Does Accelerated Dosing of Infliximab Work for Acute Severe Ulcerative Colitis?

Posted on by

MC Choy et al. The Lancet Gastroenterology 2024; Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe ulcerative colitis (PREDICT-UC): an open-label, multicentre, randomised controlled trial

Methods: In this open-label, multicenter, randomized controlled trial, patients aged 18 years or older from 13 Australian tertiary hospitals with intravenous steroid-refractory ASUC were randomly assigned (1:2) to receive a first dose of 10 mg/kg infliximab or 5 mg/kg infliximab (randomization 1). Block randomization was used and stratified by history of thiopurine exposure and study site, with allocation concealment maintained via computer-generated randomization. Patients in the 10 mg/kg group (intensified induction strategy [IIS]) received a second dose at day 7 or earlier at the time of non-response; all patients in the 5 mg/kg group were re-randomized between day 3 and day 7 (1:1; randomization 2) to a standard induction strategy (SIS) or accelerated induction strategy (AIS), resulting in three induction groups. Patients in the SIS group received 5 mg/kg infliximab at weeks 0, 2, and 6, with an extra 5 mg/kg dose between day 3 and day 7 if no response. Patients in the AIS group received
5 mg/kg infliximab at weeks 0, 1, and 3, with the week 1 dose increased to 10 mg/kg and given between day 3 and day 7 if no response.

Thus, this was the first RCT comparing an intensified induction strategy (IIS; 10 mg/kg infliximab at weeks 0 and 1, with the second dose given earlier if no clinical response), an accelerated induction strategy (AIS; 5 mg/kg infliximab at weeks 0, 1, and 3, with the second dose increased to 10 mg/kg and given earlier if no response), and a standard induction strategy (SIS; 5 mg/kg at weeks 0, 2 and 6; with an extra 5 mg/kg dose before day 7 if no
response) in steroid-refractory patients with ASUC.

Key findings:

  • There was no significant difference in the proportion of patients who had a clinical response by day 7 between the 10 mg/kg and 5 mg/kg groups: 65% vs 61%
  • In patients with a baseline albumin of less than 25 g/L, a day 7 response occurred in nine (64%) of 14 patients in the 10 mg/kg group versus 14 (45%) of 31 in the 5 mg/kg group (RR 1·43, p=0·17)
  • In patients with a baseline CRP of 50 mg/L or higher, a day 7 response occurred in six (60%) of ten patients in the 10 mg/kg group versus eight (42%) of 19 in the 5 mg/kg group (RR 1·39, p=0·34)
  • The proportions of patients with clinical response at day 14: 74% in the IIS group, 73% in the AIS group, and 68% of 44 in the SIS group.
  • The clinical remission at month 3: 50% in the IIS group, 52% in the AIS group, and 48% in the SIS group
  • The steroid-free remission at month 3: 41% in the IIS group, 42% in the AIS group, and 41% in the SIS group
  • The endoscopic remission at month 3: 46% in the IIS group, 46% in the AIS group, and 48% in the SIS group
  • The colectomy rate at month 3: 7% in the IIS group, 19% in the AIS group, and 12% in the SIS group colectomy at month 3 were not significantly different between group (P=0.20)
  • The colectomy rate at month 12: 7% in the IIS group, 22% in the AIS group, and 15% in the SIS group colectomy at month 3 were not significantly different between group (p=0.13)
  • In post-hoc analysis of second-dose salvage strategies (among the group who had not responded at day7), a clinical response was observed in 19 (59%) of 32 patients who received a 10 mg/kg salvage dose versus nine (64%) of 14 who received a 5 mg/kg salvage dose (RR 0·92). Endoscopic remission at month 3 was observed in 11 (34%) who received 10 mg/kg salvage versus six (43%) who received 5 mg/kg salvage (RR 0·80). Colectomy by 3 months occurred in ten (31%) who received 10 mg/kg salvage compared with three (21%) who received 5 mg/kg salvage (HR 1·46)
  • Higher proportions of patients with clinical and biochemical remission between weeks 2 and 6 were apparent in the IIS and AIS groups versus the SIS group, but by 3 months, these differences were lost

My take: Intensified, accelerated, and standard induction regimens in the PREDICT-UC study did not result in a statistically-significant difference in clinical response by day 14 or in remission or colectomy rates by month 3. However, there are some important caveats:

