Belén Atienza-Mateo

Objectives: To evaluate the validity of the rheumatoid arthritis–interstitial lung disease screening project of the Spanish Society of Rheumatology (AR-EPIDSER) screening criteria for detecting rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) and to estimate the prevalence of undiagnosed and subclinical ILD in patients with RA in Spain. Patients and methods: Multicentre cross-sectional observational study conducted in 15 Spanish hospitals. Adult patients with RA (American College of Rheumatology (ACR) 1987 or ACR/European Alliance of Associations for Rheumatology 2010 criteria) without a previous ILD diagnosis were included. During a rheumatology visit, the AR-EPIDSER screening criteria were applied, and all participants underwent high-resolution CT (HRCT) of the chest as the reference test, with centralised reading. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated with 95% CI as well as the prevalence of ILD and subclinical ILD. Results: A total of 477 patients were recruited; 424 had evaluable HRCT (73.6% women; median age 59 years). The prevalence of ILD on HRCT examinations was 13.0% (55/424; 95% CI 9.9% to 16.6%). Subclinical ILD (no cough, dyspnoea or ‘Velcro-like’ crackles) was 8.3% (35/424; 95% CI 5.7% to 11.1%), accounting for 63.6% of ILD cases. Screening was positive in 68.2% (289/424). The AR-EPIDSER criteria showed sensitivity=0.93 (95% CI 0.82 to 0.98), specificity=0.36 (0.31 to 0.41), PPV=0.18 (0.13 to 0.23) and NPV=0.97 (0.93 to 0.99). Conclusion: In Spanish patients with RA, undiagnosed ILD is frequent and mostly subclinical. The AR-EPIDSER criteria are useful as an initial screening tool due to high sensitivity and excellent NPV; however, low specificity suggests that positive cases should be confirmed by HRCT.

Objective: To identify clinical and therapeutic predictors of interstitial lung disease (ILD) progression in patients with RA treated with abatacept (ABA) in clinical practice. Methods: National multicentre study including 343 RA-associated interstitial lung disease patients from a national cohort of 526 individuals treated with ABA, all of them with serial pulmonary function tests available. Progressive ILD was defined as an absolute decline in forced vital capacity ≥10% or a relative decline of 5–9% combined with clinical progression (modified Medical Research Council Dyspnea Scale [mMRC]) and/or radiological progression (high-resolution computed tomography) over 24 months after starting ABA. A comparative and multivariable analysis was performed to identify factors associated with ILD progression. Results: Progressive ILD occurred in 80 patients (23.3%), while 263 (76.7%) showed a stable or improved pulmonary functional course. Baseline characteristics were comparable between groups, except for higher dyspnoea scores and lower prior exposure to MTX (63% vs 76%; p = 0.02) and tocilizumab (4 vs 34; p = 0.048) among progressive cases. Multivariable analysis showed that prior treatment with MTX had a protective role (OR = 0.453), while previous golimumab exposure (OR = 10.009) and higher DAS28-ESR values (OR = 1.284) increased the risk of ILD progression. Interestingly, no significant differences were observed according to the ILD radiologic pattern or time from ABA initiation. Conclusions: Despite ABA therapy, progressive ILD occurred in nearly one-quarter of RA patients. ABA showed good tolerability and maintained pulmonary and rheumatologic stability in most cases. However, prior treatments and joint disease activity may help to predict the risk of ILD progression.

An early and accurate diagnosis of connective tissue diseases-related interstitial lung disease (CTD-ILD) is crucial for delaying lung fibrosis, but its unknown etiology and the limitations of clinical tools make it challenging for clinicians. PDGF and TGFB are the main profibrotic genes. We evaluated PDGFA, TGFB1, TGFB2, and TGFB3 role in the diagnosis of ILD associated with rheumatoid arthritis (RA), systemic sclerosis (SSc), and inflammatory myopathies (IM). Blood was collected from 289 patients:33 RA-ILD, 31 SSc-ILD, 29 IM-ILD; and 22 RA-nonILD, 18 SSc-nonILD, 8 IM-nonILD; and 148 idiopathic pulmonary fibrosis (IPF). The relative expression was quantified by qPCR. Lower PDGFA, TGFB1, and TGFB2 expression differentiated RA-ILD from RA-nonILD patients, acting as ILD early diagnostic biomarkers in RA with cut-offs of TGFB2 expression compared to SSc-nonILD patients, with a cut-off of 0.0166 and >0.001547, respectively. PDGFA and TGFB2, as well as TGFB2 and TGFB3 expression were associated with RA-ILD and SSc-ILD prognosis, respectively. PDGFA and TGFB are promising blood biomarkers with clinical value for the early and accurate CTD-ILD diagnosis.

