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Treatment with a peroxisomal proliferator activated receptor gamma agonist has a modest effect in the allergen challenge model in asthma: a randomised controlled trial.
PURPOSE: A considerable body of non clinical evidence has accumulated to support peroxisomal proliferator-activated receptor gamma agonists as candidate anti-inflammatory drugs in asthma. We utilized rosiglitazone as a tool compound in the inhaled allergen challenge model of asthma. METHODS: A single centre, double-blind, randomised, placebo controlled, two period cross-over study. Subjects received rosiglitazone 4mg and placebo twice daily for 28 days in random order. On day 28, inhaled allergen challenge was performed 1 hour post-dose. A methacholine challenge was performed on day 29 and an adenosine monophosphate challenge on day 14. Exhaled nitric oxide was measured on days 1, 14, 28, 29. Blood was collected pre dose on days 1, 14 and 28 and analysed for markers associated with PPAR activity and systemic markers of inflammation. RESULTS: The late asthmatic reaction (LAR) change from post saline FEV(1) from 4-10 hrs post allergen on day 28 was statistically significant for the weighted mean LAR. The difference in weighted mean was 0.06 L (95% CI 0.01 to 0.11) which equates to a 15% attenuation of the response during placebo treatment. This was accompanied by trends in other markers of efficacy and anti-inflammatory activity but none were considered major effects. DISCUSSION: Treatment with a PPARgamma agonist (rosiglitazone) was associated with a modest (15%) reduction in the late asthmatic reaction in the allergen challenge model of asthma. Based on the results of this study, PPARgamma agonist monotherapy is unlikely to represent a clinically useful intervention in human asthma. Registered with www.clinicaltrials.gov (NCT00318630).
Repeat doses of antibody to serum amyloid P component clear amyloid deposits in patients with systemic amyloidosis.
Systemic amyloidosis is a fatal disorder caused by pathological extracellular deposits of amyloid fibrils that are always coated with the normal plasma protein, serum amyloid P component (SAP). The small-molecule drug, miridesap, [(R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC)] depletes circulating SAP but leaves some SAP in amyloid deposits. This residual SAP is a specific target for dezamizumab, a fully humanized monoclonal IgG1 anti-SAP antibody that triggers immunotherapeutic clearance of amyloid. We report the safety, pharmacokinetics, and dose-response effects of up to three cycles of miridesap followed by dezamizumab in 23 adult subjects with systemic amyloidosis (ClinicalTrials.gov identifier: NCT01777243). Amyloid load was measured scintigraphically by amyloid-specific radioligand binding of 123I-labeled SAP or of 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid. Organ extracellular volume was measured by equilibrium magnetic resonance imaging and liver stiffness by transient elastography. The treatment was well tolerated with the main adverse event being self-limiting early onset rashes after higher antibody doses related to whole body amyloid load. Progressive dose-related clearance of hepatic amyloid was associated with improved liver function tests. 123I-SAP scintigraphy confirmed amyloid removal from the spleen and kidneys. No adverse cardiac events attributable to the intervention occurred in the six subjects with cardiac amyloidosis. Amyloid load reduction by miridesap treatment followed by dezamizumab has the potential to improve management and outcome in systemic amyloidosis.
Studies in healthy volunteers can demonstrate bronchodilator activity of orally administered drugs.
A panel of healthy volunteers was screened by bronchial histamine provocation. The response used was the flow rate achieved during a partial forced expiratory manoeuvre at a lung volume 30% of the vital capacity above the residual volume. Those subjects who were relatively sensitive to the bronchoconstrictor effects of inhaled histamine took part in a reproducibility study. Those with consistent responses took part in a further study in which the bronchodilator, and bronchoconstriction-protective, effects of orally administered chlorpheniramine, terfenadine and salbutamol were investigated. The technique was able to demonstrate the efficacy of these drugs in non-patient volunteers. Thus it seems to be a suitable method for the early evaluation, in man, of certain drugs with an anti-asthma therapeutic potential. It also provides useful information on the dose and duration of action of compounds prior to the first efficacy trials in patients.
Selective inducible nitric oxide synthase inhibition has no effect on allergen challenge in asthma.
