Analysis and mining of Dupilumab adverse events based on FAERS database

Abstract

This study aims to explore potential adverse events (AEs) related to Dupilumab using data from the US FDA Adverse Event Reporting System (FAERS) database. The FAERS database from Q2 2017 to Q4 2023 was mined for AEs related to Dupilumab. The types of AEs reported, along with gender, age distribution, and severity, were evaluated. Signal detection methods including Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Empirical Bayesian Geometric Mean were used. A total of 11,547,571 AE reports were collected, with 5335 reports suspected of being related to Dupilumab, identifying 307 Preferred Terms involving 27 System Organ Classes. Reports from female patients outnumbered males (56.08% vs. 34.65%). Patients aged 45–65 years reported the most events (21.34%). The number of reports increased significantly in 2023 (34.25%) compared to 2017 (0.42%), with the highest reporting rate from the US (98.07%). Common AEs included Pruritus, Product use in unapproved indication, and Rash, with Product dose omission issue indicating widespread misuse of Dupilumab. High signal strength AEs included Rebound atopic dermatitis, Rebound eczema, Dermatitis atopic, and Dry skin; injection site AEs like Injection site dryness and eczema; new potential AEs such as Dry eye, Eye pruritus, Ocular hyperaemia, Eye irritation, Conjunctivitis, Vision blurred, and Sleep disorder. This study reveals various potential AEs associated with Dupilumab, including newly identified risks. Future research needs to delve deeper into the safety of Dupilumab to better guide its clinical application.

Introduction

Dupilumab (brand name: Dupixent) is the world’s first fully human monoclonal antibody (IgG4 type) that targets and recognizes the interleukin-4 receptor alpha subunit (IL-4Rα). By inhibiting the endogenous binding of key type 2 inflammation factors IL-4 and IL-13 to IL-4Rα, it blocks downstream signal transduction, reduces airway inflammation, and decreases eosinophils¹. The drug was first approved for the treatment of moderate-to-severe atopic dermatitis (AD) in adults in the United States in March 2017. Its indications have expanded in recent years to include nodular prurigo, chronic rhinosinusitis with nasal polyposis (CRSwNP), eosinophilic esophagitis, and asthma. However, Dupilumab was only approved in China in June 2020, and its indication for asthma was approved in September 2023. Due to its relatively late approval in China, clinical experience with its use is limited, and understanding of its adverse reactions is also relatively lacking. This limits the ability of clinical practitioners to access relevant information and conduct rational drug use. Therefore, this study aims to conduct an in-depth analysis of Dupilumab-related adverse event (AE) data from the FAERS database to better understand the safety profile of this drug and provide important reference information for its rational clinical use.

Bronchial asthma is a chronic inflammatory airway disease characterized by symptoms such as wheezing, shortness of breath, chest tightness, and/or coughing. It is the most prevalent chronic respiratory disease globally. Studies indicate that the global prevalence of bronchial asthma has reached 300 million, and it is expected to rise to 400 million by 2025, causing 461,000 deaths^2,3. Although current asthma treatments, including inhaled corticosteroids (ICS) and long-acting beta-agonists (LABA), can alleviate asthma symptoms and reduce acute exacerbations, a significant number of patients remain inadequately controlled, particularly those with severe asthma. These patients may face serious consequences such as airway narrowing and respiratory failure, severely impacting their quality of life and consuming substantial medical resources, making asthma a major cause of disability and death. Therefore, novel biological targeted therapies like Dupilumab have become a research focus in the field of asthma, especially for patients with moderate-to-severe asthma who remain inadequately controlled despite standard treatment.

The ERS/ATS guidelines for severe asthma⁴ recommend anti-IL-4R monoclonal antibodies for patients with severe asthma with blood eosinophils (EOS) ≥ 150/μl or fractional exhaled nitric oxide (FeNO) > 25 ppb. Castr et al.³ found that in patients aged 12 years and older with inadequately controlled moderate-to-severe asthma, Dupilumab treatment for 52 weeks significantly reduced the frequency of severe asthma exacerbations, improved lung function, and enhanced asthma control, especially in patients with type 2 inflammation-predominant asthma. Additionally, Dupilumab significantly reduced the use of oral corticosteroids (OCS) in OCS-dependent severe asthma patients while also lowering the incidence of asthma exacerbations⁴. Corren J et al.⁵ found that the more frequent the previous asthma exacerbations, the more significant the improvement in asthma symptoms with Dupilumab treatment. A real-world study from Japan on severe asthma also showed that patients with a history of biological therapy failure benefited significantly from switching to Dupilumab⁶. Recent studies^7–10 have investigated the AEs of JAK inhibitors used in atopic dermatitis. These studies have shed light on their safety profiles, which provides a new perspective for comparing different systemic therapies in atopic dermatitis.

Despite the new treatment option Dupilumab offers for asthma, information on its potential AEs and safety issues during long-term use remains relatively limited. The FDA’s Adverse Event Reporting System (FAERS) database provides crucial information for monitoring the safety of drugs post-market^11–22. To comprehensively assess the safety of Dupilumab, this study will delve into and analyze AE data related to Dupilumab from the FAERS database to further understand the drug’s safety and potential risks, thereby providing valuable reference information for clinical treatment.

Methods

Data sources

The data for this study were sourced from the FAERS database, covering all AE reports from the second quarter of 2016 to the fourth quarter of 2023. These reports were imported into the Statistical Analysis System (SAS) database for organization and analysis. The data included personal information records (DEMO), drug usage records (DRUG), treatment outcome information records (OUTC), AE information records (REAC), report source information records (RPSR), and treatment duration information records (THER).