Objective: To evaluate the real-world safety and efficacy of macitentan (MACI) in patients with systemic autoimmune rheumatic diseases (SARDs) and refractory digital ulcers (DUs). Methods: We conducted a retrospective observational study of 42 patients treated with MACI (10 mg/day) on a compassionate-use basis across Spanish reference hospitals. Given the cohort’s heterogeneity, a two-step analysis was performed: a global assessment of all patients, followed by a subgroup analysis restricted to those with systemic sclerosis (SSc) or fulfilling very early SSc (VEDOSS) criteria to explore predictors of response. Efficacy was defined as complete healing, partial response, or a lack of response based on physician assessment. Safety was evaluated through analysis of adverse events. Results: In the global cohort, MACI demonstrated a high rate of complete ulcer healing (82.9%) at the 3-month follow-up, with a significant reduction in median ulcer count (p < 0.001). Subgroup analysis within the SSc/VEDOSS cohort (n = 36) revealed that the presence of gastrointestinal involvement (GI) and a higher baseline DUs were significant predictors of a poorer therapeutic response (p = 0.022 and p = 0.028). The drug was well-tolerated; adverse events were infrequent and rarely led to treatment discontinuation. Conclusions: In this real-world refractory population, MACI was associated with rapid DU healing and a favorable safety profile. GI and higher ulcer burden predicted diminished treatment response in SSc patients. These results support the use of MACI as a valuable therapeutic option for severe digital vasculopathy in SARDs, although further prospective studies are warranted to confirm these observations.

Objective: The objective of this study was to assess the effectiveness and safety of baricitinib (BARI) in interstitial lung disease associated with RA (RA-ILD) in clinical practice. Methods: : This was a national multicentre retrospective study of 72 RA-ILD patients treated with BARI. We analysed the following outcomes at baseline and at 3, 6, 12, 18 and 24 months, and at last follow-up: (i) dyspnea (modified Medical Research Council scale), (ii) forced vital capacity (FVC), (iii) diffusing capacity of the lungs for carbon monoxide (DLCO), (iv) chest high-resolution CT (HRCT), (v) arthritis activity (DAS28-ESR), and (vi) CS-sparing effect. Additionally, we analysed the safety data and performed a literature review up to December 2023. Results: We included 72 patients (52 women; mean (s.d.) age 68 (10) years). All patients had received DMARDs. The median [interquartile range (IQR)] ILD duration up to BARI initiation was 25 [13–63] months. The most frequent ILD patterns were usual interstitial pneumonia (n = 33; 49%) and non-specific interstitial pneumonia (n = 22; 32%). BARI was used in monotherapy in 43 (60%) patients and combined with conventional synthetic DMARDs in 29 (40%). Mean (s.d.) baseline values of FVC and DLCO (% predicted) were 86 (28) and 69 (20), respectively. After a median [IQR] follow-up of 32 [13–65] months, dyspnea, FVC, DLCO and HRCT improved or stabilized in 90%, 88%, 65% and 72%, respectively. The mean DAS28-ESR improved from 4.29 to 2.99, and the median prednisone dose was reduced from 5 to 2.5 mg/day. Relevant adverse events were uncommon. Conclusion: BARI may be a useful and safe alternative in both pulmonary and joint disease in RA-ILD patients, even in refractory cases.

