Jeanette Arnold, MSN, C-FNP Instructor Division of Clinical Allergy, Immunology and Rheumatology University of Mississippi Medical Center Jackson, Mississippi,

Jeanette Arnold, MSN, C-FNP Instructor Division of Clinical Allergy,

Immunology and Rheumatology University of Mississippi Medical Center

Jackson, Mississippi, USA [email protected]

Asthma Update

AAFA No other disclosures or industry affiliations

Disclosures

At the conclusion of this presentation, participants should:1. Be familiar with recent studies on the use of anticholinergic medications in asthma2. Be able to discuss the relationship between ICS and growth in children3. Be able to interpret current data on acetaminophen and asthma

Objectives

Where we’ve been: Homogenous asthma manifested by

bronchospastic obstruction…mucus, inflammation

Owl’s blood in wine, tobacco, coffee/tea, Indian hemp, ether or opium; then systemic steroids, theophylline and SABA… then ICS with and without LABA

Control based on lung function and symptomatology

All asthmatics are not created equally

Where we’re going: Asthma is heterogeneous- Differences in pathology, symptomatology, response

to therapy and prognosis (Lotvall, JACI 2011)

70-95% w/ mild to moderate ds- managed with ICS and beta 2

5-35% fail standard tx: severe disease or “refractory” asthma

(Morjaria et al, COACI 2011)

Mixed inflammatory: Cells (neutrophils, eosinophils and basophils) Cytokines (interleukin [IL]-4, and chemokines)

B-cells and activated T-cells [Th1, Th2, Th17] (Durrani & Busse ,Chest, 2011)

All asthmatics are not created equally

Influence of co-morbidities Obesity, CRS, GERD- Atopy not as big an influence as we thought (Turato

AJRCCM 2008)

Routine ICS fail to alter remodeling (Guilbert NEJM 2006, Murray Lancet 2006)

Definition of control? - dual domains: QOL, symptoms and exacerbations Preservation (or loss ) of lung function , exacerbations

and medication risk/SE (Durrani, 2011)

All asthmatics are not created equally

Asthmatics w/ 1° neutrophilic inflammation are: More steroid resistant than eosinophilic

asthmatics. More likely to have severe asthma with more

acute exacerbations (Wenzel, 2006; Gibson, 2009).

Asthmatics who smoke are more likely to have asthma resistant to low dose ICS (Tomlinson et al., 2005; Lazarus et al., 2007).

Asthma Heterogeneity and Phenotyping

Current step up tx from a low dose ICS: Either double the glucocorticoid dose or add a LABA (or leukotriene inhibitor)

ICS have a “relatively flat dose–response curve”; controversial

LABAs are controversial (B16-Arg/Arg)

Taking a new look at an old drug: anticholinergics

Smith, L. Anticholinergics for Patients with Asthma? New Engl J Med Oct., 2010; 363:1764-1765

First Things First

Peters, SP. et al. 2010, N. Engl. J. Med. 363, 1715-1726

200 poorly controlled asthmatics 3 arms: tiotropium + ICS

salmeterol + ICS doubled the ICS per NAEPP

As effective as adding salmeterol and more effective than doubling the ICS

Tiotropium bromide step-up therapy for adults with uncontrolled asthma

Vogelmeier, C., et al., N Engl J Med. March 2011; 364:1093-1103

1-year, randomized, D-B, D-D, parallel-groupCompared # of moderate or severe exacerbations in pts with moderate-to-very-severe COPD & hx of exacerbations in the preceding 12 months7, 376 patients randomly assigned

Tiotropium (n=3707) or Salmeterol (n= 3669)Tiotropium more effective than Salmeterol:

Increased time to first exacerbation (187 days vs 145) Reduced annual # of exacerbations (0.09 vs 0.13) Incidence of adverse events similar (64 deaths/1.7% vs

78/2.1%)

Tiotropium versus Salmeterol for the Prevention of

Exacerbations of COPD

Tiotropium improves lung function in patients with severe uncontrolled asthma: A

randomized controlled trial

Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma

Measured weekly AM PEF: 1º endpoint PEF Tiotropium -3.9 ± 4.87 L/min Salmeterol - 3.2 ± 4.64 L/min Placebo -24.6 ± 4.84 L/min

