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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">A disease has two different&#44; independent&#44; but interrelated dimensions&#58; the clinical manifestations and the biological activity&#46; An asthmatic is controlled if the disease does not manifest itself clinically&#44; and asthma is in remission if there is no bronchial hyperresponsiveness &#40;BHR&#41; and inflammation &#40;the two determinants of asthma pathophysiology&#41;&#46; There may be patients who have controlled clinical manifestations but in whom disease activity persists and&#44; conversely&#44; there may be patients in remission&#44; without disease activity&#44; but with clinical manifestations &#40;e&#46;g&#46; due to non-reversible bronchial obstruction&#41;&#46; Remission is a concept imported from other inflammatory diseases &#40;rheumatoid arthritis&#44; inflammatory bowel disease&#44; etc&#46;&#41; and it has been gaining prominence in asthma in recent years&#46; In this way&#44; a group of asthma experts distinguished between clinical remission &#40;12 or more months without significant symptoms measured by an appropriate instrument&#44; lung function optimization or stabilization&#44; patient&#47;provider&#39;s agreement on remission&#44; and no use of systemic corticosteroids&#41; and complete remission &#40;clinical remission plus objective resolution of inflammation and&#44; if appropriate&#44; negative BHR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Remission can occur spontaneously or in response to treatment&#46; Remission rates in childhood asthma are highly variable&#44; depending on the population studied and the definition of remission adopted&#46; Complete remission of asthma &#40;defined as no symptoms&#44; no use of inhaled corticosteroids&#44; normal lung function&#44; and no BHR&#41; was found to be present in 22&#37; of children diagnosed with allergic asthma after a mean follow-up of 30 years&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> Data in adult-onset asthma is scarcer&#44; but complete remission is rare&#44; especially in patients with severe disease&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">From a physician&#39;s point of view&#44; clinical remission is no different from other terms that have already been used&#44; such as &#8220;super-response&#8221; or &#8220;complete response&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> However&#44; we believe that there are compelling reasons to explore this concept further&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0015" class="elsevierStylePara elsevierViewall">The pivotal clinical trials that have led to the approval of biologic drugs by the regulatory agencies have been designed to assess the efficacy of treatment on individual outcome variables &#40;exacerbations&#44; need for maintenance oral corticosteroids&#44; etc&#46;&#41;&#46; However&#44; the clinicians&#8217; perspective has shifted the focus towards a more holistic and demanding assessment of the response to biologics&#46; In this regard&#44; it should be noted that less than half of biologic-treated patients achieve clinical remission as defined above&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">5&#44;6</span></a> highlighting the need for other therapeutic options&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0020" class="elsevierStylePara elsevierViewall">The concept of complete remission establishes additional therapeutic goals&#44; such as inflammation and BHR&#44; which go beyond the four clinical and functional parameters used to define clinical remission &#40;exacerbations&#44; use of systemic corticosteroids&#44; symptoms and pulmonary function&#41;&#46; BHR can persist in patients with clinical remission&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> and it has been reported that BHR is a risk factor for the development of chronic airflow obstruction&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> On the other hand&#44; active inflammation may also be present in asthmatics in clinical remission&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> Several recently published studies showed that T2 biomarkers&#8212;blood eosinophils and fractional exhaled nitric oxide &#40;FeNO&#41;&#8212;have a predictive capacity for asthma attacks similar &#40;and additive&#41; to the independent risk seen with other well-established risk factors such as a history of an exacerbation in the prior 12 months and asthma severity graded according to the Global Initiative for Asthma &#40;GINA&#41; treatment steps&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">10&#8211;12</span></a> Moreover&#44; the prognostic value of blood eosinophils and FeNO was additive&#44; and this is something to be expected&#44; as each biomarker signals different sub-pathways of the inflammatory cascade&#58; FeNO reflects IL-4&#47;IL-13 activity&#44; while blood eosinophils reflect circulating IL-5 and the systemic pool of available effector cells&#46; This has been embedded in the development of a prototype asthma attack risk scale &#40;centred on these two biomarkers&#41; that