Screening for Rheumatoid Arthritis-Associated Interstitial Lung Disease Using Low-Dose CT: An Emerging Approach — An Observational Prospective Case-Control Study

doi:10.21203/rs.3.rs-7204385/v1

Background

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a major contributor to rheumatoid arthritis (RA) related morbidity and mortality. Early detection is challenging due to subclinical onset and limitations of conventional screening modalities. This study evaluated the diagnostic performance of low-dose photon-counting detector CT (LD PCD-CT) for RA-ILD and assessed its prevalence and risk factors in a Hungarian RA cohort.

Methods

In this prospective study (Feb 2022–June 2023), 492 consecutively enrolled RA patients without known ILD, underwent LD PCD-CT, digital chest radiography (DR) and pulmonary function testing (PFTs). Imaging was scored using a standardized LD severity scale. Clinical, demographic, and serological data were analyzed to identify ILD predictors. Statistical analyses included Kolmogorov–Smirnov, t-tests, Mann–Whitney U, chi-squared/Fisher’s exact tests, Pearson correlation, and ROC analysis. Logistic regression was used to identify independent risk factors.

Results

LD PCD-CT identified interstitial abnormalities in 35% of patients. By contrast, clinical assessment and PFTs detected abnormalities in only 44% and 22% of these cases, respectively. Among patients without CT-defined abnormalities, 42% had a positive clinical assessment and 23% had abnormal PFTs, indicating limited diagnostic specificity. The most frequent findings were interstitial reticular abnormalities (58%) and usual interstitial pneumonia (22%). Independent ILD predictors included age ≥ 50 years, male sex, ≥ 25 pack-year smoking history, rheumatoid factor (RF) positivity, and elevated lactate dehydrogenase (LDH) levels. LD PCD-CT had a mean effective radiation dose of 0.415 mSv, remaining within low-dose diagnostic thresholds.

Conclusion

LD PCD-CT demonstrated superior sensitivity and specificity for early RA-ILD detection compared to clinical assessment and PFTs, while maintaining low radiation exposure. Incorporating LD PCD-CT into risk-stratified screening protocols may facilitate earlier diagnosis and timely therapeutic interventions, ultimately improving patient outcomes.

Clinical trial registration number:

NCT05391100

rheumatoid arthritis

interstitial lung disease

screening

low-dose computed tomography

photon-counting detector computed tomography

pulmonary function tests

risk factors

Rheumatoid arthritis is a systemic autoimmune disease affecting 0.5-1% of the global population. [1] Among its various extra-articular manifestations, pulmonary involvement—particularly interstitial lung disease (ILD)—is one of the most serious. Alongside cardiovascular disease and infections, it contributes substantially to RA-related morbidity and mortality. [2, 3] RA-associated ILD (RA-ILD) carries a three-fold increased risk of death compared to RA patients without ILD [4, 5] and frequently complicates disease management, contributing to the subset of patients classified as having difficult-to-treat RA. [6, 7]

Clinically significant ILD occurs in approximately 11% of RA patients. [8] However, a substantially larger proportion may exhibit radiological features consistent with ILD despite being asymptomatic and having preserved lung function. This condition, referred to as subclinical ILD, is typically defined by the presence of mild interstitial abnormalities on high-resolution computed tomography (HRCT), normal PFTs, and the absence of respiratory symptoms. [9] The reported prevalence of subclinical ILD in RA varies widely, ranging from 5–67%, reflecting differences in study design, patient populations, imaging techniques, and the criteria used to define ILD. [10]

Considering that ILD may occur at any point during the natural history of RA, and its clinical manifestations usually appear in advanced stages, early diagnosis is challenging and requires a multidisciplinary team approach. [11, 12] This underscores an unmet need for timely, sensitive screening strategies that enable earlier diagnosis and intervention. Early detection offers a critical window of opportunity for timely adjustment of disease-modifying antirheumatic drug (DMARD) regimens and initiation of antifibrotic therapies—interventions shown to stabilize CT changes in progressive autoimmune ILDs and improve prognosis. [13, 14]

In this context, our primary objective was to assess the effectiveness of LD PCD-CT as a screening tool for RA-ILD. A secondary aim was to estimate the prevalence of ILD (including subclinical cases) among Hungarian RA patients and to develop a risk stratification model.

Ethics and study design

This study was an observational prospective case-control study, in accordance with the ethical principles of the Declaration of Helsinki, the International Conference on Harmonization, and Good Clinical Practice with the permission of the Regional Research Ethics Committee (number: IV/2683-1/2022/EKU). It has been registered on the ClinicalTrials.gov (NCT05391100) web page. It was performed between February 2022. and June 2023. All patients provided written informed consent.

