Introduction

Cholestatic pruritus in patients with primary biliary cholangitis (PBC) is frequently debilitating and lacks effective treatments. In the Phase 3 RESPONSE trial (NCT04620733), seladelpar, a first-in-class delpar (selective PPAR-delta agonist), significantly decreased pruritus in PBC patients with moderate to severe pruritus (numerical rating scale [NRS] ≥4 at baseline) vs placebo. Here, we further evaluated pruritus patterns in RESPONSE.

Aims & Methods

Patients with PBC who received ursodeoxycholic acid (UDCA) for ≥12 months or were UDCA intolerant and had alkaline phosphatase ≥1.67 x upper-limit-of-normal (ULN) and total bilirubin ≤2 x ULN were randomised 2:1 to receive daily oral seladelpar 10 mg or placebo for 12 months. We assessed trends in mean NRS over time and change in pruritus using various thresholds of improvement (eg, ≥3- and ≥4-point reductions in NRS, near resolution of itch [NRS ≤1]) in patients with NRS ≥4 or NRS ≥7 (severe itch) at baseline. Development of pruritus in patients without itch (NRS=0) at baseline and safety by subgroup of baseline NRS (≥4 or <4) were also evaluated.

Results

72 of 193 enrolled patients had a baseline NRS ≥4, with 49 randomised to seladelpar and 23 to placebo; 16 seladelpar and 12 placebo patients had NRS ≥7. Among patients with NRS ≥4 at baseline, seladelpar reduced the mean itch intensity from moderate to mild from Month 3 through 12, whereas the mean itch intensity for placebo remained moderate. For patients with baseline NRS ≥4, 46.9% of patients on seladelpar had a ≥3-point NRS decrease vs 21.7% on placebo at Month 12; a ≥4-point NRS decrease was achieved by 30.6% of seladelpar patients vs 8.7% placebo. A higher proportion of patients with baseline NRS ≥4 (26.5%) and NRS ≥7 (18.8%) on seladelpar experienced near resolution of itch at Month 12 vs 0% of patients on placebo. In patients without itch at baseline, 26.7% (4/15) of placebo patients reported pruritus at Month 12 vs 0% (0/30) of seladelpar patients. Adverse events were reported in 88.9% and 84.3% of patients with baseline NRS ≥4 and NRS <4, respectively, with similar proportions across treatment arms.

Conclusion

Seladelpar reduced pruritus severity in PBC patients with a durable effect over time and even led to near resolution of itch in some patients, an effect not observed with placebo. Seladelpar mitigated new onset of itch in patients without pruritus and was overall safe and well tolerated regardless of baseline itch.

