Biologics Versus JAK Inhibitors. Part II: Risk of Infections. A Narrative Review

Abstract

Introduction

The risk of infections associated with biological drugs (BD) and Janus kinase inhibitors (JAKi) has been extensively explored in the literature. However, there is a dearth of studies that evaluate both pharmacological groups together and, furthermore, compare them. Here, we review the risk of infections associated with BD and JAKi used in dermatology.

Methods

A narrative review was performed. All relevant articles evaluating the risk of infection and opportunistic infections with BD and JAKi between January 2010 and February 2024 were selected.

Results

Overall, the incidence of infections, serious infections, and opportunistic infections associated with BD and JAKi is low, but higher than in the general population. JAKi approved for dermatological disorders (abrocitinib, baricitinib, deucravacitinib, upadacitinib, ritlecitinib, and topical ruxolitinib) have been shown to be safe, and present a low rate of infections. We found an elevated risk, especially with anti-tumor necrosis factor (anti-TNF) agents, rituximab, and JAKi (particularly tofacitinib at high doses). Specific associations with infections include tuberculosis and tuberculosis reactivation with anti-TNF agents and tocilizumab; candidiasis with anti-interleukin (IL) 17 agents; hepatitis B virus reactivation with rituximab, anti-TNF, and JAKi; and herpes simplex and herpes zoster infections with JAKi (especially tofacitinib and upadacitinib at high doses). The incidence of infections with ustekinumab and anti-IL-23 was very low. Anti-IL-1, nemolizumab, tralokinumab, and omalizumab were not associated with an increased risk of infections. Dupilumab could decrease the incidence of cutaneous infections.

Conclusions

Anti-TNF agents, rituximab, and JAKi (particularly tofacitinib) can increase the risk of infections. Close monitoring of patients undergoing these therapies is recommended. Prospective studies with long-term follow-up are needed to comparatively evaluate the risks of infection deriving from treatment with BD and JAKi.

Key Summary Points

In general, biological drugs and Janus kinase inhibitors (JAKi) are considered safe in terms of the risk of infections and opportunistic infections (OI).

The overall incidence of infections and OI is increased with certain pharmacological groups, especially non-selective JAKi at high doses, rituximab, tocilizumab, and anti-tumor necrosis factor (anti-TNF).

The incidence of tuberculosis (TB) and TB reactivation is increased in patients undergoing anti-TNF therapy and tocilizumab; candidiasis in anti-IL-17 agents; reactivation of hepatitis B virus in rituximab (especially), anti-TNF, and JAKi; and infections by herpes simplex and varicella-zoster virus in JAKi (particularly tofacitinib and upadacitinib at high doses).

Introduction

Biologic drugs (BD) have revolutionized the treatment of numerous inflammatory dermatoses, such as psoriasis, atopic dermatitis (AD), chronic urticaria, autoimmune blistering disorders, and prurigo nodularis, among others. There is lingering uncertainty regarding the potential linkage of BD to significant safety risks, including serious infections [1]. Certain interleukins (IL), such as tumor necrosis factor alpha (TNF) or interleukin (IL)-17, or clusters of differentiation (CD), such as CD20, have been identified as key players in the immune response against specific infections. Blocking them could favor infections and their progression in predisposed individuals [2].

Recently, Janus kinases (JAK) inhibitors (JAKi) have emerged. They act by inhibiting JAK phosphorylation through the occupation of the catalytic ATP-binding site. Their effectiveness has been demonstrated in numerous diseases, both dermatological [AD, vitiligo, and alopecia areata (AA)] and non-dermatological [rheumatoid arthritis (RA), myelodysplastic syndrome, inflammatory bowel disease (IBD)]. The JAK–STAT pathway involves intracellular tyrosine kinases, comprising four isoforms: JAK1, JAK2, JAK3, and TYK2. While more selective JAKi may avoid adverse events associated with non-desired JAK isoforms, the long-term safety implications of this selectivity remain unclear [3]. JAKi have been associated with various adverse events (AEs), including cytopenias, urinary and upper respiratory tract infections, herpes virus reactivation, alteration of liver function tests, and hypercholesterolemia. More serious and rare adverse events include thromboembolic events, reactivation of hepatitis B virus (HBV), disseminated tuberculosis (TB), gastrointestinal perforation (particularly tofacitinib), and malignancies [4]. Infections and opportunistic infections (OI) have been scrutinized as a frequent and potentially serious AE related to JAKi. A Boxed Warning was issued by the US Food and Drug Administration (FDA), primarily for tofacitinib (based on its clinical trials), and subsequently extended to other JAKi that had not been evaluated in those studies.

There are few articles that evaluate the safety of both BD and JAKi, and even fewer attempt to make a comparison between both pharmacological groups. In Part I (“Biologics versus jak inhibitors. Part I: cancer risk. A narrative review”), the cancer risk associated with BD and JAKi was evaluated. In this Part II, we review the available evidence regarding the relationship between BD and JAKi used mainly for dermatological disorders, and the risk of infections [4, 5].

Methods

We conducted a narrative review. Searches were performed on Medline and Google Scholar using the key terms: “infection”, “opportunistic infection”, “tuberculosis”, “hepatitis”, “herpes”, “herpes zoster”, “dermatology”, “cutaneous”, “anti-TNF”, “etanercept”, “infliximab”, “adalimumab”, “certolizumab”, “anti IL-17”, “secukinumab”, “ixekizumab”, “brodalumab”, “bimekizumab”, “anti IL-23”, “guselkumab”, “tildrakizumab”, “risankizumab”, “anti IL-12/23”, “ustekinumab”, “anti IL-1”, “anti CD-20”, “rituximab”, “anti IL-4/13”, “dupilumab”, “tralokinumab”, “omalizumab”, “anti IL-31”, “nemolizumab”, “tocilizumab”, “JAK”, “JAK inhibitors”, “abrocitinib”, “upadacitinib”, baricitinib”, “ruxolitinib”, “tofacitinib”, “deucravacitinib”, “ritlecitinib”. Deucravacitinib selectively inhibits TYK2, impacting specific cytokine pathways such as IL-12, IL-23, and type I interferons without significantly affecting other members of the JAK family (JAK1, JAK2, JAK3). Thus, it is a molecule that does not fully perform all the functions of other JAK inhibitors. However, it has been included in the category of JAK inhibitors (JAKi) in this review for technical reasons. This search was conducted in Spanish and English. These articles were screened on the basis of their abstracts, and selected according to their relevance after reading the studies. Observational studies, clinical trials, post-trial analysis studies, systematic reviews (SR), and meta-analyses (MA) published between January 1, 2010 and February 10, 2024 were included. Case reports, case series with fewer than 10 patients and narrative reviews were excluded. Two authors (MMP and DMC) performed the search and article selection. In terms of ethics, this article does not require ethics committee approval as it is based on previously conducted studies and does not include any new human or animal studies conducted by any of the authors.

Results

Biological Drugs and Risk of Infections and Opportunistic Infections

Anti-TNF and Risk of Infections

Studies assessing the relationship between anti-TNF agents and infections are summarized in Table 1.

Table 1.

