Remission in the World of Severe Asthma

Attendees at recent international meetings will be aware that a very hot area of current research in asthma is the investigation of remission as a valid and achievable composite outcome. They will have learned that a definition of remission has not been settled definitively (1) but that all suggested definitions include common core elements (Table 1). I suspect that most will agree that the achievement of this state implies long-term control of disease activity, absence of significant damage, and an improvement in prognosis. There is a growing consensus that it represents an advance over current shorter-term, symptom-focused disease control definitions (2–5).

Table 1.

Components of Remission, Their Definition, and the Percentage (%) Achieving Component in the ISAR Study

Component of Remission	Definition in ISAR Analysis (for >12 mo)	Percentage Achieving in ISAR	Reflects Activity?	Reflects Damage?
Asthma attacks	None	63.2	++	+
OCS use	None	73.6	++	++
Symptoms	Well or partially controlled by ACT or ACQ	61.7	+	++
Lung function	Post-bronchodilator FEV1 >80% predicted	47.5	+	++
Type 2 inflammation*	Blood eos <300 cells/μl and/or FeNO <50 ppb	NA	++	0

Definition of abbreviations: ACQ = Asthma Control Questionnaire; ACT = Asthma Control Test; eos = eosinophils; Fe_NO = fractional exhaled nitric oxide; ISAR = International Severe Asthma Registry; OCS = oral corticosteroids; + = weak association; ++ = strong association.

Activity refers to type 2 airway inflammation as assessed by blood eosinophils and Fe_NO. Damage refers to morbidity due to people remodeling from comorbidities (including OCS related) and airway remodeling leading to fixed airflow obstruction.

^*On-treatment type 2 inflammation was not reported in ISAR study, but biological remission potentially reflects an additional useful domain with definition derived from Couillard and colleagues (15).

These attendees will have seen an explosion of post hoc analyses investigating whether this desirable clinical state can be achieved with biologics targeting type 2 cytokines (6–8). It is a testament to what can sometimes be achieved with these therapies that our first foray into remission has been in severe asthma. The studies show that the four-component remission criteria are achieved in between one in six and one in three patients, with higher rates in patients with high disease activity (as reflected by raised blood eosinophils and fractional exhaled nitric oxide) and low disease damage (as reflected by a higher post-bronchodilator FEV₁, lower levels of oral corticosteroid [OCS] use, and lower rates of comorbidities) (4, 7, 8).

In this issue of the Journal, we have a new analysis from the International Severe Asthma Registry (ISAR) (pp. 869–880) investigating remission in 3,717 patients with severe asthma recruited from 23 countries and treated with anti-IgE (38%), anti–IL-5/5R-α (54%) or anti–IL-4R-α (8%) (9). This is a remarkable collaborative achievement in a field that is already well known for fruitful collaborations. It is the largest prospective analysis and the most useful information we have on remission and its determinants in severe asthma. The proportion of patients achieving remission was similar between centers and between different biologics, varying from 50% to 20%, depending on the number of domains of remission achieved. There is increasing interest in whether biological remission (Table 1) adds value to clinical remission (10). This was not reported. Failure to achieve a post-bronchodilator FEV₁ >80% predicted was a common reason for failure. This is perhaps the most contentious component of the remission definition, and some see stabilization as a more appropriate and achievable goal (1). I share the views of the authors of the ISAR study: If we are serious about predicting and preventing, we should set a high lung function bar.

The ISAR analysis provides valuable information on factors associated with the likelihood of achieving remission. It showed a 15% reduction in the odds of remission for every 10 years of disease duration and, as with other smaller analyses, a higher likelihood of remission in patients with high biomarkers, lower OCS exposure, fewer comorbidities, fewer exacerbations, better lung function, and fewer symptoms. It is clear that if we are to increase the likelihood of achieving remission, we need to move away from patients with low disease activity/high damage to those with high disease activity/low damage. This is what has been done so successfully by the rheumatologists with biologic treatment of rheumatoid arthritis (11). This change is more of a challenge in obstructive airway disease because diagnostic criteria may mandate the presence of damage, putting us on the back foot from a predict and prevent perspective. Moreover, the tests we tend to rely on to quantify disease (lung function, symptom scores) cannot distinguish activity from damage and, in severe disease, mainly reflect damage (12) (Table 1).

What is needed is a paradigm shift in diagnosis and clinical practice, allowing us to move toward a predict and prevent approach with remission very much at the forefront of what we are trying to achieve (13, 14). This requires early identification of high disease activity (by measuring type 2 inflammatory biomarkers) and prompt intervention with adequate antiinflammatory therapies to prevent downstream damage. We need to move the focus from severe asthma (which is often “too late asthma”) to highly active asthma. Asthma attacks are the main clinical readout of high disease activity (Table 1) (15), and their prediction and prevention are not only strongly evidence based but also associated with important reductions in mortality and healthcare costs (14). This should therefore be the initial focus. However, other key long-term outcomes, such as airway remodeling with associated lung damage and lung function decline (16), and people remodeling due to associated comorbidities, as well as prolonged illness and use of OCS (13), may also be predictable and preventable.

Why are we not doing this? A fundamental issue is that our most influential asthma management statement recommends measurement of fractional exhaled nitric oxide and blood eosinophil count and biologic treatment very late (17). The central but untested tenet of asthma management for 30 years has been a symptom- and lung function–based, one-size-fits-all treatment escalator culminating in the largely non–evidence-based step 4, in which every known asthma treatment is added in an increasingly desperate fashion, and step 5, in which biomarker assessment and precision medicine are finally allowed. This is the ultimate “wait and react,” “treat to fail” approach, and its continued propagation in the postbiologic era is disappointing. Management is dangerously wrong in two sizable groups of patients: those with symptom-high/damage-high/activity-low disease, who get futile (and difficult to reverse) antiinflammatory treatment escalation and treatment-associated morbidity as a result of “chasing the symptoms” (18); and those with symptom-low/activity-high disease, who, if they get on the treatment escalator, are allowed to get progressively damaged by following a series of illogical treatment steps that have no prospect of dealing with the dominant cause of their problems (12).

Will remission help us get where we need to be? I hope it will, but we need to move the debate from definitions to the bigger picture. This is the view of the Lancet Commission on Asthma (14), which advocates type 2 inflammation, risk-based management on top of a background of antiinflammatory reliever therapy. These recommendations are built on solid evidence from randomized clinical trials (19) and risk stratification that allows risk to be identified prospectively (15). There is a need for studies of earlier biomarker-based intervention with biologics to achieve remission. However, I believe that we have more than enough evidence to switch off the escalator and go downstairs to look for high-risk, biomarker-high patients. Payers have nothing to fear and much to gain from this approach: We are seeking to treat not more patients but the same patients at a more appropriate time.