Disproportionality analysis of ixekizumab-associated adverse events in the FAERS database: A real-world pharmacovigilance study

Abstract

Ixekizumab, a monoclonal antibody that neutralizes interleukin-17A, was approved by the Food and Drug Administration in 2016 for the treatment of plaque psoriasis and psoriatic arthritis. This study assesses the postmarketing safety profile of ixekizumab. Data from the Food and Drug Administration Adverse Event Reporting System were analyzed using disproportionate analysis methods, including the reporting odds ratio, the proportional reporting ratio, the Bayesian confidence propagation neural network, and the multi-item gamma Poisson shrinker algorithms. A total of 26,867 reports identified ixekizumab as the “primary suspected” drug. These ixekizumab-related adverse events (AEs) were observed across 27 targeted system organ classes. Notably, upon satisfying the criteria of all 4 algorithms, we identified 23,595 signals spanning 167 preferred terms. The most common signals were injection site reaction (broad), psoriasis, COVID-19, nasopharyngitis, urticaria, and sinusitis. New AEs identified include ear infections, tooth infections, necrotizing fasciitis, lichen planus, and pyoderma gangrenosum. The number of reports exhibited significant monthly fluctuations. There was a noticeable downward trend in reports each May, whereas December consistently showed an increase in reports. In recent report data, a trend of decrease has been observed starting from 2023. While our findings align with clinical trial results and the product label, our data revealed some new AEs. Noteworthy is the decline in reports starting from 2023.

1. Introduction

Ixekizumab (IXE), marketed under the trade name Taltz, is a humanized immunoglobulin G4 monoclonal antibody specifically designed to target and neutralize interleukin-17A (IL-17A).^[1] Primarily used in the treatment of psoriasis, IXE offers substantial advantages over first-generation cytokine antagonists that inhibit tumor necrosis factor-alpha (TNF-α)-dependent pathways. IXE has demonstrated enhanced efficacy in a significant proportion of patients with psoriasis,^[2,3] particularly in terms of the rapid onset and long-term sustainability of its therapeutic effects.^[4,5] IXE received its initial approval from the U.S. Food and Drug Administration (FDA) in March 2016 for the treatment of moderate-to-severe plaque psoriasis in adults.^[6,7] The therapeutic indications for IXE have expanded to include psoriatic arthritis, active ankylosing spondylitis, and non-radiographic axial spondyloarthritis.^[8–10]

Psoriasis is an immune-mediated skin disease affecting approximately 2% of the global population, significantly impacting patients’ quality of life and work productivity.^[11] The pathogenesis of psoriasis is driven by the overactivity of Th17 cells, which secrete pro-inflammatory cytokines including IL-17A, interleukin-22, and TNF-α. IL-17A, a pivotal cytokine, induces keratinocytes to release additional cytokines, exacerbating inflammation and promoting skin cell proliferation.^[12,13] IXE specifically binds to IL-17A, preventing its interaction with receptors, thereby reducing the inflammatory response and hyperproliferation associated with psoriasis. This targeted mechanism alleviates symptoms, leading to significant improvements in patient outcomes.^[14–16]

Clinical trials have established safety profile of IXE. In 2 phase 3 studies conducted by Dougados et al, adverse events (AEs) were reported by 61.1% of patients in the COAST (Clinical Outcomes in Ankylosing Spondylitis Trials)-V study and 63.7% in the COAST-W study. Furthermore, 2.4% of patients in the COAST-V study and 3.6% in the COAST-W study discontinued treatment due to AEs.^[10] Clinical studies reveal that 58.6% to 85% of patients treated with IXE experienced at least one AE.^[4,17,18] These studies indicate that although the majority of AEs are not severe enough to necessitate discontinuation of treatment, the occurrence of AEs is relatively common. As IXE expands its indications in clinical settings, there is a critical need to thoroughly investigate the adverse drug reactions (ADRs) of IXE. This study aims to rigorously evaluate the safety of IXE by utilizing updated AE reports from the FDA Adverse Event Reporting System (FAERS) database, thereby providing valuable references for its clinical application and future research.

