Is There An Increased Risk of Infections with Anti-TNF Therapy?

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J Holmgren et al. Inflamm Bowel Dis 2023; 29: 339-348. Open Access! The Risk of Serious Infections Before and After Anti-TNF Therapy in Inflammatory Bowel Disease: A Retrospective Cohort Study 

Methods: Retrospective study with 980 patients at 5 centers participating in the Swedish IBD Quality Register. Serious infections, defined as infections requiring in-patient care, the year before and after the start of anti-TNF treatment were evaluated.

A decline in the incidence rate can first be seen beyond 1 year of treatment with anti-TNF, with an incidence rate of 1.22 (95% CI, 0.90-1.66) events per 100 person year compared with 2.19 (95% CI, 1.43-3.36) events per 100 person year the year before treatment. This is a significant reduction of infections, with an incidence rate ratio of 0.56 (95% CI, 0.33-0.95; P = .030).

Key findings:

  • A 72.0% reduction in the incidence rate of perianal abscesses and intra-abdominal abscesses during treatment with anti-TNF was found compared with before treatment.
  • Figures 2 & 3 show than most infection rates decreased with treatment. CMV infection did not change significantly with 0.10 per 100 person-years prior to treatment and 0.14 per 100 person-years after starting anti-TNF therapy
  • ” In the current study, patients younger than 20 years old experienced a substantial decrease of infection incidence rate ratio (0.11) with the introduction of anti-TNF treatment. The results could be explained by the fact that young patients have a more active disease with increased risk of infection before treatment with anti-TNF.”
  • “The most common type of infection after anti-TNF treatment was pneumonia. The high incidence of pneumonia confirms earlier data.9,36,37” However, the authors show that the rate of pneumonia dropped from 0.51 to 0.27 per 100 person-years after starting anti-TNF therapy.

The authors note that a prior study by “Zabana et al showed that patients with IBD had an increased risk for serious infection after starting immunosuppressive treatment compared with before treatment (median follow-up 3 years before and 5 years after)… the discrepancy in the result may be explained by selection bias. We included all patients starting anti-TNF treatment. However, Zabana et al included only patients who suffered from infections during immunosuppressive treatment and retrospectively examined the risk of infection before start of treatment.24“

Limitations of study: several other important factors affecting infections were not captured in this study including steroid exposure and nutritional status.

My take (from authors): “The incidence rate of serious infection among IBD patients did not increase with anti-TNF therapy. Instead, serious infections seemed to decrease more than 1 year after initiation of anti-TNF treatment.”

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More Data Showing Increased Cardiovascular Risks with COVID-19 & Vaccination Reduces This Risk

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Two recent studies show that COVID-19 infection increases the risk of major cardiovascular outcomes.

This case-control study leveraged a large commercial insurance database and found increased rates of adverse outcomes over a 1-year period for a post-COVID-19 cohort surviving the acute phase of illness. Methods: An index month was set by adding 30 days to the COVID-19 diagnosis date (this study looked at outcomes starting one month after diagnosis).

This study used the data from the US Collaborative Network in TriNetX. From a cohort of more than 42 million records between 1 January 2019 and 31 March 2022, a total of 4,131,717 participants who underwent SARS-CoV-2 testing were recruited.

Eric Topol: Summary of studies relating cardiovascular outcomes:

My take: Many detractors of vaccination have focused on potential cardiac adverse events. These studies indicate that COVID vaccination provides protection against major cardiovascular outcomes

Liver Updates: Statin Protection from HCC, PSVD -new name, novel finding and Hypothyroidism with Hepatic Hemangiomas

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B Zou et al. Clin Gastroenterol Hepatol 2023; 21: 435-444. Open Access! Statin Use and Reduced Hepatocellular Carcinoma Risk in Patients With Nonalcoholic Fatty Liver Disease

This study, in agreement with prior studies of individuals with chronic liver disease, showed that statin use is associated with a lower risk of hepatocellular carcinoma in NAFLD as well, with a Hazard Ratio of 0.47 in a database with 272,431 adults with NAFLD. The authors note the concern about hepatotoxicity from statins; however, “severe liver injury from statins is fairly low. Indeed, the incidence of lovastatin-associated fulminant liver failure is about 2 in a million users.”

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J Shan et al. Hepatology 2023; 77:501-511. Open access! Genetic predisposition to porto‐sinusoidal vascular disorder: A functional genomic‐based, multigenerational family study

Porto‐sinusoidal vascular disorder (PSVD; also previously described as idiopathic noncirrhotic portal hypertension [NCPH]…”is a group of liver vascular diseases featuring lesions encompassing the portal venules and sinusoids unaccompanied by cirrhosis, irrespective of the presence/absence of portal hypertension. It can occur secondary to coagulation disorders or insult by toxic agents. However, the cause of PSVD remains unknown in most cases.”

