Silent Interstitial Lung Disease in Early Autoimmune Disorders: A Systematic Review

Table 2: Quality assessment of Newcastle–Ottawa scale (NOS) for cross-sectional studies
Study	Year	Selection				Comparability	Outcome		Total
		Representativeness of sample (★)	Sample size (★)	Non respondents (★)	Ascertainment of exposure (★★)	Confounding factors controlled (max?★)	Assessment of outcome (★★)	Statistical test (★)
Mohanty et al., 2019 (16)	2019	★	-	-	★★	-	★★	★	6
Paulin et al., 2021 (15)	2021	★	-	-	★★	★★	★★	★	8
Palalane, et al., (20)	2022	★	-	-	★★	★★	★★	★	8

Demographic characteristics of the included studies

This systematic review included nine studies spanning a range of countries, study designs, and patient populations, offering a comprehensive overview of the prevalence and characteristics of subclinical ILD in the context of systemic autoimmune disorders (Table 3).

The majority of studies were retrospective in design, with only a few employing cross-sectional methodologies. These studies were conducted across diverse geographic locations, including France, Japan, China, India, Brazil, and South Africa, reflecting a global interest in the early detection of ILD among patients with autoimmune conditions.

Participant numbers varied widely from as few as 72 (Mohanty et al., 2019) (16) to as many as 781 (Mori et al., 2025) (17), with mean or median ages typically in the middle-aged to elderly range. Notably, there was a consistent predominance of female participants across all studies, aligning with the known gender distribution of systemic autoimmune diseases such as rheumatoid arthritis (RA) and Sjögren’s syndrome (SS).

The autoimmune diagnoses investigated were primarily RA, but also included primary Sjögren’s syndrome (pSS), systemic sclerosis (SSc), and other connective tissue diseases (OCTD). Several studies, such as those by Kawano-Dourado et al. (14) and Lin et al., (12) provided focused insights into ILD or ILA among these populations. For instance, Kawano-Dourado et al. (2020) (14) provided stratified data comparing patients with ILA/ILD, no ILA, and indeterminate ILA, offering a nuanced view of disease presence and progression.

Table 3: Baseline characteristics of included studies
Study	Country	Published Year	Study Period	Study Design	Total Participants	Mean/median age of total participants (Years)	Gender (M/F) %	Diagnosis Of Systemic Autoimmune Disorders
Roca et al., 2016 (13)	France	2017	1996-2012	Retrospective	263	63	11.98%/88.02%	SS
Mohanty et al., 2019 (16)	India	2019	NR	Descriptive cross sectional	72	37.5	76.39%/23.61%	RA
Yamakawa et al., 2019 (18)	Japan	2019	2012 -2017	Retrospective cohort	96	69.0±10.3	39%/61%	RA
Kawano-Dourado et al., 2020 (14)	Brazil	2020	2014 – 2016	Retrospective	Total=293, ILA/ILD =64 No ILA=204 Indeterminate ILA=25	ILA/ILD =65.6± 9.9 No ILA= 59.5 ±10.9	17.54%/82.46%	RA
Paulin et al., 2021 (15)	NR	2021	2017-2020	Cross-sectional	83	46.49 ±17.09	83%/17%	RA
Lin et al., 2022 (12)	China	2022	2016-2019	Retrospective	333	54	6.91%/93.09%	pSS
Palalane et al., 2022 (20)	South Africa	2022	2018-2019	Cross-sectional	124	45	13.7% /86.3%	RA, SSc, OCTD
Chai et al., 2023 (19)	China	2023	2017-2021	Retrospective cohort	371	62	30.7%/69.3%	RA
Mori et al., 2025 (17)	Japan	2025	2001-2023	Retrospective	781	63.2 ±12.8	25.9%/74.1%	RA

NR: not reported; SS: Sjogren’s syndrome; pSS: primary Sjogren’s syndrome; RA: rheumatoid arthritis; SSc: systemic sclerosis; OCTD = other connective tissue diseases