  1. There appeared to be a trend towards a lower colectomy rate in the IIS group.
  2. There appeared to be a favorable trend towards an improved response to IIS group in those with low albumin (<25 g/L) and high CRP (>5 mg/L). The smaller numbers in these subgroups could have precluded statistical significance
  3. Also, even the SIS group were able to receive a 4th induction 5 mg/kg dose between days 3-7 if they had not responded to treatment
  4. In patients who had not responded to either 10 mg/kg or 5 mg/kg, a salvage dose at day 7 resulted in a >60% response rate
  5. It is possible that a sustained strategy of more aggressive dosing (not done in this study) aided with therapeutic drug monitoring could result in better outcomes following IIS

I Call BS -Consolidation in GI is Not a Good Trend

Posted on by

D Marino et al. Clin Gastroenterol Hepatol 2024: 22: 1770-1773. Trends in Consolidation of Gastroenterology Practices

This article describes trends and rationale for consolidation of gastroenterology practices.

Trends:

  • “From 2012 to 2022, the share of physicians who work in private practices dropped 13 percentage points, from 60.1% to 46.7%.” (In the 1980s, 76% of physicians owned their practice)
  • “Ownership among physicians younger than 45 dropped more than 12 percentage points from 2012 to 2022, from 44.3% to 31.7%.”

My Views (in bold) on the Authors’ Rationales for Consolidation:

  • “The potential advantages of consolidation include achieving economies of scale, increasing choices for patients beyond large hospital-based systems of care, enhancing the infrastructure to support high-quality value-based independent practices…whereas drawbacks …diminished authority.” The driving force for consolidation is money not improvement in “high-quality value-based” care. PE investors are tapping into health care to extract profits from the healthcare sector.
  • “The long-term implications for individual practices, physicians and patient care remain uncertain.” Some of the implications are already evident –increased costs for patients and without improvement in quality. PE consolidation does allow improved negotiation with insurers and hospitals.
  • “Large PE-backed groups provide resources to help independent practices stay independent.” This is quite a paradox. PE acquisition is a not a way to maintain independence.

My take: While consolidation, driven by financial incentives, is affecting all areas of healthcare, it is NOT resulting in improvement in patient care or physician satisfaction. This is true whether consolidation is acquisition by private equity or by hospitals. This article’s attempt to provide a different narrative is BS.

As an aside, in some ways, acquisition by hospitals is harder to justify than acquisition by PE; hospitals state that their main goal is patient care. Yet, when hospitals consolidate physician practices, this often runs counter to that goal by increasing costs for patients without improvement in quality.

Related blog posts:

BRUEs in Boston –Two Punch Study

Posted on by

DR Duncan et al. J Pediatr 2024; 272: 114128. Brief Resolved Unexplained Events Symptoms Frequently Result in Inappropriate Gastrointestinal Diagnoses and Treatment

In this prospective cohort study from Boston Children’s (2017-2022, n=157), the authors examined diagnostic evaluations in children presenting with Brief Resolved Unexplained Events (BRUEs).

Key findings:

  • Only 28% (20% during the hospitalization, 8% afterwards) underwent VFSS with 71% abnormal.
  • 42% of infants had their BRUE attributed to GERD, and 33% were treated with acid suppression during follow-up
  • Provision of GERD diagnosis was associated with a delay in making an aspiration diagnosis. 10% (6/66) of patients with “GERD” diagnosis subsequently had swallow studies –all were abnormal. Mean diagnostic delay was 56 days.

Discussion points:

  • The approach of using symptoms to determine evaluation of BRUEs has been advised by AAP clinical practice guidelines (2016 & 2019); “however, our results suggest that reliance on these clinical characteristics may result in negative outcomes.”
  • Most aspiration in infants is silent aspiration and not detected by clinical feeding evaluation (CFE) in the absence of a VFSS. “It is concerning that 63% of patients had CFE alone without confirmatory VFSS in the present cohort, and it may be that this practice is even more common in other centers.” Silent aspiration can lead to repeat hospital visits and even long-lasting pulmonary damage including bronchiectasis.
  • Establishing a GERD diagnosis likely increases unnecessary (& potentially harmful) acid suppression

My take: The two punches in this study:

  1. Clinicians cannot diagnose aspiration based on history or bedside feeding evaluations. Objective testing (e.g. VFSS) is needed if there are concerns for dysphagia
  2. Inappropriate diagnosis of GERD may cause harm. GERD medications have been associated with increased infections and may increase risk for allergies.

