Download Bronchial Asthma: Traditional, Evolving and Biological Therapies For a Difficult Disease

G. Krishnaswamy, MD
9/28/2010
Mr. B
Bronchial Asthma: Traditional, Evolving and Biological Therapies For
Evolving and Biological Therapies For a Difficult Disease
Guha Krishnaswamy, M.D., FACP., FCCP, FAAAI, FACAAI
Professor, Medicine
Chief, Allergy, Asthma and Immunology
Adjunct Professor, Pediatrics and Physiology
Quillen College of Medicine and James. H. Quillen VA Medical Center
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67 year old patient with chronic severe wheezing
Coughs up plugs of mucus and casts
Frequent hospitalization
CBC reveals eosinophilia
Immunoglobulin E levels are elevated
Immunoglobulin E levels are elevated
– Allergy tests show multiple positivity
• Chest roentgenogram demonstrates air trapping and a patchy opacity
• Chest CT scan demonstrates wedge shaped opacity of the LUL
• V/Q scan, LE doppler and spiral CT/angio of the chest show no evidence of PTE
Airway Remodeling
Normal
• Smooth muscle/goblet cell hyperplasia
– Mucus secretion
Coughed up mucus
Sinus CT scan
• Epithelial denudation
Histopathology of mucus
– Collagen deposition
– Airway thickening
FEV1: 39%
FEV1/FVC: 44% Asthma
• Smooth muscle hyperplasia
• Cartilage remodeling
• Inflammation
– Th2 cytokines
• Angiogenesis
Evolution Of Complex Phenotypes
The interconnected immune universe
Mast cells
Eosinophils
•B cells make IgE
•T cells make IL-4 and IL-5 (Th2)
•T regs make IL-10 that inhibit allergy
•TLR- important to hygiene hypothesis
•C3- complement accessory role
•Gene-by-environment interactions pivotal to asthma
Host factors
•Genes
•Immune response genes
•IgE
•Airway hyper-response
•Cytokine SNPs
•Pharmacogenomics
•Drug
D
response
•Drug toxicity
•Sex
•Hormones
•Puberty
•Pregnancy
Airway Inflammation
•Rhino-sinusitis
Asthma
Environmental factors
•Major
•Allergen exposure
•HDM, cockroach
•Alternaria*
•Infections
•Virus (RSV
•Mycoplasma others
•Mycoplasma,
•Other factors
•Smoke (ETS)
•Pollution
•SO2, ozone, particulate
•Occupation
•Diet
•GERD
G. Krishnaswamy, MD
9/28/2010
8
IgE
1=Anti-IgE
2=Anti-Cytokine
3=Immunotherapy
4=Anti-adhesion Rx
5,6=Glucocorticoids
7=LT antagonists
8=MC stabilizers
IL-10
2. What is the severity?
• Impairment and risk
3. How well-controlled is asthma
5. Co-morbid and trigger factors
IL-5
•Allergy immunotherapy: Increased T regs, increased IL-10 and decreased Th2
•Steroids: Bind to intracellular receptors and inhibit transcription factors, NF-kappaB
1: Is It Asthma?
6. Education
•Crisis plan
•Avoidance
7. Follow up
•Exacerbations
•Disease QOL and Control
2. How Severe Is The Asthma?
• Definition
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1. Is it asthma?
4. Treatment
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•Upper airway: rhinitis/sinusitis
•Lower airway: Controller, reliever
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5-LO
LTs-CysLTR
IL-4
Therapy Of Asthma
Episodic symptoms of airway obstruction
Airway hyper‐responsiveness
Reversibility of airway obstruction
Alternative diagnosis are excluded
Di
i
h d
• Diagnostic methods
– Detailed medical history and examination
– Chest roentgenography to exclude other pathology
– Spirometry before and after BD
• >12% reversibility compared to baseline pre‐BD*
• >10% reversibility using predicted FEV1
• Symptoms
– Nocturnal awakenings
– Need for SABA
– Work/school days missed
– Ability to engage in normal or desired activity
Abili
i
l d i d i i
– QOL assessments (ACT)
• Lung functions
– Spirometry: preferred method
– PEFR to monitor control or progression over time
*Patients with COPD may demonstrate 12‐14% reversibility
Reviewed by Dr Mehta
2: How Severe Is The Asthma?
