Key factors associated with 6-thioguanine and 6-methylmercaptopurine nucleotide concentrations in children treated by thiopurine for acute leukaemia and inflammatory bowel disease.

AIMS: Azathioprine (AZA) and 6-mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6-thioguanine (6TGN) and 6-methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. METHODS: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200-500, <6000 pmol/8 × 108 RBC for 6TGN and 6MMPN. RESULTS: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P < .0001). ALL received 6-mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti-inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. CONCLUSION: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.

Risk factors for surgery in stricturing small bowel Crohn's disease: A retrospective cohort study from the GETAID pédiatrique.

OBJECTIVES: Previous studies have shown rates of surgical resection of up to 41% in stricturing pediatric Crohn's disease (CD). In this retrospective multicenter study, our aims were to identify clinical risk factors and magnetic resonance enterography (MRE) features of small bowel strictures associated with surgery. METHODS: Pediatric patients with symptomatic stricturing small bowel CD (defined as obstructive symptoms or proximal dilatation on MRE) confirmed by MRE between 2010 and 2020 were recruited from 12 French tertiary hospitals. Patient characteristics were compared by surgical outcome multivariable Cox regression. RESULTS: Fifty-six patients (61% boys) aged 12.2 ± 2.7 years at diagnosis of CD were included. Median duration of CD before diagnosis of stricture was 11.7 months (interquartile range [IQR]: 25-75: 1.2-29.9). Nineteen (34%) patients had stricturing phenotype (B2) at baseline. Treatments received  before stricture diagnosis included MODULEN-IBD (n = 31), corticosteroids (n = 35), antibiotics (n = 10), anti-TNF (n = 27), immunosuppressants (n = 28). Thirty-six patients (64%) required surgery, within 4.8 months (IQR: 25-75: 1.8-17.3) after stricture diagnosis. Parameters associated with surgical resection were antibiotic exposure before stricture diagnosis (adjusted odds ratio [aOR]: 15.62 [3.35-72.73], p = 0.0005), Crohn's disease obstructive symptoms score (CDOS) > 4 (aOR: 3.04 [1.15-8.03], p = 0.02) and dilation proximal to stricture >28 mm (aOR: 3.62 [1.17-11.20], p = 0.03). CONCLUSION: In this study, antibiotic treatment before stricture diagnosis, intensity of obstructive symptoms, and diameter of dilation proximal to small bowel stricture on MRE were associated with risk for surgical resection.

PERFUSE: Non-Interventional Cohort Study of Patients Receiving Infliximab Biosimilar SB2: Results in Pediatric Patients.

OBJECTIVES: PERFUSE is a non-interventional study of 1233 patients [inflammatory rheumatic disease, n = 496; inflammatory bowel disease (IBD), n = 737] receiving infliximab (IFX) biosimilar SB2 therapy. This analysis describes response to treatment and persistence on SB2 for up to 12 months in pediatric IBD patients (n = 126). METHODS: Pediatric IBD patients with Crohn disease (CD) or ulcerative colitis (UC), either naïve or switched from originator IFX, who started SB2 in routine practice after September 2017 were eligible. Data were captured for 12 months following SB2 initiation. Disease activity was measured using C-reactive protein (CRP) levels and the Harvey-Bradshaw Index or Pediatric Ulcerative Colitis Activity Index for CD and UC patients, respectively. Body mass index and height z scores were used to assess patient growth between initiation (M0) and month 12 (M12). RESULTS: One hundred twenty-six pediatric IBD patients were included (102 CD patients, 51 naïve and 51 switched; 24 UC patients, 9 naïve and 15 switched). Naive patients' disease scores decreased between M0 and M12. CRP measurements also decreased in naïve CD patients. Switched patients' disease scores and CRP levels remained stable between M0 and M12. Height z scores improved significantly over the course of the treatment for all groups except for naïve UC patients. CONCLUSIONS: SB2 provides effective disease control for naïve and switched pediatric patients. Clinical remission rates improved in naïve patients and no loss of control was observed in switched patients after 1 year. Growth failure is not observed in IBD patients under SB2 treatment.

Ustekinumab Use in Pediatric Inflammatory Bowel Disease: A French Multicenter Study From the Pediatric GETAID.