2. Materials and methods

2.1. Data source

The FAERS database includes 7 types of data: patient demographic and administrative information, drug information, coded adverse events, patient outcomes, report sources, therapy start and end dates for reported drugs, and indications for drug administration. In our study, we analyzed FAERS database records from the first quarter of 2016 to the first quarter of 2024, initially comprising 13,611,553 reports. Data were imported into MySQL 8.0, and to manage duplicates, we applied FDA guidelines^[19,20]: selecting the most recent FDA_DT and the highest PRIMARYID for identical CASEIDs, which reduced the dataset to 11,663,277 unique cases.

2.2. Adverse event and drug identification

The extracted data were encoded using the medical dictionary for regulatory activities (MedDRA). The structure of the MedDRA terminology consists of 5 levels: system organ class (SOC), high-level group term, high-level term, preferred term (PT), and lowest-level term.^[21,22] In the FAERS database, there are 4 types of reports: primary suspected (PS), secondary suspected, concomitant, and interacting.^[23] We then focused on identifying IXE-associated AEs by using the search terms “Ixekizumab” and “Taltz.” We retained reports where IXE was listed as PS in the drug information files. We collected data on the clinical characteristics of patients with IXE-associated AEs, including sex, age, reported country (top 5), event date, and serious adverse events (SAEs). SAEs included death, life-threatening, hospitalization, and disability.

2.3. Data mining

Disproportionality analysis is a widely utilized method in pharmacovigilance investigations.^[24] In this study, it was employed to identify potential signals between IXE and all reported AEs. A signal is considered positive when the incidence of a specific AE associated with the drug significantly exceeds the background frequency in the database, reaching a predefined threshold within a specified period. Four algorithms (detailed formulas and thresholds can be found in Table 1) were used to evaluate the potential association between IXE and AEs: the reporting odds ratio (ROR), the proportional reporting ratio, the Bayesian confidence propagation neural network, and the multi-item gamma Poisson shrinker (see Fig. 1 for the specific data processing workflow). Among these, the ROR is a primary indicator for assessing signal strength; a higher ROR value indicates a stronger signal and a higher likelihood of an AE being associated with the drug. All data processing and statistical analyses were conducted using MySQL 8.0, Navicat Premium 15, Microsoft Excel 2019, and GraphPad Prism 8 (GraphPad Software, CA, USA).

Table 1.

Four main algorithms are used to evaluate the association between ixekizumab and adverse events.

Algorithms	Equation	Criteria
ROR	ROR = ad/b/c 95% CI = eln(ROR)±1.96(1/a+1/b+1/c+1/d)0.5	Lower limit of 95% CI > 1, N ≥ 3
PRR	PRR = a(c + d)/c/(a + b) χ2 = [(ad − bc)2](a + b + c + d)/[(a + b)(c + d)(a + c)(b + d)]	PRR ≥ 2, χ2 ≥ 4, N ≥ 3
BCPNN	IC = log2a(a + b + c + d)(a + c)(a + b) 95% CI = E(IC) ± 2V(IC)^0.5	IC025 > 0
MGPS	EBGM = a(a + b + c + d)/(a + c)/(a + b) 95% CI = eln(EBGM)±1.96(1/a+1/b+1/c+1/d)0.5	EBGM05 > 2

a, number of reports containing both the target drug and target adverse drug reaction; b, number of reports containing other adverse drug reactions of the target drug; c, number of reports containing the target adverse drug reaction of other drugs; d, number of reports containing other drugs and other adverse drug reactions.

95% CI = 95% confidence interval; BCPNN = Bayesian confidence propagation neural network; EBGM = empirical Bayesian geometric mean; EBGM05 = lower limit of 95% CI, of EBGM; E(IC) = IC, expectations; IC = information component; IC025 = lower limit of 95% CI, of the IC; MGPS = the multi-item gamma Poisson shrinker; N = number of reports; PRR = proportional reporting ratio; V(IC) = variance of IC; χ2 = Chi-squared.

Figure 1.

The process of selecting ixekizumab-associated adverse events from Food and Drug Administration Adverse Event Reporting System. BCPNN = Bayesian confidence propagation neural network; DEMO = patient demographic and administrative information; DRUG = drug information; MGPS = the multi-item gamma Poisson shrinker; PRR = proportional reporting ratio; PS = primary suspect; REAC = coded for the adverse events; ROR = reporting odds ratio.

