Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.

IL-33/IL-31 Axis in Immune-Mediated and Allergic Diseases.

Several allergic and immunologic diseases including asthma, food allergy (FA), chronic spontaneous urticaria (CSU), atopic dermatitis (AD), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis (RA), and Behçet's disease (BD) are characterized by the involvement of Th2 immunity. Several mediators lead to immunoglobulin (Ig)E production, thus including key cytokines such as interleukin (IL)-4, IL-5, and IL-13. Among them, IL-31 and IL-33 have been recently studied as novel biomarkers and future therapeutic targets for allergic and immunological disorders. IL-31 is a proinflammatory cytokine-it regulates cell proliferation and is involved in tissue remodeling. IL-33, acting through its receptor suppression of tumorigenity (ST2L), is an alarmin cytokine from the IL-1 family, whose expression is mediated by tissue damage. The latter has a pleiotropic effect, as it may modulate specific and innate immune cells functions. To date, several researchers have investigated the involvement of IL-31 and IL-33 in several allergic and immune-mediated diseases. Further studies are needed to understand the future applications of these molecules as novel therapeutic agents. This paper aims to give the readers a complete and updated review of IL-31 and IL-33 involvement among the most common autoimmune and allergic disorders.

Effects of AntagomiRs on Different Lung Diseases in Human, Cellular, and Animal Models.

INTRODUCTION: MiRNAs have been shown to play a crucial role among lung cancer, pulmonary fibrosis, tuberculosis (TBC) infection, and bronchial hypersensitivity, thus including chronic obstructive pulmonary disease (COPD) and asthma. The oncogenic effect of several miRNAs has been recently ruled out. In order to act on miRNAs turnover, antagomiRs have been developed. MATERIALS AND METHODS: The systematic review was conducted under the PRISMA guidelines (registration number is: CRD42019134173). The PubMed database was searched between 1 January 2000 and 30 April 2019 under the following search strategy: (((antagomiR) OR (mirna antagonists) OR (mirna antagonist)) AND ((lung[MeSH Terms]) OR ("lung diseases"[MeSH Terms]))). We included original articles, published in English, whereas exclusion criteria included reviews, meta-analyses, single case reports, and studies published in a language other than English. RESULTS AND CONCLUSIONS: A total of 68 articles matching the inclusion criteria were retrieved. Overall, the use of antagomiR was seen to be efficient in downregulating the specific miRNA they are conceived for. The usefulness of antagomiRs was demonstrated in humans, animal models, and cell lines. To our best knowledge, this is the first article to encompass evidence regarding miRNAs and their respective antagomiRs in the lung, in order to provide readers a comprehensive review upon major lung disorders.

Update upon efficacy and safety of etanercept for the treatment of spondyloarthritis and juvenile idiopathic arthritis.

TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, ankylosing spondylitis (AS), psoriasis (Ps) and/or psoriatic arthritis (PsA) and may be administered off-label to treat disseminated granuloma annulare, systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. In this article, we discuss the efficacy and safety of etanercept in the treatment of spondyloarthritis and juvenile idiopathic arthritis (JIA). Etanercept is effective in the treatment of PsA, AS, JIA and uveitis. Independent predictors of achieving a sustained clinical improvement or MDA in children with JIA include shorter disease duration, no concurrent oral corticosteroid use, history of chronic anterior uveitis and age <9 years. IBD incidence was lower in patients receiving etanercept plus MTX. Intra-articular administration of etanercept seems to favor a prompt target joint improvement without serious adverse events. Etanercept improve endothelial function reducing the risk of acute cardiovascular and/or cerebrovascular events. The most commonly reported adverse events were nasopharyngitis, epidermal and dermal conditions, upper respiratory tract infection, cough, headache and fatigue.

Pharmacogenetics and future therapeutic scenarios: what affects the prediction of response to treatment with etanercept?

