Dr Subroto Ghoshal, Manager – Human Resources, Mindteck (India), talks about how sublingual immunotherapy can be a safe alternative to subcutaneous immunotherapy globally for treatment of allergy
Sublingual Immunotherapy (SLIT) has become a topic of interest globally and is being debated by the allergists in recent years. Allergen immunotherapy has been focusing on subcutaneous immunotherapy (SCIT) for many years, but now the interest has been shifted towards sublingual immunotherapy (SLIT) globally to study the efficacy and safe alternative to subcutaneous immunotherapy (SCIT). Numerous studies have been carried out to establish the efficacy and superiority of sublingual immunotherapy over subcutaneous immunotherapy. Even though USFDA approval has been obtained only for SLIT in the form of tablets for ragweed and grass pollen, other doses forms are also under development like drops and stripes. SLIT is being used in Asia, Australia, Europe and the US for treatment of specific allergic diseases.
Immunotherapy and allergy
Allergy is a very common disease condition which is caused by allergens where the immune system is over sensitive. An allergen is any substance that cause allergic reaction while antibody (IgE) is substance produced by body’s natural system to defend against infection and other disease. Immune system generally protects the body against allergies such as bacteria and virus. In persons whose immune system is over sensitive, it releases chemicals like histamines which trigger allergic reaction. Allergens produce reactive antibodies (IgE) and allergy symptoms in the body. Allergies are managed by using drugs but it provides temporary relief and the chances of re-occurrence again arises once the usage of drug is discontinued.
Allergen specific immunotherapy is one of the most accepted line of treatment for general allergic conditions. Subcutaneous immunotherapy (SCIT) is a very old therapy but still followed for treating allergic diseases particularly in the treatment of allergic rhinitis, rhinoconjunctivities and asthma, where its efficacy and safety has been established.
For certain allergy patients, there are two types of immunotherapy treatment available; (1) Allergy shots and (2) Sublingual immunotherapy (SLIT). In the allergy shots treatment, injection of allergens are administered by gradual increase of the dose. It has been observed that allergy shots have been effective for people having allergy to pollen, pets, dust, asthma or stinging insects but not much with allergy to food, medicine or eczema. SLIT on the other hand is a line of treatment without injection. The treatment is administered by placing small doses of allergen under the tongue. This helps improve tolerance to the allergens. SLIT has been found effective and recommended for treatment of nasal allergies and asthma 1. The ideal mechanism to manage allergy is by developing tolerance in the body for allergens which cause allergy symptoms.
Present scenario on allergy
According to the World Allergy Organisation (WAO), industrialisation and changing lifestyle are causing the rise of allergic diseases, especially among children in India. It estimates around 20 to 30 per cent of India’s population suffer from different kinds of allergic diseases 2. There are numerous factors which causes allergy like dust allergy, pollen allergy, contact allergy, food allergy etc. Food allergy alone is becoming a global scenario. In countries like Spain, Italy and Greece, melon, peach and apple allergy is common while in Switzerland celery and celeriac allergy is prevalent. UK and US hosts a lot of allergy related to peanut, nuts, sea food, egg and dairy. In India alone, food allergy causes around 30,000 emergency treatments per year3. Allergic rhinitis is a cause of concern for pediatric disorder. The International Study for Asthma and Allergies in Childhood (ISAAC) found that 14.6 per cent rhinoconjunctivities symptoms were seen in children in the age group of 13 to 14 years and 8.5 per cent was seen in children in the age group six to seven years considering global average. In India, the ISAAC showed that children with nasal symptoms in the age group of six to seven years accounted for 12.5 per cent and in the age group of 13 to 14 years accounted for 18 per cent4. As per the report of Indian Journal of Medical Research 141, April 2014, it is estimated globally the prevalence of asthma is approximately 4.5 per cent. There are about 334 million asthma patients spread across all age group. In India, it is estimated that asthma patients are around 17.23 million 5. Allergic rhinitis in India has been underestimated in terms of severity in spite of the fact that 75 per cent of children and 80 per cent of asthmatic adults suffer from this disease 6.
SCIT is specific to allergy related diseases. This therapy provides symptomatic relief to the patients by targeting the immunological mechanism. It is given by subcutaneous route and known as allergy shots. The main focus of allergen specific immunotherapy is to decrease the symptom which gets aggravated by allergens and to restrict the disease to reoccur in the future. This therapy is known as SCIT which involves the administration of specific allergen dose by modifying the immunological mechanism7. Many studies have indicated that efficacy and safety of SCIT is dependent on the dose. SCIT has shown to be effective in reducing the clinical symptoms related to asthma, allergic rhinitis/ rhinoconjunctivitis and venom hypersensitivity.
