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Asthma: Current status and future directions

Severe asthma: Advances in current management and future


therapy
Peter J. Barnes, FMedSci, FRS

London, United Kingdom

Effective treatment of severe asthma is a major unmet need


because patients symptoms are not controlled on maximum
treatment with inhaled therapy. Asthma symptoms can be
poorly controlled because of poor adherence to controller
therapy, and this might be addressed by using combination
inhalers that contain a corticosteroid and long-acting b2-agonist
as reliever therapy in addition to maintenance treatment. New
bronchodilators with a longer duration of action are in
development, and recent studies have demonstrated the benefit
of a long-acting anticholinergic bronchodilator in addition to
b2-agonists in patients with severe asthma. Anti-IgE therapy is
beneficial in selected patients with severe asthma. Several new
blockers of specific mediators, including prostaglandin D2, IL-5,
IL-9, and IL-13, are also in clinical trials and might benefit
patients with subtypes of severe asthma. Several broadspectrum anti-inflammatory therapies that target neutrophilic
inflammation are in clinical development for the treatment of
severe asthma, but adverse effects after oral administration
might necessitate inhaled delivery. Macrolides might benefit
some patients with infection by atypical bacteria, but recent
results are not encouraging, although there could be an effect in
patients with predominant neutrophilic asthma. Corticosteroid
resistance is a major problem in patients with severe asthma,
and several molecular mechanisms have been described that
might lead to novel therapeutic approaches, including drugs
that could reverse this resistance, such as theophylline and
nortriptyline. In selected patients with severe asthma, bronchial
thermoplasty might be beneficial, but thus far, clinical studies
have not been encouraging. Finally, several subtypes of severe
asthma are now recognized, and in the future, it will be
necessary to find biomarkers that predict responses to specific
forms of therapy. (J Allergy Clin Immunol 2012;129:48-59.)
Key words: Corticosteroids, bronchodilator, cytokine, chemokine,
IgE, kinase, p38 mitogen-activated protein kinase, bronchial thermoplasty, corticosteroid resistance, macrolide

Severe asthma is defined by a failure to achieve control with


maximum doses of inhaled therapies and represents one of the
major unmet therapeutic needs in asthma. Although current
From the National Heart and Lung Institute, Imperial College.
Disclosure of potential conflict of interest: P. J. Barnes receives research support from
GlaxoSmithKline, AstraZeneca, Novartis, Boehringer Ingelheim, and Pfizer.
Received for publication October 18, 2011; revised November 8, 2011; accepted for publication November 10, 2011.
Corresponding author: Peter J. Barnes, FMedSci, FRS, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse St, London SW3 6LY, United
Kingdom. E-mail: p.j.barnes@imperial.ac.uk.
0091-6749/$36.00
2012 American Academy of Allergy, Asthma & Immunology
doi:10.1016/j.jaci.2011.11.006

48

Abbreviations used
COPD: Chronic obstructive pulmonary disease
CRTH2: Chemoattractant homologous receptor expressed on TH2
cells
59-LO: 59-Lipoxygenase
HDAC2: Histone deacetylase-2
ICS: Inhaled corticosteroid
LABA: Long-acting b2-agonist
LAMA: Long-acting muscarinic antagonist
LT: Leukotriene
MAPK: Mitogen-activated protein kinase
MIF: Migratory inhibitory factor
NF-kB: Nuclear factor kB
Nrf2: Nuclear factor erythroid 2related factor 2
PDE: Phosphodiesterase
PG: Prostaglandin
PI3K: Phosphoinositide 3-kinase
PPAR: Peroxisome proliferatoractivated receptor
Syk: Spleen tyrosine kinase
TSLP: Thymic stromal lymphopoietin

management of asthma is highly effective, most patients symptoms are well controlled if they take regular inhaled corticosteroids (ICSs) with or without long-acting b2-agonists (LABAs)
in combination inhalers. Yet despite the availability of highly effective therapies, more than half of the patients with asthma in the
real world have disease that is apparently poorly controlled,
largely because of poor adherence to controller therapy.1,2 In patients with difficult-to-treat asthma, more than 80% show poor adherence with regular inhaled therapy.3 Even in the patients with
the most severe asthma treated with maintenance oral prednisolone (steroid-dependent asthma), only about half of the patients
take the oral steroid based on plasma prednisolone assays. This
suggests that poor adherence is a major factor contributing to
poor control of asthma. In patients with refractory asthma with
persistent sputum eosinophilia despite prescription of high doses
of ICSs or maintenance oral steroids, treatment with high-dose intramuscular injection of triamcinolone results in disappearance of
sputum eosinophilia in the majority of patients.4 This suggests
that poor compliance with inhaled and even oral corticosteroids
might be a major factor contributing to difficult-to-treat asthma
and that poor compliance with controller therapy is an important
determinant of asthma severity.
The reasons for poor compliance with regular therapy, especially in patients with severe asthma, are not well understood, but
the lack of immediate symptom relief, as seen with antiinflammatory treatments, such as corticosteroids, is probably
important. Steps need to be taken to more accurately determine
adherence to therapy, and strategies to overcome this problem

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need to be devised. These findings also indicate that patients


with poorly controlled asthma might need additional antiinflammatory therapy.
This review discusses some of the currently available and
developing approaches to the management of severe or refractory
asthma. Several new classes of drugs are currently in development
for the treatment of severe asthma, but it has proved challenging
to find effective and safe therapies.5 Although severe asthma comprises only approximately 5% to 10% of all asthmatic patients, it
accounts for more than half of the health care spending on asthma
because patients with severe asthma consume more expensive
drugs and are more likely to be hospitalized or require additional
medical attention.

