Bibliographic updates

Claude MOLINA* & Jacques GAYRAUD**

Sublingual immunotherapy (SLIT) to grass pollen (GP) : recent data
2. Chronic urticaria (CU) treated by single-dose Omalizumab (O) : a randomised study
3. Obesity (O) surgery in asthmatics (A)
4. Psoriasis (P) vs atopic eczema (AE) : clinical coexistence and biological antagonism
5. Treating atopic dermatitis (AD) with narrow-band UVB phototherapy (NB-UVB)

1. Sublingual immunotherapy (SLIT) to grass pollen (GP) : recent data

specific immunotherapy
Key words: sublingual immunotherapy – grass pollen – Oralair – pollen calendar – symptom score

SLIT efficiency in treating GP allergic rhino-conjunctivitis is well known and recent data mainly concerns its administration modes and length of efficacy. This was the purpose of the survey conducted by the Euro-Canadian group led by A.Didier (Toulouse) in a multicenter randomised study whose carefully elaborated protocol made use of Oralair tablets (5-grass 300-IR Stallergens)® for 2- or 4-month periods before co-seasonal treatment (A.Didier et al : JACI 2011 128 3 September  559-566).
633 adults, aged 18 to 50, were then taken in charge from 2007 to 2009, firstly by watching the region-specific pollen calendar (23 countries took part in the survey), secondly by adjusting the individual symptom score according to the intensity of observed signs and the more or less urgent need for rescue medication, i.e. inhaled or per os antihistaminic drugs or corticosteroids.
Three consecutive seasons were monitored with three groups: 1 Placebo (P, 216 subjects) and 2 patient groups respectively treated for 2 months (147) and 4 months (149) before the beginning of the co-seasonal treatment, a treatment undertaken when the atmospheric pollen concentration was over 30 grains/m3 for three consecutive days.

The first goal was to statistically calculate an mean score adjusted for the study’s various parameters, at the end of the 3rd season, by comparing it to group P’s. The second was to compare the overall and individual symptomatology (including the rescue medication score) and the treated patients’ quality of life to those of group P. and, finally, to appreciate the general tolerance of the drug.

Results showed a significant reduction in the mean adjusted symptom score, respectively by 36% and 34.5% in the 2- and 4-month pre-seasonally treated groups (P ?.0001), for the mono- as well as the poly-sensitised subjects, whereas the questionnaire on quality of life showed marked improvement in both active groups. Finally, most adverse effects (essentially local) decreased in number and intensity over the 3 seasons, thus making it possible to compute 97% treatment compliance. Moreover, this favourable evolution was sustained without treatment for the 2 following seasons.

In conclusion, this long-term, very carefully conducted 5-year survey offers two interesting lessons :
1) It is not necessary to start the treatment long before the pollen season (2 months are generally sufficient), on the condition that it is followed by the co-seasonal treatment
2) It is not necessary to continue the treatment longer than the usual 3 years, since SLIT remains efficient for at least 2 more years

Overall, this is an accurate and convincing argument in favour of an economical treatment which will surely be appreciated by doctors and patients.

2. Chronic urticaria (CU) treated by single-dose Omalizumab (O) : a randomised study

urticaria / treatment
Key words: chronic urticaria – auto anti-IgE antibodies, auto anti-Fc€R antibodies– urticaria activity score

It is a fact that the treatment of CU is particularly difficult and several isolated observations in recent publications have mentioned a variety of drug trials.

This is the case of beneficial effect recently observed with O, which, according to the authors, can be explained by the presence in some patients of IgG auto-antibodies, anti-IgE or anti-Fc€, its high affinity receptor, which cause degranulation of mast cells and skin basophils and release of histamine. We have here the first randomised, multicenter, US-German, phase II study, with a substantial number of patients (90), which brings in convincing results on the efficacy of single-dose Omalizumab (Xolair ®) in CUs resistant to usual antihistaminic treatment (S.Saini et al : JACI 2011 128 3 567-73).

The US patients were aged 12-75 and the Germans 18-75, all suffering from idiopathic CU, i.e. with daily or almost daily occurrence, in the form of pruriginous papules and erythema, sometimes of angio-oedema, an eruption lasting for more than 6 weeks without a known cause and needing the permanent use of antihistamines (AH) which can usually be recommended in quadruple dose in case of insufficient efficacy.
These subjects, AH-resistant and presenting an urticaria activity score (UAS) of 7-12 days (prurit, papules) and severity-graded from 0 to 6, were divided into 4 groups : a Placebo group (21 patients), and the 3 others respectively treated by a single O injection of 75mg  (23 patients), 300mg  (25), or 600mg (20).

