Immunoprecipitation-mass spectrometry can identify new and rare autoantigens in persons with ANA-positive usual interstitial pneumonia without a diagnosis of a definite systemic autoimmune disease https://bit.ly/4iAIRK5.

Objectives Physical activity is reduced in patients with interstitial lung disease (ILD) and physical inactivity is related to poor health outcomes. We investigated the effect of a telecoaching intervention to improve physical activity in patients with ILD. Methods Eighty patients with ILD were randomized into the intervention or control group. Patients in the intervention group received a 12-week telecoaching program including a step counter, a patient-tailored smartphone application, and coaching calls. Patients in the control group received usual care. Physical activity (primary outcome), physical fitness and quality of life were measured at baseline and 12 weeks later with an accelerometer, 6-min walking test and quadriceps muscle force and the King’s Brief Interstitial Lung Disease questionnaire (K-BILD). Results Participation in telecoaching did not improve physical activity: between-group differences for step count: 386 ± 590 steps/day, p = .52; sedentary time: 4 ± 18 min/day, p = .81; movement intensity: 0.04 ± 0.05 m/s2, p = .45). Between-group differences for the 6-min walking test, quadriceps muscle force and K-BILD were 14 ± 10 m, p = .16; 2 ± 3% predicted, p = .61; 0.8 ± 1.7 points, p = .62 respectively. Conclusions Twelve weeks of telecoaching did not improve physical activity, physical fitness or quality of life in patients with ILD. Future physical or behavioural interventions are needed for these patients to improve physical activity.

Telomere-related gene (TRG) mutations are detected in ±5% of sporadic and 20-30% of familial IPF patients. Up to 30% of asymptomatic relatives of IPF patients have interstitial lung abnormalities on CT. Fibrosis in non-mutation carriers has been described. We aimed to assess the prevalence of preclinical interstitial lung abnormalities (pILAs: ground-glass or reticular abnormalities, traction bronchiectasis, honeycombing ≥5% of a lung zone) in asymptomatic relatives of IPF patients with a TRG mutation. First-degree relatives (≥30 years) of IPF patients with a TRG mutation were included. HRCT, pulmonary function test, Sanger Sequencing of TRG mutation and MUC5B promoter polymorphism and telomere length assessment (FLOW-FISH) were performed. We included 43 relatives (10 families). In 19/43 relatives (44.2%) the TRG mutation was detected. pILAs were observed in 4/24 non-mutation (16.7%) and 4/19 mutation carriers (21.1%). Age (p=0.01) and DLCO%pred (p<0.01) were significantly associated with presence of pILAs; gender, smoking history, FVC%pred, presence of TRG mutation or MUC5B variant and telomere length were not. Of the 4 non-mutation carriers with pILAs, 2 had normal telomere length and 2 did not carry the MUC5B variant. pILAs were observed in a high proportion of non-mutation carriers. pILAs in non-mutation carriers were not explained by short telomeres or the MUC5B variant. Genetic counseling is therefore difficult.

Current pharmacological treatment of idiopathic pulmonary fibrosis (IPF) consists of antifibrotics. Disease progression is in part monitored by pulmonary function tests (PFT). We aimed to assess the prognostic role of short-term PFT response to antifibrotics. We quantified individual slopes per year using linear regression for functional vital capacity (FVC%pred) and diffusion capacity (DLCO%pred) evolution in the 18 months after the start of antifibrotics. Cox Proportional Hazards models were used to associate FVC%pred and DLCO%pred evolution (corrected for baseline disease extent, gender, and age) with survival. Optimal cutoffs were determined by Maximally Selected Rank Statistics. Survival curves and Logrank-tests were computed for these cut-offs and a clinical cut-off of 5% decline. We retrospectively collected the data of 162 patients (PFT=733, 77.8% male, 2012-2016). Median age at antifibrotic initiation was 72.3y. Median overall survival after initiation of antifibrotics was 6.42y. 95.7% received pirfenidone, 4.3% nintedanib. Greater DLCO decline (per %, p <0.001, HR=1.03) and greater FVC decline (per %, p= <0.001, HR=1.05) were associated with increased risk of death or transplantation. Survival curves and optimal cutoffs are shown in figure 1. To conclude, both steeper DLCO and FVC decline in the year after antifibrotic initiation were associated with higher mortality and could be used as a prognostic factor.

Immune checkpoint inhibitor (ICI) pneumonitis is the most common fatal immune-related adverse event (irAE) from PD-1/ PD-L1 blockade, and a diagnosis of exclusion. Based on single-cell transcriptomics, we identified pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid (BALF), putatively engaging with pro-inflammatory "M1-like" monocytes, as a key pathophysiologic mechanism. Herein, we present the cytokine profile of ICI-pneumonitis BALF, aiming to identify further mechanistic insights and diagnostic biomarkers.

Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Background: An outbreak of silicosis occurred—despite periodic health surveillance—in a plant producing novel applications of silica-based composites. Methods: Five workers were referred to our clinic for occupational medicine. Using past spirometry data from periodic health surveillance, we calculated individual yearly declines in FEV1 and FVC using robust multivariable linear regressions. Respirable quartz was measured in the workplace (after the first case had been diagnosed). Results: The five men (38 to 59 years), all ex-smokers, had been employed for 8 to 30 years at a Belgian company producing skirting boards—made from a polyester-silica composite material—for use as hygienic wall protection in food/pharmaceutical industry. We diagnosed enlarged mediastinal/hilar lymph nodes without radiological lung involvement in one worker, simple silicosis in two workers (one also with emphysema), and progressive massive fibrosis in two workers. Periodic spirometries—but no chest X-rays—had been performed since 8 to 10 years prior to diagnosis. The four men with silicosis proved to have undergone excessive declines in FEV1 (98 to 221 mL/year) and FVC (17 to 220 mL/y). High respirable quartz concentrations (>100 µg/m³) were measured during various operations, especially during dry finishing of the cured skirting boards (1,080 µg/m³). No personal respiratory protection was used. Conclusions: The outbreak shows that the hazards of silica-based artificial stone production/processing reach beyond the kitchen/bathroom countertop industry. Improving prevention and establishing workers’ health surveillance programs—or improving the quality of existing programs—are crucial.

Introduction: Physical activity (PA) is decreased in patients with interstitial lung diseases (ILD) and is an independent predictor of mortality in patients with idiopathic pulmonary fibrosis (IPF). Whether this decrease can be reversed by PA interventions is unknown. Aim: To investigate the effect of a 3-month telecoaching program on PA in patients with ILD. Methods: Patients with ILD were randomized into the usual care group (UCG) or intervention group (IG). The IG received 3 months of telecoaching via a pedometer, a smartphone application and coaching calls. PA was measured as a primary outcome with an accelerometer (Dynaport Movemonitor) for one week at baseline and after 3 months. Secondary outcomes were exercise capacity (EC), using 6-minute walk test (6MWT), and quadriceps strength (QS). ANCOVA was performed for between-group comparisons. Results: Baseline characteristics of the IG (n=18) were similar to the UCG (n=22) (mean±SEM 64±2y; FVC 92±4% pred; DL,CO 51±3% pred; IPF 73%; 6MWT 491±17m; QS 88±4% pred; PA 5659±411 steps/day), except for gender (IG 39% male, UCG 77% male, p=0.013). Participation in telecoaching did not improve PA outcomes (fig 1). Also, 6MWT (between-group difference 15±19m, p=0.430) and QS (between-group difference 8±7% pred, p=0.300) did not show significant differences compared to baseline. Conclusions: Three months of telecoaching did not result in benefits of PA, exercise capacity or muscle strength in patients with ILD.

Introduction Physical activity (PA) is reduced in patients with interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). Evidence about the PA pattern of patients with ILD is scarce. If PA of patients with ILD would be comparable to COPD, it is tempting to speculate that existing interventions focusing on enhancing PA could be as effective in ILD as already shown in COPD. Therefore, we aimed to compare PA and the correlates with PA in matched patients with ILD, COPD, and healthy subjects. Materials and methods Patients with ILD (n = 45), COPD (n = 45) and healthy subjects (n = 30) were propensity matched. PA level, pattern, and PA correlations with lung function and physical performance (6-minute walking distance and quadriceps force) were compared between groups. Results Daily number of steps was similar in both patient groups (mean±SE: 5631±459 for ILD, 5544±547 for COPD, p = 0.900), but significantly lower compared to healthy subjects (10031±536, p<0.001 for both). Mean intensity of PA tended to be lower in the ILD group (mean±SE metabolic equivalents of task per day: 1.41±0.04) compared to COPD (1.52±0.05, p = 0.074) and healthy individuals (1.67±0.04, p<0.001). The pattern of PA over one day was found to be similar between the three groups. Lastly, the correlation between PA and 6-minute walking distance was significantly weaker in patients with ILD compared to patients with COPD (respectively r = 0.348 and r = 0.739; p<0.05 for both). Conclusions For a given functional reserve, patients with ILD perform an equal amount of steps but perform PA at lower intensity compared to patients with COPD. Both groups are less active compared to healthy control subjects. Functional exercise capacity was shown to be only moderately related to PA. This can potentially influence the effectiveness of PA interventions that can be expected.

