Claude MOLINA and Franz MARRACHE

• Recent data on Sublingual Immunotherapy : (SLIT)
• Simvastatine: a candidate for the treatment of respiratory allergy?
• Masitinib and Severe Asthma
• Allergy and  Indoor  renovation
• Quadrupling  the dose of inhaled corticosteroids to prevent Asthma exacerbations?
  

Recent data on Sublingual Immunotherapy: (SLIT)
Four articles supply new informations on practical aspects and mode of action of SLIT:
1) Monotherapy or Multitherapy : At the University of Colorado (S. Amar et al. J. Allergy Clin. Immunol. 124: 1 150-156) 54 pollen allergic patients were randomized to 1 of 3 treatment arms: Placebo, Timothy extracts (19µg Phl p5/day) as SL monotherapy or the same dose plus 9 additional allergen extracts. After10 months, clinical (symptoms and skin prick tests) and biological (IgE, IgG4, INFã) data confirmed the efficacy of monotherapy versus placebo. But the differences between multiple allergen SLIT and placebo only in skin sensitivity suggest a reduction in efficacy of this multitherapy .
2) Co-seasonal ultra-rush treatment:
German authors (H.Ottet al. Allergy 2009 ;  64 : 1394-1401) performed a randomized study in 183 pollen allergic patients, by using a mixture of 5 grass pollen extracts in increasing doses (30, 90, 150 and 300 IR every 20 minutes at the start of the season, followed by 300 IR/day until the end of the season), for 3 consecutive years. They observed a significant efficacy, an excellent tolerance, and a carry-over effect extending into the following season.
3) Mode of action of SLIT:
4) (R. E. O’Hehir et al. AJRCCM : ahead of print August 2009).In Australia,  a study involving 30 allergic patients treated during 12 months by SLIT with House Dust Mite extracts, significant clinical efficacy was assessed in terms of rhinitis and asthma. The novel finding is that  the TGF-â mediates the immunological suppression seen early (decrease CD4+ T cells proliferation) in addition to increase in regulatory T cells (Treg), with suppressor function , whereas IL10 secretion and specific IgG4  are maximal at the 24th month  treatment.
5) Early onset of action
A French-Austrian group (F. Horak . J. Allergy Clin. Immunol. 2009 ; 124 (3) : 471-477) using  an experimental allergen challenge chamber, in order to avoid the unpredictability of pollen seasons, carried out a randomized study in 89 patients with rhinitis. SLIT tablets with a mixture of 5 grass pollen extracts at 300 IR were given at baseline and 1 to 4 months.  A significant efficacy was observed  from the first month onwards, as reflected in  improvement in the symptom score, followed by an increase in the serum levels of allergen-specific IgGs,. There were a few strictly local adverse effects.

Simvastatine: a candidate for the treatment of respiratory allergy?
Many publications focused attention upon the immunomodulation effects of statins and improvement of lung health in asthma and COPD by these molecules (see in www.cefcap.com 2006 our  notes entitled « Statins and allergy »).
A recent article has clarified the various mechanisms involved: Amir A. Zeki et al. Simvastatine Inhibits Airway Hypereactivity: Implications for the Mevalonate Pathway and Beyond.  AJRCCM July 16 2009 [Epub ahead of print].
In  mice sensitized to ovalbumin (OVA) and re-exposed to this antigen, Simvastatin  lead to significant reduction in the number of cells of  bronchoalveolar lavage fluid (BALF) in comparison with the control group.In addition, the levels of Th1- and Th2 chemokines as well as those of cytokines  IL-4, IL1-3 and TNF-á were also reduced, in BALF. Moreover there was an improvement in pulmonary compliance associated with a reduction in bronchial hyperreactivity. Conversely association of Simvastatin with Mevalonate  suppressed the anti-inflammatory effect of the molecule.
The “statins” like Simvastatin inhibit mevalonate via blocking the 3-hydroxy-3-methyl-glutaryl-CoA enzyme (rate-limiting step in the biosynthesis of cholesterol).This important experiment highlights the central role of mevalonate-dependent pathways in the pathophysiology of this model of allergic asthma.
Improvement in lung function is likely due to direct action of Simvastatin on resident lung cells (muscle fibres, in particular)
It is now important to extrapolate these results to humans, through clinical studies.

Masitinib and Severe Asthma
According to the role of dendritic and mast cells present in the bronchial mucosa, in the pathogenesis of severe Asthma, , and  their activation by the Stem Cell Factor (SCF) c-kit receptor, a group of French authors (M. Humbert et al  Allergy 64 (8) : 1194-1201) attempted to use, for the treatment of this type of asthma,  a tyrosine-kinase which inhibits c-kit, and which has demonstrated efficacy in vitro: masitinib. This drug also inhibits PGDF (Platelet Derivating Growth Factor), which contributes to bronchial remodeling,factor of disease severity.
This drug (as well as its homologue imatimib, already used in various chronic diseases) was administered in  44 adult patients with severe asthma treated with oral corticosteroids . The primary endpoint was the per cent reduction in the doses of oral corticosteroids and, subsequently, the possibility of reducing the frequency of exacerbations and improvement in lung function. Masitinib was administered for16 weeks (3 to 6mg/Kg/day ; per os) in 15 french hospitals. In terms of the first objective, the results were not significant (versus placebo). In addition, there was no improvement in lung function or a decrease in the frequency of exacerbations. Some side effects such as skin rash, œdema or neutropenia were observed.However, the symptom score as well as the medication score were clearly better in the Masitinib group. These results, although disappointing, prompt the authors to continue to explore this pathway,  since, apart from Omalizumab ( a recent alert regarding its risk of toxicity was launched by FDA)no therapy has until now proven its efficacy in severe Asthma.

Allergy and  Indoor  renovation
Within the context of relationship between indoor air quality and allergy, (discussed in our May 209 BUA) the interesting work by the German group LYSA (Life Style Immune System Allergy) (G. Herbert et al. Ped. Allergy Immunol. 2009 ; 20 : 563-570), has studied the effects of renovation activities in flats (painting, floor renovation, new furniture) on children, knowing that they are frequently responsible for inflammation in the airways and allergic reactions. The authors included 250 six year-old, volunteers, from a cohort of children followed up since birth, and studied the presence of blood markers of inflammation: IL-8, IL-6, TNF-á, MCP-1 and IL-10. They observed (after taking into account all co-variables such as atopy, presence of pets, parental smoking) a significant correlation between increased blood levels of IL-8 and MCP-1 and works at home,  particularly new floor covering.  By contrast, painting or introduction of new furniture were not associated with changes in the blood levels of these markers. Thus, IL-8 and MCP-1were regarded by the authors as reliable markers and they must be taken into account in the follow-up of children, particularly those who are allergic and are exposed to risk factors. These results concerning indoor  works confirm classical notions, well known by allergists, and mainly riks for allergic patients induced by  wall-to-wall carpets .
However, they do not identify factors  responsible for these findings (such as Volatile Organic Compounds: VOC suggested by the authors or Formol and Aldehydes, for example, as recently underlined by a French group, or even house dust mites or fungi, in the case of carpets).

Quadrupling  the dose of inhaled corticosteroids to prevent Asthma exacerbations?
Taking into account that doubling the doses of inhaled corticosteroids is rarely enough to prevent asthma exacerbations, the English team from Nottingham            (J. Osborne et al. AJRCCM  9 July 2009 ; ahead of print) examined whether a policy of quadrupling  the dose is able to reduce their frequency.
In a large, randomized study performed between 2004 and 2008, the authors defined a self-treatment plan for 403 patients for 6 to 12 months. The plan, apart from the usual management, included inhalers containing a quadruple dose of corticosteroids, which were given to patients, and to be used in case of worsening asthma situations (15-30% drop in FEV1), thus needing treatment with oral corticosteroids.
A  clear decrease, albeit  non statistically significant , was observed in the frequency of exacerbations (9% versus 14% for the placebo).
Moreover, in the sub-group of 94 patients who started the study inhaler, fewer required oral  corticosteroids in the active group  compared with the plaebo group: 21% versus 50%) .Side-effects, mentioned in the study, were relatively minimal : 12 cases (glossitis, laryngitis, airway infection, digestive upset). However this therapeutic trend towards increasing drug doses  of corticosteroids may not be so benign in the long run.

Translation from French was performed by Luis Taborda.

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