Chronische rhinosinusitis (CRS) is een heterogeen ziektebeeld waarbij CRS met neuspoliepen (CRSwNP) in Westerse landen met name is geassocieerd met type 2 inflammatie. Symptomen van CRS met neuspoliepen zijn vaak onvoldoende onder controle door huidige medicamenteuze behandeling (zoals intranasale en systemische corticosteroïden) en ook na chirurgie van de neusbijholten wordt in een groot aantal patiënten nog onvoldoende ziektecontrole bereikt (regelmatig uitmondend in revisiechirurgie). Dit leidt tot significante ziekte-gerelateerde beperking van kwaliteit van leven en hoge consumptie van medische zorg, met bijbehorende hoge kosten.

Biologicals (of “biologics”) is een wat algemene term voor medicijnen die zijn geproduceerd door een biologisch proces. Een specifiek type biological betreft de monoklonale antilichamen. Deze antilichamen richten zich op specifieke ontstekingsmediatoren of immuuncellen die betrokken zijn bij chronische inflammatoire ziekten.

Tot circa 2010 was het meeste onderzoek naar de rol van deze biologicals gericht op de behandeling van ziekten als allergie, astma en reumatologische/immunologische aandoeningen. In recente trials zijn biologicals onderzocht in patiënten met (matig-)ernstige CRS met neuspoliepen. Deze biologicals zijn gericht op ontstekingsfactoren en -receptoren die betrokken zijn bij type 2 inflammatie. Er is hierbij sprake van een verhoogd IL-4, IL-5, IL-13 of totaal IgE. Voor CRS met neuspoliepen (primaire diffuse type 2 CRS) zijn momenteel de volgende drie biologicals beschikbaar.  Dupilumab is een monoclonaal antilichaam tegen IL-4Rα en IL-13Rα; mepolizumab is een monoklonaal antilichaam tegen IL-5;. omaluzimab is een antilichaam tegen IgE. Benraluzimab, een monoklonaal antilichaam tegen de IL-5 receptor, is (vooralsnog) alleen geregistreerd voor ernstig ongecontroleerd eosinofiel astma en (nog) niet voor CRSwNP.

In deze module wordt de werking, effectiviteit en veiligheidsaspecten/bijwerkingen van de verschillende biologicals voor de behandeling van CRS met neuspoliepen besproken. Aanbevelingen ten aanzien van patiëntenselectie en de waarde van deze biologicals in het totale therapeutisch arsenaal voor patiënten met CRS met neuspoliepen worden gegeven.

Anti-IL-4Rα mAb (dupilumab)

Critical outcomes

Important outcomes

Anti-IL-5 mAb (mepolizumab)

Critical outcomes

Important outcomes

Anti-IgE mAb (omalizumab)

Critical outcomes

Important outcomes

Description of studies

Chong (2021) performed a Cochrane living review. The aim of the review is to see if any of the biologicals (monoclonal antibodies, mAb) are effective in treating people with chronic rhinosinusitis. In the 2021 edition of the review, the search was performed up to September 2020. The review included trials where patients with chronic rhinosinusitis were treated for at least three months with either one of the new biologic drugs or a placebo (dummy) treatment and that reported the effect of the drug on people's symptoms, their general health and any adverse effects. The review found 10 studies, looking at three different drugs: dupilumab (anti-IL-4Rα mAb, 3 RCTs with 784 participants in total), mepolizumab (anti-IL-5 mAb, 2 RCTs with 137 participants in total) and omalizumab (anti-IgE mAb, 5 RCTs with 329 participants in total). All the studies were sponsored or supported by industry. A total of 1262 participants were included. With the exception of two participants in one study (Pinto 2010), all the participants were adults with moderate to severe chronic rhinosinusitis with nasal polyps and a significant number of participants (43% to 100%) also had asthma as a co-morbidity. Overall, the risk of bias was low or unclear for most domains. Two studies were published after publication of the Cochrane review.

