Introduction

The distinction between intestinal tuberculosis (IT) and Crohn's disease (CD) is difficult because of the numerous clinical, endoscopic and histological similarities between these two diseases, essentially in the ileo-cecal localization, which poses a problem of positive diagnosis and therefore of therapeutic management of these patients. The diagnosis of IT can be easy when it is associated with a pulmonary or peritoneal localization, more difficult when it is isolated.
The aim of our work is to show the interest of quantiferon in the differential diagnosis between these two pathologies.

Aims & Methods

This is a retrospective, descriptive monocentric study conducted over a period of 15 years from January 2007 to July 2022. 666 cases of CD were identified including 189 patients with ileocecal localization and during the same period 53 cases of TI were included. All our patients had an endoscopic evaluation with biopsies, an entero-CT scan and a phthisiological check-up. We included all patients with ileocolitis having chronic transit disorders.

Results

The average age of our patients was 39 years for IT and 32 years for CD. The sex ratio F/H=1.4 for IT and F/H=1.2 for CD.
The circumstances of discovery were dominated by chronic abdominal pain, then diarrhea and finally subocclusive syndrome in 46.5% (n=88), 38.6% (n=73) and 15.8% (n=30) respectively in patients with a retained diagnosis of CD, and by abdominal pain, chronic diarrhea and finally constipation and/or subocclusive syndrome in 41.5% (n=22), 39.6% (n=21) and 22.6% (n=12) of the patients diagnosed with IT respectively.
Quantiferon was performed in 79 patients and was positive in 35.4% of patients (n=28) with CD and 64.5% of those with TI (n=51). ASCA was performed in 63 patients and was positive in 60% (n=38) and negative in 40% (n=25) of patients.
In cases where ASCA was positive/Qantiferon negative, the sensitivity, specificity, positive predictive value and negative predictive value for the diagnosis of CD were 80%, 98%, 93% and 50%, respectively.

Conclusion

Quantiferon has an important contribution in the differential diagnosis between IT and CD, the association with ASCA allows to refine the diagnosis between these two entities for a better therapeutic management.

Introduction

Ustekinumab has been proven to be effective for treatment of patients with Crohn's disease; however, 30–40% of patients have been reported to lose clinical response within 2 years. We aimed to evaluate the efficacy of ustekinumab and identify predictors of short- and long-term efficacy in Crohn's disease.

Aims & Methods

Patients with Crohn's disease receiving their first ustekinumab infusion in our hospital between June 2017 and September 2020 were prospectively enrolled. Concentrations of serum cytokines and chemokines were measured using a multiplex bead array assay. Trough concentration of ustekinumab in serum samples collected after 8 weeks of intravenous administration were measured by ELISA.

Results

Fifty-nine Crohn's disease patients were enrolled in this study. Among 34 clinically active patients, 38.2% achieved a clinical response at week 8. None of the assayed factors were associated with short-term clinical response. Cumulative persistence rates of ustekinumab were 77.6% at 1 year and 58.9% at 2 years. Univariate Cox regression analysis revealed that Harvey–Bradshaw Index scores at baseline, concomitant immunomodulator treatment, and concentrations of interferon gamma-induced protein-10, monocyte chemoattractant protein-1 (MCP-1), and interleukin (IL)-1RA, IL-4, IL-6, and IL-8, but not other baseline parameters and trough concentrations of ustekinumab (hazard ratio (HR): 0.9846, 95% confidence interval (CI): 0.9561–1.014), were significantly associated with loss of efficacy. Multivariate Cox regression analysis found that biologic naïve status (HR: 0.1264, 95% CI: 0.02595–0.6158) and MCP-1 concentrations (HR: 1.037, 95% CI: 1.014–1.062) were significantly and associated with loss of sustained efficacy for ustekinumab treatment.

	Univariate analysis HR	Lower limit of the 95% CI	Upper limit of the 95% CI	p value	Multivariate analysis HR	Lower limit of the 95% CI	Upper limit of the 95% CI	p value
Biologic naïve, Yes	0.2367	0.05582	1.004	0.05061	0.1264	0.02595	0.6158	0.01047
Concomitant IM, Yes	2.644	1.144	6.113	0.02297
IL-4, pg/mL	1.562	1.028	2.375	0.03685
IL-6, pg/mL	1.07	1.02	1.123	0.00568
IL-8, pg/mL	1.067	1.025	1.111	0.001415
IL-1RA, pg/mL	1.003	1.001	1.005	0.00439
IP-10, pg/mL	1.001	1.001	1.001	0.02067
MCP-1, pg/mL	1.022	1.003	1.04	0.02055	1.037	1.014	1.062	0.001754
Trough level of UST at week 8	0.9846	0.9561	1.014	0.3029

Furthermore, if patients were divided into four groups according to prior biologics use and MCP-1 level which cut-off value was determined from receiver operating characteristics (ROC) at 1 year, MCP-1 low and biologics naïve group had 100% cumulative persistence rate of ustekinumab at week 140. On the other hand, MCP-1 high and biologics exposure group had below 20%.

