Baseline FVC Research Articles

Does regression of skin thickening predict improvement of internal organ involvement and survival in patients with diffuse cutaneous systemic sclerosis? A EUSTAR analysis

ObjectivePatients with diffuse cutaneous systemic sclerosis (dcSSc) frequently show spontaneous improvement of skin fibrosis. Our aim was to examine whether an improvement in skin fibrosis predicts lower likelihood of visceral organ progression and better survival.MethodsPatients from the European Scleroderma Trials and Research (EUSTAR) cohort with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, and valid mRSS at 12±3 months follow up were included. Regression/progression of skin fibrosis was defined as a decrease/increase in mRSS >5 points and≥25% from baseline to follow up. The outcomes included progression of lung, renal, cardiac and gastrointestinal manifestations using consensus derived definitions and all-cause death. Regressive, stable and progressive patients were compared by univariate, Kaplan-Meier survival curve and Cox regression analysis.ResultsOf 1257 included patients, 883 (70.2%) were stable, 282 (22.4%) regressive, and 92 (7.3%) progressive. Regressive patients, adjusted for baseline mRSS, baseline immunosuppression, baseline FVC, and disease duration, showed a significantly lower probability of FVC decline ≥10% than progressive patients (p=0.00003), lower probability of all-cause mortality during follow up (p=0.035) compared to progressive patients. .Improvement of skin fibrosis was not associated with progression of other organ manifestations.ConclusionWe found that regression of skin fibrosis is associated with a lower probability of lung progression and better survival at follow up. The link between the disease course of skin and lung fibrosis in SSc can help to better stratify patients in clinical practice and enrich for ILD progressive patients in clinical trials.

Deep-learning CT imaging algorithm to detect usual interstitial pneumonia pattern in patients with systemic sclerosis-associated interstitial lung disease: association with disease progression and survival.

Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc), although disease behavior is highly heterogeneous. While a usual interstitial pneumonia (UIP) pattern is associated with worse survival in other ILDs, its significance in SSc-ILD is unclear. We sought to assess the prognostic utility of a deep-learning HRCT algorithm of UIP probability in SSc-ILD. Patients with SSc-ILD were included if HRCT images, concomitant lung function tests, and follow-up data were available. We used the Systematic Objective Fibrotic Imaging analysis Algorithm (SOFIA), a convolution neural network algorithm which provides probabilities of a UIP pattern on HRCT images. These were converted into the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED)-based UIP probability categories. Decline in lung function was assessed by mixed-effect model analysis and relationship with survival by Cox proportional hazards analysis. 522 patients were included in the study. 19.5% were classified as UIP not in the differential, 53.5% as low probability of UIP, 25.7% as intermediate probability of UIP, and 1.3% as high probability of UIP. A higher likelihood of UIP probability expressed as PIOPED categories was associated with worse baseline FVC, as well as with decline in FVC (p= 0.008), and worse 15-year survival (p= 0.001), both independently of age, gender, ethnicity, smoking history, and baseline FVC or Goh et al. staging system. A higher probability of a SOFIA-determined UIP pattern is associated with more advanced ILD, disease progression, and worse survival, suggesting that it may be a useful prognostic marker in SSc-ILD.

Evaluation of e-Lung automated quantitative CT biomarkers in idiopathic pulmonary fibrosis

BackgroundIn patients with idiopathic pulmonary fibrosis (IPF), there is a need to identify biomarkers that i) are associated with increased risk of adverse outcome and ii) can be used to monitor treatment response or identify disease progression over time.MethodsTwo consecutive cohorts of patients with IPF were accessed from the Open Source Imaging Consortium database. Automated CT biomarkers of disease severity incorporating fibrotic and pulmonary vascular features (the reticulovascular score and weighted reticulovascular score (WRVS)), were studied. Relationships between imaging biomarkers, lung function and survival were analysed.ResultsIn separate test and validation cohorts, 168 and 176 patients with IPF respectively (median survival 2.6 years) were studied. A threshold of WRVS ≥15% at baseline CT was most strongly associated with transplant free survival (HR 3.00, 95% CI 1.47, 6.10, p=0.002) when adjusted for baseline FVC and age. In patients with 12 month follow up CT and lung function tests (n=89) an increase in 3% of WRVS (the minimal clinically important difference) was also significantly associated with reduced survival independent of FVC, and outperformed visual evaluation of progressive fibrosis.ConclusionsWRVS is an automated CT biomarker which can identify patients with IPF at increased risk of progression and is able to reliably capture disease progression over time.

