recent advances in the management of bronchial asthma
TRANSCRIPT
As we go along
• Introduction
• Pathophysiology
• Current Management Guidelines.
• Recent Advances
Pharmacotherapy
Monoclonals & Anti cytokines
Immunotherapy
Non Pharmacological
Introduction
• Asthma represents a global public health issue due to high
prevalence rates in the general population( 1% to 18% of
the population in different Countries),
• Affects approximately 300 million people worldwide
• Rising prevalence in developing countries which is
associated with increased urbanization.
Asthma is defined as a chronic inflammatory disease
Airway hyper responsiveness
Recurrent symptoms such as wheezing, dyspnea
(shortness of breath), chest tightness and coughing.
Episodes are associated with widespread ,variable,
airflow obstruction within the lungs that is reversible
spontaneously or with appropriate asthma treatment
IMMEDIATE RESPONSE
Eliciting agent: allergen ornon-specific stimulus activates:
Mast cells, platelets, alveolar macrophages, causing release of:
Spasmogens: H, PAF, LTC4, LTD4,
causing:
Chemotaxins: LTB4, PAF, MNC,
ECF-A which cause:
BRONCHOSPASMReversed by
agonists & Theophylline
Aggregation & activation of platelets, infiltration & activation of
neutrophils, eosinophils, monocytes/macrophages :
PAF, LTB4, LTD4, platelet
factors& susbstance P Neurotensin
ODEMA, MUCOUS SECRETION &
BRONCHOSPASM
LATE-PHASE RESPONSE
Bronchial hyper
responsiveness
Endothelial damage
& stimulation ofC Fibes and
irritant receptors
Inflammation IgE
Histamine
Tryptase
Serotonin
Leukotrienes (LTC4, LTD4 LTB4)
Platelet activating factor (PAF)
Prostaglandins (PGD2)
Interleukins (IL-4, IL-5,IL- 9 ,IL- 13, IL-17 )
Granulocyte-macrophage colony stimulating factor (GM-CSF)
Tumor Necrosis Factor (TNF)
Major Basic Proteases (MBP)
Eosinophil Cationic Protein (ECP)
Eosinophil neurotoxin
Substance P
Neurotensin
Controller Medications
Inhaled Glucocorticosteroids
Leukotriene modifiers
Long acting inhaled β2 agonists
low dose sustained release
Theophylline
Cromones
Long acting oral β2 agonists
Anti – Immunoglobin E
Systemic glucocorticosteroids
Reliever Medications
Rapid acting inhaled β2
agonists
Systemic glucocorticosteroids
Anticholinergics
Theophylline imediate release
Short acting oral β2 agonists
Current Management of Asthma .
Short acting beta 2 agonist for symptom relief Step
1
Mild
intermittent
asthma
Mild
Persistent
asthma
Moderate
Persistent
asthma
Severe
asthma
ICS+ Leukotriene modifier add onStep
2
Step
3 Low dose ICS +LABA
High dose ICS+ LABA
Leukotriene modifier
Step
4
Severe
Persistent
asthma
Step
5
Oral steroid+ high
dose ICS+ LABA
Inhalational corticosteroids &
Advances in Steroid resistance
Beta 2 agonists
Phosphodiesterase Inhibitors
Methyl xanthines
Anticholinergics
Anti IgE
Anti cytokines
Novel class of
bronchodilators
Immunomodulatory therapies
Newer anti-inflammatory
therapies
Miscellaneous approaches
CTRH
Toll like receptors
Marcolides
Endothelin antagonists
Inhalational corticosteroids ICS Pharmacokinetics Safety
Triamcinolone Greater systemic side
effects Beclomethasone
Fluticasone High first Pass
Metabolism (liver )
Fewer systemic side
effects
Safe at higher doses Budesonide
Momethasone
Ciclesonide Prodrug
High First Pass
metabolism
High plasma protein
binding
Minimal systemic side
effects
Ciclesonide
Prodrug, converted to active ingredient
des-ciclesonide by lung esterases
Oral Bioavailability <1 %
Highly Plasma protein bound 99%
Half-life: 0.71 hr (ciclesonide); 6-7 hr
(des-ciclesonide)
Clearance: 152 ML/hr high
Lipid Binding to fatty acids in lung
Decreased
systemic toxicity
Increased Local
action
Soft steroids
They have improved local, topical selectivity and have
much less steroid effect outside target area.
