Important research questions in allergy and related diseases: nonallergic rhinitis: a GA 2 LEN paper Nonallergic rhinitis (NAR) can be defined as a chronic nasal inflammation which is not caused by systemic IgE-dependent mechanisms. It is common and probably affects far more than 200 million people worldwide. Both children and adults are affected. However, its exact prevalence is unknown and its phenotypes need to be evaluated using appropriate methods to better understand its pathophysiology, diagnosis and management. It is important to differentiate between infectious rhinitis, allergic/NAR and chronic rhinosinusitis, as management differs for each of these cases. Characterization of the phenotype, mechanisms and management of NAR represents one of the major unmet needs in allergic and nonallergic diseases. Studies on children and adults are required in order to appreciate the prevalence, phenotype, severity and co-morbidities of NAR. These studies should compare allergic and NAR and consider different age group populations including elderly subjects. Mechanistic studies should be carried out to better understand the disease(s) and risk factors and to guide towards an improved diagnosis and therapy. These studies need to take the heterogeneity of NAR into account. It is likely that neuronal mechanisms, T cells, innate immunity and possibly auto-immune responses all play a role in NAR and may also contribute to the symptoms of allergic rhinitis.

We found no quantitative or qualitative differences in nasal hyper-reactivity between AR and NAR patients. It is not possible to differentiate NAR subpopulations based on physical or chemical stimuli.

Meta-analysis of both large outcome studies as well as cohort studies support the safety and efficacy of Endoscopic Sinus Surgery for Chronic Rhinosinusitis. The efficacy of endoscopic sinus surgery is demonstrated in the improvement of both disease-specific and generic QOL as well as objective measures. However, this must be interpreted together with a well-recognized long-term 15-20 % revision rate, seen more often in patients with ASA trias and cystic fibrosis as well as osteitis and previous surgery. The effect of surgery is higher in managing nasal obstruction (effect size 1.7) and less so hyposmia (effect size 0.8). Allergy has an additive role on the symptomatology of CRS; however, its role if any on the outcome of ESS for CRS is unclear. The concurrent presence of aspiring sensitivity and asthma is associated with increased disease burden and more revision surgeries. Improved phenotyping of CRS may lead in the future to better tailoring of surgical treatments.

Aims To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB‐705498, a selective TRPV1 antagonist. Methods Two randomized, double‐blind, placebo‐controlled, clinical studies were performed: (i) an intranasal SB‐705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non‐allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB‐705498 against nasal capsaicin challenge. Results Single and repeat dosing with intranasal SB‐705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB‐705498 and placebo and no dose‐dependent increase was observed. Administration of SB‐705498 resulted in less than dose proportional AUC(0,12 h) and Cmax, while repeat dosing from day 1 to day 14 led to its accumulation. SB‐705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB‐705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2‐ to 4‐fold shift in capsaicin potency. Conclusions Intranasal SB‐705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin‐provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB‐705498 may have in rhinitis treatment deserves further evaluation.

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