Potential Rheumatoid Arthritis-Associated Interstitial Lung Disease Treatment and Computational Approach for Future Drug Development.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by swelling in at least one joint. Owing to an overactive immune response, extra-articular manifestations are observed in certain cases, with interstitial lung disease (ILD) being the most common. Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is characterized by chronic inflammation of the interstitial space, which causes fibrosis and the scarring of lung tissue. Controlling inflammation and pulmonary fibrosis in RA-ILD is important because they are associated with high morbidity and mortality. Pirfenidone and nintedanib are specific drugs against idiopathic pulmonary fibrosis and showed efficacy against RA-ILD in several clinical trials. Immunosuppressants and disease-modifying antirheumatic drugs (DMARDs) with anti-fibrotic effects have also been used to treat RA-ILD. Immunosuppressants moderate the overexpression of cytokines and immune cells to reduce pulmonary damage and slow the progression of fibrosis. DMARDs with mild anti-fibrotic effects target specific fibrotic pathways to regulate fibrogenic cellular activity, extracellular matrix homeostasis, and oxidative stress levels. Therefore, specific medications are required to effectively treat RA-ILD. In this review, the commonly used RA-ILD treatments are discussed based on their molecular mechanisms and clinical trial results. In addition, a computational approach is proposed to develop specific drugs for RA-ILD.

The impact of nintedanib and pirfenidone on lung function and survival in patients with idiopathic pulmonary fibrosis in real-life setting.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of usual interstitial pneumonia (UIP). A mean survival of 2-5 years was reported previously to the advent of antifibrotics. According to clinical trials, nintedanib and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival. METHODS: A real-life retrospective and longitudinal study was conducted to assess the efficacy and tolerability of antifibrotics in IPF patients, between January 2014 and December 2020. Two groups (under nintedanib or pirfenidone) were analyzed at diagnosis through their clinical features and radiological patterns. Lung function was assessed at diagnosis (time 0) and after 6, 12 and 24 months of treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with immunosuppressive drugs and/or N- acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®. RESULTS: A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC and DLCO mean predicted percentages at 6, 12 and 24 months of treatment. The mean decline in FVC and DLCO, at 12 months, was -40.95 ± 438.26 mL and -0.626 ± 1.31 mL/min/mmHg, respectively. However, during this period, 34.2% of the patients died mostly due to acute exacerbation associated with a poorer lung function at diagnosis. Mean survival in the naïve antifibrotic cohort was significantly lower than in the antifibrotic cohort (39.9 months versus 58.2 months; p < 0.005). Regarding lung function evolution and survival, we found no differences between definitive or probable UIP radiological patterns, both on patients under nintedanib and pirfenidone (p = 0.656). CONCLUSIONS: In this real-life observational study, the positive impact of antifibrotic therapy on the IPF clinical course and on survival was corroborated. Regarding efficacy, there was no difference between patients taking nintedanib or pirfenidone. The need for an early treatment was also demonstrated, since a worse outcome is clearly associated with lower lung volumes and lower diffusing capacity at diagnosis.

Lung cancer in patients with idiopathic pulmonary fibrosis: A retrospective multicentre study in Europe.

BACKGROUND AND OBJECTIVE: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry. METHODS: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021. RESULTS: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/µl than patients with monocyte count ≥0.95 K/µl (HR [<0.60 vs. ≥0.95 K/µl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/µl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02). CONCLUSION: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed.

Racial and ethnic disparities in antifibrotic therapy in idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Racial disparities have been documented in care of many respiratory diseases but little is known about the impact of race on the treatment of interstitial lung diseases. The purpose of this study was to determine how race and ethnicity influence treatment of idiopathic pulmonary fibrosis. METHODS: Adults with idiopathic pulmonary fibrosis (>18 years) were identified using TriNetX database and paired-wised comparisons were performed for antifibrotic treatment among White, Black, Hispanic and Asian patients. Mortality of treated and untreated IPF patients was compared after propensity score matching for age, sex, nicotine dependence, oxygen dependence and predicted FVC. Additional comparisons were performed in subgroups of IPF patients older than 65 years of age and with lower lung function. RESULTS: Of 47,184 IPF patients identified, the majority were White (35,082), followed by Hispanic (6079), Black (5245) and Asian (1221). When subgroups were submitted to matched cohort pair-wise comparisons, anti-fibrotic usage was lower among Black patients compared to White (6.2% vs. 11.4%, p-value <0.0001), Hispanic (10.8% vs. 20.2%, p-value <0.0001) and Asian patients (9.6% vs. 14.7%, p-value = 0.0006). Similar treatment differences were noted in Black individuals older than 65 years and those with lower lung function. Mortality among White patients, but not Hispanic, Black, or Asian patients, was lower in patients on antifibrotic therapy versus not on therapy. CONCLUSION: This study demonstrated that Black IPF patients had lower antifibrotic use compared to White, Hispanic and Asian patients. Our findings suggest that urgent action is needed to understand the reason why racial disparities exist in the treatment of IPF.

