A Review of Selected Presentations From the 2019 DDW Meeting
• May 18-21, 2019 • San Diego, California
Vedolizumab Shows Superior Efficacy Versus Adalimumab: Results of VARSITY—The First Head-To-Head Study of Biologic Therapy for Moderate-to-Severe Ulcerative Colitis
The VARSITY trial (A Double-Blind, Double-Dummy, Randomised, Controlled Trial of Vedolizumab Versus Adalimumab in Patients With Active Ulcerative Colitis) was the first head-to-head clinical trial to directly compare 2 biologic therapies for the treatment of ulcerative colitis.1 VARSITY evaluated the intravenous (IV) agent vedolizumab, a gut-selective humanized immunoglobulin (Ig) G1 monoclonal antibody that targets the α4β7 integrin, and adalimumab, a subcutaneously (SC) administered recombinant human IgG1 monoclonal antibody that binds to tumor necrosis factor alpha (TNFα).2,3 Initially reported at the 14th Congress of the European Crohn’s and Colitis Organisation (ECCO), the primary results of the VARSITY trial showed that vedolizumab was associated with superior clinical and endoscopic efficacy outcomes compared with adalimumab.4 At the 2019 Digestive Disease Week (DDW) meeting, Dr Bruce E. Sands and colleagues presented further results, which more fully characterized the treatment effects of vedolizumab vs adalimumab across clinical, endoscopic, and histologic outcomes.1
VARSITY was a phase 3b double-blind, double-dummy, multicenter, active-controlled trial in patients with moderately to severely active ulcerative colitis. Patients were randomly assigned to treatment with vedolizumab at 300 mg IV at weeks 0, 2, and 6, and every 8 weeks thereafter until week 46 (n=385) or adalimumab at 160 mg SC at week 0, 80 mg SC at week 2, and 40 mg SC every 2 weeks thereafter until week 50 (n=386). To control for the different routes of administration, patients in the vedolizumab arm also received an SC placebo every 2 weeks until week 50, and patients in the adalimumab arm also received IV placebo on the same schedule as vedolizumab until week 46.
The study enrolled adult patients (ages 18 to 85 years) diagnosed more than 3 months prior with moderately to severely active ulcerative colitis (defined as a Mayo score of 6-12 and an endoscopic subscore of ≥2). Patients had at least 15 cm of involved colonic tissue. Previous use of adalimumab or vedolizumab was not permitted. Previous exposure to a TNFα inhibitor other than adalimumab was allowed, but limited to a maximum of 25% of the total enrolled study population.
The mean patient age in each arm was similar (40.8 years in the vedolizumab arm vs 40.5 years in the adalimumab arm), as was the proportion of patients who were male (60.8% vs 56.0%, respectively). The proportion of patients with moderate ulcerative colitis (defined as a Mayo score of 6-8) was 40.0% in the vedolizumab arm and 43.8% in the adalimumab arm. The proportion of patients with severe ulcerative colitis (defined as a Mayo score of 9-12) was 56.4% vs 54.4%, respectively. At baseline, use of a concomitant corticosteroid was reported in 36.1% of the vedolizumab arm and 36.3% of the adalimumab arm. Use of immunomodulators was reported in 26.2% vs 25.9%, respectively. Prior use of a TNFα inhibitor was reported in 20.8% vs 21.0%.
The primary endpoint of the VARSITY trial was clinical remission at week 52, which was defined as a complete Mayo score of 2 points or less, coupled with no individual subscore greater than 1 point. This endpoint was achieved by 31.3% of the vedolizumab arm vs 22.5% of the adalimumab arm (95% CI, 2.5%-15.0%; P=.0061; Figure 1). A prespecified subgroup analysis of the primary endpoint evaluated the rate of clinical remission at week 52 according to prior use of TNFα inhibitors. Among patients who had not received a TNFα inhibitor, the rates of remission were 34.2% with vedolizumab vs 24.3% with adalimumab (95% CI, 2.8%-17.1%; P=.0070). Among patients who had received a TNFα inhibitor, these rates were 20.3% with vedolizumab vs 16.0% with adalimumab, a difference that did not reach statistical significance (95% CI, –7.8% to 16.2%; P=.4948).1
Endoscopic improvement at week 52, a secondary endpoint, was defined as mucosal healing with a Mayo endoscopic subscore of 1 point or less. The rate of endoscopic improvement was 39.7% with vedolizumab vs 27.7% with adalimumab (95% CI, 5.3%-18.5%; P=.0005; Figure 2). Among patients who had not received a TNFα inhibitor, endoscopic improvement was seen in 43.1% of the vedolizumab arm vs 29.5% of the adalimumab arm (95% CI, 6.0-21.2; P=.0005). The difference in endoscopic imp-rove-ment was not statistically sig-nificant among patients who had been exposed to TNFα inhibitors, at 26.6% with vedolizumab vs 21.0% with adalimumab (95% CI, –7.7 to 18.8; P=.4136).
The study’s secondary endpoint of corticosteroid-free clinical remission at week 52 was assessed among those patients who were receiving corticosteroids at baseline. The study design advised that corticosteroid tapering should be initiated starting at week 6 if the patient achieved a response. However, this decision was left to the treating physician, and there was no forced taper. There was no statistically significant difference between the treatments for this key secondary endpoint. The rates were 12.6% with vedolizumab vs 21.8% with adalimumab (95% CI, –18.9 to 0.4; P=.0641). Similar trends were observed in the prespecified analysis according to prior TNFα inhibitor use. The rates of corticosteroid-free clinical remission in the TNFα inhibitor–naive group were 14.9% with vedolizumab and 21.7% with adalimumab (95% CI, –18.1 to 4.5; P=.2412). Among patients treated with a TNFα inhibitor, these rates were 4.2% with vedolizumab and 22.2% with adalimumab (95% CI, –44.2 to 10.0; P=.1034).1
Predefined and post hoc analyses of efficacy outcomes at week 52 showed that in the patients with no concomitant use of corticosteroids or immunomodulators at baseline, vedolizumab was superior to adalimumab (Figure 3).1 However, among patients using concomitant corticosteroids or immunomodulators at baseline, the 2 biologic therapies were essentially equivalent in terms of efficacy.
Rates of histologic remission at week 52 were 10.4% with vedolizumab vs 3.1% with adalimumab (95% CI, 3.8-10.8; P<.0001) using a Geboes score of less than 2. When using a Robarts Index of less than 3, these rates were 37.6% with vedolizumab vs 19.9% with adalimumab (95% CI, 11.3-23.8; P<.0001). Using slightly less stringent criteria for each—a Geboes score of less than 3.2 and a Robarts Index of less than 5—there was again a statistically significant difference in favor of vedolizumab, with an effect size of 19.6% (P<.0001) with the Geboes criteria and 16.6% (P<.0001) with the Robarts criteria. Clinical response according to patient visits throughout the study is shown in Figure 4.
Both of the biologic agents exhibited expected safety profiles. Adverse events required drug discontinuations in 4.4% of the vedolizumab arm and 6.5% of the adalimumab arm. The 1 death that occurred in the study was not considered related to the treatment (vedolizumab). The rate of infections and infestations was 23.4% in the vedolizumab arm and 34.6% in the adalimumab arm. There was no difference between the 2 treatment groups in the incidence of arthralgia (4.1% vs 4.5%, respectively). The rate of psoriasis was 1.7% with adalimumab vs 0.2% with vedolizumab.
Dr Sands therefore concluded that vedolizumab showed superior clinical and endoscopic efficacy compared with adalimumab in the treatment of moderately to severely active ulcerative colitis. These treatment effects seemed most pronounced among patients who were naive to TNFα inhibitors. Both drugs were generally safe and well tolerated. According to Dr Sands, these results provide the most direct evidence to date on the comparative efficacy of biologics to support clinical decision-making in the management of moderately to severely active ulcerative colitis.
