Tag Archives: Ulcerative colitis

What happens when anti-TNF therapy is stopped

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Another study (NA Kennedy et al. Aliment Pharmacol Ther 2016; 43: 910-23) has examined the issue of outcomes after anti-TNF therapy withdrawal among patients with inflammatory bowel disease.

This study included 166 UK patient cohort (117 with Crohn’s disease [median 31 yrs], 19 with ulcerative colitis [median 40 years]) as part of a retrospective observational study and a meta-analysis incorporating 11 further cohorts totalling 746 patients (624 with Crohn’s dissease, 122 with ulcerative colitis).

Key findings:

  • In the UK cohort, relapse rates were 36% at year and 56% at 2 years for Crohn’s disease
  • In the UK cohort, relapse rates were 42% at year and 47% at 2 years for ulcerative colitis
  • Increased relapse rates were noted for those with a diagnosis prior to age 22 years (hazard ratio (HR) 2.78), calprotectin >50 mcg/g (HR 2.95).
  • In meta-analysis, 1-year relapse rates were 39% for CD and 35% for UC/IBDU patients
  • Retreatment with anti-TNF was successful in 88% for CD and 76% of UC/IBDU patients

To understand this study, it is important to note some of the study criteria.  In the UK cohort, inclusion criteria required the patient to have had at least 12 months of ant-TNF therapy and be in corticosteroid-remission for at least 6 months.  In addition, the relapse rate is likely to be underestimated due to using a definition of relapse that required either commencement of steroids, immunomodulator or anti-TNF therapy.  The meta-anlaysis cohort studies also used clinical relapse rather than endoscopic or other objective markers.

My take: Relapse of clinical symptoms occur in about 40% after withdrawal in highly-selected groups who were doing well prior.  Significantly higher rates of endoscopic relapse are likely.  This study provides strong reasons for not interrupting therapy when it is working.

Related blog posts:

Cures Tshirt

 

CCFA Conference Notes 2016 (part 3) -Malignancy and IBD

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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.

3rd Lecture: Prevention and management of malignancy in IBD –Dr. Thomas Ullman

Malignancy risk (colorectal cancer [CRC]) is present with prolonged ulcerative colitis, though more recent studies have shown lower risk than in the past –not much higher than the general population.

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  • CRC surveillance–colonoscopy monitoring after 8-10 years. Typically colonoscopy every other year for most patients, every year in higher risk patients (eg. PSC).

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  • Unclear if chemoprevention is effective (5-ASA, thiopurines, others).
  • Chromoendoscopy “has not been consensus on its use in our field (yet).” It is time consuming and expensive and unclear if it will improve outcome.

Does medical therapy for IBD predispose to developing cancer?

  • Thiopurines increase the risk of malignancy. (Pasternak et al) though the risk returns to near baseline when stopped according to study below.

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  • No overall increased risk with anti-TNF agents with RCTs (may not follow patients long enough) but also not seen in Danish registry either (JAMA study)
With Anti-TNFs

No increased risk of malignancy in this study with Anti-TNFs

  • Lymphoma risks: age, immunodeficiency, EBV
  • EBV negative are at risk for HLH with thiopurines
  • HTSCL ~200, >90% men and >90% <35 years. NOT EBV-related. Has not been identified in anti-TNF monotherapy.

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  • Skin cancer –main concern is in non-melanoma skin cancer (possibly melanoma too). Skin cancer increase has not been noted with methotrexate. Prevention: Skin care, and annual dermatology visits.
  • Cervical cancer—likely increased risk in IBD, probably due to thiopurine exposure and reduced immune surveillance. Prevention: HPV vaccination, Pap testing.
  • Urinary Tract cancers –especially in those >65 years with thiopurine exposure

 

Should Methotrexate Be Used For Ulcerative Colitis?

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A recent study (F Carbonnel et al. Gastroenterol http://dx.doi.org/10.1053/j.gastro.2015.10.050, article in press; thanks to KT Park twitter feed for reference) with 111 patients provides more questions than answers.  It appears that methotrexate improved clinical remission but the overall difference is fairly small; the abstract is below.