There are five tumor necrosis factor alpha (TNF-α) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of immune-mediated diseases. These include the anti-TNF-α monoclonal antibodies infliximab, adalimumab, golimumab, and certolizumab pegol, and the fusion protein, etanercept. The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to, or toxicities from, TNF-α inhibitors, and could be used to individualize therapy. Several studies have reported associations between genetic polymorphisms and the response to etanercept, but most are small and insufficiently powered to detect effect, and markers tend to be more prognostic than predictive of therapeutic response. Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms (SNPs), genes in linkage with other loci, interaction of environmental factors, and cohort heterogeneity, all of which can complicate the relationship between genetic polymorphisms and treatment response. Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice.

Acute and chronic eosinophilic pneumonia: an overview.

Acute and chronic eosinophilic pneumonia (AEP and CEP) include a group of rare interstitial lung diseases characterized by peripheral blood eosinophilia, increased eosinophils in bronchoalveolar lavage fluid, or eosinophilic infiltration of lung parenchyma. AEP is characterized by rapid onset, fast response to steroid treatment, and no relapse. CEP is characterized by marked tissue and peripheral blood eosinophilia, rapid response to steroid therapy, and tendency to disease recurrence. In addition, we briefly describe other eosinophilic lung diseases that must be considered in differential diagnosis of AEP and CEP. Eosinophilic pneumonias may be idiopathic or due to known causes such as medications or environmental exposure. At variance with previous reviews on this topic, a particular look in this overview was directed at pathological findings and radiological patterns.

A multi-peptide, dual-adjuvant telomerase vaccine (GX301) is highly immunogenic in patients with prostate and renal cancer.

BACKGROUND: Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. OBJECTIVE: The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. EXPERIMENTAL DESIGN: GX301 was administered by intradermally injecting 500 µg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization. RESULTS: No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. CONCLUSION: GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.

Lymphatic microsurgery to treat lymphedema: techniques and indications for better results.

This study aimed to report new clinical approaches to the treatment of lymphatic disorders by microsurgical techniques based on histological and immunohistochemical findings. The authors' wide clinical experience in the treatment of patients with peripheral lymphedema by microsurgical techniques is reported. Microsurgical methods included derivative lymphatic-venous anastomoses and lymphatic reconstruction by interpositioned vein grafted shunts. In all patients, lymphatic and lymph nodal tissues were sent for histological assessment, together with specimen of the interstitial matrix. Diagnostic investigations consisted in venous duplex scan and lymphoscintigraphy. Results were assessed clinically by volumetry performed preoperatively and postoperatively at 3 to 6 months and at 1, 3, and 5 years. The outcome obtained in treating lymphedemas at different stages was analyzed for volume reduction, stability of results with time, reduction of dermatolymphangioadenitis attacks, necessity of wearing elastic supports, and use of conservative measures postoperatively. Microsurgical lymphatic derivative and reconstructive techniques allow bringing about positive results in the treatment of peripheral lymphedema, above all in early stages when tissular changes are slight and allow almost a complete restore of lymphatic drainage.

Early COPD diagnosis and treatment: A case report.

Chronic obstructive pulmonary disease (COPD) refers to a group of widely diffuse diseases that cause airflow blockage characterized by persistent respiratory symptoms such as dyspnea, chronic cough, recurrent wheezing, chronic sputum production, and progressive restricted airflow associated with exacerbations. COPD is the third leading cause of death worldwide and can only be treated not cured. Pulmonary function tests do not permit the identification of initial obstructive airways disease. Forced expiratory flow (FEF25-75), which calculates obstruction severity at small and medium bronchial airways levels, allows an early COPD diagnosis. We report a 72-year-old ex-smoker male not exposed to occupational risk with symptoms suggesting early COPD. Baseline pulmonary function tests were normal, except FEF25-75. The patient did not respond to the first 6 months of treatment with long-acting muscarinic antagonist (LAMA), whereas he showed a clear clinical and FEF25-75 response to 1-year treatment with LAMA associated with long-acting ß2 agonist (LABA). This clinical case report highlights the usefulness of FEF25-75 evaluation in early COPD diagnosis and monitoring and confirms the efficacy of LAMA-LABA association for small airways obstruction treatment.

