Introduction: Recently, the exploration of biologics for the treatment of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) stands out as a pivotal area of interest. W.J. Fokkens et al., who previously contributed the monumental work – EPOS 2020, have returned with another significant contribution. Their recent publication titled “EPOS/EUFOREA update on indication and evaluation of Biologics in Chronic Rhinosinusitis with Nasal Polyps 2023” in the esteemed Rhinology journal provides a comprehensive assessment of this topic. In this follow-up piece, they meticulously analyze and present data, shedding light on the intricate nuances of biologics application in CRSwNP.
Chronic rhinosinusitis with nasal polyps (CRSwNP) affects approximately 1-2% of Europeans and significantly impacts quality of life. The mainstay treatments include long-term corticosteroids and surgeries. Newer biological drugs targeting type 2 immune responses offer fresh therapeutic avenues. The European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) provides guidance on using biologics for CRSwNP treatment. This updated report, a collaboration with EUFOREA—a global non-profit focused on respiratory diseases—involves input from otorhinolaryngologists, allergists, and pneumologists. Key discussions revolved around the use, benefits, duration, and cessation of biologics, and identified knowledge gaps in the domain.
Ideal candidate for biologic treatment:
The expert panel discussed the EPOS2020 criteria regarding the use of biologics in chronic rhinosinusitis with nasal polyps (CRSwNP). EPOS2020 recommends biologics for patients uncontrolled despite medical treatment and sinus surgery who meet three of five criteria. Key considerations include the positive impact of traditional treatments, the cost of biologics, and uncertainty about their long-term usage and risks. It was suggested to make type 2 inflammation mandatory but was not accepted due to unclear definitions. The eosinophil count criterion was adjusted. Despite the effectiveness of biologics in type-2 diseases, only certain associated conditions were included in the criteria. For pregnant women, only omalizumab has shown safety; other biologics lack conclusive evidence.
Defining the disease modification or remission
Disease modification or remission in chronic rhinosinusitis (CRSwNP) implies treatment that eradicates symptoms and hinders disease progression by targeting its root cause. While definitions for disease modification remain ambiguous, possible approaches include histological examination of barrier remodelling or evaluating functional and clinical aspects like the Asthma Control Questionnaire. Potential parameters for CRSwNP could be the SNOT-22, smell tests, and resolution of nasal polyps. Dupilumab has shown a decrease in respiratory infections in CRS patients. Presently, no evidence supports biologics as preventive for CRS. Though biologics have potential as early tertiary prevention, their high cost limits early prescription.
Criteria to Assess the Effectiveness of Biologics
To assess the effectiveness of biologics for chronic rhinosinusitis (CRSwNP), the EUFOREA expert panel advocates for a combination of patient and physician-reported outcomes. These include patient feedback on aspects like SNOT-22 scores, smell loss, congestion, and benefits on comorbidities (like asthma), and physician evaluations using nasal polyp scores, CT scans, and smell tests. While earlier criteria for gauging biologic response were more complex, the panel streamlined them into three categories: No response, Poor-Moderate response, and Good-Excellent response. The advised evaluation time was extended from 16 weeks to 6 months, with subsequent yearly evaluations. The response dictates whether to continue, switch, or discontinue the biologic treatment. Different patients prioritize symptoms differently, and this personal variation should be factored into evaluations.
Anticipated Outcomes of Biologics Beyond OCS/ESS
Biologics generally have a 60% success rate in improving the sense of smell, with the onset of effects typically appearing within 4 weeks, though the exact time varies. Notably, there isn’t a direct link between polyp size and improvement in smell. Once smell improves, initiating smell training can reactivate associated neurogenic pathways. The expert panel anticipates biologics may have better real-world effectiveness than observed in clinical trials. This expectation stems from two reasons: real-life selection of patients with type 2 inflammation and the severity of the disease in patients chosen for biologic treatment compared to those in trials. It’s crucial to acquire real-life data and further information on cost-effective measurement of type 2 inflammation.
