Category Archives: inflammatory bowel disease

Pediatric Home and Office Biologic Infusions -What is Needed

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A recent clinical report (E Barfield et al. JPGN 2018; 66: 680-86) will be influential.  This guideline is from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.  Congratulations to my partner, Chelly Dykes, who is one of the coauthors.

Full text: Assuring Quality for Non-Hospital Based Biologic Infusions in Pediatric Inflammatory Bowel Disease: A Clinical Report from the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

For many years, our office has had an office-based infusion center which has provided infusions in a safe and cost-effective manner.  Recently, there have been some situations in which home-based infusions have been proposed either to lower costs and/or for convenience.  This report succinctly describes the hurdles that need to be addressed before recommending this treatment pathway. As noted below, patient safety encompasses a great deal more than infusion reactions. Delays in infusions (which can increase risk of loss of response) due to reactions and lapses in communication are additional issues.

Recommendation 1: Home- or office-based infusions should ensure safe administration of the biologic infusion, provide reliable execution of infusion-related orders (eg, laboratories for therapeutic drug monitoring, dose optimization protocols, etc), and be equipped to recognize and respond to potential complications.

  • Infusion reactions:  ” Infusion reactions associated with infliximab and vedolizumab can range from mild reactions such as fever and chills, dyspnea, pruritus, or urticaria (in approximately 5%–10%), to severe reactions including anaphylaxis, convulsions, and hypotension (<1%)”
  • Emergencies: “In the event of an urgent or emergent reaction during home- or office-based infusions, the in-home services agency (IHSA) nurse needs to be able to contact the appropriate ordering medical team member expeditiously by phone or pager to review/clarify specific concerns or needs to have an established clear policy on how to proceed with managing the reaction.” 
  • Communication: “We identified the lack or inconsistency of on-call coverage by the primary medical team when home- or office-based infusions occur as a significant barrier to safely initiating or continuing home- or office-based infusion programs. Difficulty in reaching a knowledgeable team member is a breach in reliable care and represents serious patient risk.”
  • Related work: “In addition to administering the biologic infusion, executing all other infusion-related orders is an important safety consideration. Implementing unique home infusion protocols is linked to treatment efficacy.”  

Recommendation 2: Pediatric home- or office-based infusions, particularly for patients 12 years and younger, should be staffed by a pediatric nurse professional with Pediatric Advanced Life Support (PALS) certification and clinical experience with pediatric patients.

Recommendation 3: Evidence-based standard of care for biologic therapy maximizing effectiveness and treatment sustainability should be established before initiating home or office-based infusions.

Recommendation 4: Home- or office-based infusion pathways that decrease opportunity loss for patients and families and deliver high-quality, patient-centered care should be supported and reproduced.

Recommendation 5: Pediatric gastroenterologists should ensure appropriate shared liability with IHSAs to deliver high-quality care in home-based infusions for children by executing pragmatic steps as outlined below:

  1. “Document discussion with the patient and family about the indication, risks, and adverse event management …
  2. Refer the patient to an accredited, licensed IHSA based on patient’s insurance coverage. If no accredited, licensed IHSA for the pediatric patient exists, this is grounds for not initiating home- or office-based infusions…
  3. & 4. Use an infusion protocol… with clear directives on recognition of signs/symptoms of reactions and administration of reaction medications and use of EMS or parent transport to an emergency room.
  4. Maintain accurate documentation and communication of therapy type, dose, and frequency.
  5. Provide a reliable communication mechanism for the IHSA to notify provider of changes or infusion-related events
  6. Regularly reviewing ongoing IHSA performance with regard to delivery of services, accurate laboratory ordering and turnaround time, safety and quality concerns and timely redressal of these issues.
  7. Switch to another IHSA if the performance reliability is unsatisfactory. …we acknowledge that changing IHSAs may be difficult.”

Recommendation 6: A more equitable division of labor should be established to offset increased administrative burden placed on the pediatric gastroenterologist and medical team to effectively facilitate and maintain home- or office-based infusions, especially when driven by payer-mandated policies.

Recommendation 7: …Among patients receiving home- or office-based infusions, unreliable follow-up care with the provider as scheduled is grounds for discontinuation of home- or office-based biologic therapy.

Recommendation 8: A proper appeals process should be in place to prevent cost transference from payer to patient in payer-mandated decisions for home- or office-based infusions.

Our office practice:

  • Emergencies: In our office, there is always one physician dedicated to being available to assess patients who are receiving infusions.  This helps insure safety and in addition, helps to make sure that minor medical problems do not needlessly postpone important treatment.
  • Documentation: With our office-based infusions, each infusion is documented by the administering nurse.  This documentation along with labs are embedded in the medical record (EPIC) to help modify treatment.
  • Communication: In our office, prior to each infusion, each patient’s chart is reviewed and specific orders are given.  This assures that needed blood tests/imaging, additional treatments (eg. iron infusion), insurance authorizations, necessary followup, and personalized adjustments are made.  This type of communication needs to be replicated for home-based infusions; hence, the use of home-based infusions could result in a huge increase in uncompensated work for the treating physician.

