Briefly noted: C Ma et al. Inflamm Bowel Dis 2017; 23: 833-9. This retrospective study examined the response to ustekinumab in 104 patients with Crohn’s disease. All patients had achieved a steroid-free ustekinumab induction. 92.3% had failed anti-TNFα therapy.
Key findings:
C Ma et al. Inflamm Bowel Dis 2017; 23: 833-9. This retrospective study examined the ongoing response to ustekinumab in 104 patients with Crohn’s disease. All patients had achieved a steroid-free ustekinumab induction. 92.3% had failed anti-TNFα therapy.Key findings:
Related blog post: Closer Look at Ustekinumab Data
O Truffinet et al JPGN 2017; 64: 721-25. This small study with 8 children with Crohn’s disease examined the use of tacrolimus. Six of eight showed a response to tacrolimus (target 8-15) with a clinical response at 2 months and 4 of 8 in clinical remission. Adverse effects were common, occurring in 6 of 8. These included renal dysfunction, diabetes, paresthesia and tremor.
J Adler et al. JPGN 2017; 64: e117-e124. Using ImproveCareNow registry, the authors identified perianal disease (PD) in 1399 of 6679 cases (21%). PD was more common in blacks than whites: 26% vs. 20%. Overall, this study showed a higher rate of PD than previously recognized.
J Amil-Dias et al JPGN 2017; 64: 818-35. This is an ESPGHAN IBD Porto Group guideline for surgical Crohn’s disease management in children. There are 25 graded statements. Here are a few:
Related blog post:
Musee d’Orsay
At a recent dinner, we had the opportunity to hear a review of some of the recent data on ustekinumab. These notes may include some errors in transcription and errors of omission. Most of this data is derived from a recent publication that has been summarized in this blog: Landmark Publication for Ustekinumab (Stelara) | gutsandgrowth
Some key points:
Also -some tweets from IBD meeting:
A recent study (BG Feagan, WJ Sandborn et al NEJM 2016; 375: 1946-60) provides extensive data regarding the effectiveness of ustekinumab for Crohn’s disease.
This publication combines three trials (industry-sponsored): UNITI-1, UNITI-2, and IM UNITI. The first two trials with 741 and 628 patients respectively examined intravenous ustekinumab for induction. Patients (18 years or older with Crohn’s disease) received either 130 mg, 6 mg/kg or placebo. UNITI-1 were patients with primary or secondary nonresponse to TNF antagonists. UNITI-2 were patients in whom conventional therapy failed or in which unacceptable side effects developed. The majority of UNITI-2 patients had not received a TNF antagonist.
IM UNITI with 397 patients followed patients who completed the first two trials for maintenance (90 mg SC every 8 weeks or every 12 weeks). For this study, the primary end point was remission at week 44 (CDAI score <150).
The IM UNITI study involved 260 sites in 27 countries.
Key findings:
When looking at more objective results, both UNITI-1 and UNITI-2 showed significant drops in calprotectin and CRP values; both of these objective markers favored 6 mg/kg over 130 mg fixed induction dose.
Safety:
Extensive safety data are reported and more than 60% of all patients, including placebo-treated patients reported potential adverse effects. Adverse effects and serious adverse effects were similar in treatment and control groups. During 1 year of therapy, there were no deaths or instances of the reversible posterior leukoencephalopathy syndrome.
Other points:
My take: These data support the use of ustekinumab for Crohn’s disease, particularly in patients who have not responded to other therapies.
Here’s a link summarizing FDA approval: Medscape: FDA Clears Ustekinumab (Stelara) for Crohn’s Disease
An excerpt:
The US Food and Drug Administration (FDA) has approved ustekinumab (Stelara, Janssen Biotech, Inc) for the treatment of moderately to severely active Crohn’s disease in patients aged 18 years or older.
Specifically, the interleukin-12/23 inhibitor is indicated for Crohn’s patients who have failed or were intolerant to immunomodulator or corticosteroid therapy but who never failed treatment with a tumor necrosis factor (TNF) blocker or who failed or were intolerant to treatment with one or more TNF blockers, according to a company news release.
Ustekinumab is already approved in the United States for treatment of patients with plaque psoriasis and psoriatic arthritis…The clinical development program for ustekinumab for Crohn’s disease included more than 1300 patients across three pivotal phase 3 studies, which served as the primary basis for FDA approval.
In clinical studies of patients who were either new to, experienced with, or failed anti-TNF therapy, between 34% and 56% of patients experienced symptom relief in the 6 weeks after receiving a one-time intravenous induction dose of ustekinumab. “Noticeable improvement was observed as early as 3 weeks,” the company said.
Most patients who responded to induction dosing and who continued ustekinumab treatment with subcutaneous maintenance doses every 8 weeks were in remission at the end of 44 weeks (52 weeks from initiation of the induction dose), the company said.
Full prescribing information and a medication guide are available online.
G Wahbeh et al. JPGN 2016; 63: 348-51. This retrospective case series with 4 children (aged 12-17 years) indicated that 2 had a ‘clinical response’ to ustekinumab therapy, though one of these had ongoing elevation of CRP. The dosing may have been too low: 90 mg at week 0 and 4, then every 8 weeks. My take: This study shows that ustekinumab’s use in pediatric IBD seems to be a ‘shot in the dark’ given the lack of coherent data.