Switching Biologics
Although the united airways hypothesis has previously highlighted similarities between upper and lower airways, recent studies using biologics have identified significant differences in treatment effects targeting the type 2 inflammatory cascade. In certain patients, some biologics are more effective for asthma than for CRSwNP and vice versa. While algorithms suggesting which biologics to begin with for severe asthma exist, they remain incomplete. Notably, a subset of patients benefits from different biologics for upper and/or lower airways, which sometimes necessitates a combination or switch of biologics. The ultimate aim is to establish real-life data registries to identify biomarkers predicting a positive response and to formulate guidelines for biologic switching.
When to Decrease/Stop Biologics?
Stopping biologics due to side effects is rare. However, transient hypereosinophilia, an effect of anti-IL4ralpha treatment, can potentially cause organ damage if persistent. The panel recommends monitoring blood eosinophil levels regularly after biologic initiation and checking for vasculitis/hypereosiniphilia symptoms. Elevated blood eosinophils could warrant treatment modifications or specialist consultation. More research is required for biomarkers that could screen for hypereosinophilic syndrome.
Treatment termination with Biologics
Trials for CRSwNP suggest a 12-month maximum treatment duration with biologics. Notably, a reduction in the dose of dupilumab showed negligible differences in outcomes. Determining an end of treatment schedule for biologics is essential. Some asthma studies offer insights: the Xolair Persistency Of Response After Long-Term Therapy (XPORT) study found that approximately half of the patients remained well-controlled a year after discontinuation, and the COMET-study observed only a minor increase in asthma exacerbations post-discontinuation. Therefore, stopping biologics could be viable for certain patients, but co-morbidities might pose a failure risk. Currently, there are no definitive guidelines regarding the discontinuation of biologics in CRSwNP due to the lack of evidence-based data.
Gaps in Biologics Research for CRSwNP and Asthma
The expert panel highlighted multiple crucial areas that are pertinent to both clinical practitioners and foundational researchers. These unaddressed needs have been examined from the viewpoints of various stakeholders. Patient education on biologics is being expanded through webinars, community platforms, and leaflets. Standardized guidelines are being developed to guide physicians in CRSwNP treatment. Efficacy of biologics is assessed through mechanistic studies, RCTs, and real-world data. Research focuses on identifying biomarkers for CRSwNP activity and treatment response, refining treatment pathways, and determining optimal dosage. Safety registries are monitoring pregnancy effects, long-term usage, and criteria for treatment transition. Lastly, in-depth studies address smell recovery and the role of smell training during biologic treatments.
Conclusion: The journey of understanding and implementing biologics in the realm of CRSwNP is rife with complexities, demanding rigorous research and clinical exploration. W.J. Fokkens and the team have demonstrated commendable diligence and expertise in their work. The scientific community, and more importantly, patients across the globe, stand to benefit from their invaluable contributions. We extend our gratitude and appreciation for their relentless efforts in advancing our understanding in this field.
Expert comment: The deep dive into biologics for CRSwNP by W.J. Fokkens et al. is a commendable effort, showcasing the potential of these treatments in reshaping patient care. Their analytical approach offers valuable insights into optimizing biologic therapies, setting a benchmark for future research and clinical practice in rhinology.
Prof. Dr. Prahlada N. B
26 March 2024
Chitradurga.
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Prahlada Sir,
Well-written blog on Chronic rhinosinusitis with nasal polyps( CRSwNP ) …
CRSwNP is a common & heterogenous inflammatory disease of upper respiratory tract.
W J Fokkens & his team's ongoing research in understanding & implementing biologics , is definitely going to benefit CRSwNP patients in coming days.
In general for now, there is agreement that for patients with symptomatic CRSwNP who have failed a trial of a course of at least 3 months of intranasal steroids and a short course of oral corticosteroids, a surgical intervention will often be the next treatment of choice. Biologics may be considered before an initial surgery in patients with comorbid severe asthma and in those for whom surgery is less available, refused by the patient, or likely to be associated with a higher-than-average complication rate. Biologic use immediately following surgery may be considered in patients who have a history of nasal polyp recurrence within 12 months of a prior surgery. For many patients with recalcitrant disease, a combination of sinus surgery and use of a biologic that is targeted to their precise endotype may be the optimal treatment strategy, though which surgical approach and which biologics are best for each patient are debates that remain ongoing.
Currently, the only biologic with Food and Drug Administration-approval status for CRSwNP is 'dupilumab'.
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