Disclosure

AEK reports receiving grants or contracts from Gilead Sciences, Inc., Intercept Pharmaceuticals and Roche; consulting fees from AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; Astellas; AstraZeneca; Attovia Therapeutics; Avior Bio; Bayer; Bristol Myers Squibb; Böhringer-Ingelheim; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Rectify Pharma; Roche; and Takeda; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Advanz Pharma; AOP Orphan Pharmaceuticals; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Johnson & Johnson; Medscape; Merck Sharp & Dohme; Mirum Pharma; NewBridge Pharmaceuticals; Novartis; Roche; Vertex Pharmaceuticals; and Viofor; support for attending meetings and/or travel from Gilead Sciences, Inc.; participation on a data safety monitoring board with AbbVie; Advanz Pharma; Alentis Therapeutics; Alfasigma; AstraZeneca; Avior Bio; Bayer; Bristol Myers Squibb; CymaBay Therapeutics; Escient Pharmaceuticals; Falk; Gilead Sciences, Inc.; GSK; Guidepoint; Intercept Pharmaceuticals; Ipsen; Merck Sharp & Dohme; Mirum Pharma; Novo Nordisk; Roche; and Takeda; and a leadership or fiduciary role in other board, society, committee, or advocacy groups (paid or unpaid) with PBC Foundation, Swiss Association for the Study of the Liver (SASL), Swiss Gastroenterology Society (SGG), Swiss Hepa, and Swiss Transplant Society (STS). CL reports receiving research grants paid to her institution from Calliditas Therapeutics; CymaBay Therapeutics; Escient Pharmaceuticals; EWR; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Kowa; Mirum Pharma; Target; and Zydus Pharmaceuticals; consulting fees from Calliditas Therapeutics; CymaBay Therapeutics; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Kowa; and Mirum Pharma; and participation on a data safety monitoring board with COUR Pharmaceuticals. MJM reports receiving grants or contracts from CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; Ipsen; and Mirum Pharma; consulting fees from CymaBay Therapeutics, GSK, Intra-Sana Laboratories, Ipsen, Ironwood Pharmaceuticals, Mallinckrodt Pharmaceuticals, and Mirum Pharma; and support for attending meetings and/or travel from CymaBay Therapeutics, GSK, Ipsen, and Mallinckrodt Pharmaceuticals. CLB reports receiving grants or contracts to his institution from Boston Scientific; Bristol Myers Squibb; Calliditas Therapeutics; Cara Therapeutics; Chemomab; COUR Pharmaceuticals; CymaBay Pharmaceuticals; Gilead Sciences, Inc.; GSK; and Hanmi Pharmaceuticals; and consulting fees from Alnylam Pharmaceuticals; Chemomab; CymaBay Therapeutics; Gilead Sciences, Inc.; GSK; Ipsen; and NGM Bio. KVK reports receiving grants or contracts from 89Bio; Boston Scientific; Corcept Therapeutics; CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; Hanmi Pharmaceuticals; Intercept Pharmaceuticals; Ipsen; Janssen; Madrigal Pharmaceuticals; Mirum Pharma; Novo Nordisk; NGM Bio; Pfizer; Pliant Therapeutics; Terns Pharmaceuticals; Viking Therapeutics; and Zydus Pharmaceuticals; royalties or licences from UpToDate; consulting fees from 89Bio; CymaBay Therapeutics; Genfit; Gilead Sciences, Inc.; GSK; HighTide Biopharma; Inipharm; Intercept Pharmaceuticals; Ipsen; Madrigal Pharmaceuticals; Mirum Pharma; NGM Bio; and Zydus Pharmaceuticals; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AbbVie; Gilead Sciences, Inc.; and Intercept Pharmaceuticals; participation on a data safety monitoring board or advisory board with CTI and Medpace; and stock or stock options with Inipharm. GMH reports having consulted for Advanz Pharma; CymaBay Therapeutics; Falk; Gilead Sciences, Inc.; GSK; Intercept Pharmaceuticals; Ipsen; Kowa; Mirum Pharma; and Pliant Therapeutics. CH, SC, KY, and DBC are employees of Gilead Sciences, Inc., and may own stock in Gilead Sciences, Inc. CAM reports former employment with CymaBay Therapeutics, a Gilead Sciences, Inc., company, from 2007 to 2024; receiving consulting fees from Gilead Sciences, Inc.; being listed as an inventor on seladelpar patents; and a leadership or fiduciary role (paid or unpaid) with 89Bio (independent director). DEJJ reports receiving consulting fees for CymaBay Therapeutics, Ipsen, Kowa, and Umecrine, grants from Intercept, and participation on a speakers’ bureau for Falk, GlaxoSmithKline, Intercept, and Ipsen.

Introduction

Pain in chronic pancreatitis (CP) varies between patients in pattern, severity, and psychological impact. CP pain assessment has been focused on intensity, missing the complexity. To address the importance of multidimensional pain evaluations, we aimed to identify pain phenotypes based on multidimensional pain assessments and examine their association with clinical factors.

Aims & Methods

We studied 248 patients with painful CP from Asia, Europe, and the USA. A cluster analysis was performed on patients with painful CP, including five pain dimensions from the COMPAT-SF questionnaire (severity, fluctuation, provocative factors, spreading pain, and qualitative descriptors). The resulting clusters were compared based on demographics and clinical data, including patient-reported outcomes and quantitative sensory testing.

