Tag Archives: Ulcerative colitis

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

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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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Active Colitis More Likely in Children in Clinical Remission Who Have PSC and IBD

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A recent study (A Ricciuto et al. Clin Gastroenterol Hepatol 2018; 16: 1098-1105) provides more data regarding the lack of symptom correlation and inflammatory bowel disease (IBD) activity in children with primary sclerosing cholangitis (PSC).

In a prospective study of children with colonic IBD with and without PSC, the authors followed clinical features (eg. PUCAI), fecal calprotectin and endoscopy severity.

Key findings:

  • Patients with PSC-IBD (n=37) in clinical remission had higher endoscopic scores and greater odd of active endoscopic disease than IBD-only controls (n=50) (odds ratio 5.9, with CI 1.6-21.5)
  • Fecal calprotectin level <93 mcg/g were identified mucosal healing with 100% sensitivity and 92% specificity when compared with UC Endoscopic Index of Severity (UCEIS)

Overall, this study is in agreement with a prior adult study showing higher levels of active disease in those with PSC-IBD compared to those with IBD alone, despite clinical remission (Why does PSC increase the risk of colorectal cancer in UC?).

My take: Particularly in individuals with the combination of IBD-PSC, objective biomarkers (eg. Calprotectin) are needed to identify the accuracy of clinical remission; though, even in patients with IBD without PSC, objective biomarkers are needed as well due to the limitations of clinical symptom indices.

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Management of Pediatric Ulcerative Colitis -ESGHAN/ECCO Recommendations

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Two complementary articles provide extensive guidance on the management of ulcerative colitis and acute severe colitis:

  • D Turner et al. JPGN 2018; 67: 257-91
  • D Turner et al. JPGN 2018; 67: 292-310

Between the two articles there are more than 60 practice recommendations, more than 120 practice points, and more than 700 references.  As such, these articles are probably better for a journal review meeting rather than a brief blog post.

Figure 1 (2nd article, page 299) provides a handy algorithm for management of acute severe colitis:

  • On day 1-2, the algorithm recommends stool studies, starting methylprednisolone, and withholding 5-ASA.
  • On day 3, if PUCAI <45, suggests continuing steroid and transitioning to oral therapy when PUCAI <35.  On day 3, if PUCAI ≥45, the authors suggest screening for second line therapy, involve surgery (to discuss colectomy if there is nonresponse to medical treatment), and looking for CMV infection (eg. sigmoidoscopy).
  • On day 5, if PUCAI >65, recommendation is to start 2nd line Rx (eg. infliximab, tacrolimus, or cyclosporine). If PUCAI 35-65, continue corticosteroids for additional 2-5 days. The authors note that infliximab is preferred 2nd line Rx unless planning to transition to vedolizumab.
  • The authors recommend weaning corticosteroids when 2nd line Rx is started
  • The authors recommend addition of an immunomodulator for at least 6 months in responders to infliximab in effort to lower the risk of colectomy.
  • The authors state “urgent colectomy is recommended following failure of 1 second-line therapy.”

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.

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Is it really necessary to check for Cytomegalovirus in Children with Inflammatory Bowel Disease?

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A recent retrospective study (W El-Matary et al. JPGN 2018; 67: 221-24) examined the practice of looking for Cytomegalovirus (CMV) in children with a flareup of their inflammatory bowel disease (IBD) which is currently recommended by expert consensus (JPGN 2018; 67: 292-310 –recommendation #3).

Key findings:

  • “Four of 61 patients encounters (6.6%) with UC/IBD-U, two with corticosteroid refractory disease, had positive biopsies for CMV by PCR but negative H&E and IHC.  They responded to escalated medical therapy, without needing anti-viral therapy.”
  • All children who had colectomy during the study did not have CMV detected in colonic mucosa.

The authors note that the rationale for looking for CMV is derived mainly from adult populations.  Since age is a known risk factor for CMV reactivation, the risk of CMV causing refractory IBD in children is less.

My take (borrowed in part from authors): “The low frequency of CMV in our study challenges current guidelines that recommend assessment for CMV in all pediatric patients with acute severe UC refractory to corticosteroids.”  This issue would be another that would benefit by collecting the experience of a large cohort (eg. ICN).

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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.

Serology Titers Associated with Clinical Expression of Ulcerative Colitis in Children

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Briefly noted: A recent study (EA Spencer et al.Inflamm Bowel Dis 2018; 24: 1335-42) examined phenotype and serology in 399 children with newly diagnosed ulcerative colitis (PROTECT study).

Key findings:

  • 65% had positive serology for pANCA; 62% in those <12 and 66% in those ≥12 years
  • 19% had positive serology for anti-CBir1; 32% in those <12 and 14% in those ≥12 years
  • High titer (≥ 100)) pANCA positivity was associated with more extensive disease but not with PUCAI values or Mayo endoscopic subscores.