Patient enrollment

Consecutive RA patients aged > 40 years were recruited from the Rheumatology Outpatient Department of Semmelweis University (Polyclinic of the Hospitaller Brothers of St. John of God, Budapest, Hungary). All participants underwent regular follow-up at the institution, received standard RA medications, and had annual chest X-rays following their diagnosis. None of them had a previous indication for HRCT to rule out ILD.

Inclusion required RA diagnosis per 2010 ACR/EULAR criteria. [15] To limit radiation exposure, reproductive-age patients were excluded. Further exclusion criteria included pregnancy, breastfeeding, prior ILD or lung cancer, and recent (within 2 months) lung infection.

Serological data

Demographic, clinical, and serological data, including RF, anti-citrullinated peptide antibodies (ACPA), and RA treatment history (synthetic/biological DMARDs and corticosteroids) were recorded at enrollment.

RF, C-reactive protein (CRP), LDH, and cancer antigen 15 − 3 (CA 15 − 3) levels were measured using quantitative immunoturbidimetric assays on the Roche platform (F. Hoffmann–La Roche AG, Basel, Switzerland), with RF cutoff at 14 U/mL, CRP < 5 mg/L, and LDH reference ranges of 135–214 U/L for women and 135–225 U/L for men. Anti-cyclic citrullinated peptide (CCP) antibodies were measured using the Immunoscan CCPlus kit (SVAR Life Science, Malmö, Sweden) with a 25 U/mL cutoff. Erythrocyte sedimentation rate (ESR) was assessed using the Vacuette SRS100 system (Greiner Bio-One GmbH, Kremsmünster, Austria), with reference values of < 30 mm/h for women and < 20 mm/h for men.

Imaging

Patients underwent DR and consecutive chest LD PDC-CT scans on the same day at the Clinic for Medical Imaging, Semmelweis University. Anteroposterior and lateral digital radiographs were performed on a GE Discovery XR 656 HD system (GE Healthcare, Chicago, IL, USA). High-resolution (slice thickness: 0.4 mm) CT scans were carried out with a PCD-CT scanner (Naeotom Alpha Peak®, Siemens Healthineers, Erlangen, Germany). CT measurements were performed with a large field of view (FOV) [median (interquartile range): 35 (32–38) cm] and a 512 x 512 matrix. Additionally, 3 strength-level quantitative iterative reconstruction algorithms were utilized to enhance image quality. To exclude ground-glass opacity (GGO) from dependent atelectasis, prone inspiratory HRCT measurements were performed. Radiological findings were assessed by two radiology specialists according to the Fleischner Society White Paper statement on the diagnosis of idiopathic pulmonary fibrosis. [16] Then the images were reviewed by an interdisciplinary ILD board to reach an agreement with the pulmonologists.

Evaluation of parenchymal abnormalities

Interstitial abnormalities were classified into four categories: ground-glass opacity, reticulation, bronchiectasis, and honeycombing, and their extent was scored for each lung lobe using a Likert-type scale (0 = absent; 1 = 1–25%; 2 = 26–50%; 3 = 51–75%; 4 = 76–100%). [17] A total ILD CT score was obtained by summing all scores, the final value ranging from 0–80. The CT pattern of disease was recorded as usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), pleuro-parenchymal fibroelastosis (PPFE), respiratory bronchiolitis interstitial lung disease (RB-ILD), organizing pneumonia (OP), non-specified small extension parenchymal changes (NSSEPC) and other patterns. [18]

Dose considerations

Effective radiation dose (E) for DR and LD PCD-CT was assessed using dose area product (DAP) and area product (tDLP) values extracted via IMPAX (Agfa Corporate, Mortsel, Belgium) and syngo.via software (Siemens Healthineers, Heidelberg, Germany). Approximate E (mSv) was calculated using standard conversion factors: E = DAP × 0.16 mSv/mGy*cm for radiographs/tomosynthesis and E = tDLP × 0.014 mSv/mGy*cm for CT. [19, 20]

Pulmonary Function tests

All patients were asked for pulmonary symptoms, underwent physical examination and detailed pulmonary function tests (PFTs) were performed by pulmonologists at the Department of Pulmonology, Semmelweis University as described previously. The percent of predicted forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1, FEV1/FVC), total lung capacity (TLC) the percent of predicted diffusing capacity of the lung for carbon monoxide (DLCO) according to the American Thoracic Society and European Respiratory Society (ARS/ETS) guidelines [21], and 6-minute walking tests (6MWT) were assessed. [22] PFT values were expressed as a percentage of predicted values.

