Vedolizumab More Effective Than Adalimumab for Ulcerative Colitis

Gastroendonews: Tea Leaves No More: Biologics Head-to-Head Produces a Winner

An excerpt:

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.

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AGA Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis

A recent AGA Clinical Practice Guideline on the Management of Mild-to-Moderate Ulcerative Colitis was published along with patient guide (pg 766-67), a brief summary (pg 768) (“spotlight”) and technical review.

  • CW Ko et al. Gastroenterol 2019; 156: 748-64.
  • S Singh, JD Feuerstein et al. Gastroenterol 2019; 156: 769-808.

Summary of Recommendations for the medical management of mild-to-moderate ulcerative colitis: (available from AGA Website, my comments in blue & I bolded some of the recommendations):

1.    Use either standard dose mesalamine (2-3 grams/day) or diazo-bonded 5-ASA [Balsalazide or Olsalazine] rather than low dose mesalamine, sulfasalazine or no treatment in patients with extensive mild-moderate UC. (Strong recommendation, moderate quality evidence) [The article notes several potential exceptions for sulfasalazine: doing well on current treatment, prominent arthritic symptoms, or cost]

2.    In patients with extensive or left-sided mild-moderate UC, add rectal mesalamine to oral 5-ASA. (Conditional recommendation, moderate quality evidence)

3.    In patients with mild–moderate UC with suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA or with moderate disease activity, use high-dose mesalamine (>3 g/d) with rectal mesalamine. (Conditional recommendation, moderate-quality evidence [induction of remission], low-quality evidence [maintenance of remission])

4.    In patients with mild–moderate UC being treated with oral mesalamine, use once-daily dosing rather than multiple times per day dosing. (Conditional recommendation, moderate quality evidence) [In the commentary, the authors note that 4 RCTs have shown no differences when using equivalent dose once a day compared to divided dose and that once a day promotes adherence]

5.    In patients with mild–moderate UC, use standard-dose oral mesalamine or diazo-bonded 5-ASA, rather than budesonide MMX or controlled ileal-release budesonide for induction of remission. (Conditional recommendation, low quality of evidence)

6.    In patients with mild–moderate ulcerative proctosigmoiditis or proctitis, use mesalamine enemas (or suppositories) rather than oral mesalamine. (Conditional recommendation, very-low-quality evidence) [In commentary, the authors note that oral mesalamine can be given based on patient preference, but that for distal disease there is likely a higher response with topical therapy]

7.    In patients with mild–moderate ulcerative proctosigmoiditis who choose rectal therapy over oral therapy, use mesalamine enemas rather than rectal corticosteroids.(Conditional recommendation, moderate-quality evidence)

8.    In patients with mild–moderate ulcerative proctitis who choose rectal therapy over oral therapy, use mesalamine suppositories. (Strong recommendation, moderate-quality evidence)

9.    In patients with mild–moderate ulcerative proctosigmoiditis or proctitis being treated with rectal therapy who are intolerant of or refractory to mesalamine suppositories, use rectal corticosteroid therapy rather than no therapy for induction of remission. (Conditional recommendation, low-quality evidence)

10.    In patients with mild–moderate UC refractory to optimized oral and rectal 5-ASA, regardless of disease extent, add either oral prednisone or budesonide MMX. (Conditional recommendation, low-quality evidence)

11.    In patients with mild–moderate UC , AGA makes no recommendation for use of probiotics. (No recommendation, knowledge gap)

12.    In patients with mild–moderate UC despite 5-ASA therapy, AGA makes no recommendation for use of curcumin. (No recommendation, knowledge gap)

13.    In patients with mild–moderate UC without Clostridium difficile infection, AGA recommends fecal microbiota transplantation be performed only in the context of a clinical trial. (No recommendation for treatment of ulcerative colitis, knowledge gap)

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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

Joshua Tree National Park, Hike to Warren Peak

Experimental Use of FMT for Ulcerative Colitis

In a recent randomized, double-blind study (SP Costello et al. JAMA. 2019;321(2):156-164. doi:10.1001/jama.2018.20046), the use of fecal microbiota transplantation (FMT) was effective in 32% in inducing remission in adult patients with ulcerative colitis (UC).