Main studies that assess the relationship between anti-TNF agents and infections

Year, author	N	Study type/design	Results
2013, Galloway et al. [6]	11,881 anti-TNF and 3673 nbDMARDs patients were analyzed	Multicenter prospective study Includes patients with RA	Crude IR for SSSI were anti-TNF 1.6/100 patient-years (95% CI 1.4–1.8); nbDMARD 0.7/100 patient-years (95% CI 0.5–1.0); crude IR for HZ were anti-TNF 1.6/100 patient-years (95% CI 1.3–2.0); nbDMARD 0.8/100 patient-years (95% CI 0.6–1.1) Adjusted HR were SSSI 1.4 (95% CI 0.9–2.4), HZ 1.8 (95% CI 1.2–2.8) For SSSI, no significant differences were seen between anti-TNF agents For HZ, lowest risk was observed for adalimumab (aHR vs. nbDMARD) 1.5 (95% CI 1.1–2.0) and highest for infliximab (HR 2.2; 95% CI 1.4–3.4)
2013, Long et al. [7]	108,604 patients with IBD vs. 434,416 controls	Retrospective multicenter study Includes patients with IBD	IBD cohort had increased HZ risk compared with non-IBD (IRR 1.68, 95% CI 1.60–1.76) Anti-TNF medications (OR 1.81, 95% CI 1.48–2.21), corticosteroids (OR 1.73, 95% CI 1.51–1.99), and thiopurines (OR 1.85, 95% CI 1.61–2.13) were independently associated with HZ Risk of HZ was highest with combination of anti-TNF and thiopurine therapy (OR 3.29, 95% CI 2.33–4.65)
2013, Winthrop et al. [8]	Anti-TNF users (n = 33,324) vs. patients initiating nbDMARDs (n = 25,742)	Multicenter retrospective study Includes patients with RA, IBD and Pso, PsoA, or AS	Crude incidence rates of infections among anti-TNF users were 12.1 per 1000 patient-years (95% CI 10.7–13.6) for RA, 11.3 per 1000 patient-years (95% CI 7.7–16.7) for IBD, and 4.4 per 1000 patient-years (95% CI 2.8–7.0) for Pso, PsoA, or AS For patients with RA, adjusted incidence rates were similar between anti-TNF and nonbiologic DMARD initiators (adjusted HR 1.00 [95% CI 0.77–1.29]) and comparable between all 3 anti-TNF therapies studied Among patients with RA and other inflammatory diseases, those who initiated anti-TNF therapies were not at higher risk of HZ compared with patients who initiated nonbiologic treatment regimens
2014, Dulai et al. [9]	5528	SR with trials and observational studies with > 5 patients Includes patients with infliximab therapy for children with UC or CD, or adalimumab therapy for children with CD	Rate of severe infections among pediatric patients treated with anti-TNF agents (352/10,000 PYF) was similar to that of pediatric patients who received immunomodulator monotherapy (333/10,000 PYF; SIR 1.06; 95% CI 0.83–1.36), but significantly lower than the expected rate for pediatric patients treated with steroids (730/10,000 PYF; SIR 0.48; 95% CI 0.40–0.58) or adults treated with anti-TNF agents (654/10,000 PYF; SIR 0.54; 95% CI 0.43–0.67)
2014, Cobo-Ibañez et al. [10]	3301 patients on anti-TNF (n = 3166) or rituximab (n = 135)	Multicenter retrospective study Most of the patients had rheumatoid arthritis (95%)	RTX-treated patients were more likely to suffer an infection in the first 12 months compared to anti-TNF patients Compared to infliximab, other anti-TNF had significantly less SI, even after adjustment
2015, Jung et al. [11]	Of 8421 patients in the study population, 1729 patients with LTBI prophylaxis were identified and 102 patients developed TB	Multicenter retrospective study All indications	Incidence of TB was highest in patients with IBD (IRR 5.97, 95% CI 3.34–10.66), followed by patients with RA (IRR 1.02, 95% CI 0.57–1.83) and those with PsoA (IRR 1.00, 95% CI 0.14–7.30) Comparison between drugs showed a significantly lower incidence of TB in patients treated with etanercept (reference), highest incidence in those treated with infliximab (IRR 6.8, 95% CI 3.74–12.37) and an intermediate incidence in patients treated with adalimumab (IRR 3.45, 95% CI 1.82–6.55)
2015, Ai et al. [12]	> 100,000	SR with MA Includes 13 RCTs and 50 cohort studies Includes patients with RA	No significant difference in TB risk was found in the RCT because of the short observational periods In the non-RCT, TNFα antagonist was associated with higher TB risk in patients with RA (RR 4.03, 95% CI 2.36–6.88), and TB incidence rates of IFX and ADA were 2.78 and 3.88 times, respectively, higher than that of ETN Further, preventive treatment for LTBI reduced TB risk by 65% (RR 0.35, 95% CI 0.15–0.82)
2015, Kalb et al. [13]	11,466	Multicenter prospective study Patients with psoriasis	Cumulative incidence rate of SI was 1.45 per 100 patient-years, and rates were 0.83, 1.47, 1.97, and 2.49 per 100 patient-years in ustekinumab, etanercept, adalimumab, and infliximab cohorts, respectively, and 1.05 and 1.28 per 100 patient-years in non-methotrexate/non-biologics and methotrexate/non-biologics cohorts, respectively The most reported types of SI across the registry were pneumonia and cellulitis This study suggested a higher risk of SI with adalimumab and infliximab compared with non-methotrexate and nonbiologic therapies. No increased risk was observed with ustekinumab or etanercept
2017, Liao et al. [14]	24,656	MA Includes 12 studies, all observational studies Includes patients with RA	Compared with mono-antibodies, etanercept has a lower risk for TB and general infections
2017, Zhang et al. [15]	11,879	SR with MA Includes 29 RCTs of patients with infliximab, adalimumab, etanercept, golimumab, and certolizumab pegol All diagnosis	Of 7912 patients allocated to TNFα antagonists, 45 (0.57%) developed TB, while only 3 cases occurred in 3967 patients allocated to control groups, resulting in an OR of 1.94 (95% CI 1.10–3.44, p = 0.02) Subgroup analyses indicated that patients with RA had a higher increased risk of TB when treated TNFα antagonists (OR 2.29 (1.09–4.78), p = 0.03) There was no difference between the different drugs
2017, Yiu et al. [16]	1352, 3271, and 994 patients with etanercept, adalimumab, ustekinumab cohorts, respectively vs. 3421 in a non-biologic cohort	Prospective multicenter study Includes patients with psoriasis	283 patients had an SI; the incidence rates with 95% CI per 1000 person-years were as follows: non-biologic, 14.2 (11.5–17.4); etanercept, 15.3 (11.6–20.1); adalimumab, 13.9 (11.4–16.6); and ustekinumab, 15.1 (10.8–21.1) No significant increases in the risk of SI were observed for etanercept (HR 1.10, 95% CI 0.75–1.60), adalimumab (HR 0.93, 95% CI 0.69–1.26), or ustekinumab (HR 0.92, 95% CI 0.60–1.41) compared with non-biologic systemic therapies or methotrexate only (etanercept: HR 1.47, 95% CI 0.95–2.28; adalimumab: HR 1.26, 95% CI 0.86–1.84; ustekinumab: HR 1.22, 95% CI 0.75–1.99)
2018, Hou et al. [17]	2032 subjects receiving TNF inhibitors vs. 1030 subjects receiving placebo and/or traditional DMARDs	SR with MA Includes 12 studies, all RCTs Includes patients with AS	Risk of SI events (OR 1.59; 95% CI 0.63–4.01) in patients treated with TNF inhibitors as a group was not significantly different from those treated with placebo in the control group
2018, Kirchgesner et al. [18]	190,694	Multicenter retrospective study Only patients with IBD	Compared with anti-TNF monotherapy, combination therapy was associated with increased risks of SI (HR 1.23; 95% confidence interval [CI] 1.05–1.45) and opportunistic infection (HR 1.96; 95% CI 1.32–2.91) Compared with thiopurine monotherapy, anti-TNF monotherapy was associated with increased risks of SI (HR 1.71; 95% CI 1.56–1.88), mycobacterial infection (HR 1.98; 95% CI 1.15–3.40), and bacterial infection (HR 2.38; 95% CI 1.23–4.58, respectively) Conversely, anti-TNF monotherapy was associated with decreased risk of opportunistic viral infection compared with thiopurine monotherapy (HR 0.57; 95% CI 0.38–0.87)
2019, Aydin et al. [19]	413,500 patients with rheumatological disease, with 2117 patients with anti-TNFα therapy	Retrospective multicenter study Includes RA, ankylosing spondylitis, juvenile idiopathic arthritis, or PsoA	Incidence of TB in the anti-TNF group vs. the control group was 189 versus 31 cases per 100,000 patients, respectively), giving a 2-year RR of 6.07 (95% CI 2.25–16.42) with an attributed risk of 0.16% Risk was higher in RA and PsoA
2019, Ritchlin et al. [20]	4315	Multicentric prospective study Includes patients with PsoA	138 SI were reported, with incidence rates per 100 patient-years as follows: ustekinumab, 1.00; TNF inhibitors, 2.22; infliximab, 2.12; etanercept, 2.58; adalimumab, 1.99; non-biologic/MTX, 3.01; non-biologic/non-MTX, 2.31
2020, Law et al. [21]	> 100,000	SR and MA Includes 63 studies, all observational studies Includes patients with IBD	Overall infectious complications were increased in patients who received anti-TNF agents (OR 1.26; 95% CI 1.07–1.50) and corticosteroids (OR 1.34; 95% CI 1.25–1.44) and decreased in those who received 5-aminosalicylic acid (OR 0.63; 95% CI 0.46–0.87)
2020, Li et al. [22]	11,590	Multicentric retrospective study Includes patients with Pso or PsoA	Class-specific IRs were similar among IL-17 and TNF, yet significantly lower for IL-12/23 After adjustment for potential confounding factors, there was no increased risk with IL-17 compared with either TNF (HR 0.89, 95% CI 0.48–1.66) or ustekinumab (HR 1.12, 95% CI 0.62–2.03) By contrast, ustekinumab was associated with a lower risk of infections than TNF (HR 0.59, 95% CI 0.39–0.90)
2020, Kedia et al. [23]	130,114 patients	SR with MA Includes 128 studies (all type of studies), in patients with IBD Includes patients with ADA or IFX	373/130,114 developed TB (prevalence 0.08% [95% CI 0.05–0.10%]) Risk increased with increasing TB burden 73% of patients who developed TB had no evidence of latent TB on screening, the proportion being independent of TB burden There was no effect of disease or treatment type, study type, gender, age at IFX/ADA initiation, and follow-up duration on TB prevalence
2021, Li et al. [24]	75,406	SR with MA 23 studies, all clinical trials Includes patients with RA, PsoA, and AS	Exposure to anti-TNFα agents was associated with increased risk of SI under the random-effects model (OR 1.72, 95% CI 1.56–1.90, p < 0.00001) However, exposure to anti-TNFα agents was not associated with increased risk of TB under the random-effects model (OR 2.55, 95% CI 0.40–16.23, p = 0.32)
2021, Penso et al. [25]	44,239	Multicenter prospective study Includes patients with psoriasis Includes various type of drugs for psoriasis: anti-TNF, anti-IL-17, anti-IL-23 (only guselkumab, ustekinumab, and apremilast)	Risk of SI was higher for adalimumab (HR 1.22; 95% CI 1.07–1.38) or infliximab (HR 1.79; 95% CI 1.49–2.16) vs. etanercept, whereas ustekinumab was associated with lower risk of having an SI (HR 0.79; 95% CI 0.67–0.94) Risk of SI was not increased in anti-IL-17 and guselkumab vs. etanercept The most frequent SI were gastrointestinal infections (645 patients [38.9%]) Risk of SI was increased with concomitant nonsteroidal anti-inflammatory drugs or systemic corticosteroids
2022, Redeker et al. [26]	13,991	Multicenter prospective study Includes patients with RA	Cumulative incidence of HZ was highest for tsDMARDs (21.5, 95% CI 16.4–27.9), followed by B cell targeted therapy (10.3, 95% CI 8.0–13.0) and anti-TNF (9.3, 95% CI 7.7–11.2), IL-6 inhibitors (8.8, 95% CI 6.9–11.0)
2022, Davidson et al. [27]	16,343,451 ISCR; 17,398 ICSR for ustekinumab, 15,768 for secukinumab, and 896,709 for TNFα inhibitors (etanercept, infliximab, and adalimumab)	World-wide dataset of WHO Pharmacovigilance program Includes all diagnosis	For bacterial skin infections, ustekinumab showed the strongest association (ROR 6.09; 95% CI 5.44–6.81); among the TNFα inhibitors, infliximab showed the strongest association (ROR 4.18; 95% CI 3.97–4.40) Risk was comparable between infliximab and secukinumab (ROR 3.51; 95% CI 3.00–4.09) Secukinumab showed the strongest association with herpes simplex infection (ROR 4.80; 95% CI 3.78–6.10) All biologics were equally associated with HZ Infliximab was the only biologic associated with cytomegalovirus infection (ROR 5.66; 95% CI 5.08–6.31) and had the strongest association with Epstein–Barr virus infection (ROR 6.90; 95% CI 6.03–7.90)
2022, Wang et al. [28]	15,464	SR with MA Includes 48 RCTs Patient with psoriasis	MA demonstrated a slightly increased overall infection risk (RR 1.09; 95% CI 1.02–1.15) but no SI risk (RR 0.95; 95% CI 0.61–1.49) among patients receiving anti-TNF There were also no increased risks of upper respiratory infections (RR 1.10; 95% CI 0.94–1.28) or nasopharyngitis (risk ratio 1.14; 95% CI 1.00–1.30) Only etanercept and certolizumab pegol were, respectively, associated with an increased risk of overall infection (RR 1.14, 95% CI 1.03–1.27) and upper respiratory infections (RR 1.42, 95% CI 1.02–1.98)
2022, Jin et al. [29]	123,383	Multicenter retrospective study Includes patients with Pso and PsoA	Compared with ustekinumab, the combined weighted HRs (95% CI) for SI 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, 1.74 (95% CI 1.00–3.03) for golimumab, 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 of Candida infection compared with placebo, but there was no difference in Candida 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)
2022, Jung et al. [31]	4736	Retrospective multicentric study Includes patients with RA Includes patients treated with anti-TNF and tocilizumab	When compared with etanercept, infliximab showed a higher risk of TB (aIR 2.71, 95% CI 1.05–7.01), especially in patients without evidence of LTBI Other TNF inhibitors and tocilizumab showed a comparable incidence of TB, regardless of treatment for LTBI No significant difference in TB incidence after biologic therapy between patients with and without LTBI treatment (627.9/100,000 vs. 529.5/100,000 person-years) In patients treated for LTBI, no differential risk of TB was observed among biologic drugs
2023, Glintborg et al. [32]	23,938	Retrospective multicentric study Includes patients with axial SpA 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)
2023, Feng et al. [33]	3564	SR with MA Includes 18 RCTs Includes patients with AS	Compared with the placebo group, the incidences showed no difference and were only slightly increased numerically for serious adverse events, SI, upper respiratory tract infection, and malignancies in patients treated with TNFα inhibitors
2023, Kim et al. [34]	40,322	Multicentric retrospective study Includes patients with AS, Pso, and PsoA	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 axial spondyloarthritis	Statistically significant increased risk of infections for patients with axial SpA (RR 1.32, 95% CI [1.14–1.52]), but not for patients with PsA (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 shown
2023, Kridin et al. [36]	40,824	Global cohort study Includes patients with psoriasis Includes patients with anti-IL-23, anti-IL-17, and TNF inhibitors	Compared with anti-TNF, IL-23 inhibitors had a lower risk of otitis media (HR 0.66; 95% CI 0.44–0.97), encephalitis (HR 0.18; 95% CI 0.04–0.78), HZ (HR 0.58; 95% CI 0.41–0.82), HBVR (HR 0.24; 95% CI 0.12–0.47), cytomegalovirus (HR 0.25; 95% CI 0.07–0.86), influenza (HR 0.52; 95% CI 0.38–0.71), and parasitic diseases (HR 0.78; 95% CI 0.64–0.95) Compared with anti-TNF, IL-17 inhibitors were associated with a decreased risk of pneumonia (HR 0.76; 95% CI 0.68–0.85), septicemia (HR 0.84; 95% CI 0.72–0.97), upper respiratory tract infection (HR 0.84; 95% CI 0.77–0.92), HZ (HR 0.79; 95% CI 0.67–0.92), HBV (HR 0.59; 95% CI 0.46–0.76), and HCV reactivation (HR 0.71; 95% CI 0.57–0.88), cytomegalovirus (HR 0.58; 95% CI 0.36–0.93), Epstein–Barr virus (HR 0.38; 95% CI 0.19–0.75), influenza (HR 0.70; 95% CI 0.61–0.81), and parasitic diseases (HR 0.80; 95% CI 0.72–0.88)
2024, Lazaridou et al. [37]	1696	SR with MA Includes trials and observational studies Includes patients with HS 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

