Category Archives: inflammatory bowel disease

Don’t be Fooled About Withdrawing Immunomodulator Cotherapy -Look Past the Headline

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The coverage on a recent study (Clinical Gastroenterology and Hepatology 2015: 13(3): 514-521.e4) suggests that it should be fine to stop immunomodulator co-therapy.  I recommend reading the entire study (or at least this blog post)–you will probably come to a different conclusion.
Brief summary from AGA website: Withdrawal of Immuonomodulators after Co-therapy Does Not Reduce Trough Level of Infliximab in Crohn’s Patients

“The addition of immunomodulators increases the efficacy of maintenance therapy with infliximab for up to one year in patients with Crohn’s disease who have not been previously treated with immunomodulators. However, there are questions about the effect of withdrawing immunomodulator therapy from these patients. David Drobne and colleagues studied the effects of treatment with infliximab and immunomodulators (co-treatment) and then immunomodulator withdrawal on long-term outcomes of patients, as well as trough levels of infliximab and formation of anti-infliximab antibodies (ATI). Reporting in Clinical Gastroenterology and Hepatology, they find that, in a retrospective analysis, withdrawal of immunomodulators after at least six months (median, 13 months) of co-treatment with infliximab does not reduce the trough levels of infliximab in patients with Crohn’s disease. Detectable trough levels of infliximab at the time of immunomodulator withdrawal are associated with long-term response.”

Clinical Gastroenterology and Hepatology 2015: 13(3): 514-521.e4

Some additional details:

This was a retrospective open-label cohort study with 223 patients and median followup of 34 months. At baseline, 65 received infliximab (IFX) monotherapy and 158  received co-therapy with an immunomodulator (46 methotrexate, 112 thiopurine).  Immunomodulators were withdrawn “only in patients with durable response (ongoing clinical benefit with lasting disease control with low C-reactive protein [CRP] [below 10 mg/L]).”  Among the 158 on co-therapy, 117 reached a durable response and had withdrawal of immunomodulator after >6 months of combination therapy (median time 13 months).

Key findings:

  • At baseline, co-therapy patients, compared to monotherapy patients, had higher IFX trough levels (adjusted mean increase of 1.44-fold) and lower likelihood of antibodies to infliximab (ATI): 35/158 (22%) compared with 25/65 (38%), P=.01.
  • When immunomodulator was withdrawn, IFX levels remained stable: before 3.2 mcg/mL compared with after 3.7 mcg/mL. However, 45 of 117 (38%) required increasing doses of IFX and 21 of 117 (18%) discontinued IFX.
  • Trough levels of IFX and CRP  were most strongly associated with response to IFX dosing on monotherapy.
  • “Only 9 of 74 patients (12%) with detectable IFX trough levels at the time of immunomodulator withdrawal developed undetectable IFX trough levels during the subsequent follow-up.”
  • None of the 27 patients with IFX trough level >5 mcg/mL at time of immunomodulator withdrawal lost response to IFX during median follow-up of 29 months.

Though the headlines covering this article have suggested that IFX levels will stay stable when immunomodulators are withdrawn after >6 months, the authors proposed algorithm only recommends withdrawal for those with IFX trough level >5 mcg/mL.  In addition, the data showed that a large number of patients required dose escalation and/or lost detectable IFX levels. Despite their proposed algorithm to withdraw in this small group, the authors further backtrack in their conclusion:  “a prospective parallel group trial during a period of 5-10 years in a large group of patients is required to ascertain the real long-term benefit to risk ratio of continuing combined infliximab and immunomodulator treatment.”

Bottomline: If a patient is doing well, withdrawing immunomodulator co-therapy still has risks. I worry that the misleading reporting of this article will result in detrimental outcomes.

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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.

 

Methotrexate Dosing in Dual Therapy

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A recent retrospective study (DOI: http://dx.doi.org/10.1093/ecco-jcc/jjv027 first published online: 23 January 2015 -reference from KT Park’s twitter feed) has suggested that high-dose methotrexate (MTX) (15-25 mg/week) is more effective than low-dose MTX (≤12.5 mg/week) as part of dual therapy for inflammatory bowel disease.

Here’s the abstract: Optimal Doses of Methotrexate

Background and Aims: Methotrexate is sometimes used as part of combination therapy for the treatment of inflammatory bowel disease (IBD), however the optimal MTX dose for combination therapy has not been established. This study compared the efficacy of lower dose and higher dose methotrexate with anti-TNF therapy among IBD patients.

