Clinical Response and Remission in Patients With Severe Asthma Treated With Biologic Therapies

Abstract

BackgroundThe development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal.Research QuestionHow many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment?Study Design and MethodsThe Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined “clinical response” to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. “Clinical remission” was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV1 > 80%) and an Asthma Control Questionnaire-6 score ≤ 1.5 following 12 months of treatment.ResultsFollowing 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy.InterpretationClinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy. The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal. How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment? The Danish Severe Asthma Register is a nationwide cohort including all adult patients receiving biologic therapy for severe asthma in Denmark. This observational cohort study defined “clinical response” to treatment following 12 months as a ≥ 50% reduction in exacerbations and/or a ≥ 50% reduction in maintenance oral corticosteroid dose, if required. “Clinical remission” was defined by cessation of exacerbations and maintenance oral corticosteroids, as well as a normalization of lung function (FEV1 > 80%) and an Asthma Control Questionnaire-6 score ≤ 1.5 following 12 months of treatment. Following 12 months of treatment, 104 (21%) of 501 biologic-naive patients had no response to treatment, and 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled the study criteria of clinical remission, corresponding to 19% of the entire population. Remission was predicted by shorter duration of disease and lower BMI in the entire population of patients treated with biologic therapy. Clinical response was achieved in most adult patients initiating biologic therapy, and clinical remission was observed in 19% of the patients following 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission with biologic therapy. Take-home PointsStudy Question: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment?Results: This study highlights that almost one in five patients with severe asthma achieve remission following treatment with biologic therapy. Remission was predicted by shorter disease duration at time of treatment initiation and lower BMI.Interpretation: Clinical remission is an achievable treatment goal in adult patients with severe asthma. Larger prospective studies are needed to describe the impact of remission on treatment on longer-term clinical outcomes. Study Question: How many patients with severe asthma treated with biologic therapy achieve clinical remission, and what predicts response to treatment? Results: This study highlights that almost one in five patients with severe asthma achieve remission following treatment with biologic therapy. Remission was predicted by shorter disease duration at time of treatment initiation and lower BMI. Interpretation: Clinical remission is an achievable treatment goal in adult patients with severe asthma. Larger prospective studies are needed to describe the impact of remission on treatment on longer-term clinical outcomes. Severe asthma is a highly burdensome condition, affecting approximately 5% to 10% of patients with asthma whose disease remains uncontrolled despite high-dose controller therapy and in whom other causes, including lack of adherence, inadequate inhaler technique, and influence of untreated comorbidities, have been ruled out.1Porsbjerg C. Ulrik C. Skjold T. et al.Nordic consensus statement on the systematic assessment and management of possible severe asthma in adults.Eur Clin Respir J. 2018; 51440868Crossref Scopus (36) Google Scholar, 2Global Initiative for Asthma (GINA)Global Strategy for Asthma Management and Prevention, 2021 report.2021Google Scholar, 3Chung K.F. Wenzel S.E. Brozek J.L. et al.International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma.Eur Respir J. 2014; 43: 343-373Crossref PubMed Scopus (2722) Google Scholar, 4Bel E.H. Sousa A. Fleming L. et al.Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI).Thorax. 2011; 66: 910-917Crossref PubMed Scopus (307) Google Scholar Severe asthma is associated with high morbidity, loss of quality of life, and iatrogenic side effects to treatment, most notably from oral corticosteroids (OCS) prescribed either intermittently to treat exacerbations or as maintenance therapy (maintenance OCS [mOCS]).5Volmer T. Effenberger T. Trautner C. Buhl R. Consequences of long-term oral corticosteroid therapy and its side-effects in severe asthma in adults: a focused review of the impact data in the literature.Eur Respir J. 2018; 521800703Crossref PubMed Scopus (179) Google Scholar,6Sullivan P.W. Ghushchyan V.H. Globe G. Schatz M. Oral corticosteroid exposure and adverse effects in asthmatic patients.J Allergy Clin Immunol. 