Key findings:

  • In a group of 4 patients, a novel heterozygous mutation in the FCHSD1 gene was identified but not in 2 familial controls.
  • When this variant was introduced in mice using CRISPR, ” Nine out of the 15 mice carrying the human FCHSD1 R183W variant mimicked the phenotype of human PSVD, including splenomegaly and enlarged portal vein.”
  • Aberrant FCHSD1 structure and function led to mTOR pathway overactivation

Related blog post: Time to Adjust the Knowledge Doubling Curve in Hepatology

MA Siano et al. JPGN Reports. 2022; 3(4):p e270,.  Consumptive Hypothyroidism due to Hepatic Hemangiomas: A Case Series and Review of the Literature

“Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to thyroid hormone inactivating enzyme type 3 (Deiodinase) overexpressed by hepatic/hepatic and cutaneous hemangiomas, and occasionally by some other extrahepatic visceral hemangiomas…Pediatric hepatologists should recognize the importance of periodical assessments of thyroid function in patients with hepatic hemangiomas”

“MRI of the abdomen in one of our patients (patient 1), before (A) and after (B) 19 months of treatment with propranolol/10 months of treatment with levothyroxine. The T2-weighted axial MRI images shows the regression of a diffuse infantile hepatichemangioma with innumerable T2 hyperintense masses throughout the liver with central hypointense central regions.”

Cold vs Hot Polypectomy for Small Polyps

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L-C Chang et al. Ann Intern Med. [Epub 21 February 2023]. doi:10.7326/M22-2189. Cold Versus Hot Snare Polypectomy for Small Colorectal Polyps

In this multicenter randomized open-label, single-blind trial of patients (n=4270) 40 years or older (mean age 62 years) with polyps of 4 to 10 mm, cold snare polypectomy (CSP) was compared with hot snare polypectomy (HSP).

Key findings:

  • Eight patients (0.4%) in the CSP group and 31 (1.5%) in the HSP group had delayed bleeding (w/in 14 days) (risk difference, −1.1% [95% CI, −1.7% to −0.5%]).
  • Severe delayed bleeding (drop in Hgb of 2 g/dL) was also lower in the CSP group (1 [0.05%] vs. 8 [0.4%] events; risk difference, −0.3% [CI, −0.6% to −0.05%])
  • The CSP group had fewer emergency service visits than the HSP group (4 [0.2%] vs. 13 [0.6%] visits
  • Polyp type (in Table 2): 70% were adenomas, 5% were sessile polyps, and 23% were nonneoplastic which includes hyperplastic polyps, inflammatory polyps, and nonsignificant lesions. ~56% had a “polypoid morphology” and ~ 44% had a “nonpolypoid morphology.”
  • “Besides an improved safety profile, another advantage of CSP is its high efficiency. This study’s results showed that the time required for polypectomy is reduced by 26.9% with CSP (difference in mean, -44.0 seconds)”

Why is CSP safer?

“The shallower resection depth in CSP is one of the factors contributing to the lower bleeding risk. Besides the tearing force, electrocautery also applies more energy to the soft tissue… (28). Profound submucosal destruction may occur in 60% of cases, and the muscularis propria may be damaged in 20% of patients receiving HSP; however, all cold resections are limited to the shallow submucosa. Because larger vessels are usually located in the deeper submucosa, the shallow resection depth of CSP causes less arterial injury, thereby reducing the risk for delayed bleeding (29).”

My take: It would be helpful to replicate these findings in children mainly due to differences in polyp types that are found. Nevertheless, this study suggests that it is likely more risky to use cautery for small polyps (“including persons using antiplatelet agents or anticoagulants”).

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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.

Lecture: IBAT Inhibitor for Alagille Syndrome

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I recently attended an online lecture which reviewed Alagille Syndrome and the emergence of an IBAT inhibitor for the management of cholestatic pruritus. Selected slides from Mirum Pharmaceutical Lecture: “Updates in the Treatment of Cholestatic Pruritus in Patients With Alagille Syndrome.” *I have no financial disclosures or conflict of interests in this medication or company.

  • The severe itching which is seen in most patients with Alagille is often quite detrimental to quality of life. It impacts sleep, causes irritability, skin damage, and physical distcomfort
  • Typically, the first week of receiving the medication, it is started at1/2 the maintenance dose.
  • Monitoring response can be done with the ItchCheck App, Itch score or Clinical scratch score
  • Monitoring hepatic blood tests and periodic monitoring of fat soluble vitamins is recommended

My take: Though Alagille syndrome is a multisystem disease, improvement in pruritus due to cholestasis with an oral daily medication is an important advance/option. There is little systemic absorption and thus far a reassuring safety profile.