Cluster analysis of blood biomarkers to identify molecular patterns in pulmonary fibrosis: assessment of a multicentre, prospective, observational cohort with independent validation

Pulmonary fibrosis results from alveolar injury, leading to extracellular matrix remodelling and impaired lung function. This study aimed to classify patients with pulmonary fibrosis according to blood biomarkers to differentiate distinct disease patterns, known as endotypes. In this cluster analysis, we first classified patients from the PROFILE study, a multicentre, prospective, observational cohort of individuals with incident idiopathic pulmonary fibrosis or non-specific interstitial pneumonia in the UK (Nottingham University Hospitals, Nottingham; and Royal Brompton Hospital, London). 13 blood biomarkers representing extracellular matrix remodelling, epithelial stress, and thrombosis were measured by ELISA in the PROFILE study. We classified patients by unsupervised consensus clustering. To evaluate generalisability, a machine learning classifier trained on biomarker signatures derived from consensus clustering was applied to a replication dataset from the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR). Biomarker associations with mortality and change in percentage of predicted forced vital capacity (FVC%) were assessed, adjusting for age, gender, baseline FVC%, and antifibrotic treatment and steroid treatment before and after baseline. Mortality risk associated with the clusters in the PROFILE cohort was evaluated with Cox proportional hazards models, and mixed-effects models were used to analyse how clustering was associated with longitudinal FVC% in the PROFILE and AIPFR cohorts. 455 of 580 participants from the PROFILE study (348 [76%] men and 107 [24%] women; mean age 72·4 years [SD 8·3]) were included in the analysis. Within this group, three clusters were identified based on blood biomarkers. A basement membrane collagen (BM) cluster (n=248 [55%]) showed high concentrations of PRO-C4, PRO-C28, C3M, and C6M, whereas an epithelial injury (EI) cluster (n=109 [24%]) showed high concentrations of MMP-7, SP-D, CYFRA211, CA19-9, and CA-125. The third cluster (crosslinked fibrin [XF] cluster; n=98 [22%]) had high concentrations of X-FIB. In the replication dataset (117 of 833 patients from AIPFR; 87 [74%] men and 30 [26%] women; mean age 72·9 years [SD 7·9]), we identified the same three clusters (BM cluster, n=93 [79%]; EI cluster, n=8 [7%]; XF cluster, n=16 [14%]). These clusters showed similarities with clusters in the PROFILE dataset regarding blood biomarkers and phenotypic signatures. In the PROFILE dataset, the EI and XF clusters were associated with increased mortality risk compared with the BM cluster (EI vs BM: adjusted hazard ratio [HR] 1·88 [95% CI 1·42-2·49], p<0·0001; XF vs BM: adjusted HR 1·53 [1·13-2·06], p=0·0058). The EI cluster showed the greatest annual FVC% decline, followed by the BM and XF clusters. A similar FVC% decline pattern was observed in these clusters in the AIPFR replication dataset. Blood biomarker clustering in pulmonary fibrosis identified three distinct blood biomarker signatures associated with lung function and prognosis, suggesting unique pulmonary fibrosis biomarker patterns. These findings support the presence of pulmonary fibrosis endotypes with the potential to guide targeted therapy development. None.

Bexotegrast in Patients with Idiopathic Pulmonary Fibrosis: The INTEGRIS-IPF Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare and progressive disease that causes progressive cough, exertional dyspnea, impaired quality of life, and death. Objectives: Bexotegrast (PLN-74809) is an oral, once-daily, investigational drug in development for the treatment of IPF. Methods: This Phase-2a multicenter, clinical trial randomized participants with IPF to receive, orally and once daily, bexotegrast at 40 mg, 80 mg, 160 mg, or 320 mg, or placebo, with or without background IPF therapy (pirfenidone or nintedanib), in an approximately 3:1 ratio in each bexotegrast dose cohort, for at least 12 weeks. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included change from baseline in FVC, quantitative lung fibrosis (QLF) extent (%), and changes from baseline in fibrosis-related biomarkers. Measurements and Main Results: Bexotegrast was well tolerated, with similar rates of TEAEs in the pooled bexotegrast and placebo groups (62/89 [69.7%] and 21/31 [67.7%], respectively). Diarrhea was the most common TEAE; most participants with diarrhea also received nintedanib. Participants who were treated with bexotegrast experienced a reduction in FVC decline over 12 weeks compared with those who received placebo, with or without background therapy. A dose-dependent antifibrotic effect of bexotegrast was observed with QLF imaging, and a decrease in fibrosis-associated biomarkers was observed with bexotegrast versus placebo. Conclusions: Bexotegrast demonstrated a favorable safety and tolerability profile, up to 12 weeks for the doses studied. Exploratory analyses suggest an antifibrotic effect according to FVC, QLF imaging, and circulating levels of fibrosis biomarkers. Clinical trial registered with www.clinicaltrials.gov (NCT04396756).

