Category Archives: inflammatory bowel disease

Ustekinumab Over Vedolizumab as 2nd Line Agent for Crohn’s Disease

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A recent study: Ustekinumab is associated with superior effectiveness
outcomes compared to vedolizumab in Crohn’s disease patients with prior failure to anti-TNF treatment. VBC Biemans et al. Aliment Pharmacol Ther 2020; 52: 123-134.  Thanks to Ben Gold for this reference.

Methods: Crohn´s disease patients, who failed anti-TNF treatment and started
vedolizumab or ustekinumab in standard care as second-line biological, were
identified in the observational prospective Dutch Initiative on Crohn and
Colitis Registry.  128 vedolizumab- and 85 ustekinumab-treated patients fulfilled
the inclusion criteria. Median age in the cohorts were 37 and 39 respectively.

Key findings (at 52 weeks):

  • After adjusting for confounders, ustekinumab-treated patients were more likely to achieve corticosteroid-free clinical remission (odds ratio [OR]: 2.58, 95% CI: 1.36-4.90, P = 0.004), biochemical remission (OR: 2.34, 95% CI: 1.10-4.96, P = 0.027), and combined corticosteroid-free clinical and biochemical remission (OR: 2.74, 95% CI: 1.23-6.09, P = 0.014).
  • Safety outcomes (infections: OR: 1.26, 95% CI: 0.63-2.54, P = 0.517; adverse events: OR: 1.33, 95% CI: 0.62-2.81, P = 0.464; hospitalisations: OR: 0.67, 95% CI: 0.32-1.39, P = 0.282) were comparable between the two groups

My take: This study indicates that ustekinumab is likely a more effective 2nd line agent for Crohn’s disease.

Related blog posts:

IBD Update -July 2020

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X Roblin et al. Gut 2020; DOI: 10.1136/gutjnl-2019-319758 Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial. Key Findings:

  • Rates of clinical failure and occurrence of unfavourable pharmacokinetics were higher in monotherapy compared with combination therapy
  • At 24 months, survival rates without clinical failure and without appearance of unfavourable pharmacokinetics were respectively 22% versus 77% and 22% versus 78% (p<0.001 for both) in monotherapy versus combination therapy

RC Ungaro et al. Clin Gastroenterol Hepatol 2020; 18: 1152-60.  The authors retrospectively analyzed 3178 patients with Crohn’s disease and found that stopping mesalamine therapy in individuals who were starting biologic therapy did NOT increase their risk of adverse clinical events.  They caution that their findings should be validated in a prospective study.

J Wang et al. AP&T. https://doi.org/10.1111/apt.15766. Full Text: Risk factors and treatment outcomes of peristomal pyoderma gangrenosum in patients with inflammatory bowel disease Key finding: “Complete resolution with topical corticosteroids and calcineurin inhibitors alone were low (14% and 13% respectively). Higher rates of complete resolution were reported with anti‐tumour necrosis factor (TNF) agents (63%) and surgical interventions (80%).”

B Verstockt et al. Clin Gastroenterol Hepatol 2020; 18: 1142-51. The authors found that expression of 4 genes in colon tissue could be used to predict which patients will enter endoscopic remission with vedolizumab therapy.  Given the increasing number of expensive therapies for IBD, the ability to predict likely success with treatment rather than selecting empirically would be a huge advance.

ST Leach et al. JPGN 2020; 70: 580-5. The authors found that fecal calprotectin was overall the best fecal biomarker for pediatric Crohn’s disease (=156 patients); however, FA12  (aka S100A12) at 5 mcg/g predicted mucosal healing with greater specificity (87% vs 70%) –though this is related in part to the cut-off values. For calprotectin to have greater specificity (>90%), a cut-off of <100 mcg/g lowered the sensitivity to 63%. FA12 also performs better in younger children as calprotectin levels are higher in this age group in healthy children.

