Efficacy of Dupilumab in CRSwNP treatment: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-4974256/v1

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Efficacy of Dupilumab in CRSwNP treatment: A systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-4974256/v1

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Objective

to evaluate efficacy of dupilumab in the treatment of CRSwNP.

Background

Chronic rhinosinusitis with nasal polyps (CRSwNP) represents an inflammation of the nasal and sinus mucosa, it is not uncommon disease. Patient with CRSwNP is presented nasal obstruction, facial pain, recurrent sinus infections, and anosmia. Dupilumab is an inhibitor of interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling pathways.

Method

A systematic review was conducted, strictly following the PRISMA guidelines. Search went through many databases including PubMed, Cochrane Library, Consensus, and Google scholar. 60 studies were acquired from the search and only four study included in this systematic review. Risk of biases were evaluated with acceptable results.

Results

Four studies included in this systematic review, primary outcomes including Lund-Mackay CT total score, Loss-of-smell score, Smell test (UPSIT) score, SNOT-22 total score, Bilateral endoscopic nasal polyp score, and Nasal congestion or obstruction score have shown a non-significant difference between placebo and dupilumab groups. Dupilumab group is associated. With higher level of blood eosinophils when compared with placebo group.

Conclusion

Dupilumab has shown a beneficial use in treating CRSwNP, its works on inhibiting the signaling pathways of interleukin-4 (IL-4) and interleukin-13 (IL-13).

Dupilumab

systematic review

CRSwNP

treatment

meta-analysis

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common and debilitating inflammatory disease of the nasal and sinus mucosa. CRSwNP severely reduces patients' quality of life by causing symptoms like nasal obstruction, anosmia (loss of smell), facial pain, and recurrent sinus infections [1]. conventional therapies such as intranasal corticosteroids and endoscopic sinus surgery, often have a high recurrence rates and less ideal outcomes [2].

A potential therapy approach for CRSwNP has developed in the form of dupilumab, a completely human monoclonal antibody that inhibits the interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling pathways. Dupilumab efficiently modulates type 2 inflammatory response, which is essential to the development of CRSwNP, by targeting the common IL-4 receptor alpha subunit [3]. Promising outcomes from clinical trials have been observed, including notable decreases in the size of nasal polyps, ameliorations in nasal congestion, and improvements in general quality of life [3, 4].

This systematic review and meta-analysis aim to critically assess the efficacy of dupilumab in the treatment of CRSwNP. We aim to provide a thorough assessment of dupilumab's therapeutic benefits and its potential to revolutionize the management of CRSwNP by compiling data from several high-quality studies. The results of this analysis influence clinical procedures and lead future rhinology research efforts.

The methodology follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [6].

Literature Search

A comprehensive search has been conducted using the following electronic databases: PubMed, Cochrane Library, Google scholar, and Consensus. The search terms included combinations of keywords and Medical Subject Headings (MeSH) terms such as "Dupilumab," "Chronic Rhinosinusitis," "Nasal Polyps," and "Efficacy."

Example search string for PubMed:("Dupilumab" OR "Anti-IL-4 Receptor Alpha Antibody") AND ("Chronic Rhinosinusitis" OR "CRSwNP" OR "Nasal Polyps") AND ("Efficacy" OR "Treatment Outcome" OR "Therapeutic Use")

Inclusion and Exclusion Criteria

- Inclusion Criteria:
- Studies involving patients diagnosed with CRSwNP.
- Studies evaluating the efficacy of Dupilumab as a treatment.
- Randomized controlled trials (RCTs), and Observational studies.
- Exclusion Criteria:
- Studies that do not focus on CRSwNP.
- Studies not evaluating Dupilumab.
- Non-original research articles (e.g., reviews, editorials).
- Animal studies.

Study Selection, Data Extraction, Quality Assessment

Screening Process has been performed by two independent reviewers by screening titles and abstracts of identified articles. The full texts of potentially eligible studies has been retrieved and assessed for eligibility based on the inclusion and exclusion criteria. Discrepancies will be resolved through discussion, and a third reviewer is consulted if necessary.

A standardized data extraction form will be used to collect relevant information from the included studies.

The quality of the included studies is assessed using the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. Each study has been evaluated for selection bias, performance bias, detection bias, attrition bias, and reporting bias.

Data Synthesis and Statistical Analysis

The primary outcome measure will be the efficacy of Dupilumab in reducing the size of nasal polyps and improving the quality of life. Secondary outcomes will include adverse events and overall safety.