References
1. Sands BE, Peyrin-Biroulet L, Loftus EV, et al. Vedolizumab shows superior efficacy versus adalimumab: results of VARSITY—the first head-to-head study of biologic therapy for moderate-to-severe ulcerative colitis [DDW abstract 416a]. Gastroenterology. 2019;156(suppl 1).
2. Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2019.
3. Humira [package insert]. North Chicago, IL: AbbVie Inc; 2019.
4. Schreiber S, Peyrin-Biroulet L, Loftus EV, et al. VARSITY: a double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis [ECCO abstract OP34]. J Crohns Colitis. 2019;13(suppl 1).
Real-World Effectiveness and Safety of Vedolizumab and Anti-TNF in Biologic-Naive Ulcerative Colitis Patients: Results From the EVOLVE Study
In a poster presentation, Dr Andres Yarur and coworkers presented findings from the EVOLVE study (Vedolizumab Outcomes in Real-World Bio-Naive Ulcerative Colitis and Crohn’s Disease Patients), a multicountry, multicenter, retrospective chart review that com-pared the efficacy and safety of treatment with vedolizumab or TNFα inhibitors in patients with ulcerative colitis.1 The analysis included adult patients from Canada, Greece, and the United States who had not received prior treatment with a biologic agent. Outcomes were assessed using data from the patients’ medical records.
Among the 527 patients included in the analysis, 325 had received vedolizumab and 202 had received infliximab, adal-imumab, or golimumab. The disease duration was 5.0 years among patients treated with vedolizumab vs 2.0 years among those treated with a TNFα inhibitor. However, differences in baseline characteristics led the authors to believe that patients treated with a TNFα inhibitor may have had more severe disease at initiation compared with patients treated with vedolizumab. Patients treated with a TNFα inhibitor had higher rates of extensive colitis, elevated C-reactive protein, and ulcerative colitis–related hospitalizations, and a lower rate of left-sided disease.
The analysis found no significant differences in the rates of clinical remission or mucosal healing between the treatment groups. At 24 months, clinical remission was reported in 79.0% of the vedolizumab group vs 66.2% of the TNFα inhibitor group (P=.37). Mucosal healing at 24 months was seen in 92.0% vs 84.4%, respectively (P=.67).1
At the time points of 12, 18, and 24 months, the cumulative probability of treatment persistence was significantly higher with ved-olizu-mab than with a TNFα inhibitor (Figure 5). The unadjusted rates of treatment persistence were 82.5% with vedolizumab vs 65.0% with a TNFα inhibitor at 12 months, 79.1% vs 60.3% at 18 months, and 75.1% vs 53.8% at 24 months (P<.01 at each time point). After adjusting for baseline characteristics, patients treated with vedolizumab were twice as likely to persist on-treatment compared with patients treated with a TNFα inhibitor.
After adjusting for the baseline characteristics, patients treated with vedolizumab were significantly less likely to develop an exacerbation of ulcerative colitis (hazard ratio [HR], 0.7; 95% CI, 0.5-0.9). However, rates of colectomy were similar between the 2 treatment groups (HR, 0.9; 95% CI, 0.3-2.9). The rates of serious adverse events were 4.9% with vedolizumab vs 10.4% with TNFα inhibitors. The most frequently documented serious adverse events were anemia for vedolizumab and pain for the TNFα inhibitors.
The authors of the EVOLVE study concluded that these results support the long-term effectiveness and safety of first-line vedolizumab for the treatment of biologic-naive patients.
Reference
1. Yarur AJ, Mantzaris GJ, Silverberg MS, et al. Real-world effectiveness and safety of vedolizumab and anti-TNF in biologic-naive ulcerative colitis patients: results from the EVOLVE study [DDW abstract 1858]. Gastroenterology. 2019;156(suppl 1).
Subgroup Analyses of Upadacitinib as Induction Therapy From the U-ACHIEVE Trial
The U-ACHIEVE study eval-uated the efficacy and safety of upadacitinib, an oral selective Janus kinase (JAK) 1 inhibitor, as an 8-week induction therapy in patients with moderately to severely active ulcerative colitis who developed an inadequate response, loss of response, or intolerance to corticosteroids, imm-unosuppressants, or biologic therapies. U-ACHIEVE was a double-blind, placebo-controlled, dose-ranging phase 2b study that included 250 patients with moderately to severely active ulcerative colitis who were treated with either placebo or upadacitinib (at daily doses of 7.5 mg, 15 mg, 30 mg, or 45 mg). The results of the U-ACHIEVE study demonstrated that upadacitinib was associated with significantly greater efficacy in the overall population compared with placebo.1 Two abstracts presented at the 2019 DDW Meeting discussed subgroup analyses from the study.
A subgroup analysis presented by Dr Remo Panaccione and coworkers examined differences in efficacy outcomes between patients with an inadequate response, loss of response, or intolerance to biologic therapies (referred to as Bio-IR) and patients in whom treatment was successful (referred to a non–Bio-IR).2 In general, efficacy outcomes in the non–Bio-IR group were numerically greater than in the Bio-IR group. In the overall study population, the primary endpoint of clinical remission per adapted Mayo score at week 8 was 19.6% with 45 mg, 13.5% with 30 mg, 14.3% with 15 mg, and 8.5% with 7.5 mg, vs 0% with placebo.1 Statistical significance vs placebo was seen with the doses of 45 mg (P<.01), 30 mg (P<.05), and 15 mg (P<.05). In the Bio-IR group, the rates of clinical remission at week 8 were 11.9% with 45 mg, 10.0% with 30 mg, 8.3% with 15 mg, and 5.9% with 7.5 mg, vs 0% with placebo.2 For this group, none of the improvements seen with upadacitinib were statistically significant vs placebo. In the non–Bio-IR group, the rates of clinical remission at week 8 were 42.9%, 25.0%, 30.8%, and 15.4%, respectively, vs 0% with placebo. Of these, only the difference for the 45 mg group was significantly improved vs placebo (P<.05).
A similar trend was observed in the Bio-IR and non–Bio-IR groups with regard to multiple secondary endpoints, including clinical response per adapted Mayo score at week 8, clinical response per partial Mayo score at week 2, endoscopic improvement and remission at week 8, and histologic improvement at week 8. In each of these efficacy outcomes, in general, the non–Bio-IR group achieved greater benefit with upadacitinib than the Bio-IR group. Both groups showed a dose response in benefit compared with placebo. The study authors noted that the patient numbers in both groups were small, and that these findings must be confirmed in larger phase 3 studies.
Dr William J. Sandborn and colleagues presented an analysis of the U-ACHIEVE study that evaluated endoscopic outcomes and mucosal healing.3 At week 8, patients were assessed for endoscopic improvement and remission, histologic improvement and remission, and mucosal healing. Each of these outcomes showed an overall dose-response relationship with upadacitinib. The rates of endoscopic improvement (defined as an endoscopic subscore of ≤1) were 35.7% with 45 mg, 26.9% with 30 mg, 30.6% with 15 mg, and 14.9% with 7.5 mg, vs 2.2% with placebo (Figure 6). Similar trends were also observed with rates of endoscopic remission, histologic improvement, and histologic remission. The rates of mucosal healing defined by an endoscopic subscore of 0 and a Geboes score of less than 2 were 14.3% with upadacitinib at 45 mg vs 0% with placebo (P=.01).
References
1. Sandborn WJ, Ghosh S, Panés J, et al. Efficacy and safety of upadacitinib as an induction therapy for patients with moderately-to-severely active ulcerative colitis: data from the phase 2b study U-ACHIEVE [UEG abstract OP195]. United European Gastroenterol J. 2018;6(8 suppl).
