Protective Effects of Apolipoprotein A and High-Density Lipoprotein Cholesterol Against Interstitial Lung Disease in Rheumatoid Arthritis: The Mediating Role of Systemic Inflammation

Abstract

Introduction

Interstitial lung disease (ILD) is a progressive fibrotic condition that markedly reduces survival and increases mortality in patients with rheumatoid arthritis (RA). Dysregulated lipid metabolism is associated with the progression of both RA and ILD. However, its relationship with the risk of ILD in the RA population remains uncertain. This study aimed to determine the association between lipid traits and incident ILD in an RA population, as well as the mediating role of systemic inflammation.

Methods

This prospective cohort study included 4229 UK Biobank participants with RA and no baseline ILD. Cox proportional-hazards models were used to investigate the association between six lipid traits and ILD risk. Systemic inflammation was estimated using the INFLA-score. Generalized structural equation modeling was employed to investigate the mediating effect of the INFLA-score on the relationship between lipid traits and ILD incidence.

Results

After a mean follow-up of 14.736 years, 152 incident ILD cases were recorded. High serum levels of apolipoprotein A (ApoA) and high-density lipoprotein cholesterol (HDL-C) were independent protective factors against incident all-cause ILD in RA, associated with a 61.5% and 51.3% risk reduction in ILD per standard deviation (SD) increase in ApoA and HDL-C, respectively (ApoA: HR 0.385, 95% CI 0.189–0.783, p = 0.008; HDL: HR 0.487, 95% CI 0.280–0.847, p = 0.011). These associations were more pronounced in males, relatively young patients and ever-smokers. Systemic inflammation accounted for 88.5% of the association with ApoA and 63.6% with HDL-C, respectively.

Conclusions

Elevated ApoA and HDL-C were independently associated with a lower risk of incident all-cause ILD in RA. The associations appear to be largely driven by low-grade systemic inflammation.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40744-026-00866-x.

Key Summary Points

Why carry out this study?

Interstitial lung disease (ILD) is a severe complication of rheumatoid arthritis (RA) and is associated with high mortality. However, its risk factors remain not yet fully understood.

Dysregulated lipid metabolism is commonly observed in both RA and ILD. Nevertheless, it remains unknown whether this dysregulated lipid metabolism is associated with, or contributes to, the risk of ILD in RA, and whether systemic inflammation mediates this relationship.

We hypothesized that specific lipid traits are associated with incident ILD in patients with RA, and that these associations are mediated by systemic inflammation.

What was learned from the study?

In this large prospective cohort, higher serum levels of apolipoprotein A (ApoA) and high-density lipoprotein cholesterol (HDL-C) were independently associated with a lower risk of incident ILD in RA. These associations were largely mediated by low-grade systemic inflammation.

These findings suggest that routine examination of HDL-C and ApoA may aid in stratifying the risk of incident ILD in RA, and that strategies to improve these lipid markers may offer a novel preventive approach.

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory, and autoimmune disorder characterized by progressive joint damage, systemic complications, and elevated mortality rates [1]. It affects approximately 0.5–1.5% of the global adult population, with an estimated 18 million individuals worldwide suffering from the disease [2, 3]. Interstitial lung disease (ILD) is a serious but rare extra-articular manifestation in RA, affecting 1.7–2.2% of patients each year [4]. RA-associated ILD (RA-ILD) is a progressive fibrotic lung condition that significantly reduces survival, leading to a mortality rate up to tenfold higher in patients with RA-ILD compared to those with RA alone [5–7]. Several demographic and clinical factors, including male sex, smoking, aging, and obesity, are established risk factors for the incidence of ILD in patients with RA [8, 9]. Although dysregulated lipid metabolism is commonly observed in patients with RA, it remains unknown whether this dysregulated lipid metabolism is associated with, or contributes to, the risk of developing ILD during the course of RA [10].

Numerous studies have reported that patients with active or untreated RA often present a distinctive lipid profile, characterized by decreased serum levels of high-density lipoprotein cholesterol (HDL-C) and increased levels of total cholesterol and low-density lipoprotein cholesterol (LDL-C) [11–13]. Typically, serum total cholesterol and HDL-C levels in RA are inversely correlated with disease activity [12]. Notably, dysregulated lipid metabolism is also one of the major metabolic alterations in patients with progressive ILD. A cross-sectional analysis measuring lung attenuation by cardiac CT scans in 6700 adults demonstrated that HDL-C exerted a protective effect against ILD, independent of demographics, smoking, and inflammatory biomarkers [14]. However, the specific association between lipid traits and ILD in patients with RA has been rarely evaluated. No prospective cohort study has yet examined this relationship to determine whether lipid abnormalities are associated with incident ILD in an RA population. Understanding this relationship is clinically relevant, as lipids are modifiable and could offer a novel target for prevention or risk stratification if a causal link is confirmed.

