Immunotherapy – The Cutting Edge – by Alex Gazzola

On 11thOctober 2011, King’s College London Allergy Academy held an immunotherapy (IT) study day at St Thomas’ Hospital. Alex Gazzola attended a series of talks examining the ‘cutting edge’ of IT as it stands today.

Dr Caroline Bussmann, assistant physician and research fellow in the laboratory of immunobiology at the University of Bonn, Germany, opened proceedings with her talk, IT for atopic dermatitis: what is the evidence?

She began by explaining the strong genetic component involved in atopic dermatitis (eczema): 15% and 20% of children with one parent or both parents respectively with allergic rhinitis (hay fever) will develop atopic dermatitis, while 80% of children with two parents with atopic dermatitis will develop it themselves.

The atopic career (or allergic march) tends to begin with atopic dermatitis and food allergy in the first two years of life, with asthma manifesting at early school age, and allergic rhinitis in older children. Early treatment of atopic dermatitis with IT can potentially halt the progress of this march.

70% of patients with atopic dermatitis are sensitised to more than one allergen, and aeroallergens of relevance include the seasonal ones – birch, grass pollens – and the perennial – like house dust mite, which is the most frequent cause of sensitisation and difficult to eliminate completely in everyday life. RASTs and skin prick tests can help confirm sensitisations, but specialised centres can also make use of atopy patch tests.

Treatment involves allergen avoidance. With house dust mite, encasings for the bed, mattress and pillows, and freezing of soft toys, are good tactics; with pollen, keeping windows closed, showering before bed, and keeping clothing in a different room than the bedroom are recommended. Nevertheless, often, these precautions don’t provide symptomatic improvement. With atopic dermatitis, there is rarely reduction in symptoms through encasing alone. Dust mite allergens are widely encountered in public places.

Subcutaneous/sublingual immunotherapy (SCIT / SLIT) are possible next steps, if there is clear IgE sensitisation, a correlation with clinical symptoms, excellent quality standardised allergen extract available, and the elimination of the allergen is impossible.

The positives of IT are that it may prevent new sensitisations and the development of further atopic disease, while on the negative side, symptoms can be exacerbated, relapse of latent atopic dermatitis may result, and IgE levels can increase.

The majority of studies show a positive effect – but some show no benefit, and we must always take into consideration a strong placebo effect of up to 30%.

Concluding, Bussmann said IT might represent an option for the future treatment of a subgroup of eczema patients and especially those with severe forms, but we still need to investigate which patients would profit most from this therapy and select them carefully. Further randomised double-blind placebo-controlled studies are needed to evaluate the effect of IT in atopic dermatitis as at the moment there is no real strong evidence.

Sublingual Immunotherapy (SLIT) for Perennial Rhinitis: Are we ready for House Dust Mite? was the title of the talk from Dr Edouard Letellier, now consultant immunologist at Frimley Park Hospital NHS Trust and Royal Surrey County Hospital Trust after having previously worked in France.

He told the audience that “we love” SLIT in France and it is very common, safe, and effective for allergic rhinitis and for respiratory allergies. Letellier spoke at length about two recent studies.

The first was a China-based study from Stallergenes – a European biopharmaceutical company dedicated to IT – aimed at assessing the safety and efficacy of SLIT in adults with allergic asthma triggered by house dust mites, using the Staloral® Mites 300 vaccine.

Lowering the steroid requirement

The randomised, double-blind and placebo-controlled study was a multi-centre study conducted over 15 months in a number of China’s main cities. Almost 500 patients with mild to moderate asthma, well-controlled by corticosteroid therapy, were divided into placebo and Staloral® groups for a year’s treatment. Gradually reduced dosages of corticosteroids were given for the duration, and asthma control levels assessed. Staloral® group members with moderate asthma demonstrated statistically significant improvements, and a lowered requirement for steroids – however, those with mild asthma showed little improvement. No real side effects or worsening of lung function was found, and there were few withdrawals.

It is the moderate asthmatics who probably need to be targeted more, speculated Letellier, as this group of sufferers is more vulnerable to the consequences of the allergic march.