My take: The serology titers for IBD, in my view, have academic interest but do not routinely enhance patient care.

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VICTORY Consortium Showing Good Results for Vedolizumab

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A presentation at the 13th Congress of the European Crohn’s and Colitis Organization (ECCO, Feb 2018) indicated that Vedolizumab had similar effectiveness as anti-TNF agents for both ulcerative colitis and Crohn’s disease. This data has been presented at a recent meeting in our office, some of the GI news magazines, and also ImproveCareNow listserv.

From Takeda website: Entyvio® (vedolizumab) Shows Higher Rates of Mucosal Healing Versus TNFα-Antagonist Therapy in Ulcerative Colitis and Crohn’s Disease Patients in Comparative Effectiveness Real-World Data Analysis

These analyses observed that patients with UC treated with Entyvio compared to TNFα-antagonist therapy had statistically significant higher 12-month cumulative rates of mucosal healing (50% vs 42%, hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.10‑2.73) and clinical remission (54% vs 37%; HR 1.54, 95% CI 1.08‑2.18), and numerically higher steroid-free clinical remission rates (49% vs 38%; HR 1.43, 95% CI 0.79‑2.60). In CD, results reported statistically significant higher 12-month cumulative rates of mucosal healing (50% vs 41%; HR 1.67, 95% CI 1.13‑2.47), and numerically higher rates of clinical remission (38% vs 34%; HR 1.27, 95% CI 0.91‑1.78) and steroid-free clinical remission (26% vs 18%; HR 1.75, 95% CI 0.90‑3.43) compared to TNFα-antagonist therapy. These analyses were conducted by the VICTORY (Vedolizumab Health OuTComes in InflammatORY Bowel Diseases) Consortium.

My take: While the data compare anti-TNFs to vedolizumab in a “real-world setting,” the reported outcomes for anti-TNFs are lower than in other studies.  Vedolizumab had the best results in those with colonic disease.  Patients with Crohn’s disease with isolated small bowel disease had lower response rates.

Related study: AK Waljee et al Inflamm Bowel Dis 2018; 24: 1185-95. Using phase 3 clinical trial data with 594 subjects, the authors note that the majority of patients who will respond to vedolizumab can be identified by week 6 using a laboratory algorithm based on hemoglobin, albumin, vedolizumab level and CRP. Fformula: Hgb*Albumin*VDZ level/CRP*Weight. A cutoff of 185.96 predicted success with an AuROC of 0.75.   Higher hemoglobin, higher albumin, and higher vedolizumab level, and lower CRP are associate with higher response rates.

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Opiates, Inflammatory Bowel Disease and Mortality

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A recent retrospective study (NE Burr et al. Clin Gastroenterol Hepatol 2018; 16: 534-41) with 3517 patient’s with Crohn’s disease (CD) and 5349 with ulcerative colitis (UC) examined the frequency of opioid prescriptions and the relationship to fatal outcomes.

Key findings:

  • Compared to 1990-93, the period of 2010-13 saw a sharp rise in the use of opiods in England: 10% compared to 30%.
  • Prescription of strong opioids (>3 prescriptions per calendar year) was associated with premature mortality: Hazard ratio 2.18 for CD and 3.3 for UC.

This study is in agreement with other data showing increasing use of opiate prescriptions worldwide for chronic noncancer pain (although there has been a drop in the past year).  As with other studies of patients with inflammatory bowel disease, this study shows an association between opioid use and mortality.

My take: Needing an opioid may be a marker for more severe disease. Whether the opioid use directly contributes to mortality remains unclear.

 

Time Will Tell: Granulomatous Upper GI Inflammation

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A recent retrospective study (K Queliza et al. JPGN 2018; 66: 620-23) describes seven patients with granulomatous disease in the upper GI tract who were diagnosed with ulcerative colitis.

This study examined patients at a single center between 2007-2016 with ages ranging from 2 years to 17 years.  Median time of followup is not provided.  Two patients required colectomy.  All patients had non-casseating granulomas identified in either the stomach or duodenum (or both) along with moderate to severe pancolitis.  All of the patients had extensive investigations, generally cross-sectional imaging (MRE or CT) or capsule endoscopy

Key point::

  • “The final classification of IBD was based on expert opinion from gastroenterologists, radiologists, and pathologists upon thorough review of the medical records.”

My take: This study highlights the confusion of the essentially binary classification of IBD into either Crohn’s disease or ulcerative colitis, when in fact there are hundreds of genetic mutations which give rise to inflammatory bowel disease.  Given that granulomas are a hallmark of Crohn’s disease and there are no pathognomic features of ulcerative colitis, only time will tell if these patients have an ulcerative colitis phenotype.  I wonder how many centers would take exception to this classification and describe these patients as ‘indeterminate’ colitis/IBDU (IBD unclassified).

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