My take: In my experience, office-based infusions can be provided safely and in a cost-effective manner.  While the convenience of home-based infusion is desirable, before implementing broadly, issues regarding communication, safety protocols, and documentation to allow modifications in therapy need to be proactively addressed. Families may not realize some of the complexities involved in managing infusions and how these issues could affect their child’s long-term response to biologic therapy.

Related blog posts:

The following image relates to another convenience-related health trend:

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.

Interchangeability, Immunogenecity and Infliximab Biosimilars

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A recent study (G Fiorino et al. IBD 2018; 24: 601-6, editorial by KH Katsanos et al 465-6) provides more data on “full interchangeability” in regards to infliximab (IFX) and biosimilars CT-P13 and SB2. Full abstract below.

Key finding in study:

  • Antibodies to infliximab (ATI) cross-reacted with any type of IFX or IFX-biosimilar

Points from the editorial:

  • “The landmark NOR-SWITCH randomized controlled trial showed that 1-time switching from RMC [Remicade] to CT-P13 is not inferior to continued treatment with the infliximab originator…there are no data regarding multiple switches…Consequently, cross-switching (switching between 2 biosimilars), reverse switching (switching from biosimilar to its originator) or multiple/repeated switching is not currently recommended.”
  • This study, however, shows that “if you have already developed antibodies to 1 infliximab product, there is no point in switching to another infliximab product.”

Abstract:

Background: Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2.

Methods: Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naïve patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearman’s coefficient and percentages of agreement were used to study the correlation between each assay.

Results: In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearman’s 0.98 to 1.0, P < 0.0001).

Conclusions: ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

My take: In patients doing well with IFX, switching to a biosimilar is not currently recommended.  In patients naive to IFX, use of IFX or biosimilar is expected to have similar efficacy.

Related study: B Kang et al. IBD 2018; 24: 607-16.  This prospective study of 36 pediatric patients did not identify any significant differences in efficacy…or immunogenicity after switching from IFX to CT-P13.

Related blog posts:

IBD Shorts -March 2018

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T Piester et al. Inflamm Bowel Dis 2018; 24: 227-34.  Stanford group published data on 49 patients which highlight the utility of a point of care (mobile) infliximab (IFX) dosing calculator: http://med.stanford.edu/gastroenterology/infliximab-calc/  In their cohort, the IFX calculator recommendations were for IFX dosing escalations in 13% of the 222 calculations.  Overall, the IFX calculator was part of a larger quality initiative (QI) to achieve therapeutic drug levels >5 mcg/mL which occurred in 81% during the QI period.

JC deBruyn et al. JPGN 2018; 66: 268-77. This was a retrospective review of infliximab (IFX) in pediatric Crohn’s disease with 180 children. The authors determined that IFX had good therapeutic durability with 91% remaining on IFX after 2 years of treatment.

FS Macaluso et al. Inflamm Bowel Dis 2018; 24: 394-401. In this 2-year study, among 630 patients, 46 had a modestly-dosed immunomodulator added to anti-TNF therapy due to loss of response (31 to IFX or biosimilar, 10 with adalimumab, and 5 with golimumab).  This resulted in a steroid-free remission in 15 (32.6%) and a clinical response in 6 (13.0%). The immunomodulators were azathioprine in 15, 6-mercaptopurine in 5, methotrexate in 20, and mycophenolate mofetil in 6. The median doses for immunomodulators were 1.64 mg/kg/day, 0.84 mg/kg/day, 15.6 mg/week, and 1500 mg/day respectively.

C Reenaers et al. Clin Gastroenter Hepatol 2018; 16: 234-43. This retrospective study examined 7-year outcomes from a STORI cohort of 115 adults with Crohn’s disease (CD) with combination therapy who had infliximab withdrawal after achieving sustained remission. Among those restarting infliximab, treatment failed in 30.1%; 70.2% “had no failure of de-escalation strategy.” Major complicatins occurred in 18.5% of patients. Risk factors for failure included anemia (Hgb <12.5), increased white blood cell count >5.0, and upper GI location of CD.

VM Merrick et al. JPGN 2018; 66: 274-80.  This UK “real-life” review of 37 centers and 524 patients (429 with Crohn’s disease) found a remarkably poor rate of documentation.  They could determine the remission rates in only 71 of these patients (65% 46 of 71).  Thus, in the real-world, presumably in adults and children, most institutions do not know their remission rates.  While the determination of remission still relies on imperfect measures, the centers who participate in ImproveCareNow have high documentation rates –this is also a real-world experience as more than 29,000 patients and more than 900 pediatric GI doctors participate.