Limitations of SCIT
A major drawback with SCIT is the use of subcutaneous injection. Studies carried out points that there is a potential risk of severe systemic reactions with SCIT, including anaphylaxis. Though the numbers have been very less, but there have been some cases of fatal reactions to subcutaneous immunotherapy reported in the study conducted by American Academy of Allergy, Asthma and Immunology (AAAAI) 8. The other concern is that it is non patient friendly due to regular injections, which are sometime painful locally, fear among children and few adults, increased indirect cost due to frequent visit to doctor’s office.
SLIT is the new interest of study to treat allergies without injection. Patient is given a small dose of allergen under the tongue to boost tolerance to the substance and reduce symptoms. In order to determine the allergens causing allergy symptoms, tests are carried out in the form of blood test or skin prick test (SPT). Once the allergens are tested and determined, they are introduced into the body through the sublingual (under the tongue) route. Currently FDA has approved SLIT only in the form of tablets for ragweed and grass pollen 9. Apart from tablets, drops and stripes are also being administered under the tongue generally on a daily basis.
Management of allergy with SLIT
SLIT formulations are to be placed under the tongue because it dissolves with saliva and is absorbed directly into blood circulation. By this method maximum allergens are absorbed by the body as against swallowing where it loses its potency in the stomach. Once the allergy is confirmed for the patient, customised tablet or drop is prepared for the patient. The dosage is administered by taking the drops or tablet under the tongue daily. During the initial period also known as the escalation period, the dosage of drops is increased gradually. In the case of tablets, maintenance dose is given for a four to five year period. The general prescribed period for the SLIT is a minimum of five years 10.
The purpose behind the long treatment period is to ensure that the symptoms do not recur after withdrawal. If there is a premature withdrawal of usage of medication, although there are no side effects indicated but the chances of recurrence of the symptom gets high due to the incomplete enhancement of the immune system. There are different dosage form of SLIT available for SLIT drops, SLIT tablets and SLIT stripes.
Advantages of SLIT
Reaction to SLIT is very rare. It has been found very safe for children and adults. Unlike going to the doctor’s chamber to take allergy shots, tablets or drops can be taken conveniently at home. ‘The World Health Organisation (WHO) has endorsed SLIT as a viable alternative to injection therapy’ 11.
Even though SLIT is considered a very safe therapy, there are some known mild side effects like sneezing, itchy tongue, lips, mouth, skin rashes diarrhoea, headache etc. which last only for a few days. It is advised to take an antihistamine for immediate relief. SLIT does not induce any kind of toxicity on long term use and no anaphylactic reaction has been observed. SLIT can be used with all drugs except with oral steroids.
Various studies show that SLIT is very safe when administered in children. It has been suggested that the efficacy of SLIT has been higher if it is started early. But the study does not establish the age of the children when the administration can be started 12. However in one of the studies on children, a few cases of oral itching, abdominal pain and gastrointestinal side effects were cited which was later brought under control by reducing the dose. Certain studies discourage the usage in children below five years of age while certain other study showed it is safe to use SLIT in preschool age children for treatment of allergy 13.
SLIT research and treatment in Bengaluru
Bengaluru is witnessing the research and treatment in the field of SLIT segment. Bengaluru Allergy Centr was established in 1980. This allergy centre headed by Dr Nagendra Prasad K, founder director, expert in allergy disorder provides complete allergy treatment. Bengaluru Allergy Centr has introduced sSLIT and is carrying out research activities in this therapy segment. The research team is headed by their principal scientist Dr Paranjothy Kanni who introduced sublingual therapy formulations in Bangalore. This centre had carried out research in the management of allergic rhinitis with custom made SLIT tablets.
Bengaluru Allergy Centr selected 390 subjects who were suffering from rhinitis sensitive to house dust mite (HDM). 173 subjects were male and 217 were female and age ranged from 2 to 74 years. Clinical confirmation of sensitivity was done by skin prick test (SPT). The SLIT tablets were dispensed for two months with one tablet once daily. The patients were instructed to keep the tablet under the tongue for five minutes before dinner. SLIT tablet disintegrated within 90 seconds. The patients were instructed to keep the saliva for three to five minutes below the tongue to generate maximum tolerance and minimum adverse effect. The SLIT tablets were initiated with maintenance dose from day one. The SLIT tablets were dispensed once in two months after every follow-up visit monitoring the symptoms. The personalised SLIT medication with sublingual tablets initiated for six months with observing the adverse effects, symptom score and medication score. It was observed that there were no adverse effect with these subjects and noticed good symptoms relief 14.
