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.

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.

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.

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.

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 the infection risk in patients receiving TNF alpha inhibitors.

INTRODUCTION: TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory drugs or DMARDs in the treatment of chronic immune-mediated diseases. AREAS COVERED: Patients receiving TNF-α inhibitors are at high risk of infections. An update is made on the risk of infection in patients receiving TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events. EXPERT OPINION: Infliximab than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis infection and the overall risk of opportunistic infections should be considered before beginning a course of TNF-α inhibitors. A careful medical history, Mantoux test/quantiferon-TB Gold In-tube Test and chest-X-ray should always be performed before starting TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitors treatment. Finally, appropriate vaccinations for influenza, S. pneumoniae, and HBV should be administered to decrease the risk of infection, and patients who are at high risk of herpes zoster reactivation would benefit from a second vaccination in adulthood.

HLA-G expression in gastric carcinoma: clinicopathological correlations and prognostic impact.

To analyze expression of human leukocyte antigen-G (HLA-G) in gastric adenocarcinoma and correlate its expression with histological and clinical variables. A continuous series of 94 unselected patients with gastric adenocarcinoma (stage I to III) were selected. All histological and clinical variables were collected including the intensity of intra- and peri-tumor lymphocytic infiltration. HLA-G expression was investigated using immunohistochemistry. All histological samples analyzed for HLA-G expression were taken from the primary gastric lesion and included non-neoplastic mucosa. Evaluation of HLA-G expression was performed on the transition zone between tumor and non-neoplastic mucosa, and the invasive front of the tumor and assessment was performed as follows: percentage of positive (strong expression vs weak) cells. A variable amount of HLA-G-positive tumor cells was found in 24 out of 94 cases (25.5%). No significant correlation was found between HLA-G expression and other clinicopathological variables (sex, age, stage, grade, histotype). The overall median survival was worse in patients with HLA-G-positive adenocarcinoma (24.3 months, CI95% 7.7-41.0) compared to those with HLA-G-negative tumors (66.3 months, CI95% 53.0-79.7; p < 0.0001). Two- and 5-year survival rates of HLA-G-negative patients were 88 and 44%, respectively, while were 42 and 11% in those HLA-G-positive. This trend was observed in all stages but was more marked in stage III. HLA-G expression is associated with poor survival in stage III gastric cancer patients and represents a possible immunoescape mechanism of cancer cells.

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.

Impact of pharmacogenomics upon the therapeutic response to etanercept in psoriasis and psoriatic arthritis.

INTRODUCTION: 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. Etanercept is a decoy receptor" for TNF-α and it is composed of two p75 TNF-α receptors fused to human IgG1. Areas covered: We discuss the potential role of pharmacogenetics in predicting the response to etanercept in patients with Ps and PsA. Expert opinion: Pharmacogenetics represents the new frontier for the discovery of potential genetic markers of biological response to TNF-α inhibitors. Clinical studies showed that TNF-α -308 G/G, +489 GG and the +489 GA, TNF-α -857C (rs1799724), TNFRSF1B 676T (rs1061622), TNFAIP3 G SNP (rs610604), FcγRIIIA-V158F, HLA-C*06, IL-17 A (rs2275913 and rs10484879), IL-17F (rs763780) and IL17RA (rs4819554) SNPs favor the response to etanercept. However, most of these studies are often small and not sufficiently powered to detect an effect and markers tend to be more prognostic than predictive of therapeutic response. Furthermore, studies often examines only the effects of a single SNP, while it would be more useful to analyze more haplotypes in contemporary in the same patients. Appropriately designed clinical trials are needed before a pharmacogenetic approach may be applicable in daily clinical therapeutic practice.

Behavior of soluble HLA-A, -B, -C and HLA-G molecules in patients with chronic hepatitis C virus infection undergoing pegylated interferon-α and ribavirin treatment: potential role as markers of response to antiviral therapy.

The serum levels of soluble HLA class I antigens (sHLA-A, -B, -C and sHLA-G) were determined in 40 HCV genotype 1-infected patients before (T 0), after 3, 6, and 12 months (T 3, T 6, and T 12) of pegylated-IFN-α plus ribavirin therapy and 6 months (T 18) after the end of treatment. Twenty patients were sustained virological responders (SVR), and 20 were non-responders (NR). sHLA-A, -B, -C levels at T 0 were significantly higher in both SVR (mean 10.48 µg/ml) and NR (mean 11.87 µg/ml) patients as compared to healthy controls (mean 0.34 µg/ml, p < 0.0001) and HIV-infected subjects (mean 1.22 µg/ml, p < 0.0001). sHLA-G levels at T 0 were significantly higher in SVR (mean 24.78 ng/ml) and NR (mean 24.93 ng/ml) patients as compared to healthy controls (mean 10.34 ng/ml, p = 0.015 and p = 0.014, respectively) but were lower as compared to HIV-infected subjects (mean 48.00 ng/ml, p < 0.0001). The levels of sHLA-A, -B, -C and sHLA-G significantly decreased in SVR from T 0 to T 18 (mean 1.64 and 1.43 ng/ml, respectively, p < 0.0001) and correlated with HCV-RNA, AST, ALT, γGT, and ALP levels. The determination of soluble HLA class I levels could be proposed as a surrogate marker to discriminate SVR and NR HCV-infected patients during PEG-IFN-α plus ribavirin therapy.

