A Dige et al. Gastroenterol 2019; 156: 2208-16. This study evaluated the efficacy of freshly collected autologous adipose tissue injection for healing of perianal fistulas in Crohn’s disease. The overall healing rate was 57% and the treatment had a good safety profile.
HK Somineni et al. Gastroenterol 2019; 156: 2254-65. The researchers found that DNA methylation patterns (from ~850,000 sites) in blood samples from pediatric patients with Crohn’s disease (n=164) were associated with inflammation and resolved with treatment of inflammation; thus, the changes in DNA methylation are less likely to be a causative agent in disease development or progression and more likely a biomarker of inflammation.
OB Kelly et al. Inflamm Bowel Dis 2019; 25: 1066-71. Among 316 patients who underwent A/P CT scan for any reason, 49 (16%) had evidence of sacroilitis, indicating this is underdiagnosed in patients with IBD.
BG Feagan et al. Inflamm Bowel Dis 2019; 25: 1028-35. In a post hoc analysis of GEMINI 1 trial (n=769 patients: 149 placebo, 620 vedolizumab), a randomized placebo-controlled trial of vedolizumab for ulcerative coliis, compared to placebo ~40% more patients receiving a full induction of vedolizumab had a sustained clinical remission after 52 weeks of therapy. Of patients in clinical remission at week 14, 66.5% achieved a sustained clinical remission at week 52 compared with 267% of placebo-treated patients based on partial Mayo score.. Sustained clinical remission was based on partial Mayo score and rectal bleeding subscore..
Gastroendonews: Tea Leaves No More: Biologics Head-to-Head Produces a Winner
In the first head-to-head trial of biologic treatments for inflammatory bowel disease, vedolizumab (Entyvio, Takeda) was nearly 50% more effective than adalimumab (Humira, AbbVie) in inducing clinical and mucosal remission in patients with moderate to severe ulcerative colitis…
They enrolled 771 patients with moderate to severe ulcerative colitis in the VARSITY study and randomly assigned them to receive 52 weeks of treatment with either vedolizumab or adalimumab…
They had failed other conventional therapies, including 25% in each group that had received an anti–tumor necrosis factor (TNF) agent…
- 31.3% of vedolizumab recipients and 22.5% of those taking adalimumab were in clinical remission after 52 weeks (P=0.0061). Clinical remission was defined as a complete Mayo score of 2 or lower and no subscore greater than 1
- Nearly 40% of patients who received vedolizumab achieved mucosal healing at 52 weeks, compared with 27.7% of adalimumab recipients (P=0.0005).
My take: This study provides a rationale for vedolizumab to be used as a first-line biologic agent for ulcerative colitis.
A recent retrospective study (A Favale et al. Comparative Efficacy of Vedolizumab and Adalimumab in Ulcerative Colitis Patients Previously Treated With Infliximab Inflammatory Bowel Diseases, izz057, https://doi.org/10.1093/ibd/izz057 Published: 01 April 2019) suggests that vedolizumab is more effective for ulcerative colitis with secondary infliximab failure.
Here’s the abstract:
Adalimumab (ADA) and vedolizumab (VDZ) have shown efficacy in moderate to severe ulcerative colitis (UC) patients who failed infliximab (IFX). Although, a comparative efficacy evaluation of ADA and VDZ in this clinical setting is currently missing.
The aim of this study is to compare the efficacy of ADA and VDZ in patients affected by UC who failed IFX.
Clinical records of UC patients from 8 Italian IBD referral centers who failed IFX and were candidates to receive either ADA or VDZ were retrospectively reviewed. The primary end point was therapeutic failure at week 52. Secondary end points included therapy discontinuation at weeks 8, 24 and 52, the discontinuation-free survival, and safety.