Conclusion

Our findings suggest that pre-treatment serum MCP-1 analysis, combined with a history of biologic use could be a novel biomarker for predicting the long-term efficacy of ustekinumab in patients with Crohn's disease. However, predicting of long-term efficacy by a trough concentration of ustekinumab at week 8 might be limited.

Disclosure

The authors declare no conflicts of interest associated with this manuscript.

Introduction

Cystic fibrosis (CF) is a chronic, progressive, autosomal recessive disease caused by mutations of a single gene on the long arm of chromosome 7 that codes for the CF transmembrane regulator (CFTR)¹. Gastrointestinal symptoms and pancreatic insufficiency occur in more than 70% of people with CF (pwCF) and 96% of them showed at least one abnormal sign at intestinal ultrasound (IUS)².
Several studies^3,4,6 also documented a significant reduction of pancreatic stiffness in pwCF with pancreatic insufficiency as compared to those without. Elexacaftor-Tezacaftor-Ivacaftor (ETI), a triple combination of CFTR modulators, increases CFTR protein activity and significantly reduces morbidity and improves quality of life in pwCF⁸.

Aims & Methods

The aim of this prospective study, which is still ongoing, was to assess intestinal symptoms, IUS signs and pancreas elastography findings at baseline (T0) and their modification after different predefined lengths (T6 and T 12) of treatment with ETI.
Between October 2021 and March 2023 all consecutive pwCF candidate for starting ETI were enrolled. Clinical, biochemical, IUS signs and pancreas elastography (2D-shear-wave elastography, Philips) were collected at T0, T6 and T12.
The results of pancreatic elastography in CF were compared to those of a group of healthy controls.
Statistical analysis was performed using statistical package (SPSS) trial version 27.0.

Results

At T0, 141 patients (mean age 20±5.8; females 40.4%) were enrolled, 84 (60%) of them were re-assessed at T6 and 34 (24%) at T12. The healthy control group included 22 participants (mean age of 22.5 ±6.6 years, female 50%).
Main gastrointestinal symptoms and IUS signs are summarized in Table 1.
As previously reported, median pancreatic stiffness in pwCF was significantly lower than in controls (4.774 kPa ±0.864 vs 6.178 kPa ± 0.649, p<0.05). In addition, pancreatic stiffness values were similar at T0 and T6 (4.67 kPa ± 0.4 vs 4.774 KPa ±0.864, p=0.7) and significantly increased after one year of ETI treatment (5.442 kPa ±1.275 vs 4.774 kPa ± 0.864, p < 0.05).

Table

	T0 (n 141)	T6 (n 84)	T12 (34)
Abdominal pain	47 (33%)*	5 (6%)	0
Diarrhoea	15 (10.3%)*	1 (1.2%)	1 (3%)
Constipation	8 (5.7%)	3 (3.6%)	0
IUS pathological signs	48 (34.0%)*	13 (15%)^	4 (12%)§
TBW (> 3 mm)	32 (22.7%)*	8 (9.5%)^	2(5.8%)§
BW dilatation	25 (18.0%)*	7 (8.3%)	3 (8%)
Abnormal intestinal content (corpuscular, mixed)	85 (60%)*	32 (38%)	13 (38%)
Mesenteric hypertrophy	13 (9%)	6 (7.1)	0
Thickened appendix	41 (29%)	19 (22.6%)^	2 (6%)§

T0 vs T6 *< 0.05; T0 vs T12 §< 0.05; T6 vs T12 ^< 0.05

Conclusion

In pwCF, ETI significantly reduced gastrointestinal symptoms and pathological IUS signs. Pancreatic stiffness values, significantly lower than in healthy controls at T0, increased to normal values in PwCF treated for one year.