Single-Cell Profiling Reveals Immune Aberrations in Progressive Idiopathic Pulmonary Fibrosis.

Rationale: Changes in peripheral blood cell populations have been observed, but not detailed, at single-cell resolution in idiopathic pulmonary fibrosis (IPF). Objectives: We sought to provide an atlas of the changes in the peripheral immune system in stable and progressive IPF. Methods: Peripheral blood mononuclear cells (PBMCs) from patients with IPF and control subjects were profiled using 10× chromium 5' single-cell RNA sequencing. Flow cytometry was used for validation. Protein concentrations of regulatory T cells (Tregs) and monocyte chemoattractants were measured in plasma and lung homogenates from patients with IPF and control subjects. Measurements and Main Results: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched control subjects yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in patients with progressive and stable IPF compared with control subjects (32.1%, 25.2%, and 17.9%, respectively; P < 0.05). Total lymphocytes were decreased in patients with IPF versus control subjects and in progressive versus stable IPF (52.6% vs. 62.6%, P = 0.035). Tregs were increased in progressive versus stable IPF (1.8% vs. 1.1% of all PBMCs, P = 0.007), although not different than controls, and may be associated with decreased survival (P = 0.009 in Kaplan-Meier analysis; and P = 0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of patients with IPF. The fraction of Tregs out of all T cells was also increased in two cohorts of lung single-cell RNA sequencing. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF. Conclusions: The single-cell atlas of the peripheral immune system in IPF reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

Reduced sensitivity to thyroid hormones is associated with lung function in euthyroid individuals

BackgroundThe thyroid gland exhibits a subtle interconnection with the lungs. We further investigated the correlation between thyroid hormone sensitivity and lung function in euthyroid individuals. MethodsData on spirometry and mortality for participants aged 19–79 years were extracted from the NHANES database. Obstructive lung function was defined as a forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC) < 0.70, while restrictive lung function was considered when FEV1/FVC ≥0.70 and baseline FVC <80 % predicted. Central and peripheral sensitivities to thyroid hormones were mainly evaluated by Thyroid Feedback Quantile-based Index (TFQI) and Free Triiodothyronine/Free thyroxine (FT3/FT4) ratio. Logistic regression and subgroup analysis were used to examine potential associations between thyroid hormone sensitivity and lung function. The association between TFQI and all-cause mortality risk was also investigated. ResultsA total of 6539 participants were analyzed, 900 with obstructive lung function and 407 with restrictive lung function. The prevalence of impaired lung function, both obstructive and restrictive, increased with higher TFQI levels. Logistic regression analysis showed that increased TFQI and decreased FT3/FT4 levels were independent risk factors for obstructive and restrictive lung function (P < 0.05). After adjusting for the impact of lung function, TFQI (HR = 1.25, 95 % CI 1.00–1.56, P = 0.048) was an independent risk factor for all-cause mortality. ConclusionReduced sensitivity to thyroid hormones has been linked to impaired lung function. TFQI and FT3/FT4 are potential epidemiological tools to quantify the role of central and peripheral thyroid resistance in lung function.

Disease trajectories in interstitial lung diseases – data from the EXCITING-ILD registry

BackgroundInterstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to 50% of patients and is associated with increased mortality.MethodsThe EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for disease trajectories in different ILD. The course of disease was classified as significant (absolute forced vital capacity FVC decline > 10%) or moderate progression (FVC decline 5–10%), stable disease (FVC decline or increase < 5%) or improvement (FVC increase ≥ 5%) during time in registry. A second definition for PF-ILD included absolute decline in FVC % predicted ≥ 10% within 24 months or ≥ 1 respiratory-related hospitalisation. Risk factors for progression were determined by Cox proportional-hazard models and by logistic regression with forward selection. Kaplan-Meier curves were utilised to estimate survival time and time to progression.ResultsWithin the EXCITING-ILD registry 28.5% of the patients died (n = 171), mainly due to ILD (n = 71, 41.5%). Median survival time from date of diagnosis on was 15.5 years (range 0.1 to 34.4 years). From 601 included patients, progression was detected in 50.6% of the patients (n = 304) with shortest median time to progression in idiopathic NSIP (iNSIP; median 14.6 months) and idiopathic pulmonary fibrosis (IPF; median 18.9 months). Reasons for the determination as PF-ILD were mainly deterioration in lung function (PFT; 57.8%) and respiratory hospitalisations (40.6%). In multivariate analyses reduced baseline FVC together with age were significant predictors for progression (OR = 1.00, p < 0.001). Higher GAP indices were a significant risk factor for a shorter survival time (GAP stage III vs. I HR = 9.06, p < 0.001). A significant shorter survival time was found in IPF compared to sarcoidosis (HR = 0.04, p < 0.001), CTD-ILD (HR = 0.33, p < 0.001), and HP (HR = 0.30, p < 0.001). Patients with at least one reported ILD exacerbation as a reason for hospitalisation had a median survival time of 7.3 years (range 0.1 to 34.4 years) compared to 19.6 years (range 0.3 to 19.6 years) in patients without exacerbations (HR = 0.39, p < 0.001).ConclusionDisease progression is common in all ILD and associated with increased mortality. Most important risk factors for progression are impaired baseline forced vital capacity and higher age, as well as acute exacerbations and respiratory hospitalisations for mortality. Early detection of progression remains challenging, further clinical criteria in addition to PFT might be helpful.

Disease Behaviour Classification: A pragmatic model for predicting outcomes in Interstitial Lung Disease

Background and objectiveThe interstitial lung diseases (ILD) are a heterogenous group of disorders with similar clinical presentation, but widely varying prognoses. The use of a pragmatic disease behaviour classification (DBC), first proposed in international guidelines in 2013, categorises diseases into five behavioural classes based on their predicted clinical course. This study aimed to determine the prognostic utility of the DBC in an ILD cohort. MethodsConsecutive patients presented at the weekly multidisciplinary meeting (MDM) of a specialist ILD centre were included. MDM consensus was obtained for diagnosis and DBC category (1–5). Baseline and serial clinical and physiological data were collected over the study period (median 3.9 years, range 0–5.4 years). The relationship between DBC and prognostic outcomes was explored. Results137 ILD patients, [64 (47%) female] were included with mean age 67.0 ± 1.1 years, baseline FVC% 72.7 ± 1.7, and baseline DLco% 57.8 ± 1.6%. Patients were stratified into DBC by consensus at MDM: DBC1 n = 0 (0%), DBC2 n = 16 (12%), DBC3 n = 10 (7.3%), DBC4 n = 55 (40%), and DBC5 n = 56 (41%). On univariable Cox regression, increasing DBC class was associated with poorer progression-free survival (HR 1.6, 95% CI 1.2–2.0, p < 0.001). On multivariable Cox regression, DBC remained predictive of PFS when combined with age and gender (HR 1.4, 95% CI 1.1–1.9, p = 0.011), baseline FVC% (HR 1.5, 95% CI 1.1–1.8, p = 0.003) and ILD diagnosis (HR 1.6, 95% CI 1.2–2.2, p < 0.0001). ConclusionDBC as determined at ILD multidisciplinary meeting may be a useful prognostic tool for the management of ILD patients.

Development of a Novel Biomarker for the Progression of Idiopathic Pulmonary Fibrosis.

The progression of idiopathic pulmonary fibrosis (IPF) is diverse and unpredictable. We identified and validated a new biomarker for IPF progression. To identify a candidate gene to predict progression, we assessed differentially expressed genes in patients with advanced IPF compared with early IPF and controls in three lung sample cohorts. Candidate gene expression was confirmed using immunohistochemistry and Western blotting of lung tissue samples from an independent IPF clinical cohort. Biomarker potential was assessed using an enzyme-linked immunosorbent assay of serum samples from the retrospective validation cohort. We verified that the final candidate gene reflected the progression of IPF in a prospective validation cohort. In the RNA-seq comparative analysis of lung tissues, CD276, COL7A1, CTSB, GLI2, PIK3R2, PRAF2, IGF2BP3, and NUPR1 were up-regulated, and ADAMTS8 was down-regulated in the samples of advanced IPF. Only CTSB showed significant differences in expression based on Western blotting (n = 12; p < 0.001) and immunohistochemistry between the three groups of the independent IPF cohort. In the retrospective validation cohort (n = 78), serum CTSB levels were higher in the progressive group (n = 25) than in the control (n = 29, mean 7.37 ng/mL vs. 2.70 ng/mL, p < 0.001) and nonprogressive groups (n = 24, mean 7.37 ng/mL vs. 2.56 ng/mL, p < 0.001). In the prospective validation cohort (n = 129), serum CTSB levels were higher in the progressive group than in the nonprogressive group (mean 8.30 ng/mL vs. 3.00 ng/mL, p < 0.001). After adjusting for baseline FVC, we found that CTSB was independently associated with IPF progression (adjusted OR = 2.61, p < 0.001). Serum CTSB levels significantly predicted IPF progression (AUC = 0.944, p < 0.001). Serum CTSB level significantly distinguished the progression of IPF from the non-progression of IPF or healthy control.

