Tocilizumab plus Nintedanib for progressive interstitial lung disease in systemic sclerosis: a one-year observational study.

Randomized controlled trials have recently shown that both the IL-6 inhibitor Tocilizumab and the antifibrotic Nintedanib are efficacious for Systemic Sclerosis (SSc)-associated progressive interstitial lung disease (ILD). Since real-world clinical data on Tocilizumab/Nintedanib combination are lacking, we report on their long-term safety and efficacy. Consecutive patients who received off-label Tocilizumab for SSc plus Nintedanib for progressive ILD were retrospectively studied. Adverse events, and changes in Forced Vital Capacity (FVC), Diffucing Capacity for Carbon Monoxide (DLCO) and high resolution chest tomography (HRCT) between baseline and 6 and 12 months were assessed. Tocilizumab/Nintedanib combination was well tolerated by all 20 patients [aged 52 ± 13 years (mean ± SD), 14 women, 15 diffuse SSc, disease duration of 5.7 ± 4.9 years]; 7 of 20 patients received concomitant mycophenolate mofetil safely. No serious adverse events or laboratory abnormalities were noted. Five patients developed persistent diarrhea and 2 of them reduced dosage of Nintedanib. Baseline FVC (74%±12%) and DLCO (45%±10%) remained overall stable both at 6 months (73.5%±13% and 46%±11%, respectively) and 12 months (73%±14% and 45%±11%, respectively), regardless of disease duration. The extent of fibrotic reticular pattern in available pairs of HRCTs (n = 12) remained also stable at 12 months, whereas proportion (%) of ground glass opacities decreased from 29%±16 to 21%±14% (p = 0.048); improvement in HRCTs by almost 75% was noted in 2 of these12 patients. Tocilizumab/Nintedanib combination for one year was safe and stabilized lung function in real-world SSc patients with progressive ILD. Additional studies of this combination treatment in SSc-ILD are warranted.

Diagnostic Utility of Bronchoalveolar Lavage Lymphocytosis in Patients with Interstitial Lung Diseases.

BACKGROUND: Interstitial lung diseases (ILDs) are extremely challenging in terms of diagnosis. Extreme bronchoalveolar lavage (BAL) lymphocytosis is thought to strongly point towards the diagnosis of hypersensitivity pneumonitis (HP). OBJECTIVES: Explore the range of different ILD that can present with BAL lymphocytosis, including cases of pronounced lymphocytosis and its diagnostic utility. METHODS: Patients with ILD that were subjected to BAL were identified retrospectively from a cohort of consecutive patients. RESULTS: BAL lymphocytosis ≥20% was recorded in 106 patients (27%), while pronounced BAL lymphocytosis ≥40% was recorded in 49 patients (12.5%). The most common diagnoses in patients with BAL lymphocytosis ≥20% and ≥40%, were HP (32.1%), connective tissue disease (CTD)-ILD (26.4%), sarcoidosis (16%), and HP (38.8%), CTD-ILD (24.5%), sarcoidosis (14.3%), respectively. CONCLUSIONS: Neither the presence nor the degree of BAL lymphocytosis can point to a specific diagnosis.

Safety and Effectiveness of Mycophenolate Mofetil in Interstitial Lung Diseases: Insights from a Machine Learning Radiographic Model.

