IBD Briefs June 2020

SA Draiweesh et al. Safety of Combination Biologic and Antirejection Therapy Post-Liver Transplantation in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis 2020; 26: 949-59. In this case series of 19 patients, 14 who had liver transplantation for PSC, there was no increased risk of serious infections among patients receiving biologic therapy in combination with antirejection medications.

A Malian et al. Pedictors [sic] of Perianal Fistula Relapse in Crohn’s Disease. Inflamm Bowel Dis 2020; 26: 926-31. In this retrospective study with 137 patients, fistula relapse rates were not different in patients receiving infliximab or adalimumab (P = 0.66). In patients treated by anti-TNF at inclusion, discontinuation of anti-TNF therapy (odds ratio 3.49, P = 0.04), colonic location (OR 6.25, P = 0.01), and stricturing phenotype (odds ratio 4.39, P = 0.01) were independently associated with fistula relapse in multivariate analysis.

M-H Wang et al. Unique Phenotypic Characteristics and Clinical Course in Patients With Ulcerative Colitis and Primary Sclerosing Cholangitis: A Multicenter US Experience. Inflamm Bowel Dis 2020; 26: 774-81. Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001).  In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar.

B Barberio et al. Matrix Metalloproteinase 3 Predicts Therapeutic Response in Inflammatory Bowel Disease Patients Treated with Infliximab. Inflamm Bowel Dis 2020; 26: 756-62. Retrospectively, 73 IBD patients who had received IFX for at least 1 year were enrolled: 35 patients were responders and 38 were nonresponders at 52 weeks…The MMP3 levels were similar at baseline (19.83 vs 17.92 ng/mL), but at postinduction, patients who failed to respond at 1 year had significantly higher levels than patients who responded (26.09 vs 8.68 ng/mL, P < 0.001); the difference was confirmed at week 52 (29.56 vs 11.48 ng/mL, P < 0.001)…The MMP3 serum determination may represent an early marker of response to infliximab.

 

What Happens After The First Anti-TNF Agent Doesn’t Work?

A recent intriguing retrospective study (MJ Casanova et al. Inflamm Bowel Dis 2020; 26: 606-16, editorial 617-18) examines a large cohort (n=1122) who received either a 2nd or 3rd anti-TNF agent.  This relied on the ENEIDA registry which is a prospectively maintained registry from Spain with 11,866 patients. In this study, clinical remission was gauged with a Harvey Bradshaw Index score of ≤4 in Crohn’s disease (CD) or a partial Mayo score of ≤2 in ulcerative colitis (UC).

Key findings:

  • 45% of patients achieved remission with the second anti-TNF at 12 weeks (short-term); loss of response was 19% per patient-year subsequently. Patients with intolerance to the first drug had higher remission rates compared to those who switched due to secondary failure (52% vs 42%) or primary failure (52% vs 39%).
  • Among the 45% who responded to a second anti-TNF agent, 77% maintained remission at 1 year following switch.
  • There was similar initial response to a second anti-TNF among patients with CD and UC: 46% vs 41%, though patients with UC were more likely to lose efficacy.
  • Combination therapy was associated with a higher likelihood of failure, HR 2.4 (possibly as an indicator of more aggressive disease)
  • Among the 71 patients who progressed to a 3rd anti-TNF agent, 55% achieved remission at 12 weeks. 

Discussion:

  • The authors in their discussion not that “primary failure is considered a class effect phenomenon…However, our results indicate that remission may still be achieved with a second anti-TNF in approximately 50% of patients.”
  • The editorial notes that the results need to be interpreted with caution.  Therapeutic drug monitoring (TDM) which is not incorporated in this study is crucial in optimizing response and switching.  “Importantly, nearly two-thirds of patients with therapeutic drug levels in the study form the Mayo Clinic had no active inflammation.  Thus, a change in therapy would be inappropriate in this population.”

My take: This study indicates that a 2nd anti-TNF agent can be effective in those who do not respond to a 1st.  At the same time, careful assessment including TDM is needed when changing agents, especially in view of the limited number of effective therapies.

Related blog posts:

From Atlanta Botanical Garden

Video for Patients: Benefits and Risks of IBD Treatment & Risks of Untreated IBD

A recent study (NE Newman, KL Williams, BJ Zikmunde-Fisher, J Adler. JPGN 2020;70: e33-36) highlights work to communicate the benefits and risks of the treatment for inflammatory bowel disease (IBD) along with the risks of untreated IBD.  “We developed a simple video aid to illustrate competing risks associated with medications and underling disease in context of inflammatory bowel disease…Those who viewed the video aid had more realistic perceptions than those who did not view it.”

Here is a link to the ~13 minute online video: IBD: Risk of Disease and Treatments

Overall, the presentation is very helpful and thoughtful.  I think this would be an excellent overview for families.  For practitioners, a few points that could benefit from some nuance are noted below some screenshots.  It is worth stating that the authors had started this project a few years ago and some of the points below are related to more information that has emerged.

In the section of treatment benefits (above), the presentation suggests that thiopurines (azathioprine, 6-mercaptopurine) and methotrexate both are effective in about 50%; this is probably an overestimate; in addition, methotrexate as monotherapy is definitely less effective (if effective at all) for ulcerative colitis .  Also, it would be worthwhile to indicate that anti-TNF monotherapy with therapeutic drug monitoring may help achieve similar benefits as dual therapy.

In the section of colon cancer, the authors provide useful data that current treatments lower this risk substantially.  It is notable that more recent reports suggest that there have been improvements in the rates of colon cancer associated with IBD.

Overall, the section on lymphoma is very good.

In the section on other complications, the presentation suggests that there may be impaired wound-healing with anti-TNFs.  I think this risk is overstated in this slide. Also, I think the risk of severe infection with thiopurines is a little bit higher than stated; though, this can be mitigated with careful monitoring.

I think this summary slide could be improved by noting that the overall risk of serious cancers is likely lowered by treating IBD.  Since colon cancer is a fairly common cancer and IBD treatment reduces the risk, this likely outweighs the increased risk of other cancers (eg. lymphoma) which are much less common.

Another link to video: https://tinyurl.com/IBDTreatments

Related 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.

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