References

1. Shteinberg M, et al. Cystic Fibrosis. Lancet 2021; 397 (10290): 2195-2211.
2. Fraquelli M, et al. Bowel ultrasound imaging in patients with cystic fibrosis: Relationship with clinical symptoms and CFTR genotype. Dig Liver Dis. 2016 Mar;48(3):271-6.
3. Friedrich-Rust M, et al. Non-invasive measurement of liver and pancreas fibrosis in patients with cystic fibrosis. J Cyst Fibros. 2013 Sep;12(5):431-9.
4. Piskin FC, et al. A comparative study of the pancreas in pediatric patients with cystic fibrosis and healthy children using two-dimensional shear wave elastography. J Ultrasound. 2020 Dec;23(4):535-542.
5. Sigrist RMS, et al. Ultrasound Elastography: Review of Techniques and Clinical Applications. Theranostics. 2017 Mar 7;7(5):1303-1329
6. Yılmaz K, et al. Evaluation of children and adolescent with cystic fibrosis by pancreatic elastography. Pediatr Int. 2022 Jan;64(1): e14951.
7. Middleton PG, et al. Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele. N Engl J Med. 2019 Nov 7;381(19):1809-1819.
8. Bacalhau M, et al. Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis. Pharmaceuticals (Basel). 2023 Mar 8;16(3):410.

Clinical Case Summary

Introduction: Tuberculosis (TB) is a transmissible disease associated to a high morbidity and mortality. Within the extrapulmonary forms, peritoneal TB corresponds to 11% of reported cases in the literature (1). Despite its high prevalence, its diagnosis remains a challenge due to its pauci-bacillary nature, and its nonspecific clinical findings.
Clinical case: 29 years old male patient, who consulted for abdominal pain and ascites. Abdominal and pelvis Contrast enhanced tomography revealed infiltrative material in the omental fat, ascites, irregular peritoneal thickening, and retroperitoneal mesenteric adenopathies (Fig.1). Paracentesis fluid: seroascitic albumin gradient (SAAG) estimated 1.8. The adenosine deaminase (ADA) of the ascitic fluid 181.1U/L. In diagnostic laparoscopy, it was observed miliary infiltration in the peritoneum. The pathology report described a caseating necrotizing granulomatous inflammatory process (Fig.2); confirming the diagnosis of PTB. Isoniazid, rifampicin, pyrazinamide, and ethambutol was initiated for 2 months, followed by isoniazid and rifampicin for 4 months with total improvement of the patient.
Discussion: The diagnostic approach of the patient with ascites is based on the study of ascitic fluid and the determination of SAAG; a value of >1.1 points towards ascites due to portal hypertension (PHT) and <1.1 towards ascites due to non-PHT. (2) In our patient, the biochemical analysis of the ascitic fluid determined (SAAG>1.1) with a high probability of PHT, leading the physician to initially suspect this cause and dismiss other neoplastic, infectious, and granulomatous diseases. However, the medical history did not correlate with PHT. In contrast, ADA study was positive. The sensitivity and specificity of this measure in PTB is 98 and 95% respectively, with a positive predictive value of 100% and a negative predictive value of 98%. (3)
Conclusión: The measurement of ADA in ascitic fluid , constitutes an essential, rapid diagnostic tool, with high sensitivity and negative predictive value for diagnostic PTB.

References

1. Gómez-Piña JJ. Tuberculosis peritoneal. Med Int Méx. 2018 mayo-junio;34(3):490-496
2. Rodríguez Brainy, Monge Eduardo, Montes Pedro, Salazar Sonia, Guzmán Edson. Eficacia de gradiente de albúmina sangre-ascitis y los análisis de proteínas en líquido ascítico en el diagnóstico de ascitis hipertensiva portal. Rev. gastroenterol. Perú 2014
3. Vasen Walter, Mauriño Eduardo, Ferro Diego, Brotto Claudia, Fernández Marty, Cabanne Ana. Acta Gastroenterol Latinoam 2016;46: 205-212.

Disclosure

No conflict of interest.

Introduction

Tofacitinib (TOF) is an effective treatment for ulcerative colitis (UC). However, compared with biologics, it is associated with a higher incidence of herpes zoster and malignant tumors, and it is contraindicated in pregnant women. Therefore, TOF is used in the second line or later for patients with UC in whom remission cannot be induced or maintained by biologics. However, patients might elect to discontinue TOF because of malignant disease or the desire to become pregnant. However, the risk of UC recurrence is high if TOF is discontinued. TOF and ustekinumab (UST) have similar mechanisms of action involving the JAK pathway¹⁾. The inflammatory cytokines suppressed by these drugs partially overlap²⁾.

Aims & Methods

The aim of this study was to investigate the efficacy and safety of active switching to UST as an alternative to TOF withdrawal. Four patients were included, and the following patient information was recorded: age, gender, duration of disease, disease severity, steroid resistance/dependence, duration of biologic and TOF use before the active switch, reason for the active switch, observation period after the active switch, remission therapy after the active switch, side effects of UST, and outcomes.

