be affected by interobserver variation and sampling error (8,9). These disadvantages limit its clinical application to some extent (10). HRCT is another gold-standard method for diagnosing ILD (11). The advantage of HRCT is its non-invasiveness, but it has the disadvantages of high cost and radiation exposure. In addition, the diagnostic accuracy of HRCT largely depends on the radiologists’ experience. In general, both biopsy and HRCT are far from perfect for diagnosing and following up patients with CTD.

By contrast to biopsy and HRCT, serum biomarkers offer the advantages of non-invasiveness, objective results, and short turnaround time, and thus represent an alternative tool for estimating the risk of ILD, diagnosing ILD, and predicting treatment response in patients with CTD (12-14). Currently, many serum biomarkers have been reported to have diagnostic and prognostic value for CTD-ILD, such as interleukin-6 (IL-6), Krebs von den Lungen-6 (KL-6), chemokine (C-C motif) ligand 2 (CCL2), and chemokine (C-X-C motif) ligand 10 (CXCL10) (15,16). However, these biomarkers used alone are unsatisfactory. There are two methods to enhance the value of serum biomarkers in CTD-ILD management: the multi-biomarker approach and the development of high-performance novel biomarkers.

Here, we plan to perform a prospective diagnostic test accuracy study, named “The value of serum biomarkers in diagnosing interstitial lung disease in connective tissue disease: a prospective diagnostic accuracy study” (VELD). The VELD study plans to establish a CTD cohort to: (I) evaluate the diagnostic value of serum biomarkers for ILD in patients with ILD uncertainty; (II) investigate the value of serum biomarkers in predicting ILD in CTD patients without ILD; (III) assess the prognostic value of serum biomarkers in CTD patients with ILD; (IV) screen novel serum biomarkers with multi-omics approaches for better management of CTD-ILD.

Methods

Trial registration

The study has been registered on the Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.aspx) under registration number ChiCTR2600120197.

Setting, periods, inclusion and exclusion criteria, and ethical statement

We intend to enroll patients visiting the Department of Rheumatology and Immunology at The Affiliated Hospital of Inner Mongolia Medical University between 2026 and 2028. Patients who meet all of the following criteria will be included: (I) with definite CTD, including SSc, RA, pSS, polymyositis (PM), dermatomyositis (DM), anti-synthetase syndrome (ASS), SLE and MCTD (17); (II) with ILD uncertainty.

Participants will be excluded if any of the following criteria are met: (I) pregnant; (II) aged <18 years; (III) patients who have undergone HRCT or lung biopsy to confirm or exclude ILD within the last 6 months; (IV) patients with a life expectancy of less than 1 year, such as cancer, end-stage organ failure; (V) patients who refused to receive biopsy or HRCT.

CTD was defined according to established international classification criteria for the underlying rheumatic diseases, in conjunction with clinical manifestations, serological autoantibody profiles, and organ involvement (18-24).

The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The VELD study has been approved by the Ethics Committee of The Affiliated Hospital of Inner Mongolia Medical University (KY2025185). Written informed consent will be obtained from all participants or their legally authorized representatives prior to enrollment. The results of VELD will be submitted to international peer-reviewed scientific journals or conferences in the fields of laboratory medicine, rheumatology, respirology, and immunology.

Specimen and data collection

After enrollment, all participants will donate 10 mL of blood into a coagulant-free tube. The blood specimens will be centrifuged within four hours after collection, and the serum will be aliquoted and stored at −80 ℃. Only baseline serum will be obtained.

We will use a case report form to record participants’ clinical details, including demographics, history, type and duration of CTD, serum chemistries, organ involvement, signs, and symptoms.

Sample size estimation

This is not a hypothesis-driven study, and we thus did not estimate the sample size before enrolling subjects. This study does not involve treatment, and the blood will be connected along with routine chemistries; therefore, the associated side effects are theoretically negligible. It is estimated that more than 500 subjects will be enrolled.

Diagnostic criteria for ILD and its treatment response

The diagnostic criteria for ILD were based on HRCT and lung biopsy with multidisciplinary discussion whenever feasible (25). All participants will receive HRCT after enrollment. The final diagnosis will be made independently by two investigators (G.L.D. and Z.Y.D.) without knowledge of the biomarkers under investigation.

All participants, either with or without ILD, will undergo routine follow-up every 3 months to confirm: (I) when patients without ILD will progress to ILD; (II) whether the patients with ILD are responsive to treatment. The attending physician decides whether to perform HRCT and pulmonary function tests at each follow-up, based on the patient’s condition and wishes. The definition of treatment responsiveness was: improvement in clinical symptoms, pulmonary function, or HRCT findings; in fibrosing ILD, disease stabilization without further progression was also considered a favorable response. In addition to data obtained from routine follow-up visits, information from patients seeking medical attention for worsening symptoms, increased disease activity, or other reasons will also be used in the analysis.