Key Finding:  In this randomized clinical trial that included 73 adults with mild to moderately active ulcerative colitis, the proportion achieving steroid-free remission at 8 weeks was 32% with donor FMT vs 9% with autologous FMT, a significant difference

Abstract:

Importance  High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity.

Objective  To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool.

Design, Setting, and Participants  A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017.

Interventions  Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months.

Main Outcomes and Measures  The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ≤2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events.

Results  Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group.

Conclusions and Relevance  In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety.

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Golden Gulch Trail, Death Valley

 

Fish Oil for Ulcerative Colitis?

A small randomized, double-blind, placebo-controlled study (E Scaioli et al. Clin Gastroenterol Hepatol 2018; 16: 1268-75) examined the use of Eicosapentaenoic acid-Free Fatty Acid Form (EPA-FFA) a component of n-3 fish oil for patients with ulcerative colitis UC).

From 2014-2016, the investigators enrolled 60 patients who had partial Mayo score <2 and fecal calprotectin >150 mcg/g who had been receiving stable therapy for at least 3 months.  Then they were randomized 1:1 to receive EPA 1000 mg BID or placebo for 6 months.

Key findings:

  • 19 of 30 (63%) EPA-FFA group compared with 4 of 30 (13.3%) of placebo-treated group had achieved the primary endpoint of a 100-point reduction in fecal calprotectin at 6 months.  OR 12.0, P<.001
  • The secondary endpoint of clinical remission was noted in 23 of 30 (77%) in the EPA-FFA group compared with 15 of 30 (50%), OR 3.29, P=.035)
  • No serious adverse effects were reported.

Limitations:

  • Small number of patients from a single center
  • Short follow-up
  • In those without clinical relapse, a followup colonoscopy was not performed

My take: In this study EPA-FFA was associated with lower calprotectin and higher rates of remaining in remission.  More data are needed.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  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.

Near Banff

Sex-Based Differences in Incidence of Inflammatory Bowel Disease

Briefly noted: SC Shah, H Khalili et al. Gastroenterol 2018; 155: 1079-89.

This study evaluated pooled data with 207,600 incident cases of IBD from a population of 478 million. Key findings:

  • Female patients had lower a lower risk of Crohn’s disease during childhood until 10-14 years of age, but then a risk afterwards
  • For ulcerative colitis, there was a divergence in risk after 45 years of age, when men had a significantly higher incidence.

My take: the differences indicate that genetic factors (men with a Y chromosome and only one chromosome X) along with sex hormones play a role in the pathogenesis of IBD.

Graphs depict Female/Male Incidence Rate Ratio

AGREE proceedings: Briefly noted: ES Dellon, CA Liacouras, J Molina-Infante, GT Furuta et al. Gastroenterology 2018; 155: 1022-33.  This report provides updated recommendations from AGREE conference –which have been widely cited previously on this blog and elsewhere.  One of the remarkable features on this report is the fact that there are 64 authors (by my count) –thus reading the affiliations and the conflict of interest disclosures alone would take some time.

For a good review on this topic:

Methotrexate -Not Effective as Monotherapy for Ulcerative Colitis

A recent study (H Hansfarth et al. Gastroenterol 2018; 155: 1098-1108) examined the use of methotrexate for ulcerative colitis (UC).  The authors performed a 48-week trial (MERIT-UC trial) with 179 patients with a mean age of 42 years in the induction period.  In those who improved during induction, methotrexate was continued in 44 patients and compared to 40 patients who received placebo; this was a double-blind, placebo-controlled trial.