Human Lung Tissue Implanted on the Chick Chorioallantoic Membrane as a Novel In Vivo Model of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with no curative pharmacological treatment. Current preclinical models fail to accurately reproduce human pathophysiology and are therefore poor predictors of clinical outcomes. Here, we investigated whether the chick embryo chorioallantoic membrane (CAM) assay supports the implantation of xenografts derived from IPF lung tissue and primary IPF lung fibroblasts and can be used to evaluate the efficacy of antifibrotic drugs. We demonstrate that IPF xenografts maintain their integrity and are perfused with chick embryo blood. Size measurements indicate that the xenografts amplify on the CAM, and Ki67 and pro-collagen type I immunohistochemical staining highlight the presence of proliferative and functional cells in the xenografts. Moreover, the IPF phenotype and immune microenvironment of lung tissues are retained when cultivated on the CAM and the fibroblast xenografts mimic invasive IPF fibroblastic foci. Daily treatments of the xenografts with nintedanib and PBI-4050 significantly reduce their size, fibrosis-associated gene expression, and collagen deposition. Similar effects are found with GLPG1205 and fenofibric acid, two drugs that target the immune microenvironment. Our CAM-IPF model represents the first in vivo model of IPF that uses human lung tissue. This rapid and cost-effective assay could become a valuable tool for predicting the efficacy of antifibrotic drug candidates for IPF.

Statins' still controversial role in pulmonary fibrosis: What does the evidence show?

Pulmonary fibrosis (PF) represents the end stage of a broad range of interstitial lung diseases (ILDs). Statins are among the compounds which have been implicated in drug-induced ILD development. However, recent studies (both in vitro and in vivo) have provided evidence that statins may exert anti-inflammatory and anti-fibrotic effects potentially offering benefits to patients with PF. Several protective molecular mechanisms including the suppression of mevalonic acid pathway, the inhibition of NADPH oxidase activation in macrophages and the inhibition of several profibrotic mediators have been proposed to explain the observed in vivo decrease of the oxidative stress in the lung and the preservation of lung function in patients. Earlier clinical studies relating statins with drug-induced ILD development are contradicted by increasing new data showing the beneficial effects of statins in clinical outcomes in ILD patients who receive statins for concomitant cardiovascular indications. Future research may further elucidate the wide spectrum of pathways of IPF pathogenesis, and genetic heterogeneity, identifying clinically applicable biomarkers and specific endotypes thus recognizing in which patients statins could confer benefit and in which they might cause detrimental effects.

Antifibrotics Modify B-Cell-induced Fibroblast Migration and Activation in Patients with Idiopathic Pulmonary Fibrosis.

B-cell activation is increasingly linked to numerous fibrotic lung diseases, and it is well known that aggregates of lymphocytes form in the lung of many of these patients. Activation of B-cells by pattern recognition receptors (PRRs) drives the release of inflammatory cytokines, chemokines, and metalloproteases important in the pathophysiology of pulmonary fibrosis. However, the specific mechanisms of B-cell activation in patients with idiopathic pulmonary fibrosis (IPF) are poorly understood. Herein, we have demonstrated that B-cell activation by microbial antigens contributes to the inflammatory and profibrotic milieu seen in patients with IPF. B-cell stimulation by CpG and ß-glucan via PRRs resulted in activation of mTOR-dependent and independent pathways. Moreover, we showed that the B-cell-secreted inflammatory milieu is specific to the inducing antigen and causes differential fibroblast migration and activation. B-cell responses to infectious agents and subsequent B-cell-mediated fibroblast activation are modifiable by antifibrotics, but each seems to exert a specific and different effect. These results suggest that, upon PRR activation by microbial antigens, B-cells can contribute to the inflammatory and fibrotic changes seen in patients with IPF, and antifibrotics are able to at least partially reverse these responses.