2018; 141: 110-116.e7Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar Previously, asthma treatment has been focused on achieving disease control.7Thomas D. McDonald V.M. Pavord I.D. Gibson P.G. Asthma remission—what is it and how can it be achieved?.Eur Respir J. 2022; 602102583Crossref Scopus (40) Google Scholar,8Menzies-Gow A. Bafadhel M. Busse W.W. et al.An expert consensus framework for asthma remission as a treatment goal.J Allergy Clin Immunol. 2020; 145: 757-765Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar However, with the development of novel biologic therapies targeting the underlying inflammatory mechanisms, it is natural to consider remission as an achievable treatment target in severe asthma. A similar shift in disease management has been observed in rheumatology. Disease-modifying antirheumatic drugs and targeted biologic therapies have transformed the view on the course of rheumatoid arthritis from a chronic disease to a potentially curable condition, and remission on treatment has been associated with minimal or no clinically detectable disease activity persisting in some patients even after tapering or discontinuing the biologic therapy.9Brahe C.H. Krabbe S. Østergaard M. et al.Dose tapering and discontinuation of biological therapy in rheumatoid arthritis patients in routine care—2-year outcomes and predictors.Rheumatology. 2019; 58: 110-119Crossref Scopus (28) Google Scholar Remission as a treatment outcome is clinically important at two levels. First, patients who achieve complete control of their asthma may have a better long-term prognosis in terms of a reduced risk of excessive lung function decline and future exacerbations. Second, patients achieving clinical remission may also have a better chance of tapering biologic therapy.10Hamada K. Oishi K. Murata Y. Hirano T. Matsunaga K. Feasibility of discontinuing biologics in severe asthma: an algorithmic approach.J Asthma Allergy. 2021; 14: 1463-1471Crossref PubMed Scopus (17) Google Scholar Hence, understanding the likelihood and predictors of remission is clinically important and a key step toward describing the longer term beneficial implications of achieving short-term remission on a biologic treatment. There is currently no clear consensus as to what constitutes clinical response or remission in severe asthma, but a definition has been proposed by Menzies-Gow et al.8Menzies-Gow A. Bafadhel M. Busse W.W. et al.An expert consensus framework for asthma remission as a treatment goal.J Allergy Clin Immunol. 2020; 145: 757-765Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar They include definitions of remission on and off treatment, using varying combinations and cutoffs of absence of symptoms, no OCS use for asthma, stabilization of lung function, and agreement by health care professional and patient about remission assessed over a period of 12 months. This definition of remission may be regarded as a more clinically relevant outcome than previous definitions of super-response,11Upham J.W. Le Lievre C. Jackson D.J. et al.Defining a severe asthma super-responder: findings from a Delphi process.J Allergy Clin Immunol Pract. 2021; 9: 3997-4004Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar as it describes whether the patient achieves complete control following treatment rather than the magnitude of response, which is dependent on the baseline level of control. The aim of the current study was to describe the real-life effectiveness of biologic therapy in severe asthma, to evaluate the proportion of patients who achieve a clinical response and clinical remission, and to identify predictors of nonresponse and remission. Patients were included from the Danish Severe Asthma Register (DSAR), a nationwide cohort of all patients treated with a biologic for severe asthma in Denmark.12Hansen S. Hilberg O. Ulrik C.S. et al.The Danish Severe Asthma Register: an electronic platform for severe asthma management and research.Eur Clin Respir J. 2021; 81842117Crossref Scopus (5) Google Scholar Patient information in DSAR is collected prospectively and follows a clinical protocol with a baseline visit when biologic treatment is commenced, following 4 and 12 months of treatment, and then annually. DSAR is approved by Videnscenter for Dataanmeldelser in the Capital Region (VD-2018-31), and all patients provide written consent for their data to be used for research. For the current analysis, biologic-naive patients commencing biologic therapy between January 1, 2016, and December 31, 2021, were included. All but two patients were aged ≥ 18 years at time of treatment start (the remaining two patients were 16 and 17 years of age, respectively). Indication criteria for all biologic therapies in Denmark are described in e-Table 1. As illustrated, in addition to fulfilling the criteria for biologic therapy (high-dose inhaled corticosteroids plus a second controller), adherence to treatment, and a complete systematic assessment, all patients must have had ≥ 2 exacerbations in the