OBJECTIVES: Ustekinumab is known to be efficient in adult patients suffering from moderate to severe Crohn disease (CD) and ulcerative colitis (UC) resistant to anti-tumor necrosis factor-alpha (TNF-α). Here, we described the clinical course of treatment with ustekinumab in French pediatric inflammatory bowel disease (IBD) patients treated with ustekinumab. METHODS: This study includes all pediatric patients treated by ustekinumab injection for IBD (CD and UC), between January 2016 and December 2019. RESULTS: Fifty-three patients were enrolled, 15 males and 38 females. Forty-eight patients (90%) had a diagnosis of CD and 5 (9.4%) had UC. Sixty-five percent of CD patients presented an ileocolitis. Perineal disease was observed in 20 out of 48 CD patients (41.7%), among them 9 were treated surgically. All patients included were resistant to anti-TNF-α treatment. Fifty-one percent had presented side effects linked to anti-TNF-α, including psoriasis and anaphylactic reaction. The average Pediatric Crohn Disease Activity Index (PCDAI) at induction was 28.7 (5-85), 18.7 (0-75) at 3 months of treatment and 10 (0-35) at the last follow-up. The average Pediatric Ulcerative Colitis Activity Index at induction was 47 (25-65), 25 (15-40) at 3 months of treatment and 18.3 (0-35) at the last follow-up. No severe side effects were observed. CONCLUSION: In this retrospective, multicentral study, ustekinumab proved to be efficient in pediatric patients resistant to anti-TNF-α. PCDAI has been significantly improved in patients with severe disease, treated with ustekinumab.

IgA vasculitis in patients with inflammatory bowel disease: new insights into the role of TNF-α blockers.

OBJECTIVE: The association of IgA vasculitis (IgAV) and IBD is rarely described, mainly during anti-TNF-α therapy. We aimed to describe the association of IgAV and IBD. METHODS: We retrospectively analysed the association of IgAV and IBD through the implication of the GETAID and FVSG networks. Characteristics of IBD and IgAV were collected using a standardized case report form. RESULTS: Forty-three cases were included. IBD [mainly Crohn's disease (CD) in 58%] preceded IgAV in 38 (88%), with median interval of 9.2 (IQR 5.4-15.4) years. In these 38 patients, at IgAV diagnosis, five (13%) had active IBD and 28 (74%) were treated with anti-TNF-α for a median duration of 31.5 (IQR 19-56) months. Main IgAV manifestations were purpura all patients (100%), joints in 20/35 (57%), renal in 15/35 (43%) and gastrointestinal in 11/35 (31%) involvement. IgAV was treated with glucocorticoids in 25 (66%), colchicine in six (16%), CYC in six (16%) and anti-TNF-α were discontinued in 15/28 (54%). No IgAV relapse occurred when TNF-α blockers were stopped, vs 23% in patients pursuing it. Conversely, five (33%) had IBD flare or complication after anti-TNF-α cessation vs one (8%) in those continuing biologics. Anti-TNF-α were resumed in six (40%), with subsequent IgAV relapse in four (67%). CONCLUSIONS: This large cohort suggests that TNF-α blockers may promote the onset of IgAV in IBD. Discontinuation of anti-TNF-α was associated with vasculitis remission but increased risk of IBD relapses, whereas continuation of anti-TNF-α was associated with IBD remission but vasculitis relapse.

Improved HPLC Quantification of 6-Mercaptopurine Metabolites in Red Blood Cells: Monitoring Data and Literature Analysis.

Thiopurine drugs azathioprine (AZA) and 6-mercaptopurine (6-MP) are used extensively in pediatric and adult patients with inflammatory and neoplastic diseases. They are metabolized to 6-thioguanine nucleotides (6-TGN) or to 6-methyl-mercaptopurine nucleotides (6-MMPN). The balance between 6-TGN and 6-MMPN is highly variable and monitoring is recommended, but its benefit in outcome gives rise to conflicting results, potentially increased by differences in quantifying 6-MP metabolism. Our aim was to report (1) the HPLC-UV procedure used in our laboratory to quantify red blood cells (RBCs) with 6-TGN and 6-MMPN (as its derivate: 6-MMP(d)) in patients treated with thiopurines and (2) additional tests, sometimes confirmatory, to improve method standardization. The comparison of two methods to count RBCs shows that metabolite concentrations were slightly lower in the washed and resuspended RBCs than in whole blood. Perchloric acid (0.7 M), dithiothreitol (DTT, final 0.013 M sample concentration) and 60 min hydrolysis were selected for acid hydrolysis. (3) Monitoring data from 83 patients receiving AZA or 6-MP showed that at steady state, only 53/183 (29%) had 6-TGN and 6-MMPN in the recommended therapeutic range. Our method is discussed in light of the technical conditions and sample stability data from 17 publications identified since the first analytical report in 1987. Monitoring data demonstrate, if required, that inter-patient variability in 6-TGN and 6-MMPN concentrations is high in samples from treated patients.