Data processing

The search targeted “Dupilumab” as the specific drug. According to the FAERS database guidelines, duplicate AE reports were identified and removed. Specifically, reports were considered duplicates if they had identical values for key identifiers such as the patient’s unique identifier (when available), the date of the AE, the reported drug, and the nature of the adverse event description. In cases where multiple reports from the same patient with the same drug—related AE were found, only the most recent record was retained. This was done to ensure that each unique AE instance was counted only once, minimizing the potential for over—representation of certain events in the analysis. When identifying reports suspecting Dupilumab as the primary agent, reports were selected if Dupilumab was clearly listed as the suspected drug in the ‘DRUG’ field of the FAERS database records. Additionally, reports where the adverse event description strongly suggested a relationship with Dupilumab use, even if not explicitly stated as the sole suspect, were also included. For example, if the patient’s medical history showed no other recent medications that could plausibly cause the reported AE, and the onset of the AE occurred within a reasonable time frame after starting Dupilumab treatment, such reports were considered suspect for Dupilumab—related AEs. However, in cases of concurrent use of multiple drugs where it was unclear which agent was responsible for the AE, a more conservative approach was taken, and the report was included only if there were additional supporting details implicating Dupilumab. This study utilized the Medical Dictionary for Regulatory Activities (MedDRA) AE terminology set. AE reports were classified and described using MedDRA’s system organ class (SOC) and preferred terms (PT), where SOC represents the category of the AE and PT is the standard term for the AE.

Data mining

During the data mining process, this study employed methods from disproportionality analysis, including Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM). Disproportionality analysis is based on the classical four-fold table (Table 1) and calculates ROR, PRR, BCPNN, and EBGM values using specific formulas (Table 2). Higher values indicate stronger signals of AEs associated with Dupilumab, suggesting a higher statistical correlation between Dupilumab and specific AEs.

Table 1.

Four grid table.

	Target AEs	Non-target AEs	Total
Dupilumab	a	b	a + b
Non- Dupilumab	c	d	c + d
Total	a + c	b + d	N = a + b + c + d

Table 2.

ROR, PRR, BCPNN, and EBGM methods, formulas, and thresholds.

Method	Formula	Threshold
ROR		a ≥ 3 and 95% CI (lower limit) > 1
PRR	SE(lnPRR) =  =	a ≥ 3 and 95% CI (lower limit) > 1
BCPNN	IC =  V(IC) =  IC-2SD = E(IC)−2	IC025 > 0
EBGM		EBGM05 > 2

Results

Overview of AE reports

In the FAERS database, from Q2 2017 to Q4 2023, a total of 11,547,571 AE reports were collected, with 205,359 reports primarily suspecting Dupilumab. Among these reports, the proportion of male patients (71,160, 34.65%) was lower than that of female patients (111,517, 56.08%). The age group with the most reports was 45–65 years (43,819, 21.34%), followed by 18–45 years (39,215, 19.10%). Over time, the number of reports increased annually, with a significant rise in 2023 (70,329) compared to 2017 (866). Reports mainly came from physicians (57.47%), followed by consumers (34.77%) and pharmacists (6.82%). Nearly all reports originated from the United States, accounting for 98.07%. In terms of AE severity, the majority were classified as Non-Serious (89.16%), while Life-Threatening (0.12%), Hospitalization—Initial or Prolonged (4.56%), Disability (0.44%), and Death (0.39%) were relatively low. Regarding the timing of events, 85.64% of the reports did not provide clear information on the onset of AEs or drug usage dates. Among the provided data, the highest rate of AEs occurred within 0 to 30 days of drug use (8.32%), indicating that AEs may occur shortly after starting the medication. Additionally, AEs reported over 360 days post-medication accounted for 1.82%, suggesting that AEs may still occur after long-term use (Table 3).

Table 3.

Basic information on AEs related to Dupilumab.

Factors	Number of events (%)
Gender
Female	115,170 (56.08)
Male	71,160 (34.65)
Unknown	19,029 (9.27)
Age
< 18	17,785 (8.66)
18–45	39,215 (19.10)
45–65	43,819 (21.34)
65–75	14,411 (7.02)
≥ 75	8663 (4.22)
Unknown	81,466 (39.67)
Reporter
Pharmacist	14,009 (6.82)
Consumer	71,404 (34.77)
Physician	118,010 (57.47)
Other health professionals	1771 (0.86)
Lawyer	9 (0.00)
Unknown	156 (0.08)
Reported countries
United States	200,438 (97.60)
Not specified	959 (0.47)
Japan	764 (0.37)
Germany	517 (0.25)
France	435 (0.21)
UK	401 (0.20)
Canada	209 (0.10)
Australia	187 (0.09)
Report year
2017	866 (0.42)
2018	5894 (2.87)
2019	12,635 (6.15)
2020	20,229 (9.85)
2021	38,021 (18.51)
2022	57,385 (27.94)
2023	70,329 (34.25)
Serious outcomes
Death	792 (0.39)
Disability	904 (0.44)
Hospitalization—Initial or Prolonged	9365 (4.56)
Life-Threatening	247 (0.12)
AE occurrence time—medication date (days)
0–30	17,088 (8.32)
31–60	2028 (0.99)
61–90	1439 (0.70)
91–120	1110 (0.54)
121–150	808 (0.39)
151–180	737 (0.36)
181–360	2545 (1.24)
> 360	3742 (1.82)

Signal mining results

Using signal mining methods, this study identified 307 PTs involving 27 SOCs. Table 4 lists the SOCs by the number of reports. The highest incidence SOCs were Skin and subcutaneous tissue disorders, General disorders and administration site conditions, Injury, poisoning and procedural complications, Eye disorders, Infections and infestations, Respiratory, thoracic and mediastinal disorders, and Musculoskeletal and connective tissue disorders, consistent with the information recorded in Dupilumab’s package insert. However, AEs such as Psychiatric disorders, Investigations, Metabolism and nutrition disorders, and Reproductive system and breast disorders were not mentioned in the package insert.