The MUC5B promoter polymorphism (rs35705950) has been associated with interstitial lung disease (ILD) and with prolonged pre-transplant survival in idiopathic pulmonary fibrosis (IPF), but no information is available regarding its prevalence in other respiratory diseases and its influence on post-transplant outcome. We included the Leuven lung transplantation cohort between 1991 and 2015 (n = 801). We assessed the minor allele frequency (MAF) of the MUC5B variant in the entire study cohort and investigated the influence of recipient MUC5B promoter polymorphism on post-transplant outcome in patients who were transplanted after 2004. MUC5B was successfully genotyped in 746 patients. The MAF was significantly higher in ILD (17.6%) compared to chronic obstructive pulmonary disease (COPD)/emphysema (9.3%), cystic fibrosis (CF)/bronchiectasis (BRECT) (7.5%) and pulmonary hypertension (PHT) (7.4%) (p < 0.001). No association was observed between rs35705950 and chronic lung allograft dysfunction (CLAD)/graft loss in the ILD population [CLAD: HR 1.37 95% CI (0.70-2.68); graft loss: HR 1.02 95% CI (0.55-1.89)], nor the entire study cohort [CLAD: HR 0.96 95% CI (0.69-1.34); graft loss: HR 0.97 95% CI (0.70-1.35)]. The MUC5B promoter polymorphism is a very specific predictive factor for the presence of pulmonary fibrosis as it is only associated with pulmonary fibrosis and not with other chronic respiratory diseases. While the MUC5B promoter variant is associated with better pre-transplant survival among IPF patients, recipient MUC5B promoter variant does not play a role in post-transplant outcome.

Advanced flexible bronchoscopy techniques in its current form mainly target for pulmonary nodules >20 mm. These advanced bronchoscopy techniques consist of (ultra)thin bronchoscopes with or without virtual planning for navigation and radial EBUS miniprobes for realtime target verification. 2 This has led to improved detection capabilities and diagnostic ability for peripheral pulmonary nodule(s) in daily clinical practice compared with classical flexible bronchoscopy. Detection rates around 85% and a diagnostic yields 70%–75% have been reported for pulmonary nodules >20 mm within experienced interventional pulmonology centres. More recently, innovative bronchoscopy techniques leverage current advanced techniques for peripheral pulmonary nodules as small as 15–20 mm. In prospective studies, bronchoscopy guided by cone beam CT and augmented fluoroscopy or robotassisted bronchoscopy techniques improved the access to target lesions with toolinlesion navigation reporting success rates from 90% to 97%. A diagnostic yield (considering inflammation as nondiagnostic) ranging from 52% to 78% has been reported in these studies with high cancer probability. The discordance between a high toolinlesion navigation success rate and a moderate diagnostic yield remains a matter of concern despite radial EBUS miniprobe for realtime target verification at the macroscopic level. Optical endomicroscopy, such as fibrebased confocal laser fluorescence endomicroscopy (CLE), is a highresolution imaging technique, which enables autofluorescence visualisation of individual cells and structures of the respiratory tract and distal lung parenchyma at a near microscopic level. Probebased confocal laser endomicroscopy (pCLE) is available since 2008 using a thin semiflexible 1.2 mm probe (Alveoflex, Cellvizio System; Mauna Kea Technologies, Paris, France), which is inserted through the working channel of a bronchoscope. 8 It consists of 30 000 optical fibres enabling a lateral resolution of 3 μm, confocal depth of focus of 0–50 μm and a 600 μm field of view. Studies on pCLE imaging with a laser source at 488 nm excitation found it a feasible method to identify a peripheral pulmonary nodule during flexible bronchoscopy distinguishing autofluorescence characteristics of the normal distal lung from aberrant alveolar lung structures, but labelfree pCLE autofluorescence imaging has not been shown to discriminate a benign from a malignant nodule in a clinical setting. 10 More recently, needlebased confocal laser endomicroscopy (nCLE) has been introduced using a ultrathin 0.85 mm miniprobe (AQFlex, Cellvizio System; Mauna Kea Technologies, Paris, France), which fits into a 18gauge needle. It consists of 10 000 optical fibres enabling a lateral resolution of 3.5 μm, confocal depth of focus of 30 μm and a 320 μm field of view. nCLE of peribronchial lesions might enable realtime target verification at the needle tip once punctured. In this situation, intravenous injection of fluorescein sodium solution is administered during nCLE imaging to enhance fluorescence imaging of the stromal background thereby enabling visualisation of individuals cells. Three nCLE imaging characteristics of lung cancer (dark enlarged pleomorphic cells; dark clumps; directional streaming) have been recently described. In their proofofprinciple study, Kramer et al prospectively demonstrated the feasibility of bronchoscopic nCLE imaging, which aids accurate detection of peripheral pulmonary nodules at the needle tip in a selected patients. Good quality nCLEvideos were obtained in 24 out of 26 (92%) patients with suspected peripheral lung cancer (final pathological diagnosis of malignancy in 23 patients). A bronchus sign was present in 23 patients and nCLE characteristics of malignancy were detected in 22 patients, in whom good quality nCLEvideos were obtained. In addition, the authors prospectively validated the three nCLE malignancy criteria. Blinded raters, unexperienced with CLEimaging, were able to consistently distinguish cCLEvideos of malignancy from normal lung parenchyma with high accuracy after a short training in nCLE video interpretation. A high interobserver agreement was obtained (kappa=0.78). This highlights the ability to interpret nCLE image sequences and the learning potential after formal nCLE trainings. These aspects are requirements to elaborate further on this CLE technique in several ways. First, it will be of great importance to include nonmalignant pulmonary nodules and/or develop nCLE criteria of benign pathologies in order to evaluate the likelihood ratios in diagnostic testing of these nCLE criteria during diagnostic bronchoscopy in unselected patients. So far, it remains speculative whether nCLE has the potential to enable an accurate distinction between malignant and benign nodules in a clinical context. Moreover, it remains unproven whether nCLE will ultimately improve the diagnostic yield. A second challenge is the exploration of its potential to aid in the identification of the optimal biopsy site through needle positioning based on the nCLE imaging findings. Finally, it has to be proven that through nCLE repositioning the entire lung nodule can be examined thereby streamlining the diagnostic optical pathway, guiding the tissue sampling and ultimately increasing the diagnostic accuracy of peripheral pulmonary nodules. To conclude, the study by Kramer et al demonstrates the potential of nCLE imaging technology and will further contribute to the innovative bronchoscopy platforms combining a high toolinlesion navigation success and optical endomicroscopy based tissue verification. A near microscopy optical biopsy might complement invasive tissue sampling in order to optimise clinical lung nodule management in the near future.

