FormalPara Key Summary Points

Novel biologic therapies have quickly emerged as an effective psoriasis treatment; however, psoriasis is a life-long disease, and long-term inhibition of the immune system comes with a few safety concerns, including increased risk of infections and malignancies.

Cumulative evidence from clinical trials demonstrates the favorable safety profile of interleukin (IL)-23 p19 inhibitors.

Safety concerns associated with other biologics occurred infrequently, and the most common adverse events were nasopharyngitis, upper respiratory tract infection, and headache.

Real-world studies support the safety of long-term use of IL-23 p19 inhibitors in a wider population of patients with psoriasis, including older patients, patients for whom multiple biologics have failed, and patients with comorbidities.

Introduction

Psoriasis is an immune-mediated disease characterized by chronic inflammation in skin, joints, and other tissues, with an estimated prevalence of 3% in US adults [1]. It is associated with a number of comorbid conditions, including psoriatic arthritis (PsA), cardiometabolic diseases, gastrointestinal diseases, kidney disease, malignancy, infection, and mood disorders [2,3,4]. Topical therapy is the mainstay of psoriasis treatment in patients with limited disease (about 70–80% of patients), while systemic therapies, including biologics, are used in patients with more widespread disease, disease resistant to topical therapy, and/or involvement of special skin areas [5,6,7].

Biologics target cytokines involved in psoriasis physiopathology (e.g., tumor necrosis factor-alpha [TNF-α] and the interleukins [IL] IL-23 and IL-17). Of these cytokines, IL-23 is considered the major regulatory cytokine in psoriasis pathogenesis, whereas IL-17 is considered the main effector cytokine [8]. IL-23 acts “upstream” of T-helper 17 cells, which are dependent on IL-23 for survival, proliferation, and IL-17A/F production [3, 9]. Currently approved drugs that selectively target IL-23 via its unique p19 domain include guselkumab, tildrakizumab, and risankizumab [3]. These agents offer robust efficacy, favorable safety profiles, and convenient dosing (every 2–3 months) for patients with psoriasis. The p40 subunit of IL-23, which is shared with IL-12, was also identified as a therapeutic target for psoriasis [9]. Currently, ustekinumab is the only human monoclonal antibody targeting the p40 subunit of IL-12 and IL-23 indicated for the treatment of moderate-to-severe psoriasis [10]. Overall, the effectiveness and safety of ustekinumab were demonstrated in patients with psoriasis regardless of age and sex [10, 11].

The aim of the current review is to describe in detail the safety of selective IL-23 p19 inhibitors. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Methods

A literature search was performed using PubMed from inception to 1 November, 2022, to identify clinical trials and real-world evidence publications using the keywords “guselkumab,” “tildrakizumab,” and “risankizumab.” Only studies published in English were considered.

Overview of General Safety Concerns of Biologics

Table 1 lists biologics approved by the US Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe plaque psoriasis, with an overview of safety concerns for each agent/class [3, 4]. TNF inhibitors are associated with increased risk of serious infections, including opportunistic infections, tuberculosis (TB), and hepatitis B reactivation. Although reactivation of latent TB is listed as a safety consideration for all biologics used for psoriasis, this problem is most commonly reported with TNF inhibitors [4]. TNF inhibitors also have labeled warnings for lymphoma, nonmelanoma skin cancer (NMSC), congestive heart failure, demyelinating disease, lupus, infusion reactions (with infliximab), and transaminitis [12,13,14,15]. Concerns with the use of IL-17 and IL-17 receptor inhibitors include infections (notably candidiasis), neutropenia, inflammatory bowel disease (IBD), and suicidal ideation and behavior [16,17,18]. Regarding immunogenicity, adalimumab and infliximab are associated with higher rates of antidrug antibody development versus other biologics used for psoriasis [19]. The effect of immunogenicity on efficacy and safety of newer biologic agents does not seem to be clinically relevant [20]. For the IL-12/23 inhibitor ustekinumab, safety considerations include infections, TB, malignancies, hypersensitivity reactions, posterior reversible encephalopathy syndrome, and noninfectious pneumonia [10]. For the IL-23 p19 inhibitors guselkumab, tildrakizumab, and risankizumab, listed safety precautions are limited to infections, hypersensitivity reactions, and TB [21,22,23].