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The Eosinophilic Esophagitis Diagnostic Cup is Half Empty with the Esophageal Sponge

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JA Alexander et al. Clin Gastroenterol Hepatol 2023; 21: 299-306. Open Access! Use of the Esophageal Sponge in Directing Food Reintroduction in Eosinophilic Esophagitis

Methods: In this prospective non-blinded trial, 22 responders to 6-food elimination diets underwent sequential food reintroduction guided by esophageal sponge cytology

Key findings:

  • At the post food reintroduction evaluation, sponge cytology and biopsy histology were in agreement in 59% (13/22) of cases using a cutoff of <15 eos/hpf and 68% (15/22) of cases using a cutoff of <6 eos/hpf. With the cutoff of <15 eos/hpf, the median absolute difference was 38 eos/hpf.
  • Interestingly, the authors noted a high rate (23%) of dietary responders who had dietary reintroduction without a dietary trigger being identified; this is possibly related in part to lower sponge sensitivity, and possibly due to a short food reintroduction period of 2 weeks prior to testing.

The authors in their discussion note that it is unclear whether the values from the sponge or from the biopsy is more reliable.

My take: This is a disappointment for those of us waiting for a reliable non-invasive measure of EoE activity. Those with abnormal sponge results are fairly likely to have abnormal endoscopy; however, many of those with normal values with sponge testing are likely to have active EoE.

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Stratifying the Risk of Asymptomatic Gallstones

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G Morris-Stiff et al. Clin Gastroenterol Hepatol 2023; 21: 319=327. The Natural History of Asymptomatic Gallstones: A Longitudinal Study and Prediction Model

Using a retrospective cohort design with 22,257 patients (51% female) with a mean age of 61 years, Key Findings:

  • There was a 2% per year rate of developing symptomatic gallstones
  • Overall, 14.5% developed symptoms with a median followup of 4.6 years
  • Cumulative incidence of becoming symptomatic: 10.1% at 5 years, 21.5% at 10 years, and 32.6% at 15 years
  • The strongest predictors of developing SGs were female gender (hazard ratio [HR], 1.50), younger age (HR per 5 years, 1.15), multiple stones (HR, 2.42), gallbladder polyps (HR, 2.55), large stones (>9 mm) (HR, 2.03), and chronic hemolytic anemia (HR, 1.90). Elevated BMI was associated with increase risk; for example a BMI >40 had a HR of 1.60.
  • Statin use was associated with a reduced risk of with HR 0.61

My take: This large retrospective study of adults indicates that if given enough time, more than 1/3rd of individuals will develop symptomatic gallstones. Surgical intervention should be considered in those with significant risk factors.

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Dog’s viewpoint at the Chattahoochee River in Sandy Springs, GA

Why GlaxoSmithKline v Teva is Important for Medication Affordability and “Please Look at My Baby”

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SS Tu, A Sarpatwari. NEJM 388: 483-485. A “Method of Use” to Prevent Generic and Biosimilar Market Entry

This article explains how generic and biosimilar companies have tried to navigate the ‘patent gamesmanship’ that brand-name manufacturers have used to delay competition for their products beyond the typical 20 years after an application is filed.

Key points from this article:

  • “The Hatch–Waxman Act, provided a partial solution by explicitly authorizing manufacturers to market generic drugs if they don’t claim any indications protected by active method-of-use patents.3 Such skinny labeling enables generics manufacturers to market their products for older, non–patent-protected indications without infringing later-issued method-of-use patents…43% of products that were the first available generic formulation of a brand-name drug included skinny labels”
  • The article delves into the  GlaxoSmithKline v. Teva case which centers on the overlapping potential indications for the beta-blocker carvedilol. Teva had used skinny labeling to get approval for hypertension (HTN) but was sued by GlaxoSmithKline as carvedilol can be used for congestive heart failure (CHF).
  • Much of the case centers on the paradox that “by law, generics [& biosimilars] manufacturers are required to use very similar labels” as the labeling of original products even though the generic has requested approval for a much narrower approval. In this case, when the Teva generic was used for CHF, GlaxoSmithKline sued since the product was approved for HTN.
  • Another example: Humira has “more than 70 patents on inventions ranging from the active pharmaceutical ingredient and primary indications to the drug’s purity, various formulations, and secondary indications.” For a generic/biosimilar to address all of these (potentially-endless) patents is a huge barrier.
  • Based on this ruling, “brand-name manufacturers can thus now create labels that reference material related to new method-of-use patents and then sue generics manufacturers for patent infringement.”
  • “Lack of action by both the Supreme Court and Congress would allow brand-name drug manufacturers to wield a powerful new weapon to delay or deter the entry of generic and biosimilar drugs, which could have important implications for health care costs and patient welfare.”