Related posts:
L Zimmerman et al. JPGN 2016; 63: 352-56. Among a cohort of 123 children who had underwent a bowel resection, from 1977-2011, the overall postoperative complication rate was 13%. This included 3 of 24 who had prior infliximab and 9 of 99 who had not received infliximab. It is noteworthy that the infliximab group had more corticosteroid exposure. The authors concluded that preoperative infliximab was not associated with increased complications but noted that their sample size was small. My take: Studies of adults with Crohn’s disease have yielded conflicting results on whether preoperative infliximab increases the risk of complications. This study shows that children likely have a lower rate of postsurgical complications and more pediatric specific data are needed.
Related post:
From KT Park’s Twitter Feed:
More data emerging that indicates that subcutaneous ustekinumab will be useful for refractory Crohn’s disease: S Khorrami et al. Inflamm Bowel Dis 2016; 22: 1662-69.
Another strategy for managing inflammatory bowel disease is using allopurinol which can help low-dose azathioprine achieve therapeutic levels. In the largest cohort to date, Pavlidis et al (Inflamm Bowel Dis 2016; 22: 1639-46) showed that at the end of followup (median 19 months after treatment initiation) 113/164 (69%) of patients with Crohn’s disease and 83/136 (61%) with ulcerative/unclassified colitis had a clinical response; 52% and 54% respectively were in remission. The azathioprine dose was 25% of weight-based monotherapy dose adjusted based on TPMT status; thus, for normal/high TPMT activity, azathioprine was dosed at 0.5 mg/kg whereas for heterozygous/intermediate activity, azathioprine was dosed at 0.25 mg/kg.
Related blog posts:
Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
Vickery Creek, Sandy Springs
This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries (can use search function to find additional relevant material) but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.
Emerging Therapies in IBD –Dr. Gary Lichtenstein
Background: This lecture started with a review of current therapies. We have learned how to use our current therapies better. There still remain a large number of patients that face surgery with IBD; though there has been improvement (?50% reduction).
Issues with thiopurines were reviewed. May take 2-6 months to take effect, though monotherapy with thiopurines are fairly ineffective for Crohn’s disease as initial therapy.
Leukocyte Trafficking Agents:
PF-00547,659
S1P Modulators:
Fingolimod
Ozanimod (RPC1063) (oral agent, fairly rapid onset) causes S1P-r on lymphocytes to be internalized –more selective than Fingolimod. Good safety has been noted thus far. No notable cardiac problems. Infrequent elevations of transaminases; this issue will need to be followed.
Tofacitinib oral Janus Kinus (JAK) Inhibitor (Sanborn WJ et al. NEJM 2012; 367: 616-24). Dr. Lichtenstein thinks 10 mg will be recommended dose. Follow lipids. For UC
Mongerson related post: Mongerson -Phase II Data Available in NEJM | gutsandgrowth
Ustekinumab
Related article from GI & Hep News: Ustekinumab for complex Crohn’s from ECCO conference/UNITI-1 Study (n=741)
FMT. Further studies are needed
This blog entry has abbreviated/summarized this terrific presentation; most of the material has been covered in this blog in prior entries but still this was a useful review. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.
2nd Lecture: What is Next in Treatments for Pediatric Patients? –Dr. Michael Rosen
I really enjoyed meeting Dr. Rosen. He is super-friendly and knowledgeable.
Combination therapy. Grossi V et al showed improvement in infliximab durability with concomitant therapy.
Now starting COMBINE trial (ImproveCareNow)–randomized to low dose MTX or placebo in combination with anti-TNF agent.
Therapeutic drug monitoring in pediatrics. Is this an alternative to combination therapy? Rationale (see slide): lower antibody formation if trough levels maintained. IFX level >5.5 associated with persistent remission (Singh et al 2014). Children are growing and they may need more adjustments. In Cincy, checking levels at week 14 after initiation and then every 6-12 months.
Acute Severe Ulcerative Colitis. High rates of dose escalation in this population. Some of this is due to more rapid clearance of anti-TNF –leaking in gut and other mechanisms as well. Week 8 level of 40 associated with clinical response. Thus, this population may benefit from 10 mg/kg at start (in those with albumin <3) and may need more frequent dosing, especially early into treatment (?0, 2, 6, 10). ARCH study to look into this further
Vedolizumab. Conrad MA 2015. About 1/3rd of these refractory patients in this abstract responded.
Ustekinumab . IL-12 & IL-23 blockage. No studies in pediatrics. Case report reviewed of good response in a refractory case.
Enteral therapy. Specific carbohydrate diet experience. These diets have some published data, most retrospective studies. Our group (Cohen SA et al) did perform a small prospective study. Sigall-Boneh R et al showed improvement with partial enteral nutrition.
Very early-onset of IBD. IL-10 receptor deficiency was a key early discovery and can be treated with stem cell transplant. STAT3 mutation case reviewed which was managed with tocilizumab. More targeted therapy expected based on specific mutations.
gutsandgrowth 