Han (2021) reported the results of the SYNAPSE trial, a randomised, double-blind, placebo-controlled, phase 3 trial studying treatment with mepolizumab. The multicentre trial (93 centres in 11 countries) included patients with recurrent, refractory, severe, bilateral nasal polyp symptoms (nasal obstruction symptom visual analogue scale [VAS] score of >5), were eligible for repeat nasal surgery (overall symptoms VAS score >7 and endoscopic nasal polyps score of ≥5, with a minimum score of 2 in each nasal cavity) despite standard of care treatment, and had to have at least one nasal surgery in the past 10 years. The coprimary endpoints were change from baseline in total endoscopic nasal polyp score at week 52 and in mean nasal obstruction VAS score during weeks 49–52, assessed in the intention-to-treat population (407 patients). The study was funded by GlaxoSmithKline, who also funded editorial support of the manuscript.

Results

Results are presented per outcome measure. The included studies compared dupilumab, mepolizumab or omalizumab with placebo, all in addition to standard of care, including topical steroid application.

Health-related quality of life

Six studies reported health-related quality of life assessed by SNOT-22 (0-110, lower is better) up to 25 weeks (figure 1), one study at 40 weeks and six studies at 52 to 56 weeks.

Anti-IL-4Rα mAb (dupilumab)

For dupilumab, three trials with in total 784 patients found a pooled mean difference (MD) of -19.50 in favor of treatment up to 25 weeks, with a 95% confidence interval (CI) from -22.43 to -16.58. At 52 weeks, the LIBERTY SINUS 52 trial reported a MD of -22.38 (95% CI -27.10 to -17.66; N=303) in favor of treatment. These differences are considered clinically relevant.

Anti-IL-5 mAb (mepolizumab)

For mepoluzimab, Bachert 2017 reported a MD of -13.26 (95% CI -22.08 to -4.44) in favor of treatment compared to placebo in 105 patients up to 25 weeks. Han (2021) found a of -16.49 (95% CI -23.57 to 9.43) in favor of mepoluzimab in 407 patients at 52 weeks. Taken together (figure 1), the MD of -13.60 (95% CI -17.76 to -9.44) is considered clinically relevant.

Anti-IgE mAb (omalizumab)

The POLYP1 and POLYP2 trial reported SNOT-22 in 265 patients and found a MD of -15.62 (95% CI -19.79 to -11.45) in favor of treatment. The difference is considered clinically relevant.

Figure 1. Health-related quality of life (SNOT-22) up to 25 weeks.

SNOT-22 score 0-110, lower is better. Follow-up up to 25 weeks unless stated otherwise.
 Random effects model. Z: p-value of pooled effect; df: degrees of freedom; I²: statistical heterogeneity; CI: confidence interval.

Disease severity

Anti-IL-4Rα mAb (dupilumab)

Based on 3 publications on dupilumab with 784 patients in total, the MD in disease severity (VAS 0-10, lower is better) was -3.00 (95% CI-3.47 to -2.53) in favor of treatment (figure 2). This was considered clinically relevant.

Anti-IL-5 mAb (mepolizumab)

Two mepolizumab trials reported disease severity and found MDs of -2.03 and -1.65 in 479 patients in favor of treatment (figure 2). The differences are considered clinically relevant.

Anti-IgE mAb (omalizumab)

Disease severity was not reported in an omalizumab trial.

Figure 2. Disease severity (VAS).

Visual analogue score 0-10, lower is better. Random effects model. Lower score is better. Z: p-value of pooled effect; df: degrees of freedom; I²: statistical heterogeneity; CI: confidence interval.

Nasal polyp score

Anti-IL-4Rα mAb (dupilumab)

Three studies reported nasal polyp score (0-8, lower score is better) after dupilumab treatment. Up to 24 weeks, MD was -1.80 (95% CI -2.25 to -1.35) based on 3 studies with 784 patients (figure 3). At 52 weeks, the LIBERTY SINUS 52 trial reported a MD of -2.34 (95% CI -2.77 to -1.91) in 303 patients. The differences are considered clinically relevant.