My take: My prediction is that these tactics by drug manufacturers, despite their extensive financial connections with lawmakers, will eventually backfire and result in extensive changes to the regulations regarding exclusivity and pricing.

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In an unrelated article in the same issue, Golda Grinberg provides a first-hand account of how families could benefit by the consideration of hospice in children with extensive medical problems. NEJM 2023; 388: 486-487. Please Look at My Baby — When Clinicians Should Say the Word “Hospice”

“To the surprise, perhaps even shock, of the SICU team, we tossed an option B onto the table: if we truly could not extubate, we suggested, maybe we should skip the trach and transition to comfort care….When presented with a child in whom previous extubation attempts had failed and who was becoming more deconditioned by the day, the SICU team had made the standard, safe, and familiar recommendation for an acute problem: place a trach… It would have been tremendously helpful if, from the beginning, we’d had an open conversation with our son’s medical team and discussed all the options.”

My take: Most parents are happy with their medical decisions for their children. However, it is not uncommon to hear parents say many years later that they wished that they had been informed of the long-term dire outlook of their children and the possibility of deescalation of care in children with severe medical conditions before embarking down the ‘standard’ path.

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AASLD 2023 Practice Guidance for Primary Sclerosing Cholangitis and Cholangiocarcinoma

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CL Bowlus et al. Hepatology 2023; 77: 659-702. Open Access! AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma

This is a lengthy article with a great deal of useful information. Here are some of the important recommendations most relevant for pediatric gastroenterologists/hepatologists:

  • In patients with PSC without known inflammatory bowel disease (IBD), diagnostic colonoscopy with histological sampling should be performed and may be repeated every 5 years if IBD is not initially detected
  • In patients with PSC in whom IBD is diagnosed, high‐definition surveillance colonoscopy with biopsies should start at age 15 years and be repeated at 1‐year to 2‐year intervals to evaluate for colonic dysplasia
  • New clinical risk tools for PSC are available for risk stratification, but probabilities of events in individual patients should be interpreted with caution
  • All patients with PSC should be considered for participation in clinical trials; however, ursodeoxycholic acid (13–23 mg/kg/day) can be considered and continued if well tolerated with a meaningful improvement in alkaline phosphatase (γ‐glutamyl transferase in children) and/or symptoms with 12 months of treatment
  • Upper endoscopy to screen for varices should be performed if the LS is >20 kPa by TE or the platelet count is ≤150,000/mm3
  • Bone density examinations should be performed to exclude osteopenia or osteoporosis at diagnosis and at 2‐year to 3‐year intervals thereafter based on risk factors

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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.

How to Lower Pediatric Liver Transplantation Waitlist Mortality

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From the editorial, Key Points:

  • Esmati et al.1 present a fascinating analysis of the impact on waitlist outcomes of a 2014 Eurotransplant (ET) policy that prioritizes patients younger than the age of 2 years with biliary atresia for deceased donor liver transplantation (DDLT) offers
  • Waitlist mortality decreased from 6.7% before to 2.3% after implementation of the new policy. Unexpectedly, this was not associated with an increase in DDLTs
  • During the same time period, the proportion of young patients with BA who underwent living donor liver transplantation (LDLT) increased from 55% to 74%.
  • Without adaptions to the pediatric Model for End‐Stage Liver Disease (MELD) or Pediatric End‐Stage Liver Disease scores, children can never fairly “compete” for deceased donor livers because of the tremendous volume and demand from the adult candidate list

My take (borrowed from editorial): There are many potential ways to achieve the desired goal of zero pediatric waitlist mortality. And, multiple strategies can successfully be pursued in parallel: prioritize children, increase use of LDLT, and increase/mandate use of split livers.

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Another (unrelated) study in this issue -easy way to assess mobility (a key element of frailty) in adults with decompensated liver disease: AJ Groff et al. Liver Transplantation 29: 226-228. Open Access! A novel method using the level of mobility to predict mortality in patients admitted for decompensated cirrhosis: A prospective study The authors found the following: a value of <8 on The Johns Hopkins Highest Level of Mobility score (JH‐HLM, see below) was associated with much higher risk of mortality compared with those with a JH‐HLM score of 8.