Table 4.

The signal strength of AEs of Dupilumab at the SOC level.

System organ class	SOC code	Case reports	ROR (95% CI)	PRR (95% CI)	χ2	IC (IC025)	EBGM (EBGM05)
Skin and subcutaneous tissue disorders	10,040,785	112,752	4.91 (4.88–4.95)	4.03 (4.01–4.05)	255,001.46	1.94 (1.93)	3.83 (3.80)
General disorders and administration site conditions	10,018,065	103,596	1.22 (1.21–1.23)	1.18 (1.17–1.18)	3258.52	0.23 (0.22)	1.17 (1.16)
Injury, poisoning and procedural complications	10,022,117	86,606	1.57 (1.55–1.58)	1.47 (1.46–1.48)	14,264.29	0.54 (0.53)	1.46 (1.44)
Eye disorders	10,015,919	42,589	5.04 (4.99–5.10)	4.70 (4.65–4.74)	116,716.59	2.14 (2.13)	4.41 (4.37)
Infections and infestations	10,021,881	28,442	1.05 (1.04–1.06)	1.05 (1.03–1.06)	59.23	0.06 (0.05)	1.04 (1.03)
Respiratory, thoracic and mediastinal disorders	10,038,738	24,477	1.08 (1.07–1.10)	1.08 (1.07–1.09)	149.56	0.11 (0.09)	1.08 (1.06)
Musculoskeletal and connective tissue disorders	10,028,395	18,963	0.74 (0.73–0.75)	0.75 (0.74–0.76)	1631.36	− 0.41 (− 0.43)	0.75 (0.74)
Nervous system disorders	10,029,205	17,112	0.43 (0.42–0.43)	0.44 (0.44–0.45)	12,741.77	− 1.15 (− 1.18)	0.45 (0.44)
Gastrointestinal disorders	10,017,947	14,099	0.32 (0.32–0.33)	0.34 (0.34–0.35)	19,139.29	− 1.53 (− 1.55)	0.35 (0.34)
Psychiatric disorders	10,037,175	13,594	0.48 (0.47–0.49)	0.50 (0.49–0.51)	7253.64	− 1.00 (− 1.02)	0.50 (0.49)
Investigations	10,022,891	8132	0.26 (0.26–0.27)	0.28 (0.27–0.28)	16,297.73	− 1.84 (− 1.87)	0.28 (0.27)
Surgical and medical procedures	10,042,613	6822	0.98 (0.95–1.00)	0.98 (0.95–1.00)	3.97	− 0.03 (− 0.07)	0.98 (0.95)
Immune system disorders	10,021,428	4644	0.75 (0.73–0.78)	0.76 (0.74–0.78)	362.94	− 0.40 (− 0.44)	0.76 (0.74)
Social circumstances	10,041,244	3257	1.44 (1.39–1.49)	1.43 (1.38–1.48)	416.12	0.51 (0.46)	1.42 (1.37)
Vascular disorders	10,047,065	2570	0.26 (0.25–0.27)	0.27 (0.26–0.28)	5238.09	− 1.88 (− 1.94)	0.27 (0.26)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	10,029,104	1919	0.11 (0.10–0.11)	0.11 (0.11–0.12)	14,129.79	− 3.15 (− 3.22)	0.11 (0.11)
Cardiac disorders	10,007,541	1909	0.18 (0.17–0.19)	0.18 (0.18–0.19)	7068.95	− 2.43 (− 2.49)	0.19 (0.18)
Product issues	10,077,536	1837	0.20 (0.19–0.21)	0.20 (0.19–0.21)	5784.26	− 2.27 (− 2.34)	0.21 (0.20)
Metabolism and nutrition disorders	10,027,433	1768	0.17 (0.16–0.18)	0.17 (0.17–0.18)	7059.33	− 2.50 (− 2.57)	0.18 (0.17)
Blood and lymphatic system disorders	10,005,329	1348	0.16 (0.15–0.17)	0.16 (0.15–0.17)	6025.48	− 2.62 (− 2.70)	0.16 (0.15)
Ear and labyrinth disorders	10,013,993	1299	0.61 (0.57–0.64)	0.61 (0.57–0.64)	330.07	− 0.71 (− 0.79)	0.61 (0.58)
Renal and urinary disorders	10,038,359	1161	0.11 (0.10–0.12)	0.11 (0.11–0.12)	8378.42	− 3.14 (− 3.23)	0.11 (0.11)
Reproductive system and breast disorders	10,038,604	1036	0.28 (0.26–0.30)	0.28 (0.27–0.30)	1897.31	− 1.81 (− 1.90)	0.29 (0.27)
Hepatobiliary disorders	10,019,805	369	0.09 (0.08–0.10)	0.09 (0.08–0.10)	3511.37	− 3.48 (− 3.63)	0.09 (0.08)
Endocrine disorders	10,014,698	266	0.20 (0.17–0.22)	0.20 (0.18–0.22)	864.99	− 2.31 (− 2.49)	0.20 (0.18)
Pregnancy, puerperium and perinatal conditions	10,036,585	215	0.11 (0.10–0.13)	0.11 (0.10–0.13)	1536.45	− 3.15 (− 3.34)	0.11 (0.10)
Congenital, familial and genetic disorders	10,010,331	147	0.11 (0.09–0.13)	0.11 (0.09–0.13)	1070.82	− 3.17 (− 3.40)	0.11 (0.09)