Methods: Retrospective chart review was performed of 88 IBD patients at our center between 2010-2013. Low-dose methotrexate was defined as ≤ 12.5mg/week and high-dose methotrexate as 15-25mg/week. Patients who met the criteria for clinical remission (Harvey-Bradshaw Index ≤ 4, Simple Clinical Colitis Activity Index ≤ 2) at baseline were followed for up to 42 months. Chart review occurred in six-month intervals. The primary outcome was consecutive months in remission prior to relapse. Secondary outcomes included other indicators of worsening disease (endoscopic inflammation, steroid use, therapy escalation/addition, or surgery) and adverse events. Regression analysis and Kaplan-Meier survival analysis were completed.

Results: We identified 73 (83%) dual-therapy patients, of which 32 low-dose and 14 high-dose individuals achieved remission. When compared with high-dose patients, low-dose patients were more likely to relapse (log-rank test, P<0.01). Secondary indicators of worsening disease occurred during 34.4% of low-dose review periods and 31.4% of High-dose review periods (P=0.67). 3/52 (6%) low-dose patients and 3/21 (14%) high-dose patients (P=0.34) discontinued methotrexate therapy due to adverse events.

Conclusions: When combined with anti-TNF therapy, methotrexate at doses of >12.5mg/week were more effective at maintaining clinical remission than lower doses. These findings will guide management of combination therapy in IBD patients.

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Emigration -One Way to Acquire Inflammatory Bowel Disease

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A recent study (Shitrit AB, et al. Inflamm Bowel Ds 2015; 21: 631-35) highlights the phenomenon of acquiring inflammatory bowel disease (IBD) by moving from a non-developed country to a developed country; the implication is that the changes in environment and diet predispose towards the development of IBD.

This study examined Ethiopian Jews who migrated to Israel.  Using a case-control study, the authors compared 32 Ethiopian immigrants to 33 Ashkenazi patients with IBD.

Key findings:

  • No Ethiopian immigrants had a positive family history compared with 42% of Ashkenazi group.
  • Crohn’s disease was more prevalent in the Ethiopian immigrants: 94% versus 73%.
  • The Ethiopian immigrants lived in Israel for at least 8 years before developing IBD an da median duration of 13 years.

The study discusses the difficulty of diagnosing IBD in rural Africa but speculates that rather than an underdiagnosis of IBD, it is likely to have a true low prevalence of IBD.

Take-home message: It takes many years for the environment exposures to allow for the development of IBD.  Additional work is needed to establish the clinical, genetic, and microbial factors that influence the acquisition of IBD in immigrants to developing countries.  Understanding the susceptibility of immigrants would have widespread application.

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Withdrawing Therapy Leads To Relapse, Even if in Deep Remission

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A recent study, presented as an oral abstract (thanks to Jeff Lewis for forwarding this reference), indicates that even in patients in deep remission, withdrawal of anti-TNF therapy leads to relapse in about 50% even when thiopurines are continued; this is in agreement with previous posts (see below).

Full abstract: OP007 Relapse after Deep Remission in Crohn’s disease. Here are the results and conclusion from the abstract:

Results

Sixty one patients were included and followed-up for a median of 28 months (range 7-47). After withdrawal of anti- TNFa therapy (44 infliximab and 17 adalimumab) 47 (77%) patients continued thiopurines. 32 (52.5%) patients relapsed until the end of follow-up with a median time to relapse of 8 months (range 1-25). The cumulative probability of maintaining remission was 82% at 6 months, 59% at 1 year and 51% at 2 years. Analysis of 28 patients who were in deep remission (endoscopic healing; faecal calprotectin <150mg/kg; CRP <5mg/l) revealed no better survival (82%, 64% and 40% at 6 months, 1 and 2 years, respectively). Four (8%) of relapsing CD patients required surgery 5 to 19 months after anti-TNFa cessation (2 for new stricture development, 1 for medically refractory flare and 1 for high grade dysplasia). In multivariate model only disease localization was risk factor of disease relapse (colonic vs. ileal/ileocolonic: OR 0.16, 95%CI: 0.03-0.72; p=0.02). Type of anti- TNFa preparation, smoking, disease behaviour, corticosteroid or thiopurine therapy, biological markers and anti-TNFa trough levels did not impact disease relapse.

