IBD Updates December 2019

SR Gupta et al. JPGN 2019; 69: 544-50.  This article reports on preliminary experience in 54 children who received external (non-hospital) infliximab infusions. The average age was 17.6 years. The authors noted no serious safety concerns.  Prior to arranging these infusions, the authors insisted on the following:

  • Infusion services had to guarantee pediatric trained nurses with PALS certification
  • Emergency medications had to be available
  • A plan for emergency communication was arranged
  • Postinfusion communication would occur with each infusion

BN Limketkai et al. Inflamm Bowel Dis 2019; 25: 1828-37.  This study, using Truven Health MarketScan database (2007-16) reviewed proactive or reactive mucosal monitoring after biologic initiation in IBD.  Early (< 6 months) proactive monitoring (88% endoscopy-based) was performed in 11% (n=2195/19,899) of patients with Crohn’s and 12.8% (925/7247) of patients with ulcerative colitis.

  • “Early proactive monitoring was associated with a reduction in disease-related complications for CD (aHR 0.90) and UC (aHR 0.87) and predominantly driven by a reduction in corticosteroid use.”
  • Another interesting finding was that ~40% of patients had biologic therapy initiated without assessment of mucosal disease activity within 6 months.
  • The authors state that disease monitoring is typically more useful in CD than UC because with the latter, cessation of bleeding and diarrhea appear to be adequate surrogates.
  • This study was not able to assess whether a biomarker like fecal calprotectin would be suitable due to its low utilization.

RZ Cohen, BT Schoen, S Kugathasan, CG Sauer. JPGN 2019; 69: 551-6. In this chart review, the authors identified anti-drug antibodies (ADA) in 24.8% (n=58) of patients undergoing therapeutic drug monitoring (n=234) with both infliximab and adalimumab.  54% of this group had antibody suppression with dose optimization. Of note, 37 patients had detectable ADA at time of initial drug monitoring. Dose optimization was 10 mg/kg every 4 weeks with infliximab or 40 mg weekly with adalimumab. Patients who were switched to a second anti-TNF agent (n=23) were not more likely to develop ADA to the second agent (small sample size). Also, the authors caution that in the five patients with ADA levels (>10 U/mL), dose optimization failed and patients required a therapeutic switch. My take: This study provides some useful information about the frequency of ADA.  My view is that the actual drug level is more critical than the presence of ADA; though, the presence of high ADA often precludes the ability to deliver a therapeutic drug level.

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

CCFA: Updates in IBD Conference (part 1)

My notes from a recent Georgia Chapter of CCFA’s conference. There could be errors of omission, transcription and/or errors in context based on my understanding.

Adam Cheifetz, MD Harvard School of Medicine

Optimizing IBD Treatments

  • Earlier treatment with effective therapies
  • Utilizing therapeutic drug monitoring

Goals are clinical and endoscopic remission

  • Imaging if not visible on endoscopy
  • Biomarker remission -adjunctive goal
  • Symptoms and endoscopy do not have good correlation in Crohn’s disease
  • Endoscopic healing associated with better outcomes
  • Treatment –>assessment –> adjust treatment if goal is not met

Biologic Agents:

  • First agent works best; TNF-exposed patients do not respond as well as TNF-naive patients to subsequent biologic
  • High rate of secondary loss of response

Therapeutic Drug Monitoring:

  • Combination therapy in Sonic study was associated with higher infliximab levels. It appears that optimized monotherapy is as effective as combination therapy (Colombel study).
  • Fistula treatment requires higher biologic levels
  • Lower biologic drug levels associated with development of antidrug antibodies
  • Proactive monitoring –recommended
  • Both infliximab and adalimumab are frequently underdosed, especially in pediatrics –>another reason for proactive monitoring
  • If sicker patients, consider checking TDM at week 10; less sick patients, reasonable to consider TDM at week 14

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.

Appropriate Proactive Therapeutic Drug Monitoring

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

Key Recommendations:

  • 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

1-4: Anti-TNFs:

  • 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.

 

Toronto Consensus Guidelines for Luminal Crohn’s Disease

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 . 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

Canadian Pediatric Guidelines for Crohn’s Disease

DR Mack et al. Gastroenterol 2019; 157: 320-48Full 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

Psoriasis Due to Infliximab –Latest Data

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.

Related blog posts:

Wahkeena Falls Trail, OR

Combination Therapy Study Points to Central Role of Adequate Drug Levels

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

Key findings:

  • 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