Stem cells treatment in chronic ischemic heart disease: a narrative review.

Chronic ischemic heart disease remains a major cause of morbidity and mortality worldwide. Several trials have been performed to evaluate benefit of stem cells transplantation to restore cardiac function in short- and long-term period after myocardial infarction. This narrative review analyzes 24 clinical trials between 2005 and 2023 comprising 1824 patients with chronic heart disease without heart failure. Percent increase in left ventricular ejection fraction (LVEF) and decrease in New York Heart Association (NYHA) class at 6/12 months after stem cells transplantation are reported. Thirteen trials showed a statistically significant percent LVEF increase between 4% to 19% at 6/12 months after stem cells transplantation (p values from 0.05 to 0.0001). No significant differences in LVEF were observed between patients who underwent intracoronary or intramyocardial transplantation. NYHA class decrease from severe to mild/moderate was demonstrated in 10 trials reporting a significant LVEF increase. Patients transplanted with bone marrow and peripheral blood CD133+ stem cells showed a doubling of percentage LVEF increase in comparison to patients transplanted with CD133- cells. This narrative review reports the conflicting results on this topic. Multicenter randomized clinical trials should be performed to define the efficacy of stem cells transplantation in chronic ischemic heart disease.

Pulmonary hypertension in systemic sclerosis with usual interstitial pneumonia.

Retrospective study comparing pulmonary hypertension risk in systemic sclerosis (SSc) and non-SSc interstitial lung disease patients with usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). Retrospective analysis of 144 interstitial lung disease patients, 53 SSc (32 UIP and 21 NSIP) and 91 non-SSc (47 UIP and 44 NSIP). Pulmonary hypertension was diagnosed as pulmonary systolic artery pressure (PAPs) > 25 mmHg. All SSc and non-SSc patients with pulmonary hypertension were classified WHO Group 3. Pulmonary hypertension was identified in 21/32 (65.6%), 9/21 (42.8%), 14/47 (29.7%), and 28/44 (45.4%) SSc-UIP, SSc-NSIP, control-UIP, and control-NSIP groups, respectively. PAPs mean of SSc-UIP group was higher than control-UIP group (32.6 ± 9.8 vs 28.5 ± 6.6, p-value = 0.02). PAPs mean of SSc-NSIP group was lower than control-NSIP group (27.0 ± 7.1 vs 33.9 ± 8.8, p = 0.002). Frequency of patients with PAP > 25 mmHg in SSc-UIP group was 60% higher in comparison to control-UIP (OR = 1.62, 95% CI 0.51-5.16) and SSc-NSIP (OR = 1.60, 95% CI 0.45-5.70) groups. Logistic regression analysis estimating the linear trend per ten-unit increase in PAPs levels demonstrated an increment for the SSc-UIP group compared to the control-UIP (OR = 2.64, 95% CI 1.25-5.58, p = 0.01) and the control-NSIP (OR = 6.34, 95% CI 2.82-14.3, p < 0.001) groups. The case-control study confirms that pulmonary hypertension is frequently found in SSc patients and demonstrates, for the first time, a significant increased risk of pulmonary hypertension among SSc-UIP patients.

Systemic sarcoidosis with pituitary adenoma.

Involvement of the nervous system with sarcoidosis is seen clinically in approximately 5-15% of cases. In most cases, lesions are localized to the leptomeninges and cranial nerves, and rarely to the pituitary gland, leading to endocrinologic abnormalities. We report on an original clinical case demonstrating the effectiveness of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) scan in the diagnosis and monitoring of systemic sarcoidosis with probable pituitary involvement.

In-111 octreotide SPECT/CT in the early diagnosis of pulmonary sarcoidosis: A case report.

