The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 49 S Afr Fam Pract ISSN 2078-6190 EISSN 2078-6204 © 2016 The Author(s) REVIEW Introduction Allergies refer to a hypersensitivity disorder of the immune system, and are the fifth leading chronic disease group globally. The broader name, allergic rhinoconjunctivitis (the involvement of the eyes and nose), is not that well known, and is commonly referred to as allergic rhinitis. Allergic rhinitis presents with the nasal symptoms of congestion and rhinorrhoea, and is commonly associated with ocular symptom complaints.1–4 Allergic conjunctivitis constitutes an inflammatory response of the conjunctivae to allergens, such as pollen (grass pollen), environmental antigens (dust) and animal dander.1,3–6 Allergic conjunctivitis or rhinitis is an acute or chronic illness, and is classified according to the type of allergen and occurrence of symptoms during the course of a year, i.e. seasonal or perennial. The seasonal form usually occurs during the spring and autumn when the level of outdoor allergens, i.e. pollen, is elevated, whereas perennial conjunctivitis or rhinitis is present throughout the year, is more chronic in nature and is caused by indoor allergens, i.e. house dust mites, pets and cockroaches. Recently, this classification was revised by Allergic Rhinitis and its Impact on Asthma (ARIA). The new classification does not involve the type of allergen, but rather involves the duration of symptoms and impact on the patient’s quality of life. The classification was revised to differentiate between intermittent (≤ 4 weeks in duration) or persistent (≥ 4 weeks in duration) allergic conjunctivitis or rhinitis.1,7 The symptoms that are associated with allergic rhinoconjunctivitis due to an immunoglobulin (Ig) E-mediated inflammatory response include nasal symptoms, such as congestion, nasal itching, sneezing and rhinorrhoea; and ocular symptoms, such as itching, redness, watering, tearing and burning. These symptoms are frequently reported by allergic rhinitis patients, and are more prominent in patients experiencing seasonal allergic rhinitis.1–6 Allergic rhinitis symptoms can affect patients’ quality of life, including a reduction in sleep quality, the performance of daily activities, cognitive function, work productivity and examination performance in the case of learners. These symptoms also have an impact on patients’ psychosocial well-being.4,7–10 Atopy in allergy “Atopy” is derived from the Greek word, atopia, meaning “different” or “out of place”. The atopic triad refers to three allergic conditions of atopic dermatitis (eczema), allergic rhinitis and asthma. Atopic dermatitis usually presents as the first allergy in this triad, indicative of the start of subsequent allergic diseases. This sequence of progression is referred to as “the atopic march”, with some clinical signs becoming more prominent, while others subside.11 The prevalence of atopic dermatitis was found to be 17% in South Africa, and up to 20% in Kenya in a systematic review performed in 2012. Atopic dermatitis was also found to be on the increase.12 An estimated 5–20% of children worldwide are affected by it.13 Atopic dermatitis is characterised as an inflammatory, relapsing and itchy skin disorder which is not contagious. Dry and scaly patches are present on the skin of the scalp, forehead and face, especially the cheeks, as well as the flexor surfaces of the limbs. The affected areas can be extremely itchy, to such an extent that sleep is affected. The skin can become infected because of scratching, leading to further complications. The disease is debilitating and affects all aspects of patients’ quality of life.13 Atopic dermatitis has an impact on health-related quality of life, Abstract The treatment of allergies often involves pharmacological therapy and recommendations by healthcare workers that the allergen should be avoided. Allergen-specific immunotherapy has emerged as an alternative to effectively decrease the immunoglobulin (Ig) E:IgG4 ratio. Two routes of administration are described, namely subcutaneous immunotherapy, which has always been considered to be the gold standard of treatment, and sublingual immunotherapy, which has recently been shown to have fewer systemic side-effects and improved compliance by patients. Keywords: AIT, allergic disease, allergen-specific immunotherapy, allergic rhinitis, clinical efficacy, SCIT, SLIT, subcutaneous