Table 1 Overview of general safety concerns of biologics approved for the treatment of plaque psoriasis
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Safety of IL-23 p19 Inhibitors

Guselkumab

The safety profile of guselkumab 100 mg in the Phase 3, double-blinded, active comparator-controlled studies (VOYAGE 1, VOYAGE 2, NAVIGATE, and ECLIPSE) was favorable for up to 60 weeks in adult patients with moderate-to-severe plaque psoriasis (Table 2). Nasopharyngitis (7–25%) and upper respiratory tract infection (URTI; 3–16%) were the most commonly reported adverse events (AEs); 1–7% of patients experienced a serious AE (SAE), and 1–3% of patients discontinued the study because of an AE. For AEs of interest, infection was commonly reported (22–59%), although few patients had serious infections (0–1%).

Table 2 Guselkumab: summary of adverse events from pivotal Phase 3 clinical trials
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In VOYAGE 1 and VOYAGE 2, the SAEs reported for guselkumab and adalimumab during the active comparator-controlled period (5% in both groups for weeks 0–48 and 4% in both groups for weeks 0–28, respectively) were similar to those reported during the placebo-controlled period [24, 25]. In NAVIGATE, 7% of patients receiving guselkumab and 5% of those receiving ustekinumab had at least one serious AE between weeks 16 and 60; the rate of infections requiring antibiotic treatment was slightly higher in guselkumab-treated patients (16% vs. 10%) [26]. The AEs observed in the ECLIPSE trial were generally similar between guselkumab-treated and secukinumab-treated patients, with the exception of slightly higher rates of Candida (6% vs. 2%) and Tinea (5% vs. 2%) infections during secukinumab versus guselkumab treatment [27]. Rates of serious infections, malignancies, and major adverse cardiovascular events (MACE) were comparable across treatment arms [24,25,26,27].

Periodic assessment of long-term guselkumab treatment has shown a consistent safety profile after 2 years [28], 3 years [29], and 5 years of treatment [30]. Overall, 78% (1349/1721) of guselkumab-treated patients continued treatment through 5 years [30]. There were no safety signals of concern for serious infection, malignancy (including NMSC), or MACE among guselkumab-treated patients, and the rates of these AEs of interest were either stable or decreased over time [29]. Over 7166 patient-years (PYs), the rates of overall AEs and SAEs were 149.0 and 5.0 events per 100 PYs, respectively. Individual AEs of interest occurred at event rates of < 1 per 100 PYs; these included serious infections (0.9 per 100 PYs), NMSC (0.3), malignancies other than NMSC (0.5), and MACE (0.3) [30]. Over the entire study period, 32 guselkumab-treated patients were diagnosed with malignancies, most commonly breast cancer, colorectal cancer, melanoma, prostate cancer, head and neck cancer, and lymphoma. Rates of malignancy (excluding NMSC) were generally consistent with estimates in the general US population and observations in patients with psoriasis (PSOLAR population), suggesting no association between guselkumab and increased risk of cancer in patients with psoriasis [31]. During the 5-year study period, five deaths occurred in VOYAGE 1 and four deaths in VOYAGE 2 among guselkumab-treated patients [30].

Long-term treatment with guselkumab was well tolerated in patients receiving treatment for latent TB. In the VOYAGE 1 and VOYAGE 2 studies, 69 (8%) patients in the guselkumab group and 36 (6%) patients in the adalimumab group had latent TB at baseline and received treatment for TB through week 100; no new cases of active TB, including no reactivation of latent TB, were reported in either group [32]. No cases of inflammatory bowel disease (IBD) were observed in pooled data from VOYAGE 1 and VOYAGE 2, and the rate of gastrointestinal SAEs was 0.5 events per 100 PYs through 4 years [33].

A post hoc analysis of VOYAGE 1 and VOYAGE 2 results reported generally similar tolerability at weeks 16 and 28 for Asian (n = 94) and non-Asian patients (n = 729) treated with guselkumab [34]. Compared with non-Asian patients, a higher frequency of Asian patients had ≥ 1 AE at week 16 (Asian versus. non-Asian patients, 61% vs. 48%) and week 28 (72% vs. 59%); the frequency of SAEs was 1% versus. 4%, and the frequency of discontinuation due to AEs was 2% in both groups, at week 28 [34]. A subgroup analysis of Korean patients from VOYAGE 1 and VOYAGE 2 (n = 126) reported similar frequencies of AEs in all treatment arms at weeks 16 and 28, with the exception of a much higher frequency of injection site reactions in adalimumab-treated patients (24% vs. 3–7%) [35]. A placebo-controlled Phase 3 trial conducted in 159 Japanese patients with palmoplantar pustulosis also reported good tolerability for guselkumab 100 and 200 mg, with similar or lower rates of AEs, SAEs, treatment-related AEs, and AEs leading to discontinuation in patients treated with guselkumab versus placebo [36]. In another post hoc analysis of 18 patients in VOYAGE 1 and VOYAGE 2 with a history of malignancy with no recurrence for ≥ 5 years at baseline, three patients had SAEs of malignancy (excluding NMSC) during guselkumab treatment [37]. There were also two diagnoses of NMSC among the 18 patients [37].