One hundred sixty-one UC patients, 15 (9.2%) primary, 83 (51.6%) secondary IFX failures, and 63 (39.2%) IFX intolerants were included. Sixty-four (40%) patients received ADA and 97 (60%) VDZ as second line therapy. At week 52, 37.5% and 28.9% of patients on ADA and VDZ, respectively, had therapeutic failure (P = 0.302). However, the failure rate was significantly higher in the ADA group as compared with VDZ group among IFX secondary failures (48.0% ADA vs 22.4%VDZ, P = 0.035). The therapy discontinuation-free survival was significantly higher in the group of IFX secondary failures who received VDZ as compared with ADA at both the univariate (P = 0.007) and multivariate survival analysis (OR 2.79; 95% CI, 1.23–6.34; P = 0.014). No difference in the failure and biologic discontinuation-free survival was observed in the IFX primary failure and intolerant subgroups.
KP Quinn et la. Inflamm Bowel Dis 2019; 25: 460-71. This is a terrific review of evaluation and management of pouch disorders.
A Armuzzi et al. Inflamm Bowel Dis 2019; 25: 568-79. This prospective cohort study examined infliximab biosimilar in 810 patients (PROSIT cohort). This included 459 patients naive to anti-TNF therapy (group a) , 196 with previous exposure (group b), and 155 who were switched while on original infliximab (group c). At 12 months, patients without a loss of response were 71%, 64%, and 82% respectively in these three groups.
S Coward et al Gastroenterol 2019; 156: 1345-53. This study from Canada used population-based health administrative data from multiple provinces and then applied autoregressive integrated moving average regression to predict prevalence of IBD in 2030. Key point: “In 2018, 267,983 Canadians were estimated to be living with IBD, which was forecasted to increase to 402,853 by 2030.” This is approximately 1% of the population (981 per 100,000).
F Castiglione et al. Aliment Pharm Ther 2019; 49: 1026-39. This observational longitudinal study with 218 patients with Crohn’s disease who completed 2-years of anti-TNF treatment examined transmural healing via ultrasonography (≤3 mm bowel wall thickness). “Transmural healing was associated with a higher rate of steroid-free clinical remission (95.6%), lower rates of hospitalization (8.8%) and need for surgery 0%).” The authors conclude that transmural healing is associated with better long-term clinical outcomes than mucosal healing.
“Magic Fountain” Barcelona
Two recent studies highlight more rapid onset of action for vedolizumab and tofacitinib than previous reports.
In the first study (BG Feagan et al. Clin Gastroenterol Hepatol 2019; 17: 130-8), the authors performed a post-hoc analysis of data from phase 3, randomized controlled trials of vedolizumab vs placebo in adult patients (UC, N=374; CD, N=784).
- In patients with UC, 19.1% overall and 22.3% of anti-TNF naive achieved a composite score of rectal bleeding of 0 and stool frequency of ≤1 at week 2 compared to 10% and 6.6% respectively in the placebo group. By 6 weeks, this response rate was 40.8% among anti-TNF naive patients.
- In patients with CD, 15.0% of anti-TNF naive patients achieved a composite score of abdominal pain ≤1 and loose stool frequency ≤3 at week 2 compared to 7.9% of placebo; at 4 weeks, the vedolizumab group, the rate was 23.8% compared to 10.3% with placebo.
My take: This study shows that a substantial portion of patients respond fairly quickly to vedolizumab, especially among patients who are naive to anti-TNF therapy. This is in contrast to the impression that vedolizumab is slow-acting and needs closer to 14 weeks to see clinical effects.
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Jardines de Cecilio Rodríguez; Retiro Park, Madrid
Link (from KT Park’s twitter feed): What New Treatments for Crohn’s disease and Ulcerative Colitis Are Being Developed?
R Wittig et al. JPGN 2019; 68: 244-50. This study from Germany, using health insurance data, identified an overall pediatric inflammatory bowel disease (IBD) incidence of 17.41 per 100,000 in 2012 compared to 13.65/100,000 in 2009. This is one of the highest incidence rates reported and agrees with other data suggesting increasing rates of IBD in pediatric populations.
B Christensen et al. Clin Gastroenterol Hepatol 2019; 17: 486-93. This study provides data from 20 patients (CD =9, UC =11) who were treated with a combination of a calcineurin inhibitor and vedolizumab. The calcineurin inhibitor was used as a ‘bridge’ treatment until the slower acting vedolizumab could be effective. After 52 weeks of treatment, 33% of the CD patients and 45% of the UC patients were in steroid-free clinical remission. Three serious adverse events associated with calcineurin treatment.
