Asthma Severe DMAAD Thai thoracic 67 PDF

Asthma

1. Siwasak Juthong. M.D.
Respiratory and Respiratory Critical Care Unit, Division of Internal Medicine,
Faculty of Medicine, Prince of Songkla University, Songkhla
Time to Thinking of the Disease-Modifying
Anti-Asthma Drugs for Treatment of Severe Asthma

2. Outlines
The Disease-Modifying Anti-Asthma Drugs (DMAAD) for
treatment of asthma
Asthma remission; the future goal for asthma treatment!

3. Nolasco, SJ. Pers. Med. 2023,13,1459
Asthma treatment and outcomes

4. Lommatzsch M. et al. Lancet 2022; 399: 1664–68
Comparison of asthma treatment concepts in the 20th and 21st centuries
20th century21st century
Maintenance or intermittent treatment
Systemic corticosteroids
Short-acting beta-2-agonist monotherapies or cromones
Ephedrine or methyxanthines
Biologics
Allergen Immunotherapy
Inhaled corticosteroids or leukotriene receptor antagonists
Reliever (as needed)
Early 20th century
Scopolamine or epinephrineInhaled corticosteroids and formoterol
Short-acting beta-2 agonist monotherspies
Rescue medications
Side-effects
Short-term benefits:
Acute relief of symptomsTreatment concept and aim
Treatment with
Application to patients?
Patient perspectives
Long-tern benefits:
Disease modification
Remission
Major adverse effectsCollateral efficiency
One size fits allIndividual treatment
Anxiety
Recurrence symptoms
Safety
No symptoms
Preventive medications

5. Asthma guidelines should include a definition for remission as a treatment goal
GOALs for the treatment of asthma
Asthma treatment
SymptomsFuture Risks
Dyspnea
Exercise limitation
Nocturnal symptom
Exacerbation
Lung function tests
Mortality
Disease modification and asthma remission as therapeutic goals

6. Focus on targeting type 2 inflammation (eg, ICS-containing inhalation, biologics,
allergen immunotherapy) are highly effective in reducing asthma exacerbations
and improving asthma control with few adverse effects by preventing
symptoms as well as by reducing future risks
Asthma treatments recommended by GINA
GINA 2023

7. Lommatzsch M, et al. Disease-modifying anti- asthmatic drugs. Lancet 2022; 399: 1664–68.
Definitions of asthma remission independent of the current treatment
status and combined with a long-term view of the partial or complete
remission of signs and symptoms (ie, for at least 12 months) unlike the shorter
periods considered in the concept of asthma control
With the advent of effective biologics for the treatment of severe asthma
and a growing number of symptom-free patients on treatment in real life,
this perspective has changed
The new era of asthma treatment goals

8. The management of asthma has changed fundamentally for the past 20 years
DMAADs = ICS-containing inhalations, leukotriene receptor antagonists,
biologics, and allergen immunotherapy
Disease-modifying anti-asthmatic drugs
Precise assessment and phenotyping are now required to establish
individually targeted treatment with disease-modifying anti-asthmatic drugs
(DMAADs)
LommatzschM. et al. Lancet Respir Med 2023; 11: 573–76

9. Disease modification and asthma remission as therapeutic goals
The development and approval of DMAADs has fundamentally changed the
asthma therapy concept from symptom control to symptom prevention
The concept new asthma treatment goal of asthma remission:
- long- term absence of symptoms (good asthma control)
- absence of exacerbations
- stable lung function
- no use of systemic steroids
Marek Lommatzsch. Allergologie select, Vol. 8/2024 (1-5)

10. Marek Lommatzsch. Allergologie select, Vol. 8/2024 (1-5)
A treat- to-target approach
Used as in rheumatoid arthritis or chronic inflammatory bowel disease
The goal is to achieve asthma remission, through individually tailored
treatment with highly effective drugs with minimal side effects
Requires precise phenotyping, including detailed history taking, pulmonary
function, allergological diagnostics, and measurement of type 2 biomarkers

11. .
Changes in asthma therapy: symptom prevention as a goal
This paradigm shift was made possible by modern ICS (either ICS, ICS/LABA,
ICS?LABA/LAMA), biologics and modern allergen immunotherapies (AIT)
Analogous to disease-modifying antirheumatic drugs (DMARDs) in
rheumatology)
DMAADs are not only highly effective, but also have few side effects