Conclusion

Approximately half of CD patients relapsed within 2 years after anti- TNFa discontinuation despite being in endoscopic remission when anti-TNFa was stopped. The highest relapse rate was observed during the 1st year. Ileal disease increased the risk of disease flare, while no other risk factor was identified.

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Bryce Canyon

Bryce Canyon

Short Takes on IBD Articles

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Singh S, et al. Gastroenterol 2015; 148: 64-76.  In this study, the authors identified 21 trials with 2006 participants to examine the comparative efficacy of pharmacologic interventions to prevent relapse of Crohn’s disease (CD) after surgery.  Conclusion: “anti-TNF monotherapy appears to be the most effective strategy for postoperative prophylaxis for CD.” The relative risk of clinical relapse and endoscopic relapse with anti-TNF monotherapy was estimated to be between 0.02-0.20 and 0.005-0.04, respectively. Thus, those at highest risk for recurrence, including younger individuals, smokers, penetrating CD, perianal CD, and recurrent surgeries) are most likely to benefit.(Related blog post: More Lessons in TNF Therapy (Part 1) | gutsandgrowth)

Pariente B, et al. Gastroenterol 2015; 148: 52-63. The researchers in this cross-sectional study developed the Lémann Index which measures cumulative structural bowel damage in patients with CD.  My only complaint with this study was the associated editorial on pages 8-10, titled “The Holy Grail, or Only Half Way There?”  There are too many medical advances compared to ‘the holy grail’ and, in my opinion, this shouldn’t be one of them.

Zitomersky NL et al. Inflamm Bowel Dis 2015; 21: 307-14.  In this study the authors examine the relationship between the development of antibodies to infliximab (ATI) and the risk of surgery in a cross-sectional cohort of pediatric and young adult patients.  Not surprisingly, development of ATI, which was noted in 20% of cohort, correlated with reductions in infliximab levels and higher risk of surgery.  Interestingly, prior (but not current) immunomodulator therapy was associated with lower antibody levels (P=0.007).  Perhaps, “step-up” therapy may lower the risk of ATI. (This was a point noted by James Markowitz in a previous post: More NASPGHAN Meeting Notes: IBD Hot Topics | gutsandgrowth)

Rogler G, Vavricka S. Inflamm Bowel Dis 2015; 21: 400-08. This review article discusses the exposome in IBD.  Exposures include air pollution, diet, drugs, infections, water pollution, food additives, and smoking.  These exposures influence the gut microbiome and genetic susceptibility. “Only environmental influences…explain the rising incidence in IBD worldwide. The investigation of the exposome…is an enormous challenge…[but] of crucial importance.” (Related blog post: What do you know about the “exposome”? | gutsandgrowth)

Kalmon RS. Inflamm Bowel Dis 2015; 21: 428-35. Review article provides information when there is a prior personal or family history of malignancy (=avoid thiopurines).  Figure 2 is a suggested algorithm for those with IBD and a previous diagnosis of cancer.

  • In those in which the cancer is adequately controlled, the recommendations indicate that if it has been more than 2 years since completion of therapy to use a ‘step-up’ management and favor methotrexate over thiopurines
  • In those with less than 2 years since completion of cancer treatment and not responsive to 5-ASAs/antibiotics, then “consider monotherapy with biologic agents.”
  • In those still receiving chemotherapy, the authors suggest “hold immunosuppression and follow course of IBD.  If IBD not well controlled despite chemotherapy, 5-ASAs and antibiotics, treat flares with steroids, then consider biologic agents.”

Accelerated Infliximab Dosing in Acute Severe Ulcerative Colitis -plus one link

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A small retrospective study (n=50) suggests that more rapid induction with infliximab may improve response and lower colectomy rate in acute severe ulcerative colitis (UC).

Link: Accelerated Infliximab in Acute UC

Here’s the abstract:

Background & Aims

Administration of infliximab to patients with acute severe ulcerative colitis (ASUC) (rescue therapy) can reduce the rate of early colectomy (within 12 months), but long-term rates of colectomy are the same as those of the pre-biologic era for these patients. The half-life of infliximab is shorter in patients with ASUC than in patients with non-severe UC, so more frequent dosing might be required to produce a therapeutic effect.