ADA adalimumab, AE adverse events, ALT alanine aminotransferase, AS ankylosing spondylitis, b/tsDMARDs biological/targeted synthetic disease-modifying antirheumatic drugs, CD Crohn’s disease, CI confidence interval, CZP certolizumab pegol, DMARD disease-modifying antirheumatic drugs, ESI events of special interest, EY exposure years, ETN etanercept, HBV hepatitis B virus, HBVR HBV reactivation, HCV hepatitis C virus, HR hazard ratio, HSV herpes simplex virus, HZ herpes zoster, IBD inflammatory bowel disease, IFX infliximab, Ig immunoglobulin, IL interleukin, IMIDs immune-mediated inflammatory diseases, INH isoniazid, IRR incidence rate ratio, IR incidence ratio, JIA juvenile idiopathic arthritis, LTBI latent TB infection, MA meta-analysis, MTX methotrexate, nbDMARD nonbiological disease-modifying antirheumatic drugs, OI opportunistic infection, OR odds ratio, PDE4 phosphodiesterase 4, Pso psoriasis, PsoA psoriatic arthritis, PY person-years, PYF person-years follow-up, RA rheumatoid arthritis, R receptor, RCT randomized clinical trial, RR relative risk, ROR relative odds ratio, RTX rituximab, SAE serious adverse events, SI serious infections, SIE serious infection events, SIR standardized incidence rate, SSSI serious skin and soft tissue infections, SR systematic review, SpA spondylarthritis, TB tuberculosis, TCZ tocilizumab, TNF tumor necrosis factor, UST ustekinumab, UC ulcerative colitis

Anti-TNFs

We found 33 studies regarding anti-TNF agents and the risk of infections and OI [6–38].

In the first study documented in 2013, involving more than 10,000 patients with RA in a multicenter prospective study, the use of TNF inhibitors did not result in a higher rate of skin infections compared to patients undergoing other disease-modifying antirheumatic treatments (hazard ratio [HR] 1.4, 95% CI 0.9–2.4) [6]. Diverse SR and MA have also analyzed this risk. An SR performed by Dulai et al., including more than 5000 patients, revealed that the rate of severe infections in children with IBD treated with anti-TNF was similar to patients receiving immunomodulatory therapies, but lower than those treated with corticosteroids and adults treated with anti-TNF [9]. This low risk was subsequently supported by another SR with MA, which included 12 randomized clinical trials (RCTs), where it was concluded that the rate of severe infections in patients with ankylosing spondylitis undergoing anti-TNF was similar to patients receiving a placebo (odds ratio [OR] 1.59, 95% CI 0.63–4.01) [17], or in the recent SR with MA by Feng et al., including 18 RCTs and more than 3500 patients with axial spondyloarthritis (AS), where the risk was equally low [30]. However, other SRs and MAs have reported a higher incidence of infections and OI in patients undergoing anti-TNF [21, 24, 28, 35]. In this regard, an MA by Wang et al., including 48 RCTs and more than 15,000 patients, showed a slightly increased overall infection risk with anti-TNF (relative risk [RR] 1.09; 95% CI 1.02–1.15), but not a serious infection risk (RR 0.95; 95% CI 0.61–1.49) [28]. Multiple studies have evaluated the comparative risks of different anti-TNF agents: some revealed that there are no differences between the different anti-TNF agents [8, 15, 16, 20, 29]. However, other studies have reported a lower incidence with etanercept (both globally and in OI) [10, 12–14, 36]. Similarly, a higher incidence with infliximab than with adalimumab has been reported (both globally and in OI) [6, 13, 25, 36].

Regarding TB, numerous studies have assessed the specific risk of TB reactivation with anti-TNF agents [12, 14, 15, 19, 23, 24, 36]. Overall, most studies indicated an increased risk compared to the general population or to other agents. Recently, an SR with MA by Kedia et al., comprising 128 studies and more than 130,000 patients, analyzed the risk of TB reactivation in patients with IBD and calculated a prevalence of 0.08%. Additionally, 78% of patients who developed TB had no evidence of latent TB on screening, and this proportion was independent of TB burden [23].

There are also several studies that specifically evaluate the risk of HZ or herpes simplex virus (HSV) with anti-TNF agents [7, 8, 27, 38]. Overall, most studies indicate anti-TNF medication as a risk factor for herpes zoster (HZ) infection and progression. A multicenter retrospective study by Santella et al., involving more than 15,000 patients with IBD, concluded that the use of anti-TNF was associated with an overall increased risk of HZ (OR 1.5; 95% CI 1.1–2.1). This risk was increased among those older than 50 years (OR 2.1; 95% CI 1.2–3.6) and those also using steroids and immunosuppressants (OR 4.1; 95% CI 2.3–7.2) [38].

Regarding hepatitis, we found two studies specifically addressing the relationship between anti-TNF and the risk of HBV reactivation (some also discussing the risk of hepatitis C). Both revealed an augmented risk in patients undergoing anti-TNF [39, 40].

Anti-TNF Versus Other Biologics

Most studies showed an increased incidence of infections and OI in patients with anti-TNF compared to ustekinumab [20, 22, 25, 29]. The comparison between anti-TNF and anti-IL-17 yielded varied results. A recent study on a global cohort by Kridin et al. (> 40,000 patients) indicated that the infectious risk is generally lower in patients undergoing anti-IL-17 than anti-TNF, especially in certain infections such as pneumonia, septicemia, upper respiratory tract infection, HBV, HZ, hepatitis C virus, cytomegalovirus, Epstein–Barr virus, influenza, and parasitic disease [36]. However, multiple studies have shown that the risk of infection deriving from treatment with anti-TNF and anti-IL-17 can be comparable [22, 25, 30, 35, 37], or even higher with the latter [32].

The risk of infection has been reported to be lower with anti-IL-23 than with anti-TNF [36]. Regarding rituximab, a multicenter retrospective study (n = 3500) found similar infection rates between anti-TNF and rituximab [41]. However, another multicenter retrospective study (n = 3301 individuals, most of them with RA) showed an increased rate of infection in rituximab patients in the first 12 months compared to anti-TNF individuals [10].

Anti-TNF Versus JAK Inhibitors

Studies comparing infection rates between biologics and JAK inhibitors are summarized in Table 2 [39, 42–55].

Table 2.

