Table 3.

Main studies that assess the relationship between infections and anti-IL-17, IL-23, and ustekinumab

Agent	Year, authors	N	Study design	Results
IL-17 inhibitors (as a group)	2021, Davidson et al. [56]	> 1,000,000	Data from WHO and EMA and Population-based drug prescriptions registry databases Includes all diagnosis	Strong association between IL-17 inhibitors and candidiasis (ROR 10.20) was found in the WHO database, particularly for cutaneous (ROR 12.28), oropharyngeal (ROR 19.18), and esophageal candidiasis (ROR 21.20) Risk was higher relative to TNFα inhibitors (4–10-fold, depending on candidiasis type) In the psoriasis cohort, 58% of IL-17 treatment episodes were associated with candidiasis
	2022, Jin et al. [29]	123,383	Multicenter retrospective study Includes patients with Pso or PsoA Includes secukinumab and ixekizumab	Compared with ustekinumab, the combined weighted HRs (95% CI) for serious infections were 1.66 (95% CI 1.34–2.06) for adalimumab, 1.09 (95% CI 0.68–1.75) for certolizumab, 1.39 (95% CI 1.01–1.90) for etanercept, 2.92 (95% CI 1.80–4.72) for infliximab, 2.98 (95% CI 1.20–7.41) for ixekizumab, and 1.84 (95% CI 1.24–2.72) for secukinumab Other biologics were associated with a 1.4 to 3 times higher risk of hospitalization for SI in patients with Pso/PsoA when compared to ustekinumab
	2022, Feng et al. [30]	27,297	SR with MA Includes 52 RCTs Includes patients with psoriasis treated with adalimumab, infliximab, etanercept, ustekinumab, guselkumab, secukinumab, ixekizumab, and brodalumab	IL-17 agents, especially secukinumab, (95% CI 1.54–3.45,p < 0.0001) and anti-IL-12/23 agents (95% CI 1.69–3.83,p < 0.0001) were associated with an increased risk ofCandida infection compared with placebo, but there was no difference inCandida infection risk between anti-IL-17 agents and anti-TNF (95% CI 0.92–3.07, p = 0.09) There was no evidence that the biological agents increased the risk of SI in adult psoriasis (95% CI 0.93–2.06, p = 0.11) or that the biologics differed in the risk of SI
	2022, Liu et al. [57]	7106	SR with MA Includes 9 observational studies Includes patients with psoriasis	Pooled effect showed no significant differences in the rates of SARS-CoV-2 infection (p = 0.94; I2 = 19.5%), COVID-19 hospitalization (p = 0.64; I2 = 0.0%), and COVID-19 mortality (p = 0.32; I2 = 0.0%) in patients with psoriasis using IL-17 inhibitors compared with using non-biologics Use of IL-17 inhibitors in patients with psoriasis does not increase the risk of SARS-CoV-2 infection or worsen the course of COVID-19
	2023, Kim et al. [34]	40,322	Multicenter retrospective study Includes patients with AS, PsoA, and Pso	IL-17 and TNFα inhibitor users, both treatments conferred comparable risk of SI, while IL-17 inhibitors use only (OR 0.126, p = 0.0457) may be advantageous for TB
	2023, Séauve et al. [35]	20,418	SR with MA Includes 60 RCTs Includes patients with PsoA and AS	Statistically significant increased risk of infections for patients with AS (RR 1.32, 95% CI [1.14–1.52]), but not for patients with PsoA (RR 1.05, 95% CI [0.97–1.14]) Infection risk was highest with TNF inhibitors (RR 1.23, 95% CI [1.11–1.37]) and IL-17 inhibitors (RR 1.30, 95% CI [1.07–1.59]) No increased risk of SI was found
	2024, Lazaridou et al. [37]	1696	SR with MA Includes trials and observational studies Includes patients with hidradenitis suppurativa with anti-TNF, anti-IL-1, anti-PDE4, and anti-IL-17	Pooled incidence rate for any infection was 24.2%, primarily consisting of mild respiratory and skin infections Pooled incidence of 7.77% for anti-IL-1, 14.24% for anti-PDE4, and 21.96% for anti-TNF Patients receiving anti-IL-17 had the highest incidence rate of infection at 33.6%, but the relative risk compared to placebo was not significantly elevated (0.99, 95% CI 0.86–1.14) SI were rare, with pooled incidences of 0.39% for anti-IL-17 and 0.03% for anti-TNF