SMART STRATEGIES
Several studies have shown that in patients with moderate-tosevere asthma, there is an improvement in asthma control and
significant reduction in severe exacerbations if a budesonide/
formoterol combination inhaler is used as a reliever instead of a
short-acting b2-agonist, whereas maintenance therapy with budesonide/formoterol is administered twice daily as usual.6 This
strategy is now known as single inhaler maintenance and reliever
therapy (SMART) and could presumably be used with any combination inhaler containing formoterol, irrespective of the corticosteroid used. However, this strategy is not possible with
salmeterol or the once-daily b2-agonists, such as indacaterol
and vilanterol, all of which have cumulative side effects. The scientific rationale for SMART is now well understood because the
ICS used as rescue therapy has a rapid onset of its antiinflammatory effect and prevents the build-up of inflammation
that precedes an acute exacerbation.7,8 The SMART strategy is effective in patients with moderate and severe asthma, although
studies confined to severe asthma have not yet been conducted.6
This strategy might also be effective even when patients forget
doses of their maintenance therapy and therefore addresses the
key issue of poor adherence with controller therapy discussed
above. Indeed, studies are now needed looking at inhaled formoterol/steroid combination inhalers as rescue therapy, even in the
absence of the maintenance dose.9
NEW CORTICOSTEROIDS
Several ICSs are currently available for clinical use, and all
have similar clinical efficacy, but there are differences in pharmacodynamic properties so that systemic exposure might differ.
Because patients with severe asthma might require higher doses
of ICSs, there is an advantage in developing systemic corticosteroids with fewer systemic side effects. Ciclesonide is a recently
developed ICS and appears to have the least systemic effects and
local side effects because the prodrug is activated in the lungs to
the active principle des-ciclesonide by esterases, whereas there is
little activation in the oropharynx.10 This suggests that high doses
of ciclesonide might be useful in the treatment of severe asthma.
ICSs in pressurized metered-dose inhalers are now administered
with hydrofluoroalkane 134a rather than chlorofluorocarbon as
a propellant, and this results in smaller particle sizes, so that the
drugs are more likely to be deposited in the small airways.11 Theoretically, this should more effectively treat patients with severe
asthma in whom there is inflammation of peripheral airways
with evidence of small-airway inflammation.12 More studies are

BARNES 49

needed on ICSs with hydrofluoroalkane 134a propellants in patients with severe asthma.
All currently available ICSs are absorbed from the lungs and
thus have the potential for systemic side effects. This has led to a
search for safer ICSs with reduced oral bioavailability, reduced
absorption from the lungs, or inactivation in the circulation
because this would allow higher doses to be administered safely
in patients with severe asthma. Dissociated steroids attempt to
separate the side-effect mechanisms from the anti-inflammatory
mechanisms. This is theoretically possible because side effects
are largely mediated through transactivation and the binding of
glucocorticoid receptors to DNA, whereas anti-inflammatory
effects are largely mediated through transrepression of transcription factors through a nongenomic effect.13 Dissociated steroids
are designed to have a greater effect on transactivation than on
transrepression and thus might have a better therapeutic ratio
and might even be suitable for oral administration.14 Nonsteroidal
selective glucocorticoid receptor activators, such as AL-438 and
mapracorat, are in clinical development. However, some of the
anti-inflammatory effects of corticosteroids might be due to transactivation of anti-inflammatory genes, and therefore selective
glucocorticoid receptor activators might not be as efficacious as
existing ICSs.15 Corticosteroids switch off inflammatory genes
by recruiting the nuclear enzyme histone deacetylase-2
(HDAC2) to the activated inflammatory gene initiation site so
that activators of this enzyme might also have antiinflammatory effects or might enhance the anti-inflammatory effects of corticosteroids.13

NEW BRONCHODILATORS
Bronchodilators play an important role in reducing symptoms
in patients with severe asthma, and currently, LABAs are the
bronchodilators of choice, usually given in combination with
ICSs in a fixed-dose inhaler. Bronchodilators are essential in the
management of asthma because they relieve and prevent bronchoconstriction. There have been several advances in the development of bronchodilators for the treatment of severe asthma.
Once-daily b2-agonists
b2-Agonists are the most effective bronchodilators because
they act as functional antagonists of airway smooth muscle contraction, irrespective of the constricting stimulus. The LABAs
salmeterol and formoterol have been a major advance in the
management of severe asthma and are usually administered
through combination inhalers with corticosteroids. There have
been concerns about the safety of LABAs, and there is convincing evidence that LABAs used without a corticosteroid cover increase severe exacerbations and mortality. However, there is no
clear evidence that LABAs pose any risk if combined with corticosteroids and therefore should only be used in the form of
combination inhalers.16,17 Several once-daily b2-agonists (ultra-LABAs) are in clinical studies, including indacaterol
(already available for chronic obstructive pulmonary disease
[COPD] in several countries), carmoterol, vilanterol, and olodaterol.18 For asthmatic patients, these ultra-LABAs should only
be available with a corticosteroid in a fixed combination. Currently, fluticasone furoate/vilanterol and mometasone/indacaterol are in clinical development for asthma as once-daily
combination inhalers.18