The second study, also by Stallergenes, looked at the Actair® house dust mite IT tablet for perennial allergic rhinitis. Over 500 adults with moderate to severe persistent allergic rhinitis to dust mites were given a full year of treatment in 2008 – this consisted of two treated groups (with 300- and 500-strength tablets, respectively) and a placebo group.

An unexpected quick onset of action and good safety profile were discovered, with highly statistical differences between both treated groups and placebo, with no difference between the two treated groups. The effects were found to last in the subsequent year, although a one-year treatment period is unlikely to be optimal. With fewer side effects, the 300-strength tablet was selected in moving forward.

So – how long should SLIT or SCIT be used for? Three years according to one study, said Letellier, but this question needs much more work.

Early IT can reduce symptoms

In conclusion, it was suggested that early treatment with desensitisation therapy via IT can not only improve the allergy being treated, but perhaps also reduce the symptoms triggered by other allergens: in other words, if you treat a dust mite allergy, you may find – perhaps thanks to reduced tissue inflammation – that pollen allergy symptoms improve too. If you treat atopic children early in life, he added, any asthma they go on to develop may not be as severe as it might otherwise have been.

Severity of birch pollen allergy

On this last point, Letellier says he was struck by the severity of birch pollen allergy in this country, and the associated Oral Allergy Syndrome that occurs with it (OAS is a food allergy caused by cross-reactions between raw food proteins and the proteins in birch pollen – typically with foods such as carrot, celery, apple and stone fruits). He said that OAS-related anaphylaxis is becoming more common in the UK, yet was exceptionally rare in France. This may be due to the early desensitisation preferences in France. Have opportunities to benefit from this been missed in the UK?

On a final precautionary note, he did warn that dust mite desensitisation increases IgE levels – and associated cross-reactions with shrimp / prawn and snail must be borne in mind. Snail (escargot) is not an issue in the UK, but of course it is very much so in France. Letellier told the sad tale of a young boy undergoing IT who died following the consumption of half a dozen escargot – not of anaphylaxis but of an acute asthma reaction. Professor Anthony Frew of the Department of Respiratory Medicine at Royal Sussex County Hospital followed by speaking on Politics and Economics of Immunotherapy.

IT used to be a well-established treatment in the UK, he began, where it was offered by GPs, supported by peripatetic nurses who advised on skin testing and helped arrange vaccines. This model ‘worked’ until around 1980 as the vaccines had barely any allergen in them, but in the 80s vaccines were strengthened and this led to a flurry of deaths in the first half of the decade. In 1986, IT was restricted to those centres using it extensively: because there were so few such centres, it was effectively stopped. Many GPs told their patients it was banned, but this was never the case.

Frew spoke of the difference in attitudes towards IT in the US, UK and Europe. Unlike in the UK, in the US IT is always considered the correct treatment for asthma: one doesn’t go to a chest physician for asthma in America (chest physicians deal in, say, lung cancer) but instead one visits an allergist who handles both primary and secondary care. The Europeans, meanwhile, moved towards embracing sublingual in preference to subcutaneous IT, as it was felt to be safer.

Asthma can be treated with IT but only in mild cases, and only with great care, Frew said. Treating asthmatics’ rhinitis results in improvement in their asthma. In the UK, our approach is to treat a polysensitised individual for their key allergen, with a high dose. In the case of two closely related key allergens – birch and grass, for instance – dual concurrent treatment may be performed. With two unrelated key allergens – cat and birch, for example – a sequential treatment may be offered, but it is rare. This is a hugely different approach to the US model, where all allergens are treated concurrently, albeit with small doses.

Both SCIT and SLIT work, argued Frew, with 80% of treated patients feeling better from it. A typical year’s improvement is around 30%, and ongoing years of treatment consolidates that. Frew said he supported an approach which talked about the median results, rather than average results, when dealing with patients: he argued that a statement such as “You have a 50% chance of deriving this much benefit” is one which patients find much easier to process and understand.

Knowing what patients want

Allergists should also look more at what matters to patients when designing trials. He admitted that the community had been guilty of assuming it knows more than patients about what patients want: a 10 litre per minute change in peak flow is statistically meaningful to scientists but meaningless to patients if it doesn’t make them feel any better. Allergists need to find language and figures to explain how patients will improve in quality-of-life terms.

