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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G Horneff et al. J Pediatr 2018; 201: 166-75. This industry-funded analysis of 577 pediatric patients who received adalimumab (1440 patient-years) identified no new safety signals. The most common serious infection was pneumonia (0.6 events per 100 patient-years). The most common adverse events were respiratory tract infections/nasopharyngitis. Serious infections were more common in the subset of patients with Crohn’s disease (CD), (n=189), occurring in 13%.
PS Dulai et al. Gastroenterol 2018; 155: 687-95. This study, using data from GEMINI 2 phase 3 trial with 814 patients, developed a clinical prediction tool for determining the likelihood of a clinical response to vedolizumab. Common predictors for response:
- No prior bowel surgery
- No prior anti-TNF exposure
- No prior fistulizing disease
- Higher baseline albumin
- Lower baseline CRP
R Matro et al. Gastroenterol 2018; 155: 696-704. The authors performed a prospective study of women with IBD and their infants (n=72). They “detected low concentrations of infliximab, adalimumab, certolizumab, natalizumab, and ustekinumab in breast milk samples. We found breastfed intants of mothers on biologics, immunomodulators, or combination therapies to have similar risks of infection …compared to non-breastfed infants or infants unexposed to these drugs.”