My initial impression: Immunomodulators (including methotrexate and thiopurines) have some efficacy as monotherapy agents in patients with inflammatory bowel disease. Their role as part of combination therapy (with anti-TNF agents) has been associated with improved outcomes but how long to use combination therapy and at what dosage is still being worked out.

Here’s the abstract and a link: Methotrexate is not Superior to Placebo in Inducing Steroid-free Remission, but Induces Steroid-free Clinical Remission in a Larger Proportion of Patients with Ulcerative Colitis

Background & Aims

Parenteral methotrexate is an effective treatment for patients with Crohn’s disease but has never been adequately evaluated in patients with ulcerative colitis (UC). We conducted a randomized controlled trial to determine its safety and efficacy in patients with steroid-dependent UC.

Methods

We performed a double-blind, placebo-controlled trial to evaluate the efficacy of parenteral methotrexate (25 mg/week) in 111 patients with corticosteroid-dependent UC at 26 medical centers in Europe, from 2007 through 2013. Patients were given prednisone (10 to 40 mg/day) when the study began, and randomly assigned to groups (1:1) given placebo or methotrexate (intramuscularly or subcutaneously, 25 mg weekly) for 24 weeks. The primary endpoint was steroid-free remission (defined as a Mayo score ≤ 2 with no item > 1 and complete withdrawal of steroids) at week 16. Secondary endpoints included clinical remission (defined as a Mayo clinical subscore ≤ 2 with no item > 1) and endoscopic healing without steroids at weeks 16 and/or 24, remission without steroids at week 24, and remission at both weeks 16 and 24.

Results

Steroid-free remission at week 16 was achieved by 19/60 patients given methotrexate (31.7%) and 10/51 patients given placebo (19.6%)—a difference of 12.1% (95% confidence interval [CI], –4.0% to 28.1%; P=.15). The proportions of patients in steroid-free clinical remission at week 16 were 41.7% in the methotrexate group and 23.5% in the placebo group, for a difference of 18.1% (95% CI, 1.1%–35.2%; P=.04). The proportions of patients with steroid-free endoscopic healing at week 16 were 35% in the methotrexate group and 25.5% in the placebo group—a difference of 9.5% (95% CI, –7.5% to 26.5%; P=.28). No differences were observed in other secondary endpoints. More patients receiving placebo discontinued the study because of adverse events (47.1%), mostly caused by UC, than patients receiving methotrexate (26.7%; P=.03). A higher proportion of patients in the methotrexate group had nausea and vomiting (21.7%) than in the placebo group (3.9%; P=.006).

Conclusions

In a randomized controlled trial, parenteral methotrexate was not superior to placebo for induction of steroid-free remission in patients with UC. However, methotrexate induced clinical remission without steroids in a significantly larger percentage of patients, resulting in fewer withdrawals from therapy due to active UC.

Related blog posts:

Banning Mills

Banning Mills

Why the Genetics of Inflammatory Bowel Diseases Matter Now

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A terrific update on the genetics of inflammatory bowel diseases (DPB McGovern, S Kugathasan, JH Cho. Gastroenterol 2015; 149: 1163-76) explains why and how this information matters right now.  The article is a little difficult to read due to its review of highly technical material.

Here’s what I think were the key points:

  • Big advances in understanding the genetics started with the first genome-wide association studies (GWAS) using genome-wide single nucleotide polymorphisms (SNP) chips in 2005.  “The conceptual basis of GWAS is that most complex (ie, not single-gene Mendelian) genetic disorders are polygenic, being driven by multiple common genetic polymorphisms.”
  • “Early GWAS identified the most significant loci.”  Now, more than 200 loci associated with IBD have been identified with GWAS and Immunochip data. Table 1 lists these loci over 4 pages.  About 2/3rds of these are associated with Crohn’s disease (CD) and ulcerative colitis (UC) whereas the remaining 1/3rd are unique to either CD or UC.
  • These loci provide insight into disease mechanisms. NOD2 mutations result in “impaired activation of NF-κB” This supported “the general concept that deficiencies of innate immune cell function represent a central factor in Crohn’s disease, distinguishing it from ulcerative colitis.”
  • ATG16L1 gene mutation “establish the fact that the CD risk allele is correlated with impaired autophagy.”  This is leading directly into treatment efforts.
  • IL23R.  “The most significant association is Arg381Gln…confers a 2- to 3-fold protection against development of IBD.”  The protective effect is thought to be due to “decreased numbers of interleukin (IL)-23 dependent CD4+ Th17 and CD8+ Tc17 cells…decreasing IL-23 signaling, such as through monoclonal antibody blockade of anti-p40 or anit-p19 may be beneficial.”
  • FUT2 mutations.  These mutations affect the mucus layer in Crohn’s disease.
  • Studies in non-Caucasians highlight other susceptibility regions.
  • “Currently, sequencing of the whole exome has become not only a practical method but also a cost-effective option to identify functionally relevant variants in the protein encoding regions of the genome.”

Very Early Onset IBD:

  • Whole exome sequencing (WES) identified XIAP (X-linked inhibitor of apoptosis) in a case of boy with very early onset (VEO) IBD.  XIAP is a positive regulator of NOD2 function.  WES has also identified FOXP3, and IL10RB genes.
  • “The VEO group experiences a more severe disease course and more frequently shows a positive family history for IBD in support of higher genetic load.”  Table 2 lists ~40 genes associated with VEO.  These genes are involved in epithelial barrier function, neutropenia/defects in phagocyte function, hype-and autoinflammation, and  regulatory T cells and immune regulation.

Genetic Testing Will Impact Current Therapies and Help Explain Extraintestinal Manifestations:

  • Currently testing for TPMT variations is recommended prior to use of thiopurines due to concerns of toxicity in individuals with decreased metabolism of these medications.  However, genetic testing can identify other individuals with propensity to leukopenia (eg. NUDT15 polymorphism) and those with increase risk for pancreatitis (eg. HAL-DQA1-HLA-DRB1)
  • Primary Sclerosing Cholangitis (PSC) is associated with numerous genetic loci as well. PSC “genetically is more similar to UC than to CD.” Most other extraintestinal manifestation studies have been underpowered.
  • IBD share more genetic similarity to spondyloarthropathy (SpA) than any other immune-mediated diseases.  “The vast majority of shared susceptibility loci are concordant between IBD and SpA.”
  • With regard to psoriasis, the genetic relationship to IBD is complex.  Anti-TNF agents can cause psoriaform lesions in IBD patients.  In addition, anti-IL17a therapy, “so successful in psoriasis, appears to worsen Crohn’s disease” but not in those with a TNFSF15 variant.  Specific genotyping may help identify which patients with CD are susceptible to psoriaform lesions and those who may improve with therapy typically given for psoriasis.

My take: This article shows how understanding genetics of IBD is providing insight into pathophysiology and more personalized treatment approaches.

Briefly noted: EM Stoffel, CR Boland. Gastroenterol 2015; 149: 1191-1203. Excellent review of the genetics and genetic testing for Hereditary Colorectal Cancer.  The review includes polyposis syndromes and Lynch syndrome.

Atlanta Botanical Gardens

Atlanta Botanical Gardens

Be Aggressive! Treating Anemia Associated with Inflammatory Bowel Disease

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A number of recent publications have made the point that anemia is a biomarker for severe inflammatory bowel disease and undertreatment affects quality of life. Reading one of the more recent studies (IE Koutroubakis et al. Clin Gastroenterol Hepatol 2015; 13: 1760-66) brought to mind the high school football cheer: Be Aggressive!

This particular retrospective study involved 410 patients (245 with Crohn’s disease, 165 with ulcerative colitis) from 2009-2013.  This study is from the same group that published data on a somewhat smaller cohort and showed that IBD treatment alone often will not resolve anemia (Koutroubakis, IE et al. Inflamm Bowel Dis 2015; 21: 1587-93–see previous blog links).