2. Panaccione R, D’Haens GR, Sandborn WJ, et al. Efficacy of upadacitinib as an induction therapy for patients with moderately to severely active ulcerative colitis, with or without previous treatment failure of biologic therapy: data from the dose-ranging phase 2b study U-ACHIEVE [DDW abstract 799]. Gastroenterology. 2019;156(suppl 1).
3. Sandborn WJ, Schreiber S, Lee SD, et al. Improved endoscopic outcomes and mucosal healing of upadacitinib as an induction therapy in adults with moderately-to-severely active ulcerative colitis: data from the U-ACHIEVE study [DDW abstract 800]. Gastroenterology. 2019;156(suppl 1).
Analyses of Vedolizumab From the VISIBLE 1 and 2 Trials
An SC formulation of ved-olizumab was investigated in the double-blind, random-ized, placebo-controlled VISIBLE 1 (Efficacy and Safety of Vedolizumab Subcutaneously [SC] as Maintenance Therapy in Ulcerative Colitis) and VISIBLE 2 (Efficacy and Safety of Vedolizumab Subcutaneous [SC] as Maintenance Therapy in Crohn’s Disease) trials. The recently completed VISIBLE 1 trial found that SC vedolizumab was efficacious and generally well tolerated as maint-enance therapy in patients with ulcerative colitis.1 VISIBLE 2 is an ongoing trial in patients with Crohn’s disease.2 These trials followed a similar design. They enrolled patients with moderately to severely active ulcerative colitis (VISIBLE 1) or Crohn’s disease (VISIBLE 2) who demonstrated an inadequate response, loss of response, or intolerance to 1 or more therapies (including corticosteroids, immunosuppressive agents, and/or TNFα inhibitors). For both trials, patients were enrolled into an open-label induction phase, in which they received IV vedolizumab at 300 mg at weeks 0 and 2. After evaluation of clinical response at week 6, responders were randomly assigned into the double-blind maintenance phase, where they received either SC vedolizumab (108 mg every 2 weeks), IV vedolizumab (300 mg every 8 weeks), or placebo up to week 50. Additionally, patients who were not responding at week 6 received an additional dose of open-label IV vedolizumab at week 6, and were then evaluated for clinical response at week 14.1,2 At the 2019 DDW meeting, 2 studies with data from these trials were presented.
Dr Edward V. Loftus Jr and colleagues examined the efficacy and safety of either 2 or 3 doses of IV vedolizumab when administered as open-label induction therapy in VISIBLE 1 and VISIBLE 2.3 The authors noted that only preliminary efficacy results were available for VISIBLE 2. In the 383 patients with ulcerative colitis from VISIBLE 1, 56.1% achieved a clinical response at week 6 after receiving 2 IV infusions. Among the remaining patients who were not responding at week 6 and who went on to receive a third dose of IV vedolizumab, the rate of clinical response at week 14 was 79.1%. Together, 84.9% of patients with ulcerative colitis achieved a clinical response after 2 or 3 IV infusions of vedolizumab.
Among the 644 patients with Crohn’s disease from VISIBLE 2, 60.6% achieved a clinical response at week 6 after 2 IV infusions. Among the remaining patients who were not responding at week 6 and received a third dose of IV vedolizumab, the rate of clinical response at week 14 was 63.0%. Overall, 79.3% of patients with Crohn’s disease achieved a clinical response after either 2 or 3 IV infusions of vedolizumab.
Safety data reported in this study were limited to results from VISIBLE 1. A treatment-related adverse event occurred in 17% of patients. Severe adverse events were reported in 6.5%, and 5.5% experienced an adverse event leading to treatment discontinuation.3
A report from Dr Séverine Vermeire and coworkers focused on patients with ulcerative colitis from VISIBLE 1.4 The study analyzed the effects of vedolizumab maintenance treatment on patient-reported quality of life (assessed by the Inflammatory Bowel Disease Questionnaire [IBDQ] and EQ-5D Visual Analogue Scale instruments) and work productivity (assessed by the Work Productivity and Activity Impairment Questionnaire: Ulcerative Colitis instrument). The mean total IBDQ improved substantially throughout the study in both the SC and IV vedolizumab groups compared with the placebo group (week 52 mean IBDQ total scores of 180.7, 170.7, and 135.2, respectively). Each individual component of the IBDQ score also showed substantial clinical improvement with both SC and IV vedolizumab compared with placebo (Figure 7). The changes in total IBDQ scores from baseline to week 52 were significantly greater with both the SC (+65.3) and IV (+58.6) formulations of vedolizumab compared with placebo (P<.001 for both comparisons).
References
1. Sandborn WJ, Baert F, Danese S, et al. Efficacy and safety of a new vedolizumab subcutaneous formulation for ulcerative colitis: results of the VISIBLE 1 phase 3 trial [UEG abstract LB03]. United European Gastroenterol J. 2018;6(8 suppl).
2. ClinicalTrials.gov. Efficacy and safety of vedolizumab subcutaneous (SC) as maintenance therapy in Crohn’s disease. https://clinicaltrials.gov/ct2/show/NCT02611817. Identifier: NCT02611817. Accessed July 14, 2019.
3. Loftus EV, Sandborn WJ, Wolf DC, et al. Efficacy and safety of 2 or 3 vedolizumab intravenous infusions as induction therapy for ulcerative colitis and Crohn’s disease: results from VISIBLE 1 and 2 [DDW abstract 1713]. Gastroenterology. 2019;156(suppl 1).
4. Vermeire S, Krznaric Z, Kobayashi T, et al. Effects of subcutaneous vedolizumab on health-related quality of life and work productivity in patients with ulcerative colitis: results from the phase 3 VISIBLE 1 trial [DDW abstract 1878]. Gastroenterology. 2019;156(suppl 1).
Ustekinumab in Ulcerative Colitis: Results From the UNIFI Trial
Two abstracts presented at the 2019 DDW Meeting by Dr Bruce E. Sands and colleagues provided results from the phase 3 UNIFI study (A Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Participants With Moderately to Severely Active Ulcerative Colitis). In the UNIFI study, a single IV induction dose of ustekinumab was associated with a benefit in multiple efficacy endpoints in patients with moderately to severely active ulcerative colitis.1 Among patients in the induction portion of UNIFI, 50.5% had previously received at least 1 TNFα inhibitor and/or vedolizumab, but they did not initially respond, responded initially but then lost response, or were intolerant to treatment (classified as biologic failures); and 49.5% were biologic-naive or had prior biologic exposure but did not show inadequate response or intolerance to treatment (classified as non–biologic failures).2 Patients with a clinical response at week 8 after the single induction dose entered into a maintenance portion of the study. Patients were randomly assigned to treatment with either SC ustekinumab at 90 mg every 12 weeks or every 8 weeks, or placebo.
At week 8, the rates of clinical remission were 15.5% with IV ustekinumab at 6 mg/kg and 15.6% with IV ustekinumab at 130 mg, compared with 5.3% with placebo (P<.001 for both comparisons with placebo).2 Among patients with an unsuccessful response to biologic therapy, rates of clinical remission were 12.7%, 11.6%, and 1.2%, respectively (P<.001 for both comparisons with placebo). Among patients who were biologic-naive or who responded adequately to biologic therapy, these rates were 18.6%, 19.9%, and 9.5%, respectively (P<.05 for both comparisons with placebo). Similar trends were observed at week 8 in endoscopic improvement, clinical response, and mucosal healing outcomes.