3. Results

3.1. Descriptive analysis

From the first quarter of 2016 to the first quarter of 2024, the FAERS database recorded 26,867 reports in which IXE was identified as the PS drug. The gender distribution of these reports was notably skewed, with 14,877 (55.5%) reports involving women and 9689 (36.0%) involving men. Among cases with available age data, most patients were aged 18 to 65 years (10,666 cases, 81.4%), followed by those over 65 (2225 cases, 17.0%) and under 18 (219 cases, 1.7%). Among cases with known outcomes, hospitalization was reported in 1851 cases (76.3%), followed by 381 deaths (15.7%), 117 life-threatening events (4.8%), and 76 disabilities (3.1%). Geographically, the vast majority of reports originated from the United States (94.2%, n = 25,319), followed by Germany (0.8%, n = 211), France (0.7%, n = 190), Japan (0.6%, n = 166), and China (0.4%, n = 122).

Since its launch in 2016, reports of AEs have shown significant monthly fluctuations. There is a trend of decreased reporting in May each year, contrasted with an increase in December. The annual reports of AEs are as follows (please note that these data reflect the time of AE occurrence rather than the reporting time, and thus some missing values are expected): 276 reports in 2016, 780 reports in 2017, 1020 reports in 2018, 1425 reports in 2019, 1064 reports in 2020, 1142 reports in 2021, 1231 reports in 2022, and a decrease to 980 reports in 2023 (refer to Table 2). The data depicted in the figure show that at the beginning of 2020 and 2023, there has been an overall month decline in AE reporting, albeit with some fluctuations during the descent (see Fig. 2). Injection site pain, the most frequently reported AE associated with IXE, showed a fluctuating trend over the years. A total of 73 cases were reported in 2016, increasing to 228 in 2017, 285 in 2018, and 361 in 2019. The number remained relatively stable in 2020 with 359 cases. Reports then rose sharply to 570 in 2021 and peaked at 961 cases in 2022, before declining to 300 cases in 2023.

Table 2.

Baseline characteristics of patients with ixekizumab-associated adverse events from the Food and Drug Administration Adverse Event Reporting System.

Characteristics	Case number (n)	Case proportion (%)
Total	26,867	–
Gender
Male	9689	36.0
Female	14,877	55.5
Unknown	2301	8.5
Age (yr)
<18	219	0.8 (1.7)*
18–65	10,666	40.0 (81.4)*
>65	2225	8.2 (17)*
Unknown	13,757	51.2
Outcome
Death	381	1.4 (15.7)*
Disability	76	0.3 (3.1)*
Hospitalization	1851	6.8 (76.3)*
Life-threatening	117	0.4 (4.8)*
Unknown	24,442	91
Event occurrence year
2016	276	1.0 (3.4)*
2017	780	2.9 (9.7)*
2018	1020	3.7 (12.7)*
2019	1425	5.3 (17.7)*
2020	1064	3.9 (13.2)*
2021	1142	4.2 (14.2)*
2022	1231	4.5 (15.3)*
2023	980	3.6 (12.2)*
2024 (only the first quarter)	145	0.5 (1.8)*
Unknown	18,804	70.0
Reported countries (top 5)
United States	25,319	94.2
German	211	0.8
France	190	0.7
Japan	166	0.6
China	122	0.4

^*Percentages in parentheses represent the proportion of patients within each group after excluding cases with unknown data.

Figure 2.

Number of ixekizumab-associated adverse events reported from the first quarter of 2016 to the first quarter of 2024.

3.2. Disproportionality analysis

At the SOC level, the signal strengths and reports for IXE corresponding to 27 SOCs are detailed in Table 3. Following the disproportionality analysis, AEs targeting 6 SOCs were identified, meeting the criteria of at least one of the 4 algorithms. These SOCs include general disorders and administration site condition, infections and infestations, skin and subcutaneous tissue disorders, surgical and medical procedures, immune system disorders, and congenital, familial, and genetic disorders.