Disease progression was defined as a decline in forced vital capacity (FVC) of ≥10% predicted, or a decline in FVC of 5–9% predicted accompanied by a decline in lung diffusing capacity for carbon monoxide (DLCO) of ≥15% (26,27). A lung biopsy will be performed if HRCT is inconclusive or necessary. However, in our experience, the proportion of patients who make an informed refusal of lung biopsy exceeds 95% at our institution. Treatment responsiveness will also be assessed independently by two investigators (G.L.D. and Z.Y.D.), who are blinded to the biomarkers under investigation.

Biomarkers will be investigated in the VELD study

Some serum biomarkers intended to be investigated are listed in Table 1. ELISA, electrochemiluminescence, Luminex, and quantitative proteomics assays will detect the protein markers. The metabolites will be detected by liquid chromatography tandem mass spectrometry (LC-MS/MS). The nucleic acid will be detected by transcriptomics, and quantitative polymerase chain reaction (qPCR) will be used to verify differentially expressed genes screened by transcriptomics. Novel biomarkers not listed in Table 1 can also be studied (validation study). The predictive or diagnostic value of routine biomarkers, such as complete blood counts and liver and kidney function tests, will be investigated at the single-biomarker level or using a predictive model. In addition, we will use metabolomics, proteomics, and transcriptomics approaches to screen novel serum biomarkers that can help predict or diagnose ILD (e.g., cell-free nucleic acids, cytokines, exosomal biomarkers), as shown in Table 2.

In addition to serum biomarkers, this observational study will also evaluate the efficacy and safety of some interventions for CTD-ILD.

Study framework

A flowchart depicting the VELD study framework is shown in Figure 1. Subjects who meet the inclusion and exclusion criteria will be invited to participate in this study. They will be scheduled for a routine diagnostic procedure at the discretion of their attending clinicians.

Figure 1 Summary of the VELD study. ANOVA, analysis of variance; CTD, connective tissue disease; HRCT, high-resolution computed tomography; ILD, interstitial lung disease.

Subsequently, patients were followed up every 3 months to confirm: (I) when patients without ILD progressed to ILD; (II) the treatment response of the patients with ILD. We plan to investigate the following topics: (I) the predictive value of serum biomarkers for ILD in CTD patients without ILD; (II) the diagnostic value of serum biomarkers for ILD in CTD patients with uncertainty of ILD; (III) the predictive value of serum biomarkers for treatment response in CTD patients with ILD. In addition, the efficiency and safety of some ILD treatment approaches will also be investigated.

Statistical analysis

The normality of continuous data will be tested using the Kolmogorov-Smirnov test. For normally distributed data, independent t-tests or one-way analysis of variance (ANOVA) will be used for comparison; otherwise, the Mann-Whitney U test will be used to assess the clinical characteristics and biomarker levels of patients with and without ILD. The Chi-square test will be used to compare categorical data. The Spearman or Pearson method will be used to analyze the relationship between biomarkers or routine laboratory tests and patient clinical characteristics.

Receiver operating characteristic (ROC) curve analysis will be used to analyze the diagnostic accuracy of serum biomarkers for ILD. The area under the ROC curve (AUC) will be used to assess the overall diagnostic accuracy of the biomarkers. Decision curve analysis (DCA) will be used to evaluate the potential net benefit of serum biomarkers. A diagnostic model will be established using a logistic regression or other machine learning methods, and nomograms and forest plots will be used for graphical visualization. We will analyze whether biomarkers provide incremental diagnostic information beyond traditional diagnostic tools and clinical details (e.g., age, sex, smoking history, type of autoimmune disease) using the net reclassification index (NRI) and integrated discrimination index (IDI) (36). Propensity score matching will be used to evaluate the efficiency of some ILD treatment approach.

All analyses will be performed using SPSS and R (http://www.r-project.org).

Discussion

ILD is a common and serious complication of CTD, and it can markedly worsen patient prognosis (37). HRCT and lung biopsy are considered the gold standards for diagnosing ILD; however, both are costly, and HRCT exposes patients to ionizing radiation. Therefore, it is of substantial clinical importance to investigate whether serum biomarkers can assist in diagnosing, risk-stratifying, and prognosticating CTD-associated ILD.

The VELD study aims to establish a cohort of patients with CTD and to collect baseline serum specimens. The primary objective is to evaluate the diagnostic value of serum biomarkers for ILD in patients with CTD. Currently, the most widely used biomarkers for ILD in clinical practice include KL-6, SP-D, and several tumor markers (13,38). In this study, we will validate the diagnostic performance of these established biomarkers. In addition, we will assess emerging biomarkers such as MMP7 (25) and CXCL10 (34). Certain conventional indices, including erythrocyte sedimentation rate and the neutrophil-to-lymphocyte ratio, have also been reported to be elevated in patients with ILD, although their diagnostic accuracy remains modest (38). The diagnostic value of these conventional indices will be used. Predictive models based on these conventional indices are easy to perform and may thus facilitate the management of CTD-ILD.

