Allergen immunotherapy (AIT) has been in practice for more than 100 years. However, research in novel routes and delivery methods of immunotherapy to treat allergic rhinitis (AR) and conjunctivitis has only recently occurred in the United States, where the predominant form of AIT provided is largely via a subcutaneous immunotherapy (SCIT) route. AIT may prevent new sensitizations, improve symptoms, decrease medication usage, and prevent allergic asthma. Although AIT is the only potentially curative treatment for AR, access and adherence continue to be problematic. Only a fraction of eligible patients actually undergo treatment, and attrition rates are high. An obvious limitation of SCIT includes the requirement of regular injections to be provided in the physician's office due to the potential for anaphylaxis. Sublingual immunotherapy (SLIT) for home administration has been investigated as a potential alternative to address this limitation of SCIT.
Methods
A literature review was performed including the current findings from randomized clinical trials and meta-analyses with a discussion of the most recent evidence for the efficacy, safety, and dosing of allergen SLIT.
Results
The current data suggest that SLIT is effective for treatment of seasonal allergies, can potentially prevent asthma, and has a favorable safety profile. Head-to-head studies, however, are few, and comparative effectiveness still remains to be answered. Optimal treatment algorithms for SLIT have not yet been established, with wide variation in dosage selection and schedules. Similarly to SCIT, only a few allergens such as ragweed and grass pollen have been found to be effective in large clinical trials.
Conclusion
Recent data indicate that SLIT is an effective treatment modality for seasonal AR, improve quality of life, and can potentially prevent asthma but head-to head studies comparing SLIT to SCIT are needed.
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References
1.
BousquetJ., KhaltaevN., CruzA.A.Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen).Allergy63: 8–160, 2008.
2.
National Ambulatory Medical Care Survey:2010 Summary Tables: Centers for Disease Control. 2010.
3.
BieloryL., SkonerD.P., BlaissM.S.Ocular and nasal allergy symptom burden in America: The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) surveys.Allergy Asthma Proc35: 211–218, 2014.
4.
CoxL., and JacobsenL.Comparison of allergen immunotherapy practice patterns in the United States and Europe.Ann Allergy Asthma Immunol103: 451–459; quiz 459–461: 495, 2009.
5.
FockeM., SwobodaI., MarthK., and ValentaR.Developments in allergen-specific immunotherapy: From allergen extracts to allergy vaccines bypassing allergen-specific immunoglobulin E and T cell reactivity.Clin Exp Allergy40: 385–397, 2010.
6.
SkonerD.P., BlaissM.S., DykewiczM.S.The Allergies, Immunotherapy, and RhinoconjunctivitiS (AIRS) survey: Patients' experience with allergen immunotherapy.Allergy Asthma Proc35: 219–226, 2014.
7.
CoxL.S., HankinC., and LockeyR.Allergy immunotherapy adherence and delivery route: Location does not matter.J Allergy Clin Immunol Pract2: 156–160, 2014.
8.
HsuN.M., and ReisacherW.R.A comparison of attrition rates in patients undergoing sublingual immunotherapy vs subcutaneous immunotherapy.Int Forum Allergy Rhinol2: 280–284, 2012.
9.
BrożekJ.L., BousquetJ., Baena-CagnaniC.E.Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision.J Allergy Clin Immunol126: 466–476, 2010.
10.
Full Prescribing Information.Ragwitek (short ragweed pollen allergen extract tablet for sublingual use).Whitehouse Station, NJ: Merck & Co., Inc., 2014.
11.
Full Prescribing Information.Grastek (Timothy grass pollen allergen extract tablet for sublingual use).Whitehouse Station, NJ: Merck & Co., Inc., 2014.
12.
Full Prescribing Information.Oralair (Sweet vernal, Orchard, Perennial Rye, Timothy, and Kentucky Blue Grass mixed pollens allergen extract tablet for sublingual use).Antony, France: Stallergenes S.A., 2014.
13.
DretzkeJ., MeadowsA., NovielliN.Subcutaneous and sublingual immunotherapy for seasonal allergic rhinitis: A systematic review and indirect comparison.J Allergy Clin Immunol131: 13611366, 2013.
14.
CalderónM.A., CoxL., CasaleT.B.Multiple-allergen and single-allergen immunotherapy strategies in polysensitized patients: Looking at the published evidence.J Allergy Clin Immunol129: 929–934, 2012.
15.
SeagerH.Drug-delivery products and the Zydis fast-dissolving dosage form.J Pharm Pharmacol50: 375–382, 1998.
16.
MoingeonP., and MascarellL.Induction of tolerance via the sublingual route: Mechanisms and applications.Clin Dev Immunol2012: 623474, 2012.
17.