Comparison of Pirfenidone and Nintedanib: Post Hoc Analysis of the CleanUP-IPF Study

Antifibrotics are effective in slowing FVC decline in idiopathic pulmonary fibrosis (IPF). However, whether antifibrotic type is differentially associated with FVC decline remains inconclusive. Are there significant differences in 12-month FVC decline between pirfenidone and nintedanib? A post hoc analysis was performed using the Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic Design in IPF (CleanUP-IPF) trial (No. NCT02759120). Participants who reported using pirfenidone or nintedanib on enrollment into the trial were in the primary analysis. Spirometry was scheduled at baseline and the 12- and 24-month study visits. Linear mixed-effects models with random intercept and slope were used to examine changes in FVC over time. Models were adjusted for age, sex, smoking history, coronary artery disease history, baseline FVC, and 12-month spline term. Survival and nonelective respiratory hospitalization by antifibrotic type were determined using Cox regression models with adjustment for age, sex, smoking history, coronary artery disease history, and baseline FVC and diffusing capacity for carbon monoxide. Out of the 513 participants with IPF randomized in the CleanUP-IPF trial, 407 reported using pirfenidone (n= 264, 65%) or nintedanib (n= 143, 35%). The pirfenidone group had more participants with a history of coronary artery disease than the nintedanib group (34.1%vs20.3%, respectively). Patients treated with nintedanib had a higher 12-month visit FVC than patients treated with pirfenidone (mean difference, 106mL; 95%CI, 34-178). This difference was attenuated at the 24-month study visit. There were no significant differences in overall survival and nonelective respiratory hospitalization between the pirfenidone- and nintedanib-treated groups. Patients with IPF who used nintedanib had a slower 12-month FVC decline than pirfenidone in a post hoc analysis of a clinical trial.

Reduced lung function and cause-specific mortality: A population-based study of Norwegian men followed for 26 years

Background and aimReduced lung function is associated with increased mortality, but it is unclear how different spirometric patterns are related to specific deaths. Aim of this study was to investigate these associations in a large general population cohort. MethodsThe study population consisted of 26,091 men aged 30–46 years from the Pneumoconiosis Survey of Western Norway conducted in 1988–1990 with follow-up on date and cause of death for 26 years. Cox proportional hazard models were used to estimate the association between baseline FEV1, FVC, obstructive (OSP) and restrictive spirometric pattern (RSP) (z-scores calculated according to GLI-2012 equations) and mortality (European 2012 shortlist classification (E−2012)), after adjustment for age, body mass index, smoking habits, and education. ResultsIn total, 2462 (9%) subjects died. A predominant reduction of FEV1 (and OSP) were associated with respiratory non-cancer (E−8) (HR for one unit FEV1 z-score decrease 2.29 (95% CI 1.90, 2.77) and lung cancer mortality (E−2.1.8) (1.27(1.12, 1.44)). A similar reduction of FEV1 and FVC (and RSP) were associated with diabetes (E−4.1) (FEV1 2.21(1.67, 2.92), FVC 2.41(1.75, 3.32)), cerebrovascular (E−7.3) (1.52(1.21, 1.91), 1.54(1.19, 1.98)), ischemic heart disease (E−7.1) (1.22(1.10, 1.35), 1.21(1.08, 1.36)), neurological (E−6.3) (1.56(1.21, 2.01), 1.61(1.22, 2.13)), suicide (E−17.2) (1.37(1.13, 1.65), 1.29(1.04, 1.59)) and hematological cancer mortality (E−2.1.19–21) (1.29(1.05, 1.58), (1.26(1.00, 1.58)). No association was found between reduced lung function and mortality due to accidents, alcohol abuse, digestive and genitourinary cancer. ConclusionsSpirometric obstruction was mainly related to pulmonary mortality. Spirometric restriction was mainly related to extra-pulmonary mortality.

