Costs of Biologics for Inflammatory Bowel Disease

A recent study examines the market share and costs of biologic therapies for inflammatory bowel disease:

Excerpt from abstract:

The average biologic-taking patient accounted for $25 275 PMPY in 2007 and $36 051 PMPY in 2015. The average paediatric biologic-taking patient accounted for $23 616 PMPY in 2007 and $41 109 PMPY in 2015. In all patients, the share of costs for biologics increased from 72.9% in 2007 to 85.7% in 2015 (81.7% in 2007 to 94.9% in 2015 in paediatrics).


The vast majority of costs allocated to out-patient IBD medications in the USA is attributed to increasing use of biologic therapies despite the relative minority of biologic-taking patients.

My take: Biologic therapies are costly but also very effective.

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The Original Anti-TNF Therapy: Thalidomide

A recent study (M Lazzerini et al. Clin Gastroenterol Hepatol 2017; 15: 1382-9) used data from 2 multicenter trials of 70 children to assess the efficacy of thalidomide in pediatric patients with refractory inflammatory bowel disease (37 with Crohn’s disease, 23 with ulcerative colitis)

Key findings:

  • 42 patients (60%) had clinical remission & 45 (64%) had clinical response at week 8
  • 38 patients (54%) had clinical remission or response at week 52. 29 of these patients had mucosal healing (no erosions or ulcerations) & 20 patients had histologic healing
  • 7 patients dropped out from study prior to 52 weeks due to side effects (n=5) or clinical relapse (n=2)

My take: I have not used thalidomide therapy and remain concerned about long term side effects (eg. peripheral neuropathy).  Though, the authors are correct that its safety “may be acceptable compared with the safety of other” treatments, especially if there are few remaining options.

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“Data-free Zone” and mHealth

A recent study (J Kamgno et al. NEJM 2017; 377: 2044-52) used an innovative cell-phone-based device (the LoaScope) to improve treatment of onchocerciasis (river blindness).

Background (summarized in editorial: pg 2088-90): Ivermectin has been distributed in Africa since 1988 to treat onchocerciasis; in fact, the 2015, Nobel Prize in Medicine was shared by the discoverers of ivermectin.  However, in 1996, it was recognized that central nervous system adverse events were occurring in ivermectin-treated patients with coexistent Loa loa infection.

Kamgno et al show that not treating patients with L loa counts >20,000 microfilariae per mL helps target ivermectin to those who will benefit.  The LoaScope identified 340 persons who were at high risk for serious adverse events; the authors estimate that 62 serious central nervous system complications and 8 deaths were avoided with this approach.

Despite the apparent success of this mobile Health (mHealth) application, a separate editorial cautions that most mHealth has little data to support its use (A Roess.  NEJM 2017; 377: 2010-11). Key points:

  • To date, more than 1200 mHealth tools or apps have been catalogued
  • Determining which are effective is difficult  With breastfeeding, there are >340 apps, yet only “15 had any evidence supporting their use, and that was from pilot evaluations.:
  • Most apps involve data collection and delivering health education messages.  The latter are usually one-way messages. “The evidence to support their rapid and widespread use is limited.”
  • mHealth in remote areas may enhance collaboration; though, practical infrastructure problems like poor wireless networks and unreliable electricity hamper their utility.
  • mHealth could improve point-of-care diagnostics. Current products include blood-glucose monitors, blood-pressure monitors, and electrocardiography
  • While many have suggested these apps will be cost-effective, these analyses typically do not evaluate the costs of misinformation and the diverse workforce requirements needed for implementation

My take (with help from editorial): mHealth tools are here and increasing.  Advances like the LoaScope for treating river blindness has been shown to improve outcomes.  Before recommending other mHealth tools, we need to insist on adequate evaluation or we will “arrive in an increasingly fragmented mHealth landscaped littered with poor-quality, unproven apps.”

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Sunrise at the Grand Canyon’s South Rim

Will We Still Need Liver Biopsies to Diagnose Biliary Atresia in a Few Years?

A recent study (C Lertudomphonwanit, R Moura, L Fei, Y Zhang, S Gutta, L Yang, KE Bove, P Shivakumar, JA Bezerra. Sci Transl Med. 2017; 9: eaan8462) may change how we diagnose biliary atresia (BA) and provides an insight into potential pathogenesis. Link to studyLarge-scale proteomics identifies MMP-7 as a sentinel of epithelial injury and of biliary atresia

Using large-scale proteomics, the authors screened 1129 proteins in a discovery cohort (n=70) of patients with BA.  They identified several proteins that were increased with BA. Matrix metalloproteinase-7 (MMP-7) was the lead biomarker.  Subsequently, they used two additional validation cohorts.  Human subjects were infants in enrolled in the Prospective Database of Infants with Cholestasis (PROBE) which is part of the NIDDK-funded ChiLDRen (

Key findings:

  • 76 proteins were significantly overexpressed or underexpressed in BA compared with children with intrahepatic cholestasis (IHC).
  • MMP-7 was more accurate than gamma glutamyltranspeptidase (GGT).  The combination of MMP-7 and GGT had a AUROC of 0.94 in validation cohorts.
  • The authors further studied the role of MMP-7 by immunostaining and found it primarily was detected in cholangiocytes of intrahepatic bile ducts in infants with BA.  It was also identified in a few hematopoietic cells.
  • MMP-7 expression in the liver did not correlate with fibrosis.
  • MMP-7 serum levels increased in neonatal mice after bile duct epithelial injury induced by intraperitoneal rotavirus administration.
  • Using a mice model, they found that a MMP-7 inhibitor (batimastat) could block the development of BA in a mouse model (in 86% of cases) compared with 0% in control mice.
  • Overall, the authors note that coupled with GGT, MMP-7 serum levels result in “sensitivity and specificity of 97 and 94% respectively, at optimal cutoff, which provided positive and negative predictive values of 85 and 99% respectively, if one considers the prevalence of BA of 25.9% among infants with conjugated hyperbilirubinemia.”