The other research carried out was on formulation and evaluation of custom made sublingual films (stripe) of house dust mite extract. House dust mite (HDM) is one of the common cause of asthma and allergic symptoms. Bengaluru Allergy Centr’s objective is to formulate the sublingual films (Stripe) with purified extract of HDM for SLIT. The sublingual immunotherapy films (Stripe) have been evaluated. In-vitro dissolution test have been performed as per USP type II apparatus using distilled water as the medium at a speed of 50 rpm, maintaining a temperature of 37oC. more than 80 per cent of biologically active content was released in five minutes15. Dr Paranjothy Kanni, Principal Scientist of Bengaluru Allergy Centr states “SLIT stripes are emerging as an alternate to the traditional drops, spray and tablets. SLIT stripe containing HDM extracts are prepared using hydrophilic polymers that dissolve under the tongue, delivering the allergens into the systemic circulation via dissolution when in contact with saliva”.
This centre is equipped with various instruments and software to diagnose, develop and deliver SLIT treatment to the patients using the process of allergen ultra-filtration and lyophilisation. Lyophilisation is a process where in the liquid allergen is converted to powder form at -500C under vaccum. Most of the diagnostic process is carried out by (enzyme-linked immunosorbent assay) ELISA method.
Kanni opines, “There is a need to have better diagnostic software which will give results faster and have more parameters applicable to the Indian patients with various types of allergy. Software
available in the West, which are trying to enter the Indian market, have considered allergens from Europe and American origin but not with respect to allergens from India.”
It is understood that Mindteck (India), a Bengaluru -based software development company, providing services in the niche domain of medical device segment with specialisation in medical imaging, remote diagnostics and patient monitoring system, is in talks with Bengaluru Allergy Centr to explore the opportunity to develop software which can cater to their needs. Mindteck specialises in offering software solutions related to compliance regulation, in the areas of laboratory informatics, data management. It has vast experience in laboratory data management and the quality management system which is governed by ISO 13485:2003, 21 CFR Part 11 and 21 CFR part 820 standards and confirm to FDA regulations16.
Conclusion and future of SLIT
SLIT appears to be better tolerated than SCIT. The majority of the adverse reaction seen in SLIT were local reactions that were found to occur during the starting of the treatment and were brought under control by adjustment of doses and medication. But no case has been reported for fatalities. There are still certain issues which remains unresolved. “Some of the issues where we still need more data, is regarding the safety on SLIT in patients who have systemic reaction with SCIT and whether the gastrointestinal and oropharyngeal infections and lesions (e.g., apthous ulcer, gingivitis, eosinophilic esophagitis) risk factors for SLIT systemic reaction,” indicates Prasad. SLIT is a safe and effective in the treatment of allergic rhinitis and allergic rhinoconjunctivitis. Although US Food and Drug Administration (FDA) has approved three SLIT tablets, there is still a long way to go as approval of other formulations is under review and still pending. Research is still being conducted on SLIT on allergic asthma, food allergies, atopic dermatitis and others 17.
Extraction procedure and standardisation of the allergens to the purest level need further extensive research to provide a precise allergen in SLIT dosage forms.
3. Foodsmatter.com /allergy_intolerance/miscellaneous/articles/food_allergy_india
4. Asia Pac Allergy. 2012 Apr;2(2):93-100. English. Published online http://dx.doi. org/ 10.5415/apallergy. 2012.2.2.93
5. Icmr.nic.in/ ijmr/2015/april/editorial2
6. Ncbi.nlm.nih.gov/ pubmed/19548632
7. Aris aacijournal.biomedcentral.com/articles/10.1186/1710-1492-7-S1-S5
13. Ncbi.nlm.nih.gov/ pubmed/15898975
14. Komarla Nagendra, paranjothy kanni, European academy of allergy & clinical immunology (EAACI) conference 2014, Copenhagen, abstract No 1116
15. Kanni paranjothy et al, isolation and characterization of house dust mite and formulation of its extract into sublingual tablets for sublingual immunotherapy, ISMA 2013 Abstract 2484129
17. Ncbi.nlm.nih.gov/ pubmed/26149585
(Views expressed by the author are personal)