In the maintenance phase of the study, 523 patients were randomly assigned to treatment with a SC 90 mg dose of ustekinumab administered every 8 weeks or every 12 weeks, or placebo.3 The patients’ baseline characteristics were consistent with moderately to severely active disease activity, and included a median Mayo score of 9.0. A score of more than 10 was seen in 13.1% of patients, 47.1% had evidence of extensive disease, and the median duration of disease was 6.1 years. Nearly half of the patients (47.6%) had a history of biologic therapy failure, and 49.3% were considered biologic-naive.
The primary endpoint of the maintenance portion was clinical remission, defined as a Mayo score of 2 points or less, with no individual subscore higher than 1.3 At week 44, this rate was 43.8% with SC ustekinumab given every 8 weeks (P<.001 compared with placebo), 38.4% with SC ustekinumab given every 12 weeks (P=.002 compared with placebo), and 24.0% with placebo (Figure 8). A similar trend was observed with the rates of corticosteroid-free remission, a major secondary endpoint. These rates were 42.0% with SC ustekinumab given every 8 weeks (P<.001 compared with placebo), 37.8% with SC ustekinumab given every 12 weeks (P=.002 compared with placebo), and 23.4% with placebo. Rates of clinical remission were slightly lower in patients classified as biologic failures, at 39.6% (P<.001), 22.9% (P<.05), and 17.0%, respectively, and slightly higher in patients classified as non–biologic failures, at 48.2%, 49.0%, and 31.0%, respectively (P<.05 for both comparisons with placebo).
Maintenance of clinical response was seen in 71.0%, 68.0%, and 44.6%, respectively (P<.001 for both comparisons with placebo). The rates of key safety events, including infections, were similar between the ustekinumab and placebo arms.
References
1. Sands BE, Sandborn WJ, Panaccione R, et al. Safety and efficacy of ustekinumab induction therapy in patients with moderate to severe ulcerative colitis: results from the phase 3 UNIFI study (late-breaking abstract) [UEG abstract LB01]. United European Gastroenterol J. 2018;6(8 suppl).
2. Sands BE, Peyrin-Biroulet L, Marano CW, et al. Efficacy in biologic-failure and nonbiologic-failure populations in a phase 3 study of ustekinumab in moderate-severe ulcerative colitis: UNIFI [DDW abstract 833a]. Gastroenterology. 2019;156(suppl 1).
3. Sands BE, Sandborn WJ, Panaccione R, et al. Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from UNIFI [DDW abstract 833]. Gastroenterology. 2019;156(suppl 1).
The Impact of Vedolizumab on Rates of Surgery in the GEMINI Trials
Studies presented at the 2019 DDW Meeting examined the impact of vedolizumab on surgical rates in patients enrolled in the pivotal phase 3 GEMINI trials, which evaluated the efficacy and safety of vedolizumab as induction and maintenance therapy for the treatment of either ulcerative colitis (GEMINI 1) or Crohn’s disease (GEMINI 2).1,2 A post hoc analysis of patient data from GEMINI 2 and the GEMINI long-term safety (LTS) study investigated whether rates of Crohn’s disease–related surgery (defined as any resective bowel surgery) were affected if vedolizumab was administered earlier vs later in the disease course.3 A total of 1253 patients with Crohn’s disease were included. Across the study population, 55.1% were female, and the mean patient age was 36.4 years. Most patients (83.5%) had colonic or ileocolonic disease involvement; 16.5% had ileum disease only. Approximately one-third of patients (36.3%) had a history of fistulizing Crohn’s disease. A total of 43.8% of patients had undergone a prior bowel surgery (before study enrollment), and 65.6% of patients had an inadequate response to previous treatment with a TNFα inhibitor. At baseline, use of concomitant corticosteroids was reported in 51.6% and use of immunomodulators was noted in 30.9%. The study investigators utilized a previously validated clinical decision support tool to stratify each patient’s baseline probability of clinical response to vedolizumab.
Throughout the 7-year follow-up period, 113 patients (9.0%) underwent at least 1 bowel surgery related to Crohn’s disease.3 These surgeries included bowel resection in 58.4% and colectomy in 41.6%. The patients were stratified according to their probability of clinical response. Surgical rates were 12.9% for the low-probability group, 8.1% for the intermediate-probability group, and 6.0% for the high-probability group. Patients with a low probability of response to vedolizumab were more than twice as likely to undergo Crohn’s disease–related bowel surgery compared with patients with a high probability of response (HR, 2.32; 95% CI, 1.29-4.30). Patients with an intermediate probability of response also had a heightened risk of surgery compared with patients in the high-probability group (HR, 1.37; 95% CI, 0.77-2.52).
Additionally, this study identified a trend toward lower rates of Crohn’s disease–related bowel surgery among patients treated with vedolizumab earlier in their disease course.3 For example, among patients with a low or intermediate probability of response to vedolizumab, those with a disease duration of 5 years or less had 39% lower odds of requiring Crohn’s disease–related bowel surgery compared with patients who had a low or intermediate probability of response and a disease duration of more than 5 years (odds ratio, 0.61; 95% CI, 0.36-0.99; Figure 9). For patients with a high probability of response, those with a disease duration of 5 years or less had 29% lower odds of requiring Crohn’s disease–related bowel surgery vs patients with a high probability of response and more than 5 years of disease duration (odds ratio, 0.71; 95% CI, 0.25-2.03).
Another post hoc analysis compared the surgical incidence rates between the vedolizumab and placebo arms of the GEMINI 1 and 2 studies.4 In addition, this study was designed to describe the surgical incidence rates reported with vedolizumab in the GEMINI LTS trial. During the first year of observation, surgery rates were lower among patients treated with vedolizumab compared with patients who received placebo in these trials. It also appeared that this benefit was durable. Patients with either ulcerative colitis or Crohn’s disease who received vedolizumab had lower rates of surgery for up to 5 years. Detailed results from this post hoc analysis are expected to be published in the near future.
References
1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710.
2. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721.
3. Dulai PS, Peyrin-Biroulet L, Hahn K, et al. The impact of early disease control with vedolizumab on surgery rates among patients with Crohn’s disease: a post hoc analysis of the GEMINI trials [DDW abstract 1726]. Gastroenterology. 2019;156(suppl 1).
4. Feagan BG, Sands BE, Lirio RA, et al. Effect of vedolizumab on surgical rates in IBD: post hoc analysis from the GEMINI trials [DDW abstract 1734]. Gastroenterology. 2019;156(suppl 1).
Long-Term Analyses of Vedolizumab From the GEMINI Trials
Two studies presented at the 2019 DDW meeting discussed safety and immunogenicity findings from the GEMINI program, which evaluated the efficacy and safety of vedolizumab in ulcerative colitis and Crohn’s disease.1,2 A study provided the final results from the GEMINI LTS study in patients with ulcerative colitis and Crohn’s disease.3 GEMINI LTS was a multinational, multicenter, open-label phase 3 study in which patients received vedolizumab at 300 mg IV every 4 weeks. Among the 894 patients with ulcerative colitis, the median duration of exposure to vedolizumab was 43.0 months (range, 1 day to 113.7 months). Among the 1349 patients with Crohn’s disease, the median vedolizumab exposure was 31.9 months (range, 1 day to 101.7 months).
Serious adverse events according to the patient cohort are shown in the Table. Among patients with ulcerative colitis, adverse events were mild in 18%, moderate in 50%, and severe in 24%.3 Common adverse events, as calculated by incident rate per 1000 patient-years, included disease exacerbation (105.2), nasopharyngitis (93.9), arthralgia (51.6), abdominal pain (34.4), headache (55.5), and upper respiratory tract infection (55.7). Additionally, several adverse events of special interest were noted, including infections (388.9), neoplasms (17.2), and hepatic events (8.4). A total of 4 deaths occurred among patients with ulcerative colitis, although only 1 was considered treatment-related.