Committee for Medicinal Products for Human Use.Guideline on the clinical development of products for specific immunotherapy for the treatment of allergic diseases.London, UK: European Medicines Agency, 2008.
18.
CanonicaG.W., Baena-CagnaniC.E., BousquetJ.Recommendations for standardization of clinical trials with allergen specific immunotherapy for respiratory allergy. A statement of a World Allergy Organization (WAO) taskforce.Allergy62: 317–324, 2007.
19.
PfaarO., Kleine-TebbeJ., HormannK.Allergen-specific immu-notherapy: Which outcome measures are useful in monitoring clinical trials?Immunol Allergy Clin North Am31: 289–309, x, 2011.
20.
CalderonM.A., BernsteinD.I., BlaissM.A comparative analysis of symptom and medication scoring methods used in clinical trials of sublingual immunotherapy for seasonal allergic rhinitis.Clin Exp Allergy44: 1228–1239, 2014.
21.
LinS.Y., ErekosimaN., KimJ.M.Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: A systematic review.JAMA309: 1278–1288, 2013.
Di BonaD., PlaiaA., ScafidiV.Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A systematic review and meta-analysis.J Allergy Clin Immunol126: 558–566, 2010.
24.
KimJ.M., LinS.Y., Suarez-CuervoC.Allergen-specific immuno-therapy for pediatric asthma and rhinoconjunctivitis: A systematic review.Pediatrics131: 1155–1167, 2013.
25.
Larenas-LinnemannD.Sublingual immunotherapy in children: Complete and updated review supporting evidence of effect.Curr Opin Allergy Clin Immunol9: 168–176, 2009.
26.
RadulovicS., WilsonD., CalderonM., and DurhamS.Systematic reviews of sublingual immunotherapy (SLIT).Allergy66: 740–752, 2011.
27.
WilsonD.R., Torres LimaM.T., and DurhamS.R.Sublingual immunotherapy for allergic rhinitis: Systematic review and meta-analysis.Allergy60: 4–12, 2005.
28.
CalderonM.A., PenagosM., SheikhA.Sublingual immunotherapy for allergic conjunctivitis: Cochrane systematic review and meta-analysis.Clin Exp Allergy41: 1263–1272, 2011.
29.
RöderE., BergerM.Y., de GrootH., and van WijkR.G.Immunotherapy in children and adolescents with allergic rhinoconjunctivitis: A systematic review.Pediatr Allergy Immunol19: 197–207, 2008.
30.
SopoS.M., MacchiaioloM., ZorziG., and TripodiS.Sublingual immunotherapy in asthma and rhinoconjunctivitis; systematic review of paediatric literature.Arch Dis Child89: 620–624, 2004.
31.
TaoL., ShiB., ShiG., and WanH.Efficacy of sublingual immunotherapy for allergic asthma: Retrospective meta-analysis of randomized, double-blind, and placebo-controlled trials.Clin Respir J8: 192–205, 2014.
32.
WilsonD.R., Torres-LimaM., and DurhamS.R.Sublingual immuno-therapy for allergic rhinitis.Cochrane Database Syst RevCD002893, 2003.
CompalatiE., PassalacquaG., BoniniM., and CanonicaG.W.The efficacy of sublingual immunotherapy for house dust mites respiratory allergy: Results of a GA2LEN meta-analysis.Allergy64: 1570–1579, 2009.
35.
MaloneyJ., BernsteinD.I., NelsonH.Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: A large randomized controlled trial.Ann Allergy Asthma Immunol112: 146–153.e2, 2014.
36.
CoxL.S., CasaleT.B., NayakA.S.Clinical efficacy of 300IR 5-grass pollen sublingual tablet in a US study: The importance of allergen-specific serum IgE.J Allergy Clin Immunol130: 1327–1334, 2012.
37.
NolteH., HébertJ., BermanG.Randomized controlled trial of ragweed allergy immunotherapy tablet efficacy and safety in North American adults.Ann Allergy Asthma Immunol110: 450–456.e4, 2013.
38.
CreticosP.S., MaloneyJ., BernsteinD.I.Randomized controlled trial of a ragweed allergy immunotherapy tablet in North American and European adults.J Allergy Clin Immunol131: 1342–1349.e1346, 2013.
39.
CreticosP.S., EschR.E., CourouxP.Randomized, double-blind, placebo-controlled trial of standardized ragweed sublingual-liquid immunotherapy for allergic rhinoconjunctivitis.J Allergy Clin Immunol133: 751–758, 2014.
40.
CalderonM.A., CasaleT.B., NelsonH.S., and DemolyP.An evidence-based analysis of house dust mite allergen immunotherapy: A call for more rigorous clinical studies.J Allergy Clin Immunol132: 1322–1336, 2013.