Anti-IL-5 mAb (mepolizumab)

In two studies evaluating mepoluzimab in 137 patients (figure 3), improvement in nasal polyp score was more substantial in the experimental groups, with a MD of -1.23 (95% CI -1.79 to -0.68). In addition, Han (2021) reported change from baseline in total endoscopic nasal polyp score at week 52, and found a mean change of -0.9±1.90 in the mepoluzimab group versus -0.1±1.46 in the placebo group. The differences are not considered clinically relevant.

Anti-IgE mAb (omalizumab)

Four omalizumab trials reported nasal polyp score. The pooled MD for 312 patients was -1.26 (95% CI -2.21 to -0.31) in favor of omalizumab treatment (figure 3). The difference is not considered clinically relevant.

Figure 3. Nasal polyp score.

Polyp score 0-8, lower is better. Random effects model. Lower score is better. Z: p-value of pooled effect; df: degrees of freedom; I²: statistical heterogeneity; CI: confidence interval.

Sense of smell/olfactory dysfunction

Anti-IL-4Rα mAb (dupilumab)

Chong (2021) did not report sense of smell or olfactory dysfunction for dupilumab.

Anti-IL-5 mAb (mepolizumab)

Han (2021) reported loss of smell change from baseline (VAS 0-10, lower is better) at week 49 to 52 in 407 patients and found a MD of -0.37 (95% CI -0.65 to -0.08) in favor of mepolizumab, which is not considered clinically relevant. Bachert (2022) reported difficulty in sense of smell as DSS score, which was derived from daily Nasal Polyposis Symptom Diary entries in which patients rated their worst difficulty in sense of smell over the past 24 hours on a scale of 0 (none) to 3 (severe). The MD in 272 patients at week 40 was -0.218 (95% CI -0.361, -0.074) and -0.237 (95% CI -0.389, -0.084) at week 52, in favor of benralizumab, which was not considered clinically relevant.

Anti-IgE mAb (omalizumab)

Chong (2021) did not report sense of smell or olfactory dysfunction for omalizumab.

Revision surgery

Anti-IL-4Rα mAb (dupilumab)

Chong (2021) reported the number of patients who had revision surgery as a rescue treatment. Based on 2 dupilumab trials with 725 patients, the relative risk (RR) was 0.17 (95% CI 0.05 to 0.52) in favor of treatment (figure 4), a clinically relevant difference.

Anti-IL-5 mAb (mepolizumab)

Chong (2021) reported one study (Bachert, 2017) with patients still meeting criteria for surgery at 24 weeks, and one study with patients requiring 'rescue' surgery during trial (Gevaert, 2011), as presented in figure 4. In addition, Han (2021) reported the proportion of patients having nasal surgery up to week 52. Taken together, the RR was 0.58 (95% CI 0.28 to 1.20), which is considered a clinically relevant difference.

Anti-IgE mAb (omalizumab)

For omalizumab, Chong (2021) reported avoidance of surgery. Based on 2 studies with 265 patients the RR was 5.60 (95% CI 1.99 to 15.76) in favor of omalizumab. This is considered clinically relevant.

Figure 4. Revision surgery

Random effects model. Z: p-value of pooled effect; df: degrees of freedom; I²: statistical heterogeneity; CI: confidence interval.

Serious adverse events

Anti-IL-4Rα mAb (dupilumab)

Three studies reported serious adverse events for dupilumab and found a pooled RR of 0.47 (95% CI 0.29 to 0.76) in favor of treatment (782 patients), as presented in figure 5. This RR is considered clinically relevant.

Anti-IL-5 mAb (mepolizumab)

Based on three studies with 524 patients, the RR for serious adverse events was 0.93 (95% CI 0.44 to 1.94) in favor of treatment (figure 5). This is not considered clinically relevant.

Anti-IgE mAb (omalizumab)

For serious adverse events, Chong (2021) reported a RR of 0.32 (95% CI 0.05 to 2.00) in favor of omalizumab in five studies with 329 patients (figure 5), which is considered clinically relevant.