Based on the frequency of PT occurrences and EBGM values, the top 30 ranks were listed in Tables 5 and 6, respectively. By occurrence frequency (Table 5), the top 10 PTs included Pruritus, Product use in unapproved indication, Rash, Product dose omission issue, Dermatitis atopic, Injection site pain, Product use issue, Eczema, Dry skin, and Condition aggravated. High incidence rates of Product use in unapproved indication, Product dose omission issue, Incorrect dose administered, Product dose omission in error, and Accidental exposure to product suggest serious issues with product indications and improper use and handling, which should be clinically emphasized. From the EBGM value ranking in Table 6, although AEs like Conjunctival papillae, Periorbital dermatitis, and Cutaneous T-cell lymphoma stage III were not highly frequent, their signal strength was significant, indicating they may be new potential AE signals.

Table 5.

The top 50 AEs of Dupilumab ranked by case reports.

SOC	PTs	Case Reports	ROR (95% CI)	PRR (95% CI)	χ2	IC (IC025)	EBGM (EBGM05)
Skin and subcutaneous tissue disorders	Pruritus	19,061	7.13 (7.02–7.24)	6.90 (6.80–7.00)	86,178.74	2.64 (2.62)	6.26 (6.16)
Injury, poisoning and procedural complications	Product use in unapproved indication	18,805	7.07 (6.96–7.17)	6.84 (6.74–6.94)	84,079.06	2.63 (2.61)	6.21 (6.11)
Skin and subcutaneous tissue disorders	Rash	17,302	5.17 (5.09–5.25)	5.02 (4.95–5.10)	51,582.41	2.23 (2.21)	4.69 (4.62)
Injury, poisoning and procedural complications	Product dose omission issue	16,199	3.51 (3.45–3.57)	3.43 (3.38–3.48)	26,531.41	1.72 (1.69)	3.29 (3.24)
Skin and subcutaneous tissue disorders	Dermatitis atopic	14,885	557.25 (528.81–587.22)	540.72 (513.20–569.72)	756,704.62	5.69 (5.66)	51.90 (49.25)
General disorders and administration site conditions	Injection site pain	12,531	6.96 (6.83–7.09)	6.81 (6.68–6.93)	55,609.42	2.63 (2.60)	6.18 (6.07)
Injury, poisoning and procedural complications	Product use issue	10,575	7.38 (7.23–7.53)	7.25 (7.10–7.39)	50,616.65	2.71 (2.68)	6.53 (6.40)
Skin and subcutaneous tissue disorders	Eczema	8653	44.04 (42.81–45.29)	43.29 (42.10–44.52)	202,249.76	4.63 (4.60)	24.91 (24.22)
Skin and subcutaneous tissue disorders	Dry skin	8442	6.62 (6.47–6.77)	6.53 (6.38–6.67)	35,502.60	2.57 (2.54)	5.95 (5.82)
General disorders and administration site conditions	Condition aggravated	7653	2.95 (2.88–3.02)	2.92 (2.85–2.99)	9234.73	1.50 (1.46)	2.83 (2.76)
Musculoskeletal and connective tissue disorders	Arthralgia	7391	2.25 (2.20–2.31)	2.24 (2.18–2.29)	4888.89	1.13 (1.10)	2.19 (2.14)
Eye disorders	Dry eye	6125	21.29 (20.67–21.93)	21.04 (20.44–21.67)	85,186.01	3.96 (3.92)	15.59 (15.14)
Injury, poisoning and procedural complications	Inappropriate schedule of product administration	5887	2.49 (2.43–2.56)	2.47 (2.41–2.54)	4972.40	1.27 (1.23)	2.41 (2.35)
Skin and subcutaneous tissue disorders	Skin exfoliation	5494	7.30 (7.09–7.51)	7.23 (7.03–7.43)	26,176.67	2.70 (2.66)	6.52 (6.34)
Skin and subcutaneous tissue disorders	Erythema	5443	2.97 (2.89–3.05)	2.95 (2.87–3.03)	6679.33	1.51 (1.47)	2.85 (2.77)
Eye disorders	Eye pruritus	5389	30.11 (29.13–31.13)	29.80 (28.84–30.80)	98,140.13	4.30 (4.26)	19.83 (19.19)
Respiratory, thoracic and mediastinal disorders	Asthma	5297	6.34 (6.16–6.52)	6.28 (6.11–6.46)	21,199.14	2.52 (2.48)	5.75 (5.59)
General disorders and administration site conditions	Injection site erythema	4833	8.22 (7.97–8.47)	8.15 (7.91–8.39)	26,505.27	2.85 (2.81)	7.24 (7.03)
General disorders and administration site conditions	Injection site swelling	4823	12.06 (11.69–12.44)	11.95 (11.59–12.33)	39,965.84	3.32 (3.28)	10.03 (9.73)
Psychiatric disorders	Sleep disorder	4624	9.20 (8.91–9.49)	9.12 (8.84–9.41)	28,801.40	3.00 (2.95)	7.99 (7.74)
Eye disorders	Ocular hyperaemia	4486	15.53 (15.02–16.05)	15.40 (14.90–15.92)	47,468.25	3.62 (3.57)	12.31 (11.91)
Injury, poisoning and procedural complications	Incorrect dose administered	4309	2.43 (2.36–2.51)	2.42 (2.35–2.50)	3458.08	1.24 (1.19)	2.36 (2.29)
General disorders and administration site conditions	Therapeutic response decreased	4109	11.31 (10.94–11.70)	11.23 (10.86–11.61)	31,938.24	3.25 (3.20)	9.53 (9.21)
Eye disorders	Eye irritation	3843	10.50 (10.14–10.87)	10.43 (10.08–10.79)	27,660.10	3.16 (3.11)	8.95 (8.65)
Infections and infestations	Conjunctivitis	3791	38.59 (37.02–40.22)	38.30 (36.76–39.91)	81,991.11	4.53 (4.47)	23.20 (22.26)
Eye disorders	Vision blurred	3182	3.41 (3.29–3.54)	3.40 (3.28–3.52)	5082.17	1.70 (1.65)	3.26 (3.14)
Injury, poisoning and procedural complications	Product dose omission in error	3025	18.66 (17.91–19.44)	18.55 (17.81–19.33)	37,799.99	3.82 (3.76)	14.20 (13.63)
Injury, poisoning and procedural complications	Accidental exposure to product	2859	3.06 (2.95–3.18)	3.05 (2.94–3.16)	3739.16	1.56 (1.50)	2.94 (2.83)
General disorders and administration site conditions	Discomfort	2751	5.74 (5.51–5.97)	5.71 (5.49–5.94)	9712.91	2.40 (2.34)	5.28 (5.07)
General disorders and administration site conditions	Injection site pruritus	2743	7.71 (7.40–8.02)	7.67 (7.37–7.98)	14,011.42	2.78 (2.72)	6.87 (6.60)