INTRODUCTION: Treatment of interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) often includes systemic corticosteroids. Use of steroid-sparing agents is amenable to avoid potential side effects. METHODS: Functional indices and high-resolution computed tomography (HRCT) patterns of patients with non-IPF ILDs receiving mycophenolate mofetil (MMF) with a minimum follow-up of 1 year were analyzed. Two independent radiologists and a machine learning software system (Imbio 1.4.2.) evaluated HRCT patterns. RESULTS: Fifty-five (n = 55) patients were included in the analysis (male: 30 [55%], median age: 65.0 [95% CI: 59.7-70.0], mean forced vital capacity %predicted [FVC %pred.] ± standard deviation [SD]: 69.4 ± 18.3, mean diffusing capacity of lung for carbon monoxide %pred. ± SD: 40.8 ± 14.3, hypersensitivity pneumonitis: 26, connective tissue disease-ILDs [CTD-ILDs]: 22, other ILDs: 7). There was no significant difference in mean FVC %pred. post-6 months (1.59 ± 2.04) and 1 year (-0.39 ± 2.49) of treatment compared to baseline. Radiographic evaluation showed no significant difference between baseline and post-1 year %ground glass opacities (20.0 [95% CI: 14.4-30.0] vs. 20.0 [95% CI: 14.4-25.6]) and %reticulation (5.0 [95% CI: 2.0-15.6] vs. 7.5 [95% CI: 2.0-17.5]). A similar performance between expert radiologists and Imbio software analysis was observed in assessing ground glass opacities (intraclass correlation coefficient [ICC] = 0.73) and reticulation (ICC = 0.88). Fourteen patients (25.5%) reported at least one side effect and 8 patients (14.5%) switched to antifibrotics due to disease progression. CONCLUSION: Our data suggest that MMF is a safe and effective steroid-sparing agent leading to disease stabilization in a proportion of patients with non-IPF ILDs. Machine learning software systems may exhibit similar performance to specialist radiologists and represent fruitful diagnostic and prognostic tools.

Increased monocyte count and red cell distribution width as prognostic biomarkers in patients with Idiopathic Pulmonary Fibrosis.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) represents a chronic lung disease with unpredictable course. METHODS: We aimed to investigate prognostic performance of complete blood count parameters in IPF. Treatment-naïve patients with IPF were retrospectively enrolled from two independent cohorts (derivation and validation) and split into subgroups (high and low) based on median baseline monocyte count and red cell distribution width (RDW). RESULTS: Overall, 489 patients (derivation cohort: 300, validation cohort: 189) were analyzed. In the derivation cohort, patients with monocyte count ≥ 0.60 K/µL had significantly lower median FVC%pred [75.0, (95% CI 71.3-76.7) vs. 80.9, (95% CI 77.5-83.1), (P = 0.01)] and DLCO%pred [47.5, (95% CI 44.3-52.3) vs. 53.0, (95% CI 48.0-56.7), (P = 0.02)] than patients with monocyte count < 0.60 K/µL. Patients with RDW ≥ 14.1% had significantly lower median FVC%pred [75.5, (95% CI 71.2-79.2) vs. 78.3, (95% CI 76.0-81.0), (P = 0.04)] and DLCO%pred [45.4, (95% CI 43.3-50.5) vs. 53.0, (95% CI 50.8-56.8), (P = 0.008)] than patients with RDW < 14.1%. Cut-off thresholds from the derivation cohort were applied to the validation cohort with similar discriminatory value, as indicated by significant differences in median DLCO%pred between patients with high vs. low monocyte count [37.8, (95% CI 35.5-41.1) vs. 45.5, (95% CI 41.9-49.4), (P < 0.001)] and RDW [37.9, (95% CI 33.4-40.7) vs. 44.4, (95% CI 41.5-48.9), (P < 0.001)]. Patients with high monocyte count and RDW of the validation cohort exhibited a trend towards lower median FVC%pred (P = 0.09) and significantly lower median FVC%pred (P = 0.001), respectively. Kaplan-Meier analysis in the derivation cohort demonstrated higher all-cause mortality in patients with high (≥ 0.60 K/µL) vs. low monocyte count (< 0.60 K/µL) [HR 2.05, (95% CI 1.19-3.53), (P = 0.01)]. CONCLUSIONS: Increased monocyte count and RDW may represent negative prognostic biomarkers in patients with IPF.

Antisynthetase Syndrome Masquerading as Hypersensitivity Pneumonitis.