Key findings:

  • Prevalence of anemia: 37.2% in 2009 and 33.2% in 2013
  • Anemia was associated with increased hospitalizations (P<.01), clinic visits (P<.001), telephone calls (P<.004), surgeries for IBD (P=.001), and lower quality of life scores (P<.03)

The associated editorial (pgs 1767-69) suggests that IBD-related anemia, if mild (w/in 1 g/L below normal) to treat with oral iron replacement and if moderate-to-severe, then to replace intravenously (using Ganzoni’s formula calculator). In addition, if anemia is not improving, looking for alternative explanations (e.g. vitamin B12 or folate deficiency) is recommended.

Ganzoni Equation: Total Iron Deficit = Weight {kg} x (Target Hb – Actual Hb) {g/l} x 2.4 + Iron stores {mg}.   Iron stores: { 500 if W > 35kg } & { 15 mg/kg if W < 35kg }

My take: Anemia is a biomarker for severe disease.  While treating the underlying inflammatory bowel disease, don’t forget to make sure the patient’s anemia is addressed.

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.

Central Park

Central Park

Desperate Measures in Refractory IBD

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The often cited, ‘desperate times call for desperate measures,’ resonates in the setting of refractory inflammatory bowel disease (IBD).  [Of course, this saying could be used to justify about anything you want to do.]  For IBD, two recent studies point out potential remedies:

  • SA Merkley, et al. Inflamm Bowel Dis 2015; 21: 1854-59.
  • M Lazzerini, et al. Inflamm Bowel Dis 2015; 21: 1739-49, with editorial by A Bousvaros (1750-51)

In the first study, the authors retrospectively analyzed date from 24 IBD patients who were treated with intravenous immunoglobulin (IVIG) at a dose of 0.4 g/kg/day for 3 days, then 0.4 g/kg once a month. Key findings: 16 (67%) had a response and 3 (12.5%) obtained remission. Measures of improvement included CRP, ESR, Simple Endoscopic Score for Crohn’s disease, and the Harvery-Bradshaw Index. The researchers speculate that IVIG has anti-inflammatory and immunomodulator effects.  In addition, they note that IVIG can be given with concurrent infections.

In the second study, the authors studied thalidomide(1.5-2.5 mg/kg/day) in a double-blind, placebo-controlled randomized pediatric clinical trial in children with refractory active ulcerative colitis. Key findings: at week 8, clinical remission was achieved in 10/12 (83%) of thalidomide arm compared with 2/11 (19%) of control patients.  Then, among control patients who were switched, 8 of 11 (72%) reached remission as well. Peripheral neuropathy and amenorrhea were reported adverse effects. In the accompanying editorial, Dr. Bousvaros notes that there has been some data to suggest thalidomide efficacy in ulcerative colitis since 1979.  However, due to widespread bad publicity related to thalidomide-induced teratogenicity (eg. phocomelia) and side effects including neuropathy, it has not been used with much frequency. He notes that this study, as well, requires replication and speculates that “the primary focus on drug development will focus on newer small molecules and biologics, and this potentially useful medication may be left on the sidelines.” It is worth noting that the authors response (pg 1752) to this editorial was that the stigma of thalidomide is unwarranted and that teratogenicity can be avoided. “No case was observed out of 124,000 patients enrolled in the thalidomide distribution risk management program for more than 6 years.”

Bottomline: Both thalidomide and IVIG may be beneficial to desperate patients (and desperate doctors).  While small trials appear promising, larger trials are needed.  Don’t hold your breath waiting … will they ever happen?

Related blog posts:

1000th Tweet: GI Symptoms Preceding IBD Diagnosis

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Another milestone for this blog: since 2012, the blog has been publicized on twitter; this is the 1000th tweet. It is also 1314th blog post over nearly 4 years.

A recent study (H Singh et al. Clin Gastroenterol Hepatol 2015; 13: 1302-09) indicates that children with inflammatory bowel disease (IBD) were more likely to have gastrointestinal symptoms in each of the 4 years before the diagnosis of IBD than children without IBD.