Table 6.

The top signal strength of AEs of Dupilumab ranked by EBGM at the PTs level.

SOC	PTs	Case reports	ROR (95% CI)	PRR (95% CI)	χ2	IC (IC025)	EBGM (EBGM05)
Skin and subcutaneous tissue disorders	Rebound atopic dermatitis	250	2011.95 (949.32–4264.04)	2010.94 (948.85–4261.87)	13,679.69	5.51 (5.26)	55.75 (26.30)
Skin and subcutaneous tissue disorders	Rebound eczema	329	772.37 (510.32–1168.99)	771.87 (510.00–1168.20)	17,220.82	5.52 (5.30)	53.41 (35.29)
Skin and subcutaneous tissue disorders	Dermatitis atopic	14,885	557.25 (528.81–587.22)	540.72 (513.20–569.72)	756,704.62	5.69 (5.66)	51.90 (49.25)
Eye disorders	Conjunctival papillae	6	168.92 (34.09–836.95)	168.92 (34.09–836.94)	250.39	2.60 (1.14)	42.98 (8.67)
Eye disorders	Periorbital irritation	104	91.52 (67.03–124.95)	91.50 (67.02–124.92)	3546.27	4.73 (4.37)	35.48 (25.98)
Eye disorders	Periorbital dermatitis	10	80.44 (30.62–211.33)	80.44 (30.62–211.32)	323.03	3.07 (1.96)	33.71 (12.83)
General disorders and administration site conditions	Injection site dryness	261	70.02 (58.38–83.97)	69.98 (58.36–83.92)	7912.68	4.83 (4.60)	31.76 (26.48)
Surgical and medical procedures	Nasal polypectomy	45	66.68 (43.30–102.70)	66.68 (43.30–102.69)	1332.85	4.22 (3.69)	31.07 (20.17)
General disorders and administration site conditions	Injection site exfoliation	198	65.22 (53.15–80.03)	65.20 (53.13–80.00)	5800.18	4.74 (4.48)	30.75 (25.06)
General disorders and administration site conditions	Injection site eczema	54	64.70 (43.76–95.66)	64.69 (43.76–95.64)	1575.77	4.31 (3.82)	30.64 (20.72)
Eye disorders	Eczema eyelids	123	64.14 (49.53–83.06)	64.13 (49.52–83.04)	3573.61	4.62 (4.30)	30.51 (23.56)
Eye disorders	Eyelid skin dryness	297	51.17 (43.73–59.88)	51.14 (43.71–59.84)	7651.43	4.65 (4.44)	27.28 (23.31)
Eye disorders	Atopic keratoconjunctivitis	10	46.92 (20.27–108.61)	46.92 (20.27–108.60)	245.15	2.97 (1.91)	26.05 (11.25)
Skin and subcutaneous tissue disorders	Neurodermatitis	292	45.70 (39.16–53.33)	45.67 (39.14–53.29)	7044.59	4.56 (4.36)	25.66 (21.99)
Skin and subcutaneous tissue disorders	Eczema	8653	44.04 (42.81–45.29)	43.29 (42.10–44.52)	202,249.76	4.63 (4.60)	24.91 (24.22)
Infections and infestations	Conjunctivitis	3791	38.59 (37.02–40.22)	38.30 (36.76–39.91)	81,991.11	4.53 (4.47)	23.20 (22.26)
Eye disorders	Ocular surface disease	67	38.11 (27.95–51.97)	38.11 (27.95–51.96)	1443.79	4.12 (3.70)	23.13 (16.96)
Eye disorders	Periorbital inflammation	50	37.05 (25.93–52.94)	37.04 (25.92–52.93)	1057.69	3.99 (3.51)	22.74 (15.91)
Eye disorders	Eyelids pruritus	514	36.90 (33.02–41.25)	36.87 (32.99–41.20)	10,839.51	4.44 (4.29)	22.68 (20.29)
Respiratory, thoracic and mediastinal disorders	Chronic rhinosinusitis with nasal polyps	18	36.20 (20.02–65.44)	36.20 (20.02–65.44)	374.98	3.38 (2.60)	22.42 (12.40)
Ear and labyrinth disorders	Ear dryness	7	35.83 (13.89–92.43)	35.83 (13.89–92.43)	144.84	2.59 (1.37)	22.29 (8.64)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Cutaneous T-cell lymphoma stage III	7	35.83 (13.89–92.43)	35.83 (13.89–92.43)	144.84	2.59 (1.37)	22.29 (8.64)
Eye disorders	Vernal keratoconjunctivitis	10	35.19 (15.97–77.55)	35.19 (15.97–77.55)	204.43	2.90 (1.87)	22.04 (10.00)
Eye disorders	Giant papillary conjunctivitis	8	34.65 (14.36–83.60)	34.65 (14.36–83.60)	161.84	2.70 (1.56)	21.83 (9.05)
Skin and subcutaneous tissue disorders	Skin weeping	540	34.20 (30.73–38.06)	34.16 (30.70–38.02)	10,819.98	4.38 (4.23)	21.64 (19.45)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	Cutaneous T-cell lymphoma stage IV	12	33.78 (16.52–69.11)	33.78 (16.52–69.11)	238.60	3.04 (2.10)	21.49 (10.51)
Skin and subcutaneous tissue disorders	Eczema weeping	18	31.67 (17.78–56.43)	31.67 (17.78–56.42)	342.19	3.33 (2.55)	20.63 (11.58)
Eye disorders	Eye pruritus	5389	30.11 (29.13–31.13)	29.80 (28.84–30.80)	98,140.13	4.30 (4.26)	19.83 (19.19)
Eye disorders	Eyelid rash	175	28.49 (23.75–34.17)	28.48 (23.74–34.16)	3081.45	4.12 (3.87)	19.25 (16.05)
Surgical and medical procedures	Lung volume reduction surgery	3	28.15 (7.04–112.57)	28.15 (7.04–112.57)	52.38	1.77 (0.06)	19.10 (4.78)

