Improving Genetic Screening: The Couple Approach

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EP Kirk et al. NEJM 2024; 391: 1877-1889. Nationwide, Couple-Based Genetic Carrier Screening

One of the drawbacks with genetic screening has been identifying too many problems. Everyone has pathogenic mutations but many do not have effective treatments; in addition, many may be inconsequential if your partner does not share a similar genetic mutation (for autosomal recessive conditions). Furthermore, counseling everyone with genetic mutations is time-intensive. With this background, it is easy to see why a couple-based testing approach makes sense. In this study of an Australian genetic carrier screening program, couples had testing of at least 1281 genes with more than 750 serious diseases as part of the Mackenzie’s Mission project. Variants of uncertain significance were not reported.

Key findings:

  • An estimated 45.9% of those invited to participate underwent reproductive genetic carrier screening
  • 9107 couples completed screening, and 175 (1.9%) were newly identified as having an increased chance of having a child with a genetic condition for which we screened
  • 180 (2.0%) were known, before participation in the study, to have an increased chance of having offspring with at least one genetic condition (due to family history or consanguinity)
  • Of the 45 couples (25.7%) in which the female partner was pregnant when they received the result, 29 (64%) decided to have the fetus genetically tested, and 24 of these couples received normal test results. Of the 5 couples whose pregnancy was affected, 4 elected to end the pregnancy
  • Of the 130 couples in which the female partner was not pregnant at the time of genetic testing, 95 (73.1%) indicated an intention to use in vitro fertilization with preimplantation genetic testing for monogenic conditions. 
  • Overall, 134 of 175 couples (76.6%) with a newly identified increased chance chose to alter their reproductive plans

Discussion Points:

  • “92.7% of participants carried at least one pathogenic or likely pathogenic variant. With this prevalence and in this framework, reporting individual carrier results would be a burden on health systems. For example, one study showed a median time of 64 minutes to provide genetic counseling regarding results of reproductive genetic carrier screening.36“
  • “Decisional regret was generally low,32 a finding that suggests that most participants valued the information provided by the screening.”
  • 42% of couples had increased risks for diseases that would not have been identified using a previous list of 113 genes recommended by The American College of Medical Genetics and Genomics (ACMG).38 “As genomic testing technology advances, it is becoming possible to screen larger numbers of genes, and thus, any gene that meets criteria for inclusion, such as criteria that pertain to the severity of associated disease and to technical capability,1 can be screened.” 
  • “We limited reporting to variant combinations predicted to result in a serious childhood-onset condition or a condition in which early intervention can improve prognosis…Variants known to result in a mild condition or an adult-onset condition were not generally reported unless early intervention would improve prognosis. This approach aimed to minimize uncertain and ambiguous information and provide results that had high clinical usefulness.”

My take: Given the improvement in cost of genetic screening, this type of approach is quite practical and would not result in every family having to meet with a genetic counselor.

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Museum of Illusion

When Is It OK To Ignore Laryngeal Penetration?

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AL Miller et al. Dysphagia 2024; 39: 33-42. Predictive Value of Laryngeal Penetration to Aspiration in a Cohort of Pediatric Patients

This was a retrospective study with 97 patients over a 6 month period in 2018. The authors note that “there is no universally accepted protocol for pediatric video swallows across ages and conditions.”

Methods: Depth of penetration and/or aspiration and reaction were classified according to the 8-point Penetration–Aspiration scale [JC Rosenbek, et al. Dysphagia 11, 93–98 (1996). https://doi.org/10.1007/BF00417897]. The frequency of penetration events and aspiration was grouped into categories: none (1); infrequent or occasional episodes (at least 1 event to less than 30%) (2); intermittent episodes (30–40% of total swallows) (3); frequent episodes
(50% or greater of total swallows) (4). Data for all swallowing parameters was stratified by bolus type (thin liquid, thickened liquid, puree solid). All VFSS were independently
scored by two speech-language pathologists and two radiologists.

Key findings:

  • Aspiration was seen in 21% of patients (n=20 of 97).
  • Penetration events were more frequent and occurred in 64% of participants (n=62 of 97). . Of patients with any penetration events, 30% also had documented aspiration
  • Frequency of penetration and aspiration: 80% of patients showing frequent penetration [frequency 4] demonstrating aspiration compared to 2.3% of patients with isolated penetration [frequency 1]. There was a higher risk of aspiration at lower frequency penetration if this occurred with thicker liquids (see below)
  • Depth of penetration and aspiration:. For patients with penetration contacting the vocal folds [depth 5], nearly 95% demonstrated documented aspiration within the same study; however, those with depths 1-3 had minimal risk of aspiration (see below). There was a higher risk of aspiration at shallow depths with thicker liquids.