12. Asthma remission as a new treatment goal
The remission concepts are based on the remission can also occur during
anti-inflammatory therapy (remission on treatment)
Previously, the concept of asthma remission was limited to spontaneous
remission (especially in pediatrics) or remission after treatment (especially in
allergology, after allergen immunotherapy)

13. 1. Upham JW, James AL. Remission of asthma: The next therapeutic frontier? Pharmacol Ther. 2011; 130: 38-45.
2.. Brusselle GG, Koppelman GH. Biologic Therapies for Severe Asthma. N Engl J Med. 2022; 386: 157- 171.
Highly effective biologics for the treatment of severe asthma and the
increasing number of permanently symptom-free patients on this therapy
[2], these views have changed
The concept of asthma remission on treatment was previously rejected by
many respiratory physicians;
- not a disease modification (in contrast to all other specialties of internal medicine)
- forms of asthma (especially patients with severe asthma) could ever achieve this goal [1]

14. Lommatzsch M. et al. Lancet 2022; 399: 1664–68
Changing asthma treatment concepts: from symptom relief to symptom prevention
Treatment with DMAADs aims to prevent asthma symptoms and
exacerbations with minimal treatment-related side-effects, with the ultimate
goal of inducing and maintaining asthma remission

15. LommatzschM. et al. Lancet Respir Med 2023; 11: 573–76 LommatzschM. Lancet 2022; 399: 1664–68
Clinical definitions of asthma remission and disease-modifying anti-asthmatic drugs
These terms do not necessarily imply biological remission (absence of any airway pathology)
Proposed criteria for asthma remission
• Sustained absence of asthma symptoms
• Sustained absence of asthma exacerbations
• Stable lung function
• No need for systemic corticosteroids for the treatment of asthma
Proposed definition of disease-modifying anti-asthmatic drugs
• Any drug class that can potentially achieve the goal of asthma remission

16. LommatzschM. et al. Lancet Respir Med 2023; 11: 573–76
The new terminology (DMAAD) might even motivate physicians to
phenotype asthma and to treat asthma to target (analogous to the treatment aim in
rheumatoid arthritis or in IBD) with the currently available spectrum of treatment
options, and to motivate patients to adhere to treatment recommendations

17. Disease modification and asthma remission as
therapeutic goals

18. Thomas D . Eur Respir J 2022; 60: 2102583
Asthma Remission

19. Beasley R, et al. Eur Respir J 2023; 62: 2301844Outcomes in response to biologic treatments in severe asthma

20. Early attempts to define clinical remission include composite end points
LugogoNL, et al. CHEST October 2023, 164: 831-834
Remission on biologics
Biological therapy can raise our ambition towards asthma remission

21. Jackson D.Lancet 2024; 403: 271–81
Clinical remission in the reduction group 54% at week 48 (ACQ-5 score <1·5)

22. LommatzschM. et al. Lancet Respir Med. 2024 Feb;12(2):96-99.
Criteria for clinical remission of asthma in national guidelines
In 2023, the concept of remission on treatment has gained support, national societies
have incorporated remission as a treatment goal in asthma guidelines

23. Treatment concepts in asthmaDMAAD=disease-modifying anti-asthmatic drugLommatzschM. et al. Lancet Respir Med. Feb, 2024 Feb;12(2):96-99.
Individual tailored treatment with DMAADs
Disease control
Phenotyping optional
Disease modification
Phenotyping essential
Severe asthma
High treatment burden
- Many drugs
- High doses
- Many adverse effects
Step-up treatment
Drug ADrug ADrug ADrug A
Drug ADrug A
Drug BDrug BDrug B
Drug CDrug C
Drug D
Severe asthma
Lowtreatment burden
- Few drugs
- Lowest possible doses
- Minimal adverse effects
Standard treatment steps with standard drugs
Drug A
Drug B
Drug CDrug C
Drug CDrug D
Induction of remissionMaintenance of remission
Identify and treat with
most effective DMAADs
Reduction to lowest possible
number and dose of DMAADs
Identification of the right DMAAD(s) for the right patient at the right time

24. LommatzschM. et al. Lancet Respir Med. 2024 Feb;12(2):96-99.
The new concept of disease modification does not warrant the simple
addition of one drug to another, but the identification of the right DMAAD(s)
for the right patient at the right time.
According to this new concept, phenotyping is an essential prerequisite to
establish individually effective treatment
Treatment concepts in asthma