immunotherapy, sublingual immunotherapy South African Family Practice 2016; 58(2):49-52 Open Access article distributed under the terms of the Creative Commons License [CC BY-NC-ND 4.0] http://creativecommons.org/licenses/by-nc-nd/4.0 Sublingual immunotherapy for the treatment of allergies N Schellack,1* D Engler1 1Department of Pharmacy, Faculty of Health Sciences, Sefako Makgatho Health Sciences University *Corresponding author, email: natalie.schellack@smu.ac.za S Afr Fam Pract 2016;58(2):49-5250 The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 50 as well as on patients’ mental health, and on social and emotional functioning.14 Patients who are diagnosed with atopic dermatitis are affected, while their families also carry the associated burden, both financially and psychologically.13,14 There is an increase in the prevalence of food and skin allergies in children aged ≤ 18 years. Furthermore, it has been shown that the occurrence of skin allergy decreases with increasing age, while the incidence of respiratory allergies increases with advancing age.15 Approximately 80% of patients diagnosed with atopic dermatitis develop asthma and/or allergic rhinitis as they grow older.13 Allergic rhinitis may precede the development of asthma, especially if not diagnosed and appropriately treated.16 Therefore, the development of subsequent atopic disorders might decrease if the disease progression can be altered.11 The high prevalence of IgE-mediated hypersensitivity, which places patients at risk of life-threatening conditions such as asthma, has resulted in an increase in the use of sublingual immunotherapy (SLIT) in Europe, with increased interest in countries such as the USA.17,18 The reasoning behind this movement is that allergen-specific immunotherapy (AIT) treats the symptoms, and also the underlying cause of the disease.18 Pathophysiology of atopy The so-called T helper cell type 1 (Th1)/T helper cell type 2 (Th2) paradigm refers to the balance which exists between the Th1 and Th2 subsets of the T lymphocyte. Both Th1 and Th2 subsets differentiate from CD4+-naïve T lymphocytes, which means that whenever a raised response towards either the Th1 or the Th2 subset occurs, the other will conversely be reduced.19 A decrease in Th1 subset production results in decreased levels of interferon-gamma, interleukin (IL)-2 and tumour necrosis factor-beta. A decrease in these cytokines leads to an increase in the Th2 effect owing to a decrease in IgG production, which inhibits Th2 formation.20 Infants who are genetically predisposed have an imbalance towards an elevated Th2 cellular response. The Th2 cytokines mediate the release of IL-4, IL-5 and IL-13, as well as IgE production.21 When IgE binds to an allergen, it gains the ability to bind to the high-affinity IgE receptor (FcεRI) which is expressed on the mast cell surface. When this receptor is stimulated, mast cell degranulation takes place. This degranulation then leads to the release of potent vasodilators, such as histamine, lipid mediators, chemokines and various other cytokines.22,23 Histamine also has the ability to attract other proinflammatory substances. This cascade, created by the excessive release of histamine, leads to the typical symptoms seen in patients suffering from an atopic disease, such as urticaria, angio-oedema and anaphylaxis.4 Platelet-activating factor (PAF) is another endogenous phospholipid mediator of inflammation which is contained within the alveolar macrophages, eosinophils, mast cells, platelets, basophils and neutrophils. PAF is released upon an allergic and inflammatory reaction. The release of PAF is closely associated with increased vascular permeability, bronchoconstriction, eosinophil chemoattraction and airway hyperresponsiveness, all of which are involved in the pathophysiology of allergic rhinitis, asthma and anaphylaxis. PAF levels are often elevated in patients with allergic conditions, compared to those in healthy controls.5,24,25 Management using allergen-specific immunotherapy The first-line management of an atopic disorder is to avoid the causative allergen, if at all possible. The pharmacological management of symptoms includes antihistamines and topical corticosteroids. AIT, which modifies the natural history of atopic disorders, is another option. AIT is effective in patients with allergic rhinitis, and has been shown to alter the underlying cause of the disease.26 Two