Bone Health in Pediatric Patients With Crohn Disease.

OBJECTIVE: The aim of our study was to examine longitudinal changes in bone mineral density (BMD) of children and adolescents with Crohn disease (CD), and risk factors related to low BMD. PATIENTS AND METHODS: All patients ages from 2 to 18 years with CD who underwent dual-energy X-ray absorptiometry (DXA) at diagnosis and at the end of follow-up between 1999 and 2018 were considered for inclusion in this retrospective study. Factors related to changes in BMD at diagnosis and during follow-up were investigated. RESULTS: One hundred and ninety-three patients had the two DXA required. At diagnosis, 36 patients (18.7%) had a low BMD.At the end of follow-up, 31 patients (16%). One hundred and sixty-four patients did not have the two DXA required.In included CD, BMD values were lower in the lumbar spine (LS) than in total body less head (TBLH), as well at diagnosis (P < 0.0001) or at the end of follow-up (P = 0.001).At diagnosis, only growth impairment or low BMI was associated with low BMD (P < 0.0001), only cumulative dose of corticosteroid at the end of follow-up (P = 0.01). CONCLUSION: The high prevalence of low BMD in children and adolescents with IBD highlights the importance of evaluating BMD in these patients at the time of diagnosis and throughout the course of their treatment. Special attention must be given to patients with height delay or low BMI at diagnosis. Long-term glucocorticoid therapy is the main clinical risk factor associated with low BMD at the end of follow-up.

A European Survey on Digestive Perianastomotic Ulcerations, a Rare Crohn-like Disorder Occurring in Children and Young Adults.

OBJECTIVES: Digestive perianastomotic ulcerations (DPAU) resembling Crohn disease lesions are long-term complications of intestinal resections, occurring in children and young adults. They are known to be uncommon, severe and difficult to treat. METHODS: In the absence of recommendations, we performed a large European survey among the members of the ESPGHAN working group on inflammatory bowel disease (IBD) in order to collect the experience of expert pediatric gastroenterologists on DPAU. RESULTS: Fifty-one patients (29 boys and 22 girls) were identified from 19 centers in 8 countries. Most patients were followed after necrotizing enterocolitis (n = 20) or Hirschsprung disease (n = 11). The anastomosis was performed at a median age (interquartile range) of 6 [1-23] months, and first symptoms occurred 39 [22-106] months after surgery. Anemia was the most prevalent symptom followed by diarrhea, abdominal pain, bloating, and failure to thrive. Hypoalbuminemia, elevated CRP, and fecal calprotectin were common. Deep ulcerations were found in 59% of patients usually proximally to the anastomosis (68%). During a median follow-up of 40 [19-67] months, treatments reported to be the most effective included exclusive enteral nutrition (31/35, 88%), redo anastomosis (18/22, 82%), and alternate antibiotic treatment (37/64, 58%). CONCLUSIONS: Unfortunately, persistence of symptoms, failure to thrive, and abnormal laboratory tests at last follow-up in most of patients show the burden of DPAU lacking optimal therapy and incomplete understanding of the pathophysiology.

Comparison of three immunoassays for infliximab trough level monitoring in paediatric inflammatory bowel diseases.

Many clinical studies in paediatric inflammatory bowel diseases (IBD) use infliximab trough level (IFX-TL) and detection of antibody against infliximab (ATI). Hence, comparison of commercially available assays is needed in paediatric samples to assess their reliability and their comparability. We measured IFX-TL and ATI-TL in sera samples of 53 IBD children using three ELISA kits: Lisa-Tracker® Duo Infliximab (Theradiag®), Ridascreen® IFX monitoring (R-Biopharm®) and Promonitor® IFX (Grifols®). Regarding IFX-TL, median values were comparable (p > 0.05), a good statistical correlation has been observed (0.73 ≤ R2 ≤ 0.85) between tested assays and the Bland-Altman analysis found an excellent agreement with a bias estimated between -0.56 and 0.12 and few values outside the 95% limits of agreement. However, qualitative comparison with therapeutic interval classifications showed some discrepancies (30.2%), mainly due to values near thresholds and more often than not with Theradiag® (22.6%). For ATI, because of non-standardized units, the qualitative comparison found a sensibly good agreement (98.1%). These data show a good agreement of IFX-TL and ATI measurement between three marketed ELISA assays with a small bias obtained. Variations in some results can lead to divergent therapeutic interval classifications and prompt us to be cautious in the interpretation of values near therapeutic thresholds.

