JAK inhibitors: an evidence-based choice of the most appropriate molecule

Abstract

Janus kinase inhibitors (JAKis) represent a fundamental therapeutic tool for the treatment of patients with immune-mediated inflammatory diseases. Although JAKis are often considered a homogeneous class of drugs whose members are thought to be largely interchangeable, there are significant differences in their efficacy and safety profiles. This narrative review analyzes the pharmacokinetic and pharmacodynamic differences among JAKIs, highlighting their clinical relevance based on the most recent available evidence. The article aims to provide rheumatologists, gastroenterologists and dermatologists with practical guidance for choosing the most appropriate JAKi for each patient, given the lack of evidence-based recommendations on this topic, to improve clinical outcomes. Due to its preferential action on JAK1, intestinal metabolization and proven absence of impact on male fertility, filgotinib may be characterized by an improved benefit/risk ratio compared with other less selective JAKis.

Keywords: JAK inhibitors; efficacy; pharmacodynamic; pharmacokinetic; safety.

FIGURE 1

The JAK-STAT pathway. 1) Cytokine binds its receptor. 2) Receptor-associated JAKs transphosphorylate and activate each other. 3) JAKs phosphorylate the receptor tail. 4) STATs dock on receptor tail and are phosphorylated. 5) STATs dissociate from the receptor and dimerizes. 6) STAT dimers translocate to the nucleus where they regulate gene transcription. JAK: Janus kinase, P: phosphate group, STAT: Signal Transducer and Activator of Transcription. Adapted from Lin et al. (2020).

FIGURE 2

JAK pairing patterns, their biologic effects, and JAKis selectivity. JAK pairing patterns associated with cytokine receptors (A), biological effects of the pathway (B) and selectivity of different JAKis for each pathway (C) with higher numbers denoting lower selectivity. GS-829845 is the filgotinib active metabolite. Colours indicate the fold selectivity compared with JAK1/TYK2 pathway inhibition. Green: 1–2.5 fold reduction. Yellow: >2.5–6 fold reduction. Red: >6 fold reduction. IFN: interferon, GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor, EPO: erythropoietin. Adapted from Traves et al., 2021.

FIGURE 3

NK count changes in patients with RA treated with different JAKis. Flow cytometry-assessed NK counts in 115 RA patients treated with baricitinib, filgotinib, tofacitinib or upadacitinib in the Italian real-world study ELECTRA-i. *P = 0.0001 baseline vs. 12 months. Adapted from Benucci et al. (2024). NK: Natural Killer. RA: Rheumatoid Arthritis.

FIGURE 4

Incidence rates of malignancies excluding NMSC, MACE and VTE in general population, RA patients and RA patients treated with tofacitinib (5/10 mg twice daily) or filgotinib (100 mg/200 mg). RA: rheumatoid arthritis, PY: patient-years, NMSC: Non Melanoma Skin Cancer, MACE: Major Adverse Cardiovascular Event, VTE: Venous thromboembolism. Adapted from World Cancer Research Fund International (2024), Askling et al. (2016), Raadsen et al. (2021), Ketfi et al. (2021), Wendelboe and Raskob (2016), Winthrop et al. (2022), Ytterberg et al. (2022).