Statistics

Statistical analysis was performed using SPSS software version 26.0 (IBM, Armonk, NY, USA). Data are expressed as the mean ± standard deviation (SD) or median (interquartile range (IQR)) for continuous variables and percentages for categorical variables.The distribution of continuous variables was evaluated by the Kolmogorov–Smirnov test. Continuous variables were analyzed using the t-test when normally distributed, and using the Mann–Whitney U test when non-normally distributed. Nominal variables were compared between groups using the chi-squared or Fisher’s exact test, as appropriate. Dose values were compared with paired t-tests. Correlations were determined by Pearson’s analysis. Sensitivity, specificity, and predictive values of chest X-ray and pulmonary function tests were calculated and compared with those of LD PCD-CT. Receiver operating characteristic (ROC) curve analysis was performed to identify smoking history cut-off value associated with the development of ILD. Univariable and multivariable binary logistic regression analyses were performed using the enter likelihood method and forward selection methods to evaluate the odds ratios associated with potential independent variables. P-values < 0.05 were considered statistically significant.

Clinical data, enrollment

A total of 544 consecutive RA patients were initially recruited for the study. Of these, 39 individuals were excluded during the study period due to either the development of acute lung infections or withdrawal of consent, resulting in 505 patients completing the baseline visit. Subsequently, four patients were excluded due to discrepancies in identification or laboratory data, and nine were excluded due to non-evaluable chest X-rays. Therefore, the final analysis included data from 492 RA patients. 7% (n = 36) of them were found to have basal crackles, 18% (n = 87) had a dry cough and 29% (n = 139) had exertional dyspnoea. Detailed clinical and demographic characteristics are presented in tables 1 and 2.

Table 1. Baseline demographic, serologic and medication characteristics of RA patients
	Overall RA patients (n = 492)	LD PCD-CT total ILD score ≥ 3 (n = 171)	LD PCD-CT total ILD score < 3 (n = 321)	p-value
Demographics
Age (years)	62.79 ± 10.44	66.51 ± 9.47	60.81 ± 10.41	< 0.001
Age over 65 years, n (%)	236 (48%)	107 (63%)	129 (40%)	< 0.001
Age over 50 years at RA onset, n (%)	249 (52%)	104 (63%)	145 (46%)	< 0.001
Male sex, n (%)	88 (18%)	41 (24%)	47 (15%)	0.010
Smoking history
Ever smoking, n (%)	249 (51%)	95 (57%)	154 (48%)	0.089
Current smoking, n (%)	71 (15%)	30 (18%)	41 (13%)	0.141
Smoking (pack-years)	10.07 ± 16.26	13.28 ± 18.96	8.42 ± 14.41	0.015
Pack-year ≥ 25, n (%)	76 (16%)	39 (23%)	37 (12%)	0.001
RA characteristics
RA duration (years)	14.27 ± 10.23	15.53 ± 11.53	13.61 ± 9.43	0.250
DAS28-ESR	2.79 ± 1.29	2.85 ± 1.26	2.75 ± 1.30	0.381
BMI (kg/m²)	26.66 ± 5.00	26.98 ± 5.04	26.49 ± 4.98	0.229
RA serologies
RF (U/mL)	108.93 ± 195.21	146.37 ± 242.83	87.92 ± 159.19	0.013
RF positivity, n (%) (> 14U/mL)	335 (69%)	130 (77%)	205 (65%)	0.005
Anti-CCP (U/mL)	644.23 ± 1022.77	704.08 ± 1073.90	611.11 ± 993.66	0.086
Anti-CCP positivity, n (%) (> 25 U/mL)	311 (65%)	119 (71%)	192 (62%)	0.042
Anti-MCV positivity, n (%) (> 20 U/mL)	274 (61%)	104 (65%)	170 (58%)	0.171
RF + anti-CCP positivity, n (%)	282 (58%)	112 (67%)	170 (54%)	0.008
RA medication
JAK inhibitors, n (%)	44 (9%)	15 (9%)	29 (9%)	0.944
Rituximab, n (%)	29 (6%)	9 (5%)	20 (6%)	0.680
Abatacept, n (%)	12 (2%)	6 (4%)	6 (2%)	0.356
Anti-IL6 antibodies, n (%)	69 (14%)	28 (17%)	41 (13%)	0.257
TNF inhibitors, n (%)	209 (43%)	70 (42%)	139 (44%)	0.665
Leflunomid, n (%)	137 (28%)	44 (26%)	93 (29%)	0.477
MTX, n (%)	466 (95%)	160 (95%)	306 (96%)	0.602
Steroid, n (%)	421 (86%)	142 (85%)	279 (88%)	0.322

Results are presented as mean ± standard deviation, median (interquartile range) and frequency (percentage). Significant differences (p<0.05) are highlighted in bold.