Results

Age at diagnosis (median)(months):35–64(49), Males/Females: 0/4, Disease duration(median)(months):85–227(150),Disease severity: severe/moderate: 0/4, Steroid : resistance/dependence: 0/4.

Table

Duration of biologics and tofacitinib before active switch(months)
case1：	IFX（3）→TOF(24)
case2：	IFX(53)→ADA(40)→GLM(2)→Seitai(herbal medicine)(25) →TOF(20)
case3：	ADA(6)→GLM(22)→VED(4)→TOF(24)
case4：	GLM(3)→TOF（22）
Reason for active switch	malignant disease：3　desire to become pregnant：1
Observation period after active switch(median) (months)	4-23(14)
Maintenence therapy :5ASA/AZA	4/0
Side effect of UST	none
Outcome: relapse/remission	0/4

IFX:infliximab,TOF:tofacitinib,ADA:adalimumab,GLM:golimumab,VED:vedlizumab

As illustrated in the Table, TOF was used in the second- to fifth-line setting approximately 2 years before an active switch to UST. Treatment with 5ASA alone to maintain remission was performed in all patients, and no cases of relapse, UST-related side effects, or treatment discontinuation were observed. The pregnant patient is currently progressing with her pregnancy smoothly, and she is scheduled to give birth in July 2023.

Conclusion

For patients who require TOF withdrawal, it is possible to safely and effectively maintain remission via an active switch to UST.

References

1) Feng, Z. et al. Breaking through the therapeutic ceiling of inflammatory bowel disease: Dual-targeted therapies. Biomedicine & Pharmacotherapy 158,2023, 114174
2）Danese, S. et al. JAK inhibition using tofacitinib for inflammatory bowel disease treatment a hub for multiple inflammatory cytokines. Am J Physiol Gastrointest Liver Physiol 310 (3): G155, 2016

Introduction

Eosinophilic esophagitis (EoE) is a chronic inflammatory and progressive fibrotic condition of the esophagus characterized by the infiltration of eosinophils into the esophageal mucosa and esophageal dysfunction. There remain limited treatment options for EoE and accordingly, a substantial unmet need for effective and safe medical therapies. Drug development in EoE has been hampered by heterogeneous placebo response rates, especially for clinical outcomes, and uncertainty regarding appropriate endpoint configurations. Accurate characterization of placebo response in EoE randomized controlled trials (RCTs) will help inform more future efficient trial designs.

Aims & Methods

To conduct a systematic review and meta-analysis to characterize symptomatic, endoscopic, and histologic placebo response rates in placebo controlled EoE RCTs.
Electronic database (CENTRAL, MEDLINE, EMBASE) searching (inception to 1 JAN 2024) identified placebo controlled RCTs evaluating medical therapies for adults with EoE. Studies were screened independently by 2 reviewers (AR and SA), and full texts were then reviewed for eligibility. The proportion of clinical, endoscopic, and histologic responders (improvement and remission) assigned to placebo were pooled using a random-effect model. The Stuart-Ord inverse double arcsine square root transformation method was used to compute 95% confidence intervals (CI) for point estimates of placebo response. Heterogeneity was evaluated using the I² method. Analyses were conducted in StatsDirect 3.3.6.

Results

A total of 25 placebo-controlled RCTs (placebo sample size range: N = 4–105) were included. The pooled proportion of patients receiving placebo who achieved clinical response was 41.0% (n = 11; 95% CI 29.7%, 52.8%) with substantial heterogeneity (I² = 74.9%%). Definitions of clinical response varied between studies. The pooled proportion for histologic remission (peak eosinophil count [PEC] ≤6 eos per high power field [hpf]) was 4.3% (n = 20; 95% CI 2.6%, 6.2%) with low heterogeneity (I² = 23.6%), while a more stringent definition of histologic remission (PEC ≤1 eos/hpf) yielded a pooled placebo remission rate of 1.3% (n = 18; 95% CI 0.5%, 2.5%) with low heterogeneity (I² = 0%). The pooled histologic improvement rate was 6.2% (n = 15; 95% CI 3.3%, 10.0%) with substantial heterogeneity (I² = 50.6%). Limited studies reported on endoscopic improvement and remission (Table 1).