Among the patients with Crohn’s disease, adverse events were mild in 17%, moderate in 49%, and severe in 31%.3 Common adverse events, as calculated by the incident rate per 1000 patient-years, included disease exacerbation (121.4), nasopharyngitis (94.1), arthralgia (90.3), abdominal pain (80.0), headache (76.4), and infection of the upper respiratory tract (53.2). Adverse events of special interest included infections (492.1), neoplasms (20.8), and hepatic events (14.1). Among the 6 deaths in patients with Crohn’s disease, 1 was attributed to treatment.
Another analysis presented data on the long-term immunogenicity of vedolizumab among patients with ulcerative colitis and Crohn’s disease enrolled in GEMINI LTS.4 Two cohorts of patients from GEMINI LTS were included in this analysis. A continuous vedolizumab group included 1966 patients who received vedolizumab as induction and maintenance therapy in either GEMINI 1 or 2, and then received vedolizumab in GEMINI LTS. A vedolizumab rechallenge group consisted of 240 patients who received vedolizumab during induction followed by placebo during maintenance in either GEMINI 1 or 2, and then received vedolizumab in GEMINI LTS.
In the continuous vedolizumab group, a total of 4% of patients were positive for anti–vedolizumab antibodies.4 Of these patients, 11 were persistently positive (during ≥2 consecutive tests), and 42 developed neutralizing antibodies. In the vedolizumab rechallenge group, a total of 18% were positive for anti–vedolizumab antibodies. Among these patients, 27 were persistently positive and 23 developed neutralizing antibodies. Immunogenicity rates were higher during the GEMINI 1 and 2 trials (ie, during the first 52 weeks of treatment), compared with the GEMINI LTS trial.
An infusion reaction was reported in 5% of patients overall. None of the patients in the continuous vedolizumab group who had an infusion reaction were persistently positive for anti–vedolizumab antibodies. In contrast, 15% of patients in the vedolizumab rechallenge group who had an infusion reaction were persistently positive for the antibodies.
References
1. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710.
2. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721.
3. Loftus EV, Colombel JF, Feagan BG, et al. Long-term safety of vedolizumab in ulcerative colitis and Crohn’s disease: final results from the GEMINI LTS study [DDW abstract 835]. Gastroenterology. 2019;156(suppl 1).
4. Wyant T, Lirio RA, Yang L, Rosario M. Long-term immunogenicity of intravenous vedolizumab in ulcerative colitis and Crohn’s disease (GEMINI program) [DDW abstract 1742]. Gastroenterology. 2019;156(suppl 1).
Efficacy and Safety of Mirikizumab (LY3074828) in a Phase 2 Study of Patients With Crohn’s Disease
Dr Bruce E. Sands and colleagues presented data from the AMAG study (A Study of Mirikizumab [LY3074828] in Participants With Active Crohn’s Disease), which evaluated mirikizumab, a humanized monoclonal antibody that binds to the p19 subunit of interleukin (IL) 23.1 This multicenter, parallel-arm, double-blind, placebo-controlled, randomized trial enrolled patients with moderate to severe Crohn’s disease. A total of 191 patients were randomly assigned in a 2:1:1:2 fashion to the following treatment arms: mirikizumab at 1000 mg every 4 weeks, mirikizumab at 600 mg every 4 weeks, mirikizumab at 200 mg every 4 weeks, or placebo.
The primary endpoint of the study was endoscopic response, defined as a 50% reduction from baseline in the Simple Endoscopic Score for Crohn’s Disease (SES-CD). An endoscopic response was reported in 43.8% of the 1000 mg group (P<.001), 37.5% of the 600 mg group (P=.003), and 25.8% of the 200 mg group (P=.079), compared with 10.9% of the placebo group (Figure 10).
A secondary endpoint of the study was endoscopic remission, defined as an SES-CD score of less than 4 for ileal-colonic disease or less than 2 for isolated ileal disease, and no subscore higher than 1. The proportion of patients who achieved an endoscopic remission was 20.3% for 1000 mg (P=.009), 15.6% for 600 mg (P=.032), and 6.5% for 200 mg (P=.241), compared with 1.6% for placebo.
Treatment with mirikizumab significantly improved patient-reported response and remission outcomes, as well as response and remission outcomes according to the Crohn’s Disease Activity Index. Treatment was discontinued by 1 patient in the 200 mg group, 3 patients in the 600 mg, and no patients in the 1000 mg group. The most common treatment-emergent adverse events differed among the mirikizumab doses. In the 1000 mg group, the most common ones were headache (10.9%) and nasopharyngitis (6.3%).
Reference
1. Sands BE, Sandborn W, Peyrin-Biroulet L, et al. Efficacy and safety of mirikizumab (LY3074828) in a phase 2 study of patients with Crohn’s disease [DDW abstract 1003]. Gastroenterology. 2019;156(suppl 1).
Highlights in the Management of Ulcerative Colitis and Crohn’s Disease From the 2019 Digestive Disease Week Meeting: Commentary
Gary R. Lichtenstein, MD
Several presentations at the 2019 Digestive Disease Week (DDW) meeting provided important data that could impact the management of patients with inflammatory bowel disease (IBD). The VARSITY trial of vedolizumab vs adalimumab provided the first comparative effectiveness data of biologic therapies for IBD. Data were also presented for other biologic agents, including ustekinumab, mirikizumab, and upadacitinib. Studies offered insights into other aspects of management, including costs of hospitalization, the need for surgical intervention, and postoperative infections during treatment with anti–tumor necrosis (TNF) factor agents.
Clinical Trials of Treatments for IBD
Vedolizumab
When treating patients with IBD, one of the most important aspects of patient care is selection of the most appropriate drug for the particular clinical scenario encountered. This goal can be facilitated through acquiring data from comparative effectiveness trials. The VARSITY trial is the first comparative effectiveness trial performed in patients with IBD. Results were initially presented at the 14th Congress of the European Crohn’s and Colitis Foundation in Copenhagen, Denmark and subsequently reported at the DDW meeting.1,2 VARSITY was a multicenter, double-blind, double-dummy, randomized, controlled phase 3b trial of vedolizumab vs adalimumab in patients with active ulcerative colitis. Vedolizumab is a gut-selective humanized immunoglobulin (Ig) G1 monoclonal antibody that binds to the integrin α4β7. Adalimumab is a human IgG1 monoclonal antibody that binds and neutralizes TNF, exerting systemic anti-inflammatory effects. The objective of the VARSITY trial was to compare the efficacy and safety of intravenous vedolizumab vs subcutaneous adalimumab at week 52 in patients with moderately to severely active ulcerative colitis. Intravenous vedolizumab was administered at a standard loading dose of 300 mg at weeks 0, 2, and 6, and then given every 8 weeks thereafter until week 46. Placebo was given at week 0 and every 2 weeks until week 50. Subcutaneous adalimumab was given at a standard loading dose of 160 mg initially at week 0, then 80 mg at week 2, and 40 mg every 2 weeks until week 50. Placebo was given at 0, 2, and 6 weeks, and then every 8 weeks thereafter until week 46.
The trial initially assessed 1285 patients; 514 were excluded. The trial randomly assigned 771 patients to vedolizumab or adalimumab. Treatment was completed by 74.5% of the vedolizumab arm and 61.9% of the adalimumab arm. The demographics of both treatment arms were relatively similar. In both groups, approximately 21% of patients had received a prior anti-TNF agent. Approximately 36% had received concomitant corticosteroids, and approximately 26% had received concomitant immunomodulators. The proportion of patients with a Mayo score of 9 to 12 was a little higher than 50%. Therefore, the patients in this study were relatively ill and had refractory disease.