Comparative outcomes in patients receiving pirfenidone or nintedanib for idiopathic pulmonary fibrosis.

BACKGROUND: Real-world data regarding outcomes of idiopathic pulmonary fibrosis (IPF) are scarce, outside of registries. In France, pirfenidone and nintedanib are only reimbursed for documented IPF, with similar reimbursement criteria with respect to disease characteristics, prescription through a dedicated form, and IPF diagnosis established in multidisciplinary discussion. RESEARCH QUESTION: The data of the comprehensive French National Health System were used to evaluate outcomes in patients newly treated with pirfenidone or nintedanib in 2015-2016. STUDY DESIGN AND METHODS: Patients aged < 50 years or who had pulmonary fibrosis secondary to an identified cause were excluded. All-cause mortality, acute respiratory-related hospitalisations and treatment discontinuations up to 31 December 2017 were compared using a Cox proportional hazards model adjusted for age, sex, year of treatment initiation, time to treatment initiation and proxies of disease severity identified during a pre-treatment period. RESULTS: During the study period, a treatment with pirfenidone or nintedanib was newly initiated in 804 and 509 patients, respectively. No difference was found between groups for age, sex, time to treatment initiation, Charlson comorbidity score, and number of hospitalisations or medical contacts prior to treatment initiation. As compared to pirfenidone, nintedanib was associated with a greater risk of all-cause mortality (hazard ratio [HR], 1.8; 95% confidence interval [CI] 1.3-2.6), a greater risk of acute respiratory-related hospitalisations (HR 1.3; 95% CI 1.0-1.7) and a lower risk of treatment discontinuation at 12 months (HR 0.7; 95% CI 0.6-0.9). INTERPRETATION: This observational study identified potential differences in outcome under newly prescribed antifibrotic drugs, deserving further explorations.

Switching antifibrotics in patients with idiopathic pulmonary fibrosis: a multi-center retrospective cohort study.

BACKGROUND: Currently, there are two antifibrotics used to treat idiopathic pulmonary fibrosis (IPF): pirfenidone and nintedanib. Antifibrotics slow disease progression by reducing the annual decline of forced vital capacity (FVC), which possibly improves outcomes in IPF patients. During treatment, patients occasionally switch antifibrotic treatments. However, prognostic implication of changing antifibrotics has not yet been evaluated. METHODS: This multi-center retrospective cohort study examined 262 consecutive IPF patients who received antifibrotic therapy. Antifibrotic agents were switched in 37 patients (14.1%). The prognoses were compared between the patient cohort that switched antifibrotics (Switch-IPF) and those without (Non-Switch-IPF) using propensity-score matched analyses. RESULTS: The median period between the initiation of antifibrotic therapy and the drug switch was 25.8 (12.7-35.3) months. The most common reasons for the switch were disease progression (n = 17) followed by gastrointestinal disorders (n = 12). Of the 37 patients that switched antifibrotics, only eight patients disrupted switched antifibrotics by their adverse reactions. The overall prognosis of the Switch-IPF cohort was significantly better than the Non-Switch-IPF cohort (median periods: 67.2 vs. 27.1 months, p < 0.0001). In propensity-score matched analyses that were adjusted to age, sex, FVC (%), history of acute exacerbation, and usage of long-term oxygen therapy, the Switch-IPF cohort had significantly longer survival times than the Non-Switch-IPF group (median 67.2 vs. 41.3 months, p = 0.0219). The second-line antifibrotic therapy showed similar survival probabilities than those in first-line antifibrotic therapy in multistate model analyses. CONCLUSION: Switching antifibrotics is feasible and may improve prognosis in patients with IPF. A further prospective study will be required to confirm clinical implication of switching the antifibrotics.

Outcomes for hospitalized patients with idiopathic pulmonary fibrosis treated with antifibrotic medications.

