This blog post and tomorrow’s post highlights two articles on proactive therapeutic drug monitoring (pTDM) for inflammatory bowel disease. The first article (K Papmichael et al. Clin Gastroenterol Hepatol 2019; 17: 1655-68) summarizes a meeting of 13 international IBD specialists who reached consensus on 24 statements after a review of the literature.
Full Text Link: Appropriate Therapeutic Drug Monitoring of Biologic Agents for Patients With Inflammatory Bowel Diseases
- For anti-tumor necrosis factor (anti-TNF) therapies, proactive TDM was found to be appropriate after induction and at least once during maintenance therapy, but this was not the case for the other biologics.
- Reactive TDM was appropriate for all biologic agents both for primary non-response and secondary loss of response
Background/Rationale for pTDM:
- “Numerous studies have demonstrated a positive correlation between serum biologic drug.concentrations and favorable therapeutic outcomes”
- “Low or undetectable drug concentrations can lead to immunogenicity and treatment failures”
- “TDM…is an important tool for optimizing biologic therapy…Data suggest that pTDM, with drug titration to a target trough concentration, performed in patients with clinical response/remission can also improve the efficacy of anti-TNFs”
Table 4 Scenarios of Applying Therapeutic Drug Monitoring of Biological Therapy in Patients With Inflammatory Bowel Disease
- It is appropriate to order drug/antibody concentration testing in responders at the end of induction for all anti-TNFs.
- It is appropriate to order drug/antibody concentration testing at least once during maintenance for patients on all anti-TNFs.
- It is appropriate to order drug/antibody concentration testing of anti-TNFs at the end of induction in primary non-responders.
- It is appropriate to order drug/antibody concentration testing for all anti-TNFs in patients with confirmed secondary loss of response.
5-8: Vedolizumab -agreement only on ordering TDM in non-responders or those with loss of response
9-12: Ustekinumab -agreement only on ordering TDM in non-responders or those with loss of response
From Table 5: Biological Drug Concentrations and Anti-Drug Antibodies When Applying Therapeutic Drug Monitoring in Inflammatory Bowel Disease
- Infliximab: 15. In the presence of adequate trough drug concentrations, anti-drug antibodies are unlikely to be clinically relevant.
- Infliximab: 19. The minimal trough concentration for infliximab post-induction at week 14 should be greater than 3 μg/mL, and concentrations greater than 7 μg/mL are associated with an increased likelihood of mucosal healing.
- Adalimumab: 22. The minimum drug concentration at week 4 for adalimumab should at least be 5 μg/mL. Drug concentrations greater than 7 μg/ml are associated with an increased likelihood of mucosal healing.
- Certolizumab: 24 & 25: The minimum concentrations for certolizumab pegol at week 6 should be greater than 32 μg/mL and 15 μg/mL during maintenance.
- Golimumab 26 & 27: The minimum drug concentration at week 6 for golimumab should at least be 2.5 μg/mL and 1 μg/mL.during maintenance
My take: This article provides extensive literature to reinforce their recommendations. Most of the trough levels mentioned are minimum levels that need to be achieved.
The recommendations from the Canadian Association of Gastroenterology for luminal Crohn’s Disease in adults were published in two journals. R Panaccione et al. Clin Gastroenterol Hepatol 2019; 17: 1680-1713 and R Panaccione et al J Can Assoc Gastroenterol. 2019 Aug; 2(3): e1–e34.
Full text link : Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Luminal Crohn’s Disease
A few of the 41 statement recommendations:
- 6. In patients with mild to moderate ileal and/or right colonic Crohn’s disease, we suggest oral budesonide beginning at 9 mg/day as first-line therapy to induce complete remission. GRADE: Conditional recommendation, low-quality evidence
- 20. In patients with moderate to severe luminal Crohn’s disease with risk factors of poor prognosis, we recommend anti-TNF therapy (infliximab, adalimumab) as first-line therapy to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
- 23. In patients with active Crohn’s disease, when starting anti-TNF therapy, we suggest it be combined with a thiopurine or methotrexate over monotherapy to improve pharmacokinetic parameters. GRADE: Conditional recommendation, very low-quality evidence for infliximab, very low-quality evidence for adalimumab
- 29. We suggest against switching between anti-TNF therapies in patients who are doing well on anti-TNF therapy. GRADE: Conditional recommendation, low-quality evidence
- 30. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend vedolizumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
- 34. In patients with moderate to severe Crohn’s disease who fail to achieve complete remission with any of corticosteroids, thiopurines, methotrexate, or anti-TNF therapy, we recommend ustekinumab to induce complete remission. GRADE: Strong recommendation, moderate-quality evidence
- 37-41: Authors against the use of probiotics, omega-3 fatty acids, marijuana, naltrexone and enteral nutrition/diet therapies.
Crater Lake and Wizard Island
DR Mack et al. Gastroenterol 2019; 157: 320-48. Full Text: Canadian Association of Gastroenterology Clinical Practice Guideline for the Medical Management of Pediatric Luminal Crohn’s Disease
“When the consensus group met in October 2017, the most recent consensus guidelines for the treatment of CD in pediatric patients were those from” ESPGHAN/ECCO in 2014 with data from June 2013. Thus, the guideline attempts to provide more updated information and recommendations based on incorporating the latest studies.
The authors provide 25 consensus statements. Here are a few of interest:
- Recommendation 9: In patients with CD, we suggest exclusive enteral nutrition to induce clinical remission (Recommendation 6 recommends steroids as a treatment for clinical remission; adult Canadian guidelines recommended against using exclusive enteral nutrition)
- Recommendation 11: In patients with CD in remission, we suggest that if partial enteral nutrition is used it should be combined with other medications to maintain clinical remission.