Genetic factors and systemic sclerosis.

Systemic sclerosis (SSc) is a rare connective tissue disease of unknown etiology characterized by chronic inflammation and fibrosis of the skin, vascular abnormalities, and variable involvement of organs including kidneys, gastrointestinal tract, heart, and lungs. SSc shows a complex etiology in which both environmental and genetic factors seem to influence the onset and outcome of the disease. We provide an extensive overview of the genetic factors and epigenetic modifications and what their knowledge has revealed in terms of etiopathogenesis of SSc.

Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety?

INTRODUCTION: TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis and/or psoriatic arthritis, 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. AREAS COVERED: infliximab and adalimumab can induce the development of anti-infliximab (anti-IFX) and anti-adalimumab (anti-ADA) monoclonal antibodies (mAbs). In this review, we discuss the impact of anti-IFX and anti-ADA mAbs upon efficacy and safety of these biological agents. EXPERT OPINION: IgG/IgE neutralizing antibodies against infliximab and adalimumab decrease the possibility of achieving a minimal disease activity state or clinical remission, decrease drug survival, increase the need for doctors to prescribe a higher drug dosage and, finally, favor the occurrence of adverse events. Concomitant administration of DMARDs such as methotrexate or leflunomide prevents the development of neutralizing Abs against infliximab and adalimumab.

Autoimmune central diabetes insipidus in a patient with ureaplasma urealyticum infection and review on new triggers of immune response

Diabetes insipidus is a disease in which large volumes of dilute urine (polyuria) are excreted due to vasopressin (AVP) deficiency [central diabetes insipidus (CDI)] or to AVP resistance (nephrogenic diabetes insipidus). In the majority of patients, the occurrence of CDI is related to the destruction or degeneration of neurons of the hypothalamic supraoptic and paraventricular nuclei. The most common and well recognized causes include local inflammatory or autoimmune diseases, vascular disorders, Langerhans cell histiocytosis (LCH), sarcoidosis, tumors such as germinoma/craniopharyngioma or metastases, traumatic brain injuries, intracranial surgery, and midline cerebral and cranial malformations. Here we have the opportunity to describe an unusual case of female patient who developed autoimmune CDI following ureaplasma urealyticum infection and to review the literature on this uncommon feature. Moreover, we also discussed the potential mechanisms by which ureaplasma urealyticum might favor the development of autoimmune CDI.

Autoimmune central diabetes insipidus in a patient with ureaplasma urealyticum infection and review on new triggers of immune response.

Diabetes insipidus is a disease in which large volumes of dilute urine (polyuria) are excreted due to vasopressin (AVP) deficiency [central diabetes insipidus (CDI)] or to AVP resistance (nephrogenic diabetes insipidus). In the majority of patients, the occurrence of CDI is related to the destruction or degeneration of neurons of the hypothalamic supraoptic and paraventricular nuclei. The most common and well recognized causes include local inflammatory or autoimmune diseases, vascular disorders, Langerhans cell histiocytosis (LCH), sarcoidosis, tumors such as germinoma/craniopharyngioma or metastases, traumatic brain injuries, intracranial surgery, and midline cerebral and cranial malformations. Here we have the opportunity to describe an unusual case of female patient who developed autoimmune CDI following ureaplasma urealyticum infection and to review the literature on this uncommon feature. Moreover, we also discussed the potential mechanisms by which ureaplasma urealyticum might favor the development of autoimmune CDI.

Infection risk associated with anti-TNF-α agents: a review.

INTRODUCTION: TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of chronic immune-mediated diseases. TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs (DMARDs) to treat chronic immune-mediated diseases. AREAS COVERED: Patients receiving TNF-α inhibitors are at high risk of infections. Based on our experience, in this paper, we discuss the risk of infections associated with the administration of TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events. EXPERT OPINION: Infliximab more so than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis (LTB) infection and the overall risk of opportunistic infections should be considered before beginning TNF-α inhibitor therapy. A careful medical history, Mantoux test and chest-x-ray should always be performed before prescribing TNF-α inhibitors. Particular attention should be paid to risk factors for Pneumocystis jirovecii infection. Hepatitis B and C virological follow-up should be considered during TNF-α inhibitor treatment. Finally, patients who are at high risk of herpes zoster (HZ) reactivation would benefit from a second vaccination in adulthood when receiving TNF-α inhibitors.

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.