Results

		Cluster 1	Cluster 2	Cluster 3	p-value​
Questionnaires	Quality of life	66.3 (22.5)	64.8 (27.7)	51.1 (24.6)	<0.001
	Catastrophizing	10.7 (11.2)	19.1 (12.4)	24.3 (13.0)	<0.001
	Anxiety	5.3 (4.1)	6.2 (4.2)	8.7 (4.5)	<0.001
	Depression	4.3 (4.3)	5.5 (4.6)	7.3 (4.7)	<0.001
	Sleep	5.0 (3.5)	5.9 (3.8)	7.5 (4.5)	<0.001
QST	PPDT sum, kPa	2284 (997)	1811.5 (574.6)	1640.1 (600.4)	<0.001
	PPTT sum, kPa	2909.6 (1247.3)	2227.1 (691.3)	2184.9 (903.2)	<0.001
	Temporal summation, abdomen	1.7 (1.8)	1.9 (1.5)	1.4 (1.8)	0.178
	CPM (%)	2.3 (18.3)	5.1 (23.7)	7.2 (17.7)	0.135

Three distinct pain phenotypes were identified in the cluster analysis. Cluster 1 (n=73) included patients with low-severity pain; Cluster 2 (n=80) was characterized by severe, fluctuating pain; and Cluster 3 (n=95) comprised patients reporting constant, severe pain. Patients in Clusters 1 and 2 reported low scores across the remaining dimensions, whereas Cluster 3 consistently scored higher. Quality of life and sleep were best in Cluster 1, declined in Cluster 2, and were lowest in Cluster 3 (both p<0.001). Scores for anxiety, depression, and catastrophizing increased progressively across clusters (all p<0.001). Sensory testing revealed a pattern of increasing hyperalgesia, with Cluster 3 showing the most pronounced responses (p<0.001).

Conclusion

The COMPAT-SF questionnaire identifies three pain phenotypes in CP. Greater pain severity and persistence correlate with increased hyperalgesia, higher psychological distress, and worse overall well-being.

Introduction

Visceral artery pseudoaneurysms typically originate from the splanchnic circulation, often as a result of inflammation, trauma, or infection. If left untreated, these pseudoaneurysms carry a near 100% mortality rate. Endovascular intervention by interventional radiologists is currently the preferred treatment approach. The role of endoscopic ultrasonography (EUS)-assisted interventions in managing visceral pseudoaneurysms is an evolving area of clinical practice.

Aims & Methods

In this retrospective single-centre study conducted between January 2020 to December 2024, the technical and clinical success of EUS-guided embolisation of visceral arterial pseudoaneurysms was assessed. Technical success was defined as absence of blood flow on color doppler imaging after successful placement of coil or in combination with thrombin. Clinical success was defined as the absence of re-bleeding or pseudoaneurysm recurrence during a follow-up period of 12 weeks.

Results

A total of 26 patients (88.46% males) were included, selected based on computed tomography angiography (CTA). EUS could not visualize pseudoaneurysms in two patients, thus EUS-guided intervention could be performed successfully in 24/26 patients, yielding a technical success rate of 92.30%. The median age of the study population was 33 years (IQR 25-42). The most common underlying condition was pancreatitis, with chronic pancreatitis affecting 17/26 patients (65.38%) and acute pancreatitis affecting 7/26 patients (26.92%). The splenic artery was the most frequently involved (13/26 patients, 50%), followed by the gastroduodenal artery (9/26 patients, 34.61%). The median size of the pseudoaneurysms was 1.5 cm (IQR 1-2.6 cm). Clinical success was achieved in 20/24 patients (83.33%). Despite technical success, three patients experienced early re-bleeding. Two patients were managed with rescue procedures, while one patient succumbed to bleed despite rescue intervention. One patient had a recurrence of pseudoaneurysm.

Conclusion

EUS-guided embolization using coil, alone or in combination with thrombin, is a safe and effective method for managing visceral arterial pseudoaneurysms, even as a first-line intervention. This approach warrants further validation in larger cohorts and its direct comparison with the endovascular approach.