50 BARNES

Long-acting muscarinic antagonists


Antimuscarinic (anticholinergic) bronchodilators are the preferred first-line therapy in patients with COPD, but in patients
with asthma, they are less effective than b2-agonists because they
block only the cholinergic component of bronchoconstriction,
whereas b2-agonists reverse all bronchoconstrictors, including
the direct effects of inflammatory mediators, such as histamine,
leukotriene (LT) D4, and prostaglandin (PG) D2. Animal studies
have recently demonstrated an important role for cholinergic
mechanisms in the late response to inhaled allergen in sensitized
guinea pigs because the long-acting muscarinic antagonist
(LAMA) tiotropium bromide completely blocks the late response
in nonanesthetized animals.19 This response is also blocked by
drugs that block TRPA1, an activating ion channel on airway sensory nerves, suggesting that allergens release a mediator (thus far
unidentified) that activates TRPA1, leading to cholinergic reflex
bronchoconstriction. There is also increasing evidence that muscarinic receptors can be activated by acetylcholine released from
nonneuronal cells, such as epithelial and inflammatory cells.20,21
Choline acetyltransferase can be induced in epithelial cells by inflammatory mediators, such as TNF-a, suggesting that acetylcholine synthesis might be increased in the airways of asthmatic
patients. In sensitized guinea pigs tiotropium inhibits eosinophilic
inflammation in the airways and airway hyperresponsiveness,
even in vagotomized animals, suggesting that tiotropium is blocking the effects of nonneuronally released acetylcholine on muscarinic M3 receptors and that tiotropium also blocks eosinophilic
inflammatory mechanisms.22 Tiotropium also inhibits TH2 cytokine release in allergen-exposed sensitized mice and that from human PBMCs.23 It also reduces eosinophilic inflammation, mucin
gene expression, and airway remodeling in a murine model of
asthma, possibly through a direct effect on fibroblasts.24 Tiotropium also inhibits neutrophilic inflammation and airway fibrosis after repeated LPS challenge in guinea pigs.25 These
experimental studies suggest that tiotropium might have antiinflammatory effects through antagonism of neuronally and
extraneuronally released acetylcholine on M3 receptors on inflammatory cells. There is also evidence that blocking M3 receptors with tiotropium inhibits acetylcholine-induced release of
neutrophil chemotactic factors (mainly LTB4) from human macrophages.26 These in vitro and experimental studies have paved
the way to recent clinical studies of tiotropium in patients with
asthma, particularly in those with severe disease. Recent studies
have shown that once-daily tiotropium provides useful additional
bronchodilatation when added to a LABA in some patients with
severe asthma. In one study approximately 30% of patients with
severe asthma showed a good additional response when tiotropium was added.27 Addition of tiotropium significantly improves lung function in patients whose symptoms are not
controlled by high doses of ICSs and LABAs, although there is
no improvement in symptoms or health status.28 Another study
showed that tiotropium was comparable with salmeterol in terms
of bronchodilator response when added to an ICS in patients who
show a good response to a short-acting anticholinergic.29 In asthmatic patients with the Arg16/Arg16 genotype of the b2-receptor,
who have previously been reported to be less responsive to b2-agonists, once-daily tiotropium was no less effective than twicedaily salmeterol in patients whose symptoms are not controlled
with ICSs alone.30 These studies suggest that addition of a
LAMA to existing therapy in patients with severe asthma not

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controlled with ICSs and LABAs is beneficial and might be indicated, particularly in elderly patients with an element of fixed airway obstruction, who have similarities to patients with COPD.
There are several other LAMAs in clinical development for
COPD, including once-daily glycopyrrolate and GSK573719 and
twice-daily aclidinium bromide.31 There appears to be additivity
between LABAs and LAMAs, suggesting that a triple combination of a LABA plus a LAMA plus an ICS might be useful in
some patients with severe asthma, although the development of
such inhalers might prove difficult technically and for regulatory
reasons.32 Several bifunctional molecules that have LABA and
LAMA activity are also in development, but it might prove difficult to balance the b-agonist and anticholinergic activities.33 It
would be logistically easier to combine a bifunctional molecule
that has LABA and LAMA activity and an ICS in a combination
inhaler to provide triple activity.

Novel classes of bronchodilator


In view of the recent concerns about the long-term safety of
LABAs in asthmatic patients, there has been a search for
alternative classes of bronchodilator. Novel bronchodilators
have proved difficult to develop, and new drugs, such as vasoactive intestinal peptide analogs and potassium-channel openers,
have had side effects due to more potent vasodilator than
bronchodilator effects. A stable vasoactive intestinal peptide
analog, Ro 25-1553, has bronchodilator activity in asthmatic
patients but is less effective than inhaled formoterol.34 b2-Agonists and theophylline relax human airway smooth muscle by activating large-conductance Ca21-activated potassium channels,
leading to a search for direct large-conductance Ca21-activated
potassium channel activators, but although activating drugs
were discovered, they have not been tested in clinical studies in
asthma. Rho kinase inhibitors also have potential as bronchodilators but are likely to have significant toxicity. Recently, it has been
found that agonists of bitter taste receptors (TAS2Rs), such as quinine, chloroquine, and saccharine, relax human airways in vitro
by increasing local Ca21 release, resulting in the opening and
hyperpolarization of airway smooth muscle cells.35 In murine
models inhaled bitter tastants appear to be more effective than a
b-agonist, although this species is not very responsive to b2-agonists. Theophylline relaxes human airway smooth muscle by inhibiting phosphodiesterase (PDE) 3 in airway smooth muscle
cells, so that selective PDE3 inhibitors, such as cilostazol and milrinone, are potential bronchodilators. However, there has been
concern that PDE3 inhibitors were associated with increased cardiovascular mortality in previous clinical trials. Combined PDE3/
4 inhibitors are currently in development as inhaled therapy for
asthma and COPD.36 PGE2 relaxes human airway smooth muscle
through EP4 receptors,37 suggesting that EP4-selective agonists
might be useful bronchodilators and might avoid the coughing induced by PGE2 through EP3 receptors on sensory nerve endings.
ANTI-IgE
Omalizumab is the only novel therapy that has specifically
been approved for the treatment of severe asthma. Omalizumab
is an mAb that binds the Fc portion of IgE and thus prevents
activating its high-affinity IgE receptor (FcRI) on mast cells,
basophils, and dendritic cells, as well as a low-affinity receptor

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(FcRII) expressed on several immune and inflammatory cells,


including macrophages, eosinophils, and T and B lymphocytes.
Numerous clinical trials have demonstrated the clinical efficacy
of omalizumab in reducing maintenance doses of oral corticosteroids and ICSs and in reducing exacerbations in patients
(including children) with severe asthma.38-40 In a large study of
patients with severe asthma whose symptoms are not controlled
with high doses of ICSs and LABAs, omalizumab significantly
reduced exacerbations (by 25%) and improved symptoms and
asthma-related quality-of-life scores.39 Only a proportion of allergic asthmatic patients with the target total serum IgE concentration of 70 to 300 IU/mL show a good response, and because
of the high cost, a trial of therapy over 3 to 4 months is often
recommended to identify good responders. Unfortunately, despite extensive analyses, no clinically measurable biomarkers
have been found to predict a good response. Patients with nonatopic (intrinsic) asthma are currently excluded, but there is evidence for local IgE production in the airways of at least some
of these patients,41 and therefore future studies should investigate this group of patients who often have difficult-to-control
asthma. Similarly, there are patients with severe uncontrolled
asthma with total IgE levels of greater than 300 IU/mL who
are currently excluded because it is not feasible to give enough
antibody to effectively block IgE. In the future, antibodies with
a higher affinity for IgE might be developed so that it could be
possible to treat patients with very high total IgE levels. An
mAb (lumiliximab) directed against FcRII (CD23) reduces total IgE levels, probably by reducing synthesis by B lymphocytes, but has little clinical benefit, even in patients with mild
asthma, and therefore is no longer in clinical development.42