Sarcoidosis is a granulomatous disease of unknown etiology. At present the best diagnostic imaging procedure to assess stage and activity of sarcoidosis is controversial. We report the case of a 50-year-old male admitted with a history of dyspnea and fatigue with past medical history negative for smoking, occupational and environmental risk factors. Physical examination, routine blood tests, and pulmonary function tests were normal except for hypercalciuria. A chest radiograph showed bilateral hilar lymphadenopathy. Single photon emission computed tomography and/or computed tomography (SPECT and/or CT) In-111 Octreotide (Octreoscan) scintigraphy confirmed morphologic involvement of bilateral hilar lymph nodes and a mediastinoscopy biopsy specimen provided diagnosis of pulmonary sarcoidosis (stage 0). This clinical case shows the effectiveness of In-111 Octreotide SPECT and/or CT in the early diagnosis of pulmonary sarcoidosis.

Sjögren's syndrome: a systemic autoimmune disease.

Sjögren's syndrome is a chronic autoimmune disease characterized by ocular and oral dryness resulting from lacrimal and salivary gland dysfunction. Besides, a variety of systemic manifestations may occur, involving virtually any organ system. As a result, the disease is characterized by pleomorphic clinical manifestations whose characteristics and severity may vary greatly from one patient to another. Sjögren's syndrome can be defined as primary or secondary, depending on whether it occurs alone or in association with other systemic autoimmune diseases, respectively. The pathogenesis of Sjögren's syndrome is still elusive, nevertheless, different, not mutually exclusive, models involving genetic and environmental factors have been proposed to explain its development. Anyhow, the emergence of aberrant autoreactive B-lymphocytes, conducting to autoantibody production and immune complex formation, seems to be crucial in the development of the disease. The diagnosis of Sjögren's syndrome is based on characteristic clinical signs and symptoms, as well as on specific tests including salivary gland histopathology and autoantibodies. Recently, new classification criteria and disease activity scores have been developed primarily for research purposes and they can also be useful tools in everyday clinical practice. Treatment of Sjögren's syndrome ranges from local and symptomatic therapies aimed to control dryness to systemic medications, including disease-modifying agents and biological drugs. The objective of this review paper is to summarize the recent literature on Sjögren's syndrome, starting from its pathogenesis to current therapeutic options.

HLA-G in Allergy: Does It Play an Immunoregulatory Role?

Allergy is an inflammatory process determined by a cascade of immune events characterized by T-helper 2 lymphocytes polarization leading to interleukin-4 upregulation, IgE secretion, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, are known to play a key immunoregulatory role and their involvement in allergic diseases is supported by increasing literature data. HLA-G expression and secretion is specifically induced in peripheral blood mononuclear cells of allergic patients after in vitro incubation with the causal allergen. Elevated levels of soluble HLA-G molecules are detected in serum of patients with allergic rhinitis correlating with allergen-specific IgE levels, clinical severity, drug consumption and response to allergen-specific immunotherapy. HLA-G genetic polymorphisms confer susceptibility to allergic asthma development and high levels of soluble HLA-G molecules are found in plasma and bronchoalveolar lavage fluid of patients with allergic asthma correlating with allergen-specific IgE levels. Interestingly, allergic pregnant women have lower plasma sHLA-G levels than non-allergic women during the 3rd trimester of pregnancy and at delivery. Finally, in allergic patients with atopic dermatitis HLA-G molecules are expressed by T cells, monocytes-macrophages and Langerhans cells infiltrating the dermis. Although at present is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are specifically expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation.

HLA-G Expressing Immune Cells in Immune Mediated Diseases.

HLA-G is a HLA class Ib antigen that possesses immunomodulatory properties. HLA-G-expressing CD4+ and CD8+ T lymphocytes, NK cells, monocytes, and dendritic cells with immunoregulatory functions are present in small percentages of patients with physiologic conditions. Quantitative and qualitative derangements of HLA-G+ immune cells have been detected in several conditions in which the immune system plays an important role, such as infectious, neoplastic, and autoimmune diseases as well as in complications from transplants and pregnancy. These observations strongly support the hypothesis that HLA-G+ immune cells may be implicated in the complex mechanisms underlying the pathogenesis of these disorders.