Table 4: Outcomes of included studies
Study	Prevalence of silent ILD n (%)	Pulmonary function	HRCT findings	HRCT pattern	Markers
Lin et al., 2022 (12)	24 (7.21)	-	-	-	-
Kawano-Dourado et al., 2020 (14)	21 (7.17)		Pulmonary indications: Progressors: 3 (50%) Non-progressors: 9 (60%) Non-pulmonary/Other: Progressors: 3 (50%) Non-progressors: 6 (40%	Subpleural pattern: Progressors: 6 (100%) Non-progressors: 8 (53%) P = .06 (borderline association with progression) Centrilobular pattern: Progressors: 0 (0%) Non-progressors: 5 (33%) pattern: Progressors: 0 (0%) Non-progressors: 2 (14%)	-
Paulin et al., 2021 (15)	6 (7.5)	-	-	-	-
Mohanty et al., 2019 (16)	8 (11.1)	-	-	-	-
Mori et al., 2025 (17)	77 (9.86)	FVC, % predicted (n = 70) 95.3 (19.0) FEV1, % predicted (n = 70) 113.6 (12.6) FEV1/FVC ratio (n = 70) 125.5 (35.8) MMF, % predicted (n = 70) 70.4 (30.0) DLCO, % predicted (n = 64) 83.2 (20.3)	Honeycombing 39 (50) Traction bronchiectasis 62 (79.5) Emphysema 36 (46.2	Definite UIP pattern 29 (37.2) Probable UIP pattern 14 (17.9) Indeterminate for UIP pattern 26 (33.3) Early UIP 5 (6.4) NSIP/UIP 21 (26.9) NSIP 9 (11.5)
Palalane et al., 2022 (20)	13 (10)	-	-	-	-
Chai et al., 2023 (19)	73 (19.3)	FVC, %predicted 103.7±20.1 DLCO, %predicted 70.7±13.6 PaO2, mmHg (room air, at rest) 84.3(77.0-91.5)	HRCT score: 4.0(3.0-7.5)	Among the 73 patients with RA-pILD: 53.4% had subpleural non-fibrotic abnormalities. Among the progressors RA-pILD: 63.6% (14 out of 22) had subpleural fibrosis. 67.9% (19 out of 28) exhibited a usual interstitial pneumonia (UIP) pattern.	NLR 3.0 (2.0–4.1) MLR 0.3 (0.2–0.4) PLR 143.8 (105.0–211.9) SII 765.0 (378.8–1031.8) SIRI 1.4 (0.8–2.2) AISI 346.7 (122.4–547.6) Anti-CCP positivity, n (%) 64(87.7) Anti-CCP titer, IU/ml 865.6(293.5-2753.5)
Yamakawa et al., 2019 (18)	Over half of the 96 patients with ILD may have experienced the condition without showing any symptoms.	-	-	-	-
Roca et al., 2016 (13)	5 (1.9)	-	-	-	-

HRCT findings

HRCT findings were reported in three studies, yet they provide important insight into the structural lung changes associated with early or silent ILD in autoimmune disorders. Mori et al. (2025) (17) identified key radiologic features, with traction bronchiectasis observed in 79.5% of cases, honeycombing in 50%, and emphysema in 46.2%, reflecting substantial fibrotic and structural abnormalities even in potentially asymptomatic patients. Chai et al. (2023) (19) quantified disease burden using a semi-quantitative HRCT scoring system, reporting a median score of 4.0 (IQR: 3.0–7.5), indicating mild to moderate radiographic involvement. Kawano-Dourado et al. (2020) (14) explored the clinical context of HRCT use, noting that in both progressor and non-progressor groups, CT scans were often initiated for non-pulmonary or incidental findings as well as for pulmonary symptoms, highlighting that silent ILD may be detected during evaluations for unrelated issues. These findings underscore the importance of imaging in uncovering subclinical ILD in autoimmune patients and suggest that significant radiographic abnormalities can exist even in the absence of symptoms.