Paris Classification Quiz and Explanation

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At one of our ImproveCareNow population management meetings, Dr. Chelly Dykes reviewed the Paris Classification and frequent misconceptions in using this system.  To illustrate this point, I am going to post 6 Quiz Slides and then follow that with the answers and explanation.  These quiz slides were derived from previous ImproveCareNow community meetings.

Answers:

  1. A
  2. B (macroscopic disease counts –erythema alone does not count)
  3. A (macroscopic disease counts)
  4. B (not ileum only unless colonic disease extends beyond cecum)
  5. F (though B acceptable)
  6. F (though B acceptable)

Related blog posts:

Briefly noted: Mongersen, Aprepitant, and Anesthetic Outcomes

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BG Feagan et al. Gastroenterol 2018; 154: 61-4.  In this study of GED-0301 (Mongersen), an antisense oligodeoxynucleotide affecting Smad7, was randomly assigned to 63 patients with Crohn’s disease (160 mg/day).  Endoscopic improvement was observed in 37%  at week 12. Clinical remission (CDAI<150) was noted in  32% (4 weeks of Rx), 35%  (8 weeks of Rx) and 48% (12 weeks of Rx). No new safety signals were noted.

Related blog posts:

PJ Pasricha et al. Gastroenterol 2018; 154: 65-76.  First of all, I have to say that I like the visual abstracts in many Gastro studies.  In this randomized, double-masked “APRON” study of 126 patients with chronic nausea or gastroparesis receiving Aprepitant, a neurokinin-1 receptor antagonist, or placebo, the key findings were the following:

  • Aprepitant did not reduce symptoms of nausea significantly compared to placebo
  • Apreptiant-treated patients had improvements in secondary outcomes of symptom severity for nausea (1.8 vs 1.0, P=.005 on Gastroparesis Clinical Symptom Index) and overall symptoms (1.3 vs. 0.7, P=.001)

Related blog post:

B Bielawska et al. Gastroenterol 2018; 154: 77-85. Using data (administrative databases) and propensity matching from more than 3 million outpatient colonoscopies (2005-2012), the authors noted that the use of anesthesia assistance (AA) was associated with an increased risk of aspiration pneumonia (OR 1.63) but not perforation (OR 0.99). Though this study is limited by its retrospective design and reliance on administrative data, the authors state “the potential for residual confounding by indication for AA [is] extremely unlikely, especially because AA use in Ontario appears to be driven by institutional policy or business model rather than by patient factors.”

Related blog posts:

Bright Angel Trail

Iron Metabolism Improves after Anti-TNF Therapy for Crohn’s Disease

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A previous study has shown that low vitamin D levels improved with anti-TNF therapy for Crohn’s disease in the absence of supplemental vitamin D.  Similarly, a recent study (MA Atkinson, MB Leonare, R Herskovitz, RN Baldassano, MR Denburg. JPGN 2018; 66: 90-4) showed improvement in iron metabolism with anti-TNF therapy.

In 40 children and adolescents with Crohn’s disease, the authors measured serum hepcidin-25 and hemoglobin at baseline and then 10 weeks after anti-TNF therapy.

Key findings:

  • Median hepcidin concentrations decreased (27.9–>23.2 ng/mL) and mean hemoglobin increased (10.6–>10.9).
  • Disease activity and markers of inflammation also decreased.

My take: This study shows that improvement in inflammation is associated with meaningful improvement in anemia.  However, most patients will need additional treatment for anemia, particularly as anemia may be related to blood loss in addition to anemia of chronic disease/inflammation.

Related blog posts:

 

Crohn’s Disease Diagnosis Identified After Colectomy in Presumed Ulcerative Colitis

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A recent retrospective single-center study (I Jones et al. JPGN 2018; 66: 69-72) identified a high rate of inflammatory bowel disease (IBD) reclassification.  From 2003-2014, 570 children were diagnosed with IBD, including 190 with ulcerative colitis.  29 of these patients underwent colectomy.  Among this select group, 24% (7/29) were subsequently reclassified as having Crohn’s disease, sometimes several years later.  Only two of the seven reclassified patients were younger than 10 years of age at the time of colectomy.

My take: This rate of Crohn’s disease following colectomy is higher than in previous reports (generally 5-10%).  The larger point is that the diagnosis of ulcerative colitis is more uncertain in the pediatric population, particularly in those in the first decade of life.

