Impact of COPD Exacerbations and Burden of Disease in Spain: AVOIDEX Study.

Purpose: Chronic obstructive pulmonary disease (COPD) is characterized by high morbidity and mortality, with a considerable consumption of healthcare resources (HRU). This study aims to obtain real world evidence regarding the consequences of COPD exacerbations and to provide updated data on the burden of this disease and its treatment. Patients and Methods: A retrospective study in seven Spanish regions was conducted among COPD patients diagnosed between 1/01/2010 and 31/12/2017. The index date was the diagnosis of COPD and patients were followed until lost to follow-up, death or end of the study, whichever occurred first. Patients were classified by patient pattern (incident or prevalent), type and severity of exacerbations, and treatments prescribed. Demographic and clinical characteristics were evaluated, together with the incidence of exacerbations, comorbidities, and the use of HRU, during the baseline (12 months before the index date) and the follow-up periods by incident/prevalent and treatment prescribed. Mortality rate was also measured. Results: The study included 34,557 patients with a mean age of 70 years (standard deviation: 12). The most frequent comorbidities were diabetes, osteoporosis, and anxiety. Most patients received inhaled corticosteroids (ICS) with long-acting beta agonists (LABA), or long-acting muscarinic agonists (LAMA), followed by LABA with LAMA. Incident patients (N=8229; 23.8%) had fewer exacerbations than prevalent patients (N=26328; 76.2%), 0.3 vs 1.2 exacerbations per 100 patient-years. All treatment patterns present a substantial disease burden, which seems to increase with the evolution of the disease (ie moving from initial treatments to combination therapies). The overall mortality rate was 40.2 deaths/1000 patient-years. General practitioner visits and tests were the HRU most frequently required. The frequency and severity of exacerbations positively correlated with the use of HRU. Conclusion: Despite receiving treatment, patients with COPD suffer a considerable burden mainly due to exacerbations and comorbidities, which require a substantial use of HRU.

Efficacy and safety of lesinurad for the treatment of hyperuricemia in gout.

The aim of this review is to present current evidence about the efficacy and safety of lesinurad in combination with xanthine oxidase inhibitors (XOIs) in the treatment of hyperuricemia in patients with gout. Gout is the most common inflammatory form of arthritis. It is caused by an elevated concentration of serum uric acid (UA) that leads to the formation of monosodium urate crystals in joints and different tissues. The goal of therapy is to maintain serum UA levels at <6 mg/dL (0.36 mmol/L), to prevent the formation and deposition of monosodium urate crystals, and to dissolve existing crystals. Lesinurad, a new uricosuric, increases renal urate excretion by selectively inhibiting the renal uric acid transporter 1 (URAT1). Lesinurad is indicated in adults, in combination with a XOI, for the adjunctive treatment of hyperuricemia in patients with gout (with or without tophi) who have not achieved target serum UA levels with an adequate dose of a XOI alone. With the combination strategy, serum UA targets could be reached with the consequence of inhibiting formation of new crystals and promoting dissolution of existing crystals and, therefore, inducing improvement of outcomes such as flares and tophi. The approval of lesinurad was based on data from three pivotal phase III studies (CLEAR 1, CLEAR 2, and CRYSTAL). These clinical studies assessed lesinurad 200 and 400 mg doses. As only lesinurad 200 mg/day dose was finally approved and commercialized, it will be the focus of this paper. In the pivotal clinical trials, the target serum UA level was achieved by significantly more patients in lesinurad 200 mg plus allopurinol group (CLEAR 1 and CLEAR 2 trials) or lesinurad 200 mg plus febuxostat group (CRYSTAL study) compared with patients who received either XOI alone. In these trials, the safety profile of lesinurad 200 mg plus a XOI was comparable to allopurinol or febuxostat alone. Lesinurad, in combination with a XOI, is an effective and safe treatment that covers unmet needs in adults with gout who have not achieved target serum UA levels with a XOI alone.

Genetically engineered elastin-like polymer as a substratum to culture cells from the ocular surface.

PURPOSE: To investigate epithelial cell adhesion and proliferation on a newly developed elastin-like polymer (ELP) that mimics the functional characteristics of extracellular matrices. MATERIALS AND METHODS: A genetically engineered ELP with cell attachment sequences was adsorbed onto glass coverslips as 1, 2, or 3 molecular films. Conjunctival epithelial cells from a human cell line and human skin fibroblast cells (as controls) were plated onto coverslips with three different substrata: plain glass, Thermanox, and ELP-coated. Cells (10(4)) were plated after EDTA- or trypsin-based detachment. To test adhesion, epithelial and fibroblast cells were incubated for 4 hr, stained with hematoxylin, and counted. To study proliferation, Ki-67-positive epithelial cells were counted after 1, 3, and 5 days in culture. Immunostaining for conjunctival and adhesion markers was performed. RESULTS: Epithelial cell, but not fibroblast, adhesion on ELP was significantly enhanced compared to that of control substrata. Epithelial cells detached with EDTA alone adhered significantly better than those detached with trypsin. By day 5, epithelial cell proliferation on ELP was significantly greater than that on plain glass. Epithelial cells grown on ELP expressed conjunctival and adhesion markers. CONCLUSIONS: The recombinant ELP resembling the ocular surface extracellular matrix was a suitable substratum to sustain epithelial cell attachment and growth. This type of polymer may be suitable for tissue engineering to restore vision by reconstructing the ocular surface.

