They form reversible (non-covalent) binding interactions with the amino acids in the JAKs. The binding interactions include hydrogen bonds and hydrophobic interactions. These can be further subdivided into:

These agents form covalent bonds with JAKs, particularly JAK3, targeting the unique Cys909 residue. Ritlecitinib is a notable example currently under clinical evaluation [24].

TOFA in a 10 mg BID dose in 50-year-old or older patients induces significant cardiac risk, VTE, and pulmonary embolism (PE). This is more evident in those who had at least one pre-existing cardiovascular factor, such as smoking and/or atherosclerotic cardiovascular disease [25–27]. The risk for PE increases in older patients with prior VTE, obesity, and a history of chronic lung disease. In UPA trials, no additional risks were recorded [28]. Anticoagulants protect against thrombosis in high-risk patients [29]. An opposing opinion claims that IBD is a thrombogenic disease; this increase represents a false elevation [30, 31]. Both JAK inhibitors and anti-TNF therapies carry the same risk of cardiac and/or thrombotic events in IBD patients [32]. Recently, a meta-analysis study came to the same conclusion, minimizing the role of exposure time in amplifying the risk of cardiac and thrombotic events. Still, the lower dose of both TOFA 5 mg BID and UPA 30 mg QD slightly increased risks of thrombosis, signifying the pan-sensitivity of JAK at high doses [33].

It is mandatory for clinicians to screen patients for risk factors, such as smoking and obesity, history of previous thrombotic events, or hypercoagulable predisposition, to stratify patients prior to initiating JAK inhibitors, follow a healthy lifestyle, the lower effective dose of JAK inhibitors should be used for maintenance, and continue on anti-coagulants, especially for those with a history of VTE recurrence [34].

Dose-dependent, reversible, and within 1–2 months increases in serum lipids had been recorded during both the induction and maintenance phase that return to baseline levels during use of TOFA and UPA [35]. Both low-density lipoprotein:high-density lipoprotein-cholesterol (LDL:HDL-C) and total cholesterol:HDL-C ratios are stable without an increase. Lipid profile at baseline and half-yearly checking is mandatory. Lipid-lowering agents are a second option [34]. Filgotinib has no clinically relevant effects on lipid levels [36, 37].

Patients are at increased risk of pneumonia, fungal infections (e.g., Aspergillus, Pneumocystis jirovecii), histoplasmosis, cryptococcosis, nocardiosis, Clostridium difficile, and urinary tract infections [38]. Selective JAK1 inhibitors are safer than non-selective JAK inhibitors, like TOFA [39]. The risk of tuberculosis (TB) is higher in areas with high endemic regions [40]. The concomitant immunosuppressant use and/or underlying comorbidities increase the incidence of invasive fungal infections [41]. The risk of serious infection increases with the high 10 mg dose [25, 42]; the same as the UPA 30 mg dose, underscoring the importance of using the lowest effective dose for maintenance therapy [43]. The best example is the herpes zoster (HZ) reactivation [42, 44]. Testing for TB by serum QuantiFERON gold or T-spot should be performed in all patients before initiating a JAK inhibitor, and regularly thereafter. Latent TB should be treated prior to initiating a JAK inhibitor. No live or attenuated virus vaccines should be administered during JAK inhibitor therapy or immediately before it. Patients should follow the Centers for Disease Control (CDC) recommendations regarding COVID vaccination [45, 46]. Vaccination against influenza, pneumococcus, and varicella-zoster virus is recommended prior to therapy in addition to respiratory syncytial virus (RSV) if above the age of 50 [47].

In the IBD TOFA and UPA-treated patients, 8 cases with GI perforation had been recorded. All of them occur in risky, complicated patients with areas of deep ulcers, stricture, or fistula [42]. Concomitant use of NSAIDs or corticosteroids is an additional risk factor [48].

Lymphomas, lung cancer, melanoma, and non-melanoma skin cancer (NMSC) were recorded [49, 50]. TOFA recorded a higher incidence of malignancies compared to UPA, especially with a higher dose of 10 mg BID [51]. Sun protection should be encouraged. A regular skin examination is recommended prior to and annually after initiating JAK inhibitors [52].

It is the most common side effect and occasionally leads to treatment cessation. Higher doses and prior history of acne vulgaris are risk factors. Usually, it resolves with dose reduction; however, a few cases require pharmacological treatment and/or dermatology consultation [53].