Methods

We performed a retrospective analysis of 50 hospitalized patients who received infliximab for steroid-refractory ASUC at a single academic center from September 2005 through 2013. In 2011 an accelerated dosing strategy for infliximab was introduced; we compared outcomes of standard and accelerated dosing regimens. One group of patients (n = 35) were placed on a standard dosing regimen for infliximab and then given the drug at 0, 2, and 6 weeks and then every 8 weeks thereafter. A second group (n = 15) were placed on an accelerated regimen and received 3 induction doses of infliximab within a median period of 24 days. Rates of colectomy were compared between the groups during induction and follow-up periods.

Results

There were no differences between groups in median baseline levels of C-reactive protein, albumin, or hemoglobin. The rate of colectomy during induction therapy was significantly lower with the accelerated regimen (6.7%, 1 of 15) than with the standard regimen (40%, 14 of 35) (Fisher exact test, P = .039). The standard regimen was associated with shorter time to colectomy (log-rank test, P = .042). Among patients who completed induction therapy, subsequent need for colectomy was similar between the groups during the follow-up period. Multivariate analysis showed that factors independently associated with successful induction therapy were level of albumin (g/L) when the treatment began (P = .003) and the accelerated dosing regimen (P = .03).

Conclusions

In patients with ASUC, an accelerated infliximab induction strategy reduces the need for early colectomy. An intensified infliximab dosing strategy in response to clinical or laboratory signs of breakthrough inflammation merits consideration in prospective studies.

One other link: IBD and College: Do the two play nicely (from Jeremy Adler and UofM) -describes college transition issues for our IBD patients.  Probably the most important piece of advice: “Take your medicine.”  Many really good kids decide to see what happens off therapy, often to their detriment.

Increased Narcotic Usage in Pediatric Patients with IBD

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A summary from the AGA Journals Blog of a recent article highlights the increased use of chronic narcotics, not related to surgery, in pediatric patients with IBD.

Here’s a link:  Chronic Use of Narcotics in Children with IBD and here’s an excerpt:

Jessie P. Buckley et al used data from a large insurance claims database, collected from 2010 through 2011, to compare the prescription narcotic use among children (younger than 18 years old) with and without IBD who were not undergoing surgery. Buckley et al also searched for factors associated with narcotic treatment of pediatric patients with IBD.

Of 4344 children with IBD during the study period, 63% had Crohn’s disease, and 37% had ulcerative colitis.

Buckley et al found that 5.6% among children with IBD vs 2.3% in the general population received chronic narcotic therapy. Associations between IBD and narcotic use revealed a particularly high burden among children with concomitant anxiety or depression.

Cover of Clinical Gastroenterology & Hepatology

Cover of Clinical Gastroenterology & Hepatology –The pills look cool but wrong age depicted

Gut Microbiome, Crohn’s Disease and Effect of Diet

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At this past year’s NASPGHAN conference, Bob Baldassano indicated that a low-residue diet probably does not makes sense for the majority of patients with Crohn’s disease because it would not promote a ‘healthy’ gut microbiome.  Another article (Walter SS, Quiros A, et al. SOJ Microbiol Infect Dis 2014; 2: 1-13) supporting this argument has been published. (Thanks to Ben Gold for giving me this reference.)

In this study, the authors examined the gut microbiome from two healthy volunteers and compared them to six patients with Crohn’s disease (CD) (ages 16-50).  The CD cohort were in clinical remission and were not receiving probiotics.  Subjects were randomized to either a low-residue diet (LRD) or a specific carbohydrate diet (SCD).

Besides having some cool figures to explain their results, the key points:

  • The complexity of the gut microbiome was lower in IBD patients compared to healthy controls
  • Bacteroides fragilis was increased in fecal samples of IBD positive patients
  • There was a temporal response of gut microbiome to SCD with increased microbial diversity while the LRD diet was associated with a reduced diversity of the microbiome in patients with CD

While the number of patients participating in this study are low, the affects of these diets can still be measured due to the trillions of microbes in the gut microbiome.

Also noted: Church PC, Turner D, et al. Aliment Phamacol There 2015; 41: 153-66. “Systematic review with meta-analysis: magnetic resonance enterography for the detection of inflammation and intestinal damage in Crohn’s disease.”