Remember •that severe asthma may be well‐controlled and
mild asthma poorly
controlled
•Severity is used to
initiate treatment in naïve
Patients or newly‐dx
asthma
3. How Controlled Is The Asthma?
G. Krishnaswamy, MD
9/28/2010
•Albuterol use <2/week
/
•Albuterol use >2/week
•Albuterol use daily
•Albuterol use several times daily
Intermittent asthma
Mild persistent asthma
Moderate persistent asthma
Severe persistent asthma
Step 1
p
Step 2
Steps 3,4
Steps 5,6
>20= good control
15-19= not well-controlled
<15=very poorly controlled
4. Asthma Treatment
Cromolyn and nedocromil
Are out of vogue
Theophylline has toxic potential
Controller Medications
• Inhaled corticosteroids
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Fluticasone (Flovent) Budesonide (Pulmicort)
Mometasone (Asmanex)
Beclomethasone (QVAR)
Ciclesonide (Alvesco)
Others triamcinalone
Others‐triamcinalone
(azmacort), flunisolide (Aerobid)
• LABAs
– Salmeterol (Serevent)
– Formoterol (Foradil)
– Nebulized formoterol (Perforomist)
• Combination
C bi i
– LABA+ICS
• Cromolyn/Nedocromil
• Immunomodulators
• Fluticasone‐Salmeterol (as DPI Diskus or as HFA MDI inhalation aerosol)
• Budesonide‐Formoterol (Symbiocort)
• Mometasone‐Formoterol (Dulera)
– Omalizumab
• Leukotriene modifiers
– Leukotriene receptor antagonists
– Lipoxygenase inhibitors
Inhaled Corticosteroids
• Most potent of the asthma medications
• Many categories with different properties
– Identify and learn to use ICS and devices
– Recognize topical potency and oral bioavailability
g
p
p
y
y
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Block late phase response to allergen
Inhibit inflammatory cell migration/activation
Useful in long term control of asthma
Few adverse effects if used properly
ICS: Yin and Yang
Fitted Rate Ratio for Death from Asthma as a Function of the Number of Canisters of Inhaled Corticosteroids Used during the Year before the Index Date.
•Decrease risk of dying and hospitalization
•Improve symptom control
•Improve nocturnal asthma
•Improve pulmonary function
•Decrease airway inflammation
•Improve bronchial hyperresponsiveness
Senthilselvan et al. Chest. 2005;127(4):1‐15
Potency Mometasone/Fluticasone>budesonide>
beclomethasone>flunisolide>triamcinalone
Oral bioavailability
Low for fluticasone and mometasone (<1%)
Adverse effects
Transient reduction in height but no effect on adult height;
catch up occurs; dysphonia; varicella;
Osteoporosis; skin atrophy
Posterior subcapsular and nuclear cataracts
Adrenal suppression at high doses (cumulative)
G. Krishnaswamy, MD
9/28/2010
Large airway Small airway
Leukotriene Modifiers
93%
• Not preferred compared to LABAs
• Useful as adjunct agents with ICS
• Also useful in allergic rhinitis, steroid resistance?, and in smokers
• Leukotriene receptor antagonists (LTRA)
35%
7%
BDP CFC
65%
MBP+ Eosinophils in large and small airways before (And B) and after (C and D) BDP HFA
BDP HFA
– Category B in pregnancy
Category B in pregnancy
– Montelukast
• >1 year of age (granules, chewable, pills)
– Zafirlukast
• >7 years of age (pills)
• Coumadin interactions
• Lipoxygenase inhibitor
– Zileuton CR
• >12 years of age
• Liver function abnormalities
LT Modifier Drugs
LABAs
• LT modifier drugs demonstrate anti‐asthma efficacy
• May be especially beneficial in EIA and aspirin‐sensitive asthma
• Adding a leukotriene modifier drug to ICS offers additional anti‐inflammatory effects
• Salmeterol (onset 15 minutes) and Formoterol (onset 5 minutes)
• Not to be used as monotherapy
• Used in conjunction with ICS step 3 or higher >5 years of age and adults