Lactone GCS conjugate
Glucocorticoid with a lactone ring
Stable in the lung , not metabolized by lung esterases
Metabolized quickly by plasma paraoxonase
Soft steroids
Loteprednol
Approved for ophthalmic use
Phase 2 development in Germany
Lactone GCS
Butixocort/ Tipredane Lack clinical efficacy
Rofleponide Preclinical phase
SEGRA- Selective Glucocorticoid
receptor agonist
Desirable anti-inflammatory and immuno suppressive properties of classical
glucocorticoids drugs but with fewer side effects .
Transactivation
annexin
A1, angiotensin-
converting
enzyme, neutral
endopeptidase
Transrepression
COX,NO
synthase, TNF, TG
F BETA, ICAM-1
Mapracorat ( SEGRA )
• Topical treatment of atopic dermatitis and
inflammation following cataract surgery.
• New frontier for asthma research .
Advances in Steroid resistance
About 5-10% of asthmatics are resistant to steroids
Definition
Failure to improve baseline FEV1by more than 15% after treatment with
prednisolone (30– 40 mg daily) for 2 weeks
Type I Steroid Resistant Asthma
Reduction in glucocorticoid receptor‐binding affinity
High concentrations of IL‐2 and IL‐4 or by IL‐13 alone
Type II Steroid Resistant Asthma
Due to low numbers of glucocorticoid receptors
IV immunoglobulins:
Steroid-sparing effect appears to be present but is not used, as it is prohibitively expensive.
IL-2 & IL-4 levels can be lowered by IV immunoglobulins: 2-3 mg / kg / wk / 4wks
Methotrexate:
Methotrexate causes inhibition of T cell proliferation through inhibition
of enzyme Amidophosphoribosyltransferase.
Concomitant weekly methotrexate therapy causes clinically
significant reduction in oral prednisolone doses 15mg/day to
5mg/day.
Methotrexate therapy also increases peripheral blood T cell sensitivity
to prednisolone inhibition.
Cyclosporine:
selectively inhibits T lymphocyte proliferation, IL-2 and other cytokine
production and response of inducer T cells to IL-1.
It is used as a second line immunomodulator drug in steroid resistant
asthma.
Gold: Has been used in Japan, and isolated studies in
Europe and America have shown decreased use of steroids,
improved symptoms but no change in FEV 1
Leflunomide:
A disease modifying agent for rheumatic diseases, it also causes selective
suppression of Th cytokine expression. They have a steroid sparing effect.
Inhalers- Hydrofluroalkane HFA
Breath actuated pMDI
( AUTOHALERS )
Multiple Dose Devices DPI Ultrasonic Nebulizers
Single dose DPI
SIT - Single Inhaler therapy
• LABA monotherapy has been associated with an
increased risk of asthma-related morbidity and mortality,
• Should only be used along with an ICS
Combination therapy
Inhalational corticosteroid +LABA Maintenance
Rational of ICS + LABA
Common combinations
Beclomethasone+ salmeterol
Fluticasone + salmeterol
ICS
1. Prevents down regulation of Beta receptors
2. Prevents desensitization
LABA
Helps In enhancing the binding of Glucocorticoids to GCR
Maintenance Levosalbutamol
SMART – Single Inhaler Maintenance
and reliever therapy
Formoterol has a fast onset of action <1min compared to
other LABA like salmeterol with a onset of 30min
Therefore ICS+ LABA Combinations that contain
formoterol
Budesonide + formoterol
Fluticasone + formoterol
Maintenance and
reliever
Advances in Beta 2 agonists
Ultra LABA’s
Ultralong acting LABA . Duration > 24 hrs.
Indacaterol
Bambuterol
carmoterol,
vilanterol
olodaterol,
Indacaterol
Initial trials
Safe
Improvements in FEV1 at 4 weeks ,
Long term studies – Not established the effect
on asthma disease control
Asthma exacerbations
CysLT 2 Receptor antagonists
• Studies have revealed that Cyst LT2 mRNA is
abundantly expressed on activated eosinophils.
• Raised the possibility that Cyst LT2 antagonists
would be more effective in ameliorating the LT’s
response explaining the relative failure of the
existing Cyst LT1 antagonists.
Methyl xanthinesLow dose Sustained release theophylline
Plasma values 5 to 10 mg/l – Anti-inflammatory / Less side effects .