Secukinumab (IL-17A inhibitor)	2020, Srinivas et al. [58]	1955 new users of secukinumab (n = 848) vs. ustekinumab (n = 1107)	Multicentric retrospective study Includes patients with psoriasis	Slightly increased risk of respiratory and urinary tract infections treated in primary care among secukinumab users compared to ustekinumab users (HR 1.22, 95% CI 1.03–1.43) Non-significant differences in estimated risk of severe respiratory and urinary tract infections (HR 0.96, 95% CI 0.57–1.61) and candidiasis (HR 1.80, 95% CI 0.84–3.84) treated in the hospital setting were observed
	2021, Elewski et al. [59]	12,319	SR Includes patients with Pso, PsoA, or AS	684 patients (5.6%) had tested positive for LTBI at screening Over 5 years, LTBI as an AE during secukinumab treatment was reported in 13 patients (0.1%). Of these 13 patients, 6 had a prior positive LTBI test result, and 7 were newly diagnosed as having LTBI 4 of the 7 patients had Pso (EAIR, 0.03; 95% CI 0.01–0.07), 1 had PsoA (EAIR, 0.02; 95% CI 0.00–0.11), and 2 had AS (EAIR, 0.08; 95% CI 0.01–0.28) No cases of active TB were reported
	2023, Glintborg et al. [32]	23,938	Retrospective multicentric study Includes patients with AS and PsoA	For secukinumab, the first-year risk of hospitalized infection was 3.5% (IR 5.0; 3.9–6.3), compared with 1.7% (IR 2.3; 1.7–3.0) during 3201 courses with adalimumab, with the IRs for other anti-TNF lying in between these values Adjusted HR for adalimumab, compared with secukinumab, was 0.58 (0.39–0.85)
Ixekizumab (IL-17A inhibitor)	2019, Langley et al. [60]	5689	Pooled safety analysis of 11 RCTs Includes patients with psoriasis	Overall, the proportion of patients with any infections was 60.8% (IR [95% CI] 28.7 [27.8, 29.7]) Majority of infections reported were mild (25.4%; 12.0 [11.4, 12.6]) to moderate (32.4%; 15.3 [14.6, 16.0]) in severity. SI were reported in 3% (1.4 [1.2, 1.6]) of patients Most opportunistic infections (IR [95% CI] 1.8 [1.6, 2.1]) reported were mucocutaneous candidiasis IR (95% CI) for oral Candida infection was 0.9 (0.8, 1.1)
	2020, Genovese et al. [61]	8228	SR Includes patients with plaque psoriasis, PsoA, and AS	The most common AEs were nasopharyngitis, upper respiratory tract infection and injection-site reactions Infections were most commonly reported in the first 2 years of exposure to ixekizumab and IR decreased over the years
Brodalumab (IL-17 R inhibitor)	2017, Attia et al. [62]	4118	SR with MA Includes 6 clinical trials Includes patients with psoriasis	Rate of overall adverse events was slightly higher in the brodalumab group (RR 1.13, 95% CI 1.06–1.22) than the placebo group The most frequent infections were those of the upper respiratory tract and nasopharyngitis. Up to 4% of patients had candidiasis
	2022, Reich et al. [63]	4464	Integrated pooled data from five clinical trials Includes patients with psoriasis	The most frequently reported adverse events (≥ 3%) were nasopharyngitis and upper respiratory tract infection No Candida infections were reported
Bimekizumab (IL-17A/F inhibitor)	2023, Wang et al. [64]	2473	MA Includes 5 RCTs	The most frequently reported AEs in the bimekizumab group were infections and skin or subcutaneous tissue disorders, including nasopharyngitis (occurred in 7–10% of the patients), upper respiratory tract infection (occurred in 4–38.9% of the patients), and oral candidiasis (occurred in 2–19.3% of the patients)
	2023, Gordon et al. [65]	1495	Pooled data from up to 3 years of treatment in randomized phase 3 trials Includes patients with psoriasis	The most commonly reported AEs were nasopharyngitis, oral candidiasis, and upper respiratory tract infection [15.0/100 PY, 10.1/100 PY, and 6.5/100 PY, respectively]; 99.3% of oral 16 candidiasis events were mild or moderate in severity, none were serious, and few (17) led to discontinuation