Disclosure

No Conflict of Interest

Introduction

Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) is currently the leading cause of chronic liver disease worldwide, affecting more than 65% of patients with Type 2 Diabetes Mellitus (T2DM). The aim of our study was to determine the prevalence of MASLD among T2DM patients, with or without coexisting significant fibrosis, to assess its association with diabetic complications, and to identify the factors linked to MASLD in our population.

Aims & Methods

We conducted a retrospective, descriptive, and analytical study including T2DM patients admitted to the Endocrinology Department in 2019. MASLD diagnosis was based on the presence of hepatic steatosis detected by abdominal ultrasound or a Hepatic Steatosis Index (HSI) >36. Fibrosis was assessed using the Fibrosis-4 (FIB-4) index (with a threshold of ≥1.3 or <1.3). Chronic Kidney Disease (CKD) associated with T2DM was defined by an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m² and/or dipstick-positive proteinuria (>1+). Diabetic Peripheral Neuropathic Pain (DPNP) was assessed using the Douleur Neuropathique 4 (DN4) questionnaire, and Diabetic Retinopathy was diagnosed via dilated eye examination.

Results

Among the 202 patients included, the median age was 57 years (±12 years) with a marked female predominance (sex ratio = 2.6). Regarding comorbidities, 58.4% of patients had hypertension and 34.2% had dyslipidemia. The median Body Mass Index (BMI) was 27 kg/m² (±5.62), with overweight or obesity present in 61.4% of the cohort. The median duration of diabetes was 10 years (±7.8 years). Impaired renal function (eGFR <60 ml/min/1.73 m²) was found in 9.9% of patients, and proteinuria in 6.9%. Diabetic neuropathy (DN4 score ≥4) was present in 7.9% of patients, while diabetic retinopathy was diagnosed in 37.6% of cases.
The prevalence of MASLD in our cohort was 73.3%. The median FIB-4 score was 0.91 (±0.63), with 25.7% of patients presenting a FIB-4 >1.3. Statistical analysis identified several factors significantly associated with the presence of MASLD: female sex (p=0.004), dyslipidemia (p=0.004), BMI (p<0.001), alanine aminotransferase (ALT) levels (p<0.001), low-density lipoprotein cholesterol (LDL-C) levels (p=0.006), and triglyceride levels (p=0.013). In particular, higher BMI was strongly associated with MASLD (Odds Ratio [OR] = 1.970; 95% Confidence Interval [CI]: 1.580–2.460; p<0.001), as were elevated ALT levels (OR = 1.115; 95% CI: 1.053–1.18; p<0.001).
However, after adjustment, LDL-C levels (p=0.163), triglycerides (p=0.402), dyslipidemia (p=0.329), and sex (p=0.360) were no longer significantly associated with MASLD. Finally, a significantly higher proportion of CKD was observed in patients with MASLD (22.3%) compared to those without MASLD (9.2%, p=0.036), although this association was not maintained in the subgroup with advanced fibrosis (FIB-4 >1.3).

Conclusion

Our study confirmed the high prevalence of MASLD among patients with T2DM. Early screening is therefore essential, particularly in female patients and in those presenting with chronic kidney disease or other associated cardiometabolic risk factors such as obesity and dyslipidemia.

References

Younossi ZM, Golabi P, Price JK, Owrangi S, Gundu-Rao N, Satchi R, Paik JM. The Global Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Among Patients With Type 2 Diabetes. Clin Gastroenterol Hepatol. 2024 Oct;22(10):1999-2010.e8. doi: 10.1016/j.cgh.2024.03.006. Epub 2024 Mar 21. PMID: 38521116.