Interstitial lung diseases (ILDs) cover a wide heterogeneous group of disorders, both of unknown and known causes. Accurate diagnosis is essential but, at the same time, presents many challenges. Typically, the distinction between idiopathic pulmonary fibrosis and fibrotic hypersensitivity pneumonitis (HP) can prove extremely difficult. However, another major, but underestimated, challenge is the diagnosis of connective tissue disease-associated ILD (CTD-ILD), specifically when ILD is the initial manifestation or when extrapulmonary manifestations are subclinical. Antisynthetase syndrome (ASyS) is a characteristic example where lung involvement can be the predominant feature in the absence of other evidence suggestive of CTD. In ASyS, lung involvement can be the initial manifestation or muscle involvement can be subclinical with normal muscle enzymes. Furthermore, a negative antinuclear antibody test does not indicate autoantibody negativity in the context of ASyS. Imaging and pathology findings in ASyS are not specific and overlap with other ILDs. Finally, bronchoalveolar lavage can exhibit pronounced lymphocytosis (>30-40%). The latter, in combination with a history of exposure to an inciting antigen, can lead to an erroneous diagnosis of HP with obvious negative impact on patients' outcome. Herein, we report 3 female patients aged 61, 65, and 70 years and 1 male patient aged 43 years, with ASyS masquerading as HP and analyze the underlying reasons of misdiagnosis, aiming to raise awareness of the need for close collaboration between pulmonologists and rheumatologists.

Immune Checkpoint Inhibitor-Related Pneumonitis.

Immune checkpoint inhibitors are novel agents that have been proved efficacious in a variety of cancer types, but they are associated with a unique set of organ-specific, immune-related adverse events. Among them, immune-related pneumonitis requires special attention because it is difficult to diagnose and potentially lethal. Accumulating real-world epidemiological data suggest that immune-related pneumonitis is more frequent than previously reported. Its diagnosis requires exclusion of other causes and assessment of radiographic features on high-resolution CT of the chest. Management of immune-related pneumonitis is based on the use of immunosuppressants. Future research should be focused on finding predictive biomarkers for immune-related pneumonitis as well as optimizing its management.

Vitamin D prevents experimental lung fibrosis and predicts survival in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Vitamin D (VitD) is a steroid hormone with cytoprotective and anti-inflammatory properties. Epidemiological studies have suggested a link between VitD deficiency and risk of development of chronic lung diseases. Its role in lung fibrosis is largely unknown. The aim of our study was to investigate the role of VitD in experimental and human lung fibrosis. METHODS: VitD (25-OH-D3, 2 µg/kg) was orally administered from day 3-day 13 following bleomycin-challenge, in 8-10 weeks-old C57/BL6 mice. Mouse Lung Fibroblasts (MLFs) were pre-treated with VitD (2 µM for 24 h) and then stimulated with TGFB1 (10 ng/ml). Serum samples from 93 patients with IPF and other forms of interstitial lung diseases (ILDs) were prospectively collected for VitD measurement. RESULTS: VitD administration prevented bleomycin-induced lung fibrosis, as assessed by reductions in hydroxyproline levels, mRNA levels of col1a1, col3a1 and a-SMA (1.4-, 3.1-, 2.25-, 2.5-fold, respectively) and Masson Trichrome staining compared to the untreated group and these changes were associated with restoration of the bleomycin-induced downregulation of vitamin D-receptor (Vdr) mRNA levels. Pre-treatment with VitD reduced the responsiveness of MLFs to pro-fibrotic stimuli, as indicated by significant decreases of col1a1, col3a1 and a-SMA (3.6-, 4.1- and 2.7-fold, respectively).These changes were associated with restoration of the TGFB1-induced downregulation of vitamin D-receptor (VDR) mRNA levels. VitD treatment deactivated TGFB1-induced Smad3 phosphorylation. Patients with IPF and other forms of ILDs displayed deficient VitD serum concentrations (mean VitD = 18.76 ±â€¯8.36 vs. 18.54 ±â€¯8.39 ng/ml, respectively, p = 0.9). VitD deficiency was correlated with baseline FVC%predicted (r = 0.47, p < 0.0001), DLCO%predicted (r = 0.6, p < 0.0001), GAP score (r = -0.4, p < 0.0001) and all-cause mortality in patients with IPF (HR: 3.7, p = 0.001). CONCLUSIONS: VitD could serve as a prognosticator and potential therapeutic target in patients with IPF. Further studies are sorely needed.