IL-23 inhibitors (group)	2021, Ru et al. [66]	25,624	SR Includes all diagnosis	The most frequent type of adverse events during treatment was infections with an incidence of 36.35%; SI showed an incidence of < 1.5%. The incidence of respiratory tract infection was 8.53% and viral upper respiratory tract infection 6.73%
Guselkumab (IL-23 inhibitor)	2023, Lebwohl et al. [67]	2891	SR of RCTs Includes 7 RCTs	Rates of SI (1.1/100 PY vs. 1.2/100 PY) were low and comparable between guselkumab and placebo No cases of opportunistic infection or active tuberculosis related to guselkumab
	2024, Strober et al. [68]	1061 patients received placebo vs. 2257 received guselkumab	Integrated analysis of 11 phase II/III clinical studies in psoriasis (7 studies) and psoriatic arthritis (4 studies)	Infections were 76.0 versus 72.2/100 PYs in the guselkumab and placebo groups, respectively Rates of SI were 1.0 vs. 2.3/PYs comparing guselkumab vs. placebo, respectively. No opportunistic infections or TB were reported among guselkumab-treated patients with psoriasis. However, three opportunistic infections were reported in guselkumab-treated patients with PsA (0.14/100 PYs; all after week 52 in DISCOVER-2)
Risankizumab (IL-23 inhibitor)	2022, Gordon et al. [69]	1606	SR of RCTs Included data from 17 phase I–III trials	With long-term risankizumab treatment, rates of SI were 1.2 per 100 PY The most frequently reported infections events were nasopharyngitis and upper respiratory tract infections
	2023, Papp et al. [70]	706	Analysis of an open-label extension trial up to 5 years of follow-up Includes patients with psoriasis	The most frequently reported adverse events were nasopharyngitis (13.7/100 PY) and upper respiratory tract infection (8.0/100 PY) Rates of SI [1.7 and 1.1/100 PY, respectively]) were low
Tildrakizumab (IL-23 inhibitor)	2020, Reich et al. [71]	1862	Pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks Includes 2 clinical trials	Rates of SI was 1.1 per 100 The most common treatment emergent AEs in all treatment groups was nasopharyngitis Other frequent AEs (occurring at a frequency ≥ 5% in one or more treatment groups) were infections such as upper respiratory tract infection, influenza, bronchitis, and sinusitis Candida infections were infrequent
	2023, Tsianakas et al. [72]	412	Multicentric prospective study Includes patients with psoriasis	No new safety signals were observed in comparison with trials The most common adverse drug reaction was skin infection [folliculitis (n = 3 subjects, 0.7%)] No SI, opportunistic infections or malignancy were recorded
Ustekinumab (IL-12/23 inhibitor)	2012, Gordon et al. [73]	3117	Analyses of phase II and III clinical trials Includes 4 studies Includes patients with psoriasis	Rates of overall infections per 100 patient-years were similar among placebo (121.0), ustekinumab 45 mg (145.7), and ustekinumab 90 mg (132.2) groups, and remained stable through 3 years Rates of SI during the placebo-controlled periods were similar between placebo (1.70) and 90 mg (1.97) groups, yet lower in the 45 mg group (0.49) Rates remained stable (90 mg) or decreased (45 mg) over time, and were comparable with those for the US psoriasis population based on a managed care database
	2020, Cho et al. [74]	2803	Nationwide study Includes patients with all diagnosis	Incidence of TB in patients treated with ustekinumab was similar to the general population

AS ankylosing spondylitis, CI confidence interval, HR hazard ratio, IL interleukin, IR incidence ratio, LTBI latent TB infection, MA meta-analysis, PDE4 phosphodiesterase 4, Pso psoriasis, PsoA psoriatic arthritis, PY person-years, R receptor, RCT randomized clinical trial, ROR relative odds ratio, SI serious infections, SR systematic review, TB tuberculosis, TNF tumoral necrosis factor