Main studies comparing infection rates between biologics and JAK inhibitors

Year, authors	N	Study design	Main results
2015, Strand et al. [42]	40,512	SR with MA Includes 66 RCTs and 22 long-term extension studies Patients with RA	Estimated IRs (95% CIs) for RTX and TNF inhibitors were 3.72 (2.99, 4.62) and 4.90 (4.41, 5.44), respectively. Incidence rates (95% CIs) for tofacitinib 5 and 10 mg twice daily (BID) in phase 3 trials were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02), respectively. Corresponding IRs in long-term extension studies were 2.50 (2.05, 3.04) and 3.19 (2.74, 3.72) The risk of SI with tofacitinib was comparable to published rates for bDMARDs in patients with moderate to severely active RA
2016, Curtis et al. [43]	2526 tofacitinib patients were compared with other biologics: anti-TNF (n = 42,850), rituximab (n = 5078), and tocilizumab (n = 6967)	Multicenter retrospective study Includes patients with RA	When compared with other biologics, the risk of HSV and VZ infection was approximately double [HR 2.01 (95% CI 1.40–2.88)] with tofacitinib than with the other biologics
2020, Pawar et al. [44]	130,718	Multicentric retrospective study Includes patients with RA	Adjusted HR for SI associated with tofacitinib was 1.41 (95% CI 1.15–1.73) vs. etanercept 1.20 (0.97–1.49) The SI risk with tofacitinib was similar to adalimumab (1.06, 0.87–1.30) and certolizumab (1.02, 0.80–1.29), and was lower than infliximab (0.81, 0.65–1.00) Tofacitinib was associated with a twofold higher risk of HZ versus all bDMARDs
2021, Blauvelt et al. [45]	924 patients with upadacitinib vs. 344 patients with dupilumab	24-Week, head-to-head, phase 3b, multicenter RCTs Includes patients with AD	Rates of SI (4 [1.1%] vs. 2 [0.6%]), eczema herpeticum (1 [0.3%] vs. 0%), and HZ (7 [2.0%] vs. 3 [0.9%]) were numerically higher for patients treated with upadacitinib than those treated with dupilumab, all at generally low levels
2022, Balanescu et al. [46]	4362	Open-label, randomized controlled ORAL Surveillance trial Includes patients with RA	IRs/HRs for all infections, SI events and non-SI were higher with tofacitinib (10 > 5 mg two times per day) vs. anti-TNF For SIs, HR (95% CI) for tofacitinib 5 and 10 mg two times per day versus TNFi, respectively, were 1.17 (0.92–1.50) and 1.48 (1.17–1.87) Increased IRs/HRs for all infections and SIs with tofacitinib 10 mg two times per day versus anti-TNF agents were more pronounced in patients aged ≥ 65 vs. 50 to < 65 years
2022, Ytterberg et al. [47]	1455 patients received tofacitinib 5 mg/12 h, 1456 received tofacitinib 10 mg/12 h, and 1451 received a TNF inhibitor	Randomized, open-label, noninferiority, post authorization, safety end-point trial Includes patients with RA	Incidences of adjudicated OI (including HZ and TB), all HZ (nonserious and serious) were higher with tofacitinib than with a TNF inhibitor
2022, Vassilopoulos et al. [48]	17,197	SR with MA Includes 47 studies, all clinical trials Patients with PsoA	Cumulative incidence of OIs was as follows: JAK inhibitors, 2.72% (95% CI 1.05–5.04%); anti-IL-17, 1.18% (95% CI 0.60–1.9%); anti-IL-23, 0.24% (95% CI 0.04–0.54%); anti-TNFs, 0.01% (95% CI 0.00–0.21%) Cumulative incidence of HZ infection following treatment with JAK inhibitors was 2.53% (95% CI 1.03–4.57%) and the cumulative incidence of opportunistic Candida spp. infections following treatment with anti-IL-17 was 0.97% (95% CI 0.51–1.56%)
2022, Cheng et al. [49]	9096, 2420, and 305 patients with IBD initiating anti-TNF, UST, and tofacitinib therapy, respectively	Retrospective multicentric study Patients with IBD	Over follow-up on-treatment, 7% and 44% of anti-TNF patients had infection-related hospitalizations and developed infections, respectively, compared with 4% and 32% of UST patients and 6% and 41% of tofacitinib patients UST was associated with a significantly lower risk of infection (HR 0.93; 95% CI 0.86–0.99) compared with anti-TNF therapy Risk of infections (HR 0.97; 95% CI 0.75–1.24) or infection-related hospitalizations (HR 0.59; 95% CI 0.27–1.05) was similar between patients on tofacitinib and anti-TNF
2022, Burmester et al. [50]	2257	Post-trial analysis focalized into safety Includes patients with active PsoA undergoing upadacitinib or adalimumab	Upper respiratory tract infection was the most common AEs with upadacitinib Rates of HZ and OI (excluding TB, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab
2022, Winthrop et al. [51]	5306	Pooled analysis of six phase III clinical trials Includes patients with RA	Incidence rate of HZ/100 patient-years (95% CI) was 0.8 (0.3–1.9), 1.1 (0.5–1.9), 3.0 (2.6–3.5), and 5.3 (4.5–6.2) in the MTX monotherapy, ADA + MTX, UPA 15 mg and UPA 30 mg groups, respectively Most HZ cases with UPA (71%) involved a single dermatome
2023, Hong et al. [39]	2252	SR with MA Included 26 studies (all type of studies) of 2252 HBsAg−/HBcAb+ patients with RA	HBV reactivation rate of RTX, abatacept, JAK inhibitors, IL-6, and anti-TNFα were 9.0% (95% CI 0.04–0.15; I2 = 61%, p = 0.03), 6.0% (95% CI 0.01–0.13; I2 = 40%, p = 0.19), 1.0% (95% CI 0.00–0.03; I2 = 41%, p = 0.19), 0.0% (95% CI 0.00–0.02; I2 = 0%, p = 0.43), 0.0% (95% CI 0.00–0.01; I2 = 0%, p = 0.87), respectively There is a high potential risk of HBV reactivation in HBsAg−/HBcAb+ patients with RA receiving RTX treatment, especially HBsAb− patients. However, it could be relative safety to use the inhibitors of IL-6, TNFα, and JAK in these patients
2023, Chiu et al. [52]	54,369	SR with MA Includes 94 randomized controlled trials Includes patients with Pso and PsoA	For patients with Pso, bimekizumab, secukinumab, risankizumab, ustekinumab, apremilast, guselkumab, and adalimumab were associated with significantly higher risks of infection than placebo; the surface under the cumulative ranking area (SUCRA) ranked infliximab, deucravacitinib, and bimekizumab with the highest risks of infection For patients with PsA, bimekizumab, apremilast, and upadacitinib (30 mg daily) were associated with higher risks of infection; SUCRA ranked bimekizumab with the highest risk of infection No treatments, except for upadacitinib (30 mg daily), were associated with a higher risk of SI than placebo in PsoA
2023, Choi et al. [53]	2963 JAK inhibitors initiators vs. 5169 TNF inhibitors initiators	Retrospective multicentric study Includes patients with RA Includes patients with tofacitinib, baricitinib, adalimumab, infliximab, golimumab, etanercept, and abatacept	During a follow-up of 1.16 years, the most frequent type of infection was HZ with IR per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively IR of serious bacterial infections was 1.39 and 1.32, respectively OIs were rare with a majority being TB and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively There was an exceptionally high IR of HZ in both treatment groups, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of serious bacterial infections was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators
2023, Simpson et al. [54]	643	Post hoc analysis of the JADE COMPARE trial Includes patients with AD	Proportions of nasopharyngitis and upper tract infections were similar between dupilumab and abrocitinib No cases of HZ were recorded in either of the 2 groups
2024, Mysler et al. [55]	> 10,000	SR Includes 25 RCTs Includes patients with RA, PsoA, and AD	Most of the reported studies did not find a higher rate of infections with upadacitinib compared to other agents (especially anti-TNF)

AD atopic dermatitis, b/tsDMARDs biological/targeted synthetic disease-modifying antirheumatic drugs, HBV hepatitis B virus, HBVR HBV reactivation, HR hazard ratio, HSV herpes simplex virus, HZ herpes zoster, IBD inflammatory bowel disease, IR incidence rate, MA meta-analysis, MTX methotrexate, nbDMARD nonbiological disease-modifying antirheumatic drugs, OI opportunistic infection, OR odds ratio, Pso psoriasis, PsoA psoriatic arthritis, RA rheumatoid arthritis, RCT randomized clinical trial, RR relative risk, RTX rituximab, SI serious infections, SR systematic review, TB tuberculosis, TNF tumoral necrosis factor, UST ustekinumab

Concerning JAKi, most studies have revealed a higher rate of infections and OI with JAKi (JAKi as a group [48] and especially tofacitinib [47]) when compared to anti-TNF. An SR and MA including 47 clinical trials and more than 17,000 patients showed that the cumulative incidence of OI was 2.72% (95% CI 1.05–5.04%) with JAKi; 1.18% (95% CI 0.60–1.9%) with anti-IL-17; 0.24% (95% CI 0.04–0.54%) with anti-IL-23; and 0.01% (95% CI 0.00–0.21%) with anti-TNFs [48]. However, in a retrospective multicenter study on more than 11,000 individuals with IBD, the risks of infections (HR 0.97; 95% CI 0.75–1.24) or infection-related hospitalizations (HR 0.59; 95% CI 0.27–1.05) were similar between patients on tofacitinib and anti-TNF [49].

Regarding HZ, a higher incidence of HZ has been reported with anti-TNF than with anti-IL-23 [36], although a lower infection risk than with upadacitinib [50] or tofacitinib [43]. A recent multicentric retrospective study on 130,718 patients with RA showed that tofacitinib was associated with a twofold higher risk of HZ versus all biological disease-modifying antirheumatic drugs (bDMARDs) [44].

The risk of HBV reactivation can be increased with anti-TNF therapy, although this risk seems higher with rituximab than with anti-TNFs or with JAKi [39, 40]. A recent SR and MA, including 26 studies and 2252 HBsAg−/HBcAb+ patients with RA, showed that HBV reactivation rates of rituximab, JAKi, and anti-TNFα were 9.0% (95% CI 0.04–0.15; p = 0.03), 1.0% (95% CI 0.00–0.03; p = 0.19), and 0.0% (95% CI 0.00–0.01; p = 0.87), respectively [39].

Anti-IL-17 and Risk of Infections

Studies assessing the relationship between anti-IL-17 and infections are summarized in Table 3 [29, 30, 32, 34, 35, 37, 56–65].

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

A total of 16 studies were selected to assess the risk of infections and OI with anti-IL-17 agents: 7 with anti-IL-17 as a group [29, 30, 34, 35, 37, 56, 57], 3 with secukinumab [32, 58, 59], 2 with ixekizumab [60, 61], 2 with brodalumab [62, 63], and 2 with bimekizumab [64, 65].

