AL Granstrom et al. JPGN 2018; 66: 398-401. Using a nationwide Swedish registry, the authors determined that patients with a Hirschsprung disease had an increased risk of receiving a diagnosis of IBD (OR 4.99). In total 20 of 739 HD patients, developed IBD.
T Card et al. Inflamm Bowel Dis 2018; 24: 953-9. This article questions the ‘what is the risk of progressive multifocal leukoencephalopathy ..with vedolizumab? The authors are not certain. But they state that after reviewing 54,619 patient-years “there have been no cases of PML reported in association with vedolizumab use.”
LCT Buer et al. Inflamm Bowel Dis 2018; 24: 997-1004. This case report of 10 patients describes combination therapy with anti-TNF therapy with vedolizumab. “At the end of follow-up, all patients were in clinical remission, and 8 patients could discontinue anti-TNF treatment.”
OJ Adedokun et al. Gastroenterol 2018; 154: 1660-71. This study examined pharmocokinetics and response of ustekinumab in patients with Crohn’s disease from 701 patients in phase 3 studies.. “Trough concentrations was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals…Trough concentrations of 0.8 (or even up to 1.4 mcg/mL) or greater were associated with maintenance of clinical remission.” Also, “concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators.”
View from Pine Mountain
Two articles indicate that Vedolizumab will be an important agent for treating Ulcerative Colitis (UC). The first article, NEJM 2013; 369: 699-710, describes two integrated studies (GEMINI 1 studies) in the use of this agent for induction and then for maintenance therapy of UC.
Background: Vedolizumab is a gut-selective blocker of lymphocyte trafficking (see previous post: Vedolizumab -another new IBD treatment | gutsandgrowth). It is similar to natalizumab which was approved in 2008 for Crohn’s disease. In phase 3 trials, natalizumab was demonstrated a response in 48% of patients with moderate-to-severe disease, but its large-scale use has been precluded by the potential for reactivation of the John Cunningham (JC) virus and progressive multifocal leukoencephalopathy (PML).
Study design: this study was a phase 3, randomized, double-blind, placebo-controlled study conducted at 211 medical centers in 34 countries from 2008-2012. At baseline some of the assessments included blood tests, stool for enteric pathogens, chest radiography, stool calprotectin, QuantiFERON-TB Gold assay and sigmoidoscopy. Intravenous vedolizumab was administered at a dose of 300 mg or placebo at days 1 and 15 during induction; also patients were stratified for glucocorticosteroids, use of immunosuppressives and prior use of TNF antagonists. In total, 746 patients received vedolizumab and 149 received placebo.
Some of the baseline patient characteristics:
- Mean age: 40.3 yrs
- Median prednisone dose: 20 mg
- Average fecal calprotectin: 899 mcg/gr.
- Site of disease: 37% pancolitis, 13% rectum/sigmoid only, 37.9% left-sided disease, 12.2% disease proximal to splenic flexure.
- Prior anti-TNF therapy: 48.2%
- Induction: at week 6, 47.1% of vedolizumab and 25.5% of placebo-treated patients had a clinical response
- Maintenance: at week 52, of patients randomly assigned to continue receiving vedolizumab, 44.8% every 4 weeks, 41.8% every 8 weeks were in clinical remission compared with 15.9% receiving placebo
- Glucocorticoid-free remission at 52 weeks in 45.2% of patients receiving vedolizumab every 4 weeks, 31.4% receiving every 8 week treatment, and 13.9% of placebo-treated patients.
- Figure 1 details important changes in Partial Mayo score, IBDQ score, Fecal calprotectin, and prednisone dose changes. With regard to fecal calprotectin, at week 6 the median calprotectin level had dropped approximately 70%. Smaller decreases were noted in patients continuing vedolizumab at week 52.
- Safety: “no important differences” according to the authors between vedolizumab and placebo. Specifically, there were no cases of PML; however, routine JC virus testing was not performed in this study. Infusion reactions were seen in three cases (two with detectable antibody). a mild increase in nasopharyngitis was noted.
- Cancer: 1.1% of placebo-treated patients developed a malignancy (1 colon cancer, 1 transitional-cell carcinoma, 1 squamous-cell carcinomas of skin) and 0.2% of vedolizumab (1 colon cancer)
- Drug levels: mean vedolizumab concentrations at every 4 week dosing: 38.3 mcg/mL and at every 8 week dosing: 11.2 mcg/mL
- Antibodies: 3.7% had samples that were positive for anti-vedolizumab antibodies at any time. 1% developed persistent antibody positivity.