Inflammation is a central driver of RA disease activity and is closely associated with the development of ILD in RA [15]. Furthermore, systemic inflammation is increasingly recognized as a key driver of alterations in lipid structure, composition, and serum levels, although the precise mechanisms underlying these effects are still being elucidated [16]. A recent observational cohort study reported that the ratio of HDL-C to C-reactive protein (CRP) is a powerful predictor of clinical outcomes in patients with idiopathic pulmonary fibrosis, a chronic and progressive ILD of unknown etiology. This finding suggested that the association between ILD and dysregulated lipid metabolism may be mediated by chronic inflammation [17].

This study aimed to investigate the association between lipid traits with incident ILD in patients with RA, using the data from a large cohort of more than 4000 participants followed up for over 10 years from UK Biobank. Specifically, we aimed to: (1) examine whether the six lipid traits, including apolipoprotein A (ApoA), apolipoprotein B (ApoB), LDL-C, HDL-C, triglycerides, and lipoprotein A, were associated with the risk of developing all-cause ILD among patients with RA; (2) assess the role of age and sex in these associations; (3) investigate the potential mediating role of low-grade systemic inflammation in the association between lipid traits and all-cause ILD in RA. We hypothesized that levels of specific lipid traits would be associated with the incidence of ILD in patients with RA, and that systemic inflammation would mediate this association.

Methods

Study Design and Population

The UK Biobank is an ongoing longitudinal study that included over 500,000 adults aged 40–69 years from across the United Kingdom. The baseline examination took place at one of 22 assessment centers across the country between 2006 and 2010 [18]. To ensure the study population consisted of participants diagnosed with RA, the present analysis was restricted to individuals who had been diagnosed with RA at baseline or prior to baseline. Among these participants, those with a prevalent diagnosis of ILD at baseline were excluded. We also excluded participants without measurement of any lipid traits (including ApoA, ApoB, LDL-C, HDL-C, triglycerides, and lipoprotein A) or with invalid baseline data for any covariates or inflammatory biomarkers. Participants were followed up from the date of enrolment until their first diagnosis of ILD, death, loss to follow-up, or the censoring date of December 31, 2024, whichever occurred first.

Ascertainment of RA and ILD Cases

The UK Biobank cohort with available clinical data has been previously described [19, 20]. Briefly, RA and all-cause ILD cases were defined using hospital inpatient records, primary care records, and death registry data. Primary and secondary hospital diagnosis (hospital records) and causes of death (death register) for participants with RA and ILD were identified using International Classification of Diseases, 10th version (ICD-10) codes [20–22]. The specific codes used to ascertain RA and ILD were selected and validated by the UK Biobank outcome adjudication group (Resource 8319, version 2.0, Jan 2022, Supplementary Table S1).

Measurement of Lipid Traits

The following lipid traits were measured in the blood samples collected at baseline recruitment: ApoA, ApoB, LDL-C, HDL-C, triglycerides, and lipoprotein A. As described previously, 45 ml of blood was collected during the baseline assessment visit [23]. Serum lipid traits were measured by immunoturbidimetric analysis on a Beckman automated hematology analyzer (Beckman Coulter AU5800), and lipoprotein A was measured by immunoturbidimetric analysis using the Randox AU5800. Apolipoproteins were measured in g/l, while triglycerides were measured in mmol/l.

Calculation of INFLA-Score

Low-grade inflammation was assessed using the INFLA-score, a composite index based on four inflammatory biomarkers: C-reactive protein (CRP), white blood cell count, platelet count, and granulocyte-lymphocyte ratio (GrL). Each biomarker was divided into 10 deciles and scored from − 4 (1st decile) to + 4 (10th decile), with intermediate deciles scored accordingly. The total INFLA-score, ranging from − 16 to + 16, represents an individual’s level of low-grade inflammation, with higher scores indicating a more pronounced inflammatory status [24, 25].

Assessment of Covariates

Baseline characteristics, including sex (female and male), age (in years), body mass index (BMI, kg/m²), smoking status, ethnicity, education level, and socioeconomic status, were selected as covariates for the analysis. Specifically, smoking status was categorized as never smoker, former smoker, or current smoker according to self-report. Ethnicity was self-reported and dichotomized as White vs. non-White, with the latter including Asian British (Indian, Pakistani, Bangladeshi), Chinese, Black, multiracial, or other ethnic groups, according to the 2001 UK census categories. Education level was self-reported and categorized as follows: higher education as completion of a college/university degree or professional qualification; secondary education as completion of both the first and second/final stages of secondary education; and vocational/other education as work-related practical qualifications and other qualifications. Socioeconomic status was assessed using the Townsend Deprivation Index, which combines information on social class, employment, and car availability, with quintile one as the least deprived and quintile five as the most deprived [26]. RA medications were recorded for each patient and stratified into four categories: no RA medication; corticosteroid use only; disease-modifying antirheumatic drugs (DMARDs) use only (including use of synthetic DMARDs and biologic DMARDs), and a combination of corticosteroids and DMARDs use [22]. The full list of eligible drugs recorded by the UK Biobank is provided in Supplementary Table 2. Statin use was also recorded, and the full list of eligible statins is also included in Supplementary Table 2 [27].