My take: More work is needed.  However, these values suggest that MMP-7 and GGT combined may be more accurate than a liver biopsy in the diagnosis of BA.

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South Kaibab Trail, Grand Canyon

More on PPIs and Kidney Disease & Brain Disease

The most recent information and perspective on proton pump inhibitors and kidney disease:

From AGA: More Data on PPI Use and Kidney Disease

An excerpt:

The most recent study related to PPIs and CKD was a meta-analysis by Wijarnpreecha et al. presented at the American Society of Nephrology annual meeting and published in Digestive Diseases and Sciences. They found that any use of PPIs was associated with a 33 percent relative increase in risk for CKD/ESRD whereas no such risk was seen with H2RAs.

Talking to Your Patients
  1. Inform patients that, while this study does raise some concern about long-term PPI use and the potential contributions to kidney disease, the study does not show that PPI use causes kidney disease. No decisions should be made in haste as a reaction to this study. A brief explanation of the meta-analysis may also be helpful. 
  2. Reassure patients that the benefits of using PPIs often outweigh the possible risks. Let them know that you prescribed a PPI for a clear-cut indication, in the lowest possible dose, and for an appropriate period of time (lowest dose, shortest time). 

From the published abstract:

Results: five studies (three cohort studies and two case-control studies) with 536,902 participants met the eligibility criteria and were included in the meta-analysis. We found that individuals with PPIs use had significantly increased the risk of CKD or ESRD when compared with non-PPIs users (pooled RR of 1.33, 95% CI, 1.18-1.51). There was no publication bias of overall included studies assessed by the funnel plots.

My take: (borrowed from the AGA) This is an association, not proof of a causal relationship. Patients who use PPIs differ at baseline than those who do not. For example, patients who use PPIs are more likely to have diabetes or hypertension than patients who do not use PPIs, and are more likely to use additional nephrotoxic medications. Large retrospective studies are unable to completely adjust for these baseline differences. These differences, rather than PPIs themselves, may explain the observed association.

Related study: DCF Klatte et al. Gastroenterol 2017; 153: 702-10.  In this retrospective analysis with more than 100,000 new PPI users (Swedish cohort), PPI users (compared to H2 blocker users) had an increased risk for doubled levels of creatinine with a HR of 1.26, and an increased risk of end-stage renal disease with HR of 2.40. The risk of chronic kidney disease was increased with higher cumulative PPI exposures.

Related study: Effects of PPI on dementia –recent large study shows no association: H Taipale et al. The American Journal of Gastroenterology(2017) 112, 1802–1808 (2017) doi:10.1038/ajg.2017.196.  (Thanks to Ben Gold for this reference. This study examined more than 70,000 Finnish patients with Alzheimer’s disease (AD) (2005-2011) and 280,000 controls.  Results: PPI use was not associated with risk of AD with 3-year lag window applied between exposure and outcome (adjusted odds ratio (OR) 1.03, 95% confidence interval (CI) 1.00–1.05). Similarly, longer duration of use was not associated with risk of AD (1–3 years of use, adjusted OR 1.01 (95% CI 0.97–1.06); ≥3 years of use adjusted OR 0.99 (95% CI 0.94–1.04)). Higher dose use was not associated with an increased risk (≥1.5 defined daily doses per day, adjusted OR 1.03 (95% CI 0.92–1.14)).

Sunrise over the South Rim at the Grand Canyon

Understanding the New Therapies for Spinal Muscular Atrophy

Pediatric gastroenterologists follow children with spinal muscular atrophy type 1 (Wernig-Hoffman disease) mainly due to feeding problems associated with the profound weakness. Two recent studies show promise for spinal muscular atrophy and are summarized in a “quick take” video: Quick Take NEJM video on SMA type 1

While these new therapies have improved the outcomes, long term data are needed.  With the adenovirus vector gene therapy, if the expression of the gene therapy declines, it may not be possible to do further infusions due to antibody development against the adeonviral vector.

With nusinersen, which has been approved for clinical use, the anticipated cost of $750,000 for the first year of therapy alone and ongoing need for intrathecal administration are problematic.

Incidental Brain Imaging Findings

A recent study (PR Jansen et al. NEJM 2017; 377: 1593-5) provides some useful insight into the issue of incidental findings with pediatric brain MRIs.  Between 2013-2015, the authors examined 3966 children (mean age 10.1 years) prospectively in an effort to identify influences on development. Key findings:

  • At least one incidental finding was present in 25.6%
  • Most commonly: Pineal gland cysts 16.8% of cohort, Arachnoid cysts 2.17%, Venous anomalies 1.59%, Chiari I malformations 0.63%, subependymal heterotopia 0.48%, partial agenesis of the corpus callosum 0.05%
  • 7 children (0.18%) has suspected primary brain tumors; 2 had neurosurgical treatment
  • Imaging findings requiring clinical followup was only 0.43%

A study CT scans in asymptomatic adults, mean age 63 years, (NEJM 2007; 357: 1821) also found a high incidence of abnormalities, including 7.2% with asymptomatic infarcts, 1.8% with aneurysm, and 1.6% with benign tumors.

My take: The frequency of these incidental findings in the pediatric population is surprising to me.  Having anything reported as abnormal on an MRI is likely very unsettling for parents and often for providers due to uncertainty regarding the significance.

Grand Canyon Sunrise and  then to the South Kaibab Trail (below)