Tag Archives: infliximab

Support for Step-Up Therapy and Thiopurines

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A retrospective study (H Bar-Yoseph et al. Clin Gastroenterol Hepatol 2017; 15: 69-75) indicated that thiopurine use before infliximab (IFX) was associated with the prevention of antidrug antibody formation in patients with Crohn’s disease.

The authors had 207 eligible patients which included 93 who received IFX monotherapy, 52 who received combination therapy after response to thiopurine, 34 who received IFX after lack of response to thiopurines (but continued with combination treatment), and 28 who received de novo combination therapy.  The total number of patients followed in these centers is much higher, but they excluded those with episodic infusions and for other reasons that could affect their conclusions.

Key findings:

  • Prior thiopurine therapy was associated with lower antidrug antibodies (ADA). At 1 year, past thiopurine responders had 19.3% ADA, past thiopurine failures had 16.1% ADA; both were much lower that the monotherapy rate of 46.6%  The de novo combination group had a rate of 21.9% which did not reach significance.
  • Interestingly, after the first 5 months, the de novo combination group did not develop further ADA but during the first 5 months the rate of ADA was quite similar to the monotherapy rate. This could be related to the notion that thiopurines may take 3-6 months to achieve full effect.
  • Combination therapy (compiled)  was associated with higher rates of clinical remission (58.8% vs 40.9%) and lower rates of active disease (8.8% vs. 21.5%).

Overall, this study showed high rates of ADA compared to many studies but the conclusions are similar to other published studies.  It could be that many of those with positive ADA were lower antibody levels and that many of these levels may not be clinically significant. The study has limitations mainly related to being a retrospective study.

My take: This study supports the following:

  1. Combination therapy is more effective than monotherapy
  2. Using an immunomodulator before starting infliximab may reduce ADA formation more effectively than starting combination therapy de novo.

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Disclaimer: These blog posts are for educational purposes only. Specific dosing/usage 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.

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Role of Biosimilars in Inflammatory Bowel Disease

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A cautionary note on biosimilars has been discussed in a recent review (DT Rubin et al. Gastroenterol & Hepatol 2016; 12: 741-51)

In the recently completed NOR-SWITCH study presented at the United European Gastroenterology Week 2016 meeting, “a total of 481 patients were recruited across 40 centers: all patients had been on stable treatment with the originator infliximab for at least 6 months…When looking specifically at IBD patients, disease worsening was noted in 21.2% of originator infliximab-treated patients and 36.5% of CT-P13-treated Crohn’s disease patients (n=155).”  The 15% difference did not reach statistical significance, but is concerning.  The authors state that “subtle postranslational modifications unique to the biosimilars may be sufficient to lead to antidrug antibody formation with associated loss of response.  Also, it is noted that this study did not include endoscopic evaluation.

The authors note that therapeutic monitoring worked with biosimilar product using available infliximab assays.

My take: We still have a lot to learn.  The preliminary message, until more studies are available, indicate that switching stable patients could increase risk of losing response.

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Puerto Rico

Puerto Rico

Safer Than You Think: Biologic Therapies for IBD and Risk of Infection and Malignancy

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While there have been a number of studies which have highlighted the potential risks of biologic agents, many studies have NOT identified any risk of infection or malignancy.

Another recent systematic review/meta-analysis (S Bonovas et al. Clin Gastroenterol Hepatol 2016; 14: 1385-97) provides reassuring data regarding the following biologics: infliximab, adalimumab, certolizumab, golimumab, natalizumab, and vedolizumab.

The authors identified 49 randomized placebo-controlled studies with 14,590 participants.

Key findings:

  • There was a moderate infection risk with odds ratio of 1.19 (19% increase in odds of developing an infection) and significant increase in opportunistic infections (eg. tuberculosis) OR 1.90
  • Risk of serious infections was NOT increased in patients treated with biologics with OR 0.89.  In studies with low risk of bias, the risk of serious infections had OR of 0.56.
  • No increase in malignancy risk was identified with OR 0.90 but the authors note that data was insufficient in terms of exposure and follow-up to be conclusive.

The authors note that the studies including in this review challenge some of the findings of observational studies. “However, observational studies lack the experimental random allocation of participants…the discrepancies between observational studies and randomized trial evidence might be explained by the inability of observational designs to fully address the complex and important differences between the IBD patients receiving and those not receiving biologics.”

Study limitations include “sponsorship bias -because the trials were supported by pharmaceutical companies and limited followup of 24 months. In addition, most of the trials in the meta-analysis were judged to be at high or unclear risk of bias because of their methodological characteristics.

My take: This study indicates that biologic therapies do not appear to increase the risk of serious infections and may not increase the overall risk of malignancy.