When comparing with prior clinical trial data^23,24, the incidence of common AEs like Pruritus, Rash, and Dermatitis atopic in our FAERS—based analysis was generally in line with what was reported. For example, Castro et al.'s study on Dupilumab in moderate—to—severe asthma patients showed that skin—related AEs were frequently observed. However, the frequency of “Product use in unapproved indication” and “Product dose omission issue” was much higher in our FAERS data, which might be due to the real—world nature of the database, reflecting issues in clinical practice that may not be fully captured in controlled trials. Regarding the newly identified potential AEs such as Dry eye, Eye pruritus, and Ocular hyperaemia, a review of previous post—marketing studies²⁵ found some scattered reports, but the signal strength and frequency in our study were more prominent.

Discussion

Bronchial asthma is a heterogeneous disease characterized by chronic airway inflammation, airway hyperresponsiveness, and variable airflow obstruction. Due to issues such as air pollution, the incidence of asthma has been increasing globally²⁶. It is estimated that there are at least 300 million asthma patients worldwide, with the 2019 China Pulmonary Health (CPA) study showing an overall asthma prevalence of 4.2% in China, equating to approximately 45.7 million patients²⁷. Currently, asthma control levels in China are not ideal, with an overall control rate of only 28.5%²⁸. High doses of inhaled corticosteroids (ICS) and/or oral corticosteroids (OCS) are crucial for controlling severe asthma, yet about 44% of severe asthma patients fail to achieve effective control, leading to increased risks of osteoporosis, cataracts, and other related complications. This situation consumes significant medical resources and expenses, placing a heavy burden on patients’ families and society²⁸.

Research indicates that IL-4 and IL-13 are key targets driving diseases such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and nodular prurigo²⁹. The interaction of IL-4 and IL-13 with the IL-4Ra receptor subunit can stimulate the production of immunoglobulin E and airway remodeling mediators. Additionally, IL-13 regulates nitric oxide production in the respiratory system, increases mucus production, and enhances smooth muscle contractility³⁰. Dupilumab, a fully human monoclonal antibody (IgG4 type), inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4Rα subunit shared by IL-4 and IL-13 receptor complexes, blocking IL-4Rα and inhibiting the inflammatory response induced by these cytokines, including the release of pro-inflammatory cytokines, chemokines, nitric oxide, and IgE. However, the exact mechanism of Dupilumab is not yet fully understood. Currently, Dupilumab is indicated for maintenance treatment of asthma in adolescents and adults aged 12 years and older, particularly for: (1) patients with asthma characterized by type 2 inflammation (elevated eosinophils and/or FeNO) who remain inadequately controlled despite medium- to high-dose ICS combined with other asthma control medications; (2) OCS-dependent asthma patients. The 2020 GINA guidelines recommend biologics like Dupilumab for step 5 asthma treatment, emphasizing its ability to reduce acute exacerbations and lower ICS doses³¹.