41.
WangD.H., ChenL., ChengL.Fast onset of action of sublingual immunotherapy in house dust mite-induced allergic rhinitis: A multicenter, randomized, double-blind, placebo-controlled trial.Laryngoscope123: 1334–1340, 2013.
42.
BozekA., IgnasiakB., FilipowskaB., and JarzabJ.House dust mite sublingual immunotherapy: A double-blind, placebo-controlled study in elderly patients with allergic rhinitis.Clin Exp Allergy43: 242–248, 2013.
43.
BergmannK.C., DemolyP., WormM.Efficacy and safety of sublingual tablets of house dust mite allergen extracts in adults with allergic rhinitis.J Allergy Clin Immunol133: 1608–1614.e6, 2014.
44.
AydoganM., EifanA.O., KelesS.Sublingual immunotherapy in children with allergic rhinoconjunctivitis mono-sensitized to house-dust-mites: A double-blind-placebo-controlled randomised trial.Respir Med107: 1322–1329, 2013.
SwamyR.S., ReshamwalaN., HunterT.Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy.J Allergy Clin Immunol130: 215–224.e7, 2012.
47.
HoltP.G., SlyP.D., SampsonH.A.Prophylactic use of sublingual allergen immunotherapy in high-risk children: A pilot study.J Allergy Clin Immunol132: 991–993.e991, 2013.
ZuberbierT., BachertC., BousquetP.J.GA2LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and asthma.Allergy65: 1525–1530, 2010.
50.
National Heart, Lung, and Blood Institute Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma.2007.
51.
JacobsenL., NiggemannB., DreborgS.Specific immunotherapy has long-term preventive effect of seasonal and perennial asthma: 10-year follow-up on the PAT study.Allergy62: 943–948, 2007.
52.
MollerC., DreborgS., FerdousiH.A.Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-Study).J Allergy Clin Immunol109: 251–256, 2002.
53.
NovembreE., GalliE., LandiF.Coseasonal sublingual immunotherapy reduces the development of asthma in children with allergic rhinoconjunctivitis.J Allergy Clin Immunol114: 851–857, 2004.
54.
ValovirtaE., BerstadA.K., de BlicJ.Design and recruitment for the GAP trial, investigating the preventive effect on asthma development of an SQ-standardized grass allergy immunotherapy tablet in children with grass pollen-induced allergic rhinoconjunctivitis.Clin Ther33: 1537–1546, 2011.
55.
CiprandiG., and CirilloI.Monosensitization and polysensitization in allergic rhinitis.Eur J Intern Med22: e75–e79, 2011.
56.
BlaissM., MaloneyJ., NolteH.Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents.J Allergy Clin Immunol127: 64–71.e64, 2011.
57.
NelsonH.S., NolteH., CreticosP.Efficacy and safety of timothy grass allergy immunotherapy tablet treatment in North American adults.J Allergy Clin Immunol127: 72–80.e72, 2011.
58.
DidierA., MallingH.J., WormM.Optimal dose, efficacy, and safety of once-daily sublingual immunotherapy with a 5-grass pollen tablet for seasonal allergic rhinitis.J Allergy Clin Immunol120: 1338–1345, 2007.
59.
WahnU., TabarA., KunaP. on behalf of the SLIT Study Group. Efficacy and safety of 5-grass-pollen sublingual immunotherapy tablets in pediatric allergic rhinoconjunctivitis.J Allergy Clin Immunol123: 160–166.e3, 2009.
60.
NelsonH., BlaissM., NolteH.Efficacy and safety of the SQ-standardized grass allergy immunotherapy tablet in mono- and poly-sensitized subjects.Allergy68: 252–255, 2013.
61.
CiprandiG., CadarioG., Di GioacchinoM.Sublingual immunotherapy in polysensitized allergic patients with rhinitis and/or asthma: Allergist choices and treatment efficacy.J Biol Regul Homeost Agents23: 165–171, 2009.
62.
CiprandiG., IncorvaiaC., PuccinelliP.The POLISMAIL lesson: Sublingual immunotherapy may be prescribed also in polysensitized patients.Int J Immunopathol Pharmacol23: 637–640, 2010.
63.
LeeJ.E., ChoiY.S., KimM.S.Efficacy of sublingual immunotherapy with house dust mite extract in polyallergen sensitized patients with allergic rhinitis.Ann Allergy Asthma Immunol107: 79–84, 2011.
64.
CoxL., NelsonH., LockeyR.Allergen immunotherapy: A practice parameter third update.J Allergy Clin Immunol127: S1–S55, 2011.
65.