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Portland Fish Market

Portland Fish Market

 

 

What Happens When Infliximab Is Stopped in Patients with Ulcerative Colitis Remission

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‘If it ain’t broke, don’t fix it’

Perhaps, the above sentiment is needed for patients with ulcerative colitis who are doing well with infliximab therapy according to a recent study (G Fiorino et al. Clin Gastroenterol Hepatol 2016; 14: 1426-32).

In this multicenter retrospective cohort study, 111 patients with ulcerative colitis who had been in remission (>12 months) were followed after stopping infliximab (IFX) and compared with 82 controls who remained on therapy.  Here’s what happened (see Figure 1 in study):

  • Among those who discontinued IFX, 53 patients (47.7%) relapsed in the followup period.  This corresponded to an incidence of 23.3 per 100 person-years and with a median time to relapse of 3.6 years.
  • In comparison, for those who remained on IFX, 14 relapses (17.1%) occurred which corresponded to an incidence of 7.2 per 100 person-years at risk and with a median time to relapse of 7.6 years.
  • Thiopurine use after stopping IFX seemed to diminish the risk of relapse: 15.0 per 100 person-years compared with 31.2 per 100 person-years for those taking an aminosalicylate alone.
  • For those who restarted IFX, 77.1% had a response and 51.4% returned to remission; however, 17.1% had infusion reactions.

My take: In a real-life experience, stopping IFX in patients with ulcerative colitis who had been in sustained clinical remission resulted in a higher relapse rate.  This finding is consistent with other studies.

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The Lawn at University of Virginia

The Lawn at University of Virginia

Changes in the Use of IBD Biologic Therapy

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A recent study (W-J Lee et al. Inflamm Bowel Dis 2016; 22: 2410-17) offers a great deal of insight into changes in the use anti-Tumor Necrosis Factor Alpha (ant-TNF) therapy from 2009-2013 in patients ≤24 years.  The authors utilized databases with about 180 million people and identified 11,962 patients with inflammatory bowel disease (IBD).

Key findings:

  • 3300 of the 11,962 (27.6%) patients were treated with anti-TNF therapy.
  • Top-down treatment: 1298 of 3300 (39.3%) were treated with top-down therapy which was defined as usage of anti-TNF therapy within 30 days of first IBD medication prescription.  Interestingly, over the course of the study, there was a trend towards more top-down (versus step-up) therapy and shorter time to initiation of anti-TNF therapy. In 2009, 31.4% used a top-down approach compared with 49.8% in 2013.
  • Top-down therapy is associated with lower rates of corticosteroid use.
  • Infliximab dominant anti-TNF: infliximab was the anti-TNF in 89.2% of patients less than 12, 82.3% of patients 12-17, and 55.1% of patients 18-24.  Adalimumab accounted for the vast majority of the other TNF users. Though, the authors note a trend towards increasing use of adalimumab in both adult and pediatric patients in a separate study (Park KT et al. Inflamm Bowel Dis 2014; 20: 1242-49)
  • Cotherapy: thiopurines and methotrexate were used as cotherapy in 13.5% and 7.2% of top-down group compared with 54.8% and 14.6% respectively in step-up strategy.
  • Drug therapy among non-TNF users: 25.4% (2199) received a thiopurine, 79.3% (6871) received a 5-aminosalicylate, and 2.3% (201) received methotrexate.
  • Anti-TNF therapy discontinuation: Using top-down strategy 69.2% persisted on infliximab at 12 months and 56.8% persisted at 24 months.  In comparison, using step-up approach with infliximab, it was 72.7% at 12 months and 64.0% at 24 months.  The numbers were quite similar with all the anti-TNF agents indicating that step-up approach had significantly lower rate of anti-TNF discontinuation. The authors speculate that one factor could be use of cotherapy or possibly other adverse reactions.

The authors explain some of the limitations of their study in its reliance on databases, particularly with regard to misclassification.  However, in my opinion, these limitations do not affect any of the trends that the authors are able to document.

My take: For most of my patients, I have preferred to continue to utilize cotherapy  and/or step-up therapy because I think there is likely to be a more durable anti-TNF response.  The fairly small differences in anti-TNF durability have huge implications for those  who lose anti-TNF responsiveness given the limited treatment options.

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Briefly Noted: Inflammatory Bowel Disease Updates

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Gut Microbial Diversity is Reduced in Smokers with Crohn’s Disease. JL Opstelten et al. Inflamm Bowel Dis 2016; 22: 2070-77.  This study compared stools from 21 nonsmoking patients with Crohn’s disease (CD) with 21 smokers with CD.  Smoking was accompanied by a reduced relative abundance of multiple genera.  My take: It is unclear whether smoking’s effect on the microbiome directly contributes to worsened outcomes or whether the changes in the microbiome are only an epiphenomenon.  Regardless, smoking increases the likelihood of worse outcomes in CD.

