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