Of adjunctive therapies available LABAs are preferred
• Of adjunctive therapies available, LABAs are preferred Rx to combine with ICS
• May be used to prevent EIA but not too frequently due to “masking”
– Duration for EIA is 5 hours
• Use of LABA for acute asthma is not currently recommended
• Nebulized form is now available (Formoterol Fumarate inhalation solution [FFIS] or Perforomist )
– May be mildly effective for upper airway disease
y
y
pp
y
• Combination of a LT modifier drug and ICS
– Inferior to LABA/ICS combination
– Superior in decreasing inflammatory biomarkers
– May be added to moderate to high dose ICS and LABA in patients with moderate to severe persistent asthma
– May have steroid sparing potential
Szefler SJ - J Allergy Clin Immunol - 01-MAR-2005; 115(3): 470-7
LABA
• May have anti‐inflammatory effects on asthma
• In patients with low or moderate doses of ICS, adding a LABA provides benefit
– Alleviates asthma symptoms
– Improves lung function
– Steroid sparing effects
• LABA
LABA may help translocate GC receptors from cytosol to may help translocate GC receptors from cytosol to
nucleus
– Improve steroid efficacy
• Recent data on gene polymorphisms (Arg/Arg) may provide evidence for subsensitivity of LABA
– Patients homozygous for an arginine at 16th position had lower morning PEFR
• Concern about tachyphylaxis
Szefler SJ - J Allergy Clin Immunol - 01-MAR-2005; 115(3): 470-7
Salmeterol Study (SMART)
• Salmeterol multicenter asthma trial (SMART)
– Compared salmeterol to placebo over 28 weeks in patients with asthma in RDBPC, observational study
– Supposed to enroll 60,000 patients but halted early with 50% enrollment (26,355)
– Primary outcome of respiratory related death or life threatening experience was low (Salmeterol vs Placebo RR g p
(
of 1.4; 50 vs 36)
– Higher numbers of respiratory deaths or life threatening experience (20 vs 5) in salmeterol‐treated patients (RR 4.1) largely in African Americans
– FDA and company have added warning to drug labeling for medications containing salmeterol
– LABA drugs must be combined with an inhaled glucocorticoid to prevent adverse effects
Nelson HS - Chest - 01-JAN-2006; 129(1): 15-26
G. Krishnaswamy, MD
9/28/2010
N Engl J Med. 2006 Apr 13;354(15):1589‐600
5. Address Co‐Morbid Factors
TELICAST
• Rhinitis/sinusitis syndromes
Double‐blind, randomized, placebo‐controlled study to evaluate the efficacy of telithromycin in patients with acute exacerbations of asthma. – Endoscopy, clinical
• Nasal polyps and aspirin sensitivity
– CT
• Allergic fungal disease and SAM syndrome
The number of subjects with positive PCR results for
Mycoplasma and Chlamydia species in patients with asthma and
healthy control subjects.
– Fungal precipitins, fungal‐specific IgE, CT scan, MRI
• GERD
– 24 hour pH probe, upper endoscopy
No improvement in PEFR occurred
– Polysomnogram
5. Address Iatrogenic And Other Triggers
The patients were randomly assigned to Th
ti t
d l
i dt
receive 10 days of oral treatment with telithromycin (at a dose of 800 mg daily) or placebo in addition to usual care
Mean decrease in symptom score was 1.3 for the Telithromycin group and 1.0 for placebo
• Obstructive sleep apnea
• Psychosocial factors and depression
• Hormones and perimenopausal state
A total of 278 adults with diagnosed asthma were enrolled within 24 hours after an acute exacerbation of asthma requiring short‐term medical care. Immunoperoxidase detection of M. pneumoniae in
a bronchial biopsy specimen taken from a patient
with severe asthma. Note that particle aggregates
are found on the epithelial surface.