HRCT pattern analysis

HRCT pattern analysis revealed distinct radiologic features associated with disease progression in patients with early or silent ILD related to autoimmune disorders. Kawano-Dourado et al. (2020) (14) reported a subpleural pattern in all progressor patients (100%) compared to 53% in non-progressors, suggesting a borderline association with disease progression (P = .06). In contrast, centrilobular and mixed patterns were observed only among non-progressors, potentially indicating less aggressive disease forms. Mori et al. (2025) (17) provided a more detailed classification of ILD patterns, identifying a definite usual UIP pattern in 37.2% of cases, probable UIP in 17.9%, and indeterminate patterns in 33.3%. Additionally, 6.4% showed early UIP, while NSIP features were found either in isolation (11.5%) or mixed with UIP (26.9%), reflecting significant heterogeneity in radiologic patterns even in pre-symptomatic stages.

Chai et al. (2023) (19) specifically examined patients with rheumatoid arthritis-associated preclinical ILD (RA-pILD), reporting that 53.4% had subpleural, non-fibrotic abnormalities. Among those who progressed, 63.6% had subpleural fibrosis and 67.9% exhibited a UIP pattern, both of which are known to correlate with worse prognosis. Collectively, these findings underscore that subpleural distribution and UIP patterns on HRCT may serve as early radiologic indicators of progression in autoimmune-associated ILD, supporting their role in risk stratification and guiding surveillance strategies.

Discussion

Summary of findings

This comprehensive review consolidates existing knowledge about the frequency, diagnostic characteristics, and clinical ramifications of silent interstitial lung disease in individuals with early-stage autoimmune illnesses. The findings highlight that subclinical or asymptomatic ILD is a very common yet underappreciated presentation in this population, with significant diagnostic and prognostic consequences.

The reported prevalence of silent ILD in patients with autoimmune disorders varied from 1.9% to 19.3%, highlighting the variability of study populations and possible inconsistencies in screening and diagnostic methodologies. Chai et al. (2023) observed a prevalence of 19.3%, indicating that nearly one in five individuals may exhibit subclinical pulmonary disease. Conversely, research conducted by Roca et al. (2016) (13) revealed far lower rates (1.9%), presumably due to variations in imaging thresholds, patient selection criteria, and definitions of "early" autoimmune illness. This diversity raises significant concerns about the underdiagnosis of ILD in asymptomatic individuals. The actual prevalence of silent ILD may be considerably underestimated, as numerous cases are identified unintentionally during HRCT scans conducted for unrelated purposes. This underscores the necessity for proactive screening measures, particularly in patients with established risk factors such as RA, SSc, or ILM. Garrote Corral et al. conducted a systematic review indicating that the prevalence of ILM varies by cohort and study methodology, ranging from 5% to 61%. This prevalence range exceeds our included studies. Their study determined that between 5% and 55% of cases are considered asymptomatic (21). One of the biggest challenges in estimating the incidence and prevalence of ILD is underdiagnosis. The 2020 EULAR guidelines recommend screening for asymptomatic ILD in certain patients, particularly those with systemic sclerosis, myositis, and mixed connective tissue disease (22).

Prior studies have reported that while FVC is a well-known parameter for ILD severity and progression assessment, the DLCO is more sensitive for detecting early interstitial changes and monitoring progression (23). This aligns with the findings of the present systematic review, which explained that PFTs showed subtle yet clinically meaningful impairments in gas exchange. Specifically, DLCO was often diminished, even in patients with normal or near-normal FVC and FEV1. This indicates that gas transport anomalies may occur prior to evident restrictive deficiencies, acting as an early physiological indicator of interstitial involvement. Mori et al. (2025) (17) and Chai et al. (2023) (19) both reported relatively intact spirometry results with moderately diminished DLCO values, suggesting early impairment of the alveolar-capillary membrane despite maintained lung volumes. Furthermore, evidence of resting hypoxemia was noted, reinforcing the notion of early pulmonary compromise. These findings advocate the use of DLCO and arterial blood gas assessments in the routine monitoring of patients with early autoimmune illness, regardless of symptom presence.