TARGETING INFLAMMATORY MEDIATORS


More than 100 mediators are involved in the complex inflammation of asthma, making it unlikely that blocking the synthesis
or receptor for a single mediator could be very effective. ICSs are
highly effective in suppressing the synthesis of multiple inflammatory mediators, but in patients with severe asthma, they appear
to be less effective, making it possible that adding a mediator
antagonist to high doses of ICSs might be beneficial. In addition,
the inflammation seen in some patients with severe asthma has a
different pattern, with a predominance of neutrophils, suggesting
that targeting mediators of neutrophilic inflammation might be
effective in these patients.43
Lipid mediator blockade
The only mediator antagonists currently used in asthma
therapy are antileukotrienes, which block cysteinyl leukotriene
receptors, but these drugs are much less effective than ICSs and
have little place as add-on therapy in patients with severe
asthma.44 LTB4 is a chemoattractant of neutrophils, mast cells,
and T cells, including effector CD81 memory T cells, and its
levels are increased in patients with severe asthma.45 An
LTB4 receptor (BLT1) antagonist had no effect in patients
with mild asthma46 but has not been tested in patients with
more severe disease, in whom it would be more likely to be effective. A low-affinity BLT2 receptor is expressed on several
cell types, including T cells and mast cells, and when inhibited
by oligonucleotides, there is a reduction in allergic inflammation in a murine model.47 BLT2 receptors are upregulated on

BARNES 51

FIG 1. PGD2 might play a role in severe asthma. It is synthesized mainly in


mast cells by PDGD synthase (PGDS) and acts on DP1 receptors on vessels
to mediate vasodilatation and on dendritic cells to enhance their activation
through DP2 receptors (also known as CRTH2) to attract TH2 lymphocytes
and eosinophils and on thromboxane (TP) receptors to cause bronchoconstriction. DP2 (CRTH2) antagonists are now in a clinical trial in patients with
severe asthma. Antagonists of DP1 and receptors and inhibitors of PGDS
are now in clinical development for asthma therapy. Adapted from Barnes.5

mast cells after allergen challenge and mediate the synthesis


of TH2 cytokines.48 To target both BLT1 and BLT2, LTB4 synthesis can be reduced by an inhibitor of LTA4 hydrolase, and
such an approach is effective in a murine model of asthma.49
Phospholipase A2 inhibits the generation of all lipid mediators
(prostaglandins, leukotrienes, and platelet-activating factor) from
membrane phospholipids and therefore theoretically should be effective in patients with severe asthma, although there is uncertainty about whether to block the secretory or cytosolic
isoforms of phospholipase A2, and it has been difficult to discover
safe and selective inhibitors.50
59-Lipoxygenase (59-LO) works through 59-LOactivating
protein, and several novel 59-LO and 59-LOactivating protein
inhibitors are currently in clinical development. These drugs
could be more effective than BLT1 antagonists because they block
production of additional mediators, such as 5-HETE and 5-oxoETE, which acts through a specific OXE receptor.51 5-Oxo-ETE
is generated by oxidative stress and therefore is likely to be generated in patients with severe asthma. It is a potent attractant of
eosinophils but also attracts neutrophils and T cells.
PGD2 is released from mast cells, TH2 cells, and dendritic
cells and activates DP2 receptors, also known as chemoattractant
homologous receptor expressed on TH2 cells (CRTH2), which
mediate chemotaxis of TH2 cells and eosinophils (Fig 1).5,52
There is increased expression of PGD2 in patients with severe
asthma.53 Several CRTH2 antagonists are now in clinical development for asthma, including AMG-853, OC000459, and
MK-7246, which have shown early clinical efficacy as oral treatments for asthma and rhinitis. A study of OC00049 in steroidnaive asthmatic patients showed no improvement in lung
function but a small reduction in symptoms and no significant
reduction in sputum eosinophil numbers compared with those
values after placebo.54 PGD2 also activates DP1 receptors, which
mediate vasodilatation and enhance TH2 cell polarization by
dendritic cells, so that a dual DP1/DP2 antagonist might be
more effective, whereas an inhibitor of PGD synthase would
block PGD2 synthesis and also prevent the bronchoconstrictor
effects of PGD2 that are mediated through thromboxane receptors on airway smooth muscle.

52 BARNES

Cytokine blockade
Cytokines play a key role in orchestrating chronic inflammation and remodeling airway structure and therefore have become
important targets for blockade in asthmatic patients, particularly
patients with severe disease whose symptoms are not controlled
with high doses of ICSs.55 More than 50 cytokines have been implicated in asthma, and several have already been targeted in clinical studies, often with disappointing results.56 There is a great
redundancy of cytokines, and therefore it might be difficult to inhibit an inflammatory process effectively with a selective blocker.
Another problem is the high cost of blocking mAbs, and therefore
these drugs are likely to be cost-effective only in patients with severe disease. It is possible that production costs might be reduced
by the development of higher-affinity antibodies or the use of
fragments, such as domain antibodies, that are cheaper to
produce.
Another problem is that there has been a major focus on TH2
cytokines in the belief that TH2 cells drive allergic inflammation.57 Corticosteroids are very effective in suppressing TH2
celldriven inflammation, at least in part because they are very
potent inhibitors of the TH2 regulating transcription factor
GATA3.58 Animal models of asthma have also been developed
that highlight TH2 celldriven inflammation, and these models
might be inappropriate for the development of treatments for severe asthma.
Because different immune mechanisms are likely operate in
many patients with severe asthma, it might be necessary to target
different sets of cytokines, such as those involving TH1 and
TH17 cells. TH17 cells have been implicated in patients with severe asthma, particularly those patients with a predominantly
neutrophilic pattern of inflammation.59 Interestingly, TH17 cells
appear to be corticosteroid resistant and might therefore contribute to the corticosteroid resistance seen in patients with severe
asthma.60
Inhibiting TH2 cytokines
Inhibition of IL-4 by using inhaled soluble receptors proved to
be disappointing, but there is continued interest in blocking IL13, a related cytokine that regulates IgE formation, particularly
in patients with severe asthma. IL-13 can also induce corticosteroid resistance and therefore appears to be an appropriate
target for patients with severe asthma.61,62 Pitrakinra is a mutated form of IL-4 that blocks IL-4 receptor a, the common receptor for IL-4 and IL-13, and significantly reduces the late
response to inhaled allergen in patients with mild asthma
when administered subcutaneously or by means of nebulization,63 and larger clinical trials are currently in progress with
this protein. Several IL-13 and IL-4 receptor a blocking antibodies are also in clinical development, but thus far, clinical
studies in patients with severe asthma have been disappointing.
A blocking mAb to IL-13, lebrikizumab, has been studied in
asthmatic patients whose symptoms are not controlled with
high doses of ICSs and showed a small increase in FEV1 (approximately 5%) compared with placebo after 12 weeks but
no significant effect at 24 weeks.64 There are no significant improvements in symptoms or asthma-related health status and no
reduction in exacerbations. Interestingly, increased concentrations of the plasma biomarker periostin, which was discovered
by means of proteomic analysis of IL-13stimulated epithelial
cells, showed a slightly better response (approximately 8%)