Effect of Nintedanib in Patients with Progressive Pulmonary Fibrosis in Subgroups with Differing Baseline Characteristics.

In the INBUILD trial in patients with progressive pulmonary fibrosis other than idiopathic pulmonary fibrosis (IPF), nintedanib slowed the rate of decline in forced vital capacity (FVC; mL/year) over 52weeks compared with placebo. We assessed the efficacy of nintedanib across subgroups in the INBUILD trial by baseline characteristics. We assessed the rate of decline in FVC over 52weeks and time to progression of interstitial lung disease (ILD) (absolute decline from baseline in FVC % predicted>10%) or death over the whole trial in subgroups based on sex, age, race, body mass index (BMI), time since diagnosis of ILD, FVC % predicted, diffusing capacity of the lungs for carbon monoxide (DLco) % predicted, composite physiologic index (CPI), GAP (gender, age, lung physiology) stage, use of anti-acid therapy and use of disease-modifying antirheumatic drugs (DMARDs) at baseline. The effect of nintedanib versus placebo on reducing the rate of decline in FVC over 52weeks was consistent across the subgroups by baseline characteristics analysed. Interaction p values did not indicate heterogeneity in the treatment effect between these subgroups (p>0.05). Over the whole trial (median follow-up time ∼19months), progression of ILD or death occurred in similar or lower proportions of patients treated with nintedanib than placebo across the subgroups analysed, with no heterogeneity detected between the subgroups. In the INBUILD trial, no heterogeneity was detected in the effect of nintedanib on reducing the rate of ILD progression across subgroups based on demographics, ILD severity or use of anti-acid therapy or DMARDs. These data support the use of nintedanib as a treatment for progressive pulmonary fibrosis. ClinicalTrials.gov Identifier: NCT02999178.

Abatacept in usual and in non-specific interstitial pneumonia associated with rheumatoid arthritis

ObjectiveTo compare the effectiveness of abatacept (ABA) in Rheumatoid Arthritis-associated Interstitial Lung Disease (RA-ILD) according to the radiological patterns of usual (UIP) or non-specific interstitial pneumonia (NSIP). MethodsFrom an observational longitudinal multicentre study of 263 RA-ILD patients treated with ABA, those with UIP or NSIP were selected. Lung function, chest high resolution computerised tomography (HRCT) and dyspnoea were recorded and compared in both groups from baseline to the end of follow-up (progression definitions: improvement or worsening >10% of FVC or DLCO, changes in HRCT extension and 1-point change in the mMRC scale, respectively). Differences between final and baseline visits were calculated as the average difference (95% CI) through mixed effects models regression. ResultsWe studied 190 patients with UIP (n=106) and NSIP (n=84). General features were similar in both groups except for older age, positive rheumatoid factor, and previous sulfasalazine therapy, which were more frequent in patients with UIP. ILD duration up to ABA initiation was relatively short: median 16 [4-50] and 11 [2-36] months (p=0.36) in UIP and NSIP, respectively. Mean baseline FVC and DLCO were 82% and 63% in UIP and 89% and 65% in NSIP, respectively. Both parameters remained stable during 24 months with ABA. HRCT lesions and dyspnoea improved/stabilized in 73.1% and 90.5% and 72.9% and 94.6% of UIP and NSIP patterns, respectively. ConclusionABA seems equally effective in stabilizing dyspnoea, lung function and radiological impairment in both UIP and NSIP patterns of RA-ILD. Early administration of ABA may prevent RA-ILD progression, regardless of the radiological pattern.

Clinical Characteristics and Disease Course of Fibrosing Interstitial Lung Disease Patients in a Real-World Setting

Background and Objectives: This single-center retrospective study was conducted to describe clinical characteristics and the disease course of patients with interstitial lung diseases (ILD). Materials and Methods: The study included adult patients with fibrosing ILD (IPF, non-IPF fibrosing ILD (F-ILD), and non-IPF progressive pulmonary fibrosis (PPF)) treated between 2014 and 2017. Patients were followed annually from the first visit until the end of the study period in 2019. Data were collected from the Turku University Hospital data lake and analyzed using descriptive statistics. Results: 591 patients formed the patient cohort: 110 had IPF, 194 F-ILD, 142 PPF, and the remaining 145 patients were uncertain, F-ILD-U, whose disease progression nature could not be confirmed by FVC measurements. There were more males in each patient group and median age of the groups was similar, although there were younger patients in the PPF, F-ILD, and F-ILD-U groups. PPF patients had more UIP pattern than F-ILD patients. Exposure-related ILDs were clearly the most found ILD diagnoses for both PPF and F-ILD, followed by unclassifiable IIP. Baseline FVC % predicted reduction in every group was moderate. Half of the patients in each group had comorbidities, and the most common were cardiovascular diseases, diabetes, sleep apnea, and chronic lower respiratory diseases; F-ILD-U patients had malignant diseases as well. IPF patients had less medications than the other groups. Glucocorticoids were the most used medication in all patient groups. More PPF and F-ILD patients remained in the follow-up than IPF and F-ILD-U patients. Similarly, mortality of F-ILD-U was the highest, followed by IPF. Evolvement of lung function, oxygen use, and number of acute hospitalizations were similar for IPF and PPF patients whereas the corresponding results were always better for F-ILD patients. Conclusions: The disease course of IPF and PPF was similar, and PPF patient amount exceeded the amount of IPF patients.

