Abstract
Even though allergen immunotherapy has been studied for
more than a century, a great deal remains unknownabout this
commonly used treatment.1 Immunotherapy, which is of benefit
to the majority of appropriately
selectedpatients, still
largely relies on the injection
of relatively crude allergenextracts, often involving doses that
have not been rigorously studied.2 The renewed interest in the
study of immunotherapy over the past decade is encouraging
and has resulted in important advances, including development
of more refined allergens, assessment of different routes
of delivery, and studies on the treatment of food allergy.
In this issue of JAMA, Virchowand colleagues3 report the
results of a large, multicenter clinical trial using 1of thesenewer
approaches, referred to as sublingual immunotherapy (SLIT).
The study focuses on house dustmite (HDM) allergen, an appropriate
target for study given its importance as the allergen
that is most often implicated as a trigger for asthma and perennial
allergic rhinitis on aworldwide basis. Numerous studies
have demonstrated the efficacy of subcutaneous immunotherapy
(SCIT) using HDM allergen for both asthma and
allergic rhinitis,4-6 and a smallernumberof studies have shown
overall positive results using SLIT.7-11 Data on use of SLIT in patients
with asthma are still limited, however, and are of special
interest because SLIT is associatedwith fewer adverse reactions,
especially in patients with asthma, than SCIT.
Virchowandcolleaguesconducteda double-blind,randomized,
placebo-controlled trial that included834adultswithHDM
allergyandasthmathatwasnotwellcontrolledwith inhaled corticosteroids
(ICS) orcombination products. Patientswith severe
or unstable asthma, defined as a forcedexpiratoryvolumein the
firstsecondofexpiration(FEV1) lessthan70%of predictedvalue
or hospitalizationwithin the prior3months,wereexcluded. Participantswere
randomized to 3 treatment groups, including 1 of
2dosesofsublingualtabletsofHDMallergen,6SQ-HDM(n = 275)
or 12 SQ-HDM (n = 282) (the latter dosewith twice the allergen
biological activity of the former dose) or placebo (n = 277) delivered
in a tablet form. Efficacy was assessed during the last 6
months of treatment when ICS doseswere reduced by 50% for
3months and then completelywithdrawn for 3months.
The primary outcome, defined as the time to the firstmoderate
or severe asthma exacerbation during the ICS reduction,
wasimprovedby both doses of active SLITcomparedwith
placebo,with hazard ratios of0.69 (95%CI,0.49-0.96) for the
6 SQ-HDM group and 0.66 (95% CI, 0.47 -0.93) for the 12 SQHDM
group. The absolute risk for first exacerbation was 26%
(n = 62) for the 6 SQ-HDM group, 24% (n = 59) for the 12 SQHDM
group, and 32% (n = 83) for the placebo group, primarily
involving moderate rather than severe exacerbations,with
nosignificant differencebetweenthe2active treatmentgroups.
Although mild to moderate adverse reactionswere common,
mostly related to oropharyngeal pruritus or irritation, there
were no reports of severe systemic allergic reactions. The authors
concluded that among adultswithHDMallergy–related
asthma not well controlled by ICS, the addition of HDM SLIT
deliveredas a once-daily tablet significantly prolongedthetime
to the first asthma exacerbation during ICS reduction.
Aswith any clinical trial, the critical question is howmeaningful
is this outcome.Canthese results truly benefit similar patients
encountered in clinical practice? Addressing these questions
requires consideration ofnotjust theprimaryendpointbut
alsothesecondaryoutcomesandpotentialstudylimitations.With
regardtosecondaryoutcomes,thereweresignificantdifferences
favoring the active therapycomparedwith placebowhendifferent
criteriawere used todefine asthma exacerbations, aswell as
in immunologic changes consistentwith desensitization.However,
therewerenosignificantdifferences inpatients’ responses
toquestionnairesregardingeitherasthmacontrolorqualityoflife.
The authors addressed several study limitations, including
thatpatientswithmoresevereorunstableasthmawereexcluded
from the trial. However, there are several additional concerns,
includingthat“unblinding”mayoccurwithSLITadministration,
giventhecommonoccurrence of local adverse effects relatedto
active treatment. In addition, because the study only included
adultswithHDMallergic asthma(meanage, 33 years [range, 17-
83]), the findings cannot be generalized to children, in whom
asthma exacerbations remainamong the mostcommoncauses
of emergency department visits and hospitalizations.