In this study, the researchers identified all children with IBD from a population-based Manitoba database; Manitoba had a population of 1.27 million in 2012.  651 children were matched with 5950 controls without IBD.  The study’s Table 1 & 2 indicates that children with IBD had increased clinic visits prior to diagnosis:

  • 54-66 months prior: standardized rate ratio for number of ambulatory visits 1.15; & for ≥1 visit due to GI symptoms odds ratio 1.44
  • 42-54 months prior: standardized rate ratio for number of ambulatory visits  1.22; & for ≥1 visit due to GI symptoms odds ratio 2.05
  • 30-42 months prior: standardized rate ratiofor number of ambulatory visits 1.19; & for ≥1 visit due to GI symptoms odds ratio 2.16
  • 18-30 months prior: standardized rate ratio for number of ambulatory visits 1.23; & for ≥1 visit due to GI symptoms odds ratio 2.93
  • 6-18 months prior: standardized rate ratio for number of ambulatory visits  1.15; & for ≥1 visit due to GI symptoms odds ratio 5.23

There was not a clear trend in increased symptoms between those who developed Crohn’s disease compared with Ulcerative Colitis. In addition, the study noted a trend towards decreased colectomy and resective surgery in Crohn’s in the time period 2002-2010 compared with 1987-2001.  One limitation of this study is the few number of pediatric gastroenterologists in Manitoba (only 1 before 2003); the lack of pediatric gastroenterology availability could impact timely diagnosis.

My take: This data shows that GI symptoms still predate diagnosis in many children and indicate a potential for diagnosis delay. The authors note that noninvasive tools like stool calprotectin have not been widely adopted (at least in Manitoba) and could be helpful in reducing diagnostic delays.

Estes Park, Colorado

Estes Park, Colorado

Higher Stool Infliximab Correlates with Poor Response in Severe Ulcerative Colitis

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A recent study (full text link: “Loss of Infliximab into feces is associated with lack of response to therapy in patients with severe ulcerative colitis” Gastroenterol 2015; 149; 350-55.e2) provides information about patients with ulcerative colitis who do not respond well to infliximab therapy.

In this study, the authors obtained fecal samples from 30 consecutive patients with moderate to severe UC during the 1st 2 weeks of therapy.  In addition, they obtained serum infliximab levels as well as assessed clinical and endoscopic response at 2 weeks, 8 weeks, and 3 months after treatment began.

Key findings:

  • Fecal infliximab was detected in 129 of 195 (66%) samples.  The greatest loss was observed approximately 2 days after infusion. Low serum albumin was associated with greater infliximab levels in the stool.
  • Clinical nonresponders at week 2 had significantly higher fecal infliximab
  • The authors did not observe a correlation between fecal and serum infliximab concentrations.  However, it is possible that stool losses could indicate lower mucosal concentrations of infliximab.
From AGA twitter account

From AGA twitter account

From AGA twitter account

From AGA twitter account

From AGA twitter feed

From AGA twitter feed

Bottomline: It is not clear whether stool losses of infliximab directly contribute to drug failure or whether the loss is another biomarker of disease activity/high-risk patients.

The study authors note that “intestinal loss of IFX in moderate to severely active UC is associated with a diminished response to this treatment.  Patients with severe disease can, therefore, benefit from more intensive dosing regiments. This strategy warrants a prospective clinical trial.”

Related blog posts:

Spice It Up? Curcumin for Ulcerative Colitis

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This past week I’ve been on call and had not finished a few articles.  One article that was on the to do list: A Lang et al. Clinical Gastroenter Hepatol 2015; 13: 1444-9.

I’ve read it now.  However, even before finishing the article, I read a few good summaries of this article, including one from my colleague Stan Cohen/Nutrition4Kids: Curcumin Helps (A Lot) in Ulcerative Colitis

Here’s an excerpt:

The cover of a prestigious medical journal shows a pile of curcumin and over it, the announcement reads: Curcumin Helps Induce Remission in Mild-to-Moderate Ulcerative Colitis.  That’s big news for a lot of reasons: first, this Indian spice (derived from tumeric) is inexpensive and well-tolerated; second, in a well-designed scientific study, curcumin showed that it was more effective than some medicines; and third, it showed, again, that careful trials of long-used herbs can be done with important results being shown.  Again, because an earlier study (H Hanai, Clinical Gastroenterology 2006, pages 1502-6) had previously shown that curcumin can help keep ulcerative colitis (UC) patients from flaring for up to 12 months. 