RA: rheumatoid arthritis; RF: rheumatoid factor; anti-CCP: anti cyclic citrullinated peptide antibody; anti-MCV: anti citrullinated vimentin antibody; JAK: Janus kinases; IL-6: interleukin 6; TNF: tumor necrosis factor, MTX: methotrexate

Table 2. Baseline clinical, radiological and laboratory parameters of RA patients
	Overall RA patients (n = 492)	LD PCD-CT total ILD score ≥ 3 (n = 171)	LD PCD-CT total ILD score < 3 (n = 321)	p-value
Respiratory signs, symptoms
Basal crackles, n (%)	36 (7%)	21 (12%)	15 (5%)	0.002
Exertional dyspnoea, n (%)	139 (29%)	45 (27%)	94 (30%)	0.520
Dry cough, n (%)	87 (18%)	30 (18%)	57 (18%)	0.985
Pulmonary function tests and pulmonary parameters
FEV1 (L)	2.49 ± 0.63	2.36 ± 0.50	2.56 ± 0.68	0.015
FEV1% predicted	95.32 ± 16.57	96.17 ± 16.71	94.84 ± 16.51	0.998
FEV 1 < 80% predicted	48 (14%)	14 (12%)	34 (16%)	0.286
FVC (L)	3.14 ± 0.77	3.00 ± 0.66	3.22 ± 0.81	0.026
FVC % predicted	94.99 ± 15.48	95.61 ± 16.63	94.65 ± 14.85	0.800
FVC < 80% predicted	56 (17%)	18 (15%)	38 (18%)	0.563
TLC (L)	5.92 ± 2.08	5.76 ± 1.01	6.02 ± 2.49	0.510
TLC % predicted	114.93 ± 20.09	115.44 ± 19.19	114.65 ± 20.60	0.607
DLCO (mmol/min/kPa)	8.83 ± 2.01	8.29 ± 1.90	9.14 ± 2.01	< 0.001
DLCO % predicted	122.16 ± 20.89	117.65 ± 20.09	124.65 ± 20.95	0.003
DLCO < 75% predicted	7 (2%)	4 (3%)	3 (1%)	0.251
Radiogical findings
X-Ray
Fibrosis, n (%)	14 (4%)	11 (6%)	3 (1%)	0.001
LD PCD-CT
dUIP, n (%)	11 (2%)	10 (6%)	1	< 0.001
pUIP, n (%)	7 (1%)	7 (4%)	0	0.001
iUIP, n (%)	6 (1%)	6 (4%)	0	0.002
NSIP, n (%)	8 (2%)	8 (5%)	0	< 0.001
RB-ILD, n (%)	4 (1%)	4 (2%)	0	0.014
PPFE, n (%)	10 (2%)	4 (2%)	6 (2%)	0.744
NSSEPC, n (%)	64 (13%)	37 (22%)	27 (9%)	< 0.001
Laboratory parameters
ESR (mm/h)	18.25 ± 16.22	19.78 ± 16.45	17.40 ± 16.06	0.056
ESR > 20 mm/h, n (%)	138 (31%)	55 (35%)	83 (29%)	0.191
CRP (mg/mL)	6.97 ± 11.86	7.35 ± 11.89	6.75 ± 11.86	0.042
CA 15 − 3 (U/mL)	21.33 ± 10.08	23.89 ± 12.54	20.01 ± 8.26	0.008
CA 15 − 3 > 25 U/mL, n (%)	128 (30%)	52 (35%)	76 (27%)	0.060
LDH (U/L)	208.28 ± 44.10	217.32 ± 47.17	203.19 ± 41.50	0.003
LDH > 214 U/L, n (%)	170 (39%)	75 (47%)	95 (34%)	0.005

Results are presented as mean ± standard deviation and frequency (percentage). Significant differences (p<0.05) are highlighted in bold.

FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; TLC: total lung capacity; DLCO: diffusion capacity of the lung for carbon monoxide; dUIP: definite usual interstitial pneumonia; pUIP: probable usual interstitial pneumonia; iUIP: indeterminate usual interstitial pneumonia; NSIP: non-specific interstitial pneumonia; PPFE: pleuro-parenchymal fibroelastosis; RB-ILD: respiratory bronchiolitis interstitial lung disease; NSSEPC: non-specified small extension parenchymal changes; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; CA 15-3: cancer antigen 15-3; LDH: lactate dehydrogenase

Imaging findings

All patients underwent digital radiography and consecutive LD PCD-CT scans at baseline. The median (IQR) total ILD CT score was 2 (0; 3); a threshold score ≥ 3 was considered clinically significant. Fibrotic changes were identified in only 4% of patients on chest radiography (n = 14). In contrast, LD PCD-CT revealed interstitial alterations in 35% (n = 171), of whom only 6.5% showed fibrotic signs on X-ray.

Regarding the CT patterns UIP has been found in 22%, PPFE in 9%, NSIP in 7% and RB-ILD in 4% of the patients. Small extension interstitial lung abnormalities were identified in 58% of the cases (Fig. 1).

Radiation Exposure

The effective radiation dose of DR was 0.171 ± 0.286 mSv, with a median dose of 0.067 (0.043–0.127) mSv. LD PCD-CT showed a significantly higher but still low radiation dose of 0.415 ± 0.316 mSv, with a median of 0.378 (0.322–0.455) mSv (p < 0.001).

Pulmonary Function Parameters

Pulmonary function tests were available for 363 patients. Mean spirometric parameters fell within the physiological ranges. The mean predicted FVC was 95.00 ± 15.48%, while the diffusing capacity for DLCO was 122.16 ± 20.89%. Among patients with ILD CT score ≥ 3, only 12% had FVC < 80%, and 3% had DLCO < 75%. A mild but significant negative correlation was observed between ILD CT score and DLCO (r = − 0.224, p < 0.001). The sensitivity and specificity of pulmonary function tests for ILD detection were 21% and 77%, respectively (Table 2, Fig. 2).

Risk Profiles

Clinical and laboratory characteristics of the RA patients were analyzed to identify potential associations with interstitial lung involvement. The median age at diagnosis in our cohort was 50 (40–60) years; accordingly, age ≥ 50 years at diagnosis was used as a clinical threshold for risk stratification. Receiver operating characteristic (ROC) curve analysis of smoking history identified an optimal cut-off value of 25 pack-years, which was subsequently adopted as the threshold to define high-risk smoking exposure.

Univariate analysis using binary logistic regression (Enter method) revealed that older age, age ≥ 50 years at RA diagnosis, male sex at birth, smoking exposure ≥ 25 pack-years, RF and aCCP positivity, and elevated LDH levels were significantly associated with a total ILD CT score ≥ 3.

Multivariate logistic regression using the backward (likelihood ratio) method identified five independent predictors of interstitial lung involvement: older age (OR 2.594 [95% CI 1.686, 3.989] p < 0.001), smoking exposure ≥ 25 pack-years (OR 1.885 [95% CI 1.070, 3.322] p < 0.028), male sex (OR 1.741 [95% CI 1.003, 3.023] P = 0.049), RF positivity (OR 1.952 [95% CI 1.214, 3.319] p = 0.006), and high LDH levels (OR 1.872 [95% CI 1.214, 2.885] p = 0.005) (Table 3).