Safety and efficacy of nintedanib in idiopathic pulmonary fibrosis: A real-life observational study in Greece.

BACKGROUND: Nintedanib represents an antifibrotic compound able to slow down disease progression of patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To investigate the safety and efficacy of nintedanib in patients with IPF in a real-life setting. METHODS: This was a multicentre, retrospective, observational, real-life study for patients with IPF receiving nintedanib between October 2014 and October 2016. RESULTS: We identified 94 patients with IPF receiving nintedanib (72 males, mean age±SD: 73.8 ±â€¯7.5, mean%FVC±SD = 68.1 ±â€¯18.3, mean%DLCo±SD = 44.4 ±â€¯14.5). Diarrhea (n = 52, 55.3%) was the most commonly reported adverse event. Twenty patients (21.2%) had to permanently discontinue nintedanib due to severe adverse events. In the 6-months follow-up, median decline in %FVC predicted and %DLCO predicted were 1.36 (95%Cl: 0 to 2.97) and 4.00 (95%Cl: 2.01 to 6.20), respectively, when deaths were censored and excluded from the analysis. At 12 months, mean%FVC±SD and mean%DLCo±SD were 64.5 ±â€¯19.1 and 43.7 ±â€¯15.4, respectively. With regards to mortality, 17 patients (18.1%) died over a study period of 730 days. CONCLUSION: Nintedanib demonstrated an acceptable safety and efficacy profile in our real-world observational study. Prospective observational studies in the context of registries that collect well-defined supporting data over time are sorely needed to answer residual questions on drug's performance.

Diagnostic and prognostic challenges in Idiopathic Pulmonary Fibrosis: A patient's "Q and A" approach.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, debilitating disease of unknown etiology that leads to death nearly half of the patients within 3-3.5 years. The past 15 years, the scientific community has made tremendous progress towards standardized diagnostic and prognostic algorithms that led to the generation of the 2011 ATS/ERS/JRS/ALAT guidelines. The latest guidelines provided us with fundamental diagnostic algorithms that set the diagnosis in the majority of cases; however, they leave a significant minority of patients without diagnostic and most importantly, therapeutic umbrella. To this end current guidelines should be revisited in light of research advances, including the tools of "fibromics" and at the same time provide practical guidance to the real-world of IPF in order to address patients' needs. The scope of this review article is to summarize challenges in the everyday IPF clinical practice and make an effort to provide realistic answers to patients' questions.

Lung cancer in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease of unknown etiology. With a gradually increasing worldwide prevalence and a mortality rate exceeding that of many cancers, IPF diagnosis and management are critically important and require a comprehensive multidisciplinary approach. This approach also involves assessment of comorbid conditions, such as lung cancer, that exerts a dramatic impact on disease survival. Emerging evidence suggests that progressive lung scarring in the context of IPF represents a risk factor for lung carcinogenesis. Both disease entities present with major similarities in terms of pathogenetic pathways, as well as potential causative factors, such as smoking and viral infections. Besides disease pathogenesis, anti-cancer agents, including nintedanib, have been successfully applied in the treatment of patients with IPF while an oncologic approach with a cocktail of several pleiotropic anti-fibrotic agents is currently in the therapeutic pipeline of IPF. Nevertheless, epidemiologic association between IPF and lung cancer does not prove causality. Currently there is significant lack of knowledge supporting a direct association between lung fibrosis and cancer reflecting to disappointing therapeutic algorithms. An optimal therapeutic strategy for patients with both IPF and lung cancer represents an amenable need. This review article synthesizes the current state of knowledge regarding pathogenetic commonalities between IPF and lung cancer and focuses on clinical and therapeutic data that involve both disease entities.

