Upadacitinib Treatment Improves Symptoms of Bowel Urgency and Abdominal Pain, and Correlates With Quality of Life Improvements in Patients With Moderate to Severe Ulcerative Colitis
Abstract:Background and Aims
Bowel urgency and abdominal pain are impactful, yet underappreciated ulcerative colitis symptoms and not commonly assessed in clinical trials. We evaluated how these symptoms may improve with upadacitinib treatment and correlate with clinical and health-related quality of life (HRQOL) outcomes in the phase 2b U-ACHIEVE study.
Methods
Patients aged 18–75 years with moderately to severely active ulcerative c… Show more
“…In the phase II upadacitinib trial, bowel urgency and QoL, measured by IBD questionnaire and Short Form-36, were assessed. Urgency correlated with disease activity, biomarkers, and QoL with improvements in urgency paralleling clinical response and remission (17,18). Specifically, an absence of urgency was associated with Mayo endoscopic remission, histologic remission, and mucosal healing with an OR of 3.6 (95% CI 1.8–7.2), 4.6 (95% CI 2.4–8), and 4.9 (95% CI 2.1–11.6), respectively, at week 12 (19).…”
INTRODUCTION:Urgency, the immediate need to defecate, is common in active ulcerative colitis (UC). We investigated the association of urgency in patients with UC with (i) quality of life (QoL) domains and (ii) future hospitalizations, corticosteroid use, and colectomy for UC.METHODS:We conducted a cross-sectional and subsequent longitudinal study within Inflammatory Bowel Disease Partners, a patient-powered research network. We described associations of levels of urgency in patients with UC with Patient-Reported Outcomes Measurement Information System QoL domains. We conducted a longitudinal cohort to determine associations between baseline urgency and subsequent hospitalization, corticosteroid use, or colectomy for UC within 12 months. We used bivariate statistics and logistic regression models to describe independent associations.RESULTS:A total of 632 patients with UC were included in the cross-sectional study. After adjusting for clinical variables, rectal bleeding, and stool frequency, urgency defined as “hurry,” “immediately,” and “incontinence” increased the odds of social impairment (odds ratio [OR] 2.05 95% confidence interval [CI] 1.24–3.4, OR 2.76 95% CI 1.1–6.74, and OR 7.7 95% CI 1.66–38.3, respectively) compared with “no hurry.” Urgency also significantly increased the odds of depression, anxiety, and fatigue. Urgency was associated with a significant increase in risk of hospitalizations and corticosteroids, whereas “hurry,” “immediately,” and “incontinence” increased the odds of colectomy within 12 months by 1.42 (1.15–1.75), 1.90 (1.45–2.50), and 3.69 (2.35–5.80).DISCUSSION:We demonstrated that urgency is a patient-reported outcome independently associated with compromised QoL and future risk of hospitalizations, corticosteroids, and colectomy. Our findings support the consideration of urgency as a UC-specific patient-reported outcome and its use as an outcome in clinical trials to capture QoL and risk of clinical decompensation.
“…In the phase II upadacitinib trial, bowel urgency and QoL, measured by IBD questionnaire and Short Form-36, were assessed. Urgency correlated with disease activity, biomarkers, and QoL with improvements in urgency paralleling clinical response and remission (17,18). Specifically, an absence of urgency was associated with Mayo endoscopic remission, histologic remission, and mucosal healing with an OR of 3.6 (95% CI 1.8–7.2), 4.6 (95% CI 2.4–8), and 4.9 (95% CI 2.1–11.6), respectively, at week 12 (19).…”
INTRODUCTION:Urgency, the immediate need to defecate, is common in active ulcerative colitis (UC). We investigated the association of urgency in patients with UC with (i) quality of life (QoL) domains and (ii) future hospitalizations, corticosteroid use, and colectomy for UC.METHODS:We conducted a cross-sectional and subsequent longitudinal study within Inflammatory Bowel Disease Partners, a patient-powered research network. We described associations of levels of urgency in patients with UC with Patient-Reported Outcomes Measurement Information System QoL domains. We conducted a longitudinal cohort to determine associations between baseline urgency and subsequent hospitalization, corticosteroid use, or colectomy for UC within 12 months. We used bivariate statistics and logistic regression models to describe independent associations.RESULTS:A total of 632 patients with UC were included in the cross-sectional study. After adjusting for clinical variables, rectal bleeding, and stool frequency, urgency defined as “hurry,” “immediately,” and “incontinence” increased the odds of social impairment (odds ratio [OR] 2.05 95% confidence interval [CI] 1.24–3.4, OR 2.76 95% CI 1.1–6.74, and OR 7.7 95% CI 1.66–38.3, respectively) compared with “no hurry.” Urgency also significantly increased the odds of depression, anxiety, and fatigue. Urgency was associated with a significant increase in risk of hospitalizations and corticosteroids, whereas “hurry,” “immediately,” and “incontinence” increased the odds of colectomy within 12 months by 1.42 (1.15–1.75), 1.90 (1.45–2.50), and 3.69 (2.35–5.80).DISCUSSION:We demonstrated that urgency is a patient-reported outcome independently associated with compromised QoL and future risk of hospitalizations, corticosteroids, and colectomy. Our findings support the consideration of urgency as a UC-specific patient-reported outcome and its use as an outcome in clinical trials to capture QoL and risk of clinical decompensation.
