Dupilumab for Prevention of Recurrence of CRSwNP After ESS

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Chronic rhinosinusitis (CRS) affects an estimated one in fourteen (7%) Canadians, making it one of the most frequent inflammatory diseases. The human and economic cost of CRS are substantial. Patients affected with chronic sinus disease suffer from headache, facial pain and sinus infections, and exp...

Chronic rhinosinusitis (CRS) affects an estimated one in fourteen (7%) Canadians, making it one of the most frequent inflammatory diseases. The human and economic cost of CRS are substantial. Patients affected with chronic sinus disease suffer from headache, facial pain and sinus infections, and experience a reduced quality of life (QOL).The disease has a prolonged course and is frequently resistant to medical therapy. Current therapeutic strategies involve a combination of nasal irrigations, corticosteroids and antibiotics. Unfortunately, these are rarely curative and raise concerns regarding safety. Oral corticosteroid therapy can lead to severe short and long term adverse effects including diabetes, fractures, psychosis, depression, glaucoma and cataracts. Antibiotic over use is a major driver of development of antibiotic resistance, and antibiotic use in humans in Canada is believed to contribute significantly to this. In the absence of a response to medical therapy, endoscopic sinus surgery is indicated. Operations for CRS are among the most commonly performed, with over 400 000 surgeries for CRS performed annually in the USA and another 40 000 annually in Canada. However, success is not uniform and a high percentage of patients will continue to manifest signs and symptoms of the disease. Even when managed with a topical intranasal corticosteroid, endoscopic signs of recurrence are observed rapidly after endocopic sinus surgery (ESS) (Stjärne, 2009). In a trial comparing topical mometasone via conventional nasal spray dispenser to placebo, median time to relapse was 173 and 61 days for the mometasone and placebo groups, respectively. This may be improved by use of a more effective form of distribution, such as using budesonide irrigations which improve deposition of steroid in the sinus cavities. In a retrospective analysis of our group limited to a more severely diseased group at higher risk of recurrence, 33% of subjects still showed signs of endoscopic recurrence at 4 month point after surgery (Maniakis, 2014). Endoscopic sinus surgery may be challenging for patient and surgeon, with risk of complications from trauma to adjacent structures increased by extent of disease and bleeding at time of surgery reducing bleeding. In addition, despite the risks of ESS, recurrence after ESS represents a very important issue as it is rapid and almost ubiquitous. Patients resistant to surgery generate an individual cost estimated at $10 077/year (Rudmik, 2014). Additional therapeutic options for these patients are currently limited and these patients are currently doomed to continue to suffer despite repeated bouts of antibiotics and surgeries, with patient and society bearing the risks and costs of therapies. Given the frequency, the human and economic burden of refractory CRS, and the deficiencies in effectiveness and adverse effects of current therapies, novel avenues of therapy for CRS are urgently required. Identifying new strategies will require a better understanding of the underlying disease process and identification of new therapeutic targets. Chronic rhinosinusitis with nasal polyps (CRSwNP) recurrence following surgery is difficult to predict, and the underlying mechanism(s) are not yet well established. However, immune dysfunction with excess Type 2 inflammation, alterations in barrier function and dysbiotic microbiome changes are all believed to play possible roles, which may be targeted by dupilumab. The role of Type 2 inflammation in CRSwNP is well accepted, with the eosinophil described as a characteristic feature of CRSwNP. However, the role of the eosinophil in development of disease has been questioned as a recent trial of a small molecule solution targeting the eosinophil showed effective clearance of eosinophils in polyps, but no effect on symptoms or nasal polyp size. In contrast, Dupilumab, which targets interleukin-4/interleukin-13 (IL4/IL13) cytokines in upstream of IL5, has recently shown in a Phase 3 clinical trial that it reduced symptoms and objective indexes of polyp size and inflammation in CRS. While molecular mechanisms of this remain to be determined, this parallels the effectiveness of other disorders where Type 2 inflammation is central, such as atopic dermatitis and asthma. How a Type 2 phenotype predisposes to development of sinus disease is unknown but probably represents a multifactorial process. For the past two decades, researchers have postulated that toxic products from degranulation of eosinophilia damaged local structures leading to epithelial breaks and areas of denuded epithelium. The investigators now understand that pro-inflammatory Th2 cytokines are also implicated in epithelial barrier dysfunction. These are not necessarily secreted from the eosinophils, implicating the eosinophil as a downstream marker of the inflammatory process, rather than the primary effector cell. IL4/1L13 has been implicated in epithelial barrier dysfunction. In a series of in-vitro experiments, Wise et al demonstrated that administration of IL4 to an epithelial cell raised in an air-liquid interface, epithelial barrier permeability increased dramatically. Interestingly, this was reversed by anti-IL4. Notable is that this occurred in the absence of eosinophils in the medium, confirming that these effects can occur independently of eosinophil presence. The epithelial barrier is also