Bottom-line: This large study shows that vedolizumab is effective in a large number of patients with UC, many who were refractory to other treatments, including anti-TNF agents.
Related blog posts:
A series of articles on natalizumab were published which give practical advice for this drug which clinicians often turn to when ‘running out of options’ (Gastroenterol Hepatol 2012; 8: 4-17).
Slides from these articles should be available soon (not online on 1/2/13):
According to an algorithm on page 7, in patients with moderate-severe Crohn’s disease who have failed conventional therapies and anti-TNF drugs (or unable to tolerate), the next step is to obtain anti-JCV (John Cunningham Virus) antibody status. Patients who test negative are ‘Okay to treat with natalizumab’ due to very low risk of progressive multifocal leukoencephalopathy (PML). Repeated testing at least once a year is then recommended.
For patients who test positive for anti-JCV at any time point, natalizumab can be considered if no other treatment options are available, but the risk of PML is much greater. Previous blog entries (below) have discussed this in greater detail and have provided additional references:
Another article published the experience in 36 Mayo clinic patients between April 2008-September 2010 (Inflamm Bowel Dis 2012; 18: 2203-08). Consecutive patients who received natalizumab were prospectively followed. Of the 36 treated with natalizumab, 30 agreed to participate in the study. 23 patients had failed two anti-TNF agents and 7 had failed one anti-TNF agent. Median age was 35 years.
- 14 (46%) had a complete clinical response, 12 had a partial response, and four had no response. Cumulative probability of a complete response within 1 year was 56%.
- Time to response: 10% after 1st dose, 50% of patients had complete response after 4th dose
- Adverse events were common –though this rarely caused drug cessation. Common events included headache and infections (listed in Table 4 of article). Some infections prompted holding natalizumab for up to 8 weeks.
- 11 stopped natalizumab due to lack of improvement.
Given the limited number of treatment options for inflammatory bowel disease, when Natalizumab became available, there was a great deal of enthusiasm. This quickly diminished as reports of progressive multifocal leukoencephalopathy (PML) emerged. So far, I have not prescribed this agent.
Due to its efficacy for multiple sclerosis and IBD, there has been continued interest in understanding the risk for PML (NEJM 2012; 366: 1870-80, editorial pg 1938-39).
- 212 cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000)
- Three main risk factors: positive JC-virus antibody, previous use of immunosuppressants, and receiving natalizumab more than 2 years
Patients who were negative for anti-JC virus antibodies had an incidence of 0.09 cases or less per 1000 patients. Among patients who test positive for anti-JC virus antibodies, the risk remained <1 per 1000 patients if no use of immunosuppressants and 2 per 1000 if prior use of immunosuppressants during the first two years of therapy. The risks were five-fold higher after 2 years in both groups.
While the risks are becoming more clear, the benefits of natalizumab are fairly well-established for multiple sclerosis. Natalizumab decreased the annualized rate of relapse among patients with relapsing–remitting multiple sclerosis by 68%.
- -NEJM 2009; 361: 1067, 1075, 1081. Asymptomatic detection of JC virus common in urine noted in patients Rx’d with natalizumab (19% baseline to 63% on Rx); actual leukoencephalopathy ~1/1000 patients.
- -Gastroenterol 2007; 132: 1672. ENCORE trial.
- -JPGN 2007; 44: 185. n=31 children/adolescents. 55% response, 29% remission; dosed at 3mg/kg.
- -IBD 2007; 13: 2. n=79. Trial of combination natalizumab & infliximab.
- -NEJM 2006; 354: 899, 911, 924. Natalizumab slows progression of MS. Risk of PML due to JC virus 1:1000 in 18 months of Rx.
- -NEJM 2005; 353: 1912/1965. Natalizumab not significantly effective for Crohn’s in this study
- -NEJM 2005; 353: 362, 369, 375, 414. 3 cases of PML associated with Natalizumab
- -JPGN 2004; 39: S49 [abstract 0107]. Natalizumab in 38 adolescents was effective (Hyams et al).
- -Gastroenterol 2004; 126: 1574-81. review. Natalizumab benefitted subjects with elevated CRP. (dosing 300mg every 4 weeks.)
- -NEJM 2003; 24-32 & 68. Natalizumab improved response rates in pts c Crohn’s dz (similar to infliximab). Drug blocks alpha4 integrins which are required for lymphocytes to enter the intestine.
- -Gastroenterol 2001; 121: 268-74. Infusion of 3mg/kg decreases CDAI in Crohn’s dz.