Tiotropium and salmeterol were roughly equivocal Both were significantly more effective than

placebo

Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma

Barnes, Peter J. w/ NHLBI Expert Review article (Expert Rev. Respir. Med 5

(3), 297-300 (2011) @ www.expert-reviews.com First triple inhaler containing formoterol,

tiotropium and ciclesonide (Triohale, Cipla) marketed in India

Too soon to tell, but data might support using tiotropium as add on therapy in certain phenotypes/severe asthmatic poor responders

Future for triple inhalers?

Steroid use in growth of children

Shaheen, S. et al. Prenatal and infant acetaminophen exposure, antioxidant gene polymorhpisms and childhood asthma. JACI, Dec. 2010; 126(6): 1141-1148.

British Avon Longitudinal Study of Parents and Children (ALSPAC) 14000 children from utero to 8th year Mother reported acetaminophen exposure in utero and early

childhood, hx of early wheezing, allergy and asthma s/s, environmental exposures and family lifestyles.

PFT, blood or skin tests for allergies and genetic testing of mother and child b/w ages 7 and 8 yrs.

Longitudinal association w/ childhood asthma was limited to children who had wheezed in infancy- Suggests casual relationship

Acetaminophen and Atopy: Causality or Commonality?

Marquis, A. et. al, JACI Jan. 2011; 127(1): 270-272 1293 young adults “cured from CA” from Swiss Childhood Cancer

Registry < 16 at time of dx; > 16 @ time of survey;@ least 5 yrs post diagnosis PMH of asthma, frequency and type of analgesics:

Paracetamol alone Nonaspirin NSAIDs alone ASA alone Or different combinations of these three

Found a positive association b/w non-ASA NSAIDs and asthma = paracetamol and asthma; if this is causal, not limited to acetaminophen.

Most likely explanation is confounding by indication- more studies needed

Paracetamol, non-steroidal anti-inflammatory drugs, and risk of asthma in

adult survivors of childhood cancer

Schnabel, E. and Heinrich, J.; JACI Nov. 2010; 126(5): 1071-1073. 3097 healthy full term infants under Influences of Lifestyle-related

Factors on the Immune System and the Development of Allergies in Childhood (LISA)

Birth – 6 years; monthly diaries of febrile illnesses, type & medication use

Measured IgE to common inhalants at 2 and 6 years age by CAP-RAST < 5% of these children were tx with anything other than

acetaminophen

Children with asthma had > fever than non-asthmatics No correlation b/w allergic sensitization and acetaminophen Suggests increased incidence of URI and febrile illnesses in asthmatic

children more likely source of association.

Respiratory tract infections and not paracetamol medication during infancy are

associated with asthma development in childhood

Medication/ therapy Mechanism of action Summary of trial results

Golimumab and Etanercept

TNF-a and TNFR 2 DBPC- lacked efficacy; terminated due to > SE; no further studies planned

Mepolizumab Monoclonal Ab (Anti-IL-5) antagonizes eosinophilic pathway

2 DBPC- decreased eosinophilia with < exacerbations- further studies

CAT-354/IMA-638/QAX576

Monoclonal Ab (Anti-IL 13) Initial reports suggest efficacy; phase 2 studies

Daclizumab Anti-CD25; antagonizes IL-2

1 study; 115 pt.; small but signif. Improvements; no SE; needs more study

Masitinib Tyrosine kinase inhibitor(c-kit and PDGF receptors)

Pilot study; mixed results with lots drop outs RE drug SE and poor outcome

Upcoming therapies under investigation

Medication/ therapy

Mechanism of action

Summary of trial results

AMG 317 IL-4 receptor alpha chain used by IL-4 and IL-13; high affinity IL-4 a receptor binder

No signif. diff in 1º or 2º endpoints; well tolerated; needs more study

Altrakincept Solubilized IL-4 receptor fragment; blocks IL-4

Went to phase 3 trial; failed to show efficacy

Pascolizumab Monoclonal Ab antagonizes IL-4

Discontinued phase 2 trial; failed to show efficacy

Pitrakinra IL-4 mutant protein; binds to alpha IL-4 subunit

Inhaled form promising; phase 2a trial

Upcoming therapies under investigation

30 year old male born early @ 2#; early wheezer; frequent URI with normal immune system work up- lost to FU age 5-15 yrs.