In Statistical Analysis, Review Manager 5.4 and Openmetaanalsysis have been used.

Reporting

The results of the systematic review and meta-analysis reported according to PRISMA guidelines. The final report includes:

A flow diagram of the study selection process, Tables summarizing the characteristics of included studies and their quality assessments, Forest plots showing pooled effect sizes, and A narrative synthesis of the findings, highlighting the efficacy and safety of Dupilumab in CRSwNP treatment.

Among 60 articles identified through database search, four clinical trials were included in this systematic review and meta-analysis (Fig. 1). The included studies comprising 726 patients, the mean age is 50.21, approximately 60% of patients are males and 40% females. 62.4% of patients were suffering from Asthma. Most patients have had a previous surgery (about 78.55%), 34.8% of patients are with NSAID intolerance (Table 1). Table 2 illustrates the primary outcomes, mean bilateral endoscopic nasal polyp score for the placebo group is 5.96 is all the four clinical trials, while it is 6.02 for the dupiluma b q2w group. In the placebo group, the mean of nasal congestion or obstruction score is 2.42 and it is approximately the same in the dupiluma b q2w group. The mean of SNOT-22 total score is 51.38 in the placebo group and 51.18 in dupiluma b q2w group. Smell test (UPSIT) score was 14 as a mean in the placebo group and 14.08 in the dupiluma b q2w group. 2.74 was the loss-of-smell score for the placebo group and 2.72 for the dupiluma b q2w group. The mean of Lund-Mackay CT total score in the placebo group was 18.42, while it is 18.18 with patients in the dupiluma b q2w group (Table 2). The secondary outcomes for both groups are illustrated in Table 3, secondary outcomes represented by Weight (Kg), Daily loss of smell score, Rhinosinusitis disease severity VAS, Blood eosinophils (Giga/L), baseline peak nasal inspiratory flow, and baseline blood eosinophils. (Table 3). Figure 2 showing a result in the mean difference of primary outcomes of bilateral endoscopic nasal polyp score, which is 0.07 [95% Cl: -0.16, 0.31], with 0.02 P value (Fig. 2). The mean difference in the primary outcomes of nasal congestion or obstruction score is 0.00 [95% Cl: -0.06-0.07] (Fig. 3). The pooled analysis of the SNOT-22 total score in all studies of our meta-analysis have shown no significant trend, mean difference is -0.48 [95% Cl: -2.53, 1.56] (Fig. 4). There is no significant difference in the smell test (UPSIT) score between the two groups, mean difference is 0.01 [95% Cl: -0.80, 0.82] (Fig. 5). Loss-of-smell score have shown no significant difference in both groups of patients, the mean difference is -0.02 [95% Cl: -0.07, 0.04] with a P value of 0.55 (Fig. 6). Figure 7 illustrates the mean difference of the two groups in Lund-Mackay CT total score which is -0.18 [95% Cl: -0.73, 0.38), the result shows that there is no significant difference between groups (Fig. 7). Secondary outcome resulted in a non-significant difference in weight in the two groups, standard mean difference is -0.02 [95% Cl: -0.15, 0.12] (Fig. 8). The mean difference in daily loss of smell score is -0.02 [95% Cl: -0.15, 0.12] with a P value of 0.81 (Fig. 9). There is no significant difference in rhinosinusitis disease severity VAS (Fig. 10). The pooled analysis in Fig. 11 is showing a significant difference in blood eosinophils between the two groups, mean difference is 0.18 [95% Cl: 0.12, 0.24] with a P value of less than 0.00001 (Fig. 11). There is no significant difference in both baseline peak nasal inspiratory flow and baseline blood eosinophils between the two groups (Fig. 12 and Fig. 13). This systematic review is conducted with a very good rate of risk of bias, which is acceptable (Fig. 14 and Fig. 15).