provides a framework for preventive&#44; trait-based asthma management&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> However&#44; it has yet to be demonstrated that this therapeutic strategy&#8212;which genuinely takes into account future risk&#8212;provides an objective advantage for patients while avoiding the potential risk of overtreatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Focusing on complete remission could be helpful in our main objective&#44; to modify the natural history of asthma by bringing it back to normal&#46; The natural history of asthma results in a symptomatic burden for patients&#44; a high risk of exacerbations&#44; long-term loss of lung function and&#44; in some cases&#44; even death&#46; All these undesirable outcomes are subject to variability in disease severity among patients&#46; The current asthma strategy is aimed at controlling symptoms&#44; avoiding exacerbations and&#44; at best&#44; normalizing lung function&#44; but does not consider the accelerated loss of FEV1 &#40;&#8220;steeper decline&#8221; has been defined as FEV1 loss<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>54<span class="elsevierStyleHsp" style=""></span>ml&#47;yr&#41; that is observed in a percentage of patients&#44; which varies according to the published studies but is more frequent in patients with severe asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> Given the deleterious effect on patients&#8217; health of developing fixed bronchial obstruction&#44; optimal treatment &#40;e&#46;g&#46; a monoclonal antibody&#41; should prevent it&#46; As an example&#44; the ATLAS study will establish dupilumab&#39;s role in preventing or slowing the long-term loss of lung function over three years compared with standard of care therapy&#44; as well as its potential effect on disease modification&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Theoretically&#44; failure to attain an early clinical remission may reduce the chances of achieving it in the long term&#46; A post hoc analysis of the QUEST and TRAVERSE clinical trials showed that&#44; at week 52 of QUEST&#44; 31&#46;7&#37; dupilumab-treated vs&#46; 17&#46;7&#37; placebo-treated patients achieved clinical remission&#44; whereas&#44; at week 48 of TRAVERSE &#40;patients were included in this study once they completed QUEST&#41;&#44; 36&#46;4&#37; and 29&#46;6&#37; of dupilumab&#47;dupilumab and placebo&#47;dupilumab patients &#40;received placebo in the first trial and dupilumab in the second&#41; attained clinical remission&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> This could reflect a &#8220;missed opportunity&#8221;&#46;</p></li></ul></p><p id="par0035" class="elsevierStylePara elsevierViewall">There are major obstacles in the clinical assessment of complete remission&#46; Measurement of BHR is laborious and may be contraindicated in patients with bronchial obstruction&#59; direct assessment of airway inflammation &#40;bronchoscopy&#44; induced sputum&#41; is complex&#59; some patients may have fixed obstruction&#44; not amenable to improvement with treatment&#59; and symptoms may be greatly impacted by the co-morbidities that accompany asthma&#46; We are in the early stages of developing this concept and more evidence needs to be generated to support it&#46; In the meantime&#44; we believe it is reasonable to adopt a therapeutic strategy aimed at modifying the natural history of asthma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">Dr&#46; P&#233;rez de Llano reports grants&#44; personal fees and non-financial support from AstraZeneca&#44; personal fees and non-financial support from GSK&#44; grants and personal fees from TEVA&#44; personal fees and non-financial support from Novartis&#44; personal fees and non-financial support from Chiesi&#44; personal fees from Sanofi&#44; personal fees from Menarini&#44; grants and personal fees from Esteve&#44; personal fees from MSD&#44; personal fees from TECHDOW PHARMA&#44; grants and non-financial support from FAES&#44; personal fees from Leo-Pharma&#44; personal fees from GEBRO&#44; personal fees from GILEAD&#44; outside the submitted work&#46; Dr&#46; Veiga reports personal fees and non-financial support from Chiesi&#44; non-financial support from GSK&#44; personal fees and non-financial support from AstraZeneca&#44; non-financial support from Teva&#44; non-financial support from Menarini&#44; personal fees and non-financial support from FAES&#44; outside the submitted work&#46; Dr Dacal Rivas reports personal fees and non-financial support from Esteve&#44; personal fees and non-financial support from Boehringer-Ingelheim&#44; personal fees and non-financial support from GSK&#44; non-financial support from Novartis&#44; non-financial support from TEVA&#44; non-financial support from Chiesi&#44; non-financial support from Ferrer&#44; personal fees from FAES Farma&#44; outside the submitted work&#46;</p></span></span>"
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Editorial
Contribution of the Remission Concept to the Treatment of Asthma
Luis Pérez-de-Llano
Corresponding author
eremos26@hotmail.com

Corresponding author.