previous 12 months or use mOCS at least 50% of the time in the previous 12 months to qualify for biologic therapy. Patients were included who fulfilled these criteria and for whom complete data were available. A flowchart of the study population is presented in e-Figure 1. The current study assessed two levels of response to treatment after 12 months: clinical response and clinical remission. To define clinical response, a definition the clinical response that be as clinically Hence, in the clinical a clinically relevant response include an on the criteria that the either exacerbations and/or mOCS Clinical response was defined a reduction of at least 50% in the if the was on ≥ 2 exacerbations in the 12 months to treatment, and a reduction of at least 50% in the OCS from baseline if the was on the for a patient fulfilled a reduction in exacerbations of at least OCS was also a clinically relevant response, a reduction in OCS a reduction in exacerbations was as with OCS to some was defined as patients fulfilling the criteria for clinical response, as well as discontinuation or treatment to 12 months. For clinical remission, the definition proposed by Menzies-Gow et A. Bafadhel M. Busse W.W. et al.An expert consensus framework for asthma remission as a treatment goal.J Allergy Clin Immunol. 2020; 145: 757-765Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar was clinical remission on treatment following 12 months of treatment was defined as a complete absence of exacerbations and for mOCS and defined as a score on the Asthma Control of ≤ 1.5 after 12 months of treatment. and stabilization of lung function were as a normalization of lung function (FEV1 > of predicted are described by and are described as The effectiveness of biologic therapy was assessed in all biologic therapies by describing the in predicted and mOCS use in the study population using or for and by for the proportion of patients with no response a clinical response to biologic therapy following 12 months of treatment and the proportion of patients clinical remission in the study population and in the and of patients were to response to treatment using for and and for and This was in the entire population and in the The between baseline that in were associated with remission with were included in a to their impact on the of achieving remission. that were of the remission definition and were included in were the associated with remission to including many that to a that to duration of disease and asthma be included in the to duration of disease in the All were and at were than five in a were on the were presented if the were by using the biologic-naive patients in the 501 fulfilled the criteria for the current study of the population are in 1, and the for commencing biologic therapy in the entire study population are in e-Figure of Patients in the Danish Severe Asthma of 18 of disease ≥ at asthma ≤ 18 ≥ in and currently control score ≤ 12 use dose, mOCS dose, (5) (36) function and/or ≥ ≥ ≥ ≥ are presented as or Asthma Control with inhaled mOCS maintenance oral in a new are presented as or Asthma Control with inhaled mOCS maintenance oral The effectiveness of biologic therapy is in 1. Following 4 months of treatment, the score had from to following 12 it had to with the minimal clinically important of a of at least was observed in from to after 4 months and to after 12 which was the findings a minimal clinically important of after 4 months but after 12 months. the patients had exacerbations commencing biologic treatment. patients were after 12 months of patients were of 12 months of treatment, 397 (79%) patients fulfilled the study criteria for a clinical response in the that the treatment, 104 (21%) had no response to treatment Among the 397 clinical 97 patients of with a clinical response, 19% of the study had achieved clinical remission. For the the proportion of clinical response from in in and in the of patients achieving remission in these were and following 12 months of treatment with biologic therapy and baseline remission in with patients with a clinical response. in the entire population. the baseline predictors of a clinical response to biologic therapy with no response were more to use mOCS at baseline with clinical and to have exacerbations. They were also to have ≥ and to have Patients achieving remission were more to be to have a lower to be at asthma to be of to have a lower to have and and to have There were also to have and a the predictors of remission were BMI for and duration of disease for of and of and and was associated with an of with to Clinical Following 12 of in All Patients Patients Clinical of of disease ≥ at asthma ≤ 18 ≥ use dose, mOCS dose, control score ≤ in the 12 in the 12 function ≥ ≥ ≥ ≥ are presented as or Asthma Control with inhaled mOCS maintenance oral in a new Clinical Patients Remission Following 12 of Patients Clinical Remission of of disease ≥ at asthma ≤ 18 ≥ use dose, of the definition for remission