Despitethese limitations,theresults ofthestudybyVirchow
et al are important and clinically relevant. In particular, instead
of themorecommonapproach of studying patientswith
milder asthma or those with only allergic rhinitis, this trial focused
on themore challenging subset of patientswith asthma,
thosewith inadequatesymptomcontrol despite treatmentwith
ICS. The authors’ choice of a primary end point based on exacerbations
during ICS reduction is also unique to immunotherapy
trials,with previous trials ofHDMimmunotherapy focusing
onmedication requirements, symptomsscores, or lung
function as primary end points. Furthermore, the inclusion of
moderate exacerbations in the primary outcome is also important,
with even trials of asthma controller medications usually
focusing only on severe exacerbations. Although it is possible
to argue that severe exacerbations are the most clinically important
end points, this study aimed to identify exacerbations
before they developed intosevere events, which are both costly
and can be potentially life-threatening.
In addition, this study focused on a single allergen. Although
treatmentwitha single major allergen, considered to be
Related article page 1715
Opinion
EDITORIAL
jama.com (Reprinted) JAMA April 26, 2016 Volume 315, Number 16 1711
Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/935237/ by a Copenhagen University Library User on 01/17/2017
Copyright 2016 American Medical Association. All rights reserved.
most relevant for that individual patient, is the usual practice
inEurope,thisapproachisnottypicalintheUnitedStates,where
most immunotherapy is prescribed to include multiple allergens,
directed at asmany of the patient’s specific sensitivities
as possible.Most studies demonstrating the efficacy of immunotherapyhaveusedsingleallergens,
withconsiderablylessdata
to support the multi-allergen approach. In this study, 66% of
the participants were sensitized to other allergens in addition
toHDM,withnodifferencesinoutcomedetectedbetweenthose
patients and those monosensitized toHDM,demonstrating the
clinical efficacy of single allergenimmunotherapy evenamong
polysensitized patients.
Aside fromthisongoing question regarding single vs multiallergenimmunotherapy,
what clinical issuesandresearchquestions
remain to be addressed? Should SLIT replace SCIT as the
mainstay of immunotherapy? Although direct comparisons are
limited, SLIT appears tobeoverallsomewhat less effective than
SCIT.12-14However, SLIToffers several specific advantages over
SCIT; it can be self-administered, requires little or no dose escalation,
does not require injections, and carries a much lower
risk ofanaphylaxis.For seasonal allergens, SLIThasbeenshown
to be effectivewheninstituted prior to and continued throughout
the pollen season, as opposed to the year-round injections
requiredwith SCIT. The main disadvantage of SLIT is that it requires
adherence with daily dosing, and studies have consistently
shown lowrates of long-term adherence. For example, a
review of published studies found that 55%to 82% of patients
abandoned SLIT before completing the recommended course
of therapy,15 and in a study of SLIT refill rates, prescription renewals
occurred in only 44% of patients after 1 year of treatment,
in 28%after 2 years of treatment, and in 13% after 3 years
of treatment.16 However, these adherence rates are similar to
those seen with SCIT and even with long-term pharmacotherapy
for allergic disease and asthma.17
SLIT is currently approved for numerous allergens by the
European regulatory authorities and is inwide use throughout
Europe. In 2014, the US Food and Drug Administration announced
approval of a 5-grass pollen sublingual tablet followed
by approval of Timothy grass and ragweed pollen tablets.
Although these are the only SLIT formulations currently
approved for use in the United States, there has been and continues
to be considerable “off-label” use of liquid allergen extracts
that areapprovedonly for skin testingorSCIT.2 This is concerning
because only a few of these agents have been studied
for use by the sublingual route, sometimes without demonstrated
efficacy, and no dosing standards have been established.
Evenfewerdataareavailabletosupportuseoftheseproducts
as multi-allergen mixes as they are usually prescribed.
Accordingly, considerably more research is needed before this
off-label use of allergen extracts can be recommended.
In summary, rigorous studies of immunotherapy of all
forms are clearly needed. The study by Virchowet al is a valuable
contribution to the literature, especially given its focus
on an important patient population with highly relevant end
points. The work should not end here, as there is still a great
deal of room for refinement in the practice of immunotherapy.
As research continues and these therapies enter clinical
practice, the goal should be to optimize each patient’s immunotherapy
regimen and disease control, taking personal
preferences into account, and ideally to develop additional patient
profiling using specific biomarkers to further personalize
the use of these treatment options.
more than a century, a great deal remains unknownabout this
commonly used treatment.1 Immunotherapy, which is of benefit
to the majority of appropriately
selectedpatients, still
largely relies on the injection
of relatively crude allergenextracts, often involving doses that
have not been rigorously studied.2 The renewed interest in the
study of immunotherapy over the past decade is encouraging
and has resulted in important advances, including development
of more refined allergens, assessment of different routes
of delivery, and studies on the treatment of food allergy.