Table 3

Association between LD PCD-CT findings, clinical and serological features
	Univariate analysis			Multivariate analysis
	ODDS	95% CI	p	ODDS	95% CI	p
Categorical variables
Age over 65 years	2.488	1.699–3.645	< 0.001	2.594	1.686–3.989	< 0.001
Age over 50 years at RA onset	2.011	1.367–2.957	< 0.001
Male sex	1.839	1.151–2.936	0.011	1.741	1.003–3.023	0.049
Ever smoking	1.386	0.951–2.019	0.089
Pack-years ≥ 25	2.288	1.393–3.756	0.001	1.885	1.070–3.322	0.028
RF positivity (> 14 U/mL)	1.852	1.206–2.845	0.005	1.952	1.214–3.319	0.006
Anti-CCP positivity (> 25 U/mL)	1.518	1.014–2.272	0.043
RF + anti-CCP positivity	1.694	1.147–2.502	0.008
Anti-MCV positivity (> 20 U/mL)	1.322	0.886–1.972	0.171
JAK inhibitors	0.977	0.508–1.878	0.944
Rituximab	0.843	0.775–1.896	0.680
Abatacept	1.926	0.611–6.067	0.263
Anti-IL6 antibodies	1.351	0.802–2.277	0.258
TNF inhibitors	0.920	0.630–1.343	0.665
Leflunomid	0.858	0.564–1.307	0.477
MTX	0.784	0.314–1.958	0.603
Steroid	0.763	0.447–1.305	0.323
Elevated LDH level (> 214 U/L)	0.758	1.181–2.615	0.005	1.872	1.214–2.885	0.005
Elevated CRP level (> 5 mg/mL)	1.345	0.895–2.022	0.154
Elevated CA15-3 level (> 25 U/mL)	1.505	0.981–2.309	0,061
ESR > 20 mm/h	1.319	0.871–1.997	0.191
Basal crackles	2.886	1.446–5.761	0.003
Exertional dyspnoea	0.872	0.574–1.324	0.520
Dry cough	0.995	0.611–1.621	0.985
Continuous variables
Age	1.058	1.037–1.079	< 0.001
Pack-years	1.018	1.006–1.029	0.003
DAS28-ESR	1.063	0.920–1.230	0.406
BMI	1.020	0.982–1.058	0.304
RA duration	1.018	1.000-1.037	0.050
RF	1.001	1.000-1.003	0.004
Anti-CCP	1.000	1.000–1.000	0.355
CRP	1.004	0.988–1.020	0.611
ESR	1.009	0.997–1.021	0.139
CA 15 − 3	1.039	1.018–1.061	< 0.001
LDH	1.007	1.003–1.012	0.002

Results from univariate analysis, binary logistic regression using the enter method, and multivariate logistic regression with the backward (likelihood ratio) method. Significant predictors (p<0.05) are highlighted in bold.

The median age at diagnosis in our cohort was 50 years; thus, age ≥50 at diagnosis was considered a clinical risk threshold. Receiver operating characteristic (ROC) curve analysis for smoking history revealed an optimal cut-off at 25 pack-years, which was subsequently used as a threshold to define high-risk smoking exposure in further analysis.

At univariate analysis, older age (>65 years), age ≥50 years at RA diagnosis, male sex at birth, smoking exposure ≥25 pack-years, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (aCCP) positivity, elevated lactate dehydrogenase (LDH) levels were significantly associated with a total ILD CT score ≥3.

Multivariate analysis identified five independent predictors of lung involvement: older age (>65 years), male sex, smoking exposure ≥25 pack-years, RF positivity, and elevated LDH levels.

RF: rheumatoid factor; anti-CCP: anti cyclic citrullinated peptide antibody; anti-MCV: anti citrullinated vimentin antibody; JAK: Janus kinases; IL-6: interleukin 6; TNF: tumor necrosis factor, MTX: methotrexate; LDH: lactate dehydrogenase; CRP: C-reactive protein; CA 15-3: cancer antigen 15-3; ESR: erythrocyte sedimentation rate

Considering a horizontal multi-level hierarchy of diagnostic modalities for detecting subclinical ILD, LD PCD-CT identified interstitial lung involvement-defined as a total CT ILD score ≥ 3-in 171 of 492 RA patients (35%). In contrast, clinical assessment and PFTs detected abnormalities in only 44% and 22% of these LD PVD-CT-positive cases, respectively. DR revealed fibrotic changes in just 6.5% of this subgroup. Notably, among patients without LD PCD-CT-defined ILD, 42% had positive clinical assessments and 23% demonstrated abnormal PFTs, underscoring the limited diagnostic specificity of these conventional approaches in the absence of imaging-confirmed disease. (Fig. 3)

This prospective study provides compelling evidence that LD PCD-CT significantly enhances the detection of small extension ILD in patients with RA. In our cohort of 492 RA patients, LD PCD-CT identified interstitial alterations in 35% of individuals, a detection rate markedly higher than that achieved by conventional screening modalities as clinical assessment (44%), PFTs (15%) or DR (6.5%).

Extra-articular manifestations occur in up to 50% of RA patients [23], with ILD among the most severe and life-limiting complications. Although clinically apparent RA-ILD affects 5–10% of patients, radiographic signs of subclinical disease have been reported in 20–60%. [24, 25] Interstitial lung abnormalities (ILAs) are incidental CT findings involving at least 5% of lung parenchyma, detected in patients without prior clinical suspicion of ILD. [9] Given the elevated risk of progression to clinically significant ILD- ranging from 20% over 2 years(26) to 43% over 5 years [27, 28]- the Fleischner Society recommends that ILAs in patients with RA and other autoimmune diseases be classified as preclinical ILD. [9] In our cohort, 35% of RA patients exhibited interstitial alterations, of which 58% were identified as NSSEPC on LD PCD-CT, aligning with previously reported prevalence ranges. These findings underscore the significant burden of asymptomatic parenchymal lung involvement in patients with RA.