Objectives: The impact of autoantibody profiles on the prognosis for idiopathic inflammatory myositis–associated interstitial lung disease (IIM-ILD) and myositis spectrum ILD with myositis-specific antibodies (MSAs) remains unclear. This retrospective cohort study examined whether serological profiles were associated with mortality or longitudinal lung function change. Methods: The baseline clinical/demographic characteristics and follow-up lung function data of consecutive adult patients with IIM-ILD or interstitial pneumonia with autoimmune features (IPAF) positive for MSAs (IPAF-MSA) were extracted from three hospitals. Univariate and multivariate Cox proportional hazards analyses were used to compare mortality between groups of patients with different autoantibodies. Regression models were used to analyse their lung function trends. Results: Of the 430 included patients, 81% met the IIM criteria, and the remaining 19% were diagnosed with IPAF-MSA. On univariate analysis, the risk factors associated with mortality included higher age, Charlson Comorbidity Index, and CRP; and lower BMI, baseline TLCO% and FEV1%. Compared with anti-MDA5 negativity, anti-MDA5 positivity (MDA5+) was associated with higher mortality in the first 3 months [hazard ratio (HR) 65.2, 95% CI 14.1, 302.0], while no significant difference was seen thereafter (HR 0.55, 95% CI 0.14, 2.28). On multivariate analysis, combined anti-synthetase antibodies were associated with a reduced risk of mortality (HR 0.63), although individually, mortality was reduced in patients with anti-Jo1+ (HR 0.61, 95% CI 0.4–0.87) and increased in patients with anti-PL7+ (HR 2.07, 95% CI 1.44–2.99). Anti-MDA5+ was associated with slow improvement in %FVC over the first 3 years, while anti-PL7+ was linked with a slow decline from 12 months onwards. Conclusion: Among the autoantibody profiles in myositis spectrum disorders, anti-MDA5+ and anti-PL7+ conferred higher mortality risks in patients with IIM-ILD. Survivors of an early peak of mortality in anti-MDA5+ disease appeared to have a favourable prognosis.

Interstitial lung disease (ILD) constitutes the most critical comorbidity in autoimmune diseases (ADs) and its early diagnosis remains a challenge for clinicians. Accordingly, we evaluated whether E-selectin, ICAM-1, and ET-1, key molecules in endothelial damage, could be useful biomarkers for the detection of AD-ILD⁺. We recruited patients with rheumatoid arthritis (RA)-ILD⁺ (n = 21) and systemic sclerosis (SSc)-ILD⁺ (n = 21). We included comparison groups of patients: RA-ILD⁻ (n = 25), SSc-ILD⁻ (n = 20), and idiopathic pulmonary fibrosis (IPF) (n = 21). Serum levels of these proteins were determined by ELISA. E-selectin, ICAM-1, and ET-1 serum levels were increased in RA-ILD⁺ and IPF patients in comparison to RA-ILD⁻ patients. Additionally, SSc-ILD⁺ and IPF patients exhibited higher ICAM-1 levels than those with SSc-ILD⁻. The ability of E-selectin, ICAM-1, and ET-1 to discriminate RA-ILD⁺ from RA-ILD⁻ patients, and ICAM-1 to distinguish SSc-ILD⁺ from SSc-ILD⁻ patients was confirmed using ROC curve analysis. Furthermore, elevated levels of ET-1 and E-selectin correlated with lung function decline in RA-ILD⁺ and SSc-ILD⁺ patients, respectively. In conclusion, our findings support the relevant role of E-selectin, ICAM-1, and ET-1 in RA-ILD⁺ patients as well as of ICAM-1 in SSc-ILD⁺ patients, constituting potential screening blood biomarkers of ILD in AD. Moreover, this study suggests ET-1 and E-selectin as possible indicators of worsening lung function in RA-ILD⁺ and SSc-ILD⁺ patients, respectively.

The aim of this study was to determine the role of endothelin-1 (ET-1), a molecule involved in multiple vascular and fibrosing abnormalities, as a biomarker of interstitial lung disease (ILD), as well as its use for the differential diagnosis between idiopathic pulmonary fibrosis (IPF) and ILD associated with autoimmune diseases (AD-ILD), using a large and well-defined cohort of patients with ILD. A total of 112 patients with IPF, 91 patients with AD-ILD (28 rheumatoid arthritis (RA), 26 systemic sclerosis, 20 idiopathic inflammatory myositis and 17 interstitial pneumonia with autoimmune features) and 44 healthy controls were included. ET-1 serum levels were determined by enzyme-linked immunosorbent assay. A significant increase in ET-1 levels was found in patients with IPF compared to controls. Likewise, AD-ILD patients also showed higher ET-1 levels than controls when the whole cohort was stratified by the type of AD. Similar ET-1 levels were found in IPF and AD-ILD patients, regardless of the underlying AD. Interestingly, increased ET-1 levels were correlated with worse lung function in IPF and RA-ILD patients. Our study supports that serum ET-1 may be useful as a biomarker of ILD, although it could not help in the differential diagnosis between IPF and AD-ILD. Moreover, ET-1 levels may be associated with ILD severity.