options for the delivery of AIT are available, i.e. subcutaneous immunotherapy (SCIT) and SLIT. Although SCIT was viewed as the so-called gold standard for immunotherapy until recently, SLIT is now viewed as a safe and effective alternative.26,27 The sublingual route was proposed for AIT in 1987, and SLIT has emerged as the best option for immunotherapy, with comparable efficacy and a better safety profile.28 Both SCIT and SLIT consistently demonstrated benefit when compared to placebo, and may be more cost-effective per quality- adjusted life-years from the age of six years, when compared to symptomatic treatment.29 Postulated mode of action and delivery SCIT is the most common type of immunotherapy, and was introduced over a century ago in the form of the subcutaneous administration of gradually increasing dosages of a specific allergen. The allergic subjects would then become desensitised to the causative allergen, provided that sufficiently high dosages were administered on a regular basis for at least three consecutive years.28 The exact mechanism behind immunotherapy is still being investigated. However, it is postulated that contact by the allergen with the oral mucosa (in the case of SLIT) causes a local and systemic immune response. The allergen is “trapped” at the site by the Langerhans-like dendritic cells in the oral cavity. Subsequently, these cells mature and migrate to the proximal lymph nodes where IgG antibodies are produced and suppressor T lymphocytes are induced. Specific molecules are also produced as part of this response, e.g. Fce-receptor type I, major histocompatibility complex class I and II, and other co- stimulatory molecules. The increase in the antigen IgG antibodies antagonises and blocks the increase in IgE against the antigen. This balance between IgE and IgG is the crucial mechanism behind the success of ASI.18 The administration of SLIT to children suffering from allergic asthma, e.g. caused by house mites, has been shown to increase allergen-specific IgG4 levels, thus reducing the incidence of asthmatic attacks.30 This decrease in IgE:IgG4, brought about by the administration of SLIT, has been confirmed in children with allergic asthma and allergic rhinitis.30,31 Immunotherapy, i.e. SCIT and SLIT, is the only treatment with the potential to cure allergic respiratory disease via the modulation of immune system activity.16 Sublingual immunotherapy for the treatment of allergies 51 The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 51 After receiving an injection, the patient has to remain at the healthcare facility for at least 30 minutes to be monitored for serious side-effects. SCIT requires long-term commitment from the patient, and can result in considerable direct and indirect costs.32 SLIT is administered as a drop in the majority of instances. Tablets are used occasionally.18 SLIT can be delivered either via the “sublingual swallow” or the “sublingual spit” method of administration. The agent is kept under the patient’s tongue for a short time, i.e. 1–2 minutes, and then spat out (the sublingual spit method). The “sublingual swallow” method, whereby the agent is kept under the tongue for a short period and then swallowed, was utilised in the majority of studies conducted in the past.33 Subcutaneous immunotherapy versus sublingual immunotherapy The choice between SCIT and SLIT therapy is largely determined by the patient, based on factors such as convenience, availability, resources and personal preference. An overview of some of the factors that need to be considered when making a decision is provided in Table 1.26 Table 1: Points for consideration when choosing between subcutaneous immunotherapy and sublingual immunotherapy26 Parameter SCIT SLIT Indication Seasonal rhinitis* Seasonal rhinitis* Perennial rhinitis** Perennial rhinitis* Remission Long term** Long term* Paediatric experience More evidence is needed More evidence is needed Administration At a healthcare facility (specialist supervision is preferable) Self-administered Side-effects Local pain and swelling at the site of the injection is well tolerated Local itching and swelling is well tolerated Adherence to treatment Easily monitored Can be problematic SCIT: subcutaneous immunotherapy, SLIT: sublingual immunotherapy * high-quality evidence, **: moderate level of evidence It has been shown that patients prefer the use of SLIT when given the option, especially because