25. Asthma therapy of the future will consist of 2 phases;
1) An initial phase of remission induction (higher doses, typically a
combination of several DMAADs) and
2) Second phase of remission maintenance (as few DMAADs as possible, in
the lowest possible dose)
The future of asthma therapy

26. LommatzschM. et al. Lancet Respir Med 2023; 11: 573–76
There is a need for easy-to-understand, concise guides for general practice
Propose a one-page practical guide for asthma management, titled A2BCD, with 4 components:
A: Dual assessment (A2) of asthma (ie, diagnosis and phenotype, plus asthma control and future risks);
B: Basic measures (B); (eg, education, self- management skills, regular physical activity, and avoidance of asthma triggers);
C: identification and treatment of Comorbidities (C) of asthma (eg, chronic rhinosinusitis, obesity, or sleep apnea);
D: phenotype-specific, individually targeted treatment with DMAADs (D)

27. LommatzschM. et al. Lancet Respir Med 2023; 11: 573–76
A2BCD guide for asthma management

28. Conclusion
“Disease-modifying anti-asthmatic drugs”, (ICS, ICS/LABA, ICS/LABA/LAMA),
biologics and modern allergen immunotherapies, has fundamentally
changed the asthma therapy concept from symptom control to symptom
prevention
The new asthma treatment goal of asthma remission: long-term
absence of symptoms (good asthma control), absence of exacerbations,
and stable lung function, without the use of systemic steroids for
asthma therapy
A treat-to-target approach is used. The goal is to achieve asthma
remission, through individually tailored treatment with highly effective
drugs with minimal side effects

29. Thank you for your attention

30. The term remission is well defined in rheumatoid arthritis, Crohn’s disease,
ulcerative colitis, SLE or cancer
Remission in childhood asthma is a common (5% - 69%[1])
Remission in adults with asthma is a relatively new concept and gained attention
Might be possible to induce remission with asthma treatments
Concept of asthma remission
1.Carpaij OA,. A review on the pathophysiology of asthma remission. Pharmacol Ther 2019;201:8-24.
2.Lommatzsch M, et al. A2BCD: a concise guide for asthma management. Lancet Respir Med 2023; 11: 573–76
Asthma treatment concepts have changed, from short-term symptom control to
long-term symptom prevention, with the achievable goal of disease remission(2)

31. 1.Virchow JC, et al. Efficacy of a HDM sublingual AIT tablet in adults with allergic asthma: a randomized clinical trial. JAMA 2016; 315: 1715–25.
2.Reddel HK,et al. GINA 2021: executive summary and rationale for key changes. Eur Respir J 2022; 59: 2102730.
Disease modification and asthma remission as therapeutic goals
The first concept: allergen immunotherapy concept
MITRA study, first to show 1-year treatment with house dust mite (HDM)
sublingual immunotherapy tablet can reduce exacerbations in uncontrolled
asthma and HDM allergy, with an acceptable safety profile (1)
Led to GINA 2021 recommendation that HDM- sublingual immunotherapy
should be evaluated as an additional therapeutic option in the treatment
mild to moderate asthma (2)

32. 1. Pfaar O, et al. One hundred ten years of allergen immunotherapy: a broad look into the future. J Allergy Clin Immunol Pract 2021; 9: 1791–803.
2. Marogna M, et al. Long-lasting effects of sublingual immunotherapy according to its duration: a 15-year prospective study. J Allergy Clin Immunol 2010;
126: 969–75.
Disease modification and asthma remission as therapeutic goals
Allergen immunotherapy is currently postulated to be a disease modifier,
primarily because clinical benefits and immunological changes last beyond
the time of treatment (ie, the disease remains modified after treatment
discontinuation) (1,2)

33. Disease modification and asthma remission as therapeutic goals
The second concept: the rheumatoid arthritis concept
The European League Against Rheumatism defines a large group of modern
anti-inflammatory drugs against rheumatoid arthritis as disease modifiers or
disease-modifying anti-rheumatic drugs (DMARDs) (1)
1. Smolen JS, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis 2020; 79: 685–99.
2. Felson DT, et al. American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis 2011; 70: 404–13.
Linked to idea of rheumatoid arthritis remission, defined as a very low
disease activity (the patient must satisfy all of the following: tender joint count ≤1, swollen joint count ≤1, C-reactive
protein ≤1 mg/dl, and patient global assessment ≤1, on a 0–10 scale) during treatment with DMARDs (2)