Emerging data, including the INBUILD trial [29], affirm that early intervention in progressive fibrosing ILDs can delay progression, reinforcing the importance of early detection. Despite this, no universally accepted RA-ILD screening strategy currently exists. While national initiatives are underway [30–32], formal RA-ILD–specific guidelines have yet to be issued by the European Alliance of Associations for Rheumatology (EULAR) or the American College of Rheumatology (ACR). However, ACR and the American College of Chest Physicians (CHEST) have published recommendations for the screening and monitoring of ILD in individuals with systemic autoimmune rheumatic diseases, including RA. They proposed an initial clinical assessment and PFTs, with HRCT reserved for high-risk individuals. [33] Consistent with previous studies [34], our findings suggest this approach may miss a substantial proportion of patients with early-stage disease. Notably, the majority of patients with LD PCD-CT–identified abnormalities were clinically silent. Only 7% presented with basal crackles, 18% reported dry cough, and 27% experienced exertional dyspnoea. Moreover, just 10.5% of them had abnormal PFTs, and just 6.5% demonstrated abnormalities on DR.

While HRCT remains the gold standard for ILD diagnosis [35, 36], its high radiation dose (5–15 mSv) limits its feasibility for routine screening. By contrast, LD PCD-CT in our study achieved a significantly lower effective dose (0.415 ± 0.316 mSv) while still providing superior image quality. Although it exceeds the dose of chest radiography (0.173 ± 0.286 mSv), LD PCD-CT remains within low-dose thresholds and is comparable to a two-view chest DR. [37] Importantly, LD PCD-CT detected hallmark features of ILD—ground-glass opacities, subpleural reticulations, bronchiectasis, and honeycombing—that are often undetectable on conventional radiographs. The screening protocol used in this study builds on our earlier work [38], which demonstrated that LD PCD-CT effectively identifies early interstitial changes at minimal radiation exposure. The most common interstitial finding was NSSEPC (referred to ILA previously). The most abundant patterns were UIP, PPFE and NSIP, mirroring previous cohort findings. [27, 39] Even though the clinical implications of NSSEPC in RA are still being clarified, mounting evidence—including from our study—suggests that these early radiographic changes may predict future disease progression and warrant closer monitoring or preemptive therapy. [40, 41]

In addition to imaging, serological biomarkers may provide complementary information. Both LDH and CA 15 − 3 have been identified as markers that may help predict lung involvement in RA patients. LDH is an enzyme found in various body tissues, and elevated levels can signal tissue damage, including lung injury. In the context of RA-ILD, higher LDH levels have been strongly associated with the onset of pulmonary involvement. [42] CA15-3 and Krebs von den Lungen-6 (KL-6), encoded by the same mucin 1 (MUC1) gene, are members of the MUC1 family, which coats the surface of various epithelial cells, including those in the alveoli, breast, and gastrointestinal tract. [43] Previous studies have indicated that elevated CA15-3 levels were associated with reduced TLC, decreased DLCO, and more advanced pulmonary fibrosis, as indicated by HRCT findings. [43, 44]

Consistent with previous studies, risk factor analysis revealed that older age, male sex, high cumulative smoking exposure, RF positivity, and elevated LDH levels were independently associated with subclinical ILD. [45–48] These variables may serve as practical markers to prioritize patients for imaging-based screening. Notably, smoking exposure ≥ 25 pack-years and RF positivity have consistently emerged in prior studies as key predictors of RA-associated ILD, lending further validity to our findings. [35, 42]

One of the key strengths of our study is the application of PCD-CT technology, which provides improved spatial resolution and contrast-to-noise ratio at lower radiation doses compared to conventional CT. [49, 50]. This advantage makes it particularly well-suited for repeated imaging in longitudinal monitoring and screening protocols. Here we provide for the first time that LD PCD-CT measurements could serve as a valuable screening tool in clinical practice.

Despite these strengths, our study has limitations. First, it was conducted at a single center, potentially limiting the generalizability of the findings. Second, although radiographic abnormalities were well characterized, long-term clinical follow-up is needed to determine the progression and impact of these subclinical findings. Important to note, that in-and expiratory CT images are important to assess small airway involvement and air trapping, and no data on emphysema were collected. Future investigations should examine the natural history of small extension parenchymal changes detected by LD PCD-CT in RA and assess whether early therapeutic intervention can improve outcomes. Prospective, multicenter studies with standardized imaging protocols and longer follow-up periods are warranted. The development of AI-driven tools for automated detection and classification of ILD features may further enhance diagnostic precision. Additionally, cost-effectiveness analyses are necessary to evaluate the broader implementation of LD PCD-CT in routine RA-ILD screening.