Radiologic imaging, particularly HRCT, was essential in detecting structural problems in asymptomatic cases, even when a person has no respiratory symptoms, which supports the need for early screening in at-risk individuals. For the diagnosis and prognosis, severity assessment, pattern recognition, and therapeutic monitoring of ILD, it is the gold standard imaging method (24). Significant observations, including traction bronchiectasis, subpleural reticulations, honeycombing, and emphysema, were documented in multiple studies, particularly by Mori et al. (2025) (17) and Chai et al. (2023) (19). These alterations, however, are frequently nuanced, signify the onset of early fibrotic remodeling. Furthermore, the examination of HRCT pattern distributions indicated that specific imaging phenotypes, including subpleural fibrosis and UIP pattern, were more prevalent in patients who underwent radiographic or clinical progression. Kawano-Dourado et al. (2020) (14) identified a 100% prevalence of subpleural patterns among progressors, in contrast to 53% in non-progressors, indicating a robust correlation between HRCT patterns and disease progression. These observations endorse the application of HRCT not only as a diagnostic instrument but also as a prognostic tool to discern patients at elevated risk of ILD progression. However, its regular use is considerably restricted because of its high cost, limited availability in non-tertiary healthcare facilities, lengthy wait times in certain places, and ionizing radiation (25).

Clinical implications

The findings of this systematic review carry several significant clinical implications, particularly in the context of early detection, risk stratification, and long-term management of patients with autoimmune disorders who may develop silent or subclinical ILD. Although asymptomatic, silent ILD can precede clinically apparent disease and contribute to irreversible fibrotic changes and compromised pulmonary function. The following key implications should guide future clinical practice: Routine screening in high-risk populations, as one of the most striking findings is the relatively high prevalence of silent ILD in early autoimmune diseases such as RA, SSc, and IIM. The detection of ILD in up to 19.3% of patients, even in the absence of respiratory symptoms, warrants the consideration of routine screening protocols in newly diagnosed autoimmune disease patients, particularly those with established risk factors (e.g., older age, male sex, anti-CCP positivity in RA, or anti-synthetase antibodies in myositis) (26, 27). HRCT and DLCO should be incorporated as part of the baseline workup in selected patients, especially when lung auscultation, serological markers, or clinical history raise suspicion, even if subclinical (28).

Our study findings strengthen the American College of Rheumatology (ACR) 2023 guidelines, which recommend proactive screening and monitoring for ILD in patients with systemic autoimmune rheumatic diseases. The finding emphasizes that this proactive approach is clinically relevant because early detection of subclinical ILD can allow for intervention before the disease progresses to irreversible lung fibrosis (29).

The assumption that asymptomatic ILD may remain non-progressive is not supported by the reviewed data. Structural abnormalities detected on HRCT such as subpleural fibrosis, traction bronchiectasis, and honeycombing can exist well before symptom onset. These radiologic features, particularly when consistent with UIP or when distributed in a subpleural fashion, may predict eventual disease progression and functional decline. This challenges the traditional "watch-and-wait" approach and reinforces the need for early identification and longitudinal monitoring, even in the absence of overt symptoms (30).

Specific HRCT patterns (e.g., definite or probable UIP) are associated with worse outcomes and higher risk of fibrosis progression. Subpleural and fibrotic changes when present at baseline may help identify patients who are likely to benefit from early pulmonary referral, closer surveillance intervals, or preemptive therapeutic strategies. A structured HRCT evaluation using validated scoring systems or radiologic classification frameworks can aid in developing a risk stratification algorithm for clinical use. This can help determine which patients may benefit from closer follow-up or early therapeutic intervention, such as antifibrotics or immunomodulatory therapies (31).

PFTs, particularly DLCO, are sensitive early indicators of subclinical pulmonary involvement and should not be overlooked in patients with autoimmune disease, even when FVC and FEV1 are normal. Abnormal gas exchange or early desaturation on exertion may indicate functional compromise and warrant further imaging or specialist evaluation. Serial PFTs, including DLCO, should be used to track disease trajectory and detect early signs of progression. In practice, a combination of HRCT and DLCO offers complementary insights into structural and functional lung integrity (31, 32).

The complexity of silent ILD detection and management in autoimmune disease necessitates a multidisciplinary approach, involving rheumatologists, pulmonologists, and radiologists. Early engagement with ILD specialists allows for accurate interpretation of subtle imaging findings, appropriate risk stratification, and guidance on monitoring intervals. Multidisciplinary team (MDT) discussions are particularly important in cases where HRCT findings are indeterminate or where clinical decision-making (e.g., initiation of immunosuppression or antifibrotic therapy) may hinge on nuanced interpretation (33).