Table 1

The baseline table
Study ID	Study Design	Patients, n	Age mean (SD)	Males, n (%)	Females, n (%)	Asthma, n (%)	NSAID Intolerance, n (%)	Previous Surgery, n (%)
Claus Bachert, 2019 (15)	CT	57	51.98 ± 13.12	34/57 (61.4%)	23/57 (40.3%)	38/57 (67%)	17/57 (30%)	48/57 (84.2%)
Chien-Chia Chuang, 2021 (16)	RCT	286	51.28 (12.90)	165/286 (58%)	121/286 (42%)	170/286 (59%)	82/286 (29%)	187/286 (65%)
Shigeharu Fujieda, 2021 (17)	RCT	286	51.28 (12.90)	165/286 (58%)	121/286 (42%)	170/286 (59%)	82/286 (29%)	187/286 (65%)
Nicholas J Campion, 2023 (18)	RCT	97	46.3 [14.2]	61/97 (62.9%)	36/97 (37.1%)	63/97 (64.9%)	50/97 (51.5%)	97/97 (100%)

Table 2

The primary outcomes
Study ID	Claus Bachert, 2019		Chien-Chia Chuang, 2021		Shigeharu Fujieda, 2021		Nicholas J Campion, 2023
Study Design	CT		RCT		RCT		RCT
Outcome	Study 1 (Placebo)	Study 1 (Dupilumab q2w)	Study 2 (Placebo)	Study 2 (Dupilumab q2w)	Study 3 (Placebo)	Study 3 (Dupilumab q2w)	Study 4 (Placebo)	Study 4 (Dupilumab q2w)
Bilateral endoscopic nasal polyp score	5.86 (1.31)	5.97 (1.25)	5.96 (1.21)	6.29 (1.20)	6.07 (1.22)	5.97 (1.25)	5.97 (1.31)	5.86 (1.23)
Nasal congestion or obstruction score	2.45 (0.55)	2.40 (0.58)	2.38 (0.54)	2.44 (0.59)	2.48 (0.62)	2.40 (0.58)	2.40 (0.55)	2.42 (0.56)
SNOT-22 total score	50.87 (20.22)	50.94 (20.66)	53.48 (21.85)	51.89 (21.05)	50.16 (19.72)	50.87 (20.22)	51.01 (20.33)	51.02 (20.16)
Smell test (UPSIT) score	14.44 (8.31)	13.98 (8.21)	13.78 (8.31)	13.60 (7.57)	13.46 (8.20)	14.68 (8.66)	14.34 (8.48)	14.09 (8.30)
Loss-of-smell score	2.73 (0.51)	2.74 (0.53)	2.72 (0.52)	2.73 (0.59)	2.81 (0.46)	2.70 (0.57)	2.72 (0.54)	2.72 (0.52)
Lund-Mackay CT total score	19.55 (4.26)	18.37 (4.06)	17.65 (3.76)	17.81 (3.89)	18.42 (3.61)	18.55 (4.55)	18.09 (3.92)	17.99 (3.69)

Table 3

The secondary outcomes
Study ID	Claus Bachert, 2019		Chien-Chia Chuang, 2021		Shigeharu Fujieda, 2021		Nicholas J Campion, 2023
Study Design	CT		RCT		RCT		RCT
Outcome	Study 1 (Placebo)	Study 1 (Dupilumab q2w)	Study 2 (Placebo)	Study 2 (Dupilumab q2w)	Study 3 (Placebo)	Study 3 (Dupilumab q2w)	Study 4 (Placebo)	Study 4 (Dupilumab q2w)
Weight, kg	79.64 (14.74)	84.98 (17.68)	81.06 (18.74)	76.82 (18.39)	82.00 (15.00)	83.00 (18.00)	79.00 (15.00)	81.00 (16.00)
Daily loss of smell score	2.71 (0.57)	2.52 (0.63)	2.75 (0.59)	2.85 (0.36)	2.70 (0.50)	2.60 (0.50)	2.70 (0.50)	2.80 (0.50)
Rhinosinusitis disease severity VAS	7.65 (2.23)	7.64 (2.18)	8.22 (2.07)	8.12 (1.98)	7.80 (2.00)	7.90 (2.00)	7.80 (2.00)	8.00 (2.00)
Blood eosinophils, Giga/L	0.13 (0.09)	0.24 (0.15)	0.41 (0.31)	0.67 (0.37)	0.15 (0.10)	0.30 (0.20)	0.20 (0.10)	0.40 (0.30)
Baseline peak nasal inspiratory flow	83.52 (56.30)	87.07 (56.08)	87.47 (56.14)	84.86 (59.98)	80.96 (50.15)	98.59 (56.70)	81.27 (57.00)	89.34 (57.00)
Baseline blood eosinophils	0.44 (0.31)	0.43 (0.34)	0.45 (0.36)	0.40 (0.30)	0.45 (0.39)	0.44 (0.35)	0.44 (0.34)	0.43 (0.34)

In this systematic review and meta-analysis we evaluate the efficacy and safty of dupilumab in the treatment of CRSwNP. Analysis of the included studies provided a potential advantages and limitation of using dupilumab in CRSwNP treatment. The acquired results from the analysis suggesting a significant improvement in the management. The primary outcomes included Lund-Mackay CT total score, Loss-of-smell score, Smell test (UPSIT) score, SNOT-22 total score, Bilateral endoscopic nasal polyp score, and Nasal congestion or obstruction score, these outcomes have showed a little difference between the placebo and dupilumab groups. Most of the secondary outcomes have also shown a non significant deifference between tow groups, these includes daily loss of smell score, rhinosinusitis disease severity VAS, Baseline blood eosinophils, and Baseline peak nasal inspiratory flow.