ChelladuraiY., Suarez-CuervoC., ErekosimaN.Effectiveness of subcutaneous versus sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: A systematic review.J Allergy Clin Immunol Pract1: 361–369, 2013.
66.
CalderonM.A., EichelA., MakatsoriM., and PfaarO.Comparability of subcutaneous and sublingual immunotherapy outcomes in allergic rhinitis clinical trials.Curr Opin Allergy Clin Immunol12: 249–256, 2012.
67.
KhinchiM.S., PoulsenL.K., CaratF.Clinical efficacy of sublingual and subcutaneous birch pollen allergen-specific immunotherapy: A randomized, placebo-controlled, double-blind, double-dummy study.Allergy59: 45–53, 2004.
68.
MatricardiP.M., KunaP., PanettaV.Subcutaneous immunotherapy and pharmacotherapy in seasonal allergic rhinitis: A comparison based on meta-analyses.J Allergy Clin Immunol128: 791–799.e6, 2011.
69.
del CuvilloA., SastreJ., BartraJ.Placebo effect in clinical trials involving patients with allergic rhinitis.J Investig Allergol Clin Immunol21(suppl 3): 40–45, 2011.
70.
BenningerM., FarrarJ.R., BlaissM.Evaluating approved medications to treat allergic rhinitis in the United States: An evidence-based review of efficacy for nasal symptoms by class.Ann Allergy Asthma Immunol104: 13–29, 2010.
71.
WilsonA.M., O'ByrneP.M., and ParameswaranK.Leukotriene receptor antagonists for allergic rhinitis: A systematic review and meta-analysis.Am J Med116: 338–344, 2004.
72.
LinS.Y., and LeathermanB.Sublingual immunotherapy.Otolaryngol Clin North Am44: 753–764, x–xi, 2011.
73.
WesselF., ChartierA., MeunierJ-PSafety and tolerability of an SQ-standardized GRAss ALlergy immunotherapy tablet (GRAZAX®) in a real-life setting for three consecutive seasons - the GRAAL trial.Clin Drug Invest32: 451–463, 2012.
74.
CalderónM.A., SimonsF.E., MallingH.J.Sublingual allergen immunotherapy: Mode of action and its relationship with the safety profile.Allergy67: 302–311, 2012.
75.
CanonicaG.W., BousquetJ., CasaleT.Sub-lingual immunotherapy: World Allergy Organization Position Paper 2009.Allergy64(suppl 91): 1–59, 2009.
76.
CappellaA., and DurhamS.R.Allergen immunotherapy for allergic respiratory diseases.Hum Vaccin Immunother8: 1499–1512, 2012.
77.
LiebermanP.The risk and management of anaphylaxis in the setting of immunotherapy.Am J Rhinol Allergy26: 469–474, 2012.
78.
HorakF., ZieglmayerP., ZieglmayerR.Early onset of action of a 5-grass-pollen 300-IR sublingual immunotherapy tablet evaluated in an allergen challenge chamber.J Allergy Clin Immunol124: 471–477.e1, 2009.
79.
EifanA.O., ShamjiM.H., and DurhamS.R.Long-term clinical and immunological effects of allergen immunotherapy.Curr Opin Allergy Clin Immunol11: 586–593, 2011.
80.
DurhamS.R., EmmingerW., KappA.SQ-standardized sublingual grass immunotherapy: Confirmation of disease modification 2 years after 3 years of treatment in a randomized trial.J Allergy Clin Immunol129: 717–725.e715, 2012.
81.
DidierA., MallingH.J., WormM.Post-treatment efficacy of discontinuous treatment with 300IR 5-grass pollen sublingual tablet in adults with grass pollen-induced allergic rhinoconjunctivitis.Clin Exp Allergy43: 568–577, 2013.
82.
LinS.Y., ErekosimaN., Suarez-CuervoC.Allergen-specific immunotherapy for the treatment of allergic rhinoconjunctivitis and/or asthma: Comparative Effectiveness Review No. 111.Rockville, MD: Agency for Healthcare Research and Quality, 2013.
83.
SlaterJ.E., EschR.E., and LockeyR.F.Aerobiology and allergens: Preparation and standardization of allergen extracts. In Middleton's Allergy: Principles and Practice.AdkinsonN.F. (Ed). Philadelphia, PA: Elsevier, 2009.
84.
GrierT.J.How's my dosing? A one-step, math-free guide for comparing your clinic's maintenance immunotherapy doses to current practice parameter recommendations.Ann Allergy Asthma Immunol108: 201–205, 2012.
85.
DurhamS.R., YangW.H., PedersenM.R.Sublingual immunotherapy with once-daily grass allergen tablets: A randomized controlled trial in seasonal allergic rhinoconjunctivitis.J Allergy Clin Immunol117: 802–809, 2006.
