The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway represents a new target in IBD. Multiple inflammatory cytokines known to have a role in IBD pathogenesis utilize the JAK pathway. Tofacitinib is a non-selective inhibitor of the JAK family, influencing mostly JAK1 and JAK3 [
38]. Its effectiveness for rheumatoid arthritis has been demonstrated in several pivotal studies both as monotherapy [
39] and in combination with an immunomodulator [
40]. The first IBD phase 2 study was published in 2012 evaluating tofacitinib in different doses for treatment of moderate-to-severe UC [
41]. The primary outcome, clinical response at 8 weeks (defined as an absolute decrease from baseline Mayo score of ≥ 3 with an accompanying decrease in the rectal bleeding subscore), occurred more in the treatment group only in the higher dose of 15 mg (78% as compared with 42% of patients in the placebo group;
p < 0.001). Clinical remission at week 8 was dose-dependent, occurring in 13%, 33%, 48%, and 41% of patients receiving tofacitinib at a dose of 0.5 mg (
p = 0.76), 3 mg (
p = 0.01), 10 mg (
p < 0.001), and 15 mg (
p < 0.001), respectively, compared to 10% of patients receiving placebo. Effectiveness was also demonstrated in two phase 3 induction studies, OCTAVE 1 and 2, and the maintenance study, OCTAVE Sustain [
42]. At week 8, patients receiving tofacitinib 10 mg BID achieved significantly higher rates of remission and mucosal healing in both studies versus placebo (18.5%/16.6% and 31.1%/28.4% versus 8.2%/3.6% and 15.6%/11.6%, respectively). Tofacitinib was the first drug to show similar efficacy in both anti-TNF alpha-experienced and anti-TNF alpha-naïve patients participating in the trials. In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5 mg group and 40.6% in the 10 mg group versus 11.1% in the placebo group (
p < 0.001 for both comparisons). Mucosal healing rate was higher in the treatment groups at 52 weeks as well, when compared to placebo (37.4%, 45.7%, and 13.1%, respectively). Overall, there was no difference in the rate of adverse events between treatment groups and placebo in both induction and maintenance trials (including serious adverse events). However, the rates of overall infections and serious infections were higher with tofacitinib versus placebo. In the OCTAVE Induction trial, herpes zoster infection occurred in five patients in the 10 mg group and in one patient in the placebo group. In the OCTAVE Sustain trial, herpes zoster infection occurred in three patients (1.5%) in the 5 mg group, 10 patients (5.1%) in the 10 mg group, and one patient (0.5%) in the placebo group. No cases of herpes zoster infection were considered serious adverse events or resulted in treatment discontinuation. Large cohort studies of rheumatoid arthritis (RA) patients demonstrated higher rates of infection and malignancy. The most commonly observed infections were pneumonia, herpes zoster, and urinary tract infections [
43,
44]. Dose-related increases in low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) levels have been observed in tofacitinib studies done in IBD patients, which resolved after drug cessation [
41]. However, no increase in cardiovascular morbidity was found. Some studies suggest that despite the increase in cholesterol level, there was no significant change in the number of small dense LDL particles, which are considered to be more atherogenic than both large particles and oxidized LDL [
45]. In fact, tofacitinib decreased carotid atherosclerosis in RA patients [
46], and attenuated atherosclerosis and foam cell formation in an atherogenic murine model [
47]. On the basis of clinical trial data from more than 6000 patients, which included more than 20,000 patient-years of tofacitinib exposure over a period of over 8 years, an increase in LDL and HDL levels was reported without an increased risk of cardiovascular events [
44]. Recently, the FDA has approved the use of tofacitinib in patients with UC.
Filgotinib is another orally administered JAK inhibitor, 30 times more selective for JAK1 over JAK2. The drug was also found to be effective for RA [
50,
51]. The FITZROY study, an RCT including 174 patients, meant to examine the efficacy and safety of filgotinib for the treatment of moderate-to-severe CD [
52]. Sixty (47%) of 128 patients in the filgotinib group achieved the primary endpoint (clinical remission at week 10) compared to 10 (23%) of 44 patients in the placebo group (
p = 0.008). The efficacy of filgotinib, including clinical remission, response, and Inflammatory Bowel Disease Questionnaire (IBDQ), was shown in CD patients independently of their prior anti-TNF exposure [
53]. The effect was much less dramatic among patients with previous exposure to anti-TNF alpha therapy (29% versus 37% among treatment and placebo group, respectively). There was a greater proportion of patients achieving endoscopic remission at week 10 in the filgotinib versus the placebo group, but that difference did not reach statistical significance. An extension maintenance study demonstrated that at week 20 (while continuing 200 mg once daily), 71% of initial responders showed clinical remission and 79% showed clinical response, while maintaining improvement in quality of life [
54].As for adverse events, no change was seen in blood counts or liver enzymes. There was an 11% increase in mean HDL and a 12% increase in mean LDL at week 20, with a 4% and 13% increase in the placebo group, respectively.