Overall, the risk of infections was low, especially the risk of TB, as shown by a multicenter retrospective study with more than 40,000 patients [34]. The increased incidence of Candida infections in patients undergoing anti-IL-17 is noteworthy [30, 35, 56]. A recent study using data from over 1,000,000 records demonstrated a strong association between anti-IL-17 and candidiasis (OR 10.20), particularly for cutaneous (OR 12.28), oropharyngeal (OR 19.18), and esophageal candidiasis (OR 21.20) [56]. The risk of infections was similar for all IL-17 inhibitors [30, 32, 34, 35, 37, 56, 57].

Anti-IL-23 and Risk of Infections

Seven studies were reviewed to assess the risk of infection and OI with anti-IL-23 agents (Table 3) [66–72]: one with anti-IL-23 [66] as a group, two with guselkumab [67, 68], two with risankizumab [69, 70], and two with guselkumab [71, 72]. The rate of infections and OI was very low, and lower than other BD and JAKi. A lower rate of infections and OI (including HZ) with anti-IL-23 compared to JAKi has also been reported recently in an SR [48].

Ustekinumab (Anti-IL-12/23) and Risk of Infections and Opportunistic Infections

Twelve studies assessed the risk of infections and OI with ustekinumab [13, 16, 20, 22, 25, 27, 29, 30, 49, 52, 79, 80] (Table 3). As mentioned earlier, the overall risk of infections and OI with ustekinumab is low, and inferior to that of anti-TNF agents or JAKi [13, 20, 22, 25, 29, 52]. The risk of TB and TB reactivation is minimal with ustekinumab [80].

Anti-IL-1 and Risk of Infections

Seven studies were included to assess the risk of infection and OI with anti-IL-1 and derivatives: one evaluating anti-IL-1 as a group [37], three on anakinra [75–77], two on canakinumab [78, 79], and one on rilonacept [80]. In general, the rate of infections and OI with this group was low, comparable to the general population and other biological drugs, and it decreased over time [37, 75–80].

Rituximab (Anti-CD20) and Risk of Infections

Studies assessing the relationship between rituximab and infections are summarized in Table 4 [39–41, 43, 76, 81–87].

Table 4.

Main studies that assess the relationship between infections and rituximab, anti-IL-4/13 agents, omalizumab, anti-IL-31 agents, and omalizumab

Agent	Year, authors	N	Study design	Results
Rituximab (CD20 inhibitor)	2015, Aaltonen et al. [41]	3762	Multicentric retrospective study Includes patients with RA	341 SI were registered Adjusted incidence RR of infections compared to DMARD users were 1.2 (95% CI 0.63–2.3), 0.84 (95% CI 0.53–1.3), 0.98 (95% CI 0.60–1.6), and 1.1 (95% CI 0.59–1.9) for patients treated with IFX, etanercept, adalimumab, and RTX, respectively Crude rates of malignancies were highest among the users of cDMARD and RTX, and lowest among patients treated with IFX with no differences in aIRR
	2015, Mozessohn et al. [81]	578	MA Includes data from 15 observational studies on HBsAg-negative/HBcAb-positive patients receiving rituximab for lymphoma	Clinical HBV reactivation was estimated at 6.3% (I2 = 63%, p = 0.006). Significant heterogeneity was detected Reactivation rates were higher in prospective vs. retrospective studies (14.2% vs. 3.8%; OR 4.39, 95% CI 0.83–23.28) MA confirms a measurable and potentially substantial risk of HBV reactivation in HBsAg-negative/cAb-positive patients with lymphoma exposed to rituximab
	2016, Curtis et al. [43]	2526 tofacitinib were compared with other biologics: anti-TNF (n = 42,850), rituximab (n = 5078), and tocilizumab (n = 6967)	Multicenter retrospective study Includes patients with RA	When compared with other biologics, the risk of HSV and HZ infection was approximately double [HR 2.01 (95% CI 1.40–2.88)] with tofacitinib than with the other biologics
	2016, Cabral et al. [76]	4120	SR Includes 6 observational studies Includes patients with RA	129 patients with anakinra (5.1%) had severe infections, of which three died With respect to rituximab, 72 (5.9%) patients had severe infections, two of whom died Main site of infection for these two drugs was the respiratory tract
	2019, Grøn et al. [82]	6262	Multicentric retrospective study Includes patients with RA	Risk of infection was higher in patients with rituximab than with tocilizumab, although they were also older patients and with more comorbidities The most common infections were those of the upper respiratory tract
	2019, Shi et al. [83]	9502 patients (4595 with rituximab-RTX treatment vs. 4907 with non-RTX treatment)	MA Includes 11 observational studies in patients with RA	No significant differences between RTX and non-RTX treatment groups in overall infections rate (43.3% vs. 44.9%; OR 0.87; 95% CI 0.70–1.08) and SI rate (4.1% vs. 4.6%; OR 1.05; 95% CI 0.84–1.31) Subgroup analysis also showed no significant differences in overall infections between RTX versus placebo (OR 0.98, 95% CI 0.71–1.33); RTX versus TNFi (OR 0.47, 95% CI 0.30–1.73); and in SI between RTX versus placebo (OR 1.06, 95% CI 0.36–3.07); RTX versus TNFi (OR 1.25, 95% CI 0.96–1.63)
	2020, Grøn et al. [84]	2132	Retrospective multicenter study Includes patients with RA	164 infections: rituximab, 87 (95% CI 79, 96); tocilizumab, 77 (95% CI 71, 84) Adjusted RRs were 0.94 (95% CI 0.81, 1.03) for tocilizumab compared with rituximab There was a tendency towards rituximab having the highest risk (more than tocilizumab), but CIs were wide in all analyses
	2020, Thery-Casari et al. [85]	1343	MA Includes 33 studies with patients with ANCA-AAV	Overall prevalence and incidence of SI was 15.4% (95% CI [8.9; 23.3], and 6.5 per 100 PY (95% CI [2.9; 11.4], respectively The most common infections were bacterial (9.4%, 95% CI [5.1; 14.8]) Prevalence of opportunistic infection was 1.5% (95% CI [0.5; 3.1],) including Pneumocystis jirovecii infections (0.2%, 95% CI [0.0; 0.6]), irrespective of prophylaxis administration Mortality related to infection was estimated at 0.7% (95% CI [0.2; 1.2], I2 = 27%)
	2023, Kridin et al. [86]	Rituximab (n = 963) vs. azathioprine or MMF (n = 963)	Multicentric retrospective study Includes patients with pemphigus	During the first 12 months after initiating the drug, patients under rituximab experienced elevated risk of COVID-19 (HR 1.82, 95% CI 1.06–3.14; p = 0.028), parasitic diseases (HR 3.22, 95% CI 1.04–9.97; p = 0.032) and CMV infection (HR 1.63, 95% CI 1.04–2.58; p = 0.033) For infections developing ≥ 12 months after drug initiation, rituximab was associated with greater risk of pneumonia (HR 1.45, 95% CI 1.00–2.10; p = 0.047), COVID-19 (HR 1.87, 95% CI 1.49–2.33; p < 0.001), osteomyelitis (HR 2.42, 95% CI 1.11–5.31; p = 0.023), HSV (HR 2.06, 95% CI 1.03–4.11; p = 0.037), and CMV infections (HR 1.63, 95% CI 1.07–2.49; p = 0.023)
	2023, Pouransiri et al. [87]	668	SR with MA Includes 7 observational studies among children and adolescents with glomerular disease (LN or others)	Administration of RTX was significantly associated with lower risk of infectious complications in patients with LN and nephrotic syndrome (0.72 [95% CI 0.58, 0.85]) when compared with population data of patients without glomerular disease (p = 0.2)
	2024, Kuo et al. [40]	416	Retrospective multicentric study Includes HBsAg−/HBcAb+ patients with RA	RTX had the highest risk for HBV reactivation (IR 48.3 per 1000 PY), followed by abatacept (IR 24.0 per 1000 PY) In multivariate analysis, RTX (aHR 15.77, 95% [CI] 4.12–60.32, p = 0.001), abatacept (aHR 9.30, 1.83–47.19, p = 0.007), adalimumab (aHR 3.86, 1.05–14.26, p = 0.04), and negative baseline HBV surface antibody (anti-HBs, < 10 mIU/mL) were independent risk factors for HBV reactivation
Dupilumab (IL-4/13 inhibitor)	2018, Fleming et al. [89]	2706	SR Includes 8 RCTs in patients with AD	Relative risk of skin infection was 0.54 (95% CI 0.42–0.70) and OR of eczema herpeticum was 0.34 (95% CI 0.14–0.84) for dupilumab compared with placebo No significant association was found for dupilumab with overall herpesvirus infections (RR 1.16; 95% CI 0.78–1.74) and overall infections (RR 0.98; 95% CI 0.83–1.16)
	2020, Ando et al. [90]	2640	SR with MA Includes 3 RCTs Includes patients with allergic asthma	No significant differences in the incidence of AEs between dupilumab or benralizumab and placebo, with OR and 95% CrI of 0.830 (0.591–1.165) and 0.811 (0.619–1.061), respectively
	2021, Halling et al. [91]	3303	SR and MA Includes 22 observational studies in patients with AD	HSV was reported by a pooled proportion of 5.8% (95% CI 3.3–9.0) of 546 patients with AD (data of 6 studies). There were cases of non-ocular HSV, reactivation of herpes uveitis, and reactivation of orofacial HSV
	2021, Schneeweiss et al. [92]	1775 dupilumab vs. 1034 MTX, 186 cyclosporine, and 257 MMF users	Prospective multicentric study Includes patients with AD	Risk of SI was 0.6% in dupilumab and 1.0% in MTX initiators (RR 0.90; 95% CI 0.37–2.20) The relative risk for SI was 0.69 (95% CI 0.27–1.75) in dupilumab vs. MTX; 0.34 (95% CI 0.10–1.22) in dupilumab vs. cyclosporine; and 0.27 (95% CI 0.10–0.68) in dupilumab vs. mycophenolate
	2024, Marko et al. [93]	> 1000	MA Includes 7 RCTs in patients with AD	Statistically significant (p < 0.005) lower incidence rate in the dupilumab group compared to placebo for overall skin infections (RR 0.59, 95% CI [0.47, 0.75], p < 0.0001) and non-herpetic skin infections (RR 0.42, 95% CI [0.27, 0.66], p = 0.0001) For herpetic infections in phase 2b studies an MA demonstrated significantly higher events in dupilumab group compared to placebo (RR 3.38, 95% CI [1.98, 5.76]
Tralokinumab (IL-13 inhibitor)	2022, Blauvelt et al. [94]	1174	Post hoc analysis of clinical trials Includes patients with AD	The most reported AEs (2%) were viral upper respiratory tract infection, AD, and upper respiratory tract infection
Omalizumab (IgE receptor inhibitor)	2015, Lai et al. [95]	2749	SR with MA Includes 6 RCTs Includes patients with allergic asthma	Common AEs included upper respiratory tract infection and nasopharyngitis. No increased risk of parasitic infections was found
	2019, Rubini et al. [96]	> 2000	SR with MA Includes 13 studies (in the RS) and 6 studies (in the MA) in patients with CSU	The most frequent AEs were infections at the side injection and nasopharyngitis. No increased risk of parasitic infections was found
	2020, Jia et al. [97]	2863	SR with MA Includes 9 RCTs in patients with CSU	Adverse effects were dose dependent There were no higher rates of than in the placebo control group. No increased risk of parasitic infections was found
Nemolizumab (IL-31 inhibitor)	2022, Liang et al. [98]	809	SR with MA Includes 8 RCTs Includes patients with AD with pruritus	No significant difference was observed in the occurrence of any AEs (RR 1.03, 95% CI 0.93–1.13, p = 0.593; I2 = 0%) between nemolizumab and placebo Regarding infections, the most frequently reported AEs were infections and skin or subcutaneous tissue disorders, including nasopharyngitis (occurred in 10–32.7% of the patients)
Tocilizumab (IL-6 receptor inhibitor)	2020, Armaroli et al. [100]	2275	Multicentric retrospective study Includes patients with juvenile idiopathic arthritis	Both common and SI were significantly more frequent in IL-1 (IR 17.3, 95% CI 12.5/24 and IR 4.3, 95% CI 2.3/8.3) and IL-6 cohort (IR 16.7, 95% CI 13.9/20 and IR 2.8, 95% CI 1.8/4.4) compared to TNFα inhibitor cohort (IR 8.7, 95% CI 8.1/9.4 and IR 1, 95% CI 0.8/1.3)
	2022, Jung et al. [31]	4736	Multicentric retrospective study Includes patients with RA	No higher risk of tuberculous infections was found in patients treated with anti-TNF than with tocilizumab Risk was independent of anti-TB prophylaxis in both anti-TNF and tocilizumab
	2023, Broca et al. [101]	37	Multicentric retrospective study Includes patients with RA	25 patients (68%) had at least 1 infectious event and 15 SI occurred in 6 patients (3.2/100 patient-years), mainly bacterial Lower respiratory tract and skin were the main sites Severe bacterial infections were associated with a marked biological inflammatory syndrome, even under a cycle of administration of tocilizumab No tuberculosis or viral hepatitis reactivation was observed
	2024, Ko et al. [102]	347	SR with MA Includes 11 observational studies Includes patients with RA	Risk of HBVR in patients with RA with anti-HBs−, HBsAg+, or HBsAg−/anti-HBc+ cannot be ignored but may be avoided