The primary endpoint was clinical remission at week 52, as defined by a complete Mayo score of 2 points or less, with no individual subscore of more than 1 point. The proportion of patients who achieved clinical remission at week 52 was 31.3% with vedolizumab vs 22.5% with adalimumab (P=.0061). Among patients who were anti-TNF–naive, the rates of clinical remission were 34.2% with vedolizumab vs 24.3% with adalimumab (P=.0070). In patients with prior exposure to anti-TNF therapy, these rates were 20.3% vs 16.0% (P=.4948), respectively. Mucosal healing at week 52 was achieved in 39.7% of the vedolizumab arm vs 27.7% of the adalimumab arm (P=.0005). Among patients who were anti-TNF–naive, mucosal healing occurred in 43.1% of the vedolizumab arm vs 29.5% of the adalimumab arm (P=.0005). At week 52, the mean daily dose of oral corticosteroids was 7.4 mg in the vedolizumab arm vs 8.6 mg in the adalimumab arm. The change from baseline was 11.6 mg with vedolizumab vs 8.6 with adalimumab. The improvement in partial Mayo score from baseline was greater with vedolizumab vs adalimumab.
Adverse events, including serious adverse events, were similar in both treatment groups. Infections and infestations were numerically higher with adalimumab.
In conclusion, the VARSITY trial showed superior clinical remission and mucosal healing with vedolizumab compared with adalimumab among patients with moderately to severely active ulcerative colitis. The improvement was most pronounced among patients who were anti-TNF–naive. The differences in clinical response tended to emerge around weeks 6 and 14. Rates of corticosteroid-free remission numerically favored adalimumab, but the absolute reduction in the use of corticosteroids was higher with vedolizumab. (For both of these endpoints, the differences were not statistically significant.)
These results were exciting. A critique of the study design might be that there was no forced tapering of corticosteroids; tapering was at the discretion of the individual provider. Additionally, dose escalation of either adalimumab or vedolizumab was not permitted. In clinical practice, we often adjust the doses of these drugs among patients who do not respond to initial dosing. Nonetheless, the VARSITY trial represents an excellent start in the comparative evaluation of IBD drugs. More of these types of studies are needed to help us better understand which, if any, patient populations fare better in certain clinical scenarios.
Several other studies examined various aspects of the use of vedolizumab. The EVOLVE trial was a real-world analysis comparing outcomes and safety among biologic-naive patients with ulcerative colitis treated with vedolizumab or an anti-TNF agent.3 During the 24-month study period, patients who received vedolizumab were twice as likely to remain on treatment. These patients were less likely to develop exacerbation of their disease. The rates of clinical effectiveness were similar regardless of the treatment.
Dr Edward V. Loftus Jr and colleagues presented a long-term safety analysis of vedolizumab from the GEMINI Long-Term Safety Study.4 This analysis confirmed earlier reports.5 Long-term treatment with vedolizumab was safe and well tolerated. There was no increased risk in clinically important safety concerns, such as progressive multifocal leukoencephalopathy, serious infections, or infusion reactions. Patients who continued to receive treatment in the study had favorable clinical outcomes.
Among patients with IBD, the use of immunomodulators, including thiopurines and biologics, has been associated with an increased risk of malignancy.6 Dr Timothy Card and colleagues analyzed data from the GEMINI Long-Term Safety Study, as well as postmarketing data, to determine whether the use of vedolizumab increases the risk of malignancy.7 The study included 1034 patients with Crohn’s disease and 751 patients with ulcerative colitis who had received vedolizumab for at least a year. The use of vedolizumab did not appear to increase the incidence of malignancy among these patients with IBD.
A retrospective, multicenter obser-vational study conducted in Europe examined whether treatment with vedolizumab impacted pregnancy.8 The study compared data for 3 groups of women with IBD: those treated with vedolizumab, those treated with an anti-TNF agent, and those who had not received immunomodulatory or biologic therapies. Rates of miscarriage were 16%, 13%, and 8%, respectively. However, after excluding patients with active disease during pregnancy, these rates were adjusted to 14%, 14%, and 12%. There was no significant difference in the number of infants born prematurely or with a congenital anomaly among the 3 cohorts.
The impact of vedolizumab on quality of life and work productivity was evaluated in 2 studies. An analysis of data from the phase 3b VERSIFY trial examined these measures among 56 patients with Crohn’s disease treated with intravenous vedolizumab.9 The analysis found early, substantial improvements in quality of life and work productivity that began at week 14 and persisted through week 52. Improvements for both of these measures were greater among patients with endoscopic remission. An analysis of data for patients with Crohn’s disease enrolled in the phase 3 VISIBLE 1 trial found similar results.10 Early improvements in quality of life and work productivity were seen at week 6 after intravenous vedolizumab induction therapy and were maintained through week 52 among patients who received vedolizumab intravenously or subcutaneously. This analysis included a control arm, and subcutaneous vedolizumab showed statistically significant and clinically meaningful improvements vs placebo in quality of life and work productivity.
Ustekinumab
Dr Bruce E. Sands and coworkers presented data for ustekinumab as maintenance therapy in the double-blind, randomized phase 3 UNIFI trial for patients with active ulcerative colitis.11 Ustekinumab is already in use and approved for patients with moderate to severe Crohn’s disease. The induction portion of this study showed that ustekinumab improved clinical remission, clinical response, and other endpoints.12 The maintenance phase randomly assigned treatment to 523 patients with moderate to severe ulcerative colitis who required further treatment after receiving therapies such as vedolizumab and anti-TNF agents.11 The patients had achieved a state of clinical response at 8 weeks after a single intravenous induction dose of ustekinumab. The patients were then randomly assigned to treatment with ustekinumab at 90 mg given every 8 weeks or every 12 weeks, or placebo. The primary endpoint of clinical remission at week 44 was 43.8% with ustekinumab given every 8 weeks, 38.4% with ustekinumab given every 12 weeks, and 24% with placebo. Endoscopic healing at week 44 occurred in 51.1%, 43.6%, and 28.6%, respectively. The safety profile was consistent with other studies. Ustekinumab was already known to be effective for active Crohn’s disease.13 I anticipate that ustekinumab will be the next agent to gain regulatory approval from the US Food and Drug Administration (FDA) for the treatment of ulcerative colitis.
A study by Dr Katherine Li and colleagues examined the impact of ustekinumab induction therapy on endoscopic and histologic healing in the phase 3 UNIFI study of patients with moderate to severe ulcerative colitis.14 In this study, patients underwent biopsies from the distal colon at screening and again at week 8 of induction treatment. At week 8, patients in the placebo group who were not responding received ustekinumab at 6 mg/kg intravenously. Patients not responding to intravenous ustekinumab received a subcutaneous dose of 90 mg.