- Recommendation 20: When starting infliximab in males, we suggest against using it in combination with a thiopurine.
- Recommendation 24: In patients with moderate to severe CD who fail to achieve or maintain clinical remission with anti-TNF–based therapy, we suggest ustekinumab to induce and maintain clinical remission.
- Recommendation 25: In patients with CD, we recommend against cannabis or derivatives to induce or maintain remission.
In addition, the authors provide 13 statements with no recommendations -here are two of them:
- No consensus J: When starting infliximab in females, the consensus group does not make a recommendation (for or against) regarding combining it with a thiopurine to maintain a durable clinical remission.
- No consensus L: In patients with CD who have achieved a clinical remission with anti-TNF therapy, the consensus group does not make a recommendation (for or against) regarding assessment for mucosal healing within the first year to determine the need to modify therapy.
Crater Lake, OR
Briefly noted: O Courbette et al. JPGN 2019; 69: 189-93. In a retrospective review, among 147 children with inflammatory bowel disease treated with infliximab (IFX) (123 CD, 24 UC), 20 patients (13.6%) developed psoriaform rashes. 14 of 20 were in remission when skin rashes (especially on scalp) occurred and rash developed at median of 355 days. In this cohort, all were controlled by local steroids; no patients required IFX discontinuation.
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Wahkeena Falls Trail, OR
A recent study (JF Colombel et al. Clin Gastroenterol Hepatol 2019; 17: 1525-32) examines the effect of combination therapy and drug levels in achieving corticosteroid-free remission at week 26 (CSFR26).
The authors performed a post hoc analysis from 206 patients with Crohn’s disease (CD): 97 monotherapy with infliximab & 109 with combination infliximab/azathioprine
- The proportions of patients achieving CSFR26 were not significantly greater among those receiving combination therapy vs monotherapy within the same serum infliximab concentrations
- Mean trough infliximab concentrations in the combination therapy were higher than for monotherapy: 3.54 mcg/mL vs. 1.55 mcg/mL
- Higher levels of antidrug antibodies were seen with monotherapy: 35.9% vs 8.3% of those with combination therapy. Antidrug antibodies were detected only in those with lowest quartile of infliximab trough levels.
My take: This study indicates that combination therapy’s higher efficacy is due to favorable pharmacokinetics rather than drug synergy. If good infliximab trough levels can be achieved with infliximab monotherapy, this may obviate the need for combination therapy. The uncertain factor is whether closer attention to trough levels will minimize the development of antidrug antibodies as effectively as the use of combination therapy.
Related blog posts:
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.
Sagrada Familia, Barcelona
RM Najarian et al. JPGN 2019; 68: 835-40. This retrospective study found microscopic/’backwash’ ileitis in 16% (17/105) of patients with new-onset ulcerative colitis. This occurred predominantly in patients with pancolitis (82%). The authors note that the term “backwash ileitis” was derived from an unproven hypothesis that the inflammation was related to retrograde contact with inflammatory substances, though some now consider ileal involvement as a secondary involvement “akin to the upper tract inflammation that can be seen in a subset of patients with UC.” The authors recommend that isolated histologic inflammation of the ileum should “not be construed as being diagnostic of either ‘indeterminant colitis’ or CD [Crohn’s disease].”
K van Hoeve et al. JPGN 2019; 68: 847-53. This retrospective study of 35 children found that higher infliximab levels during induction was associated with higher rates of clinical and biologic remission at 52 weeks. Groups at risk for lower troughs included patients with a lower weight and/or lower hemoglobin level.
Rafaela Flores Calderon by Antonio Maria Esquivel, Museo del Prado (Image in Public Domain)
A recent retrospective study (A Favale et al. Comparative Efficacy of Vedolizumab and Adalimumab in Ulcerative Colitis Patients Previously Treated With Infliximab Inflammatory Bowel Diseases, izz057, https://doi.org/10.1093/ibd/izz057 Published: 01 April 2019) suggests that vedolizumab is more effective for ulcerative colitis with secondary infliximab failure.
Here’s the abstract:
Adalimumab (ADA) and vedolizumab (VDZ) have shown efficacy in moderate to severe ulcerative colitis (UC) patients who failed infliximab (IFX). Although, a comparative efficacy evaluation of ADA and VDZ in this clinical setting is currently missing.
The aim of this study is to compare the efficacy of ADA and VDZ in patients affected by UC who failed IFX.
Clinical records of UC patients from 8 Italian IBD referral centers who failed IFX and were candidates to receive either ADA or VDZ were retrospectively reviewed. The primary end point was therapeutic failure at week 52. Secondary end points included therapy discontinuation at weeks 8, 24 and 52, the discontinuation-free survival, and safety.
One hundred sixty-one UC patients, 15 (9.2%) primary, 83 (51.6%) secondary IFX failures, and 63 (39.2%) IFX intolerants were included. Sixty-four (40%) patients received ADA and 97 (60%) VDZ as second line therapy. At week 52, 37.5% and 28.9% of patients on ADA and VDZ, respectively, had therapeutic failure (P = 0.302). However, the failure rate was significantly higher in the ADA group as compared with VDZ group among IFX secondary failures (48.0% ADA vs 22.4%VDZ, P = 0.035). The therapy discontinuation-free survival was significantly higher in the group of IFX secondary failures who received VDZ as compared with ADA at both the univariate (P = 0.007) and multivariate survival analysis (OR 2.79; 95% CI, 1.23–6.34; P = 0.014). No difference in the failure and biologic discontinuation-free survival was observed in the IFX primary failure and intolerant subgroups.