and a of control score ≤ of the definition for remission and a of in the 12 of the definition for remission and a of in the 12 of the definition for remission and a of function of the definition for remission and a of ≥ ≥ ≥ ≥ are presented as or Asthma Control with inhaled mOCS maintenance oral of the definition for remission and a of remission. in a new of Clinical Remission 12 of in a Remission as the of disease in a new are presented as or Asthma Control with inhaled mOCS maintenance oral are presented as or Asthma Control with inhaled mOCS maintenance oral the that predicted remission are in and all predictors of response are presented in 2 to Remission in patients treated with was predicted by baseline and remission in patients treated with was predicted by levels. The response to biologic therapy in patients with a clinical response and remission is in patients a clinical response to treatment, had a baseline score ≤ to 50% following 4 months and to following 12 months. patients achieving remission, the proportion with score ≤ 1.5 from at baseline to after 4 months. For the proportion of patients with > in patients a clinical response was at after 4 and after 12 months. patients achieving remission, the proportion with > from at baseline to after 4 months. 12 months of treatment, of patients a clinical response had had and of patients were of mOCS nationwide DSAR cohort of all patients treated with a biologic in that most patients (79%) a clinically relevant response in the outcomes that the for biologic therapy following 12 months of treatment. approximately of all patients achieved clinical remission on treatment with an of no use of an score ≤ and a normalization of lung function of predicted findings a beneficial in the of patients with severe asthma, who criteria for biologics and that achieving remission on treatment in a goal in a proportion of The current are in with two of studies with Busse et treatment to clinical asthma remission in patients with uncontrolled asthma with 2 Allergy Clin Immunol. 2021; Full Text Full Text PDF Google Scholar and A. et remission in severe asthma: a of the patient with 2022; PubMed Scopus (36) Google Scholar that remission of to using definitions of remission similar to A study on real-life data from of patients as achieved remission following of treatment, with and achieving remission in patients treated with and K. D. et to biologics and clinical remission in the adult Asthma Severe Asthma Allergy Clin Immunol Pract. Full Text Full Text PDF PubMed Scopus Google Scholar The definition of remission from the current study on two in that it was on an Asthma Control score > and an in of > which the of remission observed in their study with the current real-life by K. A. E.H. therapy response to biologics in severe real-life Allergy Clin Immunol Pract. 2021; 9: Full Text Full Text PDF PubMed Scopus Google Scholar of patients as a to treatment using a of no use of no OCS in the score ≥ and as well as complete control of to define similar predictors of as in study that were of an adult patient with a duration of asthma the most from treatment. observed that a lower BMI the chance of achieving clinical remission, which with the that as an asthma control and may be associated with reduced C. Menzies-Gow A. in severe asthma: clinical impact and PubMed Scopus Google Scholar previous studies have that patients with severe asthma with a of 2 are who the most from biologic K. D. et to biologics and clinical remission in the adult Asthma Severe Asthma Allergy Clin Immunol Pract. Full Text Full Text PDF PubMed Scopus Google S. A. remission in asthma: from the Full Text Full Text PDF PubMed Scopus Google S. et response to biologics in a real-life from the nationwide Danish Severe Asthma 2022; Scopus Google Scholar observed a between at baseline and remission and in the of the predicted remission in level predicted remission in However, in the analysis, as an in the data of all have been in the but include patients treated with and to a 2 to identify patients by and is as that these of patients in from that target these This and be in or in of data from the current remission was achieved by of patients treated with by 19% of patients treated with and by of patients treated with The remission proportion patients in treatment may be by the that is a of and most is the of disease in The remission proportion for also be by a time from the that was the biologic for a and some patients who have been more for an or treatment may have been prescribed to by patients commencing treatment to when was on the the real-life of the current study of biologic as patient population to in criteria and clinical predictors of from clinical has the clinical effects of biologic treatment on with of to J. et al.The of treatment with an on asthma exacerbations and in patients with severe PubMed Scopus Google Scholar, M. R. J. et of as therapy in patients with severe asthma who are despite therapy step 4 PubMed