Introduction

PD-1 downregulates activated T cells and dysregulation of its signaling impacts critical T cell responses in inflammatory and autoimmune diseases, including ulcerative colitis (UC). In UC lamina propria, multiple T cell subtypes express PD-1, including peripheral helper T cells (Tph) and effector memory T cells, and the reduction of PD-1+ Tph cells is correlated with remission.¹ While PD-1 is being evaluated in UC, it has been clinically validated as a target in two Ph2 studies in RA.^2,3 Rosnilimab, an investigational antibody, aims to leverage immune homeostatic mechanisms to regulate T cell activity by depleting PD-1^high T cells and reducing the activity of remaining PD-1+ T cells.⁴ Rosnilimab, when compared to isotype control, reduced inflammation of the colon, reduced infiltration of CD4 T cells and maintained body weight of mice in a murine model of colitis induced by the transfer of CD4+CD45Rb+ T cells from human PD-1 transgenic mice.⁵ Additionally, pathway genes indicative of fibrosis and impaired barrier function in human UC were normalized in rosnilimab-treated animals while dysregulated in the control group.⁶ Myeloid cells also contribute to inflammation in human UC, and reduction of their elevated numbers are associated with disease remission.⁷ An inflammatory myeloid cell gene signature was derived from human UC and used to assess inflammatory myeloid cells and the therapeutic impact of rosnilimab in this murine model of colitis.

Aims & Methods

A UC myeloid gene signature was derived via secondary analyses of single-cell RNA sequencing data from a published atlas of human UC tissue⁷ to identify 1,652 genes that were upregulated in inflamed myeloid cells compared to non-inflamed cells. These genes were then compared with 3,859 genes upregulated in a murine model of colitis. The resultant overlap of 625 genes was used to define the mouse colitis myeloid gene signature. Overlapping genes were analyzed for regulation in the murine model of colitis following rosnilimab treatment. Myeloid cell gene transcription in colonic tissue from mice treated with rosnilimab or isotype control was assessed via spatial transcriptomics.

Results

In a murine model of colitis, rosnilimab treatment resulted in the downregulation of 399 (64%) of the mouse colitis myeloid signature genes, suggesting an ability to impact a large proportion of the overlapping genes that are similarly dysregulated in human UC. These included mediators of immune cell recruitment (Ccl3, Ccr1) and detection of bacterial components (Cd14, Tlr2 and Tlr4). Additionally, genes involved in immune activation and amplification mediated by myeloid cells were reduced by rosnilimab (Il6, Cd80, Cd86, Myd88, Trem1, and Stat4). Spatial transcriptomic analyses of colonic tissue showed that rosnilimab reduced myeloid cell numbers, including M1 and M2 macrophage subtypes, compared to isotype control treated mice.

Conclusion

In addition to reducing pathogenic T cell numbers in this murine model of colitis, rosnilimab treatment also reduced pathogenic macrophages and the inflammatory myeloid gene signature in the colon. These data support previous preclinical findings demonstrating the potential therapeutic benefits of selectively targeting activated PD-1+ T cells and depleting PD-1^high T cells in reducing inflammation and improving UC outcomes in a murine model of colitis. These results, together with existing rosnilimab safety data in humans, support the scientific rationale for evaluating rosnilimab in an ongoing Phase 2 study in UC (NCT06127043).

References

1. Long Y, et al. Immunol Letters 2021;233:2-10.
2. AnaptysBio press release February 12, 2025. Ir.anaptsbio.com/news-release-details.
3. Tuttle J, et al. N Engl J Med 2023;388:1853-62.
4. Luu K, et al. J Crohn’s Colitis 2024;18(S1):i225 (Abstract DOP81).
5. Parmley S, et al. United Eur Gastroenterol J 2024;12:482 (Abstract MP448).
6. Linggi B, et al. J Crohn’s Colitis 2025;19(S1):i475 (Abstract P0101).
7. Thomas T, et al. Nature Immunol 2024;25:2152-65.

Disclosure

All authors are employees and shareholders of AnaptysBio

Introduction

Inflammatory Bowel Diseases (IBD) are chronic immune-mediated disorders of the gastrointestinal tract. Fibrosis is a frequent manifestation in IBD driven by inflammatory cytokines. During fibrosis, extracellular matrix proteins accumulate in the tissue, causing the disruption of the epithelial barrier and stenosis, ultimately causing malabsorption and intestinal motility issues. This can eventually lead to further serious complications, strictures, fistulas, or ileus. No drugs are available targeting fibrosis, in these cases, only surgical intervention can be used. A defined primary in vitro cell culture model is not available for intestinal fibrosis modeling.