Sleep Disturbances as a Potential Risk Factor for Deterioration of Respiratory Function in Patients with Amyotrophic Lateral Sclerosis.

Sleep disturbances are common in amyotrophic lateral sclerosis (ALS). However, previous studies have explored sleep quality at the cross-sectional level and the longitudinal variability characteristics are currently unknown. Our study aimed to longitudinally explore the effect of sleep quality on disease progression in patients with ALS. All enrolled patients with ALS were first diagnosed and completed the 6- and 12-month follow-ups. Subjective sleep disturbance was assessed using the Pittsburgh Sleep Quality Index (PSQI). Based on the PSQI score at baseline, patients with ALS were classified as poor sleepers (PSQI >5) and good sleepers (PSQI ≤5). Disease progression was assessed using the rate of disease progression, the absolute change from baseline forced vital capacity (ΔFVC) and the percentage change from baseline FVC (ΔFVC%) over the follow-up period. Sixty-three patients were included in the study, 24 (38.1%) were poor sleepers and 39 were good sleepers. The percentage of patients with poor sleep quality was 38.1% at baseline, increasing to 60.3% and 74.6% at 6- and 12-month, respectively. Compared to good sleepers, ΔFVC and ΔFVC% values were greater in poor sleepers (P < 0.001 and P = 0.001, respectively). Poor sleep quality at diagnosis is associated with rapid deterioration of respiratory function during disease progression. Sleep disturbances maybe a potential risk factor for deterioration of respiratory function in patients with ALS. The role of sleep disturbances in disease progression deserves attention, and early assessment and intervention may slow disease progression and improve life quality of patients with ALS.

Baseline characteristics in patients with interstitial lung diseases as predictors for progression: a real life study

Abstract Interstitial lung diseases (ILDs) comprise a large number of different diseases, some of the patients having a progressive evolution toward irreversible fibrosis. The aim of this study is to identify baseline clinical, functional, and imaging characteristics at the date of the diagnosis, that could predict the evolution toward fibrosis. This is a retrospective descriptive study that included 126 patients diagnosed and followed-up in Department 5 of the Institute of Pneumophtisiology “Marius Nasta” Bucharest between 2014 and 2022. The authors recorded baseline demographics, symptoms, lung function tests (forced vital capacity – FVC and diffusion capacity – DLCO), high resolution CT (HRCT) imaging features. Patients were followed-up at 6 and 12 months. According to decline in lung function or imaging worsening, patients were divided in2 groups: progressors (60 patients) and non-progressors (26 patients). Baseline characteristics of the 2 groups were compared. Results: There is an important delay since onset of symptoms to diagnosis (a mean of 17 months). Lower baseline FVC, smoking history, presence of traction bronchiectasis and/or honeycombing and male gender were associated to progressive lung fibrosis.