How Very Early Onset-Inflammatory Bowel Disease is Different, Plus One

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A recent retrospective study (JR Kelsen et al. Inflamm Bowel Dis 2020; 26: 909-18) compares children diagnosed with inflammatory bowel disease at different age points and their outcomes.  During a 9 year study span (2008-16), there were 229 subjects diagnosed as very-early onset (<6 years, VEO), 221 diagnosed as intermediate onset (6-10 years), and 521 diagnosed as older onset (> 10 years)

Key findings:

  • VEO-IBD patients were significantly more likely to have had a diverting ileostomy and colectomy than the older patients.  Diverting ileostomy rates: 12.2%, 4.1%, and 1.2% respectively.  Colectomy rates: 7.4%, 4.1%, and 1.7% respectively.
  • Ileocecal resections were significantly higher in the older-onset IBD population. In the older group, these resections were noted in 64/521 (12.2%) compared to 1/229 (0.4%) in the VEO group and 10/221 (4.5%) in the intermediate group.
  • VEO-IBD patients had higher medication failure rates at 1 year into treatment and were more frequently readmitted to the hospital. For infliximab (IFX), failure rates were 62.4% for VEO subjects compared to 14.6% for older-onset subjects.  For adalimumab, the respective rates were 53.2% vs. 7.2%.
  • Targeted therapy was successfully used almost exclusively in the VEO-IBD population

My take: Children with VEO-IBD have a more severe disease course than older children.  Since monogenetic disorders occur in ~8% of the VEO population, targeted therapies are more likely; however; ~2% of older children also have a monogenetic disorder and as such, targeted therapy could be important in this group as well.

Related review article: J Ouahed et al. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis 2020; 26: 820-842.  This is a useful review.  A couple of key points:

  • “There are no quality studies assessing the use of nutritional approaches in VEO-IBD”
  • Stem Cell Transplantation NOT efficacious in these disorders (per Table 3): TTC7A, STXBP2, IKBKG (NEMO)

Related blog posts:

Can Microscopic Colitis Lead to Crohn’s Disease or Ulcerative Colitis?

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A recent prospective cohort “ESPRESSO” study (H Khalili et al. Gastroenterol 2020; 158: 1574-83) from 1990-2017 examined the risk of incident inflammatory bowel disease (IBD) in subjects with microscopic colitis, n=13,957 (& each matched with 5 controls). ESPRESSO = Epidemiology Strengthened by histoPathology Reports in Sweden.

Key findings:

  • In the microscopic colitis group, there were 323 incident cases of ulcerative colitis (UC) and 108 cases of Crohn’s disease (CD)
  • Mean times to diagnosis were 3.2 years for UC and 3.3 years for CD
  • Microscopic colitis was associated with an aHR of 12.6 for CD and 17.3 fo rUC
  • The absolute excess risk compared to matched control over a 10-year period were 2.6% for UC and 0.9% for CD

My take: Individuals with microscopic colitis are at increased risk of developing UC and CD.

Related blog post/related article:

 

IBD Briefs June 2020

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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.

 

“No Solid Conclusions” for Alternative/Complementary Therapies for Inflammatory Bowel Disease

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In this clinical review (N Chande et al Inflamm Bowel Dis 2020; 26: 843-51) assess evidence from Cochrane reviews of four popular nontraditional treatments for inflammatory bowel disease (IBD):

  • Fecal Microbiota Transplantation (FMT)
  • Nutritional Therapies including Enteral Nutrition (EN)
  • Naltrexone for Crohn’s Disease (CD)
  • Cannabis for IBD

So what does the literature have to say about these treatments:

  • FMT: FMT for mild to moderate ulcerative colitis (UC) increased the proportion of patients achieving clinical remission. “However, the number of included studies was small and the quality of evidence was low.”  Other problems included uncertainty regarding serious adverse events and short duration of followup.
  • “As a result, no solid conclusions [the authors did not indicate this as a pun] can be drawn at this time.”
  • Nutritional Therapies: For remission in CD, “EN may be more effective than corticosteroids in children, although the opposite was true in adults.”
  • “Exclusion diets did not promote clinical remission or reduce clinical relapse in UC”
  • “The overall certainty of evidence in these studies were generally very low, largely due to sparse data.”
  • Naltrexone for Crohn’s Disease (CD): “The paucity of data makes it impossible to draw any firm conclusions about the effectiveness and safety” of low dose naltrexone.
  • Cannabis for IBD: “The risk of adverse events was significantly higher in cannabis-treated patients”…though these events were generally mild (eg. sleepiness, confusion, nausea).
  • “The results of these studies suggest that cannabis is not effective for the treatment of IBD”  This conclusion is limited by the small number of patients in prior studies.  Cannabis may be helpful as an adjunct for some symptoms though this “warrants further study.”