Figure 5. Serious adverse events

Random effects model. Z: p-value of pooled effect; df: degrees of freedom; I²: statistical heterogeneity; CI: confidence interval.

Adverse events

Anti-IL-4Rα mAb (dupilumab)

As adverse events, Chong (2020) reported nasopharyngitis, including sore throat (figure 6). Based on three trials with 783 patients, the RR was 0.95 (95% CI 0.72 to 1.25) in favor of treatment, which is not considered a clinically relevant finding.

Anti-IL-5 mAb (mepolizumab)

Two studies with 135 patients reported nasopharyngitis, including sore throat as adverse events. One study with 105 patients found a RR of 0.70 (95% CI 0.34 to 1.43) in favor of mepolizumab, whereas another study with 30 patients reported a RR of 1.57 (95% CI 0.36 to 1.47) in favor of placebo (figure 6). Han (2021) reported a RR of 0.98 (95% CI 0.90 to 1.07) on any on-treatment adverse event. Taken together, the difference in adverse events is not clinically relevant.

Anti-IgE mAb (omalizumab)

As adverse events, nasopharyngitis including sore throat was reported (figure 6). Based on five studies with 329 patients, the RR was 0.71 (95% CI 0.29 to 1.73), which is considered clinically relevant.

Figure 6. Adverse events - nasopharyngitis, including sore throat

Random effects model. Z: p-value of pooled effect; df: degrees of freedom; I²: statistical heterogeneity; CI: confidence interval.

Level of evidence of the literature

Evidence was graded separately for the different types of medication.

Anti-IL-4Rα mAb (dupilumab)

For anti-IL-4Rα mAb (dupilumab), the level of evidence for all outcome measures was based on randomized studies and therefore started at high.

For the outcome health-related quality of life up to week 25, the level of evidence was HIGH.

For the outcome disease severity, the level of evidence was downgraded with one level to MODERATE due to study limitations (methods or criteria used in the measurement of the outcome were not validated).

For the outcome nasal polyp score, the level of evidence was downgraded with two levels to LOW due to study limitations (methods or criteria used in the measurement of the outcome were not validated, -1) and because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1).

For the outcome sense of smell/olfactory dysfunction, the evidence could not be graded due to a lack of data.

For the outcome revision surgery, the level of evidence was downgraded with one level to MODERATE due to study limitations (it is unclear which criteria were used to determine the need for 'rescue surgery').

For the outcomes serious adverse events and adverse events, the level of evidence was downgraded with two levels to LOW because of limited generalizability (more heterogeneous population and/or longer periods of treatment and follow-up needed, indirectness, -1) and small sample size for the outcome (imprecision, -1).

Anti-IL-5 mAb (mepolizumab)

For anti-IL-5 mAb (mepolizumab), the level of evidence for all outcome measures was based on randomized studies and therefore started at high.

For the outcome health-related quality of life, the level of evidence was downgraded with one level to MODERATE because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1).

For the outcome disease severity, the level of evidence was downgraded with two levels to LOW due to study limitations (methods or criteria used in the measurement of the outcome were not validated) and because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1).

For the outcome nasal polyp score, the level of evidence was downgraded with two levels to LOW due to study limitations (methods or criteria used in the measurement of the outcome were not validated, -1) and because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1).

For the outcome sense of smell/olfactory dysfunction, the level of evidence was downgraded with two levels to LOW due to study limitations (methods or criteria used in the measurement of the outcome were not validated, -1) and because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1). 

For the outcome revision surgery, the level of evidence was downgraded to LOW due to study limitations (it is unclear which criteria were used to determine the need for 'rescue surgery', -1) and because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1).

For the outcomes serious adverse events and adverse events, the level of evidence was downgraded to VERY LOW because of limited generalizability (more heterogeneous population and/or longer periods of treatment and follow-up needed, indirectness, -1) and because the confidence interval around the point estimate crossed both limits of clinical relevance (imprecision, -2). 

Anti-IgE mAb (omalizumab)

For anti-IgE mAb (omalizumab), the level of evidence for all outcome measures was based on randomized studies and therefore started at high.

For the outcome health-related quality of life, the level of evidence was downgraded with one level to MODERATE because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1).

For the outcome disease severity, the evidence could not be graded due to a lack of data.

For the outcome nasal polyp score, the level of evidence was downgraded with two levels to LOW due to study limitations (methods or criteria used in the measurement of the outcome were not validated, -1) and because the confidence interval around the point estimate crossed one limit of clinical relevance (imprecision, -1).

For the outcome sense of smell/olfactory dysfunction, the evidence could not be graded due to a lack of data.

For the outcome revision surgery (avoidance), the level of evidence was downgraded with two levels to LOW due to study limitations (criteria used for avoidance were not validated, -1) and limited sample size (imprecision, -1).

For the outcomes serious adverse events and adverse events, the level of evidence was downgraded to VERY LOW because of limited generalizability (more heterogeneous population and/or longer periods of treatment and follow-up needed, indirectness, -1) and because the confidence interval around the point estimate crossed both limits of clinical relevance (imprecision, -2).

A systematic review of the literature was performed to answer the following question:

What are the benefits and harms of biologicals (monoclonal antibodies) in the treatment of patients with chronic rhinosinusitis?

P: Patients with chronic rhinosinusitis with nasal polyps.

I: Monoclonal antibody treatment (dupilumab, mepolizumab, omaluzimab) plus intranasal steroids.

C: Placebo/no treatment plus intranasal steroids.

O: PROMs (disease-related quality of life (SNOT-score), total nasal symptom score or disease severity (VAS)), nasal polyp score, sense of smell/olfactory dysfunction, revision surgery, (serious) adverse events (short and long term).

In the current analysis, only biologicals approved for treatment of CRSwNP by the European Medicines Agency (i.e. dupilumab, mepolizumab, omaluzimab) were considered.

Relevant outcome measures

The guideline development group considered patient reported outcome measures (PROMs) as critical outcomes for decision making; and the outcomes nasal polyp score, sense of smell/olfactory dysfunction, revision surgery and (serious) adverse events as important outcomes for decision making.

A priori, the working group considered disease-related quality of life, as assessed by the Sino-Nasal Outcome Test (SNOT-22) score, the preferred outcome. This is a quality of life score specifically for CRS patients, in which patients score the burden of disease for 22 symptoms and social/emotional consequences from 0 (“no problem”) to 5 (“problem as bad as it can be”), resulting in a total score from 0 to 110. In case SNOT-22 was not reported, symptom severity as described by total nasal symptom score was preferred over the use of a visual analogue score (VAS). The important outcomes nasal polyp score and sense of smell/olfactory dysfunction could be assessed by any validated score. Adverse events were not defined a priori.

For the SNOT-22 score the working group defined 12.0 as a minimal clinically (patient) important difference (MCID) for medically managed patients with CRS, as described in literature (Phillips, 2018). For total symptom score, polyp score and VAS scores, the working group defined 15% of the maximum score as MCID, and 0.5 for standardized mean differences. For adverse events and revision surgery (risk ratio, RR), the working group defined 25% as a MCID.

Search and select (Methods)

The databases Embase.com and Ovid/Medline were searched with relevant search terms until October 10, 2022, for systematic reviews and RCTs about the place of biologicals as treatment for patients with CRS. The search resulted in 260 unique hits. Studies were eligible for inclusion if they were (1) randomized controlled trials (RCTs) or meta-analyses of RCTs, (2) comparing treatment with biologicals (monoclonal antibodies, any type, dose or duration) with placebo, (3) in patients with chronic rhinosinusitis, with or without nasal polyps. Based on title and abstract screening, 22 studies were initially selected. After reading the full text, twenty studies were excluded (see the table with reasons for exclusion under the ‘Methods’ tab) and two were included.

Results

One systematic review and one RCT were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.