Mechanisms :
Histone deacetylase activation- Steroid resistant asthma Effects on apoptosisInterleukin-10 Inhibition of NF-KB
Indications
Low dose sustained release theophyline as a add on to ICS in severe asthma
Doxofylline
• Novel xanthine bronchodilator
Mechanism of action
• Inhibition of phosphodiesterase 4,
• Decreased affinities towards adenosine A1 and A2
receptors,
Comparative Safety Profile
No CNS stimulation
No cardiac arrhythmias
Phosphodiesterase Inhibitors
PDE4 inhibition is thought to lead to elevated levels of
intracellular cAMP,
• suppression inflammatory cell function
• inhibition of mucin production epithelial cells
• alterations in airway smooth muscle tone
Selective PDE inhibitors
Roflumilast , Cilomilast, Rolipram, Ibudilast,
Piclamilast, Luteolin
Roflumilast
selective, long-acting inhibitor of the enzyme PDE-4
Reduces release of cytokines
Reduces migration and activation of immune cells
Results Long acting Muscarinic Agonists ( Tiotropium )
1. In moderate to severe asthma , as a add on when no response to ICS+ LABA
2. In mild persistent asthma as a add on to ICS .
Important outcomes that are not evaluated in all studies published until
now are the reduction of exacerbations and the anti-inflammatory
effects of tiotropium
Currently available data on the efficacy of tiotropium in asthmatic patients are
not sufficient to recommend the use of this drug
Novel classes of bronchodilators
Magnesium sulfate
MOA• Reduces cytosolic calcium in airway smooth
musclebronchodilatation
USES :Useful as an additional drug to SABA in A/c severe asthma
can be given by IV/nebulisation
Side effects
Include flushing and nausea
Not suitable to be employed alone as clinical benefit is small
Potassium channel openers
Potassium channel openers that open calcium activated large conductance K+ channels in smooth muscle
Calcium channel blockers Nifedipine, verapamil
-Prevent calcium entry into smooth muscle-Inhibit stimuli induced bronchoconstriction
VIP analogs
- VIP binds to VPAC1(smooth muscles of blood vessels) &
VPAC2(airway smooth muscle)couple to Gs
adenylyl cyclase stimulated-smooth muscle
relaxation
- VIP potent bronchodilator in vitro studies but in patients
it is rapidly metabolized and also has vasodilator Side
effects
Stable analog of VIP (RO 25-1533) selectively stimulate
VPAC2-produces rapid bronchodilatation but effect is
not prolonged .
ANP & related peptide Urodilatin
- Activates membrane guanylyl cyclase cGMP
bronchodilatation
- Bronchodilator effects comparable to SABA.
- Useful for additional bronchodilatation in Acute severe
asthma
Anti IgE
Omalizumab
Humanized monoclonal antibody
MOA:
•Neutralizes IgE in circulation
•Inhibits activation of IgE bound to mast cells
•Down regulates IgE receptors on mast cells
Route : S/c or IV every 2- 4 weeks
Use :
severe persistent extrinsic asthma who are resistant to
other forms of treatment.
Reduces exacerbations and requirement of oral and inhaled steroids in them
Drawback : high cost
S/E : local reaction at inj. Site
urticarial, rash, flushing
rarely anaphylactic reaction
Anti IL-5
IL-5
Anti IL-5 Antibodies
Mepholizumab
Humanized Monoconal antibody
Phase 3 trials
Reduced Eosinophil entry in the airways
Decrease asthma exacerbation
Reslizumab
Phase 2
Pronounced in a subgroup
of patients with highest blood &sputum
eosinophils,
IL5 Receptor antibodies
Benralizumab
Pre-clincial stage
Decrease of circulating eosinophills
Anti IL-4
IL-4
Th2 differentiation
Switching of B cells to IgE synthesis
Eosinophil recruitment
Development of mast cells
Anti IL4
Pitrakinra ( s.c / inhaled )
Pascolizumab
Dupilumab decrease in asthma exacerbation rate during
withdrawal of inhaled therapy with
corticosteroids and long-acting 𝛽2-
adrenergic agonists,
marked improvement of respiratory function
TH2
Anti IL-13
Lebrikizumab ( PHASE 3)
Improvement of lung function in patients
with moderate-to severe asthma
Improvement of FEV1 from baseline
Tralokinumab ( s.c) -- Phase 3
Decrease need for rescue medication
Anti IL-9
MEDI -528
Improved Asthma Symptom scores
In Trial for exercise induced asthma
TH2
Anti TNF alpha Th1 TNF alpha
Recruitment neutrophils and eosinophils via upregulation of
epithelial and endothelial adhesion molecule
Anti TNF alpha Evidence from phase 2
trials
Concern
infliximab circadian oscillations in
peak expiratory
flow
active tuberculosis,
pneumonia, sepsis, and
several different
malignancies
(breast cancer, B-cell
lymphoma, metastatic
melanoma, cervical
carcinoma, renal cell
carcinoma, basal cell
carcinoma,
and colon cancer)
golimumab Not conclusive
etanercept improve lung function,
airway hyper-
responsiveness, and
quality of life
Anti IL-17
TH1 IL-17
Neutrophilic inflammation, airway remodeling, Steroid resistant
Secukinumab Humanized anti IL17 antibody
Brodalumab Il-17 receptor antibody
On Going Phase 2 trials in severe asthma that is not adequately
controlled by ICS+LABA
IL-17 is also involved in immune protection against infectious and
carcinogenic agents
In vitro studies human anti-GM-CSF monoclonal
IgG1 antibody (MT203) has been developed,
capable of significantly decreasing survival and activation
of peripheral human eosinophils
Anti GM-CSF
GM-CSF is a growth factor over expressed in asthmatic
airways
Th1 directed
Serious infections
Neoplastic
disorders
TH2 directed
Autoimmune
diseasesRestricted to
phenotype
Needs evaluation of
cytokines &
markers
Expensive add to
the cost diagnosis
and treatment
Drawbacks
CRTH2
CRTH2 (Chemo attractant Receptor-homologous
molecule expressed on Th2 cells)
G-protein coupled receptor expressed by Th2
lymphocytes, eosinophils, and basophils.