Related blog posts:

 

 

Ionizing Radiation Exposure in Adults with Inflammatory Bowel Disease

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From The Onion:

In the largest reported cohort to date, GC Nguyen et al (Inflamm Bowel Dis 2020; 26: 898-906) describe the ionization radiation exposure (IRE) in individuals (≥18 years) with inflammatory bowel disease (IBD).

Methods: N=72,933 with IBD,1994-2016. During 1st 5 yrs after diagnosis, IRE was estimated in a retrospective matched cohort in Ontario.

Key findings:

  • IBD patients were exposed to nearly 6-fold IRE due to abdominal imaging compared to controls: 18.6 mSv vs 2.9 mSv
  • Patients with CD had higher IRE than UC: 26 mSv vs 12 mSv (P<0.001).  CD patients were more likely to have >50 mSv exposure (15.6% vs 6.2%) and >100 mSv 5.0% vs 2.1%
  • Women were less likely to have high IRE compared to males
  • Residents in the poorest neighborhoods were 27% more likely to have IRE >100 mSv.  Socioeconomic status was an independent factor after accounting for comorbidities. The authors speculate that this could be related to increased use of emergency rooms where they may be more likely to receive a CT.
  • The use of CT scan began to decline after 2007…likely explained by the rise of MRE studies.

While strict guidelines on IRE are lacking, the International Commission on Radiological Protection has suggested that occupational exposure (eg. nuclear workers) should be limited to <100 mSv over 5 years and not more than 50 mSv in a single year.

My take: We need to continue efforts to reduce IRE due to concerns about subsequent secondary malignancies. This likely means avoiding CT for non-emergencies and working with our ED colleagues to think carefully about lifetime IRE in IBD patients.

Related blog posts:

Additional references:

  • -AJR 2001; 176: 289-96. Estimated risks of radiation-induced fatal cancer from pediatric CT
  • -Br J Radiol 2012; 85: 523-28.  Justification of CTs -some not needed
  • -AJR 2010; 194: 868-73.  Lower CT radiation doses in pediatric patients.  ‘Image gently’
  • -Arch Intern Med 2009; 169: 2078-86.

From LA Times:

 

1st Cases of COVID-19 in Pediatric Inflammatory Bowel Disease –All Mild

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A recent case series, D Turner et al. JPGN June 2020 – Volume 70 – Issue 6 – p 727-733 doi: 10.1097/MPG.0000000000002729: Full text: Corona Virus Disease 2019 and Paediatric Inflammatory Bowel Diseases

  • Eight PIBD children had COVID-19 globally, all with mild infection without needing hospitalization despite treatment with immunomodulators and/or biologics. ..
  • Preliminary data for PIBD patients during COVID-19 outbreak are reassuring. Standard IBD treatments including biologics should continue at present through the pandemic, especially in children who generally have more severe IBD course on one hand, and milder SARS-CoV-2 infection on the other.

Related blog posts:

Expert Guidance on Inflammatory Bowel Disease (Part 3)

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A recent issue of Clinical Gastroenterology and Hepatology focused solely on the clinical features and management of inflammatory bowel disease. Even for those with expertise in IBD, there is a lot of useful information and concise reviews of what is known.

Here are some of my notes from this issue (part 3):

RP Hirten et al. Clinical Gastroenterol Hepatol: 2020; 18: 1336-45. A User’s Guide to De-escalating Immunomodulator and Biologic Therapy in Inflammatory Bowel Disease

This article emphasizes the need for assessment of bowel disease activity before attempting de-escalation and provides a list of risk factors for flare-up off therapy.