Key findings:

  • During induction which included 16 weeks with methotrexate at 25 mg per week SC and a 12-week steroid taper, 51% had achieved a response.
  • During maintenance, 60% of patients receiving placebo and 66% of patients receiving methotrexate had a relapse of UC.  At 48 weeks, 30% in the placebo group and 27% in the methotrexate group were in steroid-free clinical remission.
  • No new safety signals were evident with methotrexate.

The associated editorial by Dulai (pg 967-69) which reviewed this study and a prior study (METEOR) comes to the conclusion that: “there is likely no place for methotrexate monotherapy in UC.”

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Tofacitinib -Where Does it Fit in Treatment Algorithm for Ulcerative Colitis?

A few recent articles provide a lot of practical information regarding implementation of tofacitinib into treatment regimens for ulcerative colitis (UC).

  • S Danese et al. Inflamm Bowel Dis 2018; 24: 2106–12. Review article on Tofacitinib.
  • J-F Colombel.  Inflamm Bowel Dis 2018; 24: 2173–80. Review article on Herpes Zoster due to JAK Inhibitors (eg Tofacitinib).
  • KL Winthrop et al.  Inflamm Bowel Dis 2018; 24:  2258-65. Clinical study detailing the risk of Herpes Zoster in patients with UC receiving Tofacitinib.

The first of these articles reviews the mechanism of action of tofacitinib (TFB) and the relevant studies showing efficacy for UC.  A summary of the results are listed in Table 1. Some of the reported results –with TFB dosed at 10 mg BID:

  • In 2012, Sandborn et al: clinical response in 61% at wk 8 and clinical remission of 48% at wk 8.
  • In 2017 (OCTAVE Induction 1): clinical response in 18.5% at wk 8 and clinical remission of 31.3% at wk 8.
  • In 2017 (OCTAVE Induction 2): clinical response in 16.6% at wk 8 and clinical remission of 28.4% at wk 8.
  • In 2017 (OCTAVE Sustain):clinical response in 40.6% at wk 8 and clinical remission of 45.7% at wk 8.
  • In all of these studies, TFB outperformed the placebo arm and has had a good safety profile

Most common adverse effects had similar rates in the placebo arm:

  • Nasopharyngitis
  • Arthralgia
  • Headache

Other adverse effects have included pneumonia, herpes zoster (HZ) infection, and increased lipid levels (more common than with placebo group).  Trials in patients with rheumatoid arthritis have indicated an increased incidence of nonmelanoma skin cancer, lymphoma, breast cancer, lung cancer, and gastric cancers.

Preclinical studies have shown that TFB could cause fetal malformations when given at much higher doses.  Though, clinical experience in humans have not found teratogenic effects; this is based on one study with 9815 RA/psoriasis patients and 47 women who became pregnant.

Role for tofacitinib:

  • “Tofacitinib could be used in patients suffering mild, moderate and severe UC…after aminosalicylates (5-ASA)…and as second-line therapy in patients who have been treated with TNF inhibitors.”

Advantages of tofacitinib:

  • Oral administration with rapid absorption
  • Short serum half-life
  • Good experience in large number of patients with rheumatoid arthritis
  • No immunogenicity.
  • Effective in patients who have had previous anti-TNF agents

More on Herpes Zoster Infection:

  • The other two references detail the risk of Herpes Zoster infections with TFB usage.
  • Winthrop et al identified 65 (5.6%) of patients developed HZ among phase II/III open-label, long-term extension trials.
  • The review by Colombel notes that patients with UC have “an increased risk of HZ compared with the general population, and this risk can be increase by the use of immunosuppressive therapy.  JAK inhibitors, including tofacitinib, have been associated with HZ risk…The majority of HZ casees are noncomplicated.”
  • In this review, Colombel details an algorithm for treatment of HZ cases and indicates that adults receiving TFB should consider vaccination to lower the risk of HZ.

My take: A significant portion of patients with UC either do not respond to anit-TNF agents or lose response.  Tofacitinib provides an alternative treatment with a different mechanism of action.  Given the few other non-surgical treatment options, I expect it will be rapidly incorporated into treatment algorithms.

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