Our findings emphasize the diagnostic limitations of relying solely on clinical symptoms and functional assessments (even in combinations with DR) in screening for RA-associated ILD. LD PCD-CT demonstrated markedly superior sensitivity in detecting interstitial lung abnormalities,, while maintaining low radiation exposure. These results support the integration of LD PCD-CT into risk-based screening strategies to enable earlier detection, intervention, and improved patient outcomes in RA-ILD.

ACPA anti-citrullinated peptide antibodies

ACR American College of Rheumatology

ARS/ETS American Thoracic Society and European Respiratory Society guidelines

DMARD disease-modifying antirheumatic drug

CA 15-3 cancer antigen 15-3

CCP Anti-cyclic citrullinated peptide

CHEST American College of Chest Physicians

CRP C-reactive protein

DAP dose area product

DLCO percent of predicted diffusing capacity of the lung for carbon monoxide

DR digital chest radiography

E Effective radiation dose

ESR erythrocyte sedimentation rate

EULAR European Alliance of Associations for Rheumatology

FEV1 forced expiratory volume in 1 s

FVC forced vital capacity

GGO ground-glass opacity

HRCT high-resolution computed tomography

ILAs Interstitial lung abnormalities

ILD interstitial lung disease

IQR interquartile range

KL-6 Krebs von den Lungen-6

LDH lactate dehydrogenase

LD PCD-CT low-dose photon-counting detector CT

6MWT 6-minute walking tests

MUC1 mucin 1

NSIP non-specific interstitial pneumonia

NSSEPC non-specified small extension parenchymal changes

OP organizing pneumonia

PFTs pulmonary function tests

PPFE pleuro-parenchymal fibroelastosis

RA-ILD rheumatoid arthritis-associated interstitial lung disease

RA rheumatoid arthritis

RB-ILD respiratory bronchiolitis interstitial lung disease

RF rheumatoid factor

ROC Receiver operating characteristic

SD standard deviation

tDLP area product

TLC total lung capacity

UIP usual interstitial pneumonia

Ethics approval and consent to participate

Ethical approval was obtained from the Regional Research Ethics Committee (reference number: IV/2683-1/2022/EKU). Written informed consent was obtained from all participants prior to inclusion in the study.

Consent for publication

Not applicable

Availability of data and materials

The data used in this study are available upon request from the corresponding author (GN) and subject to approval by the Regional Research Ethics Committee, in accordance with institutional data sharing policies.

Competing interests

Nikolett Marton received support from the ÚNKP-23-5 New National Excellence Program of the Ministry for Culture and Innovation, funded by the National Research, Development and Innovation Fund, as well as the Bolyai Research Scholarship. Michal Tomcik received institutional support from the Ministry of Health of the Czech Republic (grant no. 023728). The authors declare no other financial or non-financial competing interests.

Funding

No additional specific funding was received from any public, commercial, or not-for-profit funding bodies to support the work described in this manuscript.

Authors’ contributions

PD, DW, TC, KPL contributed to study conception and design; PD, DW, KD, DD, VF, HC, MW, NS contributed to data acquisition and analysis; PD, DW, TC, KPL contributed to interpretation of data; DW, TC, KPL had primary responsibility for final content; all authors contributed to critical revision and approved the final manuscript.

Acknowledgements

We would like to express our sincere gratitude to the participating patients and colleagues for their contributions to this work Dora Sarvari, Kinga Kohalmi, Marianna Bonacz, Eva Lanyi, Margit Szentesi, Tamas Gati, Kinga Futo, Nikolett Mong, Angela Fulop, Katalin Imre, Bernadette Rojkovich, Gyorgyi Meszaros, Timea Petri, Erzsebet Nagy, Bernadette Bereczkine Szabo, Judit Simon, Adam Domonkos Tarnoki, David Laszlo Tarnoki, Laszlo Szakacs, Leila Szeibel, Nora Kerkovits, Klaudia Borbely and Csenge Poka.

Disclosure statement: The authors have declared no conflicts of interest.

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No competing interests reported.

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Graphical Abstract

Screening for Rheumatoid Arthritis-Associated Interstitial Lung Disease Using Low-Dose CT: An Emerging Approach — An Observational Prospective Case-Control Study

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