At week 8, endoscopic healing was seen in 26.3% of patients receiving ustekinumab at 130 mg, 27.0% of patients receiving ustekinumab at 6 mg/kg, and 13.8% of the placebo group. Compared with placebo, intravenous ustekinumab was associated with higher rates of endoscopic and histologic healing as separate endpoints, as well as for the histologic/endoscopic healing combination. About 10% of patients who did not achieve clinical response at week 8 after intravenous ustekinumab achieved histologic endoscopic healing following a second subcutaneous dose. Histologic healing was associated with reduction in clinical and endoscopic disease activity, as well as an improvement in patient-reported symptoms. Although it is now possible to achieve histologic healing, I would suggest that it should not be the ultimate endpoint. A response should still be defined as endoscopic healing in a patient who is doing well, regardless of histologic healing. Previous studies have shown that histologic healing predicts fewer future disease flares over 6 to 12 months.15
Mirikizumab
Dr Sands and colleagues presented a multicenter, randomized, parallel-armed, double-blind, placebo-controlled phase 2 study of mirikizumab in patients with active Crohn’s disease.16 Mirikizumab is an IgG4 monoclonal antibody that targets the p19 subunit of the interleukin (IL) 23 cytokine. It is more selective than ustekinumab, which inhibits the p40 components of IL-12 and IL-23. Several different agents that inhibit IL-23 are currently in development, such as the anti-p19 agents brazikumab, risankizumab, guselkumab, mirikizumab, and tildrakizumab. Previous studies have shown that mirikizumab is an effective treatment for psoriasis and ulcerative colitis.17,18 The study presented by Dr Sands evaluated whether mirikizumab was superior to placebo in inducing endoscopic response. At week 12, endoscopic findings, patient-reported outcomes, and Crohn’s Disease Activity Index score improvements were statistically greater for the mirikizumab groups vs the placebo group. Mirikizumab was associated with a relatively low rate of adverse events that was similar to placebo and consistent with the prior overall patient safety profile. This proof-of-concept study affirms that mirikizumab can induce meaningful improvements in clinical and endoscopic outcomes. The sustained efficacy and safety are currently being evaluated in a maintenance trial.19 These findings suggest that the IL-23 component of IL-12/23 lessens inflammation. I anticipate that many such compounds will move forward in development in the future.
Upadacitinib
Dr Remo Panaccione and colleagues presented results from the dose-ranging phase 2b U-ACHIEVE study, which evaluated the efficacy of upadacitinib as an induction therapy for the treatment of patients with moderately to severely active ulcerative colitis.20 Enrolled patients had already received a prior biologic therapy, and they required further treatment. Upadacitinib is an investigational Janus kinase (JAK) 1 inhibitor that shows potential for the treatment of patients with active ulcerative colitis. Initial data from an 8-week, double-blind, placebo-controlled phase 2b study showed that upadacitinib was well tolerated and had significantly greater efficacy than placebo in patients with moderately to severely active ulcerative colitis.21 This subgroup analysis focused on patients with an inadequate response, who lost response, or who were intolerant to the agent. The analysis identified a dose response in patients who were intolerant to biologic therapies compared with patients who were not intolerant to biologic therapies. Efficacy was numerically greater in the patients who were not intolerant to biologic therapy. These data are different from those in other studies. It had been presumed that the second course of biologic therapy is less effective than the first. Historically, with use of a small molecule, such as the oral JAK inhibitor tofacitinib, outcomes were similar regardless of the patient’s prior exposure to biologic therapy.
The Impact of Hospital Teaching Status on IBD Hospitalization Outcomes
A large amount of the expenditure for IBD is related to hospitalization. It is important to attempt to reduce the cost of care without compromising quality of care for IBD patients. Patient outcomes are a top priority. In general, teaching hospitals are thought to have higher costs of care and more trainees than community hospitals. It is not known how hospital teaching status influences the outcomes for patients with IBD. My colleagues and I investigated the impact of hospital teaching status on IBD hospitalization outcomes.22 Our study identified 29,863 patients with ulcerative colitis discharged from 291 hospitals, and 62,698 patients with Crohn’s disease discharged from 314 hospitals. The unadjusted mean length of stay, discharge, and 30-day readmission rates were higher among teaching hospitals for both Crohn’s disease and ulcerative colitis. The mortality rate was higher among major teaching hospitals for patients with ulcerative colitis, but not Crohn’s disease. After a multivariable analysis, however, only the 30-day readmission rate for ulcerative colitis was increased in major teaching hospitals compared with nonteaching hospitals (hazard ratio, 1.98%; 95% CI, 0.33-3.61). We concluded that the differences in outcomes when looking at cost-effective hospital care for patients with IBD seem to be driven primarily by the disease severity, rather than by hospital teaching status. Future research should be done to better characterize the factors driving resource utilization in IBD hospitalizations. Teaching hospitals were perceived to be more costly, which is likely a byproduct of the “funnel” effect, as these hospitals often treat sicker patients who were referred by other hospitals. Patients who are sicker and use more resources receive care in places with greater expertise and capability.
Surveillance With Chromocolonoscopy
My colleague Dr Anna Buchner presented our study examining surveillance with chromocolonoscopy with endoscopic mucosal resection of colitis-associated “defiant” lesions in patients with long-term IBD.23 We defined a defiant lesion as one identified during colonoscopy that defied resection by standard snare polypectomy techniques. The SCENIC Consensus Statement suggested that well-circumscribed, defined lesions that are dysplastic are potentially removable if they do not have a malignant appearance and are not malignant on biopsy.24 Since the publication of this consensus statement, there has been an increase in the number of patients with long-term IBD who have new index lesions or dysplasia and are referred to pan-chromocolonoscopy before consideration of colectomy. During pan-chromocolonoscopy, the clinician can attempt a curative colonoscopic resection of defiant lesions.
The study evaluated the characteristics of defiant lesions, as well as outcome in these patients. Among the 51 patients enrolled in the study, 7 had been referred for a known lesion that was deemed defiant. The remainder had been referred for pan-chromocolonoscopy examination after identification of dysplasia during a colonoscopy performed within the prior 12 months. The study identified 66 lesions, of which 32 were defiant. They ranged in size from 1.6 cm to 4 cm. The Paris classification of the lesions was Is in 24 and IIa in 8. Two-thirds of the lesions were located in the right side of the colon. En bloc resection was performed in 24 of the defiant lesions (75%), and piecemeal resection was done in 8 lesions (25%). The findings were low-grade dysplasia in 50%, serrated adenoma in 38%, and hyperplastic in 13%. Among 4 of 27 patients (14.8%), the procedure identified evidence of recurrent residual tissue at the site of colonoscopy, which was eradicated with endoscopic resection or ablation. It is important to perform another procedure, after 3 to 6 months, to identify any material that persists or recurs and can be eradicated. In the past, the standard approach had been to refer patients with defiant lesions to surgery to undergo complete or subtotal colectomy. In our study, most of the defiant lesions were successfully eradicated with dedicated therapeutic chromocolonoscopy using adjunctive resection and ablation techniques directly. This important finding can decrease the need for surgical intervention.
No Rise in Postoperative Infections During Anti-TNF Therapy
An abstract presented at the plenary session evaluated whether anti-TNF therapy is a risk factor for postoperative infection in a prospective cohort of patients with ulcerative colitis or Crohn’s disease.25 There has been concern that anti-TNF therapy might increase the risk of postoperative infectious complications in patients with IBD, and this treatment is sometimes discontinued in preparation for surgical procedures. This multicenter, prospective study enrolled 955 patients undergoing intra-abdominal surgery. Preoperative exposure to anti-TNF therapy was reported in 40% of patients. Anti-TNF trough drug levels were assessed in 322 patients. Detectable anti-TNF inhibitor trough levels were found in 23.7% of the entire cohort. The rates of infection were 19.4% for patients exposed to anti-TNF therapy vs 20.2% for those not exposed, a difference that was not statistically significant (P=.8). In a multivariate analysis, neither current anti-TNF therapy nor detectable anti-TNF levels were associated with infection. These data are practice-changing. They suggest that it is not necessary for patients to discontinue treatment with anti-TNF therapy when undergoing operative intervention.
Rates of Lymphopenia With Tofacitinib
Tofacitinib is approved by the FDA for the treatment of patients with ulcerative colitis. Tofacitinib is primarily an inhibitor of JAK1 and JAK3. Other JAK inhibitors in development include peficitinib, a JAK1 and JAK3 inhibitor; upadacitinib, a JAK1 inhibitor; delgocitinib, a JAK1 inhibitor; and TD-1473, a pan-JAK inhibitor. The JAK inhibitors are small molecules, not biologics. They act as immune suppressants. Studies have evaluated JAK inhibitors in ulcerative colitis and Crohn’s disease.26,27 Tofacitinib was not effective in the treatment of patients with Crohn’s disease.28 (Some might argue that this outcome was related to clinical trial design.)