The role of aspiration in causing BRUEs has been well-recognized since 2017 (see below) by the same group in Boston. It is likely that evaluation of dysphagia is even less frequent in other medical centers.

Related blog posts:

Double Arch at Arches National Park

Markers for Outcomes in Neonates with Acute Liver Failure

Posted on by

PS Rolfes et al. J Pediatr 2024; 272: 114080. Establishing Neonate-Specific Prognostic Markers in Acute Liver Failure: Admission Alpha Fetoprotein and Novel Neonatal Acute Liver Failure Scores Predict Patient Outcomes

Methods: A single-center, retrospective chart review (n=51) was conducted on neonates ≤ 30 days of life between 2005 and 2022 with ALF (international normalized ratio ≥ 2 or prothrombin time ≥ 20s and liver dysfunction).  This excluded infants who responded to a single dose Vit K injection or fresh frozen plasma. The age at presentation was 4.7 in survival with native liver (SNL) group and 6.9 in the non-SNL group.

Key findings:

  • The most common causes of neonatal ALF included ischemia (22%), infection (20%), and gestational alloimmune liver disease (16%). All three patients with HLH died. Ischemia had the highest survival rate of 64% compared to 40% for infectious ALF, and 50% for GALD-ALF.
  • Overall survival with native liver (SNL) rate was 43% (n = 22).
  • Alpha-fetoprotein levels were higher in SNL group on admission (mean 46,471) compared to transplant/non-survival group (mean 2450). Peak values were 165,000 compared to 17,650. AFP levels remained significant after removing GALD patients with SNL group now with 17,500 mean on admission compared to 1006 in non-SNL group.
  • Ammonia levels were lower in SNL group on admission 48 vs 70 and at peak: 83 vs 172.
  • A neonatal ALF (nALF) model was developed: 1.29 x Admission INR +0.985 x Admission Ammonia (micromol/L). This score was significantly lower (mean 48.1) in SNL group compared to non-SNL group of 76.2.
  • A peak nALF model: 0.982 x Peak PT +0.985 x Peak Ammonia (micromol/L) performed even better than admission nALF model. SNL group had mean value of 118 compared to 223 for non-SNL group (P <0.001)

In the discussion, the authors note that AFP may have high prognostic value at time of admission (similar to neonatal ALF model), especially in Non-GALD patients. AFP Is a “biomarker for hepatic regeneration….Similar to our findings, several adult studies have shown that elevated AFP levels are associated with favorable outcomes in non-oncologic liver diseases…Specifically, it has been shown that in ALF, rising levels of AFP during hospitalization are associated with favorable outcomes.”

My take: Both the AFP and the neonatal ALF score had similar prognostic value for SNL.

Related blog posts:

Flowers on Channel Islands (off coast of California)

ChatGPT4 Outperforms GI Docs for Postcolonoscopy Surveillance Advice

Posted on by

PW Chang et al. Clin Gastroenterol Hepatol 2024; 22: 1917-1925. ChatGPT4 Outperforms Endoscopists for Determination of Postcolonoscopy Rescreening and Surveillance Recommendations

Text input of de-identified data into ChatGPT4 from 505 consecutive patients undergoing colonoscopy between January 1 and April 30, 2023. Key findings:

  • ChatGPT4 recommendations were in closer agreement with the USMSTF Panel (85.7%) than gastroenterology practice recommendations with the USMSTF Panel (75.4%) (P < .001).
  • Of the 14.3% discordant recommendations between ChatGPT4 and the USMSTF Panel, recommendations were for later screening in 26 (5.1%) and for earlier screening in 44 (8.7%) cases. 

My take: Incorporating AI in deciding follow-up surveillance is likely to be a helpful tool.

Related article: K-H Yu et al. NEJM 2024; 390: 1895-1904. Medical Artificial Intelligence and Human Values. This article discusses how human values affect the results of AI advice.