The issue though, in these financially tight times, is that it isn’t considered cost-effective to spend hundreds of pounds to treat an element of a patient’s asthma when medication is very cheap and little is needed: there may be a 60% reduction in the amount of drugs a treated patient needs to use, but with respect to inexpensive anti-histamines, for example, this may not represent a huge saving to justify the expense of treatment.

Ten-year timeframe needed

There is undoubtedly a pool of people with severe allergic disease for whom treatment is worthwhile, as they require many hospital visits and are therefore expensive to treat. In a broader sense, though, we are hampered by the global economic situation – and the cost-effectiveness of IT might only reveal itself after a ten-year timeframe. Politically, health ministers think within a two-three-year timeframe or less – any longer is not a vote-winner.

At present, there is a low likelihood of IT programmes being expanded: setting aside the issue that there is little money and PCTs can’t think beyond the next year, there remains a problem in the perception of hay fever as being not a serious or important disease. We no longer need studies to confirm that IT makes people feel better. Instead, we need more economic-value arguments: we must place a value on people’s health improvements and how it is economically prudent in the long-term to treat people via IT.

Closing the day’s talks was Professor Stephen Durham – Head of Section for Allergy and Clinical Immunology at the National Heart and Lung Institute – with his presentation GRASS Hay fever Study: Sublingual Immunotherapy versus Subcutaneous Immunotherapy.

At present, we treat hay fever with antihistamines and intranasal steroids, with IT reserved for those who fail to respond to these usual treatments – yet allergists would like to treat patients with less severe disease, and earlier.

Quality of life issues are important considerations. Durham outlined a case study of a middle-aged woman with classic symptoms who couldn’t do everyday things – cycle, play with her young child – and her work performance was poor. IT got her back to work and enjoying life, reducing the severity of her symptoms and her medication, with the only side-effect being some itching under the tongue, which she didn’t consider bothersome.

Professor Durham agreed with the points raised by Professor Frew that to influence politicians we require evidence for long-term persistence of benefit, and we also need prevention of sensitisation. We also need to understand whether IT can prevent the progression of rhinitis to asthma: in this regard, an important European trial, involving 600 children, is currently looking at the benefit of SLIT using Grazax® (the grass pollen IT vaccine) in halting the allergic march.

There are some arguments suggesting SCIT is the more effective of the two, and that SLIT is the slightly safer – but it is important, Durham believes, to keep patient choice open, as the indications are virtually identical.

He closed with a brief discussion on his own study, the three-year GRASS Study (Gauging Responses in Allergic rhinitis to SCIT versus SLIT – www.hayfeverstudy.co.uk), in association with the Immune Tolerance Network in US, which is now being conducted at the Royal Brompton Hospital and Imperial College in London, comparing two commercially available hay fever treatments, Grazax® (SLIT) and Alutard SQ® (SCIT).

The primary objective of the trial is to see whether treatment induces tolerance, both in the broadest sense, as well as with respect to the persistence of benefit after discontinuation of treatment. Presently, there is only one trial supporting that view. The second objective is to assess the immunological mechanism through which tolerance may be induced. It is a double blind and double placebo controlled trial, with 113 severely effected patients. Participants have been divided into three groups:

*one group is receiving Grazax®and an Alutard SQ® placebo;

*one group is receiving Alutard SQ® and a Grazax® placebo;

*one group is receiving both placebos.

Looking for clinical tolerance

Patients have IgE sensitivity confirmed via RAST and SPT (skin prick testing) and nasal provocation, which were included in the entry criteria. Treatment will be for two years, with an extra year of follow-up reassessment.

Durham acknowledged that we were not going to get the definitive clinical answer out of this trial on whether SLIT is better than SCIT, because statistically the numbers involved aren’t high enough, but we will be able to see whether SLIT induces tolerance, both clinical tolerance and immunological tolerance, in a specific way.

Alex Gazzola’s book
Coeliac Disease: What You Need to Know,is available price £7.99 from Merton Books. For a copy call 020 8892 4949 or visit www.mertonbooks.co.uk..

This article was first published in Allergy Newsletter No. 103, Winter 2011.

2016-12-12T13:16:26+00:00