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