Ravi Shah, MD

 is managed with corticosteroids; however, approximately 30 - 40% of patients are refractory to corticosteroids and require medical or surgical rescue therapy.

Corticosteroid refractoriness may be attributed to genetics as well as expression of pro-inflammatory cytokines. Downstream signaling of interleukin 2 (IL-2) prevents glucocorticoid receptor translocation, but this may be dampened by Janus kinase (JAK) inhibition. Singh et al. conducted a single-center, prospective, double-blind randomized controlled trial in India to determine if the addition of tofacitinib, a JAK1 and JAK3 inhibitor, to corticosteroids was superior to corticosteroids alone in hospitalized patients with ASUC.1

The study randomized patients with ASUC to tofacitinib 10 mg 3 times daily (n = 53) versus placebo (n = 51) plus hydrocortisone 100 mg every 6 hours. An intention-to-treat analysis after 7 days of clinical assessment revealed patients in the tofacitinib group had higher responses to therapy, defined by a decline in Lichtiger index >3 points and an absolute score <10 for 2 days (difference, 24.2%; odds ratio [OR], 3.42; 95% CI 1.37 - 8.48; 

= .007), and lower need for rescue therapy (difference, -20.1%; OR, 0.27; 95% CI 0.09 - 0.78; 

Following the 7 days, patients and investigators were unblinded. The probability of infliximab or total colectomy up to 90 days was found to be significantly lower in the tofacitinib responders who were continued on tofacitinib and a prednisone taper compared to non-responders who were continued on 5-ASA or azathioprine and a prednisone taper (

Despite these positive outcomes, adverse effects were relatively high amongst the tofacitinib (24.5%) and placebo (13.7%) groups. In the tofacitinib group, most of these adverse events were not major (hair loss, acne, upper respiratory tract infections, etc.). However, 1 death and 4 deaths were noted in the tofacitinib and placebo groups, respectively. Deaths were attributed to mostly severe disease phenotype, but also systemic toxicity (n=2) and hemorrhagic venous infarct (n = 1). One venous thromboembolism event, a dural venous thrombus, occurred in a patient in the tofacitinib group.

This novel study suggests that tofacitinib plus corticosteroids may be a first-line therapy that supplements the limited options available for patients with ASUC. Limitations include external validity, objective measures of disease activity, and the non-conventional duration of 7 days of corticosteroids that may hinder clinical applicability in the US.

Future studies to personalize this approach, limit generalizability, optimize dosage and duration of up-front therapy, and further delineate adverse event rates are required to further support the use of JAK inhibition for ASUC.

Singh A, Goyal MK, Midha V, et al. Tofacitinib in Acute Severe Ulcerative Colitis (TACOS): A Randomized Controlled Trial. Official journal of the American College of Gastroenterology | ACG 9900:10.14309/ajg.0000000000002635.

Articles

Findings from a novel study supports the JAK inhibitor tofacitinib as a potential first-line therapy for ASUC.

Tofacitinib in Acute Severe Ulcerative Colitis (TACOS): A Randomized Controlled Trial

Therapies with novel mechanisms of action are required to treat patients suffering from moderate to severe 

. Given that Janus kinase (JAK)-mediated activation of signal transducers and activators of transcription (STATs) in T cells contribute to the pathogenesis of Crohn’s disease, JAK inhibition is hypothesized to be a potential therapeutic target.

Upadacitinib, a selective JAK1 inhibitor, has previously been approved for the treatment of moderate-severe ulcerative colitis, rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, and ankylosing spondylitis. Loftus et al. conducted a multicenter, randomized, double-blinded, placebo-controlled trial including a pair of phase 3 induction trials (U-EXCEL and U-EXCEED) and a maintenance trial (U-ENDURE) assessing the efficacy—including clinical remission defined as a Crohn’s disease activity index (CDAI) <150 and endoscopic response defined as a decrease in the SES-CD score of >50% from baseline—as well as the safety of upadacitinib for patients with moderate to severe Crohn’s disease who have previously failed biologic or conventional therapy.

