June 2017

Claude Molina et Jacques Gayraud

1.      Churg & Strauss Syndrome and Mepolizumab
2.      Imatinib and Severe Asthma
3.      Systemic innate immune activation in food protein–induced enterocolitis syndrome 
4.      Intradermal grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms 
5.      Benralizumab for patients with mild to moderate Asthma

1.  Churg and Strauss Syndrome (CSS) and Mepolizumab (M).
M. E.Wechsler et al NEJM 2017 376 1921-1932 (18 may)

CSS is an eosinophilic granulomatosis with polyangiitis. M, an anti–interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of this syndrome.

In a multicenter, double-blind, parallel-group, phase 3 trial, the authors randomly assigned participants who were taking a stable prednisolone or prednisone dose, to receive 300 mg of M. or placebo, administered subcutaneously every 4 weeks, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, and the proportion of participants in remission at both week 36 and week 48. The secondary end point included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed.

Among 68 participants were assigned to receive M. and 68 to receive placebo. M. treatment led to significantly more accrued weeks of remission than placebo and a higher percentage of participants in remission at both week 36 and week 48. Remission did not occur in 47% of the participants in the M. group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the M group, as compared with 2.27 in the placebo group. A total of 44% of the participants in the M group, as compared with 7% of those in the placebo group, had a lower average daily dose of prednisolone. The safety profile of Mepolizumab was similar to that observed in previous studies.                                  

Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. That is to say that M. may be beneficial for this severe disease.

2. Imatinib (I) and Severe Asthma
Katherine N. Cahill, et al N Engl J Med 2017; 376:1911-1920

Mast cells are present in the airways of patients who have severe asthma despite glucocorticoid treatment; these cells are associated with disease characteristics including poor quality of life and inadequate asthma control. Stem cell factor and its receptor, KIT, are central to mast-cell homeostasis. The authors conducted a proof-of-principle trial to evaluate the effect of I, a KIT inhibitor, on airway hyperresponsiveness, a physiological marker of severe asthma, as well as on airway mast-cell numbers and activation in patients with severe asthma.

In this randomized, double-blind, placebo-controlled, 24-week trial treatement, I. was studied in patients with poorly controlled severe asthma whith airway hyper responsiveness despite of receiving maximal medical therapy. The primary end point was the change in airway hyperresponsiveness, measured as the concentration of methacholine required to decrease the forced expiratory volume in 1 second by 20% (PC20). Patients also underwent bronchoscopy and bronchial biopsy.

Among the 62 patients who underwent randomization, I. treatment reduced airway hyperresponsiveness to a greater extent than did placebo at 6 months. I. also reduced levels of serum tryptase, a marker of mast-cell activation, to a greater extent than did placebo.   Airway mast-cell counts declined in both groups. Muscle cramps and hypophosphatemia were more common in the Imatinib group than in the placebo group.

In patients with severe asthma, Imatinib decreased airway hyperresponsiveness, mast-cell counts, and tryptase release. These results suggest that KIT- dependent processes and mast cells contribute to the pathobiologic basis of severe asthma.

3. Systemic innate immune activation in food protein–induced enterocolitis syndrome
R. Goswamiet , JACI June 2017 139 6 1885-1896.

Food protein–induced enterocolitis syndrome (FPIES) is a non–IgE-mediated, part of food allergy of infancy, whose pathophysiology is poorly understood. The authors set out to identify and phenotype allergen-responsive cells in peripheral blood of a cohort of subjects undergoing supervised food challenge for FPIES. They profiled antigen-responsive cells in PBMCs by flow cytometry, and examined cells in whole blood obtained before and after challenge by CyTOF, mass cytometry and RNA seqResults: Using a CD154-based detection approach, they observed that milk, soy, or rice-responsive T cells, and TNF-α–producing CD154+ T cells, were significantly lower in those with outgrown FPIES compared with those with active FPIES. However, levels were within the normal range and were inconsistent with a role in the pathophysiology of FPIES.

Profiling of whole blood by CyTOF demonstrated profound activation of cells of the innate immune system after food challenge, including monocytes, neutrophils, natural killer cells, and eosinophils. Activation was not observed in children with outgrown FPIES. This pattern of innate immune activation is confirmed in a larger cohort by RNAseq. Furthermore, was observed a pan–T-cell activation and redistribution from the circulation after a positive food challenge but not in those who had outgrown their FPIES.         

These data demonstrate a compelling role of systemic innate immune activation in adverse reactions elicited by foods in FPIES. Further investigation is needed to identify the mechanism of antigen specificity of adverse reactions to foods in FPIES.