, Iria Veiga-Teijeiro, David Dacal-Rivas
Pneumology Service, Lucus Augusti University Hospital. EOXI Lugo, Cervo e Monforte, Lugo, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">A disease has two different&#44; independent&#44; but interrelated dimensions&#58; the clinical manifestations and the biological activity&#46; An asthmatic is controlled if the disease does not manifest itself clinically&#44; and asthma is in remission if there is no bronchial hyperresponsiveness &#40;BHR&#41; and inflammation &#40;the two determinants of asthma pathophysiology&#41;&#46; There may be patients who have controlled clinical manifestations but in whom disease activity persists and&#44; conversely&#44; there may be patients in remission&#44; without disease activity&#44; but with clinical manifestations &#40;e&#46;g&#46; due to non-reversible bronchial obstruction&#41;&#46; Remission is a concept imported from other inflammatory diseases &#40;rheumatoid arthritis&#44; inflammatory bowel disease&#44; etc&#46;&#41; and it has been gaining prominence in asthma in recent years&#46; In this way&#44; a group of asthma experts distinguished between clinical remission &#40;12 or more months without significant symptoms measured by an appropriate instrument&#44; lung function optimization or stabilization&#44; patient&#47;provider&#39;s agreement on remission&#44; and no use of systemic corticosteroids&#41; and complete remission &#40;clinical remission plus objective resolution of inflammation and&#44; if appropriate&#44; negative BHR&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Remission can occur spontaneously or in response to treatment&#46; Remission rates in childhood asthma are highly variable&#44; depending on the population studied and the definition of remission adopted&#46; Complete remission of asthma &#40;defined as no symptoms&#44; no use of inhaled corticosteroids&#44; normal lung function&#44; and no BHR&#41; was found to be present in 22&#37; of children diagnosed with allergic asthma after a mean follow-up of 30 years&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> Data in adult-onset asthma is scarcer&#44; but complete remission is rare&#44; especially in patients with severe disease&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">From a physician&#39;s point of view&#44; clinical remission is no different from other terms that have already been used&#44; such as &#8220;super-response&#8221; or &#8220;complete response&#8221;&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">4</span></a> However&#44; we believe that there are compelling reasons to explore this concept further&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1&#46;</span><p id="par0015" class="elsevierStylePara elsevierViewall">The pivotal clinical trials that have led to the approval of biologic drugs by the regulatory agencies have been designed to assess the efficacy of treatment on individual outcome variables &#40;exacerbations&#44; need for maintenance oral corticosteroids&#44; etc&#46;&#41;&#46; However&#44; the clinicians&#8217; perspective has shifted the focus towards a more holistic and demanding assessment of the response to biologics&#46; In this regard&#44; it should be noted that less than half of biologic-treated patients achieve clinical remission as defined above&#44;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">5&#44;6</span></a> highlighting the need for other therapeutic options&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2&#46;</span><p id="par0020" class="elsevierStylePara elsevierViewall">The concept of complete remission establishes additional therapeutic goals&#44; such as inflammation and BHR&#44; which go beyond the four clinical and functional parameters used to define clinical remission &#40;exacerbations&#44; use of systemic corticosteroids&#44; symptoms and pulmonary function&#41;&#46; BHR can persist in patients with clinical remission&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> and it has been reported that BHR is a risk factor for the development of chronic airflow obstruction&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">8</span></a> On the other hand&#44; active inflammation may also be present in asthmatics in clinical remission&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> Several recently published studies showed that T2 biomarkers&#8212;blood eosinophils and fractional exhaled nitric oxide &#40;FeNO&#41;&#8212;have a predictive capacity for asthma attacks similar &#40;and additive&#41; to the independent risk seen with other well-established risk factors such as a history of an exacerbation in the prior 12 months and asthma severity graded according to the Global Initiative for Asthma &#40;GINA&#41; treatment steps&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">10&#8211;12</span></a> Moreover&#44; the prognostic value of blood eosinophils and FeNO was additive&#44; and this is something to be expected&#44; as each biomarker signals different sub-pathways of the inflammatory cascade&#58; FeNO reflects IL-4&#47;IL-13 activity&#44; while blood eosinophils reflect circulating IL-5 and the systemic pool of available effector cells&#46; This has been embedded in the development of a prototype asthma attack risk scale &#40;centred on