“… 53 Moreover, the oral administration route can improve patients’ quality of life, reducing the number of accesses to the hospital and lost workdays. 54 , 55 In fact, a significantly greater proportion of patients who responded to UPA induction phase maintained improvements in health-related quality of life (HRQOL) compared to placebo after 52 weeks of maintenance treatment. Figure 1 Pros and cons of upadacitinib in patients with moderate-to-severe ulcerative colitis.…”
Upadacitinib is a selective small molecule that inhibits Janus kinase (JAK) type 1. This molecule is administrated orally and is currently approved for the treatment of rheumatoid arthritis, atopic dermatitis, and psoriatic arthritis. Upadacitinib has been approved by the United States Food and Drug Administration for the induction and maintenance therapy of moderate-to-severe ulcerative colitis (UC) and is under investigation by the European Medicines Agency. Data from two induction and two maintenance Phase III randomized controlled trials (RCTs) proved the efficacy of upadacitinib in achieving clinical and endoscopic remission in patients with moderate-to-severe UC, regardless of previous inadequate response to other biologic therapies. The most frequently reported adverse events in the induction trials were acne, creatine phosphokinase increase, nasopharyngitis, headache, and anemia, while in the maintenance studies nasopharyngitis, elevation of creatine phosphokinase, UC exacerbation, upper respiratory tract infection, arthralgia, and anemia were reported. A limited proportion of upadacitinib-treated patients experienced adverse events of special interest, like herpes zoster infections or thromboembolic events, indicating a reliable safety profile. The aim of this review is to summarize the available evidence on upadacitinib in UC providing useful insights about the positioning of this drug in the therapeutic algorithm.
“…22,23 Several randomized, doubleblind, placebo-controlled trials have attempted to evaluate the efficacy and safety of tofacitinib, TD-1473, upadacitinib, filgotinib and peficitinib in patients with active UC. [16][17][18]20,21,24 All of these drugs have shown considerable efficacy in placebo-controlled trials, but the relative efficacy and safety of JAK inhibitors remain unclear due to a lack of head-to-head comparisons. When direct comparisons are not available, indirect comparisons through a network meta-analysis (NMA) can assist in generating evidence for decision-making.…”
Section: What Is K Nown and Objec Tivementioning
confidence: 99%
“…Two previous network meta‐analyses have demonstrated that tofacitinib is effective for achieving clinical, endoscopic and quality of life outcomes compared to placebo in patients with UC 22,23 . Several randomized, double‐blind, placebo‐controlled trials have attempted to evaluate the efficacy and safety of tofacitinib, TD‐1473, upadacitinib, filgotinib and peficitinib in patients with active UC 16–18,20,21,24 . All of these drugs have shown considerable efficacy in placebo‐controlled trials, but the relative efficacy and safety of JAK inhibitors remain unclear due to a lack of head‐to‐head comparisons.…”
What is known and objective: In the absence of head-to-head comparisons, the objective of this study was to conduct a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of Janus kinase (JAK) inhibitors for ulcerative colitis (UC).
Methods:We searched PubMed, EMBASE, Web of Science and Cochrane Library from the database inception until 13 August 2021. No randomized controlled trials (RCTs) that directly compared these interventions were identified. Therefore, a fixedeffects Bayesian NMA was conducted by identifying a connected (via comparison to placebo) network of RCTs. Ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.Results and discussion: Seven RCTs including 3190 patients met the inclusion criteria.Filgotinib 100 mg was ranked highest for induction of endoscopic remission (SUCRA, 0.67) whereas peficitinib 75 mg BID was ranked highest for induction of clinical response (SUCRA, 0.72). Peficitinib 75 mg was ranked highest for induction of mucosal healing (SUCRA, 0.71), whereas peficitinib 150 mg was ranked highest for clinical remission (SUCRA, 0.74). Tofacitinib 3 mg had the highest probability of being the best treatment in terms of change from baseline in Mayo score (SUCRA, 0.78). Adverse events (AEs) and treatment discontinuations or withdrawals from the study due to AEs did not differ between JAK inhibitors and placebo groups.What is new and conclusion: Based on indirect comparisons, peficitinib 75 mg/75 mg BID/150 mg, tofacitinib 3 mg and filgotinib 100mg were the most efficacious JAK inhibitor interventions in patients with UC. However, head-to-head trials are warranted to inform clinical decision-making with greater confidence.
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