Conclusion

More than 1 in 3 patients assigned to placebo in EoE RCTs will achieve clinical response (substantial heterogeneity detected), while less than 1 in 10 of these patients will achieve histologic remission (low heterogeneity detected). These findings highlight 1) the need to develop validated and responsive patient-reported outcome measures, which may be difficult due to the episodic nature of symptoms in EoE; and 2) the challenge of using a coprimary clinical and histologic outcome in EoE RCTs, given the discordance between symptoms and objective disease activity measures.

Table 1. Pooled proportion of placebo patients achieving measured outcomes in EoE studies

Outcome Measured in Placebo Patients (n = number of studies)	Sample Size (range)	Pooled Proportion% (95% CI)	Heterogeneity, I2% (95% CI)
Clinical Response/Improvement (n =11)	6 to 105	41.0 (29.7, 52.8)	74.9 (49, 84.8)
Clinical Remission (n = 9)	4 to 33	13.8 (5.9, 24.3)	66.2 (12.2, 81.6)
Endoscopic Response/Improvement (n = 3)	6 to 19	25.1 (12.4, 40.5)	0 (0, 72.9)
Endoscopic Remission (n = 3)	9 to 29	2.8 (0.06, 9.6)	9.1 (0, 75.3)
Histologic Response/Improvement (≤ 15 eos/hpf, n = 15)	6 to 105	6.2 (3.3, 10.0)	50.6 (0, 71.3)
Histologic Remission (n = 24) ≤ 6 eos/hpf (n = 20) ≤ 1 eos/hpf (n = 18)	6 to 105	4.3 (2.6, 6.2) 1.3 (0.5, 2.5)	23.6 (0, 55.2) 0 (0, 43.7)

Disclosure

AR: No conflicts of interest
SA: No conflicts of interest
YY: No conflicts of interest
AQ: Is an employee of Alimentiv Inc.
DBO: Is an employee of Alimentiv Inc.
BGF: consulting fees from AbbVie, Abivax, Adiso, AgomAB Therapeutics, Allianthera, Amgen, AnaptysBio, Arena Pharma, Avoro Capital Advisors, Atomwise,, BioJamp, Biora Therapeutics, Blackbird Laboratories,Boehringer-Ingelheim, Boxer Capital, Celsius Therapeutics, Celgene/BMS, Celltrion, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, Forbion, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Pharma, GSK, Hinge Bio, Index Pharma, Imhotex, Immunic Therapeutics, Intercept, JAKAcademy, Janssen, Japan Tobacco Inc., Kaleido Biosciences, Klick Health, Landos Biopharma, Lenczner Slaght, LifeSci Capital, Lument AB, Mage Biologics, Mestag, Millennium, MiroBio, Monte Rose Tx, Morgan Lewis, Morphic Therapeutics, Mylan, Nexys Therapeutics, Nimbus Therapeutics, OM Pharma, OrbiMed Origo BioPharma, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus Therapeutics and Diagnostics (Merck), Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Roivant/Televant, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Sobi, Spyre Therapeutics, Surrozen Inc., Sun Pharma, Synedgen, Takeda, Teva, Thelium, Tigenix, Tillotts, Triastek, TR1X Inc. Ventyx Biosciences, Zagbio, Zealand Pharma. Speaker fees from AbbVie, Janssen, Takeda.
VJ: consulting/advisory board fees from AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Anaptyis Bio, Astra Zeneca, Avoro Capital, Bristol Myers Squibb, Celltrion, Eli Lilly, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GlaxoSmithKline, Genentech, Gilead, Innomar, JAMP, Janssen, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus Biosciences, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion; and speaker’s fees from, Abbvie, Ferring, Bristol Myers Squibb, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi.
AJB: AJB received research funding from Nutricia, Thelial, Sanofi/Regeneron, SST, and Dr. Falk Pharma and received speaker and/or consulting fees from Laborie, Medtronic, BMS, Dr. Falk Pharma, Calypso Biotech, Eupraxia, Aqilion, Alimentiv, Sanofi/Regeneron, Reckitt and AstraZeneca
ESD: Research funding: Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, Shire/Takeda
Consultant: Abbott, Abbvie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Apollo, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, Upstream Bio
Educational grant: Allakos, Aqilion, Holoclara, Invea
CM: consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma Inc, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Pendopharm, Pfizer, Prometheus Biosciences Inc., Roche, Sanofi, Takeda, Tillotts Pharma; speaker's fees from AbbVie, Amgen, AVIR Pharma Inc, Alimentiv, Bristol Myers Squibb, Eli Lilly, Ferring, Fresenius Kabi, Janssen, Organon, Pendopharm, Pfizer, Sanofi, Takeda, Tillotts Pharma; royalties from Springer Publishing; research support from AbbVie, Ferring, Pfizer.