these two biomarkers&#41; that provides a framework for preventive&#44; trait-based asthma management&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> However&#44; it has yet to be demonstrated that this therapeutic strategy&#8212;which genuinely takes into account future risk&#8212;provides an objective advantage for patients while avoiding the potential risk of overtreatment&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3&#46;</span><p id="par0025" class="elsevierStylePara elsevierViewall">Focusing on complete remission could be helpful in our main objective&#44; to modify the natural history of asthma by bringing it back to normal&#46; The natural history of asthma results in a symptomatic burden for patients&#44; a high risk of exacerbations&#44; long-term loss of lung function and&#44; in some cases&#44; even death&#46; All these undesirable outcomes are subject to variability in disease severity among patients&#46; The current asthma strategy is aimed at controlling symptoms&#44; avoiding exacerbations and&#44; at best&#44; normalizing lung function&#44; but does not consider the accelerated loss of FEV1 &#40;&#8220;steeper decline&#8221; has been defined as FEV1 loss<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>54<span class="elsevierStyleHsp" style=""></span>ml&#47;yr&#41; that is observed in a percentage of patients&#44; which varies according to the published studies but is more frequent in patients with severe asthma&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> Given the deleterious effect on patients&#8217; health of developing fixed bronchial obstruction&#44; optimal treatment &#40;e&#46;g&#46; a monoclonal antibody&#41; should prevent it&#46; As an example&#44; the ATLAS study will establish dupilumab&#39;s role in preventing or slowing the long-term loss of lung function over three years compared with standard of care therapy&#44; as well as its potential effect on disease modification&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4&#46;</span><p id="par0030" class="elsevierStylePara elsevierViewall">Theoretically&#44; failure to attain an early clinical remission may reduce the chances of achieving it in the long term&#46; A post hoc analysis of the QUEST and TRAVERSE clinical trials showed that&#44; at week 52 of QUEST&#44; 31&#46;7&#37; dupilumab-treated vs&#46; 17&#46;7&#37; placebo-treated patients achieved clinical remission&#44; whereas&#44; at week 48 of TRAVERSE &#40;patients were included in this study once they completed QUEST&#41;&#44; 36&#46;4&#37; and 29&#46;6&#37; of dupilumab&#47;dupilumab and placebo&#47;dupilumab patients &#40;received placebo in the first trial and dupilumab in the second&#41; attained clinical remission&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> This could reflect a &#8220;missed opportunity&#8221;&#46;</p></li></ul></p><p id="par0035" class="elsevierStylePara elsevierViewall">There are major obstacles in the clinical assessment of complete remission&#46; Measurement of BHR is laborious and may be contraindicated in patients with bronchial obstruction&#59; direct assessment of airway inflammation &#40;bronchoscopy&#44; induced sputum&#41; is complex&#59; some patients may have fixed obstruction&#44; not amenable to improvement with treatment&#59; and symptoms may be greatly impacted by the co-morbidities that accompany asthma&#46; We are in the early stages of developing this concept and more evidence needs to be generated to support it&#46; In the meantime&#44; we believe it is reasonable to adopt a therapeutic strategy aimed at modifying the natural history of asthma &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">Dr&#46; P&#233;rez de Llano reports grants&#44; personal fees and non-financial support from AstraZeneca&#44; personal fees and non-financial support from GSK&#44; grants and personal fees from TEVA&#44; personal fees and non-financial support from Novartis&#44; personal fees and non-financial support from Chiesi&#44; personal fees from Sanofi&#44; personal fees from Menarini&#44; grants and personal fees from Esteve&#44; personal fees from MSD&#44; personal fees from TECHDOW PHARMA&#44; grants and non-financial support from FAES&#44; personal fees from Leo-Pharma&#44; personal fees from GEBRO&#44; personal fees from GILEAD&#44; outside the submitted work&#46; Dr&#46; Veiga reports personal fees and non-financial support from Chiesi&#44; non-financial support from GSK&#44; personal fees and non-financial support from AstraZeneca&#44; non-financial support from Teva&#44; non-financial support from Menarini&#44; personal fees and non-financial support from FAES&#44; outside the submitted work&#46; Dr Dacal Rivas reports personal fees and non-financial support from Esteve&#44; personal fees and non-financial support from Boehringer-Ingelheim&#44; personal fees and non-financial support from GSK&#44; non-financial support from Novartis&#44; non-financial support from TEVA&#44; non-financial support from Chiesi&#44; non-financial support from Ferrer&#44; personal fees from FAES Farma&#44; outside the submitted work&#46;</p></span></span>"
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Article information
ISSN: 03002896
Original language: English
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