Aims & Methods

Therefore, we aimed to establish and characterize human primary fibroblast cell culture from intestinal biopsies of control and IBD patients.
Human primary fibroblast cell cultures were generated from colonic biopsy of patients with IBD (N=4) and control (N=4). All downstream analyses were applied in passage number 3. For the phenotype observation, immunofluorescent staining was used. Targeted proteins were COL1A1, TGF-ß1, PAI-1, α-SMA, and PHH3. Proteome Profiler Human Cytokine Array Kit was used for the secreted cytokine pattern observation. For the gene expression analysis, RNA was isolated, and the qRT-PCR technique was utilized for the following target genes: COL1A1, ACTA2, TGF-ß1, FN1, PAI-1, H3C4. Scratch assay was used to examine wound closure, we monitored the closing for 48 hours taking photographs throughout. We evaluated the collected data and performed statistical analysis.

Results

We can successfully generate and maintain human colon primary fibroblast cell cultures from colonic biopsies of healthy and Crohn’s disease (CD) origins. Morphological differences were observed between control and diseased patient samples. In the protein examinations, the fluorescent intensity of fibrotic markers (COL1A1, TGF-ß1, PAI-1) and the mitosis marker PHH3 were significantly higher in the CD samples, indicating that the cells maintained fibrotic phenotype and the diseased fibroblasts had a higher proliferation rate. The myofibroblast marker, α-SMA, didn’t show a significant difference. In the cytokine pattern analysis, 22 cytokines showed a twofold increase or decreased by half between the two groups. HGF and DPPIV showed higher quantities in the CD-originated fibroblast. These cytokines are connected to the induction of fibrosis. However, the ANG, BDNF, PTX-3, VEGF, and VCAM-1 were higher in the control samples. Interestingly, no significant differences were noted between the two groups in the targeted genes examined by qRT-PCR measurements. We observed the closure of the artificial wound was faster and more effective in the Crohn’s disease culture compared to the control.

Conclusion

In conclusion, we can generate primary human intestinal fibroblast cell cultures and maintain them to passage number 3, approximately a month long. Fibrotic markers, secreted cytokines and morphological differences distinguish the diseased cultures from the healthy subjects; therefore, it could be useful for in vitro fibrosis modeling in the future. On the other hand, the gene expression analysis doesn’t discriminate between the two groups at passage number 3. To continue with our work, we will observe the fibrotic properties in earlier passage numbers.

Clinical Case Summary

A 37-year-old woman with a history of heavy alcohol use (3–4 bottles of wine weekly) presented with abdominal pain and haematemesis. She had experienced intermittent abdominal pain for two years. On assessment, she was stable apart from mild tachycardia and epigastric tenderness; melaena was confirmed on rectal exam. Blood tests revealed severe anaemia (Haemoglobin "Hb" 40 g/L from a baseline of 154 g/L). Gastroscopy showed severe oesophagitis without active bleeding. Abdominal CT showed a hyperdense focus in the neck of the pancreas, raising suspicion of a neuroendocrine tumour. After blood transfusion, she was discharged (Hb 73 g/L) with plans for outpatient colonoscopy and endoscopic ultrasound (EUS) to characterise the pancreatic neck lesion.
Two days later, she was readmitted with recurrent haematemesis and a Hb drop to 56 g/L. She was stabilized and discharged again. The day after her discharge, she underwent an EUS examination in our unit. The EUS revealed signs indicative of chronic pancreatitis, as well as a thick-walled vascular structure measuring 20 mm, adjacent to the head of the pancreas. This structure appeared to originate from a posterior branch of the gastroduodenal artery, and was consistent with a pseudo-aneurysm eroding into the wall of the duodenum. A subsequent triple phase CT scan showed an increase in the size of the hyperdense focus in the neck of the pancreas, raising concern for a pseudoaneurysm near the pancreaticoduodenal artery. Following these findings, the patient underwent successful coil embolization of the pseudoaneurysm.
Conclusion: In patients with chronic alcohol use, upper gastrointestinal bleeding (UGIB) may arise from complications of pancreatitis, such as pseudoaneurysm formation, rather than solely intraluminal causes. This case highlights the need for early identification and intervention in such rare but potentially life-threatening conditions.