A phase III randomized, double-blind, placebo-controlled study³² in patients aged 12 years and older with uncontrolled moderate-to-severe asthma used 200 mg Dupilumab (loading dose 400 mg) or 300 mg Dupilumab (loading dose 600 mg) every 2 weeks for 52 weeks. The results showed that Dupilumab significantly reduced the annual exacerbation rate of moderate-to-severe asthma and comorbid perennial allergic rhinitis (PAR), rapidly and persistently improved FEV1, and enhanced asthma control as measured by the Asthma Control Questionnaire (ACQ-5). Additionally, Dupilumab significantly reduced specific IgE concentrations in patients with baseline allergen-specific IgE positivity compared to placebo, supporting its inhibitory effect on IgE-mediated allergic inflammatory responses³².

Dupilumab was only approved for asthma indication in China in 2023, and the number of clinical treatment cases remains limited. Cohort studies on Dupilumab for asthma treatment in China are rare. According to a study by Li et al.³³ on 20 severe asthma patients treated with Dupilumab at the First Affiliated Hospital of Guangzhou Medical University from 2019 to 2022, the treatment showed good initial efficacy for type 2 inflammation phenotype severe asthma. Patients showed significant improvements in asthma control levels and lung function compared to before treatment, along with a significant reduction in OCS dosage, consistent with the findings of Castro M et al.³. For patients with a history of biological therapy, whether they responded well or poorly to monoclonal antibodies, switching to Dupilumab for four months resulted in significant improvements in asthma control levels and lung function, along with a significant reduction in OCS dosage, all with statistical significance³³. Additionally, the study³³ found few adverse reactions to Dupilumab, with observed reactions including significant eosinophilia (2 cases), but no evidence of organ damage due to elevated eosinophils. Other reactions were mainly injection site rashes (3 cases), headaches (1 case), which were alleviated with antihistamines or rest, with no other serious adverse reactions observed.

This study conducted an in-depth analysis of FAERS database data from Q2 2017 to Q4 2023, identifying a series of AE signals related to Dupilumab. The clinical relevance of these identified signals will be discussed in detail, assessing their impact on existing treatment guidelines, and proposing improvements to data quality.

Analysis of Dupilumab report composition

This study found that the number of reports from female patients exceeded those from male patients. This may reflect a higher prevalence of bronchial asthma in females or differences in drug reactions or reporting behavior between genders. The increasing trend in the number of reports over the years could be associated with a rise in drug usage, increased public awareness of reporting, or improvements in the reporting system. Physicians accounted for more than half of the reporting sources, indicating their higher awareness of drug reactions. The significantly higher proportion of reports from the United States may reflect its robust drug monitoring system and high public participation. Most AE reports were classified as non-serious, suggesting a favorable safety profile for Dupilumab in clinical treatment.

Regarding the timing of AEs, a significant proportion occurred within 30 days of medication use, indicating the need for close monitoring of patient reactions during the initial treatment period. Additionally, the possibility of AEs occurring after long-term use underscores the importance of long-term follow-up. However, the lack or abnormality of AE timing in 85.64% of the reports highlights issues with data completeness and accuracy, potentially affecting our comprehensive understanding of Dupilumab’s safety. These findings provide critical information about the safety profile of Dupilumab and emphasize the need to improve drug monitoring systems, particularly in data collection methods and reporting quality.

Known AEs

This study identified 307 PTs across 27 SOCs for Dupilumab through signal mining in the FAERS database. The incidence of AEs in most SOC categories matched the information recorded in Dupilumab’s package insert. In the PT frequency rankings, the high frequency of "Product use in unapproved indication" and "Product dose omission issue" is particularly notable, ranking second and fourth among all AEs, respectively. This indicates a widespread issue of inappropriate use of Dupilumab, highlighting the need for it to be prescribed by healthcare professionals with experience in diagnosing and treating its indications to prevent misuse and avoid missed doses. Additionally, the high frequency of AEs such as pruritus, rash, and atopic dermatitis aligns with common comorbidities in bronchial asthma patients, further validating the accuracy of the data provided by the pharmaceutical manufacturers. When comparing with JAK inhibitors used in atopic dermatitis, although both are systemic therapies, their AE profiles show some differences. For example, JAK inhibitors may have unique AEs related to their mechanism of action, such as an increased risk of infections due to immunosuppression^34,35. In contrast, Dupilumab has a different mechanism targeting IL-4Rα, and its AEs, like the newly discovered eye—related AEs, may be related to abnormal immune regulation in specific tissues.

Biological mechanisms and clinical impact of newly discovered potential AEs

Eye-related AEs

Eye-related AEs such as Dry eye, Ocular hyperaemia, Eye irritation, Conjunctivitis, and Vision blurred are common with Dupilumab. The mechanisms are not entirely clear but may include:Abnormal immune regulation of the ocular mucosa, where Th2 pathway inhibition by Dupilumab could lead to increased Th1/Th17 polarization, exacerbating Th1/Th17-dependent immune responses³⁶. This includes an increase in peripheral blood eosinophils, a hallmark of allergic conjunctivitis. Dupilumab blocks IL-4 and IL-13 signaling, increasing the activity of ligands like OX40 ligand associated with allergic ocular surface diseases, which are related to conjunctival papillary inflammatory responses³⁷. A study by Bakker et al. on conjunctival biopsy specimens from patients with Dupilumab-related conjunctivitis revealed a significant decrease in conjunctival epithelial goblet cells and an increase in T cells and eosinophils. This suggests that Dupilumab could reduce goblet cells and mucin, destabilizing the tear film and impairing the mucosal epithelial barrier function³⁸. However, goblet cell density normalized after discontinuing the drug for four months³⁹. Thyssen et al.⁴⁰ suggested that Dupilumab might exacerbate demodex infestation and IL-17 mediated ocular inflammation, causing meibomian gland dysfunction.These findings indicate a need to monitor ocular reactions during Dupilumab treatment and conduct timely ophthalmologic examinations for new or worsening eye symptoms.