Although none of the reviewed studies directly addressed therapeutic outcomes in silent ILD, the presence of fibrotic patterns and early functional decline suggests that some patients may benefit from earlier intervention. Current clinical trials and observational data in symptomatic ILD show promise for antifibrotic agents (e.g., nintedanib) in slowing progression, even in non-idiopathic fibrosing ILD. In the future, preemptive treatment strategies for high-risk silent ILD patients may evolve as evidence accumulates. Clinical trials specifically targeting subclinical ILD in autoimmune disease are needed to determine the efficacy, safety, and timing of such interventions (34).

This review also highlights the urgent need for standardized definitions and diagnostic criteria for silent or subclinical ILD. Inconsistent terminology and variable thresholds for imaging abnormalities hinder comparison across studies and limit the development of evidence-based guidelines. Professional societies should work toward consensus criteria that define the extent, distribution, and severity of ILD necessary to warrant the label of “silent” or “subclinical” ILD, and outline evidence-based pathways for management.

Limitations and recommendations

This systematic review, while providing useful insights, is constrained by various constraints that may affect the interpretation and generalizability of its findings. The included studies demonstrated considerable variability in research design, population characteristics, and diagnostic criteria for silent ILD. The discrepancies in the definitions of "silent" or "asymptomatic" ILD, along with the absence of uniform imaging or functional criteria, hinder comparability among research. Secondly, the majority of the existing evidence originates from retrospective observational studies characterized by very small sample sizes and restricted geographic variety, potentially introducing selection bias and undermining the reliability of prevalence estimates. Moreover, only a limited number of studies offered longitudinal follow-up data, complicating the determination of the authentic natural history or development patterns of subclinical ILD. The inadequate reporting of pulmonary function metrics and the variable application of HRCT scoring systems further limit the capacity to establish definitive findings on structure-function links. The lack of randomized controlled studies assessing early therapies in this population limits the formulation of evidence-based treatment options.

Based on the existing evidence, multiple clinical and research suggestions may be formulated. Clinicians ought to implement routine screening for ILD in patients with early autoimmune disorders, especially those exhibiting risk factors or serological markers indicative of pulmonary involvement, utilizing HRCT and DLCO as components of the baseline evaluation. Moreover, the establishment of consistent diagnostic criteria and categorization methods for silent ILD is crucial to unify future research and clinical practice. Radiologic characteristics, including subpleural distribution and UIP patterns, along with functional deficits such as diminished DLCO, ought to be integrated into risk stratification models to inform monitoring intervals and treatment choices. Longitudinal cohort studies are necessary to clarify progression rates, discover predictive biomarkers, and assess the long-term effects of early detection. Interventional trials evaluating the timing and efficacy of antifibrotic or immunomodulatory treatments in asymptomatic ILD patients are urgently needed to guide evidence-based therapy choices.

Conclusion

Asymptomatic ILD in the initial stages of autoimmune illnesses constitutes a clinically important yet underappreciated syndrome that may precede symptomatic and progressive lung fibrosis. This comprehensive review highlights the diversity in reported prevalence, the significance of imaging and pulmonary function tests in early diagnosis, and the prognostic impact of particular radiologic patterns. Although some individuals are asymptomatic at the time of diagnosis, structural and functional problems frequently exist, underscoring the necessity for proactive screening and vigilant monitoring. Enhancing early detection, standardizing diagnostic criteria, and conducting targeted research would enable doctors to get a deeper understanding of the natural history of silent ILD and potentially reduce long-term respiratory morbidity and mortality in affected individuals. The amalgamation of diverse knowledge and patient-centered monitoring systems will be essential for progressing care in the developing field of autoimmune pulmonary medicine.

Disclosure

Conflict of interest

There is no conflict of interest.

Funding

No funding.

Ethical consideration

Non applicable.

Data availability

All data are available within the manuscript.

Author contribution

All authors contributed to conceptualizing, data drafting, collection and final writing of the manuscript.