Table 3.

Signal strength of adverse events of ixekizumab at the system organ class level in FDA Adverse Event Reporting System.

SOC	Cases	ROR (95% 2-sided CI)	PRR (χ2)	EBGM (EBGM05)	IC (IC025)
General disorders and administration site conditions	18,861	2.97 (2.92–3.03)	2.25 (1,5613.95)	2.25 (2.21)	1.17 (1.11)
Infections and infestations	6222	2.63 (2.57–2.71)	2.44 (5535.1)	2.43 (2.37)	1.28 (1.19)
Skin and subcutaneous tissue disorders	5455	2.11 (2.05–2.17)	1.99 (2850.77)	1.99 (1.94)	0.99 (0.9)
Injury, poisoning and procedural complications	4745	0.9 (0.87–0.92)	0.91 (51.88)	0.91 (0.88)	−0.14 (−0.24)
Gastrointestinal disorders	3231	0.76 (0.73–0.78)	0.77 (235.97)	0.77 (0.75)	−0.37 (−0.49)
Musculoskeletal and connective tissue disorders	2142	0.81 (0.77–0.84)	0.81 (96.16)	0.81 (0.78)	−0.3 (−0.44)
Surgical and medical procedures	1691	3.36 (3.2–3.53)	3.29 (2708.48)	3.28 (3.12)	1.71 (1.55)
Nervous system disorders	1567	0.45 (0.42–0.47)	0.46 (1048.93)	0.46 (0.44)	−1.11 (−1.28)
Respiratory, thoracic and mediastinal disorders	1288	0.58 (0.55–0.61)	0.59 (380.01)	0.59 (0.56)	−0.76 (−0.94)
Investigations	1097	0.43 (0.41–0.46)	0.45 (796.63)	0.45 (0.42)	−1.17 (−1.37)
Immune system disorders	761	1.42 (1.32–1.52)	1.41 (92.54)	1.41 (1.31)	0.5 (0.26)
Psychiatric disorders	741	0.31 (0.29–0.33)	0.32 (1128.55)	0.32 (0.3)	−1.65 (−1.89)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)	692	0.6 (0.56–0.65)	0.61 (179.11)	0.61 (0.56)	−0.72 (−0.97)
Eye disorders	419	0.51 (0.47–0.57)	0.52 (189.94)	0.52 (0.47)	−0.95 (−1.27)
Cardiac disorders	401	0.44 (0.4–0.49)	0.45 (277.22)	0.45 (0.41)	−1.16 (−1.49)
Vascular disorders	354	0.41 (0.37–0.46)	0.42 (290.93)	0.42 (0.38)	−1.26 (−1.61)
Renal and urinary disorders	320	0.34 (0.31–0.38)	0.35 (404.51)	0.35 (0.31)	−1.53 (−1.9)
Metabolism and nutrition disorders	310	0.36 (0.32–0.4)	0.36 (349.07)	0.36 (0.33)	−1.46 (−1.83)
Product issues	298	0.5 (0.45–0.56)	0.5 (146.24)	0.51 (0.45)	−0.99 (−1.37)
Blood and lymphatic system disorders	183	0.25 (0.22–0.29)	0.26 (400.17)	0.26 (0.22)	−1.96 (−2.45)
Hepatobiliary disorders	167	0.47 (0.4–0.55)	0.47 (99.7)	0.47 (0.41)	−1.08 (−1.59)
Ear and labyrinth disorders	162	0.79 (0.68–0.93)	0.8 (8.55)	0.8 (0.68)	−0.33 (−0.84)
Reproductive system and breast disorders	117	0.56 (0.47–0.68)	0.57 (39.18)	0.57 (0.47)	−0.82 (−1.42)
Social circumstances	81	0.54 (0.43–0.67)	0.54 (32.15)	0.54 (0.43)	−0.89 (−1.61)
Pregnancy, puerperium and perinatal conditions	42	0.48 (0.36–0.65)	0.48 (23.29)	0.48 (0.36)	−1.05 (−2.03)
Endocrine disorders	23	0.27 (0.18–0.41)	0.27 (44.77)	0.27 (0.18)	−1.88 (−3.17)
Congenital, familial and genetic disorders	14	2.03 (1.2–3.44)	2.03 (7.34)	2.03 (1.2)	1.02 (−0.6)

95% 2-sided CI = 95% confidence interval; EBGM = empirical Bayesian geometric mean; EBGM05 = the lower limit of 95% CI, of EBGM; FDA = food and drug administration; PRR = proportional reporting ratio; ROR = reporting odds ratio; SOC = system organ class; χ² = Chi-squared; IC: Information Component; IC025: the lower limit of 95% CI, of the IC.