The receptor mediates the activation and chemotaxis of
these cell types in response to prostaglandin D2 (PGD2),
produced by mast cells.
Contributes to the so-called “Th2 polarization”
CRTH2 antagonists
Using indomethacin, a CRTH2 agonist, as a starting block
and have prepared novel CRTH2 DP2-selective
antagonists
An oral CRTH2 antagonist (OC0000459) showed a 7.4%
improvement in FEV1 at 28 days (p=0.037).
led to a reduction in total IgE concentration and a trend
toward decreasing sputum eosinophils
Macrolides
Clarithromycin reported to be effective in many cases asthma.
Causation of asthma linked to Chlamydia pneumonia or mycoplasma pneumonia
Statins are now under evaluation in asthma therapy by
AAAAI
It was observed that asthmatics with co-morbidities who
are on statins have 30% lower risk for ER visits &
hospitalizations due asthma than controls.
Miscellaneous approaches
Endothelin antagonists may improve structural changes in asthma. However not tested.
Antioxidants more potent than Vit C&E, N-Acetyl cysteine in development as oxidative stress important in asthma.
Bitter taste receptors agonists ---chloroquine,saccharine
Bronchial thermoplasty
Concept:Passing RF pulses through the airway tissues generates heat due to tissue resistance debulking of ASM
Devices : thermoplasty apparatus and RF compatible FOB
• In a double-blind, randomized, sham-controlled
clinical study of bronchial thermoplasty
• Improved Qol
• Reduction in asthma attacks
• Reduction in emergency room visits for
respiratory symptoms
• Reduction in days lost from work, school,
• Reduction in hospitalizations for respiratory
symptoms
FDA approved 2010
Immunotherapy
• Administration of increasing doses of allergen extracts to
induce persistent immune tolerance in patients with
allergen-induced symptoms
• Recently SubLingual immunotherapy (SLIT) is preferred
and claimed to be more effective in asthma
Benefits include: ↓ in symptom scores, ↓ in medication usage and ↓ airway reactivity
Mechanism: Increased regulatory T cell activity Restoration of Th1- Th 2 balance Switching of allergen-specific B
cells towards IgG4 production.
Usual course: 3-5 years on maintenance therapy.
Allergen peptides:The active peptides of allergens are used → down regulation of T cells without co-stimulatory signals
1. Short T cell epitope peptides: induce tolerance without mediator release (no IgE binding)
2. B cell epitope derived peptides: stimulate B cells to produce blocking IgG 1 without IgE binding
Recombinant allergens:
Reconstructed with reduced allergenic activity
CpG-DNA based immunotherapy:
• Giving cytosine guanine plasmid DNA with allergen
extract produce a strong Th-1 response with increase of
mucosal IF-ϒ and decrease IgE production
Is the insertion of a functional gene in a target cell
to exert the gene function
Genes transferred to target cells by a viral vector
or a liposome (? nanocarrier)
Target cells in the lungs are respiratory epithelium
Cytokine encoding genes:
Genes encoding for IL-12, IF-ϒ, IL-18:
Cause marked reduction in eosinophilic inflammation, IgE
production and airway hyper responsiveness
Genes encoding for IL-10 and TGF-β:
Cause suppression of both Th-1&Th-2 response
β2 receptors encoding genes:To over express β2 receptors and potentiate bronchodilation
Glucocorticoid R genes:Over expression overcomes GCR resistance and decrease systemic
SEs
Cloned Th -1 cells are now under Phase 2 trials
Aim: correction of Th1-Th2 imbalance in
asthma with correction of cytokine profile:
↑↑ IL-12, IF-ϒ & ↓↓ IL-4, IL-5, IL-13
T cell Therapy