Several burned symptoms are associated with patients suffering from CRSwNP, these symptoms include loss of smell, asthma, high polyps recurrence rates, and poor life quality [8]. Considering all aspects of the disease, dupilumab provides eary, significant, and clnically meaningful improvments in patients with unsuffciently controlled CRSwNP who are with standard care. Dupilumab is asscotiated with reduction in systemic corticosteriod and surgery [9, 10]. Its mechanism leads to a significant effect in reduction of polyp size and disease in all sinuses, also it relives major symptoms of the disease such as nasal congestion, anosmia, and rhinorrhoea [11].

In addition, dupilumab therapy was well tolerated among patients, these is no significant difference in side effects between the dupilumab and placebo groups [12]. The most significant result in secondary outcomes is that the igher levels of bloodd eosinophils in the dupilumab group, the mean differnece is 0.18 (95% Cl: 0.12–0.24), which indicates a good immunomodulatory efffects. However, This effect does not suggest a significant adverse events, affirming dupilumab saftey profile in CRSwNP patients [11, 12].

According to our aquired studies in this systematic revire and mea-analysis, Type 2 inflamation is cruical in CRSwNP pathophysiology, It can be modulated by dupilumab, which has the ability to reduce inflammation and symptoms reduction by inhibiting IL-4 and IL-13 signaling pathways. Despit that the differnce in primary outcomes is not significant, levels of blood eosinophils represents a significant outcome with a good biological effect.

Therefore, dupilumab is associated with a good safty profile for patients suffering from CRSwNP, specialy those who having asthma comorbid or an elevation of eosinophilic levels. Despit limitations in primary clinical outcomes, the significant modulation of inflammatory markers is transulated as potential benefits in specific patient subsets.

This systematic review and meta-analysis have shown the effectiveness of dupilumab in treating Chronic rhinosinusitis with nasal polyps (CRSwNP), despite that the primary outcomes have shown a non-significant differentiation between placebo and dupilumab groups, the secondary outcomes represented by increasing levels of blood eosinophils is a very beneficial outcome to improve symptoms, especially in patients who have asthma and high eosinophilic blood levels. This systematic review has experienced several limitations such as the small sample size which led to a little data which may be not enough for final decision on this treatment.

Ethics approval and consent to participate: Not applicable

Consent for publication: Not applicable

Availability of data and materials: Not applicable

Competing interests: The authors declare that they have no competing interests

Funding: No funding was received.

Authors' contributions:

Hashim Talib Hashim: Conceptualization, methodology, formal analysis, writing – original draft, supervision, project administration.

Nashmiya Khan: Data collection, resources, writing – review & editing.

Muhammad Umar: Software, formal analysis, data visualization, writing – review & editing.

Mohammedbaqer Ali Al-Ghuraibawi: Investigation, resources, writing – review & editing.

Mustafa Sabeeh Lafta Zubaidi: Data curation, validation, writing – review & editing.

Mahmoud Mussleh Al-Mukhtar: Methodology, formal analysis, writing – review & editing.

Mohamad Dawood and Ashraf: Conceptualization, supervision, writing – review & editing.

All authors read and approved the final manuscript.