Statistical Analysis

Baseline characteristics of the participants were summarized by ILD status as frequencies (percentages) for categorical variables, mean ± SD for normally distributed continuous variables, and median (25th, 75th percentile) for non-normally distributed continuous variables.

Cox proportional-hazards regression models were used to estimate the associations between each lipid trait and incident ILD. Each lipid trait was entered into the model as a continuous variable, separately, to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs). Models were first minimally adjusted for age and sex, followed by further adjustment for BMI, ethnicity, education level, socioeconomic status, smoking status, use of RA medication, and use of statin. Next, stratified Cox proportional-hazard regression models were used to explore whether the association between each lipid trait and incident ILD varied across key demographic and exposure characteristics, including sex (males vs. females), age (< 60 years vs. ≥ 60 years), and smoking history (ever vs. never smokers). Specifically, smoking history was dichotomized as ever-smokers, comprising current and previous smokers, versus never-smokers.

The association between the INFLA-score and incident ILD was evaluated utilizing restricted cubic splines, positioning four knots at fixed intervals in the INFLA-score distribution:  − 4, 0, 4, and 8. To investigate the potential mediating effect of the INFLA-score on the relationship between lipid traits and incident ILD, we employed generalized structural equation modeling (GSEM). This analysis estimated the direct, indirect, and total effects through 500 replications of bias-corrected bootstrapping and generated confidence intervals for these estimates. The mediation analysis was adjusted for age, sex, BMI, ethnicity, education level, socioeconomic status, smoking status, use of RA medication, and use of statin.

In sensitivity analyses, we repeated the primary analyses after adjusting age as the only covariate. We also assessed the associations between lipids and ILD in patients with RA across follow-up periods by performing time-restricted Cox proportional-hazards analysis. For each cutoff (5, 10, and 15 years), follow-up time was truncated at the specified duration using administrative censoring. Participants with ILD diagnoses occurred after the cutoff were censored at the cutoff time. This approach estimates the hazard of ILD occurring within the first 5, 10, and 15 years after baseline, respectively, and excludes events occurring outside the time window.

All hypotheses were two-tailed tested, and p < 0.05 was considered statistically significant. Data analyses were performed using RStudio version 4.4.3.

Ethical Approval

The present study employs data from the UK Biobank study which received approval from the National Information Governance Board for Health and Social Care and the National Health Service North West Centre for Research Ethics Committee. All participants provided electronically signed informed consent when attending baseline assessment. This study has been conducted using the UK Biobank Resource under the Application Number 199603.

Results

Baseline Characteristics of the Study Population

At baseline, a total of 6769 participants diagnosed with RA were assessed. After excluding 70 with prevalent ILD, 2150 with missing data on lipid traits, 319 with missing INFLA-score-related data, and one with missing data on medication records, a total of 4229 participants were included in the analysis (Supplementary Fig. S1). Baseline characteristics of the study participants are summarized in Table 1. The baseline characteristics of participants grouped by sex are presented in Supplementary Table S3. Of the included participants, 2,918 (69.000%) were women, and the mean age was 59.135 ± 7.193 years. A total of 152 cases (3.594%) of incident ILD were recorded, and the mean follow-up time was 14.736 ± 3.263 years. Compared to participants who eventually developed ILD, those without ILD were more likely to be younger, female, and have no history of smoking or alcohol use, and to have a higher education level at baseline. Participants who developed ILD were more likely to use statin (29.605% vs. 20.309%, p = 0.007) and to receive any RA medication, including corticosteroids and DMARDs (67.105% vs. 44.837%, p < 0.001), compared to those without ILD.

Table 1.

