B Feagan et al. Systematic review: efficacy and safety of switching patients between reference and biosimilar infliximab. Alim Pharm Ther 2019 Jan;49(1):31-40. “While available data have not identified significant risks associated with a single switch between reference and biosimilar infliximab, the studies available currently report on only single switches and were mostly observational studies lacking control arms. Additional data are needed to explore potential switching risks in various populations and scenarios.”
MP Pauly et al. Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment with Tumor Necrosis Factor Antagonists. Clin Gastroenterol Hepatol 2018; 16: 1964-73. Using data from 8887 adults, this retrospective review found “HBV reactivation iin 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy.”
D Lauritzen et al. Pediatric Inflammatory Bowel Diseases: Should We Be Looking for Kidney Abnormalities? Inflamm Bowel Dis 2018; 24: 2599-2605. In a cross-sectional cohort of 56 children with IBD, the authors found 25% “had either previously reported kidney disease or ultrasonographic signs of chronic kidney disease.” The authors note that plasma cystatin C is a useful biomarker for glomerular filtration as it less dependent on nutritional status; it is increased in the setteing of a decline in GFR.
L Pouillon et al. Mucosal Healing and Long-term Outcomes of Patients with Inflammatory Bowel Diseases Receiving Clinic-Based vs Trouhg Concentration-Based Dosing of Infliximab. Clin Gastroenterol Hepatol 2018; 16: 1276-83. This retrospective study with patients who completed TAXIT maintenance phase found that patients who received trough-based infliximab dosing had a lower discontinuation rate of infliximab compared with clinic-based dosing (2 of 21 [10%] vs. 10 of 27 [37%]). However, both groups had >75% of patients able to continue infliximab for more than 3 years after the trial.
N Ouldali et al. Early Arthritis Is Associated With Failure of Immunosuppressive Drugs and Severe Pediatric Crohn’s Disease Evolution. Inflamm Bowel Dis 2018; 24: 2423-30. In this retrospective study with 272 patients with Crohn’s disease, 23.9% (n=65) developed arthritis and this was associated with failure of immunosuppressive drugs with OR of 6.9 after 2 years. In this study, immunosuppressive drugs refers to thiopurines and methotrexate. By the completion of study, a much greater proportion of those with arthritis required biologic treatment (76% vs 32%, OR 4.3)
A recent retrospective study (E Dreesen et al Clin Gastroenterol Hepatol 2018; 16: 1937-46) with 179 consecutive patients (66 with ulcerative colitis, and 113 with Crohn’s disease) found that vedolizumab (VDZ) trough concentrations were correlated with response.
- VDZ trough >30 mcg/mL at week 2, >24 mcg/mL at week 6, and >14 mcg/mL during maintenance were associated with effectiveness endpoints including endoscopic healing, physician global assessment and biochemical response (based on CRP).
- Median VDZ trough levels during induction were 27.7 mcg/mL at week 2, 27.4 mcg/mL at week 6. With standard dosing, the maintenance VDZ trough was 13.5 mcg/mL at week 14
- Higher BMI and more severe disease, based on CRP, albumin, and/or hemoglobin, were associated with lower VDZ trough levels and lower probability of mucosal healing (P<.05).
Interestingly, in the discussion the authors note that VDZ troughs above 3 mcg/mL completely saturate α4β7 intergrin. This physiologic phenomenon is hard to reconcile with data showing better response with higher VDZ levels. The authors note that “at present, there are not enough data in our study to support the role for TDM to guide clinical decision-making on dose escalation for vedolizumab.”
My take: This study implies that VDZ levels may help predict response but are not necessarily helpful in determining whether dose escalation is warranted.
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A recent observational study (N Williet et al. Clin Gastroenterol Hepatol 2017; 15: 1750-7) provides some important information about where we are heading with regard to therapeutic drug monitoring (TDM) with vedolizumab (VDZ).
This study enrolled 47 consecutive patients with either Crohn’s disease (CD, n=31) or ulcerative colitis (UC, n=16). In those without a clinical response at week 6, an additional dose of 300 mg of VDZ was administered at week 10.
- VDZ levels were higher in responders than in nonresponders, which is in agreement with previous studies ( (NEJM 2013; 369: 711-21, NEJM 2013; 369: 699-710)
- A low therapeutic drug level as early as week 2 (<24.5 mcg/mL) and at the end of induction (week 6) (<18.5 mcg/mL) was associated with the need for drug optimization within 6 months in all patients
- All patients with a level <19.0 mcg/mL at week 6, regained a secondary response after optimization at week 10.
- The authors note that in the GEMINI trial, anti-VDZ antibodies were detected in 56 of 1434 patients (3.7%). In this cohort, no anti-VDZ were detected using the same methods.
My take: Low trough levels of VDZ at week 6 are associated with the need for drug optimization/increased dosing.
The ability to measure drug levels has changed how we think about refractory medical disease, particularly in patients with inflammatory bowel disease. Prior to the availability of therapeutic drug monitoring (TDM), in some situations poor response to therapy could be ascribed to variability in host immune response. Now, it is clear that many cases of refractory medical disease are due to insufficient drug level. TDM allows for dose individualization to target the right amount of medication.
TDM has an accepted role in anti-TNF therapy. Now, a study (R Battat et al. Clin Gastroenterol Hepatol 2017; 15: 1427-34) extends the concept of TDM to ustekinumab. This study which took place between 2014-2015 examined ustekinumab use in 62 patients with refractory Crohn’s disease (CD). Ustekinumab dosing: 90 mg SC at weeks 0, 1, and 2 for induction, then 90 mg every 4 or 8 weeks for maintenance.