AD atopic dermatitis, AE adverse events, aHR adjusted hazard ratio, ANCA anti-neutrophil cytoplasmic antibody, CI confidence interval, CMV cytomegalovirus, DMARD disease-modifying antirheumatic drugs, HBV hepatitis B virus, HBVR HBV reactivation, HR hazard ratio, HSV herpes simplex virus, HZ herpes zoster, LN lupus nephritis, MA meta-analysis, MMF mycophenolate mofetil, MTX methotrexate, OR odds ratio, PY person-years, RA rheumatoid arthritis, RR relative risk, RTX rituximab, SI serious infections, SR systematic review, TNFi tumor necrosis factor inhibitor

Thirteen studies evaluated the risk of infections and OI with rituximab [39–41, 43, 76, 81–88].

As mentioned previously, the overall infectious risk was increased with rituximab, both independently and when compared to other agents [82, 84]. A study involving nearly 2000 patients with pemphigus treated with rituximab or mycophenolate mofetil showed a higher incidence of SARS-CoV-2 (COVID-19) infection, parasites, cytomegalovirus, pneumonia, osteomyelitis, and herpes simplex virus in patients treated with rituximab [86]. However, Shi et al., with more than 9000 patients with RA, noted no significant difference between rituximab and non-rituximab treatment groups in overall infection rate (43.3% vs. 44.9%; OR 0.87; 95% CI 0.70–1.08) and serious infection rate (4.1% vs. 4.6%; OR 1.05; 95% CI 0.84–1.31) [83]. Other studies assessing the risk of infections and OI with rituximab indicate a comparable incidence between rituximab and anti-TNF [41], and a lower risk of HZ infection compared to tofacitinib [43]. In recent years, the possibility of Pneumocystis jirovecii infection in patients receiving rituximab has been highlighted. A recent series of 11 patients and review of the literature pointed out this risk, especially in patients concomitantly treated with prednisone at greater than 20 mg/day. In these individuals, cotrimoxazole prophylaxis should be considered [136]. Finally, it should be noted that rituximab treatment carried a significant risk of HBV reactivation [39, 40].

Dupilumab (Anti-IL-4/13) and Tralokinumab (Anti-IL-13), and Risk of Infections

Dupilumab

We found five studies with dupilumab which assessed the risk of infections and OIs [89–93] (Table 4).

Regarding dupilumab, the risk of infections was very low. Certain studies have reported a decreased risk of skin infections and eczema herpeticum in patients with AD [89, 93]. An MA including seven RCTs and more than 1000 patients revealed a lower incidence rate in the dupilumab group compared to placebo for overall skin infections (RR 0.59, 95% CI [0.47, 0.75], p < 0.0001) and non-herpetic skin infections (RR 0.42, 95% CI [0.27, 0.66], p = 0.0001) [93].

Dupilumab Versus JAK Inhibitors

Rates of infection were similar between dupilumab and abrocitinib in a post hoc analysis [54]. In a head-to-head trial with more than 1000 patients with AD evaluating dupilumab versus upadacitinib, rates of serious infection (4 [1.1%] vs. 2 [0.6%]), eczema herpeticum (1 [0.3%] vs. 0%), and HZ (7 [2.0%] vs. 3 [0.9%]) were numerically higher for patients treated with upadacitinib than those treated with dupilumab, all at generally low levels [45].

Tralokinumab

The rate of infections, serious infections, and OI was comparable to placebo [94].

Omalizumab (Anti-IgE) and Risk of Infections

In the three selected studies that assessed the risk of infections associated with the administration of omalizumab, the infection rate was very low, with the most common being upper respiratory tract infection and nasopharyngitis (Table 4) [95–97]. No increased risk of parasite infection was found.

Nemolizumab (Anti-IL-31) and Risk of Infections

We found one trial that analyzed the rates of infections and opportunistic infections with nemolizumab, and they were comparable to that of the general population [98] (Table 4). A retrospective real-life study of 15 patients with AD also found no increased risk of infections [99].

Tocilizumab (Anti-IL-6R) and Risk of Infections

Eight studies assessing infectious risk with tocilizumab were selected [26, 31, 39, 82, 84, 100–102] (Table 4). The risk of infections and OI in patients undergoing tocilizumab was generally higher than with anti-TNF [100], and comparable to this agents in terms of TB reactivation risk [31]. However, the risk of infections with tocilizumab has been reported to be lower than with rituximab [82, 84]. Finally, a very low rate of HBV reactivation has been demonstrated [39, 101, 102].

JAK Inhibitors and Risk of Infections

JAK Inhibitors (as a Group) and Risk of Infections

Studies assessing the relationship between JAK inhibitors and infections are summarized in Table 5 [39, 48, 52, 103–112].

Table 5.