Baseline characteristics of participants

	Non-incident ILD (n = 4077)	Incident ILD (n = 152)	p value
Follow-up time (years, mean ± SD)	14.999 ± 2.926	7.683 ± 3.874	< 0.001
Age (years, mean ± SD)	58.994 ± 7.218	62.914 ± 5.251	< 0.001
Sex (N, %)			< 0.001
Female	2841 (69.684%)	77 (50.658%)
Male	1236 (30.316%)	75 (49.342%)
BMI (kg/m2, mean ± SD)	28.328 ± 5.516	28.956 ± 5.260	0.168
Smoking status (N, %)			< 0.001
Current	485 (11.896%)	24 (15.789%)
Previous	1609 (39.465%)	89 (58.553%)
Never	1983 (48.639%)	39 (25.658%)
Alcoholic intake status (N, %)			0.019
Current	3483 (85.430%)	133 (87.500%)
Previous	298 (7.309%)	16 (10.526%)
Never	296 (7.260%)	3 (1.974%)
Ethnicity (N, %)			0.084
Non-White	226 (5.543%)	3 (1.974%)
White	3851 (94.457%)	149 (98.026%)
Education level* (N, %)			0.005
Higer	1468 (36.007%)	46 (30.263%)
Secondary	1471 (36.080%)	45 (29.605%)
Vocational, others	1138 (27.913%)	61 (40.132%)
Socioeconomic status quintile (N, %)			0.732
1 (least deprived)	736 (18.052%)	30 (19.737%)
2–4	2298 (56.365%)	87 (57.237%)
5 (most deprived)	1043 (25.583%)	35 (23.026%)
Use of statin (N, %)			0.007
No	3249 (79.691%)	107 (70.391%)
Yes	828 (20.309%)	45 (29.605%)
Treatment of RA (N, %)			< 0.001
No use of any medication	2249 (55.163%)	50 (32.895%)
Use steroids only	100 (2.453%)	7 (4.605%)
Use DMARDs (including sDMARDs and bDMARDs)	1507 (36.963%)	75 (49.342%)
Use both steroids and DMARDs	221 (5.421%)	20 (13.158%)
Lipid traits
ApoA (g/l, mean ± SD)	1.522 ± 0.264	1.443 ± 0.290	< 0.001
ApoB (g/l, mean ± SD)	1.018 ± 0.235	0.955 ± 0.232	0.237
HDL-C (mmol/l, mean ± SD)	1.421 ± 0.363	1.308 ± 0.363	< 0.001
LDL-C (mmol/l, mean ± SD)	3.496 ± 0.865	3.383 ± 0.895	0.117
Triglycerides (mmol/l, mean ± SD)	1.767 ± 0.992	1.980 ± 1.148	0.010
Lipoprotein A (mmol/l, mean ± SD)	45.528 ± 49.375	37.627 ± 42.251	0.052

Bold indicates statistically significant difference with p value 0.05

ILD interstitial lung disease, BMI body mass index, SD standard deviation, ApoA apolipoprotein A, ApoB apolipoprotein B, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, RA rheumatoid arthritis, sDMARDs synthetic disease-modifying antirheumatic drugs, bDMARDs biologic disease-modifying antirheumatic drugs

Lipid Traits and Incident ILD

Associations between each lipid trait and the incidence of ILD in patients with RA are shown in Table 2. ApoA demonstrated a statistically significant association with ILD risk in the model adjusted for age and sex (HR 0.366, 95% CI 0.182–0.737, p = 0.005). Although the effect was slightly attenuated after further adjusting for BMI, ethnicity, education level, socioeconomic status, smoking status, use of statin, and use of RA medication, the protective effect remained significant, with each standard deviation (SD) increase in ApoA associated with a 61.5% risk reduction in ILD (HR 0.385, 95% CI 0.189–0.783, p = 0.008). HDL-C also showed a significant protective effect in the minimally adjusted model (HR 0.494, 95% CI 0.291–0.836, p = 0.009). The protective effect remained significant in the fully adjusted model, with each SD increase in HDL-C associated with a 51.3% risk reduction in ILD (HR 0.487, 95% CI 0.280–0.847, p = 0.011). Additionally, an increased level of triglycerides was associated with a significantly higher risk of incident ILD in the minimally adjusted model (HR 1.162, 95% CI 1.008–1.340, p = 0.039), though this effect was attenuated to non-significant after adjusting for covariates. Conversely, lipoprotein A demonstrated a significant negative association in the fully adjusted model (HR 0.996, 95% CI 0.992–1.000, p = 0.033), but this association was not observed in the minimally adjusted model. No other lipid traits, including ApoB and LDL-C, demonstrated statistically significant associations with ILD risk in either model specification, suggesting that no association was observed between these lipid traits and ILD risk in patients with RA.

Table 2.

Risk of incident interstitial lung disease for lipid traits

Lipid traits	Proportional Cox model	β	Hazard ratio (95% CI)	p value
ApoA	Minimally adjusted model*	− 1.006	0.366 (0.182–0.737)	0.005
	Fully adjusted model†	− 0.954	0.385 (0.189–0.783)	0.008
ApoB	Minimally adjusted model	− 0.160	0.852 (0.431–1.685)	0.645
	Fully adjusted model	− 0.104	0.901 (0.421–1.928)	0.789
HDL-C	Minimally adjusted model	− 0.706	0.494 (0.291–0.836)	0.009
	Fully adjusted model	− 0.719	0.487 (0.280–0.847)	0.011
LDL-C	Minimally adjusted model	− 0.053	0.949 (0.787–1.143)	0.579
	Fully adjusted model	− 0.027	0.973 (0.785–1.207)	0.805
Triglycerides	Minimally adjusted model	0.150	1.162 (1.008–1.340)	0.039
	Fully adjusted model	0.130	1.139 (0.979–1.324)	0.093
Lipoprotein A	Minimally adjusted model	− 0.003	0.997 (0.993–1.000)	0.065
	Fully adjusted model	− 0.004	0.996 (0.992–1.000)	0.033

Bold indicates statistically significant difference with p value 0.05

ILD interstitial lung disease, BMI body mass index, SD standard deviation, ApoA apolipoprotein A, ApoB apolipoprotein B, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol. Bold indicates statistically significant difference with p value