RATIONALE: Exhaled breath nitric oxide (Fe(NO)) is increased in asthma. NO is produced predominantly by inducible nitric oxide synthase (iNOS). OBJECTIVES: We evaluated the selective and potent iNOS inhibitor GW274150 in asthma. METHODS: Twenty-eight steroid-naive patients with asthma participated in a double-blind, randomized, double-dummy, placebo-controlled, three-period cross-over study. Subjects received GW274150 (90 mg), montelukast (10 mg), or placebo once daily for 14 days. Fe(NO) was assessed predose on Days 1, 7, 10, and 14. Adenosine 5'-monophosphate (AMP) challenge was performed on Day 10, allergen challenge on Day 14 followed by methacholine challenge (MCh) 24 hours later, and then bronchoscopy. MEASUREMENTS AND MAIN RESULTS: GW274150 reduced predose Fe(NO) by 73, 75, and 71% on Days 7, 10, and 14, respectively, compared with placebo. Montelukast did not reduce Fe(NO). GW274150 did not inhibit AMP reactivity whereas for montelukast there was a trend toward inhibition: the mean doubling dose difference versus placebo was 0.64 (95% confidence interval [95% CI], 0 to 1.28). GW274150 did not inhibit early (EAR) and late (LAR) asthmatic responses to allergen, or MCh reactivity, despite reduced Fe(NO) levels. Montelukast inhibited EAR and LAR FEV1; the mean difference versus placebo for minimal FEV1 was 0.37 L (95% CI, 0.19 to 0.55) and 0.18 L (95% CI, 0.04 to 0.32), respectively. MCh reactivity was inhibited by montelukast (mean doubling dose difference vs. placebo, 0.51; 95% CI, 0.02 to 1.01). GW271540 also had no effect on inflammatory cell numbers in bronchoalveolar lavage fluid after allergen challenge. CONCLUSIONS: Selective iNOS inhibition effectively reduces Fe(NO) but does not affect airway hyperreactivity or airway inflammatory cell numbers after allergen challenge in subjects with asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00273013).
IRF5 Promotes Influenza Virus-Induced Inflammatory Responses in Human Induced Pluripotent Stem Cell-Derived Myeloid Cells and Murine Models.
Recognition of influenza A virus (IAV) by the innate immune system triggers pathways that restrict viral replication, activate innate immune cells, and regulate adaptive immunity. However, excessive innate immune activation can exaggerate disease. The pathways promoting excessive activation are incompletely understood, with limited experimental models to investigate the mechanisms driving influenza virus-induced inflammation in humans. Interferon regulatory factor 5 (IRF5) is a transcription factor that plays important roles in the induction of cytokines after viral sensing. In an in vivo model of IAV infection, IRF5 deficiency reduced IAV-driven immune pathology and associated inflammatory cytokine production, specifically reducing cytokine-producing myeloid cell populations in Irf5-/- mice but not impacting type 1 interferon (IFN) production or virus replication. Using cytometry by time of flight (CyTOF), we identified that human lung IRF5 expression was highest in cells of the myeloid lineage. To investigate the role of IRF5 in mediating human inflammatory responses by myeloid cells to IAV, we employed human-induced pluripotent stem cells (hIPSCs) with biallelic mutations in IRF5, demonstrating for the first time that induced pluripotent stem cell-derived dendritic cells (iPS-DCs) with biallelic mutations can be used to investigate the regulation of human virus-induced immune responses. Using this technology, we reveal that IRF5 deficiency in human DCs, or macrophages, corresponded with reduced virus-induced inflammatory cytokine production, with IRF5 acting downstream of Toll-like receptor 7 (TLR7) and, possibly, retinoic acid-inducible gene I (RIG-I) after viral sensing. Thus, IRF5 acts as a regulator of myeloid cell inflammatory cytokine production during IAV infection in mice and humans and drives immune-mediated viral pathogenesis independently of type 1 IFN and virus replication.IMPORTANCE The inflammatory response to influenza A virus (IAV) participates in infection control but contributes to disease severity. After viral detection, intracellular pathways are activated, initiating cytokine production, but these pathways are incompletely understood. We show that interferon regulatory factor 5 (IRF5) mediates IAV-induced inflammation and, in mice, drives pathology. This was independent of antiviral type 1 IFN and virus replication, implying that IRF5 could be specifically targeted to treat influenza virus-induced inflammation. We show for the first time that human iPSC technology can be exploited in genetic studies of virus-induced immune responses. Using this technology, we deleted IRF5 in human myeloid cells. These IRF5-deficient cells exhibited impaired influenza virus-induced cytokine production and revealed that IRF5 acts downstream of Toll-like receptor 7 and possibly retinoic acid-inducible gene I. Our data demonstrate the importance of IRF5 in influenza virus-induced inflammation, suggesting that genetic variation in the IRF5 gene may influence host susceptibility to viral diseases.
IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c+ macrophage phenotype
Mononuclear phagocytes (MNPs) play a key role in maintaining intestinal homeostasis but also in triggering immunopathology in response to acute microbial stimulation, which induces the recruitment of masses of Ly6Chi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon Regulatory Factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state, but ameliorates immunopathology during Helicobacter hepaticus induced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single cell RNA-sequencing approaches we compare the differentiation trajectories of wild type and IRF5 deficient monocytes in a shared inflammatory environment and demonstrate that IRF5 stipulates a choice in monocyte differentiation towards macrophages. Specifically, IRF5 promotes the generation of pathogenic CD11c+ macrophages and controls the production of inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional controller of pathogenic monocyte differentiation in the gut.
International league of associations for rheumatology recommendations for the management of psoriatic arthritis in resource-poor settings.
BACKGROUND: Psoriatic arthritis (PsA) is a challenging heterogeneous disease. The European League Against Rheumatism (EULAR) and the Group for Research and Assessment of Psoriasis and PsA (GRAPPA) last published their respective recommendations for the management of PsA in 2015. However, these guidelines are primarily based on studies conducted in resource replete countries and may not be applicable in countries in the Americas (except Canada and USA) and Africa. We sought to adapt the existing recommendations for these regions under the auspices of the International League of Associations for Rheumatology (ILAR). PROCESS: The ADAPTE Collaboration (2009) process for guideline adaptation was followed to adapt the EULAR and GRAPPA PsA treatment recommendations for the Americas and Africa. The process was conducted in three recommended phases: set-up phase; adaptation phase (defining health questions, assessing source recommendations, drafting report), and finalization phase (external review, aftercare planning, and final production). RESULT: ILAR recommendations have been derived principally by adapting the GRAPPA recommendations, additionally, EULAR recommendations where appropriate and supplemented by expert opinion and literature from these regions. A paucity of data relevant to resource-poor settings was found in PsA management literature. CONCLUSION: The ILAR Treatment Recommendations for PsA intends to serve as reference for the management of PsA in the Americas and Africa. This paper illustrates the experience of an international working group in adapting existing recommendations to a resource-poor setting. It highlights the need to conduct research on the management of PsA in these regions as data are currently lacking.Key Points• The paper presents adapted recommendations for the management of psoriatic arthritis in resource-poor settings.• The ADAPTE process was used to adapt existing GRAPPA and EULAR recommendations by collaboration with practicing clinicians from the Americas and Africa.• The evidence from resource-poor settings to answer clinically relevant questions was scant or non-existent; hence, a research agenda is proposed.
Best Practice Framework of Fracture Liaison Services in Spain and their coordination with Primary Care.
The coordination of Fracture Liaison Services (FLS) with Primary Care (PC) is necessary for the continuity of care of patients with fragility fractures. This study proposes a Best Practice Framework (BPF) and performance indicators for the implementation and follow-up of FLS-PC coordination in clinical practice in Spain. PURPOSE: To develop a BPF for the coordination of FLS with PC in Spain and to improve the continuity of care for patients with fragility fractures. METHODS: A Steering Committee selected experts from seven Spanish FLS and related PC doctors and nurses to participate in a best practice workshop. Selection criteria were an active FLS with an identified champion and prior contact with PC centres linked to the hospital. The main aim of the workshop was to review current FLS practices in Spain and their integration with PC. A BPF document with processes, tools, roles, and metrics was then generated. RESULTS: Spanish FLS consists of a multidisciplinary team of physicians/nurses but with low participation of other professionals and PC staff. Evaluation and treatment strategies are widely variable. Four desired standards were agreed upon: (1) Effective channels for FLS-PC communication; (2) minimum contents of an FLS clinical report and its delivery to PC; (3) adherence monitoring 3 months after FLS baseline visit; and (4) follow-up by PC. Proposed key performance indicators are (a) number of FLS-PC communications, including consensus protocols; (b) confirmation FLS report received by PC; (c) medical/nursing PC appointment after FLS report received; and (d) number of training sessions in PC. CONCLUSIONS: The BPF provides a comprehensive approach for FLS-PC coordination in Spain, to promote the continuity of care in patients with fragility fractures and improve secondary prevention. The implementation of BPF recommendations and performance indicator tracking will benchmark best FLS practices in the future.