UPA exposure to adverse pregnancy outcomes was comparable to the general population [54]. However, JAK inhibitors are not recommended during pregnancy and/or breastfeeding [55, 56]. Contraceptive methods should be used in women of childbearing age and up to a month after discontinuation of the JAK inhibitor. The risks and benefits of therapy versus uncontrolled disease should be discussed with the patient [56].

All JAK inhibitors, except for UPA, have a potential impact on fertility in animal studies. However, randomized, placebo-controlled studies confirmed safety in humans. Filgotinib is the only JAK inhibitor without an impact on male fertility [57] (Figure 2).

JAK inhibitors represent an important therapeutic class in IBD and were first introduced in 2018 with the approval of TOFA, followed by the JAK inhibitor-selective agents filgotinib and UPA [69]. Still other small molecules are under clinical trials in phase I, II, and III (Table 1).

Esophageal fibroblasts express eotaxin-3 via STAT6 signaling in response to Th2 cytokines. Unlike epithelial cells, eotaxin-3 expression in fibroblasts is not suppressed by proton pump inhibitors (PPIs), limiting the impact of PPIs on subepithelial fibrosis. To the contrary, Th2 cytokine-induced eotaxin-3 expression in both epithelial cells and fibroblasts can be blocked by JAK–STAT6 inhibitors. A potential role in treating both inflammation and fibrosis in eosinophilic esophagitis has been suggested for JAK inhibitors [101].

The safety of combining JAK inhibitors with post-transplant immunosuppression has been explored in patients with IBD following solid organ transplantation. In small cohorts, TOFA in combination with tacrolimus achieved high rates of clinical remission without significant infectious, thromboembolic, or cardiovascular complications. These findings suggest that JAK inhibitors may be a safe and effective option in this challenging population, although larger studies with longer follow-up are required [102].

Hypothalamic neurons regulate food intake, energy expenditure, and glucose homeostasis with high expression of JAK2 and STAT3 [103]. Leptin, an appetite regulator, acts through signaling through the JAK2–STAT3 pathway. Hyperactivation of this JAK–STAT–SOCS axis in leptin resistance contributes to obesity and metabolic dysfunction [104].

JAK–STAT signaling also regulates metabolic target organs, including the liver, muscle, adipose tissue, and pancreas. Overactivation of this pathway contributes to insulin resistance, inflammation, and metabolic syndrome [105, 106]. Selective JAK inhibitors may therefore offer therapeutic potential in obesity, type II diabetes, MASLD, and cardiovascular risk reduction [107].

There is significant crosstalk between the JAK–STAT pathway and insulin signaling. Hyperactivation of JAK–STAT signaling impairs Akt phosphorylation and disrupts glucose homeostasis [108]. Elevated IL-6 levels in obesity increase SOCS1 and SOCS3 expression, which inhibit insulin receptor substrates and promote insulin resistance [109]. Inhibition of JAK–STAT signaling may reduce inflammation and improve insulin sensitivity [110]. Animal studies suggest tissue-specific effects of JAK loss, highlighting the complexity of this pathway [111–113]. Further clinical studies are required to define the risk–benefit profile of JAK inhibitors in metabolic disease (Figure 3).

TOFA was reported to be safe and effective in a liver transplant recipient with UC [114]. Recently, Con et al. [102] in 2024 reported eight liver transplant recipients with IBD, seven of whom received a first-line JAK inhibitor with TOFA. All failed one or more biologic therapies prior to commencing JAK inhibitor, including six patients who had failed two or more biologic agents. JAK inhibitor was initiated in the outpatient setting. No serious adverse events were documented, nor were any interactions with transplant medications observed. Combining JAK inhibitors with post-transplant immunosuppression was a safe and clinically effective approach for the management of IBD in liver transplant recipients in both biologic-naïve and biologic-experienced patients. Larger cohorts with a longer duration of follow-up are needed [102].

aGVHD-LT is rare but associated with high mortality [115, 116]. JAK inhibitors disrupt immune cell communication and induce apoptosis in activated immune cells [117]. Ruxolitinib, a JAK1/2 inhibitor, modulates T-cell responses and cytokine signaling, attenuating the aberrant immune response [118]. Clinical studies and case reports indicate that ruxolitinib combined with corticosteroids can reduce steroid requirements and improve outcomes in steroid-refractory GVHD [119]. Further clinical trials are needed to establish optimal dosing, duration, and long-term safety in this population [120].