61% of patients with acute asthma had evidence of infection with CP, mycoplasma or both
6. Education: Environmental Control
• Beta adrenergic antagonists
– Cardio‐selective agents may be acceptable in selected patients with mild‐moderate disease
A, Dust mite of the species Dermatophagoides farinae, showing legs and mouth parts; these acarids are sightless but are sensitive to light, so they are not normally present on the surface of carpets or upholstered furniture. B, Details of the legs of a dust mite, showing the pads on the end that allow the mite
pads on the end that allow the mite to hold on to surfaces. C, Mite fecal particle, which has a chitinous peritrophic membrane that prevents it from breaking up. D, Scanning electron micrograph of a cat hair, showing the size and presence of adherent particles of dander/skin scales that carry antigen. (A to C courtesy John Vaughan; D courtesy Judith Woodfolk.) From Middleton
• ACE‐inhibitors
– Bradykinins and neutral endopeptidase inhibition
• NSAID and aspirin
and aspirin
– Leukotriene driven
• Sulfites
– Processed foods
– Shrimp
– Potato salads
– Beer and wine
– Dried fruit
Back To Our Patient
7. Follow Up
• The Expert Panel recommends that regular follow up contact is essential (Evidence B)
Before prednisone
– Contact at 1‐ to 6‐month intervals is recommended, depending on the level of control
– consider 3‐month intervals if a step down in therapy is anticipated (
(Evidence D)
)
• The Expert Panel recommends that, once asthma is well controlled and the control is achieved and maintained for at least 3 months, a reduction in pharmacologic therapy—a step down—can be considered. This will be helpful to identify the minimum therapy for maintaining good control of asthma (Evidence D)
• Assess impairment (Sx, ACT, PFT) and risk (exacerbations)
After prednisone
G. Krishnaswamy, MD
9/28/2010
Immunomodulators
• Proven to be useful
Omalizumab Blocks IgE Binding to Mast Cells
Omalizumab
Omalizumab
Antigen
– Omalizumab >12 years of age
• Probably useful
– Anti‐TNF inhibitor (adult refractory asthma)
• Uncertain usefulness
IgE
FcεRI
– Biologicals‐ shown to be ineffective
• Anti‐IL5, rIL‐12, rIL‐4 receptor (nuvance)
– BRMDs (shown top have marginal or inconsistent effect)
• IGIV, methotrexate, dapsone, colchicine, hydroxychloroquin, azathioprine, cyclosporine
Omalizumab Effects
F
FEV1, % of baseline
Omalizumab*
95
P<0.05
85
75
1
2
3
4
5
Time (hours)
6
7
Before treatment
After 56 days of treatment
*Note that during the second challenge
7 of 9 patients required 2.2 times more
allergen to cause bronchoconstriction
(compared to baseline).
Clinical Effects in Asthma
Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, Beeh KM, Ramos S, Canonica GW, Hedgecock S, Fox H, Blogg M, Surrey K: Benefits of omalizumab as add‐on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy 2005, 60: 309‐316
Fahy JV, et al. Am J Respir Crit Care Med. 1997;155:18281834.
Milgrom H et al. N Engl J Med. 1999;341(26):196673.
Before Rx
Inhibition of mediators
• Fewer exacerbations, ER visits and Fewer exacerbations ER visits and
hospitalizations
• Improved asthma scores
• Improvement in pulmonary function tests
65
0
Mediators
• INNOVATE study: omalizumab vs placebo x 28 weeks
The omalizumab group demonstrated:
n=9
105
Mast cell
Patient PFTs before and after therapy
Immune Deviation Therapies
• Specific immunotherapy (SPIT), Sublingual immunotherapy (SLIT)
• Conjugation of allergens with immunostimulatory DNA (CpG dinucleotide repeats)
– Immune deviation towards a Th1 response
After Rx
• Fusion complexes
– Allergen fusion protein with IL‐12
– DNA vaccines of cDNA of allergen fused to IL‐18 cDNA
• Mainly tried in animal models
• Skew towards a Th1 response
G. Krishnaswamy, MD
9/28/2010
Bronchial Thermoplasty
• Bronchial thermoplasty interrupts that ring of muscle so that it is incomplete and thereby decreases the constriction of the airways, and this may be of great benefit in potentially reducing the frequency and severity of asthma attacks
Immunologic changes during the course of allergen-SIT. Although significant variation occurs between donors and
protocols,an early decrease in mast cell and basophil activity and degranulation, and a decreased tendency for
systemic anaphylaxis is observed starting from the first injection.The second immunologic event in the early course
of allergen-SIT is the generation of allergen-specific Treg cells and suppression of allergen-specific Th1 and
Th2cells. A significant decrease in allergen-specific IgE/IgG4 ratio occurs after afew months, which is parallel to a
decrease in type I skin test reactivity.