Guselkumab remained well tolerated in real-world studies, most of which were small, retrospective, and/or in special populations, with similar types (nasopharyngitis, URTI, flu-like illness) and overall lower frequencies of AEs compared with clinical trial results (Table 3). Guselkumab was well tolerated in patients with a previous failure of ustekinumab and/or IL-17 inhibitor therapy [38, 39], in overweight/obese patients [40, 41], in heavily pretreated patients (mean of 4 prior biologics) [42], and in older patients (mean age 71 years) with multiple comorbidities [43]. Data from one of the larger (N = 307) real-world studies conducted in Italy reported AEs in only ten patients (3%); all AEs were mild in severity with the exception of one transient ischemic attack, and two patients (1%) discontinued guselkumab due to an AE (erythroderma and general malaise, n = 1 each) [44].

Table 3 Overview of safety of guselkumab in real-world studies
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In a larger (N = 303) prospective 52-week real-world study conducted in Germany, 15% of guselkumab-treated patients experienced at least one treatment-related AE; the majority of AEs were mild/moderate in severity, and 3% of patients discontinued due to an AE [45]. Four (1%) treatment-related SAEs were reported, including bronchitis, Epstein-Barr virus infection, malignant neoplasm, and pemphigoid (n = 1 each) [45]. A small Italian study in 31 patients with follow-up for 3 years reported common AEs of pharyngitis (23%), headache (16%), and flu-like illness (16%), with no SAEs, Candida infection, malignancy, or cardiovascular events [51].

Tildrakizumab

Tildrakizumab has a favorable safety profile for up to 5 years in patients with moderate-to-severe plaque psoriasis and is considered safe for use in patients with IBD, cardiovascular disease, and metabolic syndrome, as well as in older patients [56]. Tildrakizumab was well tolerated through week 28 in two Phase 3 pivotal trials in patients with moderate-to-severe plaque psoriasis: reSURFACE 1 and reSURFACE 2 (Table 4) [57]. In reSURFACE 1, patients received tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo; in reSURFACE 2, patients received tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg [57]. In reSURFACE 1, nasopharyngitis (4–8%) and URTI (3–7%) were the most commonly reported AEs among patients treated with tildrakizumab and placebo at weeks 12 and 28 [57]. In reSURFACE 2, nasopharyngitis (4–14%) and injection site erythema (0–9%, more frequently reported in etanercept-treated patients) were the most commonly reported AEs across all treatment arms [57]. SAEs during tildrakizumab treatment were reported in approximately 2% of patients in both trials, and approximately 1% of patients discontinued because of an AE. Frequencies of AEs of interest, including severe infections, malignancies, NMSC, MACE, and drug-related hypersensitivities, were similar across treatment arms [57]. Across both trials, seven patients had history of IBD (3 patients in tildrakizumab 200 mg arm, 3 in tildrakizumab 100 mg arm, and 1 in placebo treatment group) [58]; no new cases or exacerbations of IBD were reported [57]. Pooled data from the reSURFACE 1 and reSURFACE 2 trials as well from a Phase 2b study (N = 2081) up to 64 weeks showed reassuring event rates (calculated as patients with events) for any AEs and AEs of interest per 100 PYs of exposure to tildrakizumab 100 and 200 mg, including treatment-related AEs (23.3 and 25.2 for any AEs and AEs of interest per 100 PYs of exposure, respectively), treatment-related SAEs (0.3 and 1.0), MACE (0.4 and 0.3), severe infections (1.1 and 1.6), Candida skin infections (0.2 and 0.7), malignancies (1.7 and 1.2), NMSC (1.1 and 0.9), melanoma (0.2 and 0), injection site reactions (3.5 and 4.6), and drug-related hypersensitivity (0.5 and 0.2) [59].