BACKGROUND: Idiopathic Pulmonary Fibrosis is a chronic, progressive interstitial lung disease for which there is no cure. However, lung function decline, hospitalizations, and mortality may be reduced with the use of the antifibrotic medications, nintedanib and pirfenidone. Historical outcomes for hospitalized patients with Idiopathic Pulmonary Fibrosis are grim; however there is a paucity of data since the approval of nintedanib and pirfenidone for treatment. In this study, we aimed to determine the effect of nintedanib and pirfenidone on mortality following respiratory-related hospitalizations, intensive care unit (ICU) admission, and mechanical ventilation. METHODS: Using a large U.S. insurance database, we created a one-to-one propensity score matched cohort of patients with idiopathic pulmonary fibrosis treated and untreated with an antifibrotic who underwent respiratory-related hospitalization between January 1, 2015 and December 31, 2018. Mortality was evaluated at 30 days and end of follow-up (up to 2 years). Subgroup analyses were performed for all patients receiving treatment in an ICU and those receiving invasive and non-invasive mechanical ventilation during the index hospitalization. RESULTS: Antifibrotics were not observed to effect utilization of mechanical ventilation or ICU treatment during the index admission or effect mortality at 30-days. If patients survived hospitalization, mortality was reduced in the treated cohort compared to the untreated cohort when followed up to two years (20.1% vs 47.8%). CONCLUSIONS: Treatment with antifibrotic medications does not appear to directly improve 30-day mortality during or after respiratory-related hospitalizations. Post-hospital discharge, however, ongoing antifibrotic treatment was associated with improved long-term survival.

Regulation of cellular senescence by extracellular matrix during chronic fibrotic diseases.

The extracellular matrix (ECM) is a complex network of macromolecules surrounding cells providing structural support and stability to tissues. The understanding of the ECM and the diverse roles it plays in development, homoeostasis and injury have greatly advanced in the last three decades. The ECM is crucial for maintaining tissue homoeostasis but also many pathological conditions arise from aberrant matrix remodelling during ageing. Ageing is characterised as functional decline of tissue over time ultimately leading to tissue dysfunction, and is a risk factor in many diseases including cardiovascular disease, diabetes, cancer, dementia, glaucoma, chronic obstructive pulmonary disease (COPD) and fibrosis. ECM changes are recognised as a major driver of aberrant cell responses. Mesenchymal cells in aged tissue show signs of growth arrest and resistance to apoptosis, which are indicative of cellular senescence. It was recently postulated that cellular senescence contributes to the pathogenesis of chronic fibrotic diseases in the heart, kidney, liver and lung. Senescent cells negatively impact tissue regeneration while creating a pro-inflammatory environment as part of the senescence-associated secretory phenotype (SASP) favouring disease progression. In this review, we explore and summarise the current knowledge around how aberrant ECM potentially influences the senescent phenotype in chronic fibrotic diseases. Lastly, we will explore the possibility for interventions in the ECM-senescence regulatory pathways for therapeutic potential in chronic fibrotic diseases.

Novel targeted therapies for the management of liver fibrosis.

Introduction: Prolonged liver injury results in tissue damage and replacement by extracellular matrix and fibrosis. Cirrhosis represents a leading cause of mortality worldwide and imposes a major financial burden on health-care systems. Fortunately, fibrogenesis has proven to be reversible if halted early, encouraging the development of novel anti-fibrotic agents that may accelerate histological restoration. Preclinical data have elucidated numerous potential therapeutic targets and many anti-fibrotic agents are currently at various stages of clinical research.Areas covered: The present review summarizes recent clinical data regarding anti-fibrotic drugs including monoclonal antibodies, targeted conjugates, and small molecule agents.Expert opinion: Although undeniable progress has been made in the development of anti-fibrotic agents in recent years, most data currently available are derived from preclinical and early clinical studies. The efficacy and safety of these agents will need to be corroborated by larger clinical trials, some of which are ongoing with results expected in the upcoming years. Combination therapy with agents targeting different pathways of fibrogenesis will also be of great interest for the future and will need to be explored in clinical trials.

Therapeutic burden in interstitial lung disease: Lessons to learn.