Disease exacerbation and reduced therapeutic response

Like all therapeutic proteins, Dupilumab may be immunogenic, leading to disease exacerbation and reduced therapeutic response. In a study by Castro et al.³, involving 1,264 adults with inadequately controlled moderate-to-severe asthma, 52 reported elevated blood eosinophil levels, and 4 experienced serious AEs such as eosinophilia and chronic eosinophilic pneumonia exacerbation, leading to discontinuation. This may be explained by the persistence of Th2A cell clusters producing eosinophil chemoattractant IL-5⁴¹.

Drug use-related AEs

High incidences of Product use in unapproved indication and Product dose omission in error indicate that physicians may lack experience with Dupilumab, necessitating further education on its indications and contraindications. Issues like Product dose omission issue, Product use issue, and Inappropriate schedule of product administration suggest a need for better communication with patients about correct, regular, and sufficient drug use. Some issues might stem from patient non-compliance, such as forgetting injections or intentionally reducing doses due to concerns about side effects or misunderstanding the drug’s effects. Educating patients on asthma and Dupilumab can enhance treatment adherence, reduce oral steroid use, lower asthma exacerbation rates, and improve quality of life.

Sleep-related AEs

While Dupilumab was the first biologic approved for atopic dermatitis, showing excellent results in improving pruritus and sleep within two weeks, it may paradoxically affect sleep in some cases. The incidence of sleep-related side effects is currently unknown. A study by Alroobaea et al.⁴² using data from the WHO VigiBase™ database found that sleep-related AEs were rare, with only general sleep disorders and nighttime breathing difficulties showing statistical significance, suggesting that Dupilumab may not improve sleep quality in all patients, highlighting the need for individualized treatment/management.

Limitations

Despite providing important data for the safety assessment of Dupilumab, this study has limitations. The FAERS database relies on spontaneous reports, which may contain reporting biases, including but not limited to completeness, accuracy, and timeliness, potentially affecting the representativeness and generalizability of conclusions. To reduce reporting bias, we took several approaches. First, we cross—referenced the FAERS data with other available data sources when possible. For example, we compared the AE reports related to Dupilumab in FAERS with data from clinical trials and observational studies in the literature to identify any discrepancies or additional patterns. Second, we developed a standardized review process for the collected reports. A team of researchers with expertise in pharmacovigilance and dermatology reviewed each report to ensure that the information was accurately interpreted and classified. This process helped to minimize misclassification of AEs and improved the reliability of the data. However, it should be noted that these methods have their own limitations, and future studies should focus on more rigorous case verification processes and validation analyses using other databases to enhance the reliability of findings.

Conclusion

This study provides a comprehensive analysis of AEs associated with Dupilumab use, revealing that most related AEs are non-serious and occur mainly within 30 days of drug use. Although Dupilumab shows good efficacy for bronchial asthma in clinical trials, issues such as Pruritus, Product use in unapproved indication, Rash, Product dose omission issue, Dermatitis atopic, Injection site pain, Product use issue, Eczema, Dry skin, and Condition aggravated have been identified. The high incidence of Product use in unapproved indication, Product dose omission issue, Incorrect dose administered, and Product dose omission in error underscores the serious issues of inappropriate use and operation, warranting clinical attention. These findings emphasize the importance of detailed patient monitoring during Dupilumab use and the necessity of individualized treatment plans.

To better manage patients on Dupilumab, several actionable guidance measures are recommended. For monitoring strategies, a baseline ophthalmological examination should be conducted before starting treatment, including assessments of visual acuity, tear film stability, and conjunctival and corneal status. During treatment, patients should be regularly asked about eye symptoms at each follow-up visit, and a comprehensive ophthalmological examination should be arranged promptly if any issues are reported. In addition to eye—related monitoring, vital signs and general conditions should be closely observed during the initial 30—day treatment period and long—term follow—up, with appropriate laboratory tests performed based on the patient’s condition.

Regarding patient education, healthcare providers should ensure patients fully understand the correct injection technique, the importance of adhering to the prescribed dosing schedule, and the approved indications of Dupilumab. Written educational materials can be provided, and patients should be encouraged to ask questions. Regular follow—up appointments are also crucial for reinforcing this education.

For the early identification and management of AEs, patients should be educated to recognize the early signs of potential AEs, especially eye—related symptoms like dryness, itching, or redness, and report them immediately. Once reported, healthcare providers should conduct a timely evaluation. Mild AEs such as mild injection—site reactions or transient skin rashes can be managed with simple supportive measures, while severe AEs like severe allergic reactions or disease exacerbations require immediate medical intervention. These measures can help improve the safety and effectiveness of Dupilumab treatment in clinical practice.

Author contributions

Hui Gao and Chengying Liu conceived the study; Hui Gao, Liqiang Cao and Chengying Liu collected the report; Hui Gao and Chengying Liu wrote the manuscript and edited the manuscript. All authors have approved publishment of the manuscript.

Data availability

The dataset generated during and analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare no competing interests.