In this issue of JAMA, Virchowand colleagues3 report the
results of a large, multicenter clinical trial using 1of thesenewer
approaches, referred to as sublingual immunotherapy (SLIT).
The study focuses on house dustmite (HDM) allergen, an appropriate
target for study given its importance as the allergen
that is most often implicated as a trigger for asthma and perennial
allergic rhinitis on aworldwide basis. Numerous studies
have demonstrated the efficacy of subcutaneous immunotherapy
(SCIT) using HDM allergen for both asthma and
allergic rhinitis,4-6 and a smallernumberof studies have shown
overall positive results using SLIT.7-11 Data on use of SLIT in patients
with asthma are still limited, however, and are of special
interest because SLIT is associatedwith fewer adverse reactions,
especially in patients with asthma, than SCIT.
Virchowandcolleaguesconducteda double-blind,randomized,
placebo-controlled trial that included834adultswithHDM
allergyandasthmathatwasnotwellcontrolledwith inhaled corticosteroids
(ICS) orcombination products. Patientswith severe
or unstable asthma, defined as a forcedexpiratoryvolumein the
firstsecondofexpiration(FEV1) lessthan70%of predictedvalue
or hospitalizationwithin the prior3months,wereexcluded. Participantswere
randomized to 3 treatment groups, including 1 of
2dosesofsublingualtabletsofHDMallergen,6SQ-HDM(n = 275)
or 12 SQ-HDM (n = 282) (the latter dosewith twice the allergen
biological activity of the former dose) or placebo (n = 277) delivered
in a tablet form. Efficacy was assessed during the last 6
months of treatment when ICS doseswere reduced by 50% for
3months and then completelywithdrawn for 3months.
The primary outcome, defined as the time to the firstmoderate
or severe asthma exacerbation during the ICS reduction,
wasimprovedby both doses of active SLITcomparedwith
placebo,with hazard ratios of0.69 (95%CI,0.49-0.96) for the
6 SQ-HDM group and 0.66 (95% CI, 0.47 -0.93) for the 12 SQHDM
group. The absolute risk for first exacerbation was 26%
(n = 62) for the 6 SQ-HDM group, 24% (n = 59) for the 12 SQHDM
group, and 32% (n = 83) for the placebo group, primarily
involving moderate rather than severe exacerbations,with
nosignificant differencebetweenthe2active treatmentgroups.
Although mild to moderate adverse reactionswere common,
mostly related to oropharyngeal pruritus or irritation, there
were no reports of severe systemic allergic reactions. The authors
concluded that among adultswithHDMallergy–related
asthma not well controlled by ICS, the addition of HDM SLIT
deliveredas a once-daily tablet significantly prolongedthetime
to the first asthma exacerbation during ICS reduction.
Aswith any clinical trial, the critical question is howmeaningful
is this outcome.Canthese results truly benefit similar patients
encountered in clinical practice? Addressing these questions
requires consideration ofnotjust theprimaryendpointbut
alsothesecondaryoutcomesandpotentialstudylimitations.With
regardtosecondaryoutcomes,thereweresignificantdifferences
favoring the active therapycomparedwith placebowhendifferent
criteriawere used todefine asthma exacerbations, aswell as
in immunologic changes consistentwith desensitization.However,
therewerenosignificantdifferences inpatients’ responses
toquestionnairesregardingeitherasthmacontrolorqualityoflife.
The authors addressed several study limitations, including
thatpatientswithmoresevereorunstableasthmawereexcluded
from the trial. However, there are several additional concerns,
includingthat“unblinding”mayoccurwithSLITadministration,
giventhecommonoccurrence of local adverse effects relatedto
active treatment. In addition, because the study only included
adultswithHDMallergic asthma(meanage, 33 years [range, 17-
83]), the findings cannot be generalized to children, in whom
asthma exacerbations remainamong the mostcommoncauses
of emergency department visits and hospitalizations.