BACKGROUND: Given the plethora of pathophysiologic mechanisms described in idiopathic pulmonary fibrosis (IPF), we hypothesize that the mechanisms driving fibrosis in IPF may be different from one patient to another. RESEARCH QUESTION: Do IPF endotypes exist and are they associated with outcome? STUDY DESIGN AND METHODS: Using a publicly available gene expression dataset retrieved from BAL samples of patients with IPF and control participants (GSE70867), we clustered IPF samples based on a dimension reduction algorithm specifically designed for -omics data, called DDR Tree. After clustering, gene set enrichment analysis was performed for functional annotation, associations with clinical variables and prognosis were investigated, and differences in transcriptional regulation were determined using motif enrichment analysis. The findings were validated in three independent publicly available gene expression datasets retrieved from IPF blood samples. RESULTS: One hundred seventy-six IPF samples from three centers were clustered in six IPF clusters, with distinct functional enrichment. Although clinical characteristics did not differ between the clusters, one cluster conferred worse sex-age-physiology score- corrected survival, whereas another showed a numeric trend toward worse survival (P = .08). The first was enriched for increased epithelial and innate and adaptive immunity signatures, whereas the other showed important telomere and mitochondrial dysfunction, loss of proteostasis, and increased myofibroblast signatures. The existence of these two endotypes, including the impact on survival of the immune endotype, was validated in three independent validation cohorts. Finally, we identified transcription factors regulating the expression of endotypespecific survival-associated genes. INTERPRETATION: Gene expression-based endotyping in IPF is feasible and can inform clinical evolution. As endotype-specific pathways and survival-associated transcription factors are identified, endotyping may open up the possibility of endotype-tailored therapy.

Background Sarcoidosis is a non-caseating granulomatous disease, mostly affecting previously healthy persons in their fourth and fifth decade. In Belgium, there is a paucity of epidemiological data concerning sarcoidosis and it is unknown to what respect national data on sarcoidosis relates to the global epidemiology of the disease. Objectives In this cohort study we describe the patient population in an academic center of reference, serving both as a regional care center and a center for a tertiary referral. Methods We collected epidemiological data among 234 consecutive patients consulting the outpatient sarcoidosis clinic during a two-year time period. We manually explored the electronic patient file for data retrieval. Results Out of the 234 patients, 140 are male (60%) and 94 are female (40%) patients. Forced vital capacity showed a median decline of 2% during follow-up, whereas median diffusion capacity increased with 4% over the same period of time. Within our study cohort, we observed a preponderance in employment as construction workers (14%), the chemical industry (6%) and in the metal processing industry (6%). Conclusion The current study reports on epidemiological findings among the largest cohort of sarcoidosis patients in Belgium published to date.