How the gut micro biome may affect other diseases including Multiple Sclerosis: Study Hints Gut Microbiome Plays a Role in Multiple Sclerosis (Link to Gastroenterology & Endoscopy News)

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From NASPGHAN:  Introducing New Website for Teens with Inflammatory Bowel Diseases: JustLikeMeIBD.org  PRESS RELEASE

New York, NY- January 20, 2015 – The number of inflammatory bowel disease (IBD) patients in the U.S. has now increased to an estimated 1.6 million, with approximately 5 percent of that patient population under the age of 18. In response to the growing number of kids with IBD, the Crohn’s & Colitis Foundation of America (CCFA) along with the NASPGHAN Foundation for Children’s Digestive Health and Nutrition, has launched a new website called “Just Like Me” for teenagers with Crohn’s disease and ulcerative colitis.

The interactive site will feature stories and videos from teens with IBD as well as information on school, dating, stress, diet, and research.

 

 

What We Know Now: Therapeutic Drug Monitoring for Inflammatory Bowel Disease

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This blog has discussed the utility of obtaining drug levels for both biologic agents and thiopurines.  A recent article (Inflamm Bowel Dis 2015; 21: 182-97) provides a concise up-to-date review.

Here are the key points:

  • Primary nonresponse to anti-TNF therapy (PNR) “is most commonly defined as lack of improvement of clinical signs and symptoms after the induction phase leading to discontinuation of the drug.”
  • “We think that patients who respond but fail to achieve remission…are likely almost all due to insufficient drug.”
  • Table 2 provides a list of predicting factors, both negative and positive, for PNR.  This list includes genetic mutations (e.g.. IL23R, NOD2/CARD15 variant), mucosal gene expression, clinical factors (e.g. young age, isolated colitis, smoking, nonstricturing disease, concomitant immunomodulators) and serologic (eg. CRP, hemoglobin, and presence of pANCA).
  • Patients with PNR to a TNF antagonist, “despite therapeutic concentrations of drug and no anti-drug antibodies (ADA), would likely benefit from a switch to an alternative drug with a different mechanism of action.”
  • “Patients with a high baseline inflammatory load…and increased clearance of drug because of a high turnover would likely benefit from higher induction doses.”  This hypothesis has been proven in rheumatoid arthritis patients in which patients with high TNF concentrations had a clinical response to 10 mg/kg that was “significantly better than the response to 3 and 6 mg/kg of infliximab.”
  • Patients (with ADA) with an “early immunogenic response against the TNF antagonist are unlikely to respond to dose escalation and thus should be switched to another TNF antagonist, and it should be considered to give higher induction doses in combination with an IMM [immunomodulator] to reduce the risk of immunogenicity.”

Take-home message: New definition of primary nonresponse to anti-TNF agent: “a lack of improvement of objectively assessed signs of active inflammation at baseline, after the induction phase despite the presence of adequate concentrations of drug and the absence of anti drug antibodies.”

Also noted: “Surgical management of ulcerative colitis in the era of biologicals” Inflamm Bowel Dis 2015; 21: 208-10. Key point: “Sacrificing the non responsive diseased colon is an underused or unnecessarily delayed chance to normalize ..health and life.”  “Deconditioning of patient with unreasonably long escalations of ineffective medications adds to the morbidity of surgical intervention.”

“Automimmune Features are Associated with Chronic Antibiotic-refractory Pouchitis”Inflamm Bowel Dis 2015; 21: 110-20. Key point: “Microsomal antibody expression and elevated IgG4-positive plasma cell infiltration were independent risk factors” for chronic antibiotic-refractory pouchitis.”

Update on MOC (recent blog:Resistance to Maintenance of Certification | gutsandgrowth) American Board of Internal Medicine “We Got It Wrong” “We launched programs that weren’t ready and we didn’t deliver an MOC program that physicians found meaningful. We want to change that.”

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Not So Promising: FMT for Ulcerative Colitis

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After initial reports suggesting that fecal microbiota transplantation (FMT) may be helpful for ulcerative colitis (UC), more recent data suggest that it is not so promising (JPGN 2015; 60: 27-29, editorial 3).

In this open-label, prospective study of four patients, all boys aged 13-16 years, patients tolerated a single-dose FMT (via nasogastric tube) without adverse effects but there was no significant clinical or laboratory improvement.

The article provides a number of references regarding the experience of FMT for UC.

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