Clusters of comorbidities in fibrotic hypersensitivity pneumonitis

BackgroundHypersensitivity pneumonitis (HP) is a type of interstitial lung disease (ILD) with a variable disease course and prognosis ranging from inflammatory and self-limiting to irreversible and progressive pulmonary fibrosis. Comorbidities are common in HP and may have an impact on prognosis. Due to the heterogeneity of HP presentation and progression, the identification of specific phenotypes in relationship to disease course and outcome is essential. The aim of this study was to identify clusters of comorbidities which could represent phenotypes in fibrotic HP and examine their impact on prognosis.MethodsPatients diagnosed with fibrotic HP at a tertiary referral center for ILD were included. Comorbidities were systematically registered and clusters of comorbidities were identified using cluster analyses. Disease progression and survival was estimated for each cluster.ResultsThe cohort comprised 211 patients with 53.6% males, mean age 63.0, baseline FVC 72.7%, DLCO 44.1%. Median follow-up time was 1.8 years (IQR 0.7–3.9). Three clusters with distinct comorbidity profiles and clinical characteristics were identified. One cluster dominated by elder male patients with predominantly cardiovascular diseases was associated with more respiratory hospitalizations and a worse prognosis. Differences in pulmonary function or exercise capacity trajectories between clusters were not observed.ConclusionsThree clusters with distinct comorbidities were identified and could represent phenotypes in fibrotic HP not previously recognized. The worst prognosis was observed in a cluster dominated by elder males with cardiovascular diseases. Increased focus on prevention and treatment of comorbidities could potentially improve the prognosis of patients with fibrotic HP.

Correlation Between Neutrophil to Lymphocyte Ratio Baseline with Spirometry Test in Severe Coronavirus Disease 2019 (COVID-19)

Background/aim: The sequelae of the post-COVID-19 syndrome can affect lung function. The neutrophil-lymphocyte ratio is one of the markers of increased inflammation in SARS-CoV-2 virus infection. Based on this, the researchers wanted to assess the relationship between baseline NLR levels and spirometry tests in severe COVID-19 survivors. Methods: This research is an observational analytic study with a cross-sectional design conducted at Prof. Dr. IGNG Ngoerah Hospital Denpasar from January 2022 to July 2022. Univariate analysis displays the mean, standard deviation, and relative frequency for categorical data. Bivariate analysis was performed by chi-squared test. The multivariate analysis used was multiple logistic regression to assess the relationship between baseline NLR levels and covariates with the spirometry test. Results: Subjects who participated in the study were 80. As many as 58 subjects (72.5%), the baseline NLR value was 3.58%, and the median NLR was 5.41% (1.19-514%). On spirometry examination, there were restrictions on 41 subjects (51.2%), mild Restriction in 38 subjects (47.5%), Obstruction in 8 subjects (10%), benign Obstruction in 5 subjects (6.3%). The multivariate correlation between baseline NLR and spirometry results (FVC, FEV1, FEV1/FVC, and FEF 25-75%) showed no relationship Conclusion: There is no relationship between high baseline NLR and FVC, FEV1, FEV1/FVC, and FEF25-75% values. Keywords: COVID-19, CRP, Lymphocyte, FVC, FEV1/FVC, FEF 25-75

P.65 Consistency of changes in percent-predicted forced vital capacity between real-world data and trial placebo arms in ambulatory Duchenne muscular dystrophy

Use of real-world and natural history data (RWD/NHD) as external controls for pulmonary outcomes is of interest for drug development in ambulatory Duchenne muscular dystrophy (DMD). However, differences across patient populations and RWD/NHD settings raise appropriate concerns about risk of bias. To assess this risk, we compared change in pulmonary function, as measured by percent-predicted forced vital capacity (FVC%p) between RWD/NHD sources and trial placebo arms in ambulatory boys with DMD. RWD/NHD data came from PRO-DMD-01, UZ Leuven, the North Star UK Clinical Network and Cincinnati Children's Hospital Medical Center. Placebo arm data came from phase 3 trials of tadalafil and drisapersen, and one phase 2 trial of drisapersen. PRO-DMD-01 and drisapersen trial data were provided by CureDuchenne. Change in FVC%p over 48-week intervals was studied in ambulatory, steroid-treated boys aged ≥5 years with baseline FVC%p > 50%. Primary analyses included 409 48-week intervals (263 patients) from RWD/NHD, and 161 intervals (161 patients) from placebo arms. At baseline, average ages in these groups were 9.5 and 8.8 years, respectively, and averages for FVC%p were 97.2% and 103.6%. Mean 48-week change in FVC%p was 2.9% greater in in RWD/NHD vs. placebo arms (95% confidence interval [CI]: -1.0%, 6.7%; p=0.14) in unadjusted analyses. After adjusting for baseline status (age, FVC%p, steroid type, height, weight, body mass index, North Star Ambulatory Assessment total score, and 10-meter walk run and rise from supine velocities) the difference in FVC%p between RWD/NHD and placebo arms decreased to -0.1% (95% CI: -3.6, 3.5; p=0.97). Similarly high consistency was observed in sensitivity analyses adjusting for fewer baseline characteristics. These findings are encouraging for use of external controls for FVC%p outcomes in this population. Additional research is needed to assess consistency of FVC%p over longer-time frames, and among older and non-ambulatory boys.