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than low concentrations, suggesting that it can be used as a biomarker to predict greater responses. An mAb targeting IL-4 receptor a (AMG317), which therefore blocks the effects of IL-4
and IL-13, has been ineffective in controlling asthma symptoms
or lung function in 3 different doses over a 12-week period in
patients with mild asthma.65
One question about the poor efficacy of antiIL-13 strategies
might be whether the dose is sufficient to block endogenous IL-13
in the airways. In a recent study a blocking antiIL-13 mAb
profoundly suppressed IL-13 in nasal secretions after local
allergen challenge, yet there was no significant reduction in
eosinophil numbers or nasal symptoms.66 IL-4 and IL-13 signal
through the transcription factor signal transducer and activator
of transcription 6, and small-molecule inhibitors, such as
AS1517499, have now been developed that are active in a murine
model of asthma but have yet to be developed clinically.67
IL-5 is of critical importance for eosinophilic inflammation,
and a blocking antibody to IL-5 (mepolizumab) depletes eosinophils from the circulation and sputum of asthmatic patients but
disappointingly has no effect on the response to inhaled allergen,
airway hyperresponsiveness, symptoms, lung function, or exacerbation frequency in asthmatic patients.68,69 However, more recent studies show that mepolizumab reduces exacerbations in
highly selected patients who have persistent sputum eosinophilia
despite high doses of ICSs, although there is no improvement in
symptoms, lung function, or airway hyperresponsiveness.70,71
Another IL-5 blocking antibody, reslizumab, failed to improve
asthma control over 12 weeks in patients with sputum eosinophilia despite high doses of ICSs, but there was some reduction
in symptoms and sputum eosinophils.72 An antibody against the
IL-5 receptor a (benralizumab, MEDI-563) might more effectively deplete airway eosinophils than blocking IL-5 itself
through antibody-dependent cytotoxicity of eosinophils and is
currently being studied in clinical trials.73 Inhaled antisense
oligonucleotides that block the common b chain of IL-5 and
GM-CSF receptors together with the chemokine receptor CCR3
(TPI ASM8) have a small effect in reducing allergen responses
and airway inflammation.74 Overall, blocking IL-5, although effective in reducing eosinophilic inflammation, has been disappointing, although it might be effective in highly selected
patients, as well as in patients with other hypereosinophilic diseases, such as Churg-Strauss syndrome and eosinophilic
esophagitis.75,76
Another TH2 cytokine that is currently being targeted is IL-9,
which plays a role in mast cell proliferation, although there is
recent evidence that it is produced particularly by a subset of
CD41 T cells designated TH9 cells.77 Clinical studies have
been encouraged by animal studies showing that inhibition of
IL-9 leads to reduced allergic inflammation and mucus hypersecretion, and a blocking IL-9 antibody (MEDI-528) has been
shown to be safe after weekly subcutaneous injections, with a
trend toward reduction in exercise-induced asthma, which is mediated through mast cell activation.78 Larger clinical trials are
now in progress.
There has been considerable interest in thymic stromal
lymphopoietin (TSLP), an IL-7related cytokine that is secreted
by airway epithelial cells, because it instructs dendritic cells to
secrete chemokines that attract TH2 cells into the airways and potentiates the activation of these cells.79 TSLP expression by airway epithelial cells is increased in a subset of patients with
severe asthma treated with high doses of ICSs, suggesting that

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this might be a good target, especially because it acts as an upstream cytokine.80 Several pharmaceutical companies are developing antibodies to TSLP and its receptor, as well as to OX40
and OX40 ligand, which act as costimulatory molecules to
TSLP, although bronchial OX40/OX40 ligand expression is not
increased in patients with severe asthma compared with that
seen in patients with mild asthma.81

Other cytokines
Another cytokine targeted in asthmatic patients is TNF-a,
which might play a significant role in those with severe asthma.
Several uncontrolled or small studies suggested that anti-TNF
therapies (TNF blocking antibodies infliximab or soluble receptor
etanercept) might be useful in reducing symptoms, exacerbations,
and airway hyperresponsiveness in patients with severe
asthma,82,83 but a recent large multicenter trial with the humanized antibody golimumab showed no beneficial effect on lung
function, symptoms, or exacerbations, and there were increased
reports of pneumonia and cancer.84 A study of etanercept over
4 weeks in patients with moderate-to-severe asthma showed no
clinical efficacy, but there were no safety problems.85
Several other cytokine blockers are currently being targeted in
asthmatic patients, including IL-17, IL-25, IL-33, GM-CSF, and
stem cell factor, but thus far, no clinical studies in patients with
severe asthma have been reported.56
Chemokine receptor antagonists
Chemokines are small cytokines that attract inflammatory
cells, including mast cells, eosinophils, and TH2 cells, into the airways and are therefore appropriate targets for therapy, particularly because they signal through G proteincoupled receptors
for which small-molecule antagonists can be developed.86 The
major focus of interest in asthmatic patients has been the chemokine receptor CCR3, which is predominantly expressed on eosinophils and mediates the chemotactic response to CXCL11
(eotaxin), which is secreted in asthma. CCR3 is also expressed
on mast cells and some TH2 cells. Several small-molecule inhibitors of CCR3 have been in clinical development, but their effects
in asthmatic patients have not yet been reported because they have
usually been discontinued because of toxicology problems. An inhaled antisense oligonucleotide that targets CCR3 has some effect
in reducing sputum eosinophils, but results are difficult to interpret because IL-5 and GM-CSF b chain antisense were coadministered.87 Other chemokine receptors that are targeted for
asthma therapy are CCR2 on monocytes and T cells and CCR4,
CCR8, and CXCR4 on TH2 cells. A defucosylated antibody to
CCR4 (mogamulizumab, also known as KW-0761 and AMG761) results in prolonged cytotoxic effects on TH2 cells, marked
and prolonged depletion of TH2 cells, and reduced lung inflammation in animal models. This antibody is now in early clinical trials
for asthma and adult T-cell leukemia-lymphoma.88 CXCR2 is expressed on neutrophils and monocytes and might be involved in
the recruitment of neutrophils into the airways of patients with severe (neutrophilic) asthma. Several small-molecule inhibitors of
CXCR2 are now in clinical development.89 An oral CXCR1/
CXCR2 antagonist, navarixin (SCH-527123), is effective in
blocking ozone-induced sputum neutrophilia in healthy subjects90 and is currently in clinical trials in patients with severe
asthma.