*Adjusted for age and sex

^†Adjusted for age, sex, BMI, ethnicity, education level, socioeconomic status, smoking status, use of statin, and treatment of RA

Analyses Stratified by Age, Sex and Smoking History

There was limited evidence for a sex difference in the association between lipid traits and the risk of incident ILD in patients with RA. Sex-specific associations between lipid traits and ILD are presented in Fig. 1A. When stratified by sex, a higher level of ApoA was significantly associated with a lower risk of ILD in male patients with RA (HR 0.243, 95% CI 0.079–0.750, p = 0.014), whereas no significant association was detected in female patients with RA (HR 0.525, 95% CI 0.206–1.335, p = 0.176). Furthermore, a higher level of HDL-C was significantly associated with a lower risk of incident ILD in male patients (HR 0.362, 95% CI 0.146–0.894, p = 0.028), whereas this association was not observed in female patients with RA (HR 0.594, 95% CI 0.290–1.216, p = 0.154). No association was found between other lipid traits (including ApoB, LDL-C, and lipoprotein A) and ILD in both male and female patients with RA. These results indicated that the association between lipid traits (particularly for ApoA and HDL-C) and incident ILD showed a clear and significant separation in male and female patients with RA.

Fig. 1.

Forest plot for multivariate-adjusted hazard ratios for incident ILD in patients with RA per standard deviation increase in each lipid trait, stratified by sex (A) and smoking history (B). Adjusted for age, sex, body mass index, ethnicity, education level, socioeconomic status, smoking status, use of RA medications, and use of statin. ILD interstitial lung disease, ApoA apolipoprotein A, ApoB apolipoprotein B, HDL-C high-density lipoprotein cholesterol, LDL-C low-density lipoprotein cholesterol, HR hazard ratio, CI confidence interval

When stratified by smoking status (ever- vs. never-smokers), high levels of ApoA and HDL-C were associated with a reduced ILD risk among ever-smokers (Fig. 1B; ApoA: HR 0.346, 95% CI 0.152–0.788, p = 0.012; HDL-C: HR 0.421, 95% CI 0.220–0.807, p = 0.009, respectively), while a high level of triglycerides was associated with an increased risk in the same group (HR 1.235, 95% CI 1.052–1.452, p = 0.010). Lipoprotein A showed a modest protective effect in ever-smokers (HR 0.996, 95% CI 0.992–1.000, p = 0.045). No statistically significant associations were observed for any lipid traits among never-smokers. Our data suggested that the relationship between lipid levels and ILD risk tended to be more prominent in the RA population with a smoking history.

When stratified by age, high levels of ApoA and HDL-C were associated with a reduced ILD risk among younger participants aged < 60 years (Supplementary Figure S2; ApoA: HR 0.199, 95% CI 0.042–0.955, p = 0.044; HDL-C: HR 0.276, 95% CI 0.082–0.935, p = 0.039, respectively), while these associations were not observed in participants aged ≥ 60 years. Additionally, elevated triglycerides significantly increased ILD risk in younger patients with RA (Supplementary Figure S2, HR 1.352, 95% CI 1.115–1.641, p = 0.002), while no significant association was observed among patients aged ≥ 60 years (HR 0.984, 95% CI 0.801–1.209, p = 0.879). Lipoprotein A showed a modest protective effect only in the older group (HR 0.996, 95% CI 0.991–1.000, p = 0.044). These findings suggested that the relationship between lipid traits and ILD risk differs by age, with a more pronounced role for triglycerides, ApoA, and HDL-C in younger RA patients.

The Mediating Role of Low-Grade Inflammation

The restricted cubic spline analysis revealed a clear linear relationship between INFLA-score and incident ILD (linear model AIC: 2391.92, nonlinear model AIC: 2396.67, overall association p < 0.001, nonlinear p = 0.741). A steep increase in ILD risk was strongly associated with a higher INFLA-score (Fig. 2).

Fig. 2.

Association between chronic low-grade systemic inflammation (INFLA-score) and risk of incident ILD in patients with RA. The association between INFLA-score and risk of incident ILD was analyzed using linear regression with restricted cubic splines with 4 knots (− 4, 0, 4, and 8). The model was adjusted for age, sex, body mass index, ethnicity, education level, socioeconomic status, smoking status, use of RA medications, and use of statin. CI confidence interval

The GSEM model was employed to evaluate the potential mediating effect of the INFLA-score on the relationship between HDL-C and incident ILD (Fig. 3, Supplementary Table S4). The analysis revealed a statistically significant mediation effect of HDL-C on ILD risk through the INFLA-score (Estimate: − 0.260, p < 0.001), indicating that higher HDL-C levels were associated with a lower ILD risk via the mediation effect of reducing the chronic low-grade inflammation (INFLA-score). The model also showed a significantly protective total effect of HDL-C on the risk of ILD (Estimate: − 0.294, p = 0.014), while the direct effect of HDL-C on ILD, which represented a pathway independent of inflammation, was not statistically significant (Estimate: − 0.034, p = 0.790). The mediation analysis revealed that the INFLA-score accounted for approximately 88.5% of the total association between HDL-C and ILD risk (p = 0.023). The results indicated that the protective effect of HDL-C on the incidence of ILD in patients with RA is primarily mediated by suppressing the chronic systemic low-grade inflammation.