Diagnosis of an unusual case of idiopathic mediastinal fibrosis by 18F-FDG PET/CT.

Diagnosis of idiopathic mediastinal fibrosis was done by exclusion in a 54-year-old woman with dyspnoea, chest pain, cough and fatigue showing positivity of 2-deoxy-2-[18F]fluoro-D-glucose positron-emission tomography/computed tomography total body imaging which turned out to normal after six and eighteen months of prednisone and pirfernidone treatment.

Expression of membrane-bound human leucocyte antigen-G in systemic sclerosis and systemic lupus erythematosus.

Human leucocyte antigen-G (HLA-G) is a nonclassical class I major histocompatibility complex (MHC) molecule characterized by complex immunoregulatory and tolerogenic functions. Membrane-bound HLA-G is expressed on the surface of different cell populations in both physiological and pathological conditions. Systemic sclerosis (SSc) is a multisystem autoimmune disease characterized by widespread tissue fibrosis, vascular lesions and immunological alterations. Systemic lupus erythematosus is the prototypic systemic autoimmune disease affecting virtually any organ system, such as skin, joints, central nervous system, or kidneys. In SSc and SLE patients, the membrane expression of HLA-G on monocytes (0.88 ± 1.54 and 0.43 ± 0.75, respectively), CD4+ (0.42 ± 0.78 and 0.63 ± 0.48, respectively), CD8+ (2.65 ± 3.47 and 1.29 ± 1.34, respectively) and CD4+ CD8+ double-positive cells (13.87 ± 15.97 and 3.79 ± 3.11, respectively) was significantly higher than in healthy controls (0.12 ± 0.07; 0.01 ± 0.01; 0.14 ± 0.20 and 0.32 ± 0.38, respectively) (p < 0.0001). Our results show that in SSc and SLE the membrane expression of HLA-G by different subpopulations of peripheral blood mononuclear cells (PBMC) is increased, suggesting a potential role of HLA-G molecules in the complex immunological pathogenesis of these two autoimmune disorders.

Neutrophil Extracellular Traps Profiles in Patients with Incident Systemic Lupus Erythematosus and Lupus Nephritis.

OBJECTIVE: Neutrophil extracellular traps (NET) expose modified antigens for autoantibodies in vasculitis. Little is known about levels and removal pathways of NET in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). We determined circulating levels and defined NET removal in large subsets of patients with incident SLE (iSLE), some of whom had new-onset nephritis. METHODS: Serum levels of NET (ELISA), DNase1/DNase1L3 (ELISA), and DNase activity (functional assay) were determined in 216 patients with iSLE [103 had incident LN (iLN)], in 50 patients with other primary glomerulonephritis, and in healthy controls. Ex vivo NET production by neutrophils purified from a random selection of patients was quantified as elastase/DNA release and by immunofluorescence techniques. RESULTS: Serum NET levels were very high in iSLE/iLN compared to all groups of controls and correlated with anti-dsDNA, C3-C4, and proteinuria; iLN had the highest levels. DNase activity was decreased in iLN compared to SLE (20% had one-half DNase activity) despite similar serum levels of DNase1/DNase1L3. In these cases, pretreatment of serum with protein A restored DNase efficiency; 1 patient was homozygous for a c.289_290delAC variant of DNASE1L3. Ex vivo NET production by neutrophils purified from LN, SLE, and normal controls was similar in all cases. CONCLUSION: Patients with iLN have increased circulating NET and reduced DNase activity, the latter being explained by the presence of inhibitory substances in circulation and/or by rare DNase1L3 mutations. Accumulation of NET derives from a multifactorial mechanism, and is associated and may contribute to disease severity in SLE, in particular to renal lesions. (Clinical trial registration: The Zeus study was registered at ClinicalTrials.gov, study number NCT02403115).