Some of the Risk factors for Disease Flare with De-escalation:

  • Disease activity/abnormal biomarkers (CRP, WBC, Hemoglobin, Calprotectin)
  • Perianal disease
  • Penetrating disease
  • Extensive disease involvement
  • Abnormal bowel wall thickening on MRE
  • Young age at diagnosis
  • Short treatment duration
  • Prior surgeries

Key points:

  • In individuals on combination therapy, dropping immunomodulator therapy (but not biologic therapy) did NOT increase the short term risk of a flare up in a recent Cochrane review.  However, this did impact anti-TNF kinetics and lowers anti-TNF troughs.
  • With regard to stopping biologics, among patients in deep remission, the authors advise counseling patients (CD and UC) that stopping biologic agents results in a “40-50% relapse over the following 2 years that will further increase over time.”
  • Careful followup is recommended if a patient elects to stop biologic therapy. “CD and UC are progressive relapsing conditions…and approximately 80% of subjects” require re-initiation of biologic therapy with 7 years.”
  • “Repeat colonoscopy or imaging should be performed if a significant change in symptoms occurs or abnormal biomarkers are detected.”
  • In patients who resume infliximab, the authors advocate for an initial induction of 0, 4, and 8 weeks.  The presence of antidrug antibodies at week 2 “precludes drug administration and alternative agent should be started.”

Related blog posts:

M Kaur et al Clinical Gastroenterol Hepatol 2020; 18: 1346-55. Inpatient Management of Inflammatory Bowel Disease-Related Complications

This article reviews the approach to acute severe ulcerative colitis which has been discussed recently on this blog post and offers management recommendations for complications related to Crohn’s disease including abscesses, strictures/bowel obstruction.  With regard to abscess management, the authors note that medical therapy is more likely to be effective in those with a first-time abscess, spontaneous origin, right lower quadrant location, and smaller abscess size (<3 cm).  Stricture with upstream dilatation of bowel, multi-loculated abscesses and steroid use are features that make therapy less likely to be successful.

Related blog posts -ASUC:

Abscess-related blog posts:

EL Barnes et al Clinical Gastroenterol Hepatol 2020; 18: 1356-66. Perioperative and Postoperative Management of Patients With Crohn’s Disease and Ulcerative Colitis

This article reviews risk factors for disease recurrence after surgery, presurgical management (eg. minimize steroids, improve nutrition, do not delay surgery based on preoperative biologic exposure), postoperative strategies and management of pouchitis.

  • In those at high risk for postoperative disease recurrence, the authors advocate anti-TNF therapy plus an immunomodulator with colonoscopy at 6-12 months. In those at low risk, many are placed on no medications and have a colonoscopy at 6 months postoperatively.
  • The section on pouchitis lists alternatives to metronidazole and ciprofloxacin if these lose efficacy.  This includes amoxicillin-clavulanate, sulfamethoxazole-trimethoprim, doxycycline and vancomycin.
  • Related blog post: What’s Going on With Pouchitis?

S Singh et al Clinical Gastroenterol Hepatol 2020; 18: 1367-80. Management of Inflammatory Bowel Diseases in Special Populations: Obese, Old, or Obstetric

A Levine et al Clinical Gastroenterol Hepatol 2020; 18: 1381-92. Dietary Guidance From the International Organization for the Study of Inflammatory Bowel Diseases

  • The authors recommend more vegetables and fruits with CD (but low insoluble fiber if stricture present)
  • “Prudent to reduce intake of red and processed meat” with UC
  • “Prudent to increase dietary omega-3 fatty acids” from marine fish but not from dietary supplements with UC
  • ‘Prudent to use a low FODMAP diet for patients with persistent symptoms for CD and UC despite resolution of inflammation’

M Collins et al Clinical Gastroenterol Hepatol 2020; 18: 1393-1403.Management of Patients With Immune Checkpoint Inhibitor-Induced Enterocolitis: A Systematic Review

This study reviews colitis induced by immune checkpoint inhibitors which are similar to young patients with inherent CTLA4b deficiency.

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.

Expert Guidance on Inflammatory Bowel Disease (Part 2)

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A recent issue of Clinical Gastroenterology and Hepatology focused solely on the clinical features and management of inflammatory bowel disease. Even for those with expertise in IBD, there is a lot of useful information and concise reviews of what is known.

Here are some of my notes from this issue (part 2)

S Danese et al. Clinical Gastroenterol Hepatol: 2020; 18: 1280-90. Positioning Therapies in Ulcerative Colitis

This is a good article but recent AGA publications are probably better –there are some links below. One statement that was interesting: “the safety profile of vedolizumab seems even better than placebo in terms of risk of serious” adverse events. The authors favored infliximab in combination with azathioprine in those needing biologic therapy with moderate-severe UC.