- At week 26, 80.7% of patients had a clinical response, 66.1% had a clinical remission, and 58.9% had an endoscopic response.
- In those with an endoscopic response, the mean trough concentration of ustekinumab was 4.7 mcg/mL compared with 3.8 mcg/mL those without an endoscopic response.
- Using a trough threshold of 4.5 mcg/mL at week ≥26, 75.9% had an endoscopic response whereas those with a level below this trough had a 40.7% endoscopic response
- The authors did not detect antibodies to ustekinumab in any patient. The authors note that ustekinumab has low immunogenicity and prior UNITI studies indicated antibody formation in 0.2% after induction and 2.3% at 1 year.
- Unlike combination therapy with anti-TNF therapy, “concurrent immunosuppressive therapy does not explain low immunogenicity, as only 25.8% of patients received these and had neither improved clinical outcomes nor higher drug concentrations.”
Thus far, no clinical studies have demonstrated improved clinical outcomes with dose escalation in the setting of low ustekinumab levels. A prospective trial would be helpful.
My take: This study shows promising results for ustekinumab for refractory CD. The low immunogenicity indicates that monotherapy is likely appropriate. A target level of >4.5 mcg/mL indicates a higher likelihood of response.
Related blog posts:
In support of Dr. Baldassano’s talk (NASPGHAN17: Treat to Target and Tight Control), this poster from the Cincinnati group (A Mulgand et al) showed that therapeutic drug monitoring has been associated with improved clinical remission scores (80% to 87%). Correlation with a more objective marker of remission along with longer followup is now needed. One of the authors, Dana Dykes, has joined our group in Atlanta!
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This blog entry has abbreviated/summarized these presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.
Here is a link to postgraduate course syllabus: NASPGHAN PG Syllabus – 2017
Therapeutic Drug Monitoring
Andrew Grossman Children’s Hospital of Philadelphia
The topic of therapeutic drug monitoring, both reactive and proactive, has been discussed numerous times on this blog. This talk provided a good review of this topic.
- Greatest predictor of infliximab treatment failure was a low infliximab (<0.9 mcg/mL at anytime or <2.2 mcg/mL at 14 weeks) (Castelle et al Am J Gastro 2013; 108: 962-71)
- Low level antibodies to infliximab may be transient in ~28% and may be overcome with escalation of therapy
- Tissue levels of infliximab (and other agents) may be inadequate despite good serum levels
What if anti-TNF fails
Maria Oliva-Hemker Johns Hopkins University School of Medicine
- Discussed prevalence of problem with anti-TNF failures and main options: vedolizumab, ustekinumab, and surgery
- Vedolizumab can take a while to work, particularly for Crohn’s disease
- Limited data in pediatrics for these newer agents
- Ustekinumab has some preliminary data indicating benefit with anti-TNF induced psoriaform rashes
- Newer agents also likely to need therapeutic drug monitoring
- Overall, ustekinumab and vedolizumab have good safety profiles at this point
Prevention of postoperative Crohn’s disease
Miguel Regueiro University of Pittsburgh
- Rationale for postoperative preventative treatment: high rate of recurrent disease which can be silent for several years despite progressive damage to GI tract
- Large study (PREVENT) to compare infliximab and placebo after surgery. Primary endpoint was clinical recurrence (was endpoint demanded by FDA) even though clinical recurrence can be a late finding. Endoscopic recurrence rate was a secondary endpoint.
Dr. Regueiro’s approach
- Low risk patient –repeat scope at 6 months post-op, then every 1-3 yrs if no disease and Rx with anti-TNF or immunomodulator in those with endoscopic recurrence
- Moderate risk patient -possible use of thiopurine or use the ‘low risk’ approach
- High risk patient-combination therapy and if doing well for several years, consider monotherapy
- In pediatrics, the postoperative management is unclear due to difficulty with risk stratification. If postoperative treatment is not given, consider colonoscopy 3-4 months afterwards and treat if recurrence. Then could use calprotectin every 3 months to monitor and when >50, likely will need to be treated
PREVENT Trial Data:
From Healio Gastro: AGA releases guidelines on therapeutic drug monitoring in IBD
Key points from Healio Gastro for Adult Patients with IBD:
- Reactive monitoring: for patients with a flare or active symptoms: “For patients on maintenance therapy with infliximab, adalimumab or certolizumab pegol who flare after initially responding, if trough levels are below 5 µg/mL, 7.5 µg/mL or 20 µg/mL, respectively without anti-drug antibodies or with low-titer antibodies, then it may be reasonable to try optimizing the index therapy (escalating anti-TNF agent by increasing dose, shortening interval and/or adding immunomodulator)”
- Proactive monitoring: the guideline states that “no recommendation can be made regarding routine proactive TDM in patients with quiescent IBD being treated with anti-TNFs, as this is a critical knowledge gap in need of further study…careful and selective use of proactive TDM could be beneficial, but current evidence for its routine use is limited and its overall benefits remain uncertain”
- Thiopurines: the guideline suggests TPMT testing of enzymatic activity or genotype before adults with IBD start treatment with thiopurines.
- New biologics: the guideline does not address therapeutic drug monitoring in patients treated with Entyvio (vedolizumab, Takeda) or Stelara (ustekinumab, Janssen) due to a lack of available data.
Reference: JD Feuerstein et al. Gastroenterol 2017; 153: 827-34. Technical review: NV Casteele et al. Gastroenterol 2017; 153: 835-57.
My take: Therapeutic monitoring has become widespread and is quite helpful. My impression is that most pediatric gastroenterologists have adopted both proactive and reactive monitoring.
Related blog posts:
Looking towards the top of John Rock Hike, near Brevard, NC