BARNES 53

BROAD-SPECTRUM ANTI-INFLAMMATORY
TREATMENTS
The fact that the symptoms of patients with severe asthma
might not be controlled by high doses of ICSs plus LABAs and
sometimes even oral corticosteroids has prompted a search for
alternative anti-inflammatory therapies that can be added to
existing therapies to provide additional control. In addition,
inflammation in some patients with severe asthma is predominantly neutrophilic so that inhibitors of neutrophilic inflammation
are needed, and corticosteroids are poorly effective against
neutrophilic inflammation. Several approaches to treating neutrophilic inflammation might be applicable to the treatment of
severe asthma. Although several classes of broad-spectrum
noncorticosteroid anti-inflammatory treatments have been in
development, there have usually been problems with side effects
when the drugs are administered orally, and this has had limited
clinical development. This suggests that it might be necessary to
develop potent topically active anti-inflammatory treatments that
avoid systemic exposure, but thus far, this has proved to be a
major challenge.
PDE4 inhibitors
The most advanced of the anti-inflammatory therapies are
PDE4 inhibitors, which have a wide spectrum of antiinflammatory effects that are relevant to severe asthma, inhibiting
T cells, eosinophils, neutrophils, mast cells, airway smooth
muscle, epithelial cells, and nerves and are highly effective in
animal models of asthma.91 PDE4 inhibitors are effective against
neutrophilic inflammation, making them an attractive potential
therapy for severe asthma when there is neutrophilic inflammation. An oral PDE4 inhibitor, roflumilast, has an inhibitory effect
on allergen-induced responses in patients with mild asthma and
also reduces symptoms and lung function similar to a low dose
of ICS.92 Roflumilast is currently licensed for use in patients
with severe COPD, and therefore there has been increased interest
in its potential for the treatment of severe asthma. However, a major limitation to this class of drug is the mechanism-based side-effect profile, including nausea, headaches, and diarrhea, which is
dose limiting. On the basis of animal models, the antiinflammatory effects appear to be mediated by inhibition of
PDE4B, whereas nausea and vomiting are mediated through
PDE4D inhibition, suggesting that PDE4B-selective inhibitors
might be better tolerated.93 Another approach is to deliver
PDE4 inhibitors by means of inhalation, but thus far, these drugs
have had no efficacy. Inhaled PDE3/4 inhibitors are also in development and might have the advantage of bronchodilatation
through PDE3 inhibition.36
Kinase inhibitors
Kinases play a key role in regulating the expression of
inflammatory genes in asthmatic patients and might amplify
inflammation in patients with severe asthma.94 There are now several kinase inhibitors that might be useful in the treatment of severe asthma (Fig 2). The transcription factor nuclear factor kB
(NF-kB) regulates many of the inflammatory genes that are abnormally expressed in asthmatic patients and is activated in asthmatic airways. Small-molecule inhibitors of the key enzyme
IKK2/IKKb (inhibitor of kB kinase) block inflammation induced
by NF-kB activation and are now in preclinical testing.95

54 BARNES

FIG 2. Inhibition of proinflammatory kinase pathways for severe asthma.


Several kinases activate the expression of multiple inflammatory genes and
might therefore amplify the inflammation in asthmatic patients, leading to
more severe disease. Selective inhibitors have been developed for several
kinases, including spleen tyrosine kinase (SYK), which activates several
signaling pathways, including phospholipase Cg (PLCg); inhibitor of NFkB kinase (IKK2), which activates NF-kB; p38 MAPK, which activates
MAPK-activated protein kinase 2 (MAPKAPK2); Jun kinase (JNK), which activates activator protein 1 (AP-1); and PI3K, which activates Akt. Selective
inhibitors have now been developed for all of these enzyme targets.

p38 mitogen-activated protein kinase (MAPK) activates


similar inflammatory genes to NF-kB, is activated in cells from
patients with severe asthma,96 and has been linked to corticosteroid resistance.97 A p38 MAPK inhibitor appears to improve corticosteroid responsiveness in cells from patients with severe
asthma.98 p38 MAPK also plays a key role in activation of
GATA3, a transcription factor that regulates TH2 cell differentiation and expression of TH2 cytokines.99 Corticosteroids block
GATA3 activation and are mimicked by p38 MAPK inhibitors.58
An antisense that blocks p38 MAPK demonstrated efficacy in a
murine asthma model.100 Several small-molecule p38 inhibitors
are now in clinical development for the treatment of inflammatory
diseases, but side effects after systemic administration have
proved to be a major problem.101
Phosphoinositide 3-kinase (PI3K) also regulates inflammation
and has several isoforms, but nonselective inhibitors are likely to
be toxic.102 The isoenzyme PI3Kg is important in chemotactic responses, and selective inhibitors are in development, whereas
PI3Kd activation results in reduced corticosteroid responsiveness
through reduced HDAC2 activity, so that PI3Kd inhibitors might
potentially reverse corticosteroid resistance in patients with severe asthma.103 Theophylline is a selective inhibitor of PI3Kd,
and theophylline derivatives that lack PDE inhibition or selective
PI3Kd inhibitors might therefore be of therapeutic value.
A general concern about novel kinase inhibitors is that they might
have side effects because they target mechanisms that are found in
many cell types. Therefore it might be necessary to develop inhaled formulations for use in asthmatic patients in the future, as
proved necessary for corticosteroids.
Spleen tyrosine kinase (Syk) is involved in activation of mast
cells and other immune cells, and several small-molecule Syk
kinase inhibitors are in development, particularly for patients with
severe asthma.104 An antisense inhibitor of Syk kinase is effective
in an animal model of asthma,105 and the small-molecule inhibitor
R112 administered nasally reduces nasal symptoms in patients
with hay fever.106 More potent inhibitors, such as R343 and
Bay 61-3606, are in development for inhalation in asthmatic