Related blog posts:

S Vermeire et al. Clinical Gastroenterol Hepatol: 2020; 18: 1291-9. How, When, and for Whom Should We Perform Therapeutic Drug Monitoring?

“Although reactive TDM, testing at time of loss of response, is widely accepted in practice, especially for anti–tumor necrosis factor antibodies, there are less data for the other monoclonal antibodies belonging to other classes. Besides reactive testing, there is a movement toward proactively adjusting biologic dosing to prevent loss of response, in keeping with the tight control philosophy of inflammatory bowel disease care.” The authors favor proactive monitoring: “we are now beginning to see with well-powered proactive TDM studies” that proactive monitoring can maximize the benefits of TDM with “the potential to maximize durability of biologics and improve the outcomes of IBD patients.”

Related blog posts:

PS Dulai et al. Clinical Gastroenterol Hepatol: 2020; 18: 1300-8. How Do We Treat Inflammatory Bowel Diseases to Aim For Endoscopic Remission?

The initial part of this article reviews treatment targets -resolution of symptoms and resolution of endoscopic damage. The algorithm provides the authors’ suggested approach:

  • At initiation of therapy, patients should have a full assessment.  In addition to ileocolonoscopy, for patients with CD, the authors recommend cross-sectional imaging.
  • After treatment initiation, the authors recommend biomarker assessment every 3 months.  Mucosal assessment can occur 6-9 months after treatment initiation.
  • For UC, the authors note that fecal calprotectin (FC) “appears to be more stratightforward, and a cutoff of 250 mcg/g can be used reliably across all scenarios to make treatment adjustments.”  Though, they recommend endoscopic confirmation prior to transition to a biologic or small molecule therapy.
  • For CD, the authors suggest making treatment adjustments in those with FC >250 mcg/g and in those with lower values, followup colonoscopy is recommended.
  • The authors note that in the post-operative setting with CD, mucosal inflammation precedes symptomatic activity and “waiting for symptoms to emerge may unnecessary allow for disease progression.”
  • The authors suggest that tighter disease control will reduce disease-related complications, while acknowledging a lack of prospective clinical trials.
  • One thorny issue: :”For CD: it remains unclear what degree of residual mucosal healing is acceptable to impact important outcomes such as CD-related complications, hospitalizations, and surgeries.”

Related blog posts:

M Allocca et al. Clinical Gastroenterol Hepatol: 2020; 18: 1309-23. Use of Cross-Sectional Imaging for Tight Monitoring of Inflammatory Bowel Diseases

“Computed tomography is limited by the use of radiation, while the use of magnetic resonance enterography (MRE) is limited by its cost and access. There is growing interest in bowel ultrasound that represents a cost-effective, noninvasive, and well-tolerated modality in clinical practice, but it is operator dependent… Diffusion-weighted imaging (DWI) is a MR imaging technique that increasingly is used in both IBD and non-IBD conditions and has been shown to be a valuable and accurate tool for assessing and monitoring IBD activity.

L Beaugerie et al. Clinical Gastroenterol Hepatol: 2020; 18: 1324-35. Predicting, Preventing, and Managing Treatment-Related Complications in Patients With Inflammatory Bowel Diseases

The first part of this article reviews potential adverse effects from the medications used for IBD treatment, noting in Table 1 that there are not complications to monitor for with both vedolizumab and ustekinumab.

The article reviews infections, vaccination strategies and issues related to malignancy Some of the recommendations:

  • vaccine against pneumococcus should be given before patients begin immunosuppressive therapy
  • physicians should consider giving patients live vaccines against herpes zoster (in adults) before they begin immunosuppressive therapy or a recombinant vaccine, when available, at any time point during treatment
  • sun protection and skin surveillance from the time of diagnosis are recommended
  • despite concerns about therapy, the authors note that “the extensive use of immunosuppressive therapy leads to a substantial decrease in the incidence of IBD complications, with a globally favorable benefit-risk ratio, which can be optimized further thanks to a good degree of awareness and knowledge of drug complications.”

It is interesting that this article (and the entire issue) does not address mental health concerns related to the diagnosis of IBD.  This likely creates more morbidity and complications than most of the other issues that are discussed.

Above: Why did the picture go to jail? Because it was framed.

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.