Trough Levels of Infliximab at Week 6 Are Predictive of Remission at Week 14 in Pediatric Crohn's Disease.

OBJECTIVE: Infliximab (IFX) is a frequent therapeutic option for Crohn disease (CD) patients. Early detection of responders to IFX is critical for the management of CD in order to avoid long-term exposure to the drug without benefit. This retrospective study aimed at analysing which early parameters recorded during the induction period are able to predict response to IFX during the maintenance period in pediatric CD. PATIENTS AND METHODS: Medical records of all CD patients ages from 2 to 18 years who received IFX at a tertiary IBD center were retrospectively analyzed. Children were classified in 3 groups according to their response at week 14 (W14) remission, clinical response or , no response. The factors recorded at W0, W2, and W6, which were associated with remission at W14 were analyzed using a logistic regression. RESULTS: Among the 111 patients included, 74.8% patients were responders to IFX at W14, including 38.7% in clinical remission and 36% with partial clinical response. Clinical remission at W14 was associated with normal growth (P < 0.01), and normal albuminemia (P = 0.01) at baseline, It was also associated with trough levels to IFX >8.3 µg/ml at week 6 (P < 0.01). CONCLUSION: Trough levels to IFX >8.3 µg/ml at week 6 are predictive of remission at W14 for luminal disease.

Infliximab in young paediatric IBD patients: it is all about the dosing.

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10-18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 µg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers. •In 4.5-30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment. •Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment. •The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).

Infliximab Paradoxical Psoriasis in a Cohort of Children With Inflammatory Bowel Disease.

OBJECTIVES: In adult inflammatory bowel disease (IBD) treated by anti-TNF antibodies, paradoxical psoriasis has an estimated prevalence of 1.6 to 22%, especially in infliximab (IFX)-treated patients. Little is known in the pediatric IBD (PIBD) populations. METHODS: All patients ages from 2 to 18 years with Crohn disease (CD) or ulcerative colitis (UC) and treated for the first time by IFX between January 2002 and March 2014, were considered for inclusion in this retrospective study performed in a tertiary PIBD centre. Paradoxical psoriasis events together with clinical and biological data were collected in all patients. Comparisons between psoriasis and control groups were performed using univariate statistical analyses. RESULTS: One hundred and twenty-three CD patients and 24 UC patients were treated with IFX. Twenty patients (13.6%) experienced a paradoxical psoriasis. All of them were affected by CD. Perianal CD was more frequent in the psoriasis group (P = 0.033). Fourteen patients (70%) were in remission when skin lesions occurred. Paradoxical psoriasis was diagnosed 355 days (median, interquartile range [IQR] 239; 532) after the initiation of IFX corresponding to the eighth injection (median, IQR: 6; 15). Psoriasis lesions were controlled by local steroids in all cases and no patients discontinued IFX therapy. CONCLUSIONS: 13.6% of our IBD patients treated with IFX developed psoriasis during a median follow-up of 23.9 months (IQR: 11.6; 36.5). Crohn disease patients with perianal disease were at a higher risk to develop this common side effect.

Tacrolimus Exerts Only a Transient Effectiveness in Refractory Pediatric Crohn Disease: A Case Series.