The first objective was to evaluate the UAS improvement after 4 weeks. Only the 300mg and 600mg groups showed significant improvement vs the Placebo group, by 13 points for the first (-19 vs -6.9 i.e. P?.001) and 7 points for the second (-14.6 vs -6.9 i.e. P?.047). This improvement was confirmed during the 12 following weeks both for pruritus and eruptions. Only among the O-75mg group was no meaningful difference observed to that of the placebo.

However what is remarkable is that the onset of improvement occurred as early as week 2 (when 1 to 2 months are generally needed to appreciate O efficacy on asthma). As to tolerance, this did not differ from the placebo group : no notable side effects were observed.

Admittedly the study must continue on a larger number of patients, and in all cases this was a symptomatic treatment whose mechanism has not yet been elucidated. Besides it cannot be specified whether further injections will be necessary in the longer term.
However, and in conclusion, a 300mg (or 600mg) single-injection of O is capable of efficiently and rapidly treating chronic urticaria resistant to antihistamines ; which represents a valuable option in a disease such as CU the evolution of which often  causes despair.

3. Obesity (O) surgery in asthmatics (A)

Key words: obesity – asthmatic – inflammation marker – bariatric surgery – serum IgEs – adipokine – lymphocytic markers

Asthma is difficult to treat in an obese patient. By assuming a pathogenic interaction between the asthmatic  airway inflammation and obesity, the US authors of Burlington-Vermont (A.Dixon et al: JACI 2011 2128 508-15) wished to check whether :
1) inflammation markers were higher with O than with non-O ;
2) corrective O surgery (also known as “bariatric surgery” BS) did improve treatment of A and decrease these markers.
With this view, they enrolled 41 OAs and 35 control and eventually followed 23 OAs and 21 non- OAs. over 3, 6, 9 and 12 months. All subjects underwent BS.

Beside the BMI (Body Mass Index in Kg/m2), the study focused on respiratory functions (particularly airway hyperresponsiveness (AHR) to methacholine) and markers (among which lymphocytes in the bronchoalveolar lavage fluid) as well as levels of serum IgEs and adipokine.
At the end of the surveillance period, and whatever the BS type, (laparoscopy with derivation: by-pass or stomach ringing or strapping) the patients observed a significant improvement in their A score and quality of life (P? .0001 for both groups).
AHR was also improved (P? .03), particularly in older, non atopic subjects, with normal IgE levels suffering from late onset asthma, but without relation to airway inflammation

Paradoxically, these subjects presented increased rates of lymphocytic markers and bronchoalveolar lymphocytes after BS.
On the other hand, the younger atopic obese subjects, with high IgE levels, suffering from early onset asthma, also experience an improvement, albeit with no changes in their AHR.

Thus, post-O-surgery dissociation seems to occur between asthmatic symptomatology, airway hyperresponsiveness and airway inflammation, whether the subject is atopic or not. And this suggests that O lead to a distinct and unique A phenotype, possibly suitable for surgery.

4. Psoriasis (P) vs atopic eczema (AE) : clinical coexistence and biological antagonism

eczema / skin allergy
Key words: psoriasis – atopic eczema – interferon ? - lymphocyte Th1 - lymphocyte Th17 – lymphocyte Th2 – lymphocyte Th22 - HLA alleles - Filaggrine – IL 4 interleukin – staphylococcus aureus

These two common diseases, of an epithelial or immune origin, involving hereditary factors and environment, often associated to other body disorders (joints for P, airway for AE), have a distinct physiopathology: the former (P) is characterised by involvement of Th1 lymphocytes with release of interferon ??and Th17 with their cytokines IL17A, 17F and IL22; the latter (AE) is dominated by the Th2 with higher levels of IgEs, total or specific to one or more allergens. Such an antagonism could account for the rarity of their clinical association in the same patient. Therefore the file presented by the Munich (Germany) group of dermatologists and allergists (S.Eyerich et al NEJM 2011 365 231-238) only involves 3 patients, but these are particularly well studied, and complemented by 5 others suffering from P associated with Nickel-contact dermatitis (CD).