J ALLERGY CLIN IMMUNOL


JANUARY 2012

FIG 3. Inhibition of mast cells in asthmatic patients. Mast cell activation can
be inhibited by blocking IgE binding to FcRI; by inhibiting c-Kit, which is
activated by stem cell factor (SCF); or by inhibiting spleen tyrosine kinase
(SYK). Mast cell stabilizers, such as cromones and furosemide, might
work through specific ion channels or G proteincoupled receptors for
which novel modulators can be developed. Adapted from Barnes.5

patients. Because Syk is widely distributed in immune and neuronal cells, there are concerns about side effects. As with other
kinase inhibitors, there can be side effects with systemic administration, and therefore inhalation might be preferred.

Peroxisome proliferatoractivated receptor g


agonists
Peroxisome proliferatoractivated receptor (PPAR) g agonists
have a wide spectrum of anti-inflammatory effects, including
inhibitory effects on macrophages and T cells and neutrophilic
inflammation, and polymorphisms of the PPARg gene have been
linked to increased risk of asthma.107 The PPARg agonist rosiglitazone produced a small improvement in lung function in smoking asthmatic patients in whom ICSs were ineffective108 and a
modest (15%) reduction in late response to inhaled allergen in patients with mild asthma.109 This suggests that PPARg agonists,
such as thiazolidinediones, have little therapeutic potential in
asthma therapy.
MAST CELL INHIBITORS
Mast cell activation is important as a driving mechanism in
some patients with severe asthma.53 There are several approaches
to inhibiting mast cell activation (Fig 3),5 and anti-IgE has already
been shown to be of value in the treatment of some patients with
severe asthma. Stem cell factor is a key regulator of mast cell survival in the airways and acts through the receptor c-Kit on mast
cells.110 Plasma concentrations of stem cell factor are increased
in patients with severe asthma.111 Blockade of stem cell factor
or c-Kit is effective in animal models of asthma, suggesting that
this pathway might be a good target for new asthma therapies.
Masitinib is a potent tyrosine kinase inhibitor that blocks c-Kit
(as well as platelet-derived growth factor receptors) and provides
some symptomatic benefit in patients with severe asthma.112
More selective c-Kit inhibitors are in development.
Cromones (cromolyn sodium and nedocromil sodium) inhibit
the activation of human mucosal mast cells and are very effective
against allergen and other indirect challenges that involve mast
cell activation.113 The effects of cromones are closely mimicked

BARNES 55

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VOLUME 129, NUMBER 1

FIG 4. Corticosteroid resistance in some patients with severe asthma is due to a reduction in HDAC2 activity
and expression as a result of oxidative stress through activation of PI3Kd. This can be reversed by
antioxidants, including Nrf2 activators, theophylline, nortriptyline, and selective PI3Kd inhibitors. Macrolides also reverse corticosteroid resistance by acting further down the pathway. In the future, selective
HDAC2 activators might be developed.

by the diuretic furosemide, suggesting that they might act through


ion channels. However, the molecular target for cromones was
never identified, although recent studies suggest that an orphan
G proteincoupled receptor called GPR35 might be a target.114

THE PROBLEM OF CORTICOSTEROID RESISTANCE


Resistance to the anti-inflammatory effects of corticosteroids
might be an important factor in determining asthma severity.
Several molecular mechanisms have now been described to
account for corticosteroid resistance in asthmatic patients, including activation of p38 MAPK activity (as described above),
increased expression of an alternatively spliced variant of the
glucocorticoid receptor GRb, increased production of macrophage migratory inhibitory factor (MIF), and reduced expression
of HDAC2.115 This suggests that there might be therapies that
could potentially reverse corticosteroid resistance and that there
might be different phenotypes of corticosteroid resistance in
asthma that could require different therapeutic approaches. p38
MAPK inhibitors have been shown to increase the antiinflammatory responses to corticosteroids in PBMCs from patients with severe asthma,98 and as discussed above, p38 MAPK
inhibitors are in clinical development for the treatment of severe
asthma. MIF is reported to be increased in patients with severe
asthma and block the anti-inflammatory effects of corticosteroids,116 but the molecular mechanisms are poorly understood,
and it has been difficult to find drugs that block its actions.117
MIF can signal and cause corticosteroid resistance through the activation of p38 MAPK.118
HDAC2 activation
There is increasing evidence that corticosteroid resistance in
patients with COPD is due to a reduction in HDAC2 activity and
expression as a result of oxidative and nitrative stress.119 This results in increased acetylation of the glucocorticoid receptor,

which prevents it from inhibiting NF-kBdriven inflammation.120


There is evidence that a similar mechanism might underlie corticosteroid resistance in patients with severe asthma, in whom there
is increased oxidative stress from endogenously generated oxidants.121,122 A novel therapeutic strategy is reversal of this corticosteroid resistance by increasing the expression and activity of
HDAC2, and this can be achieved in several ways (Fig 4).
Low doses of oral theophylline increase HDAC2 expression in
alveolar macrophages from patients with COPD and thereby
restore steroid responsiveness.123,124 It has previously been
shown that addition of low-dose theophylline to moderate doses
of ICSs is more effective in patients with severe asthma than increasing the dose of ICS to the maximum tolerated dose125 and
that withdrawal of low-dose theophylline causes a loss of asthma
control in patients with severe asthma.126 In smoking asthmatic
patients who become refractory to corticosteroids, low-dose
theophylline is effective when added to a dose of ICS, which is
ineffective alone.127 The molecular mechanism of action of
theophylline in increasing HDAC2 levels is independent of
PDE inhibition and appears to be mediated by inhibition
of oxidant-activated PI3Kd.103,128 The tricyclic antidepressant
nortriptyline also reverses corticosteroid resistance by inhibiting
PI3Kd and therefore might have clinical benefit as an add-on therapy, although clinical trials have not yet been done in patients
with severe asthma.129 Selective PI3Kd inhibitors might be of
potential value in patients with severe asthma in combination
with ICSs. Selective PI3Kd inhibitors are now in clinical development for the treatment of B-cell leukemia but might also be useful
in patients with severe asthma, especially if administered by
means of inhalation to avoid any hematologic side effects.