My take (borrowed from authors): “children with shallow, intermittent penetration events
without associated aspiration are likely to be demonstrating clinically insignificant events. Such children are therefore not appropriate candidates for compensatory or alternative feeding strategies such as changes in mode of delivery (e.g., gastrostomy tube), alteration of flow rate, or modification of liquid viscosity, such as thickened feedings.”

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Endoscopically-Identified Incidental Appendicitis

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There are a lot of interesting recent case reports on the JPGN Reports website. A recent example includes the following:

Mostafavi et al report (JPGN Reports 2024; 5:511–513. Open Access! Endoscopic diagnosis of asymptomatic appendicitis in a pediatric patient) on the incidental diagnosis of appendicitis. A followup colonoscopy in a 14 year-old with ulcerative colitis identified purulent fluid from the appendiceal orifice after ileal intubation; subsequently, after MRI imaging, an appendectomy was performed. The appendicitis was thought to be unrelated to the ulcerative colitis.

Other examples of some recent JPGN case reports:

Efficacy and Safety of Odevixibat with Alagille Syndrome (ASSERT Trial)

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N Ovchinsky et al. The Lancet Gastroenterology & Hepatology, Volume 9, Issue 7, 632 – 645. Open Access! Efficacy and safety of odevixibat in patients with Alagille syndrome (ASSERT): a phase 3, double-blind, randomised, placebo-controlled trial

Methods: “The ASSERT study was a phase 3, double-blind, randomised, placebo-controlled trial that enrolled patients at 21 medical centres or hospitals in ten countries” with 52 patients (enrolled 2021-2022). “The primary efficacy endpoint was change in caregiver-reported scratching score (on the PRUCISION instrument; range 0–4) from baseline to weeks 21–24.” The treatment group received odevixibat 120 µg/kg per day.

Key findings:

  • There were improvements in both scratch scores and bile acid concentrations
  • There were improvements in sleep parameters including falling asleep and ability to sleep without a caregiver
  • Adverse events: diarrhea was reported in ten (29%) of 35 patients who received odevixibat and in one (6%) of 17 patients who received placebo; all cases were mild in severity and no cases of diarrhea led to treatment interruption or discontinuation

Scratch Scores:

Bile Acid Levels

Other points:

  • Overall, 50 (96%) of the 52 patients chose to enter the open-label extension study
  • The authors note that this is the first randomized placebo-controlled trial for Alagille syndrome
  • A direct comparison of odevixibat and maralixibat in patients with Alagille syndrome is complicated by differences in study design and endpoints across the their studies

My take (borrowed in part from authors): “As pruritus is a major driver of liver
transplantation in patients with Alagille syndrome, these results suggest that odevixibat could have the potential to delay or prevent liver transplantation”

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Hollywood Beach, FL

Safety of JAK Inhibitors Compared to Anti-TNF Agents

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C Crist. GI & Hepatology News; 11/20/24: In IBD Patients, No Increased Risk for MACE Seen for JAK Inhibitors vs Anti-TNF

Background: There have been concerns that JAK inhibitors (JAKi), like tofacitinib (Xeljanz) and upadacitinib (Rinvoq) could increase the risk of major adverse cardiovascular events (MACE); as such, the FDA has placed warnings on these medications (see blog post: FDA Slaps Restrictions on JAK Inhibitors Over Serious Safety Risks).

An excerpt:

According to a study presented at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting, .

Alsakarneh and colleagues conducted a retrospective cohort study using the TriNetX database to identify adult patients with IBD who were treated with JAKi or anti-TNF therapy after diagnosis. After matching patients in the JAKi cohort [n=3740] with patients in the anti-TNF cohort [n=3740], the research team looked for MACE and VTE within a year of medication initiation…

After excluding those with a history of a prior cardiovascular event, 57 patients (1.76%) in the JAKi cohort developed MACE, compared with 63 patients (1.94%) in the anti-TNF cohort. There weren’t significant differences between the groups in MACE (adjusted hazard ratio [aHR], 0.99) or VTE (aHR, 0.9).

Among patients aged ≥ 65, 25 patients (5.3%) in the JAKi cohort developed MACE, as compared with 30 patients (6.4%) in the anti-TNF cohort.

My take: Several studies now have not identified an increased risk of JAKi compared to other therapies for IBD. Perhaps, this will lead to a change in labeling by the FDA which has stated that JAKi should be used only in those with prior anti-TNF failure.

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Museum of Illusions (Atlantic Station)
This “bulging squares” illusion has straight lines across and vertically when you are right in front of it.