Related blog posts:

Near Bright Angel Trail, Grand Canyon

Increasing Cost/Use of Biologic Therapies for Inflammatory Bowel Disease

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As noted in a previous blog post (Changes in the Use of IBD Biologic Therapy), there has been an increased use of biologic therapy early in the course of patient’s with inflammatory bowel disease (IBD). Another retrospective study (H Yu et al AP&T 2018; 47: 364-70 -thanks to Ben Gold for this reference) examines the market share and costs of biologic therapy for IBD using the Truven Marketscan Commercial Claims and Encounters database (2007-2015).  This database consists of out-patient and in-patient pharmaceutical claims of approximately 40-50 million privately insured patients each year from patients from all 50 states (U.S.).

Key findings:

  • Among 415,405 patients with IBD (188,842 with Crohn’s, 195,183 with ulcerative colitis, 31,380 with indeterminate IBD), the proportion using biologics increased over the 9-year period (2007-2015); overall, the market share increase was from 7.1% (2007) to 20.5% (2015).
  • There were 28,797 pediatric patients with IBD (17,296 with Crohn’s, 9368 with ulcerative colitis, and 2133 with indeterminate colitis). The overall market share in pediatric patients was the highest, increasing from 19.1% to 45.9%.
  • For all patients with Crohn’s disease (CD) the proportion receiving biologic therapy increased from 21.8% to 43.8%.  For patients with ulcerative colitis (UC), the proportion increased from 5.1% to 16.2%.
  • Per-member per-year (PMPY) costs increased. “The average biologic-taking patient accounted for $25,275 PMPY in 2007 and $36,051 PMPY in 2015.”  This was similar in the pediatric population, going from $23,616 PMPY in 2007 to $41,109 PMPY in 2015.
  • The share of costs of medicines: the costs of biologics as a share of the total increased from 72.9% in 2007 to 85.7% in 2015. 95% of the pharmacy costs in children with IBD are attributed to biologics.

My take: This trend of increasing use of biologics and their associated costs is going to continue due to their effectiveness. While there are direct costs related to these medications, the net cost is unclear as they can prevent hospitalizations and surgeries. In addition, by helping to spare corticosteroids and increasing response rates, biologic therapies improve quality of life, minimize opportunity loss, and optimize long-term health outcomes.

Bright Angel Trail, Grand Canyon

 

Ketchup Packet Ingestion–Crohn’s Disease Mimic

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In the category of –“I have not seen that before”…

Link: NY Daily News Women diagnosed with Crohn’s disease actually had ketchup packet in her intestines for six years (Thanks to my son for pointing out this story)

An excerpt:

A woman believed she was suffering from Crohn’s disease for six years until doctors performed surgery and discovered a ketchup packet in the lining of her intestine.

The 41-year-old patient had symptoms consistent with the serious bowel disease — including acute abdominal pain and bloating lasting up to three days — but she did not respond to the standard treatments.

Case study reference: Visagan R, et al. BMJ Case Rep 2013. doi:10.1136/bcr-2013-009603

Related blog post: Add it to the list

 

CALM Study: Tight Control Improves Outcomes in Crohn’s Disease

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A recent study (JF Colombel et al. Lancet 2017; http://dx.doi.org/10.1016/S0140-6736(17)32641-7 ) shows that “tight control” improves outcomes in Crohn’s disease.  This study was alluded to in a previous post: CCFA 2017 Updates (part 2)

Background: The CALM study was an open-label, randomized study.  122 adult patients were randomized to typical clinical management and 122 patients received “tight control” in which treatment was modified by fecal calprotectin (≥250 mcg/g) and CRP (≥ 0.5 mg/dL) values in addition to clinical symptoms.

Treatment was escalated in both groups in a stepwise manner.  Initial treatment was with adalimumab induction and then every other week. If patient did not meet treatment objectives, which differed in the groups, then adalimumab would be given every week, and then, if still needed, azathioprine would be added. Interestingly, both groups had ~25% of participants who were smokers which is known to worsen outcomes.

Key Findings:

  • Mucosal healing (CDEIS <4) was significantly improved in tight control group at week 48: 46% vs. 30%.
  • Similarly, steroid-free remission based on CDAI <150 was better in tight control group compared with standard treatment at week 48: 59.8% vs. 39.3%.  Endoscopic response was 50.8% compared with 40.2% respectively.

My take (1st part borrowed from authors): “Tight control of inflammation in patients with Crohn’s disease, with objective markers of disease activity  and clinical symptoms to drive treatment decisions, achieved better endoscopic and clinical outcomes than conventional care based on symptoms alone.” Yet, there are a large number who do not respond adequately and better treatments in these patients are needed.

As an aside, these response rates based on objective markers are far lower than the remission rates claimed by ImproveCareNow; thus, while ImproveCareNow is forward-thinking and helping improve outcomes with inflammatory bowel disease, we need to be careful about citing remission rate trends that are not directly linked to objective markers.