The 2 induction studies randomized the study population to upadacitinib 45 mg orally versus placebo (n = 350 vs n = 176; and n = 324 vs n = 171). The upadacitinib group achieved the primary endpoints, clinical remission (49.5% vs 29.1%; 38.8% vs 21.1%; 

<.001) and endoscopic response (45.5% vs 13.1%; 34.6% vs 3.5%; 

<.001), at 12 weeks significantly more than the placebo group. Those induced with upadacitinib also achieved significantly higher rates of secondary endpoints: stool frequency and abdominal pain scores; endoscopic remission; corticosteroid-free clinical remission; fatigue scores; quality of life scores; clinical remission at 4 weeks and response at 2 and 12 weeks, but not Crohn’s related hospitalizations or resolution of extraintestinal manifestations.

The maintenance study randomized patients who achieved the primary endpoint from the two induction studies to receive upadacitinib 30 mg (n = 160), 15 mg (n = 169), or placebo (n = 165) for 52 weeks. The upadacitinib 30 mg and 15 mg groups had significantly higher rates of clinical remission (30 mg, 47.6%; 15 mg, 37.3%; placebo, 15.1%; 

<.001) and endoscopic response (30 mg, 40.1%; 15 mg, 27.6%; placebo, 7.3%; 

<.001) than the placebo group. There were also higher rates of achieving secondary outcomes, including bowel frequency and abdominal pain scores, clinical response and remission, glucocorticoid-free clinical remission, endoscopic and deep remission, and quality of life scores in the upadacitinib groups. The 30 mg upadacitinib group also reported higher rates of improved fatigue scores and resolution of extraintestinal manifestations.

The most common adverse events in the induction trial of upadacitinib 45 mg were acne (6.9%); anemia (6.3%); nasopharyngitis (7.1%); headache (6.2%); worsening of Crohn’s disease (5.9%); and upper respiratory tract infection (5.2%). Serious infections occurred in 1.1% and 2.8% as compared to 1.7% and 1.8% in the induction group compared to the placebo group, and the most common serious infection was gastrointestinal (e.g. anal abscess). Herpes zoster infection was reported in the induction group but not the placebo group (2.9%, 1.5% vs 0%).

Other non-infectious adverse events included higher rates of neutropenia and creatine kinase elevation in the upadacitinib group. In the maintenance group, exacerbation of Crohn’s disease was the most frequently reported adverse event. Rates of serious infections were similar across the three groups. Herpes zoster was higher in the 30 mg group than the 15 mg group or placebo group (7.2 events per 100 person-years vs 4.0 or 4.7 events per 100 person-years). One gastrointestinal perforation was reported in each of the upadacitinib-treated groups; however this adverse event is thought to be a byproduct of the degree of inflammation rather than one of the medication. Although thrombus formation is a feared complication of JAK inhibitors, there was only one case of thrombus in the upadacitinib group, and this was associated with concurrent Crohn’s disease exacerbation rather than the medication.

Upadacitinib, a selective JAK1 inhibitor, is an essential tool to add to current pharmacologic therapies against Crohn’s disease and especially in those who have previously failed conventional or biologic therapies. Although there are potential adverse events to the medication, preventative care (i.e, vaccination) and careful monitoring (i.e, laboratory monitoring) may be efficient methods to curb these.

Long-term five-year data on the efficacy and safety of this therapy as an extension of the U-ENDURE trial are eagerly awaited. Future studies on positioning upadacitinib and characterizing patient profiles that may benefit the most from this therapy are required.

The Cleveland Clinic fellow explains why is upadacitinib is an essential tool in treating Crohn’s disease, especially in those who have previously failed conventional or biologic therapies.

A Review of Upadacitinib in Crohn’s Disease: A Promising JAK1 Inhibitor

Despite the evolution of biologic therapy used to treat 

 (UC) over the past few decades, there remains an unmet need of options to both induce and maintain remission of 

The inhibition of Janus kinase (JAK) to prevent downstream signaling of proinflammatory cytokines has been shown to be a novel method of treating UC. 