OBJECTIVES: Tacrolimus is an immunosuppressive agent that has been proposed in the treatment of severe ulcerative colitis. The present study examined the effectiveness and safety of tacrolimus in treating refractory Crohn disease (CD) colitis in children. METHODS: All children treated by oral tacrolimus for CD colitis at a tertiary pediatric center were included in the study. All patients were refractory to steroids and infliximab. Clinical response (decreased pediatric CD activity index [PCDAI] >15 and PCDAI <30) and remission (PCDAI <10) were monitored at 2, 4, 6, 12, and 24 months after induction. Tacrolimus blood levels and adverse effects were also noted. RESULTS: Among 220 patients with CD, 8 children (including 3 girls, median age 14 [9.5-18] years) were registered with a median PCDAI of 58.7 (32.5-65) before tacrolimus initiation. In patients treated with tacrolimus, the overall clinical response rates were 6/8, 3/8, 2/8, 2/8, and 1/8 with a remission rate of 4/8, 0/8, 0/8, 2/8, and 0/8 at 2, 4, 6, 12, and 24 months, respectively. At 2 months, the PCDAI scores were lower than those at induction (median 11.2; P = 0.004) with the mean whole plasma level of tacrolimus being 8.75 ng/mL (5.9-10 ng/mL). Adverse events occurred in 6 of 8 patients, including renal dysfunction, insulin-dependent diabetes, paresthesia, and tremor. Tacrolimus interruption was required in 2 cases. CONCLUSIONS: Tacrolimus could be considered to transiently treat refractory CD colitis. Tacrolimus could be used as a "bridge" toward another medical option in pediatric CD, although its adverse events are frequent.

SKIV2L mutations cause syndromic diarrhea, or trichohepatoenteric syndrome.

Syndromic diarrhea (or trichohepatoenteric syndrome) is a rare congenital bowel disorder characterized by intractable diarrhea and woolly hair, and it has recently been associated with mutations in TTC37. Although databases report TTC37 as being the human ortholog of Ski3p, one of the yeast Ski-complex cofactors, this lead was not investigated in initial studies. The Ski complex is a multiprotein complex required for exosome-mediated RNA surveillance, including the regulation of normal mRNA and the decay of nonfunctional mRNA. Considering the fact that TTC37 is homologous to Ski3p, we explored a gene encoding another Ski-complex cofactor, SKIV2L, in six individuals presenting with typical syndromic diarrhea without variation in TTC37. We identified mutations in all six individuals. Our results show that mutations in genes encoding cofactors of the human Ski complex cause syndromic diarrhea, establishing a link between defects of the human exosome complex and a Mendelian disease.

Microvillous atrophy: atypical presentations.

OBJECTIVES: Microvillous inclusion disease (MVID) is a cause of intractable diarrhea in infancy. In its classic form, the disease is characterized by a severe persistent watery diarrhea starting within the first days of life. Parenteral nutrition and small bowel transplantation are the only known treatments for the affected children. Histologically, periodic acid-Schiff (PAS) staining shows accumulation of periodic acid-Schiff-positive staining material along the apical pole of enterocytes, whereas transmission electron microscopy exhibits microvillus inclusion bodies within the cytoplasm of enterocytes with rarefied and shortened microvilli and secretory granules. The objective of this work was to explore clinical, morphological, and genetic findings in cases of MVID with unusual presentations. METHODS: Clinical, histological, and genetic findings are reported for 8 cases of MVID with atypical presentation. RESULTS: The diarrhea started after several months in 3 cases. It was usually less abundant and 3 patients were weaned off parenteral nutrition. None required intestinal transplantation. Three patients experienced malformations, dysmorphy, sensory disabilities, and severe mental retardation. One had a hydrocephaly. Three patients had a cholestasis with low γ-glutamyl transferase levels. Light microscopy showed histological abnormalities consistent with MVID in all of the cases, but the lesions were sometimes focal or delayed. Transmission electron microscopy retrieved some criteria of MVID in 4 patients. Finally, 6 patients were homozygotes or compound heterozygotes for MYO5B mutations. CONCLUSIONS: This study extends the spectrum of MVID to less severe clinical presentations.

Paradoxical inflammatory blepharitis in a patient with Crohn's disease.

We report the case of a 15-year-old boy with severe inflammatory blepharitis who was being treated with a TNFα inhibitor for Crohn's disease (CD). This case shows the potential utility of a skin biopsy in distinguishing metastatic CD associated with granulomatous blepharitis from a paradoxical blepharitis induced by anti-TNFα. It also demonstrates that ustekinumab can be considered in patients with CD who cannot tolerate TNFα inhibitors because of cutaneous paradoxical reactions.

Robotic-assisted colectomy in children: a comparative study with laparoscopic surgery.