believed to play a key role in CRS. Response to tissue injury a key factor in the development of CRS. In CRS, epithelial repair is delayed and dysfunctional. This delayed or inappropriate regeneration of the sinus epithelium and mucosa favours persistence or acquisition of a naltered microbial flora, or microbiome, which then further contributes to the disease process. Firmicutes such as Staphylococcus Aureus and Staphylococcus epidermidis, present in a somewhat mutually exclusive fashion. This new flora may also exacerbate a polarisation of the Type 2 phenotype characteristic of CRSwNP in Caucasians. It may be possible to interfere with inflammation, epithelial regeneration and repair, and microbiome composition during healing after surgery by modulating Type 2 inflammation. Early rabbit maxillary sinus studies documented formation of polypoid structures in the sinuses following mucosal trauma induced with a cytology brush or following introduction of a respiratory pathogens, with most severe example following simultaneous administration of both. Corticosteroids administered post operatively eliminated polyp formation after injury in this model. However, Type 2-type, eosinophilic polyps only form if the animal has previously been sensitised to develop allergy, suggesting that the Type 2 shift is implicated in the development of nasal polyps. How the Type 2 environment contribute to disease development remains unknown but may either be may directly, via the toxic effect of toxic of eosinophilic granules, or indirectly, by inducing a immunopermissive environment which facilitates bacterial colonisation and persistence. T An understanding of how failures of ESS for CRSwNP develop may be extrapolated form the above experimental findings. Removal of diseased tissue during ESS debrides and removes indwelling inflammatory cells and bacteria and affords an environment which can now be shaped by positive or negative influences. This 'rebirth' concept recently popularized by Bachert et al as the 'reboot' procedure where diseased sinus epithelium is removed surgically to be replaced by 'healthy' cells. However, these new cells regenerate from pluripotential progenitor cells (basal cells, the 'stem cell" of the respiratory mucosa) which may have epigenetic imprinting, or else persistent bacteria may condition to Type 2 environment. By preventing or interfering with these influences during the critical steps of the repair process, the investigators believe they may be able to regenerate a robust epithelium with intact barrier and signaling functions, which attracts normal residential commensals and a "normal" immune status. As all inflammatory and infectious stimulus have been removed, and are not simply lying dormant, it is further theorized that this may produce changes which re-establish normalcy and prevent recurrence of disease. Taken together, the above findings suggest that a Type 2-skewing of the disease process at time of surgery makes surgery more difficult, negatively impacts healing and contributes to the development and persistence of CRS in multiple fashions, marking it as an excellent target for therapeutic intervention. Managing Type 2 inflammation during the resolution phase is thus an interesting concept which has until now been plagued by practical difficulties. Corticosteroids have historically been the mainstay of therapy for this disease given the frequent presence of Type 2 inflammation and association with asthma. The gold standard of CRSwNP management, a short burst of oral prednisone, has a rapid effect on decrease of polyp size and relief of symptoms but this is of brief duration (? 30 days). Additionally, the unfavourable side effect profile precludes long term use. Novel alternate therapies are urgently required to manage this chronic and debilitating disease. Immunomodulation targeting the Type 2 component of the disease using monoclonal antibodies targeting different aspects of the Type 2 pathway have a potential use in this area, with both anti-IL5 and anti-IL4/IL13 receptors blockers proposed as therapy. The investigators believe that Dupilumab administered during the post-ESS convalescent phase may represent an additional treatment option for CRS. Population: Thirty-six (36) patients with CRSwNP undergoing a revision surgery for recurrence of CRSwNP, both with and without asthma, will be recruited. Patients will be recruited from the list of patients scheduled for or awaiting surgery, according to usual clinical criteria of obstruction, anosmia, recurrent infections or difficulty with control of asthma. Exclusion criteria include local complications such as mucoceles and tumours, underlying systemic disorders, including sarcoidosis, EGPA (eosinophilic granulomatosis with polyangiitis), Churg-Strauss syndrome, immune deficiency, cystic fibrosis, or a history of neoplasia (excluding basocell carcinoma) within the past two years. Patients will be homogenous in terms of their symptomatology motivating the operation. In this real-world experience of Dupilumab use, patients will be selected in terms of criteria usually used by clinicians and patients. Polyp size will be required to be at least moderate. The investigators will ensure homogeneity in patients by: i) Using standardised, published criteria for definition of patients at high risk of experiencing a recurrence after ESS (Nader ME, 2009). ii) Using patients at higher risk of failure by restricting study to patients having undergone had at least one prior ESS. iii) Stipulating a minimal polyp size of at least 2 per side (out of a four point scale) on a Lilleholdt scale. iv) Rigorous exclusion criteria will exclude polyps secondary to immune deficiency or common pre-existing genetic disorders.

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