Fig. 3.

Mediation effect of chronic low-grade inflammation (INFLA-score) on the association between lipid traits and incident ILD in patients with RA. Mediation analysis was adjusted for adjusted for age, sex, body mass index, ethnicity, education level, socioeconomic status, smoking status, use of RA medications, and use of statin. Bootstrapping with 500 replications was used to estimate the coefficient and significant levels. ILD interstitial lung disease, ApoA apolipoprotein A, HDL-C high-density lipoprotein cholesterol

Similarly, the GSEM model identified the INFLA-score as a significant mediator in the relationship between ApoA and ILD risk (Fig. 3, Supplementary Table S4). A statistically significant indirect effect was observed (Estimate: − 0.245, p < 0.001), indicating that the protective association of ApoA operates predominantly by attenuating chronic low-grade inflammation. The total effect of ApoA on ILD was also significant (Estimate: − 0.385, p = 0.007), whereas the direct effect of ApoA on ILD was insignificant (Estimate: − 0.140, p = 0.371). The INFLA score mediated a 63.6% of the protective effect of ApoA against ILD (p = 0.027), explaining its role in reducing the low-grade inflammation.

Sensitivity Analyses

In sensitivity analyses, similar results were obtained when we repeated the analyses after adjusting for age only (Supplementary Table S5). Both increased levels of ApoA and HDL-C were significant protective factors against incident ILD in patients with RA. When stratified by follow-up period, the HR and its statistical significance varied markedly across the censoring intervals of 5, 10, and 15 years (Supplementary Table S6). Notably, the protective effects of higher levels of ApoA and HDL-C became more pronounced with longer follow-up. ApoA showed a significant HR of 0.312 (95% CI 0.130–0.746, p = 0.009) at 10 years and 0.385 (95% CI 0.189–0.783, p = 0.008) at 15 years. A similar pattern was observed for HDL-C, with a significant protective effect during the 10- and 15-year follow-up periods, but no effect was significant during the first 5 years. This pattern suggested that the relationship between ApoA or HDL-C and ILD risk may be time-dependent, with protective associations becoming more evident over longer observation windows.

Discussion

This large-scale, prospective cohort study demonstrated, for the first time, that specific lipid traits are associated with the long-term risk of incident ILD among patients with RA. Higher levels of ApoA and HDL-C were independently associated with a lower risk of ILD in an RA population after adjusting for BMI, ethnicity, education level, socioeconomic status, and smoking status. These protective effects were more pronounced in male patients and ever-smokers and appeared to be strongly mediated by systemic low-grade inflammation.

A few studies have suggested HDL-C is a potential protective factor for ILD in RA and other autoimmune diseases. A cross-sectional study by Wu et al. of 737 patients with RA found that those with low HDL-C had a higher incidence of ILD than those with high HDL-C, and that HDL-C levels were negatively correlated with RA disease activity [28]. A recent study in systemic sclerosis-associated ILD, another autoimmune fibrotic lung disease, showed that patients with systemic sclerosis-associated ILD displayed reduced HDL-C levels compared to those without ILD, and HDL-C levels also negatively correlated with worse lung function, supporting the concept that impaired HDL-C function may be a shared pathway in autoimmune-related lung fibrosis [29]. Our findings, built on this evidence, prospectively demonstrated that elevated HDL-C and ApoA were associated with a reduced incidence of ILD in the RA population. Although the precise physiological roles of HDL-C and ApoA in the development of ILD in patients with RA are not fully elucidated, the association likely relates to their anti-inflammatory and anti-oxidative functions [30, 31]. HDL-C, a group of complex lipoprotein particles, mediates reverse cholesterol transport out of cells, and has anti-inflammatory, anti-thrombotic, and anti-oxidative properties. It plays a significant role in lung health and in pulmonary diseases such as acute lung injury, asthma, emphysema, and pulmonary hypertension. ApoA, widely known as the major protein component of HDL-C, also modulates inflammatory and immune responses by activating the inflammasome and signaling via Toll-like receptors [32, 33]. A deficiency of ApoA could cause an accumulation of cholesterol in alveolar macrophages, leading to the formation of foam cells, which has been noted in patients with ILD [33]. Therefore, our study suggested that HDL-C and ApoA might play a protective role in the lung by mitigating the processes that lead to fibrosis.