At the PT level, AEs that met all 4 algorithmic criteria totaled 23,595 signals across 167 PTs (see Table S1, Supplemental Digital Content, https://links.lww.com/MD/P939), with the top 20 listed in Table 4. The predominant PTs included injection site reactions (broad term), psoriasis, COVID-19, urticaria, nasopharyngitis, sinusitis, ulcerative colitis, Crohn disease, rash, and pruritus. Compared to previous clinical trials, newly identified signals included necrotizing fasciitis, lichen planus, Guillain-Barre syndrome, gastrointestinal bleeding, pyoderma gangrenosum, vitiligo, impetigo, serum sickness, hordeolum, malignant melanoma, cutaneous T-cell lymphoma, invasive breast carcinoma, malignant lentigo maligna, and tuberculosis. Given that our study encompassed PTs related to medical and health issues, we also identified some signals that were deemed irrelevant, such as therapy interruption, therapy cessation, needle track marks, and underdose.

Table 4.

Signal strength of reports of ixekizumab at the preferred term level in the FDA Adverse Event Reporting System at top 20.

PTs	Cases	ROR (95% 2-sided CI)	PRR (χ2)	EBGM (EBGM05)	IC (IC025)
Injection site pain	3460	18.1 (17.48–18.74)	16.94 (51,263.68)	16.68 (16.11)	70.71 (4.01)
Psoriasis	2010	18.3 (17.5–19.15)	17.63 (31,055.4)	17.34 (16.58)	69.09 (4.05)
Injection site erythema	1925	25.39 (24.25–26.59)	24.48 (42,385.51)	23.92 (22.84)	68.5 (4.51)
Injection site swelling	1452	33.45 (31.72–35.27)	32.53 (43,028.26)	31.55 (29.92)	67.29 (4.9)
Injection site reaction	1340	33.72 (31.91–35.63)	32.86 (40,124.48)	31.86 (30.15)	67.04 (4.91)
COVID-19	726	3.16 (2.94–3.4)	3.13 (1053.04)	3.12 (2.9)	68.63 (1.54)
Product dose omission issue	660	2.53 (2.35–2.74)	2.51 (603.57)	2.51 (2.32)	68.67 (1.22)
Injection site pruritus	655	16.77 (15.52–18.13)	16.57 (9435.4)	16.32 (15.1)	65.94 (3.92)
Therapy interrupted	639	11.42 (10.56–12.36)	11.29 (5936)	11.18 (10.34)	66.42 (3.37)
Incorrect dose administered	587	3.32 (3.06–3.61)	3.3 (940.02)	3.29 (3.03)	67.94 (1.6)
Injection site urticaria	579	38.81 (35.71–42.19)	38.39 (20,317.05)	37.02 (34.05)	64.41 (5.09)
Injection site mass	525	15.73 (14.42–17.15)	15.58 (7057.81)	15.36 (14.08)	65.39 (3.82)
Injection site hemorrhage	465	8.07 (7.37–8.85)	8.01 (2833.82)	7.96 (7.26)	65.99 (2.86)
Injection site rash	448	24.21 (22.03–26.59)	24 (9650.79)	23.47 (21.36)	64.32 (4.42)
Nasopharyngitis	444	2.62 (2.39–2.88)	2.61 (440.65)	2.6 (2.37)	67.47 (1.25)
Injection site warmth	435	46.88 (42.57–51.63)	46.49 (1,8515.68)	44.49 (40.4)	63.32 (5.34)
Urticaria	409	3.73 (3.38–4.11)	3.7 (806.36)	3.69 (3.35)	66.73 (1.75)
Injection site bruising	393	6.54 (5.92–7.23)	6.5 (1820.06)	6.47 (5.85)	65.81 (2.55)
Sinusitis	369	4.17 (3.77–4.62)	4.15 (880.04)	4.14 (3.73)	66.27 (1.9)
Therapy cessation	367	8.22 (7.42–9.12)	8.17 (2293.35)	8.11 (7.32)	65.28 (2.87)

