Real-world data supports upadacitinib/Reffor in refractory Crohn's disease

The study found that the Janus kinase inhibitor Upadacitinib (Upadacitinib) was well tolerated in patients with clinically refractory Crohn's disease (CD) and was effective for more than 24 weeks. This study provides real-world insights from a UK cohort, demonstrating outcomes for a clinically challenging patient population frequently encountered in clinical practice.

The study included 312 adults from UK centers who had been diagnosed with clinically, biochemically or endoscopically active Crohn's disease. Eligible patients received 45 mg of upadatinib once daily during the induction phase and then received maintenance therapy of 15 mg or 30 mg. Participants were followed for at least 12 weeks, and 271 were assessed for 24 weeks, or until they dropped out of treatment. The median age of patients was 31-35 years, 58% were male, 57% had ileocolonic disease, and they most commonly had an inflammatory phenotype (48%).

The cohort also had difficult-to-treat disease, had received a median of three prior advanced therapies other than upadatinib, and 34% were taking steroids. Half (51%) of the participants had penetrating or stenotic disease, and 41% had undergone previous resection surgery. The trial's primary endpoint of clinical response was defined as a Harvey Bradshaw Index (HBI) of less than 4 points, which was achieved by 50% of patients at week 12 and 45% at week 24, with 93% and 96% of patients achieving steroid-free clinical response, respectively.

These findings are particularly encouraging for both patients and clinicians because they illustrate the effectiveness of upadatinib in a difficult-to-treat CD cohort. Early response predicted better long-term outcomes, as the majority (80%) of patients who achieved response at week 12 remained in response at week 24, and 47% of patients who had a clinical response (defined as a reduction in HBI of at least 3 points) at week 12 were in response at week 24.

The researchers noted that in multivariable analysis, patients with colonic and ileocolic disease had significantly higher response rates at 24 weeksthan other disease sites, specifically with 9.16-fold and 3.44-fold increased risk, respectively, compared with patients with ileal disease. This result demonstrates the need for tailored treatments, as disease location may be an important factor in predicting treatment outcome.

In addition,28% and 18% of patients experienced biochemical remission at weeks 12 and 24, respectively, with remission defined as fecal calprotectin (FCP) less than 200 µg/g or C-reactive protein (CRP) 5 mg/L or less. An additional 7% of patients with paired baseline and week 12 data showed a biochemical response, defined as a 50% or greater decrease in FCP or CRP but no increase in either parameter.

The researchers noted that at weeks 12 and 24, 6% and 12% of patients achieved endoscopic response (Simple Endoscopic Score [SES]-CD ≤3 points), respectively, while 5% of patients had an endoscopic response (SES-CD reduction ≥50%).

The relatively low" endoscopic response rate "may reflect the challenges of treating real-world populations," but acknowledged the presence of "substantial missing data," which may reflect a bias against nonremission because endoscopy may be prioritized for clinical response. Patients with inadequate response. Patients also experienced significant reductions in abdominal pain and stool frequency on the HBI, with the median pain score decreasing from 2 points at baseline to 0 points at weeks 12 and 24, and the median stool frequency score also decreasing from 5 points at baseline to 2 points at weeks 12 and 24.

Treatment duration was high, 90.3% at 12 weeks and 84.1% at 24 weeks. However, 28% of patients had adverse events (AEs), 18% had serious AEs, and 16.6% required hospitalization. A total of 10% of patients discontinued treatment due to adverse events before completing the induction phase, primarily due to worsening of symptoms.

The most common adverse events included infection (8%), lipid abnormalities (5%), and acne (5%), consistent with previous studies. The researchers said this suggests that "the safety profile of upadatinib may be comparable in practice to that observed in clinical trials."

Additionally, the most common serious adverse events were surgical resection (5%), worsening of symptoms (5%) and inoperable obstruction (2%), which "accounted for the majority of hospitalizations, suggesting that uncontrolled disease was the key driver rather than direct side effects of upapatinib ".

High drug persistence rates and favorable steroid-free remission outcomes demonstrate that upadatinib plays a positive role in treating challenging cases of CD. Nonetheless, the incidence of adverse events warrants careful patient selection and ongoing safety monitoring.

Reference materials:https://www.springermedicine.com/crohn-s-disease/janus-kinase-inhibitors/real-world-data-support-upadacitinib-refractory/51595584