of the convenience of at-home self-administration.34 Future advances A better understanding of oral mucosal immunity, with new proteomic techniques, has led to research into the development of a second-generation sublingual vaccine based on the recombinant allergens.33,34 These recombinant allergens directly elicit an IgG response and activate the T cells, subsequently reducing allergen-specific IgE, which effectively reduces IgE- specific side-effects, such as mast cell degranulation. Vaccine preparations are also receiving attention in terms of emphasis on allergen presentation, e.g. powder, biofilm or mucoadhesive tablets, which prolong mucosal contact and facilitate capturing the allergen by the immune cells.34 Apart from SCIT and SLIT, which use liquid extracts, other methods of delivering immunotherapy are available. These include sublingual immunotherapy tablets, and oral mucosal immunotherapy in which a toothpaste delivery vehicle is utilised.34 Conclusion The use of SLIT is preferred over SCIT as it involves a treatment option which can be self-administered at home, ensuring better compliance by patients. SLIT produces long-term clinical efficacy, and has been shown to reduce allergic rhinitis, asthmatic symptoms and the progression of the atopic march. However, the choice of SLIT versus SCIT therapy is still determined by patient preference. Large head-to-head, randomised, placebo- controlled trials, with known immunotherapies, will assist with prospective treatment decisions. The use of ASI, i.e. SLIT and SCIT, holds future promise in preventing and curing allergic disease. References 1. Bielory BP, O’Brien T, Bielory L. Management of seasonal allergic conjuctivitis: guide to therapy. Acta Ophthalmol. 2012;90(5):399–407. 2. Allergy (allergies). MedicineNet [homepage on the Internet]. 2013. c2016. Available from: http://www.medicinenet.com/allergy/article.htm 3. Okano M. Mechanism and clinical implications of glucocorticosteroids in the treatment of allergic rhinitis. Clin Exp Immunol. 2009;158(2):164–173. 4. Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the United States, 1988-1994. J Allergy Clin Immunol. 2010;126(4):779–783. 5. Di Bona D, Plaia A, Scafidi V, et al. Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systemic review and meta-analysis. J Allergy Clin Immunol. 2010;126(3):558–566. 6. Schad CA, Skoner DP. Antihistamines in the pediatric population: achieving optimal outcomes when treating seasonal allergic rhinitis and chronic urticaria. Allergy Asthma Proc. 2008;29(1):7–13. 7. Ciprandi G, Cirillo I, Pistorio A. 2008. Persistent allergic rhinitis includes different pathophysiologic types. Laryngoscope. 2008;118(3):385–388. 8. Keith PK, Scabbing GK. Are intranasal corticosteroids all equally consistent in managing ocular symptoms of seasonal allergic rhinitis? Curr Med Res Opin. 2009;25(8):2021–2041. 9. Nathan RA. The pathophysiology, clinical impact and management of nasal congestion in allergic rhinitis. Clin Ther. 2008;30(4):573–584. 10. Prenner BM, Lanier BQ, Bernstein DI, et al. 2010. Mometasone furoate nasal spray reduces ocular symptoms of seasonal allergic rhinitis. J Allergy Clin Immunol. 2010;125(6):1247–1253. 11. Spergel JM, Paller AS. Atopic dermatitis and the atopic march. J Allergy Clin Immunol 2003;112 (6 Suppl):S118–S127. 12. Zhao CY, Wijayanti A, Doria MC, et al. The reliability and validity of outcome measures for atopic dermatitis in patients with pigmented skin: a grey area. International Journal of Women’s Dermatology. 2015;1:150–154. 13. Lifschitz C. The impact of atopic dermatitis on quality of life. Ann Nutr Metab. 2015;66 Suppl 1:34–40. 14. Holm EA, Wulf HC, Stegmann H, Jemec GBE. Life quality assessment among patients with atopic eczema. Br J Dermatol. 2006;154(4):719–725. 15. Jackson KD, Howie LD, Akinbami LJ. Trends in allergic conditions among children: United States, 1997-2011. Centers for Disease Control and Prevention [homepage on the Internet]. c2016. Available from: http://www.cdc.gov/nchs/ data/databriefs/db121.htm 16. Poddighe D, Licari A, Caimmi S, Marseglia GL. Sublingual immunotherapy for pediatric allergic rhinitis: the clinical evidence. World J Clin Pediatr. 2016;5(1):47–56. 17. Cox L, Calderon MA. 2010. Subcutaneous specific immunotherapy for seasonal allergic rhinitis: a review of treatment practices in the US and Europe. Curr Med Res Opin. 2010;26(12):2723–2733. 