In addition to their history and clinical observations, including a severity score for P and the SCORAD index for AE, the study includes classical biological investigations, a series of allergic tests (Nickel and Dermatophagoides pteronyssinus patch-tests) and a skin biopsy for each type of lesion, divided in two parts : one is histological, the other is for studying cell lineages and their cytokine profile ; at the same time, a genomewide study of the leukocyte DNA was performed for HLA alleles and for Filaggrine gene mutations.

The results are shown in the numerous tables and graphs illustrating this article, from which a lesion-specific histological aspect appears: acanthosis, chequer plaques, neutrophilic micro-abscess and spongiosis for P, and mixed infiltrate with eosinophils, T cells and granulocytes for AE.
The cytological study confirms that P presents a number of Th1 and Th17, with secretion of interferon ? and IL17, and AE a large number of Th2 and Th22 with secretion of IL4 in vitro. IL22 (coming from Th17 and 22) is liberated in equal quantities in both lesions. As for the CD lesions resulting from Nickel allergy , they are dominated, like those of P, by Th1 and Th17, but few T cells of P react to Nickel.

Moreover, atopic lesions (and not those of P) frequently harbour microbiological colonies (Staphylococcus aureus), which proves that the immunity due to Th1 and Th17 is partially inhibited by the Th2, whereas the histochemical expression of Filaggrine is higher in P, also suggesting its inhibition by the Th2.
Therefore, the pathogenesis of these 2 diseases does not seem to be based on an intrinsic epithelial anomaly, but more likely on a migration of different T sub-populations, in response to a triggering factor, either known in AE or unknown in P, and leading to skin inflammation.
The treatment of these 2 affections confirm their antagonism: anti-TNFα molecules (Infliximab) are very efficient in P, but exacerbate AE lesions. IL4, which opposes INF ? and IL17 effects on keratocytes, could be an interesting therapy for P but would be inefficient or even contra-indicated for AE.

In fact, non-specific treatments such as the antibody Ustekinumab which targets Th1 and Th17, just like Ciclosporine which inhibits the 2 sub-populations, were efficient on P and AE conjunctive lesions in the subjects studied.

5. Treating atopic dermatitis (AD) with narrow-band UVB phototherapy (NB-UVB)

eczema / skin allergy
Key words: atopic dermatitis -  UVB phototherapy, narrow band (NB-UVB) – lymphocytes TH1 – lymphocytes Th2 – cytokine IL22 –Th2/T22 axis

Among the many treatments of AD, the NB-UVB has the advantage of being usable with young subjects and for relatively long periods of time, with no major side effects and relatively low cost.

The multicenter US-Italian-Israeli study of this issue aimed to establish the reversibility of lesions, bio-markers of therapeutic response, and to specify the immuno-modulator effects of the treatment (S.Tintle et al JACI 2011 128 3 583-593).
12 patients aged 24 to 54, 9 male and 3 female, were treated 3 times a week for 12 weeks with the same protocol. Skin biopsies before and after treatment were carried out and evaluated by using gene expression and immunohistochemistry studies.
Results are as follows :
All patients benefited from a clinical improvement with a 50% reduction in their SCORAD score.
The lesion reversibility, in close correlation with the clinical symptomatology, was accompanied by a genomic reversal of the epidermal hyperplasia and above all of the inflammatory markers: the authors observed a decrease in the expression of 372 genes and an increase for 192 others, in whose list T-cells (CD2), activated T-cells (CD69), Th2 (CCL13, CCL26, CCL18 and mostly IL10), TNF α and IL12 could be found.
It is then a strong suppression of the Th2/T22 pathogenic axis and of associated cytokines that can be found in these lesions, with elimination of inflammatory leukocytes, including T-cells and dendritic cells.
As to the reduction of epidermal proliferation (decrease in thickening and in keratocyte proliferation), it is correlated with a reduced expression of the IL22 cytokine, responsible for this hyperplasia.
Finally, a normalised expression of epidermal barrier proteins completes the therapy.

The authors believe that the reversibility of chronic AD lesions results both from a correction of epidermal alterations and a reversal of immune activation. This runs against the fixed genetic phenotype theory and underlines the usefulness of checking the impressive list of Th2/T22 axis bio-markers drawn up by the authors, in the treatment of chronic AD.

Such treatment is widely targeting the immune factor: in addition to local (corticosteroids and calcineurine inhibitors such as tacrolimus) or general treatments (such as cyclosporine, UVA with psoralens and, for the severest forms, high intensity UVB), narrow-band UVB has definitely confirmed its place.

Comments and questions welcome :
Pr. Claude Molina and/or Dr Jacques Gayraud
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Last updated 28 July 2014