Related blog posts:

Mesa Arch at Canyonland National Park

Autoimmune Diseases in Patients with Primary Sclerosing Cholangitis Plus One

Posted on by

A Lundberg Bave et al. Hepatology 2024; 80: 527-535. Autoimmune diseases in primary sclerosing cholangitis and their first-degree relatives

Methods: Using National Swedish registries, the authors evaluated a matched cohort study, 1378 individuals with PSC and 13,549 general population comparators and their first-degree relatives.

Key findings:

  • After excluding inflammatory bowel disease and autoimmune hepatitis, the prevalence of autoimmune disease was 18% in PSC and 11% in comparators, OR: 1.77
  • Highest odds were seen for celiac disease [OR: 4.3], sarcoidosis [OR: 2.74], diabetes type 1 [OR: 2.91], and autoimmune skin disease [OR: 2.15]
  • First-degree relatives of individuals with PSC had higher odds of developing IBD [OR: 3.25], autoimmune hepatitis [OR: 5.94], and any autoimmune disease than relatives of the comparators [OR: 1.34] 

My take: Keep an eye out for other autoimmune diseases in patients (& their 1st-degree relatives) with PSC.

Related blog posts:

Briefly noted: BB Lai et al. Hepatology 2024; 80: 511-526. Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency–related cholestasis Key finding: “Patients with the TJP2-C genotype carrying PPTMs [predicted protein-truncating mutation] in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.”

Mom, Can We Get a Dog (& a Sibling)? I Don’t Want to Get Crohn’s Disease

Posted on by

M Xue et al. Clinical Gastroenterology and Hepatology, Volume 22, Issue 9, 1889 – 1897.e12. Open Access! Environmental Factors Associated With Risk of Crohn’s Disease Development in the Crohn’s and Colitis Canada – Genetic, Environmental, Microbial Project

Methods: The authors prospectively followed 4289 healthy first-degree relatives (FDRs) of patients with CD from the Crohn’s and Colitis Canada – Genetic, Environmental, Microbial (CCC-GEM) project. Regression models identified environmental factors associated with future CD onset and their association with pre-disease biological factors, including altered intestinal permeability measured by urinary fractional excretion of lactulose to mannitol ratio (LMR); gut inflammation via fecal calprotectin (FCP) levels; and fecal microbiome composition through 16S rRNA sequencing.

Key findings:

  • Over a 5.62-year median follow-up, 86 FDRs developed CD
  • Living with a dog between ages 5 and 15 (hazard ratio [HR], 0.62; P = .034) was associated with decreased CD risk
  • Living with a dog was associated with reduced LMR, altered relative abundance of multiple bacterial genera, and increased Chao1 diversity.
  • Living with a large family size in the first year of life (HR, 0.43; P = .016) was associated with decreased CD risk
  • Having a bird at the time of recruitment (HR, 2.78; P = .005) was associated with an increased CD risk (though there were relatively few FDRs with birds at baseline, n=136)
  • Limitations: questionnaire-based assessments of environmental exposure can be subject to recall bias

My take (borrowed from authors): “Our findings contribute to the growing evidence supporting the potential health benefits of exposure to pets, particularly dogs, as a potential preventive strategy for individuals at risk of developing CD.” Having a dog during childhood may reduce the later risk of CD by ~40%.

Related blog posts:

Blog Case Report: A Persistent Elevated AST in Teen with IBD and ADHD

Posted on by

A recent case reminded me of the quote by Helena Ravenclaw in Harry Potter: “”If you have to ask, you’ll never know. If you know, you need only ask.”

One of my colleagues recently diagnosed a teenage boy with ulcerative colitis. His past medical history was notable for ADHD. At the time of his evaluation, he was noted to have an elevated AST.

Labs:

  • June: AST 143, ALT 8, Hepatitis B immune
  • August: AST 190, ALT 10, Albumin 4.7, T protein 7.3, T bili 0.4, D bili 0.1, Alk phos 168; GGT 10, CPK 93

The concern at the time was whether his elevated AST should preclude using his ADHD medicine and whether there was an underlying liver disease. Based on the pattern of liver enzyme abnormalities, it was suspected that the patient had macro AST. A blood test was sent to the Mayo clinic and confirmed this diagnosis:

“”The sample was investigated for the presence of macro AST by polyethylene glycol (PEG) precipitation. Serum AST activity = 316 U/L. The AST result post-PEG precipitation = 22 U/L. The results obtained are positive for the presence of macro AST (93% of activity precipitated with PEG). Based on validation studies performed at the Mayo Clinic, a cut-off of >80% AST activity precipitated by PEG indicates the presence of macro AST.” This test is rarely ordered at the Mayo Clinic and is ordered as a miscellaneous test; it is not on the Mayo Clinic’s regular test menu.

Internet description of macro AST: Macro-aspartate aminotransferase (macro AST) is a rare, benign condition that causes a persistent elevation of aspartate aminotransferase (AST) levels in the blood. It’s caused by the binding of AST to immunoglobulins, which results in a high molecular weight macroenzyme that’s excreted from the serum more slowly than normal.

My take: Macro AST diagnosis is useful –it helps eliminate the concern for other conditions. Since it is quite uncommon, it is easier to think of this problem once you have seen it before.

Related blog posts:

Grand Point View Overlook at Canyonlands National Park

Dr. Praveen Goday: Tips on Managing Feeding Problems (Part 2)

Posted on by

Dr. Goday gave our group a great lecture on pediatric feeding disorders. I’ve included many of his slides along with some of my notes. There may be errors in omission and transcription on my part.

Feeding tubes:

  • If taking >75% of feeds orally, only 13% still needing tube feeds 6 months later.  If taking <25%, 81% still needing tube feeds 6 months later (needs a GT)
  • Bridle: Dr. Goday recommends using up to 8 weeks.  If needing longer, GT placement is recommended
  • If needing an NG tube more than 3 months (possibly 6 months), GT placement is recommended
  • Pre-op studies are not predictive of who will need GJ feedings vs GT feedings

Medications:

  • Cyproheptadine -Dr. Goday prefers single night time dose, usually cycles medicine (2 weeks on, 1 week off), uses as early as 8 months of age.  Watch for adverse effects on behavior.
  • Mirtazapine -often used in older children and adolescents though effects on appetite wane with usage.  Dosed as an oral disintegrating tablet.  Typically, 7.5 mg in older children and 15 mg in adolescents.
  • Vitamins -Gummy vitamins are NOT complete vitamins, Nano VM -minimal taste powder (costly)

Choking phobia

  • Can occur with pharyngitis
  • Usually needs EGD and sometimes anxiolytic

Formulas:

  • No clear nutritional role for toddler step-up formulas
  • Dr. Goday often will use infant formula between 1-2 yrs of life rather than pediasure in those without growth concerns.  Pediasure may reduce acceptance of solid foods (due to its sweet taste)
  • Get help from your nutritionists in kids with limited diets

Autism:

  • Avoid adding medication/vitamins to the ‘one food/formula that child will take.’  He may stop taking that food/formula too

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.

Dr. Praveen Goday: Tips on Managing Feeding Problems (Part 1)

Posted on by

Dr. Goday gave our group a great lecture on pediatric feeding disorders. I’ve included many of his slides along with some of my notes. There may be errors in omission and transcription on my part.

Differences between picky eating, pediatric feeding disorder, and ARFID

  • 70% of picky eating is inherited.
  • If there are sequelae from picky eating, this indicates that the child has a pediatric feeding disorder.  There are 4 potential domains to pediatric feeding disorders: medical dysfunction, feeding skills dysfunction, nutritional dysfunction and psychosocial dysfunction (this is more subjective than other domains)
  • Pediatric feeding disorder (PFD) is a better term than “behavior” feeding disorder because many children have underlying contributing disorders like eosinophilic esophagitis (EoE) or aspiration/swallow dysfunction
  • ARFID is a diagnosis used by psychologists. It is when purely psychosocial concerns leads to nutrition dysfunction. The diagnosis is likely best used in older children who are mostly neurotypical and have normal development.  In younger children, it is important to assess for underlying disorders like oromotor discoordination and EoE

Strategies to prevent picky eating:

  • Breastfeeding (varied tastes in breastmilk)
  • Responsive feeding (feeding when hungry)
  • Solids [lumpy] (especially 6-9 months)
  • Multiple-varied exposures
  • Prevention/treatment: Praise at meal times, non-food rewards, Ellyn Satter’s advice (parents decide when, where, and what is offered & child decides how much

Increased risk of developing picky eating: FPIES, multiple allergies

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.