Despitethese limitations,theresults ofthestudybyVirchow
et al are important and clinically relevant. In particular, instead
of themorecommonapproach of studying patientswith
milder asthma or those with only allergic rhinitis, this trial focused
on themore challenging subset of patientswith asthma,
thosewith inadequatesymptomcontrol despite treatmentwith
ICS. The authors’ choice of a primary end point based on exacerbations
during ICS reduction is also unique to immunotherapy
trials,with previous trials ofHDMimmunotherapy focusing
onmedication requirements, symptomsscores, or lung
function as primary end points. Furthermore, the inclusion of
moderate exacerbations in the primary outcome is also important,
with even trials of asthma controller medications usually
focusing only on severe exacerbations. Although it is possible
to argue that severe exacerbations are the most clinically important
end points, this study aimed to identify exacerbations
before they developed intosevere events, which are both costly
and can be potentially life-threatening.
In addition, this study focused on a single allergen. Although
treatmentwitha single major allergen, considered to be
Related article page 1715
Opinion
EDITORIAL
jama.com (Reprinted) JAMA April 26, 2016 Volume 315, Number 16 1711
Downloaded From: http://jamanetwork.com/pdfaccess.ashx?url=/data/journals/jama/935237/ by a Copenhagen University Library User on 01/17/2017
Copyright 2016 American Medical Association. All rights reserved.
most relevant for that individual patient, is the usual practice
inEurope,thisapproachisnottypicalintheUnitedStates,where
most immunotherapy is prescribed to include multiple allergens,
directed at asmany of the patient’s specific sensitivities
as possible.Most studies demonstrating the efficacy of immunotherapyhaveusedsingleallergens,
withconsiderablylessdata
to support the multi-allergen approach. In this study, 66% of
the participants were sensitized to other allergens in addition
toHDM,withnodifferencesinoutcomedetectedbetweenthose
patients and those monosensitized toHDM,demonstrating the
clinical efficacy of single allergenimmunotherapy evenamong
polysensitized patients.
Aside fromthisongoing question regarding single vs multiallergenimmunotherapy,
what clinical issuesandresearchquestions
remain to be addressed? Should SLIT replace SCIT as the
mainstay of immunotherapy? Although direct comparisons are
limited, SLIT appears tobeoverallsomewhat less effective than
SCIT.12-14However, SLIToffers several specific advantages over
SCIT; it can be self-administered, requires little or no dose escalation,
does not require injections, and carries a much lower
risk ofanaphylaxis.For seasonal allergens, SLIThasbeenshown
to be effectivewheninstituted prior to and continued throughout
the pollen season, as opposed to the year-round injections
requiredwith SCIT. The main disadvantage of SLIT is that it requires
adherence with daily dosing, and studies have consistently
shown lowrates of long-term adherence. For example, a
review of published studies found that 55%to 82% of patients
abandoned SLIT before completing the recommended course
of therapy,15 and in a study of SLIT refill rates, prescription renewals
occurred in only 44% of patients after 1 year of treatment,
in 28%after 2 years of treatment, and in 13% after 3 years
of treatment.16 However, these adherence rates are similar to
those seen with SCIT and even with long-term pharmacotherapy
for allergic disease and asthma.17
SLIT is currently approved for numerous allergens by the
European regulatory authorities and is inwide use throughout
Europe. In 2014, the US Food and Drug Administration announced
approval of a 5-grass pollen sublingual tablet followed
by approval of Timothy grass and ragweed pollen tablets.
Although these are the only SLIT formulations currently
approved for use in the United States, there has been and continues
to be considerable “off-label” use of liquid allergen extracts
that areapprovedonly for skin testingorSCIT.2 This is concerning
because only a few of these agents have been studied
for use by the sublingual route, sometimes without demonstrated
efficacy, and no dosing standards have been established.
Evenfewerdataareavailabletosupportuseoftheseproducts
as multi-allergen mixes as they are usually prescribed.
Accordingly, considerably more research is needed before this
off-label use of allergen extracts can be recommended.
In summary, rigorous studies of immunotherapy of all
forms are clearly needed. The study by Virchowet al is a valuable
contribution to the literature, especially given its focus
on an important patient population with highly relevant end
points. The work should not end here, as there is still a great
deal of room for refinement in the practice of immunotherapy.
As research continues and these therapies enter clinical
practice, the goal should be to optimize each patient’s immunotherapy
regimen and disease control, taking personal
preferences into account, and ideally to develop additional patient
profiling using specific biomarkers to further personalize
the use of these treatment options.
Originalsprog | Engelsk |
---|---|
Tidsskrift | JAMA - Journal of the American Medical Association |
Vol/bind | 315 |
Udgave nummer | 16 |
Sider (fra-til) | 1711-1712 |
ISSN | 0002-9955 |
DOI | |
Status | Udgivet - 26 apr. 2016 |