Main studies that assess the relationship between JAK inhibitors and infections

Year, authors	N	Study type/design	Results
2019, Bechman et al. [103]	11,321	SR with MA Includes 21 clinical trials in patients with RA treated with tofacitinib, baricitinib, and upadacitinib	For SI, the IRRs were 1.97 (95% CI 1.41, 2.68), 3.16 (95% CI 2.07, 4.63), and 3.02 (95% CI 0.98, 7.04) for tofactiniib, baricitinib, and upadacitinib, respectively. The IRRs comparing treatment arm to placebo were statistically non-significant: 1.22 (95% CI 0.60, 2.45), 0.80 (95% CI 0.46, 1.38), and 1.14 (95% CI 0.24, 5.43), respectively For HZ, the incidence rates were 2.51 (95% CI 1.87, 3.30), 3.16 (95% CI 2.07, 4.63) and 2.41 (95% CI 0.66, 6.18), respectively. The IRR of HZ comparing baricitinib with placebo was 2.86 (95% CI 1.26, 6.50). Non-significant IRRs were seen with tofacitinib and upadacitinib: 1.38 (95% CI 0.66, 2.88) and 0.78 (95% CI 0.19, 3.22), respectively
2020, Cantini et al. [104]	35,856	SR Includes 40 clinical trials and observational studies in patients with RA treated with tofacitinib, baricitinib, upadacitinib, and filgotinib	Low frequency, not exceeding 0.25% of active TB cases in patients who were exposed to anti-JAKs Only 1 of 89 recorded cases in tofactinib and baricitinib exposure occurred in countries at intermediate or high TB risk, and most of the cases were probably due to first exposure
2020, Olivera et al. [105]	66,159	SR with MA Includes 82 studies (trials and observational studies) in patients with tofacitinib, upadacitinib, filgotinib, and baricitinib in patients with RA, IBD, psoriasis, or ankylosing spondylitis	Incidence rates of SI and HZ infection were 2.81 per 100 PY, and 2.67 per 100 PY, respectively MA showed a significant increase in risk of HZ infection among patients who received JAK inhibitors (RR 1.57; 95% CI 1.04–2.37)
2022, Wan et al. [106]	> 4000	MA Includes 10 studies (trials and observational studies) Includes patients with moderate-to-severe AD	MA suggested an increased incidence of AEs in patients treated by abrocitinib (OR 2.25, 95% CI 1.59–3.41) and upadacitinib (OR 1.48, 95% CI 1.02–2.27) compared with placebo Some of the most frequent adverse effects were upper respiratory tract infections and nasopharyngitis Subgroup network meta-analysis revealed that upadacitinib 30 mg significantly increased the incidence of AEs (OR 6.71, 95% CI 1.48–30.83) vs. other regimes
2022, Alves et al. [107]	> 100,000	SR with MA Includes 37 RCTs Patients with RA Includes all JAK inhibitors	Compared to filgotinib, adalimumab (4.81; 95% CI1.39–16.66), etanercept (6.04; 95% CI 1.79–20.37), peficitinib (7.56; 95% CI 1.63–35.12), tofacitinib (4.29; 95% CI 1.43–12.88), and upadacitinib (4.35; 95% CI 1.46–13.00) have an increased risk of HZ infection. This fact was not demonstrated in sensitivity analysis Risk of infections seemed to be similar among the currently approved JAK inhibitor drugs
2022, Sánchez-González et al. [108]	> 10,000	SR Includes 42 clinical trials Patients with RA treated with tofacitinib, baricitinib, upadacitinib, filgotinib, and peficitinib	HZ rates ranged between 1.51 and 20.22, and the incidence was proportional to the dose of the drug The most recent studies better categorized the incidence of HZ and its severity No comparisons were made between drugs
2023, Gialouri et al. [109]	> 10,000	SR Includes 78 studies: 53 clinical trials and 25 observational studies Includes patients with inflammatory arthritides or UC treated with tofacitinib, baricitinib, or upadacitinib	There was a higher HZ risk in patients with RA or UC than patients with PsoA treated with tofacitinib, in those treated with higher tofacitinib doses or with concomitant glucocorticoids
2023, Xu et al. [110]	24,142	SR with MA Includes 47 RCTs Includes patients with all inflammatory diseases	In patients with inflammatory diseases, peficitinib 100 mg QD was associated with the highest risk of HZ infection in patients with inflammatory diseases, followed by baricitinib 4 mg/day and upadacitinib 30 mg/day No difference in HZ risk was found for other JAK inhibitors compared with placebo Higher incidence of HZ was found in patients treated with baricitinib 4 mg/day, peficitinib 100 mg/day, and upadacitinib 30 mg only in patients with RA
2023, Yang et al. [111]	6802	SR with MA Includes 17 clinical trials Includes patients with psoriasis and PsoA	Considerable increase in the risk of infections including upper respiratory tract and HZ infection was observed among patients in the JAK inhibitors group For tofacitinib, upadacitinib, and filgotinib, infection was the most prevalent AE
2024, Yoon et al. [112]	7341	SR with MA Includes 14 RCTs Includes patients with AD with the following drugs: abrocitinib (10, 30, 100, and 200 mg), baricitinib (1, 2, and 4 mg), and upadacitinib (7.5, 15, and 30 mg)	Risk of HZ was significantly increased (RR 1.03–3.77, I2 = 0%) Risk of SI was not increased [0.88 (0.44–1.77, I2 = 0%)]

AE adverse events, CI confidence interval, HZ herpes zoster, IBD inflammatory bowel disease, IL interleukin, IRR incidence rate ratio, IR incidence ratio, MA meta-analysis, Pso psoriasis, PsoA psoriatic arthritis, PY person-years, RA rheumatoid arthritis, RR relative risk, SR systematic review, TB tuberculosis, TNF tumoral necrosis factor, UPA upadacitinib, UC ulcerative colitis, WHO World Health Organization

Thirteen studies were collected that evaluated the relationship between infectious risk and OI with JAKi as a group [39, 48, 52, 103–112]. This risk could be dose dependent [106, 108]. Regarding specific infections, the risk of TB reactivation, although low, has been documented for patients with JAKi [104]. Regarding HBV reactivation, a recent MA including 26 studies and more than 2000 patients showed that JAKi were safe in terms of HBV reactivation risk, unlike rituximab, which carried a significantly increased risk [39].

The rate of HZ was significantly increased in patients with JAKi [105, 107, 109, 112] especially at high doses [110], and rates were higher than those of anti-TNF agents [48] and anti-IL-17 [48]. A recent SR and MA, involving over 65,000 patients from 82 studies, showed a significant augmented risk of HZ infection among patients who received JAKi (RR 1.57; 95% CI 1.04–2.37) [105].

Abrocitinib and Upadacitinib (JAK1 Inhibitors), and Risk of Infections

Studies assessing the relationship between specific JAK inhibitors, abrocitinib and upadacitinib, and infections are summarized in Table 6.

Table 6.

Main studies that assess the relationship between specific JAK inhibitors and infections

JAK inhibitor	Year, authors	N	Study design	Results
Abrocitinib (selective JAK1 inhibitor)	2021, Simpson et al. [113]	2856	Safety data from phase II and phase III clinical trials (6 trials) Includes patients with AD	Incidence rates were 2.33/100 PY and 2.65/100 PY for SI, 4.34/100 PY and 2.04/100 PY for HZ, and 11.83/100 PY and 8.73/100 PY for HSV in the 200 mg and 100 mg groups, respectively. The risk was greater than placebo groups
Upadacitinib (selective JAK1 inhibitor)	2023, Zeng et al. [114]	2959	MA of 4 RCTs Includes patients with AD	No significant relationship was found between the risk of serious AEs or upper respiratory tract infections with upadacitinib
Upadacitinib and abrocitinib (selective JAK1 inhibitors)	2023, Guttman-Yassky et al. [115]	2485	Integrated analysis of phase 3 RCTs Includes patients with AD	Upper respiratory tract infections and oral herpes were the most frequent adverse effects both with upadacitinib and abrocitinib Cases of Kaposi's varicelliform rash and pneumonia were described with both of them
Baricitinib (JAK1 and JAK2 inhibitor)	2022, Taylor et al. [116]	3770	Long-term data in safety of clinical trial Includes patients with RA	IRs per 100 patient-years at risk were 2.6 and 3.0 for SI and HZ, respectively No clear dose differences were noted for exposure-adjusted IRs (per 100 PYE) for SI
	2023, Bieber et al. [117]	2636	Long-term data in safety of RCTs Includes patients with AD	IRs were 67.2 (any infection), 6.7 (HSV), 2.8 (HZ), and 0.3 (OI). No TB cases were reported Baricitinib maintained a similar safety profile to earlier analyses with no new safety signals
	2023, Mahmoud et al. [118]	1282	SR with MA Includes 3 RCTs on patients with AA	No higher rates of infections or malignancies were found than in the general population
Ruxolitinib (JAK1 and JAK2 inhibitor)	2018, Lussana et al. [119]	2340	SR with MA Includes 3 phase IIIa RCTs with their extended phase, 2 phase IIIb RCTs, 6 phase IV studies, and 28 case reports Includes all diagnosis	Orally administered ruxolitinib was associated with a statistically significant increased risk of HZ infection compared to control group in 3 RCTs including patients with polycythemia vera (OR 7.39 [1.33, 41.07]) and in a pooled analysis of the extended phase IIIa RCTs (OR 5.20 [ 95% CI 1.27, 21.18]) In the larger phase IV post-marketing study, the incidence of the most frequent infections was 8% for HZ, 6.1% for bronchitis, and 6% for urinary tract infections In the published case reports, the most frequent infections were TB (n = 10), HBVR (n = 5), and Pneumocystis jirovecii infection (n = 2)
	2021, Luo et al. [120]	1124	SR with MA Includes 11 RCTs in patients with MPN	Risk of overall infections was not different at the early stage of use of orally administered ruxolitinib (OR 1.23, 95% CI [0.91, 1.67]). In the extension phase, overall infection was significantly lower in patients orally administered ruxolitinib (OR 0.53, 95% CI [0.36, 0.79]) HZ infection was at higher risk both at early stage and in the extension phase (OR 7.39, 95% CI [1.33, 41.07]), (OR 5.23, 95% CI [1.46, 18.79]), respectively
	2022, Fan et al. [121]	1580	MA Includes 37 studies (trials and observational studies)	Incidence rate of infections after oral treatment with ruxolitinib for acute graft-versus-host disease was 0.61 (95% CI 0.45–0.76). The frequency was comparable between children [0.86 (95% CI 0.64–0.95)] and adults [0.75 (95% CI 0.66–0.82), p = 0.296] Regarding chronic graft-versus-host disease, the IR of infection after oral treatment with ruxolitinib was 0.47 (95% CI 0.31–0.63)
	2023, Papp et al. [122]	1072	2 clinical trials Includes patients with AD	Most common AEs were upper respiratory tract infection and nasopharyngitis 8 patients reported HZ, all which resolved without permanent withdrawal of ruxolitinib cream; none were observed at application sites Other viral skin infections (HSV, molluscum contagiosum) were reported in 9 patients; all cases were nonserious and resolved without permanent withdrawal of ruxolitinib cream, and 2 (HSV) were considered related to treatment
Tofacitinib (JAK1, JAK2, JAK3, and TYK2 inhibitor)	2016, Winthrop et al. [123]	5671	SR Includes 14 phase II, III and long-term extension clinical trials data Includes patients with RA	TB [IR 0.21, 95% CI (0.14–0.30)] was the most common OI (n = 26); median time between drug start and diagnosis was 64 weeks (range 15–161 weeks) In phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB For OIs other than TB, 34 events were reported [IR 0.25 (95% CI 0.18–0.36)] Incidence of non-TB OIs was numerically higher in patients treated with tofacitinib 10 mg twice daily [0.40 (95% CI 0.18–0.90] compared with 5 mg twice daily
	2020, Cohen et al. [124]	7061	Multicentric retrospective study Include patients with RA development program	IRs (95% CI) for serious AEs, SI, HZ (all), OI (excluding TB), and TB were 9.0 (8.6 to 9.4), 2.5 (2.3 to 2.7), 3.6 (3.4 to 3.9), 0.4 (0.3 to 0.5), and 0.2 (0.1 to 0.2), respectively
	2022, Taxonera et al. [125]	1162	SR with MA Includes 11 observational studies in patients with UC	IRs of serious AEs and HZ were 8.9 and 6.9 per 100 patient-years, respectively
	2023, Winthrop et al. [126]	1157	SR All data of clinical trials until 2022 Includes patients with UC	IRs for HZ (nonserious and serious) were numerically higher with tofacitinib 10 mg twice daily vs. placebo and tofacitinib 10 vs. 5 mg BID, respectively > 90% of HZ were nonserious; > 90% were mild/moderate; > 90% resolved without discontinuing tofacitinib; 0.6% of patients had multiple HZ events HZ risk factors included older age, lower weight, geographic region, and prior TNFi failure
	2023, Sandborn et al. [127]	1157	SR All data of clinical trials and observational studies until 2022 Includes patients with UC	IRs [95% CI] for all tofacitinib doses were SI, 1.69 [1.26–2.21]; HZ infections, 3.30 [2.67–4.04]; and OI, 1.03 [0.70–1.46] Tofacitinib could increase the risk of infections, especially HZ, but not the risk of SIs or OIs
Deucravacitinib (selective TYK2 inhibitor)	2023, Armstrong et al. [128]	666	RCT (POETYK PSO-1 trial) Includes patients with psoriasis	Side effect rates with deucravacitinib were similar to apremilast and placebo Upper respiratory tract infections and nasopharyngitis were the most common adverse effects 5 cases of HZ were recorded with deucravacitinib, 1 in placebo and 0 in roflumilast. None were serious
	2024, Lebwohl et al. [129]	1519	POETYK PSO-1 trial extension	Exposure-adjusted incidence rates per 100 person-years were similar at 1 year and 2 years, respectively, for any AEs (229.2 vs. 154.4), SI (1.7 vs. 2.6), and HZ (0.9 vs. 0.8)
Ritlecitinib (selective JAK3 inhibitor and TYK inhibitor)	2024, King et al. [130]	1269	SR of ritlecitinib trials Includes 4 trials in phase 2a/2b/III Includes patients with AA	Adverse effects were like placebo, with upper respiratory tract infections being one of the most frequent Safety profile was maintained in adolescents (12–18 years), where only the side effect of acne stood out more frequently