95% 2-sided CI = 95% confidence interval; EBGM = empirical Bayesian geometric mean; EBGM05 = the lower limit of 95% CI, of EBGM; FDA = food and drug administration; IC = information component; IC025 = the lower limit of 95% CI, of the IC; PRR = proportional reporting ratio; PT = preferred term; ROR = reporting odds ratio; χ² = Chi-squared.

4. Discussion

Previous studies have predominantly focused on the therapeutic efficacy of IXE, with most ADR research derived from strictly controlled clinical trials. However, there is a significant lack of post-marketing evidence on the AEs associated with IXE. This research collected AEs from the FAERS database, covering a diverse patient population and a wide range of clinical settings, thereby filling the gap in real-world studies on IXE-associated AEs.

In our data, SAEs accounted for 9.0% of reports (2425 out of 26,867). The most common SAE was hospitalization, with 1851 cases recorded. This was followed by death (381 cases), life-threatening (117 cases), and disability (76 cases). Deodhar et al summarized 4 clinical trials on IXE for the treatment of psoriatic arthritis, revealing that SAEs accounted for 134 out of 1130 AE patients (11.8%). Among these, 123 patients were hospitalized, 3 experienced life-threatening conditions, 2 were disabled, and 6 patients died.^[25] Our data shows a slightly lower incidence rate of SAEs (9.0%) compared to Deodhar et al’s findings (11.8%), possibly due to differences in study populations, follow-up duration, and treatment monitoring practices. Previous IXE clinical trials reported SAE incidence rates ranging from 7.6% to 16.7%,^[26–29] emphasizing the need for close monitoring of SAEs in clinical practice to avoid delays in treatment.

Our comprehensive database analysis of monthly AE reporting demonstrates substantial variability. Notably, a persistent downward trend in AE reports is observed each May, contrasted by an upward trend in December. Previous clinical studies have highlighted the beneficial effects of summer and sunlight on psoriasis, including the suppression of specific immune cells by ultraviolet light and the moisturizing benefits of a warm, humid climate.^[30,31] These seasonal advantages stand in stark contrast to the adverse conditions of winter, which may influence the number of patients utilizing IXE and consequently result in seasonal fluctuations in AE reports.

At the beginning of 2020, there was a sharp decline in AE reports. This period coincided with the onset of the COVID-19 pandemic, which likely contributed to the decrease in reported data. The reduction in reports may be attributed to a decrease in the use of IXE during the pandemic or limitations in reporting AEs during this time. Additionally, our data also indicates a marked decrease in AE reporting rates beginning in 2023, which coincides with the formulation change in 2022. Research by Chabra et al supports this, indicating fewer injection site pain incidents with the IXE citrate-free formulation compared to the original.^[32] As injection site pain is the most frequently reported ADR of IXE, its decline in 2023 may be related to the introduction of the new formulation.

At the SOC level, common AEs include general disorders and administration site conditions with an ROR of 2.97 (2.92–3.03), Infections and infestations with an ROR of 2.63 (2.57–2.71), and Skin and subcutaneous tissue disorders with an ROR of 2.11 (2.05–2.17). At the PT level, frequently reported PTs include injection site reactions, urticaria, nasopharyngitis, and sinusitis. These common PTs are consistent with previous clinical trial reports.^[8] Additionally, our data shows a high reporting rate of PT such as COVID-19 with an ROR of 3.16 (2.94–3.4), which may be related to the pandemic. Similarly, psoriasis has emerged as a notable PT with an ROR of 18.3 (17.5–19.15), warranting careful consideration. These findings may be influenced by reporters’ unfamiliarity with the pharmacovigilance system, potentially leading to errors such as misreporting AEs as indications. Moreover, the possibility of IXE exacerbating psoriasis should also be considered.