A Systematic Review on Infliximab and Adalimumab Drug Monitoring Levels, Clinical Outcomes and Assay. F Silva-Ferreira et al. Inflamm Bowel Dis 2016; 22: 2289-2301. This review selected 20 studies from an initial query of 1654 articles. Key points:

  • Different studies are difficult to compare due to distinct assays with different limitations. Thus, specific cutoffs are based on the specific assay used.
  • The authors state that proactive monitoring may be helpful at week 6, 14, 30 and 54 for infliximab.  They recommend checking infliximab level and antidrug antibodies in those with loss of response, mucosal ulceration or elevated biomarkers (eg. CRP, Fecal calprotectin).

Small Pediatric IBD Studies …Briefly Noted

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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.

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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.

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From KT Park’s Twitter Feed:

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Biologic Exposure Prenatally and Perinatally

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The widespread use of anti-TNF therapy for inflammatory bowel disease has improved clinical outcomes including fewer surgeries, hospitalizations, and complications.  One consequence of this usage has been the exposure of infants to biologics due to their usage by their mothers during pregnancy.  A recent study (M Julsgaard et al. Gastroenterol 2016; 151: 110-19) explores this topic further.

In this study, the authors prospectively followed 80 pregnant women: 36 received adalimumab & 44 infliximab. In addition, 39 received concomitant thiopurine therapy.

Key findings:

  • The time from last exposure to anti-TNF agent correlated inversely with the concentration of these drugs in the umbilical cord and in mothers at the time of birth.
  • Median ratio for infant: mother drug concentration at birth was 1.21 for adalimumab and 1.97 for infliximab.
  • Mean time for drug clearance: 4.0 months for adalimumab and 7.3 months for infliximab. Drugs were not detected after 9 months of life for adalimumab and after 12 months of life for infliximab.
  • No increased risk of adverse pregnancy outcomes were identified; preterm birth was low (n=3 or 3.8%). 48% of women experienced a disease relapse during pregnancy.
  • In this small study, the relative risk for infection was 2.7 in infants exposed to combination therapy.  Benign courses of viral infections were noted in 16 (20%) of the entire cohort and of bacterial infections in 4 (5%).

The authors recommend avoidance of live virus vaccines in biologically-exposed infants for up to 1 year unless drug clearance has been documented. Currently, this would affect only rotavirus vaccination.

My take (borrowed from editorial pgs 25-26): “For now, the sum of evidence seems to support continued use of anti-TNF therapy in pregnancy when clinically indicated and, despite measureable levels in offspring, there does not seem to be a significant clinical consequence.”

Related study: “Adverse Pregnancy Outcomes among women with inflammatory bowel disease: a population-basd study from England” Inflamm Bowel Dis 2016; 22: 1621-30. The authors identified 1969 pregnancies from a total of 364,363 singleton pregnancies.  Women with Crohn’s had increased preterm births with an Odd ratio of 1.42, babies with low birth weight (OR 1.39); women with ulcerative colitis had only a small increase risk in preterm birth (absolute risk <2.7%).

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Gold Medal Winner: Infliximab (anti-TNF competition)

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According to a recent retrospective study, (S Singh et al. Clin Gastroenterol Hepatol 2016; 14: 1120-29), infliximab outperformed its rivals.  In the spirit of the recent olympics, we’ll give infliximab a gold medal in the anti-TNF category.

Here’s the play-by-play:

This study used an administrative claims database with more than 100 million US enrollees.  In total, there were 3205 biologic-naive patients with Crohn’s disease (CD) with a mean age of 41 years.  All of the participants had not received a biologic agent for at least 12 months prior to their first study dose (between 2006-2014). In addition, the authors excluded patients who had a concomitant diagnosis which could necessitate a biologic, including rheumatoid arthritis, ankylosing spondylitis, and psoriasis.

Race details:

  • Compared to adalimumab-treated patients, inlfiximab-treated patients had a lower risk of CD-related hospitalization (aHR [adjusted Hazard Ratio] 0.80), abdominal surgery (aHR 0.76), and corticosteroid use (aHR 0.85)
  • Compared to certolizumab pegol-treated patients, infliximab-treated patients had a lower risk of hospitalization (all-cause) (aHR 0.70), and CD-related hospitalization (aHR 0.59).
  • All agents had comparable risk of serious infections

Post-race analysis:

Was this a fair race (ie study)? Definitely.  If anything, this study may have underestimated the benefit of infliximab.  Due to trouble with confounders across retrospective studies, it may be that infliximab was chosen preferentially among sicker patients.

My take: There is limited data on comparative effectiveness of anti-TNF agents.  This retrospective study  indicates that infliximab is likely superior to its competitors.  Definitive proof would necessitate a head-to-head live-action (prospective) competition.

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