Efficacy of Mirikizumab in Moderate-to-Severe Crohn’s Disease (VIVID-1 Study)

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M Ferrante et al. The Lancet 2024; https://doi.org/10.1016/S0140-6736(24)01762-8. Efficacy and safety of mirikizumab in patients with moderately-to-severely active Crohn’s disease: a phase 3, multicentre, randomised, double-blind, placebo-controlled and active-controlled, treat-through study

Methods: VIVID-1 was a global phase 3, randomized, double-blind, double-dummy, placebo-controlled and active-controlled, treat-through study which enrolled 1150 patients with moderate-to-severe Crohn’s disease. There were three treatment groups: mirikizumab group, ustekinumab group, and placebo group. In each group, 48-49%were considered “biologic-failures” including 45-46% who were anti-TNF failures.

Key findings:

Discussion points:

Early treatment effect: “Symptomatic improvement was evident as early as week 4 accompanied by a statistically significant reduction in high-sensitivity CRP and faecal calprotectin, and endoscopic response was seen at week 12.”

Compared to ustekinumab: “Mirikizumab reached non-inferiority versus ustekinumab for clinical remission by CDAI at week 52…mirikizumab showed statistically significantly greater improvements from baseline in fecal calprotectin and CRP compared to ustekinumab.
In addition, a greater percentage of patients reached the combination endpoint of endoscopic response and clinical remission by CDAI at week 52.”

Comparison across treatment trials: “. At week 52, 45∙4% of patients treated with mirikizumab met the endpoint of clinical remission by CDAI in the treat-through analysis with composite endpoint, 54∙1% met the endpoint in the treat-through analysis, and 64∙3% met the endpoint in the responder analysis. This example, with a range of nearly 20% percentage points depending on analysis type, shows the profound limitations in comparing
unadjusted outcomes across phase 3 trials.” The authors note other differences in trial design between VIVID-1 and SEQUENCE (risankizimab) and state “no conclusions on
relative efficacy can be drawn.”

My take: This study shows that mirikizumab is effective in adults with moderate-to-severe Crohn’s disease with and without prior biologic treatments. Pediatric studies are underway.

Infliximab Thresholds with Subcutaneous vs Intravenous Administration for Crohn’s Disease

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SN Hong et al. AP&T 2024; 0:1–10. doi.org/10.1111/apt.18354. Subcutaneous Infliximab Concentration Thresholds for Mucosal and Transmural Healing in Patients With Crohn’s Disease

Background: The exposure–response relationship for the intravenous (IV) formulation of infliximab is well established, with multiple studies demonstrating that higher trough concentrations (C-trough) are associated with improved patient outcomes…However, the 2-week cycle of subcutaneous administration showed many-fold higher C-trough than the 8-week cycle of IV-IFX. Direct comparison of C-trough between SC- and IV-IFX is not appropriate because of different bioavailability and concentration–time profile. It is also not appropriate to apply the C-trough thresholds that predict achieving the therapeutic targets for IV.

This was a cross-sectional retrospective study with 124 patients with Crohn’s disease (CD) who had received SC-IFX maintenance therapy for ≥6 months. SC-IFX C-trough was measured immediately before SC-IFX injection. Key findings:

  • Mucosal healing (MH) was noted in 77.9% (74/95) and transmural healing (TH) in 36.3% (37/102).
  • SC-IFX C-trough was significantly higher in patients with MH (24.1 vs.16.9 μg/mL; p=0.001) and TH (26.0 vs. 20.5 μg/mL; p=0.007) than in those without.

Discussion:

Target trough levels: In this study, the authors found that “the C-trough thresholds for clinical remission, biochemical remission, MH and TH were 12, 16, 18 and 30 μg/mL, respectively, based on ROC analysis. The C-trough of SC-IFX increased with the depth of remission.”

Why trough level targets may differ between IV administration and SC: Administration via the IV route results in early and rapid peak concentration followed by a steady decline to trough, whereas administration via the SC route has slower absorption, lower bioavailability, lower peak concentration and smaller differences between peak and trough concentrations.

The authors note that a study by Ye et al (United European Gastroenterology Journal; 2020: 8: 385–386) with 55 patients found that a C-trough >26.6 mcg/mL achieved clinical remission and fecal calprotectin levels <250 mcg/g at week 54 in 79% and 91% respectively compared to 46% and 62% in those with with C-trough <16.4 mcg/g.

These C-trough levels are significantly higher that the median C-trough levels of standard dosing (120 mg biweekly) in a phase 1 dosing RCT which was only 13.3 mcg/mL (S Schreiber et al. Gastroenterology 2018; 154: 1371). The dosing of 180 mg and 240 mg biweekly resulted in C-trough levels of 19.9 mcg/mL and 26.5 mcg/mL respectively.

My take: This study suggests that therapeutic drug monitoring will have different targets with SC-IFX than with IV-SC. SC formulations will offer more convenience. However, more effort will be needed to make sure patients are adherent with therapy in order to achieve optimal outcomes.