Although RA is more common in females, men are twice as likely as women to develop ILD among the RA population [34, 35]. The underlying mechanism is not yet fully elucidated. Our investigation revealed a significant sex-specific impact on the relationship between two lipid traits, ApoA and HDL-C, and the risk of incident ILD in patients with RA. Higher levels of both ApoA and HDL-C were significantly associated with a reduced risk of ILD in male patients, while the protective effect was absent in female patients. Sex differences in lipid metabolism are well established and are attributed mainly to the influence of sex hormones on plasma lipid kinetics [36]. In male patients, who generally experience more stable hormonal levels than females, higher levels of ApoA and HDL-C may reliably reflect a greater protective function by exerting their classic cardiopulmonary protective roles within the pulmonary parenchyma [37]. The inclusion of both pre- and post-menopausal female patients in our cohort created a heterogeneous hormonal condition, meaning the impact of HDL-C and ApoA might not be uniformly captured by their concentration alone. Furthermore, in female patients with RA, fluctuating estrogen levels may exacerbate RA, which could, in turn, impair the cholesterol efflux capacity of HDL-C and thus diminish its protective effect against ILD in RA [38, 39]. Future studies should continue to disaggregate analyses by sex to uncover potential differences and to further investigate the underlying biological mechanisms.

Smoking, a risk factor for RA itself, also increases the risk of ILD in RA, with a dose–effect relationship [40, 41]. Smoking induces oxidative stress, activates innate and adaptive immune cells, and influences epithelial cell turnover and regeneration following injury; these processes are widely believed to be involved in the pathogenesis of ILD in the RA population [1]. Previous studies have shown that exposure to cigarette smoking exerted an adverse effect on HDL-C by decreasing its levels and impairing its reverse cholesterol transport function [42]. Surprisingly, our stratified analyses revealed that the protective associations of ApoA and HDL-C with ILD risk were significant only among participants with a history of smoking (ever-smokers), and that high triglycerides were associated with increased ILD risk in this same group. However, this association was not observed in patients who are never-smokers. To our knowledge, no prior research has explored the association between lipid traits and the incidence of ILD in an RA population by comparing smokers and non-smokers. We suspected this finding reflected the amplified protective demand for the anti-inflammatory function of HDL-C or ApoA, as smoking creates a pro-fibrotic lung environment with high oxidative stress and inflammation. Smoking and RA inflammation (e.g., citrullination) may synergize to damage the lung epithelium. Functional HDL-C/ApoA may help mitigate this synergistic damage, protecting lung cells and reducing aberrant repair signals that lead to fibrosis. Although the underlying mechanism is still not fully understood, our study highlighted the significance of lipid metabolism in the smoking-induced pro-inflammatory environment in the incidence of all-cause ILD in the RA population.

Age is a well-recognized risk factor for both ILD risk in RA and abnormal lipid metabolism, with meta-analyses confirming older age as an independent risk factor for ILD in patients with RA [43]. Our analyses stratified by age revealed that higher levels of ApoA and HDL-C were significantly associated with a reduced risk of incident ILD in younger participants, while elevated triglycerides were linked to an increased risk. These associations were not observed in older patients, except for a modest protective effect of lipoprotein A in this group. Our observation aligns with several large-scale general population studies demonstrating an age-dependent relationship between HDL-C and clinical outcomes [44, 45]. In a large prospective cohort study, Li et al. reported that lower HDL-C levels had a stronger and more consistent protective effect against all-cause mortality in younger to middle-aged adults, whereas no significant association was found between HDL-C and total mortality among elderly adults [44] Similarly, Yi et al. observed that the association between HDL-C levels and all-cause mortality was significantly modified by age [45]. This age-related difference may be explained by alterations in lipid composition and function in old age. Holzer et al. demonstrated that HDL from healthy elderly subjects, despite having comparable cholesterol levels to young subjects, exhibited profound compositional and functional alterations, including reduced apolipoprotein E content, enrichment of acute-phase proteins, impaired antioxidant capacity, and decreased paraoxonase 1 activity [46]. These findings support our observation that age is a critical effect modifier in the relationship between lipid metabolism and ILD risk in RA and suggest that future research may consider exploring functional assays of lipid traits [46].

To explore the potential mechanisms underlying the association between ApoA/HDL-C and incident ILD in the RA population, we conducted a mediation analysis. The results showed that systemic inflammation, as measured by the INFLA-score, accounted for 88.5% of the association with ApoA and 63.6% with HDL-C. These findings are consistent with previous studies linking the metabolism of lipid traits, especially ApoA and HDL-C, to inflammation and, in turn, linking systemic inflammation to the development of ILD during the course of RA. In alignment with our study, which showed a negative association between HDL-C/ApoA and chronic low-grade inflammation, a follow-up study by Papa et al. showed that anti-inflammatory therapy with a tumor necrosis factor-alpha (TNF-α) inhibitor increased the levels of HDL-C and ApoA and also improved the antioxidative capacity in patients with RA [47]. A type II collagen-induced RA mouse model also showed that treatment with HDL-C could reduce the production of TNF-α and IL-6, revealing the anti-inflammatory impact in RA [48]. Previous studies have also revealed a robust association between a pro-inflammatory state and onset or progression of ILD in patients with RA, which is in agreement with our current study. Therefore, the low levels of ApoA and HDL-C observed in our cohort likely reflect an inflammatory state that degrades these protective lipids and simultaneously drives the pathogenic processes leading to ILD. A more detailed mapping of these potential mechanisms is needed for further investigation [49].