Safety and efficacy of pirfenidone in severe Idiopathic Pulmonary Fibrosis: A real-world observational study.

BACKGROUND: Pirfenidone is a novel anti-fibrotic drug that has shown efficacy in five randomized multicenter clinical trials enrolling patients with Idiopathic Pulmonary Fibrosis of mild-to-moderate disease severity. Scarce data supports the use of pirfenidone in IPF patients with more advanced disease. OBJECTIVE: To investigate the safety and efficacy profile of pirfenidone in IPF patients with severe lung function impairment. PATIENTS AND METHODS: This was a retrospective study enrolling patients with advanced IPF (FVC%predicted < 50% and/or (DLco%predicted <35%) receiving pirfenidone for at least 6 months. RESULTS: Between September 2011 and March 2013, we identified 43 patients with severe IPF (baseline meanFVC%predicted±SD: 63.8 ± 20.3, meanDLCO%predicted: 27.3 ± 8.2), of mean age±SD: 66.3 + 9.7, 34 males (81%) that received pirfenidone (2.403 mg/daily) for one year. Pirfenidone treatment was associated with a trend towards decrease in functional decline compared to 6-months before treatment initiation but failed to show any benefit after one year of treatment (ΔFVC: -3.3 ± 4.6 vs 0.49 ± 11.4 and vs. -5.8 ± 11.8, p = 0.06 and p = 0.04, respectively and ΔDLCO: -13.3 ± 15.2 vs. -10.1 ± 16.6 and vs. 28.3 ± 19.2, p = 0.39 and p = 0.002, respectively). Gastrointestinal disorders (34.9%), fatigue (23.2%) and photosensitivity (18.6%) were the most common adverse events. Adverse events led to treatment discontinuation in 9 patients (20.9%) and dose reduction in 14 (32.5%). CONCLUSION: Pirfenidone appears to be safe when administered in patients with advanced IPF. Pirfenidone efficacy in IPF patients with severe lung function impairment may diminish after 6 months of treatment.

Leukemic pulmonary infiltrates in chronic lymphocytic leukemia: Clinical and imaging features.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in Western countries. Although various patterns of lung involvement with CLL have been reported, data on clinicoradiologic presentation are sparse. METHODS: A computer-assisted search was conducted to identify patients encountered at Mayo Clinic from 1998 to 2022 and had leukemic pulmonary infiltrates (LPI) with CLL demonstrated on lung biopsy. Medical records and chest imaging studies were reviewed to identify clinical and radiologic features. RESULTS: Among 13 patients, median age was 77 years (range: 60-88) and included 10 men (77 %). All patients were known to have CLL with a median duration of 96 months (range: 50-408), and none were on treatment. Most common symptoms were dyspnea (62 %), cough (54 %), and fatigue (46 %); 2 patients (15 %) were asymptomatic. Dominant abnormality on CT consisted of single or multiple nodular/mass-like opacities in 10 patients (77 %), while diffuse centrilobular nodules, pleural mass, and diffuse bronchial wall thickening were each seen in one patient, respectively; intrathoracic lymphadenopathy was present in all. After diagnosis of LPI, treatment for CLL was administered to 7 patients (54 %); 6 patients (86 %) exhibited improvement. During follow-up (median 41 months), 8 (62 %) patients died. Causes of death included progressive CLL or treatment-related complications (2 patients), pneumonia (1 patient), unrelated causes (3 patients), and unknown in 2 patients. CONCLUSIONS: LPI in CLL is generally encountered in patients with known untreated CLL. The main imaging feature is single mass-like opacity or multiple nodular/mass-like opacities, associated with intrathoracic lymphadenopathy.