This new study (A Lang, Clinical Gastroenterology 2015, pages 1444-9) compared curcumin to a placebo in patients who were not doing well on the standard therapy (mesalamine) for mild to moderate UC.  With a single daily dose of 3 grams of curcumin in capsule form, 65% responded (compared to 12% with a placebo) and 54% actually went into remission, having essentially no symptoms.  Perhaps even, more importantly, 38% of those taking the curcumin showed improvement in the intestinal tissue when a colonoscopy was performed.  That’s comparable or better than some of the medications that are being used.

A few other details: The researchers used a product called Cur-Cure from Bara Herbs Inc (Yokneam, Israel).  Also, the associated commentary in the same journal by CN Bernstein (pages 1450-52) suggests that the study may have targeted mild ulcerative colitis (rather than moderate ulcerative colitis). He comments that the increasing rates of ulcerative colitis among Indian immigrants could be related to including less curcumin in their now more westernized diets.  He also notes, as did Dr. Cohen, that there were previous promising studies dating back to 2006.  Why has it taken nine years for this report?

My Take: This is probably an article worth reading.  Although curcumin appears promising, I worry that a lack of financial incentive may hamper research efforts to better define its place as an agent for treatment of ulcerative colitis.

Related blog posts:

Curcumin

This has been a sad week in our office.  Here are links to two poems that come to mind:

Not Using and Stopping Therapy in IBD

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Two recent articles show that a lot of patients are not receiving much therapy in inflammatory bowel disease.

  • Moreno-Rincon E et al. Inflamm Bowel Dis 2015; 21: 1564-71.
  • Melesse DY et al. Inflamm Bowel Dis 2015; 21: 1615-22.

In the first article, a multicenter retrospective study of 102 patients, the authors examined the relapse rates of patients with ulcerative colitis who had withdrawal of thiopurines.  They defined “significant clinical relapse” (SCR) as “the occurrence of UC typical signs or symptoms requiring a rescue therapy such as oral or intravenous corticosteroids, biological therapy, immunosuppressant drugs, recapture with TP [thiopurine] or surgery.”

Key findings:

  • Overall SCR was 32.35%.
  • Predictors of relapse included pancolitis (HR 5.01) and duration of treatment with thiopurines (HR 0.15).

Among those without relapse, the mean duration of remission prior to withdrawal of thiopurines was 54 months compared with 34 months in those who relapsed. In figure 2, the authors note that the rate of relapse was 19.2% for those who received >48 months of thiopurine treatment compared with a 45% rate of relapse for those who received treatment for 13-47 months.  The authors note that several studies have shown higher relapse rates than reported in this cohort and that interruption of therapy is associated with a considerable risk of relapse.

Limitations: small retrospective study and the expectation that their SCR would capture the true relapse rate.

The second study, using a Manitoba database, shows a strikingly-high rate of nonuse of medical therapy. Between 1996-2012, 3902 patients with IBD were identified; 47% with Crohn’s disease (CD) and 53% with ulcerative colitis (UC).  While only 11.7% of IBD patients did not have medication dispensed in the first year after diagnosis, beyond this period, “roughly half of all patients with IBD have not used IBD-specific medications in the previous year.”  The authors are not certain how much nonuse is due to nonadherence or nonprescription. They note that there was higher nonuse in patients with CD, possibly due to use of surgical treatment.  However, they note that multiple medications have been shown to reduce postsurgical relapse in CD.

My take: There are a lot of patients off therapy, both due to withdrawal of therapy when doing well and others due to nonadherence or nonprescription.  With or without overt symptoms, these studies make one wonder whether undertreatment will lead to long-term complications or whether there could be a significant number of patients who are overtreated.  Either way, it remains quite difficult to predict which patients will do well off medical therapy.

Broadcasters Really Know the Key Points to Winning!

Broadcasters Really Know the Key Points to Winning!