34. LommatzschM. Lancet 2022; 399: 1664–68
Today, effective, safe, phenotype-specific immunomodulatory drugs aimed
at preventing symptoms and exacerbations by targeting the underlying
inflammatory cascade, with the advantage of improving control of co-
existing co-morbidities
Drugs do not only successfully modulate inflammation, but can improve the
function of structural cells, such as epithelial cells, smooth muscle cells,
fibroblasts, and nerves, and consequently reduce airway remodelling

35. ICS molecules,
ICS doses
ICS/LABA (LAMA)
fixed combination
inhaler
Application schemes
maintenance therapy
or inhalation on an as- needed basis
Inhaled DevicesAsthma
The choice of inhaled therapies has become more and more individualize
LommatzschM. Lancet 2022; 399: 1664–68

36. Type Criteria Assessments
Clinical remissionNo symptomsSustained absence of significant asthma symptoms established
using a validated instrument (e.g. ACQ score ⩽1 or ACT score
⩾20); the use of relievers is not permitted during the remission
period
No exacerbationsThe use of systemic corticosteroids for exacerbation treatment
is not permitted during the remission period; hospitalisation or
emergency department visit or unscheduled doctor visit for
asthma exacerbation management are also not permitted
during the remission period
Optimisation of lung functionExample: post-bronchodilator FEV1 ⩾80% predicted
Complete remissionClinical remission plus
normalisationof underlying
pathology
No evidence of current inflammation established using either blood
eosinophilcount (<300 cells·μL−1), sputum eosinophil count (<3%) or
FENO (<40 ppb);other measures of underlying pathology may
include a negative bronchial hyperresponsiveness test (e.g.
histamine or methacholine provocation tests) or degree of
subepithelial fibrosis (subepithelial thickness)
Both clinical and complete remission can be achieved either on treatment or off treatment.
12 months or longer without symptoms Thomas D . Eur Respir J 2022; 60: 2102583
Types and measures of asthma remission

37. Type Criteria Assessments
Clinical remissionNo symptomsSustained absence of significant asthma symptoms established
using a validated instrument (e.g. ACQ score ⩽1 or ACT score
⩾20); the use of relievers is not permitted during the remission
period
No exacerbationsThe use of systemic corticosteroids for exacerbation treatment
is not permitted during the remission period; hospitalisation or
emergency department visit or unscheduled doctor visit for
asthma exacerbation management are also not permitted
during the remission period
Optimisation of lung functionExample: post-bronchodilator FEV1 ⩾80% predicted
Complete remissionClinical remission plus
normalisationof underlying
pathology
No evidence of current inflammation established using either blood
eosinophilcount (<300 cells·μL−1), sputum eosinophil count (<3%) or
FENO (<40 ppb);other measures of underlying pathology may
include a negative bronchial hyperresponsiveness test (e.g.
histamine or methacholine provocation tests) or degree of
subepithelial fibrosis (subepithelial thickness)
Both clinical and complete remission can be achieved either on treatment or off treatment.
12 months or longer without symptoms Thomas D . Eur Respir J 2022; 60: 2102583
Types and measures of asthma remission

38. 3. Milger K, Suhling H, Skowasch D, Holtdirk A, Kneidinger N, Behr J, et al. Response to biologics and clinical remission in the adult GAN severe asthma registry
cohort. Allergy Clin Immunol Pract 2023;11:2701-12.
.
32.1% of those initiating biologics achieved remission
9.5% of patients not receiving biologics met remission criteria
The biologic super-response rate was 61.4% (without the lung function criterion),
superresponse rate = 34.8% not receiving biologics

39. The general concept of treatment recommendations is phenotype-specific,
anti-inflammatory DMAAD therapy, moving towards clever “fire prevention”
and away from constant “fire extinguishing”

40. Varricchi G, et al. Allergy. 2022;77:3538–3552

41. Time to change the paradigm of treatment for
patients with severe asthma who have
frequent severe exacerbations, multiple OCS
bursts and severe symptom burden, to the
treatment goals from asthma control to
asthma remission by biologics