18. Kuo C, Wang W, Chu Y, et al. Sublingual immunotherapy in children: an updated review. Pediatr Neonatol. 2009;50(2):44–49. 19. Romagnani S. L1 The Th1/Th2 paradigm in disease. J Neuroimmunol. 1999;100:2–3. S Afr Fam Pract 2016;58(2):49-5252 The page number in the footer is not for bibliographic referencingwww.tandfonline.com/oemd 52 20. Noverr MC, Huffnagle GB. The ‘microflorahypothesis’ of allergic diseases. Clin Exp Allergy. 2005;35(12):1511–1520. 21. Barnes KC. An update on the genetics of atopic dermatitis: scratching the surface in 2009. J Allergy Clin Immunol. 2010;125(1):16–29. 22. Jutel M, Akdis C. Immunological mechanisms of allergen-specific immunotherapy. Allergy. 2011;66(6):725–732. 23. Leyva-Castillo J, Li M. Thymic stromal lymphopoietin and atopic diseases. Revue Française D’Allergologie. 2014;54(5):364–376. 24. Warner J, Jones C, Jones A, Warner J. Prenatal origins of allergic disease. J Allergy Clin Immunol. 2000;105(2 Pt 2):S493–S496. 25. Kawashima T, Noguchi E, Arinami T, et al. Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. J Med Genet. 1998;35(6):502–504. 26. Durham SR, Penagos M. Sublingual or subcutaneous immunotherapy for allergic rhinitis? J Allergy Clin Immunol. 2016;137(2):339–349. 27. Calderon MA, Rodriquez del Rio P, Demoly P. Sublingual allergen immunotherapy in children: an evidence-based overview. Revue Francaise D’Allergologie. 2012;52(1):20–25. 28. Incorvaia C, Rienzo AD, Celani C. Treating allergic rhinitis by sublingual immunotherapy: a review. Ann Ist Super Sanita. 2012;48(2):172–176. 29. Meadows A, Kaambwa B, Novielli N, et al. A systematic review and economic evaluation of subcutaneous and sublingual allergen immunotherapy in adults and children with seasonal allergic rhinitis. Health Technol Assess. 2013;17(27):vi, xi-xiv. 30. Lue KH, Lin YH, Sun HL, et al. Clinical and immunologic effects of sublingual immunotherapy in asthmatic children sensitized to mites: a double blind, randomized, placebo-controlled study. Pediatr Allergy Immunol. 2006;17(6):408–415. 31. Wilson DR, Lima MT, Durham SR. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy. 2005;60(1):4–12. 32. Blume SW, Yeomans K, Kim H, et al. Administration and burden of subcutaneous immunotherapy for allergic rhinitis in clinical practice in Canada. J Manag Care Spec Pharm. 2015;21(11):982–990. 33. Cox LS, Linneman DL, Nolte H, et al. Sublingual immunotherapy: a comprehensive review. J Allergy Clin Immunol. 2006;117(5):1021–1035. 34. Chester JG, Bremberg MG, Reisacher WR. Patient preferences for route of allergy immunotherapy: a comparison of four delivery methods. Int Forum Allergy Rhinol. 2016 [Epub ahead of print]. Division of Rheumatology, Department of Internal Medicine, Chris Hani Baragwanath Academic Hospital, University of the Witwatersrand HANDS ON RHEUMATOLOGY 2016 21- 22 May 2016 The Pivot Conference Centre, Montecasino Boulevard Fourways, Johannesburg Dear Colleagues It is with great pleasure that we invite you to join us for the 2nd “Hands on Rheumatology” Update to be held at The Pivot Conference Centre, Montecasino Complex. Our theme this year is “Rise of a Rheumanation!” which exemplifies our aspiration to cultivate and revitalise interest in the field of rheumatology, whilst simultaneously expanding our rheumatology community. We have endeavoured to create a programme that will be stimulating to all health care professionals including general practitioners, physicians and other specialities, registrars, allied health professionals and nurses. Our esteemed international guest speaker is Professor Naomi Schlesinger, Chief Rheumatologist at Rutgers University, New Jersey and leading authority in the field of gout. Day 1 plenary sessions include interactive talks and case discussions focusing on the management of common rheumatic conditions. In addition, we have practical workshops introducing you to musculoskeletal imaging and intervention. A separate nurse-centred workshop has been included as part of a larger initiative to encourage specialised rheumatology nursing. A half day symposium will be held at the same venue on the 22nd May 2016 for rheumatologists, other specialists and their students to present clinical research proposals and challenging rheumatologic cases. We hope to see you there! Yours sincerely Kavita Makan On behalf of the Organising committee For further information contact: Juliette Powell - Inspiration Media @ cell: 082 322 3942 or email: Jules@inspirationgroup.co.za