In our dataset, infections and infestations were among the most common AE signals observed. The most frequently reported infections included nasopharyngitis, sinusitis, influenza, cellulitis, and fungal infections, consistent with previous clinical studies.^{[27,28,33,34]} Additionally, we identified novel infection-related signals, including ear infections, tooth infections, necrotizing fasciitis, impetigo, tuberculosis, and hordeolum. Notably, in IXE clinical trials, some participants who tested negative for tuberculosis at the trial entry later tested positive; however, no cases of active tuberculosis were reported.^[25,35] In summary, respiratory tract infections remain predominant among the reported infections.

IL-17A is critical for host defense but also drives inflammatory responses. IXE, as an IL-17A neutralizing antibody, blocks IL-17A binding to its receptor, thereby reducing downstream pro-inflammatory cytokines such as interleukin-6 and TNF-α. However, this immunosuppression may impair the host’s ability to fight infections, particularly fungal and bacterial.^[36,37] Our results underscore the need for increased clinical vigilance regarding infection risks, particularly respiratory infections, in patients receiving IXE. Additionally, our data offer new signals into less commonly monitored infections in clinical trials, such as necrotizing fasciitis and impetigo. These findings are essential for clinicians to consider appropriate monitoring and preventive measures when prescribing IXE.

Skin and subcutaneous tissue disorders are also common AE signals associated with IXE treatment. Common AEs include urticaria, rash, and pruritus, which are consistent with clinical trial data.^[3,38] These findings suggest that such AEs are anticipated when using IXE treatment. Additionally, we have identified new dermatological AEs, including lichen planus, pyoderma gangrenosum, vitiligo, alopecia areata, granuloma annulare, and seborrheic dermatitis. The emergence of these new AEs raises the question of whether IXE’s immunomodulatory effects are involved or if psoriasis itself predisposes patients to autoimmune disorders. These results should be interpreted with caution, and further investigation is warranted.

In the gastrointestinal system, signal indicate that inflammatory bowel disease, including ulcerative colitis and Crohn disease, are common AEs. Yamada et al reported 12 new cases of inflammatory bowel disease among 16,690 patients treated with anti-IL-17 therapies, whereas no new cases were observed in the placebo group.^[39] Our findings are consistent with this study. Additionally, we observed new AEs such as gastrointestinal bleeding. these findings align with the known role of IL-17A in intestinal inflammation, highlighting its importance in maintaining gut barrier integrity and regulating intestinal immune responses.^[40] Past clinical trials have reported several malignancies, including nonmelanoma skin cancer, breast cancer, gastrointestinal stromal tumor, thyroid cancer, and renal cancer.^[28] Our data also report malignancy AEs such as malignant melanoma, cutaneous T-cell lymphoma, Invasive breast carcinoma, and malignant lentigo maligna. It is important to consider these new signals within the broader context of patient health, treatment duration, and possible confounding factors.

This study has several limitations. As a spontaneous reporting analysis, it cannot establish causality. The absence of a control group, substantial missing data, and potential duplicate reports limit comparative assessments. Reporting delays and inconsistencies in MedDRA coding may have affected signal detection. Regional differences in reporting behavior may also impact generalizability. These factors highlight the need for complementary real-world studies to validate these findings.

5. Conclusion

Our analysis of the safety profile of IXE, based on data from the FAERS, has provided valuable insights, revealing both expected and novel AEs. Notably, there has been a reduction in AEs following a change in the formulation. Our study offers valuable insights for clinical practice and future research, providing a robust foundation for informed decision-making.

Acknowledgments

We thank the colleagues at Suining Central Hospital, the People’s Hospital of Kaijiang, and The First Hospital of Jilin University for their support during this research. We also appreciate the data analysts and administrative personnel who facilitated access to the FAERS database. Special thanks to the patients and healthcare providers who contributed to the data used in this analysis.

Author contributions

Data curation: Guanglin Liu.

Investigation: Bing Lv.

Methodology: Bing Lv.

Supervision: Guanglin Liu.

Writing – original draft: Jia Tang.

Writing – review & editing: Jia Tang.