BACKGROUND:Immune checkpoint inhibitor (ICI)-related pneumonitis is the most frequent fatal immune-related adverse event associated with programmed cell death protein-1/programmed death ligand-1 blockade. The pathophysiology however remains largely unknown, owing to limited and contradictory findings in existing literature pointing at either T-helper 1 or T-helper 17-mediated autoimmunity. In this study, we aimed to gain novel insights into the mechanisms of ICI-related pneumonitis, thereby identifying potential therapeutic targets. METHODS:In this prospective observational study, single-cell RNA and T-cell receptor sequencing was performed on bronchoalveolar lavage fluid of 11 patients with ICI-related pneumonitis and 6 demographically-matched patients with cancer without ICI-related pneumonitis. Single-cell transcriptomic immunophenotyping and cell fate mapping coupled to T-cell receptor repertoire analyses were performed. RESULTS:We observed enrichment of both CD4+ and CD8+ T cells in ICI-pneumonitis bronchoalveolar lavage fluid. The CD4+ T-cell compartment showed an increase of pathogenic T-helper 17.1 cells, characterized by high co-expression of TBX21 (encoding T-bet) and RORC (ROR-γ), IFN-G (IFN-γ), IL-17A, CSF2 (GM-CSF), and cytotoxicity genes. Type 1 regulatory T cells and naïve-like CD4+ T cells were also enriched. Within the CD8+ T-cell compartment, mainly effector memory T cells were increased. Correspondingly, myeloid cells in ICI-pneumonitis bronchoalveolar lavage fluid were relatively depleted of anti-inflammatory resident alveolar macrophages while pro-inflammatory 'M1-like' monocytes (expressing TNF, IL-1B, IL-6, IL-23A, and GM-CSF receptor CSF2RA, CSF2RB) were enriched compared with control samples. Importantly, a feedforward loop, in which GM-CSF production by pathogenic T-helper 17.1 cells promotes tissue inflammation and IL-23 production by pro-inflammatory monocytes and vice versa, has been well characterized in multiple autoimmune disorders but has never been identified in ICI-related pneumonitis. CONCLUSIONS:Using single-cell transcriptomics, we identified accumulation of pathogenic T-helper 17.1 cells in ICI-pneumonitis bronchoalveolar lavage fluid-a phenotype explaining previous divergent findings on T-helper 1 versus T-helper 17 involvement in ICI-pneumonitis-,putatively engaging in detrimental crosstalk with pro-inflammatory 'M1-like' monocytes. This finding yields several novel potential therapeutic targets for the treatment of ICI-pneumonitis. Most notably repurposing anti-IL-23 merits further research as a potential efficacious and safe treatment for ICI-pneumonitis.

Interstitial lung disease associated with rheumatoid arthritis (RA-ILD) affects approximately 10% of RA patients. We explored the natural evolution of predicted diffusion capacity of the lung (DLCO, %) in patients presenting to the pulmonology clinic at University Hospitals Leuven (2004-2021), with confirmed RA-ILD and ≥2 pulmonary function tests available. Cox Proportional Hazards Model was used to associate DLCO evolution and survival. The effect of rheumatoid factor (RF), anti-citrullinated protein antibodies, smoking status, gender, age at diagnosis of RA, and CT pattern on DLCO evolution was assessed by linear mixed models. Median age at RA-ILD diagnosis was 66.1 years (IQR = 13.4, n=70), median time between diagnosis of RA and RA-ILD 5.8 years (IQR= 12.5), and median follow-up 5.2 years (IQR =5.1). Median DLCO at diagnosis was 47% (IQR=12). Greater DLCO decline (%) was associated with increased risk of death or transplantation (p= 0.006, HR=1.07). It was greater in RF positive patients (67.2%, p<0.001), ever smokers (58.8%, p<0.001), males (58.6%, p<0.01), and usual interstitial pneumonia (UIP) (65.7%, p<0.01) (Fig. 1). In multivariate analysis, RF positivity and smoking remained significant. To conclude, DLCO evolution could be a prognostic tool in RA-ILD. DLCO decline is significantly greater in RF positive patients, ever smokers, males, and a UIP pattern, and this was associated with worse survival.