Formally diagnosed with asthma as teenager 3 hospitalizations over the last 5 years; 1 ICU (6 months

ago)- no intubations Maximum ICS with LABA combination, leukotriene inhibitor

and PPI; pharmacy records indicate appropriate med. refill rates

Skin test mildly positive to DM but not impressive Co-morbidities include GERD, obesity and nasal polyposis Labs: normal CBC with exception of mildly elevated

peripheral blood eosinophils, normal CMP but moderately elevated IgE

Case study

You tell him:1. Only if you take your medications! Your lack

of asthma control indicates you’re non-compliant 2. Only if you lose weight! Your obesity makes it impossible to adequately treat you.

3. Hang in there! There is a lot of research currently underway that is specifically targeted towards difficult to control asthmatics and it looks promising. We’re gaining more understanding of which therapies are better suited for you and making progress. Lets schedule a visit with your doctor to sit down and discuss options.

He asks you if there is any hope for him to live a normal life, stay out of the hospital

and play sports with his newborn sons one day…

Apter, A. Advances in adult asthma diagnosis and treatment and HEDQ 2010. J Allergy Clin Immunol, 2011 , Jan; 127(1): 116-122.

Bateman ED, Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. J Allergy Clin Immunol. 2011 Aug;128(2):315-22.

Barnes PJ. Triple inhalers for obstructive airways disease: will they be useful? Expert Rev Respir Med. 2011 Jun;5(3):297-300. No abstract available. PMID: 21702649

Corren, J., et al. Effects of omalizumab on changes in pulmonary function induced by controlled cat room challenge. J Allergy Clin Immunol. 2011, Feb;127(2):398-405. (www.ncbi.nlm.nih.gov/pubmed/21281870)

Cox, Linda S., How Safe are the Biologicals in Treating Asthma and Rhinitis? Allergy, Asthma & Clinical Immunology 2009, 5:4 (doi:10.1186/1710-1492-5-4)

Resources

Durrani, S., Busse, W. ; Biological Therapy for Asthma. Chestnet.org. PCCSU Article | 03.15.11; volume 25 online.

Garcia-Marcos, L., et al. Early exposure to acetaminophen and allergic disorders. Curr Opin Allergy Clinic Immunolo. June, 2011; 11(3): 162-173.

Gonem S, et al. Evidence for phenotype-driven treatment in asthmatic patients.. Curr Opin Allergy Clin Immunol. 2011 Aug;11(4):381-5. Review. PMID: 21670666

Guilbert, T., et al. Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. JACI 2011, Nov; 128(5): 956-963.

Kerstjens HA, et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: a randomized controlled trial. J Allergy Clin Immunol. 2011 Aug;128(2):308-14. Epub 2011 Jun 2.

Resources

Marquis, A., et al. Paracetamol, nonsteroidal anti-inflammatory drugs and the risk of asthma in adult survivors of childhood cancer. J Allergy Clin Immunol 2011 Jan; 127 (1): 270-272.

Maneechotesuwan K, et al. Bronchodilator effect of Ipraterol on methacholine-induced bronchoconstriction in asthmatic patients. J Med Assoc Thai. 2011 Feb;94 Suppl 1:S66-71.

Morjaria, J, et al. Stratified Medicine in Selecting Biologics for the Treatment of Severe Asthma. Curr Opin Allergy Clini Immunolo. 2011; 11(1): 58-63. (www.medscape.com/viewarticle/735050)

Shaheen, S., et al. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma. J Allergy Clin Immunol. 2010 Dec; 126(6): 1141-1148. (http://www.jacionline.org/article/S0091-6749(10)01408-9/fulltext)

Schnabel, E. Heinric, J. Respiratory tract infections and not paracetamol medications during during infancy are associated with asthma development in childhood. JACI. 2010 Nov; 126 (5) 1071-1073.

Resources