AD atopic dermatitis, AE adverse events, HBV hepatitis B virus, HBVR HBV reactivation, HSV herpes simplex virus, HZ herpes zoster, IRR incidence rate ratio, IR incidence ratio, OI opportunistic infection, OR odds ratio, PY person-years, PYF person-years follow-up, RA rheumatoid arthritis, RCT randomized clinical trial, RR relative risk, SI serious infections, TB tuberculosis, TNFi tumor necrosis factor inhibitor, UC ulcerative colitis

Nine studies evaluating JAK1 inhibitors were selected: four on abrocitinib [54, 113, 115, 131] and five on upadacitinib [45, 51, 55, 114, 115].

Abrocitinib

An increased incidence of infections, serious infections, HZ, and HSV infections compared to placebo was recorded for abrocitinib [113]. However, a post hoc analysis of the JADE COMPARE trial (n = 643) revealed that the proportion of nasopharyngitis and upper tract infections was similar between dupilumab and abrocitinib, and no cases of HZ were seen in either of the two groups [54]. A real-life study of 41 patients with AD treated with abrocitinib showed that respiratory tract infections were the third most frequent side effect (17.2%), after gastrointestinal symptoms (27.6%) and acne (20.7%) [131].

Upadacitinib

An MA including four RCTs with almost 3000 patients did not find a relationship between serious infections and upadacitinib [114]. However, other studies have shown a higher incidence of infections than placebo, especially HZ, proportional to the administered drug dose [51]. Finally, a post-trial analysis focused on safety in 2257 patients with psoriatic arthritis (PsA), where it was demonstrated that upadacitinib had a higher rate of HZ and OI (excluding TB, HZ, and candidiasis) than adalimumab [50].

Baricitinib and Ruxolitinib (JAK1 and JAK2 Inhibitors), and Risk of Infections

Nine studies evaluating dual JAK1 and JAK2 inhibitors were selected: three on baricitinib [116–118] and six on ruxolitinib [119–122, 132, 133] (Table 6).

Baricitinib

Infections were one of the most frequent side effects of baricitinib. A long-term data safety trial in AD with more than 2000 patients treated with baricitinib revealed an incidence rate (IR) of 67.2 for general infections, 6.7 for HSV, 2.8 for HZ, 0.3 for OI, and 0 for TB [117].

Ruxolitinib

Ruxolitinib has also been associated with an increased risk of HZ infection in several studies [119, 120]. In two studies, a higher risk of HBV reactivation was reported with orally administered ruxolitinib [132, 133]. A prospective single-center study (n = 15) found an HBV reactivation rate of up to 26.7% [133].

Regarding topical ruxolitinib, Papp et al. evaluated the safety of topical ruxolitinib in two RCTs in AD. Common AEs were upper respiratory tract infection and nasopharyngitis, and eight patients reported HZ; none were observed at application sites. Other nonserious viral skin infections (HSV and molluscum contagiosum) were reported in nine patients [122].

Tofacitinib (JAK1, JAK2, JAK3, and TYK2 Inhibitor) and Risk of Infections

Thirteen studies were found evaluating the risk of infections with tofacitinib [42–44, 46, 47, 49, 123–127, 134, 135] (Table 6). Although an SR and MA from 2015, including 88 studies and more than 40,000 patients, reported a similar incidence of infections resulting from treatment with tofacitinib, rituximab, anti-TNF, and tocilizumab [42]; subsequent studies have shown that infections are one of the most frequent AEs with tofacitinib [124]. Several studies have revealed an augmented incidence of infections with tofacitinib compared to anti-IL-6 [44], anti-TNF [46, 47], and ustekinumab [49], and slightly higher than baricitinib (although not statistically significant) [134]. The infectious risk seems to be dose dependent [123]. Regarding specific infections, a double risk of HZ with tofacitinib compared to other biologics has been reported, as well as the possibility of HBV reactivation [135].

Deucravacitinib (TYK2 Inhibitor) and Risk of Infections

Three studies were selected that evaluated the safety of deucravacitinib [128, 129, 136] (Table 6). In an RCT on 666 patients with psoriasis, five cases of HZ were recorded [128]. A recent retrospective real-life study (33 Japanese patients with psoriasis) showed that deucravacitinib was not associated with an increase rate of infections [136].

Ritlecitinib (JAK3 and TYK Inhibitor) and Risk of Infections

An SR including four RCTs and more than 1200 patients revealed that the infection rate was similar to placebo, with upper respiratory tract infections being one of the most frequent [130] (Table 6). We have not found real-life studies on this drug.

Discussion

Biologic Drugs

We found numerous studies linking anti-TNF agents with an augmented risk of infections, and this risk appears to be higher with infliximab [6, 13, 25, 36, 41]. There is a noticeably higher risk with anti-TNF agents than with ustekinumab [20, 22, 25, 29]. The increased infection risk compared to anti-IL-17 agents has not been clearly demonstrated [22, 25, 30, 35–37]. The risk of TB reactivation or dissemination is higher with anti-TNF and tocilizumab than with anti-IL-17 or anti-IL-23 [34]. In fact, certain authors have suggested the omission of screening for latent TB in patients undergoing treatment with anti-IL-17 or IL-23 in diseases like psoriasis [137]. Similar to other intracellular infections, the potential of anti-TNF agents to induce HBV reactivation has been highlighted in multiple studies. However, this risk would be lower than with rituximab [39, 40]. CD20 is a membrane antigen that plays a role in the development and differentiation of B cells into plasma cells, and its blockade is related to numerous infections [138].

There are other associations between other BD and the risk of infections, such as the high prevalence of Candida infections in patients undergoing anti-IL-17 therapy [30, 48, 56, 64]. This is explained by the importance of IL-17 and the Th17 pathway in the antifungal response. Dupilumab could potentially lower the infectious risk, especially in skin infections [89, 93]. This decreased risk could be explained by the possible restoration of the cutaneous barrier, preventing colonization by pathogenic bacteria (such as Staphylococcus aureus) and herpetic infections [93].

Other agents such as anti-IL-1 [37, 75–80], nemolizumab (anti-IL-31) [98, 99], tralokinumab [94], and omalizumab [95–97] have not been associated with an augmented risk of infections.

JAK Inhibitors

The JAK-STAT pathway is involved in the anti-infectious response [4]. The intracellular inflammatory inhibition caused by JAKi could favor viral reactivation and replication [139]. We found an augmented incidence of infections in patients undergoing JAKi treatment. This risk would be higher in patients with non-selective agents like tofacitinib [124] and at high doses [106, 108], and might be superior to other agents (including anti-TNF and rituximab) in specific infections, such as HZ [105, 107, 109, 112]. The risk of JAKi has also been documented for TB infection [104, 117], although possibly lower than with anti-TNF; and for HBV, although probably lower than with rituximab [132, 135]. The following approved drugs in dermatology have been shown, overall, to be safe, and with a low risk of infection: abrocitinib, upadacitinib, baricitinib, deucravacitinib, ritlecitinib, and topical ruxolitinib [54, 55, 110].

We recommend monitoring the risk of infections and OI for patients undergoing JAKi treatment. It is especially advisable for elderly patients, those with comorbidities, or under prolonged treatment, receiving high doses, and those with non-selective JAKi. As a result of the possibility of HZ infection, vaccination against this agent is recommended [4, 139].

Limitations

Firstly, this review is narrative rather than systematic. Secondly, not all JAKi and BD available were included. The risks carried by sonidegib, vismodegib, anifrolumab, and immunotherapy were not reviewed. Thirdly, a significant portion of the included studies evaluated rheumatological conditions, digestive conditions or hematological conditions, and not exclusively dermatological disorders, and extrapolation of drug complications may be influenced by the underlying disease for which drugs were used. Fourthly, there is a bias towards studies on certain drugs (e.g., more studies on tofacitinib than abrocitinib) as a result of the limited literature on newer drugs. Finally, almost no studies analyzed drugs in subgroups such as immunocompromised patients or people with HIV.

Conclusions

Overall, the incidence of infections, serious infections, and OI associated with BD and JAKi is low, but slightly higher than in the general population. The global risk of infections is increased with certain pharmacological groups, especially non-selective JAKi such as tofacitinib at high doses, rituximab, and anti-TNF agents. Specific associations with infections include TB and TB reactivation with anti-TNF agents and tocilizumab; candidiasis with anti-IL-17 agents; HBV reactivation with rituximab, anti-TNF, and JAKi; and HSV and HZ infections with JAKi (especially tofacitinib and upadacitinib at high doses). Prospective studies with long-term follow-up are needed to comparatively evaluate the infectious risk of BD and JAKi.

Declarations

Conflict of Interest

Miguel Mansilla-Polo and Daniel Morgado-Carrasco have nothing to disclose.

Ethical Approval

In terms of ethics, this article does not require ethics committee approval as it is based on previously conducted studies and does not include any new human or animal studies conducted by any of the authors.