Scopus Google Scholar, Pavord I.D. et treatment in patients with severe 2014; PubMed Scopus Google Scholar, I.D. S. et for severe asthma a Full Text Full Text PDF PubMed Scopus Google Scholar, et an as treatment for patients with asthma a Full Text Full Text PDF PubMed Scopus Google Scholar, et and of for patients with severe asthma uncontrolled with inhaled corticosteroids and a Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Pavord I.D. et and in uncontrolled 2018; PubMed Scopus Google Scholar, M. J. et for asthma with from two Respir Full Text Full Text PDF PubMed Scopus Google Scholar is the real-life effectiveness of biologic therapy on these outcomes. the effectiveness of biologic therapy on exacerbations to be even than that observed in the clinical studies with a reduction of also observed on the score by a and a in lung function, for which the is from the clinical This may be by the that in the clinical as to in clinical are better at patients to to biologic therapy. A systematic assessment for other of asthma control is required to commencing a biologic treatment. Hence, patients with and treatment are better to commencing their biologic therapy, and their remaining of is more to asthma that to biologic therapy. the other clinical have effects on mOCS with of to E.H. Wenzel S.E. et of in 2014; PubMed Scopus Google Scholar, Wenzel S. K.F. et of in severe PubMed Scopus Google Scholar, K.F. G. et and of in severe 2018; PubMed Scopus Google Scholar DSAR patients a of mOCS as was in the clinical and are but mOCS following 12 months of with This lower clinical of biologic therapies on mOCS in the current study may a of asthma in real-life in some patients who mOCS for an and these patients may be to the clinical also highlights the in off patients treated with long-term mOCS and that with biologic therapies to with on mOCS is with also that was the most to that biologic therapy be the lung function has to a level that is to A of the current study is that it used an cohort of > patients treated with biologic therapies from a nationwide complete which all patients with severe asthma in Denmark treated with a biologic used a definition of remission that follows the definition of “clinical remission on proposed by Menzies-Gow et A. Bafadhel M. Busse W.W. et al.An expert consensus framework for asthma remission as a treatment goal.J Allergy Clin Immunol. 2020; 145: 757-765Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar which normalization of disease in to the definition of that previous real-life studies have The of the current study the lack of a control to the observed treatment effects to the treatment. of study include data and the of patients with information to be included in the study population. There were patients in DSAR that potentially be included in the but 501 were included to baseline and/or data in the remaining However, in with baseline information the of patients were similar to patients who were included the current remission was achievable in approximately one in five The chance of remission to be better with initiation of biologic that in patients with shorter disease duration and severe disease with and and use of findings that initiation of biologic therapies may better short-term treatment outcomes. the step is to whether achieving remission also better long-term asthma control and lung function, and the to or biologic therapy. severe asthma as S. Hilberg O. Ulrik C.S. et al.The Danish Severe Asthma Register: an electronic platform for severe asthma management and research.Eur Clin Respir J. 2021; 81842117Crossref Scopus (5) Google Scholar and international as Severe Asthma R. G. et al.The Severe Asthma Clinical a new in asthma research.Eur Respir J. 2018; PubMed Scopus Google S. R. et of on a to the of with severe 2021; Scopus Google Scholar and the Severe Asthma Register M. et al.International Severe Asthma protocol for a 2020; PubMed Scopus Google M. A. et al.International Severe Asthma 2020; Full Text Full Text PDF Scopus Google Scholar provide to study these the of achieving an and remission is key currently by as the and Remission C. G. et a at biological treatment of asthma and Respir J. 2021; Scopus Google Scholar in which real-life patients on biologic therapy biologic in addition to the prospective clinical these to the for patients with severe asthma in the years as the of disease in asthma targeted real-life data from 501 patients from the nationwide complete observed that most patients (79%) commencing biologic therapy a response in the outcome that the for biologic therapy following 12 months of treatment. clinical remission on treatment was an achievable treatment with 19% of patients remission following 12 months of treatment. the chance of remission was better in patients with shorter disease duration and severe that is important for achieving the long-term clinical impact of achieving clinical remission on treatment to be The DSAR is by from and

Topics & Concepts