Antioxidants
Oxidative stress is increased in patients with severe asthma,130
particularly during exacerbations, and reactive oxygen species
are likely to amplify inflammation and contribute to its

56 BARNES

pathophysiology. Oxidative stress also reduces steroid responsiveness through a reduction in HDAC2 activity and expression.
This suggests that antioxidants might reverse corticosteroid resistance and also reduce inflammation. Unfortunately, currently
available antioxidants based on glutathione are relatively weak
and are inactivated by oxidative stress, and therefore new and
more potent and stable antioxidants are needed, such as superoxide dismutase mimics and NADPH oxidase inhibitors.131 The
transcription factor nuclear factor erythroid 2related factor 2
(Nrf2) plays a key role in the regulation of endogenous antioxidant genes and might be dysfunctional in patients with severe
asthma. Several Nrf2 activators, such as sulforaphane (which
occurs naturally in broccoli) and the synthetic triterpenoid 1-(2cyano-3-,12-dioxooleana-1,9-dien-28-oyl)imidazole-methyl ester, have now been identified,132 and Nrf2 activators are now in
clinical development.

J ALLERGY CLIN IMMUNOL


JANUARY 2012

acting b2-agonists were withdrawn,141 suggesting that it would


provide no greater benefit than a bronchodilator. The safety of
the procedure has been followed for up to 5 years with no loss
of lung function, suggesting that there are no structural changes
as a consequence of the therapy.142 It is still unclear how much
benefit this procedure provides in patients with severe asthma,
and the clinical outcomes show little change and might not
even be apparent when patients are treated with long-acting bronchodilators. It is possible that this procedure is indicated in carefully selected patients in whom airway smooth muscle
hypertrophy is predominant, as evidenced by pronounced airway
hyperresponsiveness. The mechanism of action of bronchial thermoplasty has been determined from studies in normal dogs, and it
is uncertain how the procedure affects the airways of asthmatic
patients or whether it leads to reduced inflammation by reducing
airway smooth muscle cell secretion of inflammatory mediators
in the airways of asthmatic patients.

MACROLIDES
There is evidence that some patients with severe asthma are
chronically infected with atypical bacteria, such as Mycoplasma
pneumoniae and Chlamydia pneumoniae.133 In patients with infection confirmed by means of PCR and culture, there was a significant improvement in FEV1 after a 6-week course of
clarythromycin.134 However, in a larger trial of patients with
poorly controlled asthma, treatment with clarithromycin over a
16-week period did not produce any clinically meaningful improvement in asthma control, even in the patients who had positive PCR results for atypical bacteria, although there was a
significant reduction in airway hyperresponsiveness.135 It has
long been recognized that macrolides have anti-inflammatory effects that might be independent of their antibiotic effects.136 Macrolides appear to inhibit inflammation by inhibiting NF-kB and
other transcription factors, but the precise molecular mechanisms
have not yet been determined. In patients with severe neutrophilic
asthma, a course of azithromycin significantly reduced sputum
neutrophil numbers and CXCL8 concentrations, with some improvement in symptoms.137 This suggests that it might be worth
using a therapeutic trial of macrolide antibiotics in patients with
severe asthma who have predominantly neutrophilic inflammation. A nonantibiotic macrolide (EM-703) reverses corticosteroid
resistance caused by oxidative stress by increasing HDAC2 activity.138 Several nonantibiotic macrolides are now in development
as anti-inflammatory therapies.139

FUTURE DIRECTIONS
It is now becoming clear that there are several distinct
phenotypes of severe asthma and that these might require
different therapeutic approaches. For example, patients whose
symptoms were not controlled on maximal inhaled therapies that
have high sputum eosinophilia and frequent exacerbations might
benefit from antiIL-5 therapy with mepolizumab or reslizumab.
By contrast, neutrophilic asthma might respond to antiinflammatory therapies that target neutrophilic inflammation,
including PDE4 inhibitors, p38 MAPK inhibitors, CXCR2
antagonists, or macrolides. Corticosteroid resistance is likely to
be an important mechanism contributing to poor treatment control
in patients with severe asthma and might respond to therapies that
target the molecular mechanisms of corticosteroid resistance,
such as p38 MAPK inhibitors in some patients, or treatments that
increase HDAC2 levels, such as theophylline, nortriptyline, and
PI3Kd inhibitors among others. Analysis of large datasets of
adults and children with severe asthma is now beginning to
recognize distinct phenotypes.143,144 It will be important to identify biomarkers that predict response to identify therapeutic subphenotypes of asthma, and this area requires more research so that
therapy can be personalized, particularly for therapies that target
specific mediators or mechanisms, because only a small proportion of patients with severe asthma are likely to respond
adequately.

BRONCHIAL THERMOPLASTY
Bronchial thermoplasty delivers controlled thermal energy to
the bronchial wall to selectively reduce the amount of airway
smooth muscle and has been studied in patients with severe
asthma. It is usually administered as 3 outpatient bronchoscopic
procedures separated by 3 weeks. In a large controlled trial of
almost 200 patients with severe asthma, bronchial thermoplasty
compared with a sham procedure produced a small improvement
in asthma-specific quality-of-life scores (although this was far
less than the minimal clinically significant difference for this test)
and a small reduction in exacerbations after treatment.140 However, significantly more patients were hospitalized, and therefore
it is uncertain whether the small clinical benefit is justifiable. In
another study asthma control was improved compared with that
seen in a control group in patients taking ICSs in whom long-

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