There are, however, limitations in this study. First, the diagnosis of RA and ILD relied on ICD codes, without direct clinical assessment, including imaging triggers, standardized surveillance, and daily direct care of the participants, which may be subject to misdiagnosis or misclassification. Nevertheless, it is worth noting that this approach to RA and ILD ascertainment in the UK Biobank has been adopted in prior studies and has demonstrated a reasonable positive predictive value [20, 21, 50]. Second, due to the use of ICD-10 codes, we were unable to distinguish between ILD subtypes (e.g., usual interstitial pneumonia, non-specific interstitial pneumonia, organizing pneumonia). Third, due to the nature of this prospective observational study, we cannot establish causal relationships or completely rule out residual confounding and reverse causation. Although lipid measurements were collected before ILD occurrence, which reduced the possibility of reverse causation, further studies with causal inference designs are needed to clarify the temporal and causal relationships between lipid traits and the risk of ILD in patients with RA. Fourth, lipid levels and inflammatory biomarkers were measured only at baseline. Changes over time and their interaction with treatment were not captured. Fifth, although the UK Biobank is a large population-based cohort, the number of ILD events among patients with RA remained relatively small. The limited number of ILD cases prevented us from categorizing lipid traits into tertiles or quartiles to explore potential dose–response relationships. Sixth, while we adjusted for a wide range of confounders, unmeasured factors, such as RA disease activity (e.g., DAS28) and serological status, were not included as covariates. These factors may affect pulmonary function in patients with RA, potentially influencing the findings. Although the INFLA-score used in our mediation analysis is a useful tool for capturing systemic inflammatory burden, it does not serve as a substitute for comprehensive clinical measures of RA disease activity [51]. Finally, the UK Biobank population is predominantly of White ethnicity and generally healthier than the general population, which may limit the generalizability of our findings to other racial or clinical settings.

Conclusions

In conclusion, this large cohort study established a significant association between lipid traits and the risk of ILD in patients with RA, revealing that high serum levels of ApoA and HDL-C were independently associated with a lower risk of developing all-cause ILD in the RA population. These associations were pronounced in males, relatively young patients, and ever-smokers. The protective relationships of ApoA and HDL-C against ILD in RA were strongly mediated by reduced systemic low-grade inflammation. Taken together, our findings highlighted the clinical significance of lipid metabolism for developing ILD during the course of RA. Routine examination of HDL-C or ApoA levels, along with other lipid traits, may help stratify ILD risk in patients with RA. Maintaining normal lipid levels through lifestyle or therapeutic interventions may represent a potential preventive approach against ILD in patients with RA. Further research is required to clarify the causal relationship between lipid profiles and incident ILD in RA, as well as to evaluate whether lipid-modifying strategies could emerge as a novel approach to prevent or slow the progression of ILD in the RA population.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Conception and design of the study: Lianzhi Chen, Jun Yuan, Qingwen Wang; Acquisition of data: Jun Yuan, Jun Lu; Analysis and interpretation of data: Lianzhi Chen, Jun Yuan, Gengmin Zhou, Jintao Chen; Verification of the data: Lianzhi Chen, Chao Chen, Qingwen Wang, Clinical interpretation: Lianzhi Chen, Gengmin Zhou, Qingwen Wang; Drafting of the article or revising it critically for important intellectual content: Lianzhi Chen, Jun Yuan, Mingxi Gu, Yuting Yang; Final approval of the version of the article to be published: All authors.

Funding

This study was supported by funding from Perpetual’s 2023 IMPACT Philanthropy Application Program (IPAP2023/1338), provided by The Lindsay & Heather Payne Medical Research Charitable Foundation to Jun Yuan, and was also funded by the Shenzhen Medical Research Fund (C2301008, C2404002), the Guangdong Basic and Applied Basic Research Foundation (2023B1515230002), the Treatment and Prevention Integration Project of Shenzhen Municipal Health Commission (0102018-2019-YBXM-1499-01-0414), the Sanming Project of Medicine in Shenzhen (SZSM202311030). Funding for the journal’s Rapid Service Fee was provided by the Sanming Project of Medicine in Shenzhen (SZSM202311030).

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. The data that support the findings of this study are available from the UK Biobank, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. The UK Biobank resources are, however, available from the authors upon reasonable request and can be accessed through applications on its website (https://www.ukbiobank.ac.uk/).

Declarations

Conflict of interest

All authors, including Lianzhi Chen, Jun Yuan, Jun Lu, Gengmin Zhou, Mingxi Gu, Yuting Yang, Chao Chen, Jintao Chen, Qingwen Wang, have nothing to disclose.

Ethical approval

The present study employs data from the UK Biobank study which received approval from the National Information Governance Board for Health and Social Care and the National Health Service North West Centre for Research Ethics Committee. All participants provided electronically signed informed consent when attending baseline assessment. This study has been conducted using the UK Biobank Resource under the Application Number 199603.