BACKGROUND AND OBJECTIVE: Patients with interstitial lung disease (ILD) are often prescribed disease-targeted and symptomatic therapies, both of which can cause significant treatment burden due to polypharmacy and drug-disease interactions. This study aimed to evaluate medication regimen complexity before and after introduction of ILD-specific therapies. Potential drug-disease interactions were evaluated for patients who were prescribed prednisolone. METHODS: In this study, 214 patients with ILD were assessed for demographic information, co-morbidities and medication use. Medication lists were reviewed prior to and after the introduction of ILD-specific therapies. Complexity of treatment regimen was examined using the validated Medication Regimen Complexity Index (MRCI). RESULTS: Of the 214 patients, 75 had idiopathic pulmonary fibrosis (IPF) while the rest had inflammatory ILD (chronic hypersensitivity pneumonitis: 45; connective tissue disease-related ILD: 41). Polypharmacy was common at baseline (IPF: 51%, inflammatory ILD: 63%). Following introduction of ILD-specific therapies, median total MRCI scores significantly increased from 8 (interquartile range (IQR) = 8-15) to 22.5 (17.5-27.5) and 14.5 (8.5-21) to 21.5 (16-30) for IPF and inflammatory ILD groups, respectively (P < 0.0001 for both). Complex dosing instructions contributed the most to total MRCI scores for ILD-specific therapies. Among patients receiving prednisolone (n = 113), 88% had ≥1 co-morbidity which may be impacted. Common co-morbidities included gastrointestinal diseases (56%), obesity (37%), osteoporosis (24%) and diabetes mellitus (18%). CONCLUSION: Polypharmacy and complex medication regimen are common in patients with ILD of different aetiologies. There is a high frequency of potential drug-disease interactions among patients who are prescribed systemic corticosteroids. These findings highlight the need for careful evaluation of the impact of therapeutic complexity and burden in patients with ILD.

Biopsy and Noninvasive Methods to Assess Progression of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of histopathologic features, ranging from isolated hepatic steatosis, to steatohepatitis with evidence of hepatocellular injury and fibrosis, to cirrhosis. The diagnosis and determination of NAFLD prognosis requires clinical and histopathologic assessments. Liver biopsy still is regarded as the reference for differentiating steatosis (NAFL) from nonalcoholic steatohepatitis, for staging hepatic fibrosis, and for identifying NAFLD in patients with other chronic liver disease. Standardized grading and staging histologic scoring systems, such as the NAFLD activity score and the steatosis, activity, and fibrosis score, can help guide clinical decisions and assess outcomes of clinical trials. Improved understanding of the pathophysiology of NAFLD and technologic advances have led to algorithms that can be used to assess serum biomarkers and imaging methods that are noninvasive alternatives to biopsy collection and analysis. We review the advantages and limitations of biopsy analysis and noninvasive tests as diagnostic and prognostic tools for patients with NAFLD. We also discuss techniques to improve dynamic histopathology assessment, and emerging blood and imaging biomarkers of fibrogenesis.

What can target kidney fibrosis?

Fibrosis, a characteristic of all chronic kidney diseases, is now recognized to be an independent predictor of disease progression. Deposition of pathological matrix in the walls of glomerular capillaries, the interstitial space and around arterioles both predicts and contributes to functional demise of the nephron and its surrounding vasculature. Recent identification of the major cell populations of fibroblast precursors in the kidney interstitium as pericytes and tissue-resident mesenchymal stem cells, and in the glomerulus as podocytes, parietal epithelial and mesangial cells, has enabled the study of the fibrogenic process in much greater depth directly in the fibroblast precursors. These cells are not only matrix-producing cells, but are also important innate immune surveillance cells that regulate the inflammatory process, exacerbate tissue damage by release of radicals and cytokines, and contribute to parenchymal and microvascular dysfunction by aberrant wound-healing responses. Innate immune signaling in fibroblasts and their precursors is intimately intertwined with the process of fibrogenesis. In addition, genomic and genetic studies also point to defective responses in loci close to genes involved in solute transport, metabolism, autophagy, protein handling and vascular homeostasis, principally in the epithelium and endothelium, as upstream drivers of the fibrotic process, indicating that cellular crosstalk is vital for development of fibrosis. As we move beyond TGFß inhibition as a central target for fibrosis, targeting innate immune signaling and metabolic dysfunction appear increasingly tenable alternative targets for novel therapies.

Unmet needs in the treatment of idiopathic pulmonary fibrosis-insights from patient chart review in five European countries.