I presented results of a study that evaluated the rates of lymphopenia in studies of tofacitinib.29 Tofacitinib is known to lower lymphocytes.30 The study found that patients treated with tofacitinib as induction or maintenance therapy exhibited small changes in hemoglobin, absolute lymphocyte count, absolute neutrophil count, and platelet count. There was no decrease in serum hemoglobin; JAK inhibition has been known to inhibit erythropoietin, which is involved in the escalation of hemoglobin.31 In a phase 3 trial of tofacitinib, discontinuations due to laboratory abnormalities were low.32 Only 6 patients required early termination of tofacitinib based on prespecified discontinuation criteria related to decreased hemoglobin, and 2 patients discontinued owing to absolute lymphocyte count decline. There was no dose dependency in anemia, lymphopenia, or neutropenia. There were no infectious complications related to these events. These data are reassuring. However, during treatment with tofacitinib, the patient’s absolute lymphocyte count, absolute neutrophil count, and hemoglobin should be monitored.
Disclosure
AbbVie (consultant), Cellceutix (consultant), Celgene (research, consultant), Ferring (consultant), Gilead (consultant), Janssen Ortho Biotech (consultant, res-earch, funding to University of PA [IBD Fellow Education]), Eli Lilly (consultant, DSMB), Luitpold/American Regent (consulting, honorarium [CME programs]), Merck (consultant, honorarium [CME program]), Pfizer Pharmaceuticals (consultant, research, funding to University of PA [IBD Fellow Education]), Prometheus Laboratories, Inc. (consultant), Romark (consultant, honorarium for CME), Salix Pharmaceuticals/Valeant (consultant, re-search), Shire Pharmaceuticals (consultant, research), Takeda (consultant, funding to University of PA [IBD Fellow Education]), UCB (consultant, research), and Up-To-Date (author honorarium).
References
1. Schreiber S, Peyrin-Biroulet L, Loftus EV, et al. VARSITY: a double-blind, double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis [ECCO abstract OP34]. J Crohns Colitis. 2019;13(suppl 1).
2. Sands BE, Peyrin-Biroulet L, Loftus EV, et al. Vedolizumab shows superior efficacy versus adalimumab: results of VARSITY—the first head-to-head study of biologic therapy for moderate-to-severe ulcerative colitis [DDW abstract 416a]. Gastroenterology. 2019;156(suppl 1).
3. Yarur AJ, Mantzaris GJ, Silverberg MS, et al. Real-world effectiveness and safety of vedolizumab and anti-TNF in biologic-naive ulcerative colitis patients: results from the EVOLVE study [DDW abstract 1858]. Gastroenterology. 2019;156
(suppl 1).
4. Loftus EV, Colombel JF, Feagan BG, et al. Long-term safety of vedolizumab in ulcerative colitis and Crohn’s disease: final results from the GEMINI LTS study [DDW abstract 835]. Gastroenterology. 2019;156(suppl 1).
5. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369(8):711-721.
6. Jess T, Rungoe C, Peyrin-Biroulet L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clin Gastroenterol Hepatol. 2012;10(6):639-645.
7. Card T, Ungaro RC, Bhayat F, Blake A, Hantsbarger G, Travis SP. Vedolizumab use is not associated with increased malignancy incidence: GEMINI long-term safety study results and post-marketing data [DDW abstract 1835]. Gastroenterology. 2019;156(suppl 1).
8. Moens A, Van Der Woude CJ, Julsgaard M, et al. Outcomes of pregnancy in IBD patients treated with vedolizumab, anti-TNF or conventional therapy [DDW abstract 1846]. Gastroenterology. 2019;156(suppl 1).
9. Danese S, Adsul S, Lindner DL, Jones S, Patel H, Colombel JF. Effects of intravenous vedolizumab on health-related quality of life and work productivity in patients with Crohn’s disease: results from the phase 3b VERSIFY trial [DDW abstract 1881]. Gastroenterology. 2019;156(suppl 1).
10. Vermeire S, Krznaric Z, Kobayashi T, et al. Effects of subcutaneous vedolizumab on health-related quality of life and work productivity in patients with ulcerative colitis: results from the phase 3 VISIBLE 1 trial [DDW abstract 1878]. Gastroenterology. 2019;156(suppl 1).
11. Sands BE, Sandborn WJ, Panaccione R, et al. Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: week 44 results from UNIFI [DDW abstract 833]. Gastroenterology. 2019;156(suppl 1).
12. Sands BE, Sandborn WJ, Panaccione R, et al. Safety and efficacy of ustekinumab induction therapy in patients with moderate to severe ulcerative colitis: results from the phase 3 UNIFI study (late-breaking abstract) [UEG abstract LB01]. United European Gastroenterol J. 2018;6(8 suppl).
13. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375(20):1946-1960.
14. Li K, Friedman JR, Marano CW, et al. Effects of ustekinumab induction therapy on endoscopic and histologic healing in the UNIFI phase 3 study in ulcerative colitis [DDW abstract 1735]. Gastroenterology. 2019;156(suppl 1).
15. Brennan GT, Melton SD, Spechler SJ, Feagins LA. Clinical implications of histologic abnormalities in ileocolonic biopsies of patients with Crohn’s disease in remission. J Clin Gastroenterol. 2017;51(1):43-48.
16. Sands BE, Sandborn W, Peyrin-Biroulet L, et al. Efficacy and safety of mirikizumab (LY3074828) in a phase 2 study of patients with Crohn’s disease [DDW abstract 1003]. Gastroenterology. 2019;156(suppl 1).
17. Reich K, Rich P, Maari C, et al; AMAF investigators. Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study. Br J Dermatol. 2019;181(1):88-95.
18. D’Haens GR, Sandborn WJ, Ferrante M, et al. Maintenance treatment with mirikizumab, a p19-directed IL-23 antibody: 52-week results in patients with moderately-to-severely active ulcerative colitis [ECCO abstract OP38]. J Crohns Colitis. 2019;13(suppl 1).
19. ClinicalTrials.gov. A maintenance study of mirikizumab in participants with moderately to severely active ulcerative colitis (LUCENT 2). https://clinicaltrials.gov/ct2/show/NCT03524092. Identifier: NCT03524092. Accessed August 1, 2019.
20. Panaccione R, D’Haens GR, Sandborn WJ, et al. Efficacy of upadacitinib as an induction therapy for patients with moderately to severely active ulcerative colitis, with or without previous treatment failure of biologic therapy: data from the dose-ranging phase 2b study U-ACHIEVE [DDW abstract 799]. Gastroenterology. 2019;156(suppl 1).
21. Sandborn WJ, Ghosh S, Panés J, et al. Efficacy and safety of upadacitinib as an induction therapy for patients with moderately-to-severely active ulcerative colitis: data from the phase 2b study U-ACHIEVE [UEG abstract OP195]. United European Gastroenterol J. 2018;6(8 suppl).
22. Dalal RS, Vajravelu RK, Lewis JD, Lichtenstein GR. Hospitalization outcomes for inflammatory bowel disease in teaching vs. non-teaching hospitals [DDW abstract 1855]. Gastroenterology. 2019;156(suppl 1).
23. Buchner AM, Mahmud N, Elhanafi S, Ginsberg GG, Lichtenstein GR. Surveillance chromocolonoscopy with endoscopic mucosal resection of colitis-associated ‘defiant’ dysplastic lesions in patients with long term inflammatory bowel disease (IBD): results from a large tertiary referral medical center [DDW abstract 293]. Gastroenterology. 2019;156(suppl 1).
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