Expression of muscarinic and adrenergic receptors in normal human conjunctival epithelium.

PURPOSE: To study the presence of muscarinic and alpha- and beta-adrenergic receptors in a normal human conjunctival epithelial (IOBA-NHC) cell line. METHODS: Neurotransmitter receptors were determined in IOBA-NHC cells by flow cytometry, immunofluorescence, and Western blot analysis. Antibodies to M(1)-, M(2)-, and M(3)-muscarinic and to alpha(1A)-, alpha(1B)-, alpha(1D)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, beta(2)-, and beta(3)-adrenergic receptor subtypes were used. Different culture media were tested, including the addition of tumor necrosis factor (TNF)-alpha and/or interferon (IFN)-gamma. Normal human conjunctiva biopsy specimens and rat tissues were used in control experiments. RESULTS: By immunofluorescence microscopy, all receptor subtypes, except the alpha(2C)-adrenergic receptor, were detected in control biopsy specimens. By flow cytometry, the M(2)- and M(3)-muscarinic receptors and alpha(1A)-, alpha(1B)-, alpha(1D)-, alpha(2A)-, alpha(2B)-, alpha(2C)-, beta(1)-, and beta(3)-adrenergic receptors were detected intracellularly and in cell membranes of the IOBA-NHC cells. M(1)-muscarinic and beta(2)-adrenergic receptors were detected only intracellularly, but were mobilized to the cell membrane when cholera toxin and hydrocortisone were omitted from the culture medium. Confocal microscopy detected the M(2) and M(3)-muscarinic and alpha(1A)-, alpha(2A)-, alpha(2B)-, beta(1)- and beta(2)-adrenergic receptor subtypes. Western blot analyses showed bands for all receptors. M(2)-muscarinic and alpha(1B)- and alpha(2B)-adrenergic receptors expression was upregulated when cells were treated with the proinflammatory cytokines IFN gamma and/or TNF alpha. CONCLUSIONS: The IOBA-NHC cell line maintained expression of the neurotransmitter receptors expressed in normal human conjunctival epithelium. A proinflammatory medium upregulated expression of some receptors. Although the functional state of these receptors is unknown, these findings justify further use of the IOBA-NHC cell line to study the neural component of conjunctival inflammation.

Variation in the expression of inflammatory markers and neuroreceptors in human conjunctival epithelial cells.

The purpose of this research was to investigate the role of neurogenic involvement in the etiopatho-genesis of ocular surface inflammation, with the final goal of identifying new potential anti-inflammatory agents. We describe the presence of two "classic" markers of inflammation (HLA-DR and ICAM-1) and some neuroreceptors in cultured human conjunctival epithelial cells under basal and pro-inflammatory conditions. Two markers of inflammation (HLA-DR, ICAM-1) and several neuroreceptor subtypes (M1-, M2-, and M3-muscarinic; alpha1A-, alpha1B-, alpha1D-, alpha2A-, alpha2B-, alpha2C-, beta1-, beta2-, and beta3-adrenergic) were analyzed in a normal human conjunctival epithelial cell line (IOBA-NHC). These markers were studied in basal conditions and under the influence of two pro-inflammatory cytokines: tumor necrosis factor alpha (TNF-alpha) and/or interferon gamma (IFN-gamma). Immunofluorescence (confocal microscopy), western blotting, or flow cytometry techniques were used. In basal conditions, epithelial cells expressed all inflammatory markers except HLA-DR. The addition of IFN-gamma enhanced expression of HLA-DR, ICAM-1, and M2-muscarinic receptor. TNF-alpha up-regulated the expression of ICAM-1. When epithelial cells were incubated in the presence of both cytokines together, the cell surface expression of HLA-DR, ICAM-1, alpha1B-, and alpha2B-adrenergic receptors was increased. Cultured human conjunctival epithelial cells have been shown to be susceptible to up-regulation of the expression of inflammatory markers and cell membrane expression of some neuroreceptors under pro-inflammatory conditions. Consequently, pharmacologic neuro-modulation could have a role in the comprehensive management of ocular surface inflammation.