Using serum samples and clinical data from the VELD cohort, we will address several key questions in CTD-ILD diagnosis. First, whether diagnostic models based on routine clinical indices can improve the accuracy of ILD diagnosis. A strength of our study is that we will use the Least Absolute Shrinkage and Selection Operator (LASSO) regression or the Boruta algorithm to select variables, followed by the development of machine learning-based diagnostic models. Furthermore, we plan to develop a web-based calculator or mobile application to facilitate clinical implementation of the model. Second, we will employ NRI and IDI to determine whether emerging biomarkers, such as MMP7 and CXCL10, provide incremental diagnostic value beyond conventional biomarkers. Previous studies have not investigated this issue. We will also apply our previously proposed resampling method with an upper age limit to investigate the impact of age, renal function, and other factors on the biomarker’s performance (39). Third, we will compare proteomic, metabolomic, and transcriptomic profiles between CTD patients with and without ILD to identify novel diagnostic biomarkers, including proteins, cell-free nucleic acids, metabolites, and exosome-derived components, and to evaluate their diagnostic performance. Overall, we believe that the VELD study will expand current knowledge of diagnostic biomarkers for CTD-ILD.

As CTD progresses, a subset of patients will develop ILD. For CTD patients without established ILD, routine use of antifibrotic agents solely to prevent ILD is not recommended. Instead, appropriate immunomodulatory therapy should be selected based on the underlying CTD to control disease activity, with close monitoring including pulmonary function tests and HRCT. Early intervention should be initiated once subclinical or early ILD is detected. This approach is justified because the overall incidence of progression to ILD among CTD patients is relatively low, and indiscriminate use of preventive pharmacotherapy may result in adverse effects that outweigh potential benefits. Therefore, identifying risk factors for ILD in CTD patients without established disease is essential for risk stratification and individualized management. Several risk factors have been reported, including high-risk CTD subtypes (particularly SSc, pSS, IIM, and MCTD), sex, age, smoking history, disease duration, disease activity, inflammatory markers, and autoantibody positivity (40). However, the current evidence remains insufficient for accurate risk stratification.

In this study, we will use Kaplan-Meier survival analysis, Cox proportional hazards model, and restricted cubic spline to evaluate the association between diagnostically relevant biomarkers and the risk of ILD. In addition, we will develop biomarker-based prediction models and construct nomograms for visualization, thereby identifying high-risk subpopulations for ILD. These findings may facilitate the design of future randomized controlled trials to evaluate the efficacy and safety of targeted interventions in high-risk populations.

For patients with established CTD-ILD, treatment strategies generally vary by CTD subtype. For example, patients with SSc-ILD are commonly treated with tocilizumab, mycophenolate mofetil, rituximab, or cyclophosphamide. Patients with IIM-ILD, RA-ILD, pSS-ILD, MCTD-ILD, and SLE-ILD are typically managed with immunosuppressive therapy. In addition, nintedanib is recommended for patients with SSc-ILD and CTD-ILD who exhibit progressive pulmonary fibrosis, while pirfenidone is suggested for patients with RA-ILD with a usual interstitial pneumonia pattern (37). However, not all patients respond to these treatment regimens. Early identification of treatment-responsive individuals may improve therapeutic efficiency.

The results of the VELD study will be reported in accordance with the Standards for Reporting of Diagnostic Accuracy Studies (STARD) guideline (41). For studies involving multivariable prediction models, reporting will adhere to the Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis (TRIPOD) statement (42).

To ensure internal validity and external generalizability, several methodological measures will be implemented. We will preferentially use consecutive recruitment of patients to improve participant representativeness, thereby enhancing the applicability of the findings. When determining ILD status, clinicians responsible for diagnosis will be blinded to the biomarker results to minimize incorporation bias (43). Furthermore, prespecified biomarker cutoff values will be used to avoid bias introduced by data-driven threshold selection (44).

There are some limitations with the VELD study. First, it is a single-center study conducted at a teaching hospital in North China, and the disease spectrum of CTD, as well as the prevalence of CTD-ILD, varied across different areas and hospital levels. Therefore, the generalizability of our findings to other areas should be interpreted with caution. Second, we used the stored serum specimen to determine biomarker levels, and the long-term stability of these biomarkers remains unknown. Third, the prevalence and risk ratio of ILD vary across different types of CTD (45), and it is thus essential to perform subgroup analyses with specific CTD; however, approximately half of the CTD in our institution is RA. Therefore, although high statistical power can be achieved when analyzing patients with RA, it is unclear whether we can obtain sufficient power to analyze patients with CTDs other than RA. Fourth, consider that multiple blood collections may dampen the subjects’ enthusiasm for participation; only baseline serum was collected. This limitation prevents us from analyzing biomarker dynamics and participant outcomes, including treatment responsiveness and risk of ILD.

In summary, the VELD study is a prospective, double-blind diagnostic study exploring the diagnostic value of serum biomarkers in patients with CTD-ILD. Despite its limitations, this study still holds promise for providing new insights and perspectives on the diagnosis, risk stratification, and prognosis of CTD-ILD.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1073/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1073/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The VELD study has been approved by the Ethics Committee of The Affiliated Hospital of Inner Mongolia Medical University (KY2025185). Written informed consent will be obtained from all participants or their legally authorized representatives prior to enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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