G Pellet et al. Clin Gastroenterol Hepatol 2019; 17: 494-501. Retrospective study of calcineurin inhibitor induction with vedolizumab in 39 patients with refractory ulcerative colitis (36 had failed anti-TNF Rx). 11 patients (28%) required colectomy. week 14 response and remission noted in 56% and 38% respectively. Four serious adverse events were observed.
N Nalagatla et al. Clin Gastroenterol Hepatol 2019; 17: 494-501. In a retrospective study of 213 patients with steroid refractory acute severe ulcerative colitis, the authors did not find lower rates of colectomy in patients who received an accelerated infliximab dosing. However, they were unable to control for confounding by disease severity. Patients who received an intial dose of 10 mg/kg had a lower colectomy rate than patients who received an initial dose of 5 mg/kg. Colectomy rates for accelerated vs standard infliximab dosing –in-hospital: 9% vs 8% respectively, at 3 months: 20% vs 14% respectively, at 12 months: 28% vs 27% respectively.
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Shenandoah National Park
A recent cross-sectional study (B Al-Bawardy et al. Inflamm Bowel Dis 2019; 25: 580-6) correlated vedolizumab (VDZ) trough drug levels (VDT) and clinical outcomes in 171 patients (62% Crohn’s disease (CD), 31% ulcerative colitis (UC), and 7% indeterminate colitis (IC)).
- Median VDT was 15.3 microgr/mL.
- Median VDT was 17.3 microgr/mL for patients with normal CRP compared with 10.7 for patients with high CRP. This differnece was noted significantly for CD (20.3 vs 10.4) but not for UC.
- No relationship between VDT and mucosal healing was noted.
- Shorter dose intervals and lower BMO resulted in higher VTLs
- Only 1 patient had detectable antibodies to VDZ
A second systematic review (L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2019; 17: 838-46) analyzed data from 10 cohorts who had received vedolizumab. Most had prior anti-TNF exposure. Key finding: the pooled incidence rates of loss of response were 47.9 per 100 person-years of follow up among patients with CD and 39.8 per 100 person-years of follow up among patinets with UC. Dose intensification restored response to the drug in 53.8% of secondary non-responders.
My take: While VDZ dose intensification can restore response, the utility of therapeutic drug monitoring is unclear with VDZ therapy.
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One of the advantages of infusions in the office (or hospital) compared to home infusions and home injections is close communication by those giving the infusion with the physician. In addition, with each infusion, in these settings offers an opportunity to review the patient’s progress and adjust the patients orders. A recent study (Fenster M, et al. Clin Gastroenterol Hepatol. 2019;10.1016/cgh.2019.03.030.) indicates that these advantages may make infusions more successful than infusions given at home.
A summary is offered by Healio Gastroenterology: Home biologic infusions in IBD suffer from lack of monitoring
Researchers conducted a matched retrospective cohort study of patients treated with infliximab or vedolizumab with home infusion (n = 69) compared with hospital infusion at a large, tertiary care IBD center. The primary endpoint was a composite of adverse outcomes, including stopping biologic therapy, IBD-related emergency department visit or IBD-related hospitalization.
- “Patients on home infusion were more likely to experience adverse outcomes compared with control patients (43.5% vs. 21.7%; P = .006), and they also had a shorter time to adverse outcomes than patients who got hospital infusions.”
- “Patients with home infusions trended toward stopping therapy within 1 year (20.3% vs. 8.7%; P = .053) and stopping therapy within the complete follow-up window (27.5% vs. 15.9%; P = .099) compared with controls.”
- Patients with home infusions had “more emergency department visits (30.4% vs. 7.2%, P < .001), they did not have significantly more hospitalizations (17.4% vs. 11.6%).”
The authors noted that the “increase in adverse events might have been related to a reduced level of monitoring observed in home infusion patients. In the year following home infusion initiation or matching, patients who persisted on home infusions had significantly fewer IBD clinic visits (1.23 vs. 1.75; P = .018) compared with controls.”
