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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EGlucocorticoids (corticosteroids; steroids) are among the world\u0027s most widely prescribed drugs. They are effective in many inflammatory and immune diseases, but they also fail in some seemingly similar diseases. This article discusses new approaches to deal with steroid resistance.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERheumatology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EInflammatory Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EPeter J. Barnes, DM, DSc, National Heart and Lung Institute, Imperial College, London, United Kingdom, spoke about how steroids suppress inflammation, why in some diseases there is variability of response, and what new approaches are on the horizon to deal with steroid resistance.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003EGlucocorticoids (corticosteroids; steroids) are among the world\u0027s most widely prescribed drugs. They are effective in many inflammatory and immune diseases, but they also fail in some seemingly similar diseases. Understanding why this happens requires an understanding of the inflammatory process.\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003EInflammation involves the increased expression of many inflammatory proteins (eg, cytokines, chemokines, enzymes, receptors, and adhesion molecules), most of which are regulated by transcription through the activation of proinflammatory transcription factors. The genes are switched on through acetylation of core histones and remodeling of the chromatin structure to allow active gene transcription. Steroids work by suppressing this process. They block transcription of inflammatory genes by reversing histone acetylation.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EInflammatory gene activation can be reversed through histone deacetylation. There are 11 histone deacetylases (HDACs) in humans. Although all 11 HDACs reverse histone acetylation and switch off gene transcription, only HDAC-2 switches off inflammatory genes. HDAC-2 is also heavily recruited by corticosteroid receptors into activated inflammatory genes to mediate suppression of inflammation by steroids [Ito K et al. \u003Cem\u003EMol Cell Biol\u003C\/em\u003E. 2000]. Both asthma and chronic obstructive pulmonary disease (COPD) are associated with airway inflammation characterized by inflammatory gene expression that is driven by proinflammatory transcription factors. Asthma is extremely sensitive to steroids, and in most patients it can be controlled by very low doses. By contrast, COPD is completely resistant to steroids. Corticosteroid resistance is also a major barrier to therapy for a number of other severe inflammatory diseases, including severe rheumatoid arthritis (RA), inflammatory bowel disease, diabetes, atherosclerosis, and multiple sclerosis.\u003C\/p\u003E\n         \u003Cp id=\u0022p-6\u0022\u003EAlveolar macrophages from nonsmokers, smokers, and patients with COPD show significantly different levels of HDAC activity with markedly lower levels in smokers and COPD patients [Ito K et al. \u003Cem\u003EFASEB J.\u003C\/em\u003E 2001]. An examination of the lungs of patients with COPD found the expression of HDAC-2 to be extremely reduced with corresponding increases in interleukin (IL)-8 and marked increases in histone acetylation of IL-8 genes, which correlated with a reduction in HDAC-2 [Ito K et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2005].\u003C\/p\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EUnlike in nonsmoking asthma patients, in whom inflammation is switched off through recruitment of HDAC-2, leading to suppression of inflammatory genes, in smoking asthma patients, oxidative stress generates peroxynitrate, which reduces HDAC-2, leaving these patients resistant to steroids. These patients have enhanced inflammation, which is why they have more severe or refractory disease. Inhibition of oxidative stress-dependent PI3 kinase delta (PI3K-\u03b4) activation by a selective inhibitor or theophylline provides a novel approach to reversing corticosteroid insensitivity in COPD [To Y et al. \u003Cem\u003EAm J Resp Crit Care Med.\u003C\/em\u003E 2010].\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003ETheophylline activates HDAC, markedly potentiates steroid effects, and reverses steroid resistance [Cosio BG et al. \u003Cem\u003EJ Exp Med.\u003C\/em\u003E 2004; Ito K et al. \u003Cem\u003EPNAS\u003C\/em\u003E. 2002] by directly targeting PI3K-\u03b4 (which is increased in COPD) and reducing its enzyme activity [To Y et al. \u003Cem\u003EAm J Resp Crit Care Med.\u003C\/em\u003E 2010]. Other drugs that can also inhibit this pathway include nortriptyline, macrolide antibiotics (like solithromycin), and selective PI3K-\u03b4 inhibitors, as well as drugs that work further down the pathway.\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003ENrF2 is a key transcription factor that regulates oxidative stress through the regulation of multiple antioxidant genes [Ishii Y et al. \u003Cem\u003EJ Immunol\u003C\/em\u003E. 2005; Rangasamy T et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2004]. NrF2 is increased in smokers due to the oxidative stress, but in COPD patients, who have even more oxidative stress, it is not increased because it becomes acetylated. The key regulator of this acetylation is HDAC-2 [Malhotra D. \u003Cem\u003EAm J Resp Crit Care Med.\u003C\/em\u003E 2008]. When HDAC-2 is reduced by oxidative stress, it leads to acetylation of NrF2, which impairs its transcriptional activation properties, leading to reduced expression of antioxidants, which further enhances oxidative stress, driving this inflammatory pathway.\u003C\/p\u003E\n         \u003Cp id=\u0022p-10\u0022\u003EThis can be overcome by drugs that activate NrF2, some of which are naturally occurring substances like sulforaphane (found in broccoli). In COPD macrophages exposed to sulforaphane, the HDAC levels are increased, approaching normal [Malhotra D et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2011]. Sulforaphane is rather toxic and nonspecific, so investigators are searching for more effective NrF2 activators.\u003C\/p\u003E\n         \u003Cp id=\u0022p-11\u0022\u003EThe fact that steroids do not work very well in COPD and severe asthma has led to the search for new anti-inflammatory treatments such as PDE4 inhibitors, sp38 MAP kinase inhibitors, IKK-2 (NF-\u03baB) inhibitors, and pan-JAK inhibitors. Some of these are likely also being considered for RA, but there is a high risk of side effects, and thus inhaled delivery may be needed.\u003C\/p\u003E\n         \u003Cp id=\u0022p-12\u0022\u003EProf Barnes proposes an alternative approach to addressing corticosteroid resistance, which is to restore steroid sensitivity. He suggests that this could be done by repurposing existing therapies, including low-dose oral theophylline, oral nortriptyline, or macrolides, or by developing new therapies, which could include inhaled P13K\u03c3, P13K\u03b3\/\u03c3, or nonantibiotic macrolides. He believes that these studies could move ahead quickly because some of the drugs are already available and in some cases they are inexpensive. Two large long-term controlled trials with theophylline in COPD are underway: the TWICS study [\u003Ca href=\u0022\/external-ref?link_type=ISRCTN\u0026amp;access_num=ISRCTN27066620\u0022 class=\u0022external-ref external-ref-type-isrctn\u0022\u003EISRCTN27066620\u003C\/a\u003E] using low-dose oral theophylline (plasma concentration of about 5 mg\/L) plus low-dose inhaled steroid, and the TASCS study [\u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT02261727\u0026amp;atom=%2Fspmdc%2F14%2F51%2F4.atom\u0022\u003ENCT02261727\u003C\/a\u003E] with low-dose oral theophylline plus low-dose oral steroid (prednisone 5 mg). These findings may have clinically relevant applications in rheumatology.\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/51\/4\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The editors would like to thank the many members of the 2014 American College of Rheumatology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-746657837\u0022 data-figure-caption=\u0022The editors would like to thank the many members of the 2014 American College of Rheumatology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure1\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/51\/4\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/51\/4\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure1\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/51\/4\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/15622\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n               \u003Cp id=\u0022p-13\u0022 class=\u0022first-child\u0022\u003EThe editors would like to thank the many members of the 2014 American College of Rheumatology presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/51\/4.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzodp2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzodp2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}