BACKGROUND: Two antifibrotic drugs, pirfenidone and nintedanib, are approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of idiopathic pulmonary fibrosis (IPF). In this analysis, treatment patterns of European patients with IPF were investigated to understand antifibrotic prescribing and identify unmet needs in IPF treatment practice. METHODS: Between February and March 2016, respiratory physicians from France, Germany, Italy, Spain, and the UK participated in an online questionnaire designed to collect information on IPF treatment patterns in patients under their care. Patients were categorized as treated (received approved antifibrotics) or untreated (did not receive approved antifibrotics, but may have received other unapproved therapies). Classification of IPF diagnosis (confirmed/suspected) and severity ('mild'/'moderate'/'severe') for each patient was based on the individual physician's report. Patients' perspectives were not recorded in this study. RESULTS: In total, 290 physicians responded to the questionnaire. Overall, 54% of patients with IPF did not receive treatment with an approved antifibrotic. More patients had a confirmed IPF diagnosis in the treated (84%) versus the untreated (51%) population. Of patients with a confirmed diagnosis, 40% did not receive treatment. The treated population was younger than the untreated population (67 vs 70 years, respectively; p ≤ 0.01), with more frequent multidisciplinary team evaluation (83% vs 57%, respectively; p ≤ 0.01). A higher proportion of untreated patients had forced vital capacity > 80% at diagnosis versus treated patients. Of patients with 'mild' IPF, 71% did not receive an approved antifibrotic versus 41% and 60% of patients with 'moderate' and 'severe' IPF, respectively. CONCLUSIONS: Despite the availability of antifibrotic therapies, many European patients with confirmed IPF do not receive approved antifibrotic treatment. Importantly, there appears to be a reluctance to treat patients with 'mild' or 'stable' disease, and instead adopt a 'watch and wait' approach. More education is required to address diagnostic uncertainty, poor understanding of IPF and its treatments, and issues of treatment access. There is a need to increase physician awareness of the benefits associated with antifibrotic treatment across the spectrum of IPF severity.

Three-Year Follow-Up of Trabeculectomy with 5-Fluorouracil.

PURPOSE: To evaluate the long-term outcome of trabeculectomy with intra- and postoperative 5-fluorouracil (5-FU) application in glaucoma. METHODS: Eighty-six patients with glaucoma planned for primary trabeculectomy with 5-FU and a minimum follow-up of 3 years were retrospectively analyzed. Success rates, postsurgical 5-FU injections, needling procedures, and complications were analyzed. RESULTS: Mean intraocular pressure (IOP) decreased from 27.2 ± 6.7 to 13.2 ± 4.2 mm Hg at 1 year and 13.8 ± 3.7 mm Hg at the 3-year follow-up. The complete success rates (no IOP-lowering medication) were 83, 79, 73, and 45% at 1 year for IOP ≤21, ≤18, ≤16, and ≤12 mm Hg, respectively, and 64, 59, 56, and 20% for these criteria at 3 years. The average number of medications decreased from preoperatively 2.9 ± 1.4 to 0.2 ± 0.5 at 1 year and 0.7 ± 1.1 at 3 years. During the first 6 months, subconjunctival 5-FU injections were performed in 49 cases. Eleven patients underwent bleb needling during the first 6 months and 13 patients underwent the procedure between the 6th month and the 3rd year. Malignant glaucoma and bleb-related endophthalmitis occurred in 1 patient each. CONCLUSIONS: Trabeculectomy with 5-FU is an efficient surgical procedure for glaucoma treatment when combined with intensified postsurgical care.

Safety and efficacy of bridging to lung transplantation with antifibrotic drugs in idiopathic pulmonary fibrosis: a case series.

BACKGROUND: Following recent approval of pirfenidone and nintedanib for idiopathic pulmonary fibrosis (IPF), questions arise about the use of these antifibrotics in patients awaiting lung transplantation (LTx). METHODS: Safety and efficacy of antifibrotic drugs in IPF patients undergoing LTx were investigated in a single-centre retrospective cohort analysis. RESULTS: A total of nine patients, receiving antifibrotic therapy for 419 ± 315 days until subsequent LTx, were included. No major side effects were noted. Significant weight loss occurred during antifibrotic treatment (p = 0.0062). FVC tended to stabilize after 12 weeks of treatment in most patients. A moderate decline in FVC, TLC and DLCO was noted during the whole pretransplant time period of antifibrotic therapy. Functional exercise capacity and lung allocation score remained unchanged. No post-operative thoracic wound healing problems, nor severe early anastomotic airway complications were attributable to prior antifibrotic treatment. None of the patients developed chronic lung allograft dysfunction after a median follow-up of 19.8 (11.2-26.5) months; and post-transplant survival was 100% after 1 year and 80% after 2 years. CONCLUSIONS: Antifibrotic drugs can probably be safely administered in IPF patients, possibly attenuating disease progression over time, while awaiting LTx.

Effectiveness and tolerability of antifibrotics in rheumatoid arthritis-associated interstitial lung disease.

OBJECTIVE: Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD). METHODS: In this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014-2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality. RESULTS: We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (-0.3 % per year after initiation compared to -6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68). CONCLUSION: In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety.