1. Biotherapy of atopic dermatitis in adults
2. Managing asthma in pregnancy (MAP) trial: FENO levels and childhood asthma
3. Allergy and the invisible killers: air pollution and loss of biodiversity
4. Olaparib desensitization in a patient with recurrent peritoneal cancer
5. Subcutaneous immunotherapy in the UK: re-analysis
Biotherapy of atopic dermatitis in adults
The author, Professor of Dermatology in Paris (Hospital Saint-Louis) recalls that over the last years, major advances in the understanding of pathogenic mechanisms involved in chronic inflammatory skin diseases allowed the design of drugs targeting one or several inflammatory axis, leading to significant progress regarding efficacy. Severe atopic dermatitis in adulthood is one of targeted indication, with the preferential development of biologics targeting type 2 immune responses, such monoclonal antibodies: Dupilumab, Tralokinumab, Nemolizumab and the forthcoming first marketing approval of any biologic in this indication. Aside from biologicals, there are small immunosuppressive molecules administered through oral route, among which Apremilast remains the only small molecule authorized in Europe but responsible for deleterious side-effects which is not the case for Janus kinases inhibitors. These small molecules are currently developed in atopic dermatitis, such Baricitinib, selective inhibitor of jk1, the first trial of which showed a superiority compared to the placebo, but their cost poses a difficult societal problem.
M.Morten et al :JACI December 2018 142 6 1765-1772
Given that Asthma is often exacerbated in pregnancy, the Australian and New Zealand research Group had compared, in a precedent double blind randomized study, a treatment algorithm using the fraction of exhaled nitric oxide (Feno) in combination with asthma symptoms (group F), against a treatment algorithm using clinical symptoms alone (group C). The effect was a 50% reduction in exacerbations during pregnancy in the group F. In this new trial , the effect of FeNO guided management on asthma incidence in offspring was evaluated at preschool age. 179 mothers consented to participate in the study; 140 children were followed-up at 4 to 6 years of age. The results are as follows:
2) Doctor-diagnosed asthma was associated with common risk alleles for early onset at gene locus 17q21.The benefit of Feno management was observed regardless of these genotypes.
3) A causal mediation analysis suggested that effects of Feno-guided asthma management on asthma incidence in offspring are, at least in part, mediated through changes in the use and dosing of inhaled corticosteroids (any use or time to 1stchange in dose).
In conclusion Feno-guided asthma management in pregnancy resulted in optimized asthma control and improved respiratory outcomes in the offspring.
Allergy and the invisible killers: air pollution and loss of biodiversity
I.Annesi-Maesano Bulletin French Acad Med June 2018 in press
As mentioned by the author, research Supervisor (INSERM Paris) who coordinates the Heal’s European program, the prevalence of asthma and allergies has doubled in recent decades. This rise in the number of asthmatics and allergic patients is due to environmental causes, genetic modifications requiring longer periods to occur.
Indeed the environmental risk factors can act also on the epigenetic marks and thus block the functionality of genes, sometimes even by rendering them inoperative, but Air pollution and loss of biodiversity are among the environmental factors evoked more often to explain this increase.
- In the last fifty years, indoor and outdoor air pollution has increased, particularly due to urbanization. More and more experimental and epidemiological data of populations link air pollution exposure not only to aggravation but also to the development of asthma and allergies.
- At the same time, there has been a loss of biodiversity, which can affect the immunomodulatory capacity of the organs, including the intestine and lungs, and thus facilitate the development of the allergic response.
Actions are possible to fight against these two factors. However, it is through the simultaneous taking into account of the different exposures by an exposomic approach during lifespan in view of the implementation of a personalized prevention that we can stop the progression of allergies.
Olaparib desensitization in a patient with recurrent peritoneal cancer
JP .Grabowski&al. November29,2018 NEngl J Med 2018; 379:2176-2177
The German authors relate a case which illustrates the necessary collaboration between allergists and oncologists: A 49-year-old woman presented with a platinum-sensitive relapse of a peritoneal cancer with extensive peritoneal and pleural carcinomatosis and effusions. Testing for a germline BRCA1 mutation was positive. The patient had a complete remission after the most recent platinum-based chemotherapy and then began receiving maintenance therapy with Olaparib (O) capsules at a dose of 400 mg twice daily. After the patient received the first dose, an allergic reaction developed that was characterized by angioedema and cutaneous wheals. This reaction developed reproducibly within approximately 3 hours after each administration of O and lasted for several hours. Three re-challenge attempts with preventive applications of antihistamines, with or without the administration of Omalizumab, were not successful. The patient was confirmed to have type I (immediate or anaphylactic) hypersensitivity to O on skin-prick testing. To allow the continuation of O treatment, a 2-day desensitization protocol was decided that involved subsequent oral applications of incremental doses of specifically prepared O capsules, with a starting dose of 12.5mg and a final dose of 800 mg. During the desensitization phase, no additional drugs (glucocorticoids, or leukotriene blockers) were used. No adverse reactions were observed during the desensitization. With over the 16-month period after desensitization, the patient has continued to have a complete remission. Given the efficacy of O, desensitization can be suggested in patients in whom type I hypersensitivity to this drug develops and that a skin prick test alone may give evidence.
Subcutaneous immunotherapy in the UK: re-analysis
A.Frew et al JACI 2018 December 14261998-1999
In a letter to Editor, the authors recall that clinical efficacy of the products for Immunotherapy in rhino conjunctivitis with or without asthma, must be documented individually given the difference in allergen content, structure, formulation and adjuvants use. So efficacy of Alutard Phleum Pratens (ALK Denmark) has been demonstrated in several controlled clinical trials, both at the maximum dose for maintenance of 100.000 SQU and also at 10.000 SQ.U.
In a large randomized trial in 26 UK hospital clinics conducted in 2002 the symptom scores were not very different for both doses but medications scores significantly decreased only with the higher dose, however responsible of more or less side-effects.
In Position paper of EAACI and wao task Force, it was recommended combining symptom and medication scores as primary end points in our trial taking into account both symptom severity and need for anti- allergic medication; this post-hoc composite score was calculated and statistically analyzed and did not show valuable difference in efficacy between the 2 immunotherapy groups with however greater frequency of side effects with the dose of 100.000 SQ-U.This analysis confirms the main outcome of UK trial and shows that the lower maintenance dose induces a clinical relevant effect in the 1st season after 5 to 8 preseasonal injections and in line with the recommendations of experts in the field, to combine a symptom score together with a medication score equally weighted for end point in trial, allowing better discrimination capability of score comparison. In conclusion, standard subcutaneous immunotherapy with Phleum prates allergens, with either 10.000 or 100.000SQ.U is clinically effective in a phase 3 trial. Then, it may be possible to achieve an optimal outcome for patients taking into account tolerability and clinical effectiveness.
*** At the time we were writing this important article published in USA we are sadly learning the death of our colleague Professor Anthony Frew who conducted this research. Past president of EAACI, between 2005 and 2007, Anthony Frew belong to the long list of eminent British clinicians and researchers who, like W. Frankland, J.Pepys, B.Kay, S.Holgate and many others younger colleagues, have enriched our knowledge in Allergy and honored both the British and European science. We extend our sincere condolences to his wife and his family.
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