Table 4 Tildrakizumab: summary of adverse events from pivotal Phase 3 clinical trials
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Long-term pooled safety data after up to 3 and 5 years of treatment are reported for reSURFACE 1 and reSURFACE 2. At 3 years, event rates (patients with events) per 100 PYs for the most commonly reported AEs during treatment with tildrakizumab 100 mg (2014 PYs of follow-up) and 200 mg (2047 PYs) were nasopharyngitis (10.2 and 9.8, respectively), viral URTI (6.9 and 6.7), URTI (3.8 and 5.6), arthralgia (3.4 and 2.8), headache (2.7 and 3.1), and influenza (2.4 and 3.2) [60]. For overall safety outcomes, the corresponding event rates were as follows: AEs (35.2 and 37.2), SAEs (5.9 and 5.5), deaths (0.3 and 0.2), drug-related AEs (11.4 and 12.9), drug-related SAEs (0.8 and 0.5), discontinuations due to AEs (1.7 and 1.2), discontinuations due to SAEs (0.9 and 0.8), discontinuations due to drug-related AEs (0.7 and 0.3), and discontinuations due to drug-related SAEs (0.4 and 0.2) [60]. Exposure-adjusted rates of AEs were generally similar between patients treated with tildrakizumab 100 versus 200 mg and among patients treated with tildrakizumab versus placebo (205 PYs) or etanercept (153 PYs) [60]. Event rates of AEs of special interest were < 2.5 per 100 PYs in patients treated with tildrakizumab 100 mg and 200 mg, including for severe infection (1.1 and 1.1), malignancy excluding NMSC (0.6 and 0.4), NMSC (0.5 and 0.5), melanoma (0.1 and 0.0), MACE (0.4 and 0.5), injection site reactions (1.9 and 2.3), and drug-related hypersensitivity reactions (0.3 and 0.2) [60].

Five-year pooled safety data are available for reSURFACE 1 (256 weeks) and reSURFACE 2 (244 weeks) and are presented for patients who received tildrakizumab 100 mg (n = 872; 2688 PYs of follow-up) or 200 mg (n = 928; 2754 PYs of follow-up) [61]. Rates of AEs and AEs of interest did not increase over time. The types and rates (of patients with AEs) per 100 PYs for the tildrakizumab 100 mg and 200 mg groups after 5 years were similar to those reported at 3 years, including nasopharyngitis (10.5 and 10.7, respectively), URTI (3.8 and 4.6), hypertension (3.0 and 3.3), influenza (2.4 and 3.1), arthralgia (3.0 and 3.0), back pain (2.4 and 2.7), and headache (2.3 and 2.6) [61]. Over 5 years of treatment, only one suspected case of new-onset Crohn’s disease was reported; the event was mild and did not lead to discontinuation [61]. Event rates per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively, for drug-related AEs (9.3 and 9.8), drug-related SAEs (0.8 and 0.5), deaths (0.3 and 0.2), drug-related AEs leading to discontinuation (0.7 and 0.3), and drug-related SAEs leading to discontinuation (0.3 and 0.2) were similar to those reported at 3 years, as were the rates of AEs of interest [61].

In post hoc analyses of reSURFACE 1 and reSURFACE 2 data, the long-term (5 years) safety profile of tildrakizumab was similar regardless of body weight [62] or presence of metabolic syndrome (Table 5) [63]. Five-year rates of AEs and AEs of interest during treatment with tildrakizumab 100 mg and 200 mg were similar between patients with psoriasis weighing < 120 kg and those weighing ≥ 120 kg [62]. The combined rates (patients with events) of AEs of special interest (drug hypersensitivity, serious infections, malignancies, melanoma, NMSC, MACE, and injection site reactions) for patients without and with metabolic syndrome, respectively, were 2.1 and 2.0 for tildrakizumab 100 mg and 2.6 and 5.2 for tildrakizumab 200 mg [63]. For SAEs, the corresponding event rates per 100 PYs were 4.6 and 7.2 for tildrakizumab 100 mg in patients without and with metabolic syndrome, respectively, and 4.9 and 8.4 for tildrakizumab 200 mg in patients without and with metabolic syndrome; gastrointestinal disorders, neoplasm, infections and infestations, and cardiac disorders were the most common SAEs [63]. Rates of respiratory or viral infections did not appear to increase over 5 years of tildrakizumab treatment [64]. Treatment with tildrakizumab for up to 3 years did not increase the risk for cardiovascular events, including MACE, in patients with already high rates of cardiovascular- and/or metabolic-related conditions at baseline (87–88%) [65]. Measures of cardiometabolic disease risk factors (fasting serum glucose, low/high-density lipoprotein cholesterol, total cholesterol, triglyceride levels, body weight, and blood pressure) at 1 year were not significantly different between reSURFACE 1 and reSURFACE 2 patients with versus those without metabolic syndrome [66].