Acknowledgements: None

Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, Khan AH. Dupilumab for nasal polyposis with chronic sinusitis. *New Engl J Med. 2019;381(1):55–63.
Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, Khan AH. (2020). Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. *JAMA 323*(9), 909–19.
DeConde AS, Soler ZM. (2016). Chronic rhinosinusitis: epidemiology and burden of disease. *American J Rhinology Allergy, 30*(2), 134–9.
Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, Toppila-Salmi S. (2020). European Position Paper on Rhinosinusitis and Nasal Polyps 2020. *Rhinology Supplement, 29*(S30), 1-464.
Han JK, Bachert C, Fokkens W, Desrosiers M, Wagenmann M, Lee SE, Khan AH. (2016). Mepolizumab for nasal polyposis: a randomized, double-blind, placebo-controlled trial. *Journal Allergy Clin Immunol, 140*(4), 1024–31.
Page MJ, McKenzie, Bossuyt PM. al et. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Int J Surg. 2021;88;105906.
Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011.
Wells GA, Shea B, O'Connell D et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, Mullol J, Greos LS, Bosso JV, Laidlaw TM, Cervin AU, Maspero JF, Hopkins C, Olze H, Canonica GW, Paggiaro P, Cho SH, Fokkens WJ, Fujieda S, Zhang M, Lu X, Fan C, Draikiwicz S, Kamat SA, Khan A, Pirozzi G, Patel N, Graham NMH, Ruddy M, Staudinger H, Weinreich D, Stahl N, Yancopoulos GD, Mannent LP. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019;394(10209):1638–1650. 10.1016/S0140-6736(19)31881-1. Epub 2019 Sep 19. Erratum in: Lancet. 2019;394(10209):1618. doi: 10.1016/S0140-6736(19)32218-4. PMID: 31543428.
Chuang CC, Guillemin I, Bachert C, Lee SE, Hellings PW, Fokkens WJ, Duverger N, Fan C, Daizadeh N, Amin N, Mannent LP, Khan AH, Kamat S. Dupilumab in CRSwNP: Responder Analysis Using Clinically Meaningful Efficacy Outcome Thresholds. Laryngoscope. 2022;132(2):259–64. Epub 2021 Nov 24. PMID: 34817082; PMCID: PMC9299704.
Fujieda S, Matsune S, Takeno S, Ohta N, Asako M, Bachert C, Inoue T, Takahashi Y, Fujita H, Deniz Y, Rowe P, Ortiz B, Li Y, Mannent LP. Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status. Allergy. 2022;77(1):186–96. Epub 2021 Jun 4. PMID: 33993501; PMCID: PMC9290136.
Campion NJ, Brugger J, Tu A, et al. The real life efficacy of dupilumab is independent of initial polyp size and concomitant steroids in CRSwNP. J Otolaryngol - Head Neck Surg. 2023;52(1). 10.1186/s40463-023-00663-4.
Awadh NI, Gorial FI, Al-Obaidi AD, Hashim HT, Al-Obaidi MN, Hammadi RA. Unusual cause of inflammatory backache: SAPHO syndrome. Int J Rheum Dis. 2024;27(1):e14878. 10.1111/1756-185X.14878. Epub 2023 Aug 17. PMID: 37592395.
Gorial FI, Awadh NI, Al-Obaidi AD, Al-Obaidi MN, Hashim HT, Hasan HJ. Post-streptococcal scleredema an unusual rare mimicker of scleroderma: a case report. Reumatismo. 2023;75(1). 10.4081/reumatismo.2023.1551. PMID: 37154255.
Bachert, C., Han, J. K., Desrosiers, M., Hellings, P. W., Amin, N., Lee, S. E., …Mannent, L. P. (2019). Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. The Lancet, 394(10209), 1638–1650.
Chuang, C. C., Guillemin, I., Bachert, C., Lee, S. E., Hellings, P. W., Fokkens, W.J., … Kamat, S. (2022). Dupilumab in CRSwNP: responder analysis using clinically meaningful efficacy outcome thresholds. The Laryngoscope, 132(2), 259–264.
Fujieda S, Matsune S, Takeno S, Ohta N, Asako M, Bachert C, Inoue T, Takahashi Y, Fujita H, Deniz Y, Rowe P, Ortiz B, Li Y, Mannent LP. Dupilumab efficacy in chronic rhinosinusitis with nasal polyps from SINUS-52 is unaffected by eosinophilic status. Allergy. 2022;77(1):186–96. Epub 2021 Jun 4. PMID: 33993501; PMCID: PMC9290136.
Campion, N. J., Brugger, J., Tu, A., Stanek, V., Brkic, F. F., Bartosik, T. J., …Schneider, S. (2023). The real life efficacy of dupilumab is independent of initial polyp size and concomitant steroids in CRSwNP. Journal of Otolaryngology-Head & Neck Surgery, 52(1), s40463-023.

No competing interests reported.

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Efficacy of Dupilumab in CRSwNP treatment: A systematic review and meta-analysis

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Abstract

Objective

Background

Method

Results

Conclusion

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Introduction

Methodology

Literature Search

Data Synthesis and Statistical Analysis

Reporting

Results

Discussion

Conclusion

Declarations

References

Additional Declarations

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