Related study: S. N. Hong, J. Hye Song, S. Jin Kim, et al. Inflammatory Bowel Diseases 30 (2024): 517–528. One-Year Clinical Outcomes of Subcutaneous Infliximab Maintenance Therapy Compared With Intravenous Infliximab Maintenance Therapy in Patients With Inflammatory Bowel Disease: A Prospective Cohort Study. In this prospective study with 61 patients, SC IFX switch induced a higher 1-year durable remission rate than continuing IV IFX in patients with IBD during scheduled maintenance therapy.

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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.

Case Study: Pediatric Emergency from Magnet Ingestion

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G Prasad, V Jain. N Engl J Med 2024;391: e48. Small-Bowel Obstruction and Intestinal Fistula from Accidental Ingestion of Magnets

Case presentation excerpt:

A previously healthy 18-month-old girl was brought to the emergency department with sudden-onset abdominal distention that had been preceded by 3 days of diarrhea and 1 day of vomiting…an emergency exploratory laparotomy was performed. An ileocecal fistula (Panel B, circle) created by the union of three magnetic beads was identified (arrow, cecum; asterisk, ileum), and dilated loops of bowel were noted. The bowel was repaired. The patient was discharged after five days.

My take: There are a lot kids admitted for multiple magnet ingestion. Even in well-appearing children, due to concerns for complications, they are often observed until progression of the magnets. However, it does seem that many do not advance well after working their way to the cecum.

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Vonoprazan Treatment of Heartburn in Randomized Study of Patients with Non-Erosive Reflux Disease

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L Laine et al. Clin Gastroenterol Hepatol 2024; 22: 2211-2220. Open Access! Vonoprazan is Efficacious for Treatment of Heartburn in Non-erosive Reflux Disease: A Randomized Trial

This was a randomized trial (n=772) in patients diagnosed with non-erosive reflux disease (NERD) comparing vonoprazan (10 mg and 20 mg) versus placebo for heartburn relief. Reflux was NOT confirmed with ambulatory pH monitoring.

Key findings:

  • The percentage of 24-hour heartburn-free days was 27.7% for placebo vs 44.8% for vonoprazan 10 mg (P < .0001) and 44.4% for vonoprazan 20 mg ( P < .0001).
  • The results were similar between both doses of vonoprazan
  • The benefit of vonoprazan appeared to begin as early as the first day of therapy. Treatment effect persisted after the initial 4-week placebo-controlled period throughout the 20-week extension period. 
  • In a post-hoc analysis, there was a very small response in patients without prior PPI response compared to placebo: There was a possible trend to fewer (7%–9%) 24-hour heartburn-free days with vonoprazan in those without prior PPI response

Discussion points: “Post hoc analysis raised the possibility that patients who previously had not responded to PPIs may have a somewhat lower response to vonoprazan. This is not unexpected, given that patients not responding to PPIs are less likely to have heartburn due to acid reflux” and more likely to have functional heartburn. The treatment effect of vonoprazan was less clear in the subgroup of patients with NERD and with severe heartburn “It is conceivable this group included a higher proportion of subjects with functional heartburn, a condition that is generally not responsive to acid inhibition.”

My take: Vonoprazan is more effective than placebo for heartburn in patients with NERD. However, the absence of definite improvement in the patients with lack of prior PPI response along with the lack of difference between the 10 mg and 20 mg vonoprazan groups indicates that this therapy should NOT be used routinely in patients with NERD in the absence of documented reflux based on ambulatory pH studies.

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Effects of Thiopurine Withdrawal in Randomized Trial of Vedolizumab-Treated Patients with Ulcerative Colitis

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A Pudipeddi et al. Clin Gastroenterol Hepatol 2024; 22: 2299-2308. Open Access! Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial

Methods: This was a multicenter randomized controlled trial recruited UC patients (n=62) on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine.

Key findings:

  •  At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 μg/mL versus 15.9 μg/mL, respectively, P = 0.36).
  • The continue group had significantly higher fecal calprotectin remission (calprotectin <150) (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Clinical and endoscopic remission favored the continue group though this did not reach statistical significance.
  • Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6–146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3–33.8; P = .03) predicted clinical relapse after thiopurine withdrawal.

Discussion: “In Australia, requirements are for UC patients to have failed at least 3 months of an immunomodulator before vedolizumab initiation. Consequently, UC patients are typically on combination therapy initially, and hence this study was designed as a withdrawal trial.” The authors note that previous studies have not shown superior outcomes with combination therapy (See blog post: No Benefit of Combination Therapy with Ustekinumab or Vedolizumab). “However, methodological flaws, heterogenous outcomes, and shorter durations of treatment limit these findings.”

My take (borrowed from authors): “Thiopurines might provide an incremental benefit to patients with UC using vedolizumab, … independent of vedolizumab pharmacokinetics.”

Related study: C Yzet et al. Clin Gastroenerol Hepatol 2021; 19: 668-679. Full Text: No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-analysis

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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.