Table 5 Overview of safety of tildrakizumab in post hoc and real-world studies
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Tildrakizumab treatment for up to 5 years was well tolerated in patients aged > 65 years, and the rates of AEs and AEs of interest in this population were in line with those in the overall trial population; no dose-related increase in AE rates was observed (Table 5) [67]. Long-term treatment with tildrakizumab was also well tolerated in the small subgroup (n = 129) of Japanese patients in reSURFACE 1; event rates (patients with events) per 100 PYs for AEs of special interest for tildrakizumab 100 and 200 mg, respectively, were 1.0 and 1.4 for severe infection, 0.7 and 0.6 for malignancies, 0 for any skin cancer, and 1.4 and 0.3 for MACE [68].

Tildrakizumab was well tolerated in real-world studies, most of which were small and retrospective, with lower frequencies of AEs relative to those reported in clinical trials; most studies reported generally mild AEs, no safety issues, and no discontinuations due to AEs (Table 5). In one of the larger real-world studies (N = 412) of tildrakizumab, conducted in Germany, 68 (15%) patients experienced an AE (16.5 patients with events per 100 PYs) and 14 (3%) experienced a SAE (3.4 patients with events per 100 PYs) at 52 weeks of follow-up [69]. Similarly, AEs were reported in 5% of 237 Italian patients treated with tildrakizumab for 52 weeks, and no patients discontinued treatment due to an AE [70], consistent with the results from other real-world studies conducted in Germany (3/150 [2%] patients switched to another treatment due to an AE [71]) and in the UK (AEs reported in 6/113 [5%] patients; 1 patient [0.9%] discontinued due to an AE [72]).

Risankizumab

Risankizumab was well tolerated in clinical trials and in a long-term extension study for up to 4 years. The safety of risankizumab 150 mg has been assessed in five Phase 3 trials: UltIMMa 1 and 2, risankizumab versus placebo and ustekinumab; IMMvent, risankizumab versus adalimumab; IMMhance, risankizumab versus placebo; and IMMerge, risankizumab versus secukinumab (Table 6). Risankizumab was well tolerated during weeks 0–16 (part A) and weeks 16–52 (part B) in UltIMMa 1 and 2, with similar percentages of risankizumab-treated patients in both trials experiencing ≥ 1 AE (risankizumab-treated patients in UltIMMa 1 and 2: part A, 49.7% and 45.6%, respectively; part B, 61.3% and 55.7%, respectively) and ≥ 1 SAE (risankizumab-treated patients in UltIMMa 1 and 2: part A, 2.3% and 2.0%, respectively; part B, 5.4% and 4.5%, respectively); AE frequencies were similar or higher in patients treated with placebo and ustekinumab [75]. The proportion of patients with AEs leading to drug discontinuation was < 5% across all groups [75]. The most frequently reported AEs in part A in both trials were viral URTI, URTI, psoriasis, and diarrhea, while the most frequently reported AEs in part B in both trials were viral URTI, URTI, urinary tract infection, influenza, and headache (Table 6) [75]. The rates of AEs of interest were similar across treatment arms; through week 52, MACE was reported in two patients with preexisting cardiovascular risk factors, and neither event was considered related to risankizumab [75].

Table 6 Risankizumab: summary of adverse events from pivotal Phase 3 clinical trials
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In the IMMvent trial, the frequencies of AEs, SAEs, and AEs leading to study drug discontinuation were unremarkable in patients treated with either risankizumab or adalimumab during weeks 0–16 (part A) and among those patients rerandomized to risankizumab during weeks 16–44 (part B) [76]. The most frequently reported AEs were viral URTI and URTI (Table 6). Through week 48, individual AEs of interest occurred in ≤ 3.5% of risankizumab-treated patients; during parts A and B, respectively, serious infection occurred in < 1% and 1%, opportunistic infection in 0% and 1%, latent TB in 0% and < 1%, MACE in < 1% and 0%, hepatic events in 2% and 3%, and malignancy in < 1% and 1% of risankizumab-treated patients [76]. There were no reported cases of ulcerative colitis or Crohn’s disease [76].