Intradermal (ID) grass pollen immunotherapy increases TH2 and IgE responses and worsens respiratory allergic symptoms
Anna Slovick, et al JACI June 2017 139 6 1830-1839

Repeated low-dose grass pollen ID allergen injection suppresses allergen-induced cutaneous late-phase responses comparably with conventional subcutaneous and sublingual immunotherapy. The objective, here, was to evaluate ID immunotherapy in the treatment of allergic rhinitis.                                                                                      

93 adults were randomly assigned with grass pollen–induced allergic rhinitis to receive 7 pre-seasonal ID allergen injections (containing 7 ng of Phl p 5 major allergen) or a histamine control. The primary end point was daily combined symptom-medication scores during the 2013 pollen season (area under the curve). Analysis was by intention to treat. Skin biopsy specimens were collected after intradermal allergen challenges, and late-phase responses were measured 4 and 7, 10, or 13 months after treatment.

Results There was no significant difference in the primary end point between treatment arms. Among secondary end points, nasal symptoms were worse in the intradermal treatment group, as measured based on daily and visual analog scale scores. In a per-protocol analysis intradermal immunotherapy was further associated with worse asthma symptoms and fewer symptom-free days.                    

ID immunotherapy increased serum Phleum pretense – specific IgE levels compared with those in the control arm. T cells cultured from biopsy specimens of subjects undergoing ID immunotherapy had higher expression of the TH2 surface marker CRTH2 and lower expression of the TH1 marker CXCR 3 respectively. Late-phase responses remained inhibited 7 months after treatment (P = .03).            

In conclusion : Intradermal allergen immunotherapy suppressed skin late-phase responses but was not clinically effective and resulted in worsening of respiratory allergic symptoms.

5. Benralizumab for patients with mild to moderate, persistent asthma.
(In randomised, double-blind, placebo-controlled, phase 3 trial)                                          

2 studies are devoted to Benralizumab (B) which is a humanised, anti-interleukin 5 receptor α monoclonal antibody that directly and rapidly depletes eosinophils, reduces asthma exacerbations, and improves lung function for patients with severe eosinophilic asthma.

- The objective of this first trial (G.Ferguson The Lancet May 2017 on line) was to assess the safety and efficacy of B for patients with mild to moderate, persistent asthma. In this phase 3 trial, were recruited patients aged 18–75 years, weighing at least 40 kg, and with a post bronchodilator reversibility in forced expiratory volume in 1 s (FEV1) of at least 12% at screening. 52 clinical research centres participated in six countries, subcutaneous B 30 mg was injected every 4 weeks for 12 weeks. The primary end point was change from baseline prebronchodilator FEV1 at week 12. Efficacy analyses used an intention to treat approach. Between Feb 2, 2015, and April 24, 2015, 351 patients were enrolled, with 211 (60%) randomly assigned (105 [50%] to placebo and 106 [50%] to B). So B resulted in an 80 mL (95% CI 0–150; p=0·04) greater improvement (least-squares mean difference) in prebronchodilator FEV1 after 12 weeks than did placebo 44 (42%) patients in the B group had adverse events compared with 49 (47%) in the placebo group. The most common adverse events for both groups were nasopharyngitis (eight [8%] patients in each group) and upper respiratory tract infections (five [5%] patients in each group).

This study suggests that active and modifiable disease processes might be ongoing in patients with mild to moderate, persistent asthma receiving ICS. Although the lung function improvement observed does not warrant use of B in this population because it did not reach the minimum clinically important difference of 10%, further studies are necessary to assess this finding.                                                  

-  The 2nd trial studied the effect of B on oral glucocorticoid sparing in severe asthma P.Nair et al : NEJM 22 Mai 2017 online first. The authors investigated whether B affects the incidence of asthma exacerbations, if it is also effective as an oral glucocorticoid–sparing therapy in patients relying on oral glucocorticoids to manage severe asthma associated with eosinophilia. In a 28-week randomized, controlled trial, B was administered at a dose of 30 mg subcutaneously either every 4 weeks or every 8 weeks versus placebo. The primary end point was the percentage change in the oral glucocorticoid dose from baseline to week 28. Annual asthma exacerbation rates, lung function, symptoms, and safety were assessed.                                                                     

Of 369 patients enrolled, 220 underwent randomization and started receiving B or placebo. The two B dosing regimens significantly reduced the median final oral glucocorticoid doses from baseline by 75%, as compared with a reduction of 25% in the oral glucocorticoid doses in the placebo group. The odds of a reduction in the oral glucocorticoid dose were more than 4 times as high with B as with placebo. Among the secondary outcomes, B administered every 4 weeks resulted in an annual exacerbation rate that was 55% lower than the rate with placebo), and B administered every 8 weeks resulted in an annual exacerbation rate that was 70% lower than the rate with placebo ; there was no significant effect of either B regimen on the forced expiratory volume in 1 second (FEV1), as compared with placebo. Frequencies of adverse events were similar between each B group and the placebo group. So B showed significant, clinically relevant benefits, as compared with placebo, on oral glucocorticoid use and exacerbation rates. These effects occurred without a sustained effect on the FEV1.

Your comments and questions are welcome at the following addresses:

Claude Molina                             

Jacques Gayraud