My take (borrowed from a previous post): In my experience, office-based infusions can be provided safely and in a cost-effective manner. While the convenience and potential cost-savings of home-based infusion are desirable, before implementing broadly, issues regarding communication, safety protocols, and documentation to allow modifications in therapy need to be proactively addressed. These issues could affect a patient’s long-term response to biologic therapy.
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A recent retrospective study (E Dreesen et al Clin Gastroenterol Hepatol 2018; 16: 1937-46) with 179 consecutive patients (66 with ulcerative colitis, and 113 with Crohn’s disease) found that vedolizumab (VDZ) trough concentrations were correlated with response.
- VDZ trough >30 mcg/mL at week 2, >24 mcg/mL at week 6, and >14 mcg/mL during maintenance were associated with effectiveness endpoints including endoscopic healing, physician global assessment and biochemical response (based on CRP).
- Median VDZ trough levels during induction were 27.7 mcg/mL at week 2, 27.4 mcg/mL at week 6. With standard dosing, the maintenance VDZ trough was 13.5 mcg/mL at week 14
- Higher BMI and more severe disease, based on CRP, albumin, and/or hemoglobin, were associated with lower VDZ trough levels and lower probability of mucosal healing (P<.05).
Interestingly, in the discussion the authors note that VDZ troughs above 3 mcg/mL completely saturate α4β7 intergrin. This physiologic phenomenon is hard to reconcile with data showing better response with higher VDZ levels. The authors note that “at present, there are not enough data in our study to support the role for TDM to guide clinical decision-making on dose escalation for vedolizumab.”
My take: This study implies that VDZ levels may help predict response but are not necessarily helpful in determining whether dose escalation is warranted.
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DE Yung et al. Inflamm Bowel Dis 2018; 24: 2327-38. This systematic review and meta-analysis of four studies “did not detect an increased risk of postoperative complications with preoperative vedolizumab” (VDZ). This study included 281 patients who received VDZ.
SC Ng et al. Inflamm Bowel Dis 2018; 24: 2431-41. The authors examined the frequency of opportunistic infection among 4 VDZ trials and postmarketing surveillance, accounting for ~114,000 patient-years of exposure. The most common infection was C difficile (0.5 per 100 patient-years); tuberculosis was reported at 0.1 per 100 patient years. This study showed “that the rate of serious opportunistic infections in patients receiving VDZ was low and most patients could continue VDZ treatment.”
SL Gold et al. Gastroenterol 2018; 155: 981-2. This clinical image showed a case of Henoch-Schonlein Purpura (HSP) that developed in a 53 year receiving VDZ.
E Shmidt et al. Inflamm Bowel Dis 2018; 24: 2461-7. This retrospective review of a prospectively maintained IBD registry provides information of risk factors for VDZ loss of response and management. 444 patients out of 788 who received VDZ had a significant response.The majority of VDZ recipients 75) had failed prior anti-TNF Rx. Key points:
- Loss of response (LOR) at 6 months and 12 months was 20% and 35% respectively
- UC patients compared to Crohn’s disease (CD) patients were more likely to have LOR with R of 1.54.
- Shortening VDZ infusion interval from q8 weeks to q4-6 weeks recaptured response in 49% and led to remission in 18% of this cohort.
- LOR was more common (2-fold) among those who had a LOR to anti-TNF agent. Patients with primary nonresponse were less likely to have LOR with VDZ.
U Kopylov et al. Inflamm Bowel Dis 2018; 24: 2442-51. This retrospective multicenter study examined VDZ effectiveness among anti-TNF naive patients, n=184.
- For CD, 42/50 (82%) responded by week 14, and 32 (64%) were in clnical remission. At last followup (30-52 weeks), clinical remission was noted in 24/35 (69%)
- For UC, 116/134 (79%) responded at week 14 and 53 (40%) were in clinical remission. At last followup (30-52 weeks), 67% were in remission (69/103)
The authors conclude that VDZ is similarly efffective for anti-TNF naive CD and UC patients.
My take: These studies show that we still have a lot to learn about the effectiveness of VDZ as its use becomes more widespread.
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