In the IMMhance trial, patients received risankizumab at weeks 0 and 4 (weeks 0–16; part A1) and at week 16 (part A2); at week 28, patients with response (static Physician’s Global Assessment 0/1) [77] received risankizumab every 12 weeks thereafter (weeks 28–88; part B) [77]. The types and rates of AEs in IMMhance parts A1 and B were consistent with those observed in other Phase 3 trials of risankizumab (Table 6). Overall, AEs were reported in 426 patients (85%; 259.7 events per 100 PYs) and SAEs in 55 patients (11%; 13.5 events per 100 PYs) receiving risankizumab at any point during the trial [77]. The most frequently reported AEs were nasopharyngitis (23%), URTI (15%), headache (7%), and back pain (6%) [77]. There were no reports of active or latent TB or serious hypersensitivity among patients receiving risankizumab, and event rates per 100 PYs were 1.4 for serious infections and 2.2 for cancers [77]. Hepatic events were reported in 23 patients (4.6%), one (0.2%) of which was a serious event (hepatic cirrhosis) [77]. Six cases of MACE were reported in four patients (0.8%; 0.9 events per 100 PYs), including three strokes, two myocardial infarctions, and one cardiovascular death (unknown cause); none were considered to be related to risankizumab [77]. Death occurred in four patients (0.8%; 1 each for epileptic seizure and metastatic hepatic cancer, and 2 of unknown cause), none of which were considered related to risankizumab [77].

In the IMMerge trial, the rates of AEs, SAEs, drug-related AEs, and drug-related SAEs were similar between patients treated with risankizumab and secukinumab [78]. Eight (5%) patients in the secukinumab arm discontinued study treatment because of AEs, compared with two (1%) patients in the risankizumab arm [78]. The most commonly reported AEs were nasopharyngitis, URTI, headache, arthralgia, and diarrhea (Table 6) [78]. Among AEs of interest, MACE (nonfatal myocardial infarction) was reported in two risankizumab-treated patients versus no secukinumab-treated patients; both risankizumab-treated patients with MACE had multiple cardiovascular risk factors, and neither event was considered related to the study drug [78]. Three risankizumab-treated patients experienced serious infections (urinary tract infections, n = 2; histiocytic necrotizing lymphadenitis, n = 1) [78]. One case of new-onset ulcerative colitis occurred in a patient treated with secukinumab (considered to be serious and related to treatment, and led to treatment discontinuation) [78]. Candida infections (including oral and vulvovaginal candidiasis) were reported for seven patients, of whom three were treated with risankizumab and four with secukinumab [78].

Risankizumab 75 mg and 150 mg were well tolerated in a trial of 171 Japanese patients with moderate-to-severe psoriasis; rates of AEs and AEs were similar for patients treated with risankizumab and placebo, and no dose-dependent AEs were observed over 52 weeks of treatment [79]. One MACE (acute myocardial infarction; patient continued risankizumab treatment) and one malignancy (rectal carcinoma) were reported [79].

Long-term safety data for risankizumab 150 mg every 12 weeks are available from LIMMitless, an ongoing Phase 3, single-arm, open-label extension trial of patients who participated in Phase 2 and Phase 3 studies [80]. After up to 208 weeks of continuous risankizumab treatment (n = 897), the most commonly reported AEs (events per 100 PYs) were nasopharyngitis (17.3), URTI (10.7), arthralgia (3.8), headache (3.1), hypertension (2.8), back pain (2.8) and influenza (2.5) [80]. Rates of SAEs (6.7 events per 100 PYs) and AEs leading to discontinuation (1.4) were lower compared with the 16-week primary safety pool in the original clinical trials (n = 1306; 9.9 and 2.7 events per 100 PYs, respectively); rates of AEs of interest were 0.2 for MACE, 1.2 for serious infection, 0.5 for NMSC, 0.3 for malignancies excluding NMSC, < 0.1 for serious hypersensitivity reactions, and 0.6 for Candida infection [80].