Although the effectiveness of nonspecific JAK inhibition has been successful, concerns of the safety profile has limited its clinical use.

Upadacitinib (UPA) is a more selective JAK-1 inhibitor that was previously approved for use in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and atopic dermatitis. 

Danese and Vermeire et al. conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial consisting of 2 replicate induction studies and a maintenance study assessing the efficacy and safety of UPA in patients with moderately to severely active UC who had either an inadequate or loss of response to 5-aminosalicylate (5-ASA), corticosteroids, immunomodulator, or biologic.

The 2 replicate induction studies randomized patients with moderately-severely active UC to UPA 45 mg orally daily versus placebo (n = 319 vs n = 154; n = 341 vs n = 174). Patients receiving UPA more successfully achieved the primary endpoint- clinical remission, defined as an adapted Mayo score at week 8, compared to those receiving placebo (26% vs 5%; 33% vs 4%; 

The UPA group also significantly achieved the secondary endpoints, including endoscopic improvement, endoscopic remission, clinical response, histologic improvement, no bowel urgency, no abdominal pain, and quality of life questionnaire scores. In a subgroup analysis of ~50% of patients with previous biologic failure, clinical remission was achieved more in UPA-treated compared to placebo-treated patients (17.9% vs 0%; 64.6% vs 12.8%). The results of the study are summarized in the tables.

The maintenance study randomized patients who achieved clinical response from the two phase 3 induction studies and a phase 2b study to receive daily UPA 15 mg (n = 149), UPA 30 mg (n = 154) or placebo (n = 149) for 54 weeks.

Clinical remission at 52 weeks was more significantly achieved by patients treated with UPA 15 mg (42%) and UPA 30 mg (52%) compared to those who received placebo (12%; 

 <.001). Similar to the induction studies, UPA 15 mg and UPA 30 mg more significantly achieved the secondary endpoints compared to placebo. In a subgroup analysis of patients with prior biologic failure, clinical remission was achieved at higher rates in the UPA 15 mg (40.5%) and UPA 30 mg (49.1%) compared to placebo groups (7.5%). The results of the study is also summarized below in tables.

Adapted from Danese S et al. The Lancet. 2022, (399);10341:2113-2128

Rates of adverse events in the induction studies between UPA 45 mg and placebo groups (56% vs 60%; 53% vs 40%), and in the maintenance study between UPA 15 mg, UPA 30 mg and placebo groups (78% and 79% vs 76%) were relatively similar.

In both the induction and maintenance studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the UPA 45 mg group compared to the placebo group. Specifically, no events of adjudicated MACE, VTE, or gastrointestinal perforation were reported in the UPA 45 mg-treated patients. In the maintenance groups, adjudicated MACE or gastrointestinal perforation were not reported, but there were 2 non-serious VTE reported in the UPA 30 mg treated group that were deemed to be unrelated to the study drug. Rates of serious infections were similar in the UPA and placebo groups.

Herpes zoster led to discontinuation of UPA 45 mg and UPA 30 mg in 2 of 9 reported cases. There were 3 cases of cytomegalovirus that did not lead to discontinuation of therapy. There were 2 non-melanoma skin cancers reported amongst the UPA 30 mg group. Other reported non-serious side effects included nasopharyngitis, acne, mild-moderate liver test abnormalities, and total cholesterol elevations in the UPA-treated groups.

Upadacitinib, a more selective JAK-1 inhibitor, is a promising addition to the therapeutic armamentarium against UC especially in those who have previously failed or developed immunogenicity to biologic therapies.

It remains unclear whether the reported adverse events are drug or patient characteristic-specific, but preventative measures (i.e, vaccination) may dissipate some of the serious infectious risks reported in the UPA trials. Future studies assessing the positioning of UPA amongst available treatment options for UC and the long-term safety profile are needed to further solidify this promising therapy for patients suffering from moderate to severe UC.

The inhibition of Janus kinase to prevent downstream signaling of proinflammatory cytokines has been shown to be a novel method of treating ulcerative colitis.