Risankizumab remained well tolerated in real-world studies, most of which were small and retrospective; AEs were generally mild in severity, with no safety issues and few discontinuations due to AEs (Table 7). In the largest real-world study (N = 154) of risankizumab conducted in the Czech Republic in a population of 80% overweight/obese patients with psoriasis, four (3%) patients discontinued treatment due to an AE [81]. Similarly, in another larger study in 131 patients conducted in Italy, AEs were reported in five (4%) patients, and no severe AEs or AEs leading to discontinuation were reported [82].

Table 7 Overview of safety of risankizumab in real-world studies
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Discussion

Many conditions must be considered when selecting the optimal therapy for patients with psoriasis [86, 87]. To date, cumulative data from both clinical trials and real-world practice settings suggest that anti–IL-23 p19 antibodies are very safe when treating patients with moderate-to-severe plaque psoriasis. Of particular importance, given the chronic nature of psoriasis, long-term use of IL-23 p19 inhibitors did not increase the risk of AEs of interest, including serious infection, MACE, and cancer, with up to 5 years of exposure.

Guselkumab had a favorable safety profile versus placebo and active controls in patients with psoriasis, according to results from the VOYAGE 1, VOYAGE 2, NAVIGATE, and ECLIPSE clinical trials. Long-term safety results (5 years) for guselkumab were consistent with those from short-term studies [28,29,30,31]; nonserious infection was the most commonly reported AE during long-term follow-up [30]. Tildrakizumab had a favorable safety profile in the reSURFACE 1 and reSURFACE 2 trials, with similar reported rates of severe infection, malignancies, and MACE among patients treated with tildrakizumab, placebo, and etanercept [60]. Data from tildrakizumab extension studies (5 years) were consistent with the results of the base studies; overall, severe infection, malignancy, and MACE rates did not increase during the extension period [61, 64]. Risankizumab was well tolerated in clinical trials, with similar rates of AEs between patients treated with risankizumab and placebo/comparator in multiple short-term trials [75,76,77,78]. Long-term data (up to 4 years) also support the safety of risankizumab [80].

Biologics targeting IL-23 p19 are also a safe long-term treatment option for patients with psoriasis who have a variety of clinical characteristics. Notably, data from real-world studies have extended the safety of guselkumab, tildrakizumab, and risankizumab in a broader population of patients with psoriasis, including older patients, patients for whom multiple previous biologics failed, and those with comorbidities, such as obesity, metabolic syndrome, cardiovascular disease, dyslipidemia, diabetes, hypertension, and PsA [38,39,40,41,42, 44, 69,70,71,72, 81, 82]. Based on the available data, safety concerns usually associated with inhibitors of IL-17 signaling [88] (oral candidiasis, induction or worsening of IBD, and suicidal ideation and behavior) occurred infrequently with IL-23 p19 inhibitors [30, 61, 77]. Similarly, these biologics have not been linked to increased risk of TB reactivation or to triggering or worsening of demyelinating disorders, as has been reported for anti-TNF biologics [30, 32, 61, 77, 88, 89].

During the COVID-19 pandemic, safety concerns were raised regarding the administration of immunosuppressive drugs and increased susceptibility to infection, as well as psoriasis exacerbation [90, 91]. Currently, there is no solid evidence linking IL-23 p19 inhibitors to the increased risk of SARS-CoV-2 infection or disease worsening for patients with psoriasis [90, 91].

Finally, despite the well-documented positive safety profile of this class of inhibitors, the life-long management of a chronic condition like psoriasis is still complex, especially in patients with comorbidities. In this scenario, the advent of personalized medicine could help in predicting and/or minimizing the risk of potential side effects [92]. However, to date, the data collected are insufficient to support clinicians in making treatment decisions; thus, more research in this direction is needed [92].

Strengths and Limitations

The strengths of this narrative review include the comprehensive summary of the available high-quality clinical trials and real-world evidence publications on IL-23 p19 inhibitors with a focus on their safety for patients with psoriasis. Several authors independently reviewed and selected the included studies to reduce possible information bias. Long-term follow-up studies are included. Emerging safety data on IL-23 p19 inhibitors for specific groups of patients with psoriasis, including older patients, patients for whom multiple biologics have failed, and patients with comorbidities, are also discussed.

This review is limited by the lack of direct comparisons among therapeutic agents due to differences among study designs and safety data reporting methods.

Conclusions

In summary, the favorable safety profiles of these agents, combined with ease of use for both patients and physicians, support the use of IL-23 p19 inhibitors in the long-term management of patients with moderate-to-severe plaque psoriasis.