The aim of this study was to compare outcomes of laparoscopic and robotic-assisted colectomy in children. All children who underwent a colectomy with a laparoscopic (LapC) or robotic-assisted (RobC) approach in our institution (January 2010-March 2023) were included. Demographics, surgical data, and post-operative outcomes within 30 days were collected. Additional cost related to the robotic approach was calculated. Comparisons were performed using Fisher tests for categorical variables and Mann-Whitney tests for continuous variables. A total of 55 colectomies were performed: 31 LapC and 24 RobC (median age: 14.9 years). Main indications included: inflammatory bowel disease (n = 36, 65%), familial adenomatous polyposis (n = 6, 11%), sigmoid volvulus (n = 5, 9%), chronic intestinal pseudo-obstruction (n = 3, 5%). LapC included 22 right, 4 left, and 5 total colectomies. RobC included 15 right, 4 left, and 5 total colectomies. Robotic-assisted surgery was associated with increased operative time (3 h vs 2.5 h, p = 0.02), with a median increase in operative time of 36 min. There were no conversions. Post-operative complications occurred in 35% of LapC and 38% of RobC (p = 0.99). Complications requiring treatment under general anesthesia (Clavien-Dindo 3) occurred in similar rates (23% in LapC vs 13% in RobC, p = 0.49). Length of hospitalization was 10 days in LapC and 8.5 days in RobC (p = 0.39). The robotic approach was associated with a median additional cost of 2156€ per surgery. Robotic-assisted colectomy is as safe and feasible as laparoscopic colectomy in children, with similar complication rates but increased operative times and cost.

PERFUSE: a French non-interventional study of patients with inflammatory bowel disease receiving infliximab biosimilar SB2: a 12-month analysis.

Background: FlixabiTM (SB2) is a biosimilar of the reference infliximab (IFX), Remicade®. Published evidence on long-term, real-world use of SB2 in patients either IFX naive or transitioned from prior IFX is scarce. Objectives: We evaluated persistence, effectiveness, and safety of SB2 over 12 months in adults with IBD [Crohn's disease (CD) and ulcerative colitis (UC)], participating in PERFUSE. Design: PERFUSE is a long-term, non-interventional, multicenter study of patients receiving SB2 at specialist sites across France. Methods: SB2 treatment was initiated in September 2017, either as first IFX treatment (IFX naive), after transition from treatment with reference IFX (IFX ref) or another IFX biosimilar (IFX bs), or both IFX ref and IFX bs (IFX multiswitch). Outcomes up to Month 12 (±2) include persistence on SB2 (primary outcome measure), SB2 dose, disease status, immunogenicity, and safety. Results: This final 12-month analysis of patients with IBD includes 569 with CD and 168 with UC. Persistence [95% confidence interval (CI)] at Month 12 was CD: 89% (77.2; 94.9), UC: 78.5% (58.2; 89.8) for IFX naive; CD: 94% (91.0; 96.1), UC: 92.8% (84.8; 96.7) for IFX ref; CD: 91.6% (86.0; 95.0), UC: 94.2% (83.1; 98.1) for IFX bs; and CD 100% (100; 100), UC 100% (100; 100) for IFX multiswitch. In the CD and UC cohorts, disease activity among IFX naive patients declined from baseline to Month 12; with any prior IFX, the proportions of patients in remission at baseline, Month 6, and Month 12 remained unchanged in the UC cohort, and were comparable or higher in the CD cohort. No immunogenicity or safety signals were detected. Conclusions: Patients with IBD can be initiated on SB2 or transitioned from IFX ref and/or IFX bs to SB2, with no loss of disease control or safety concerns, with >75% of naive and >90% of transitioned patients continuing on SB2 treatment at 12 months.

Clinical Features and Natural History of Paediatric Patients with Ulcerative Proctitis: A Multicentre Study from the Paediatric IBD Porto Group of ESPGHAN.

BACKGROUND AND AIMS: Ulcerative proctitis [UP] is an uncommon presentation in paediatric patients with ulcerative colitis. We aimed to characterize the clinical features and natural history of UP in children, and to identify predictors of poor outcomes. METHODS: This was a retrospective study involving 37 sites affiliated with the IBD Porto Group of ESPGHAN. Data were collected from patients aged <18 years diagnosed with UP between January 1, 2016 and December 31, 2020. RESULTS: We identified 196 patients with UP (median age at diagnosis 14.6 years [interquartile range, IQR 12.5-16.0]), with a median follow-up of 2.7 years [IQR 1.7-3.8]. The most common presenting symptoms were bloody stools [95%], abdominal pain [61%] and diarrhoea [47%]. At diagnosis, the median paediatric ulcerative colitis activity index [PUCAI] score was 25 [IQR 20-35], but most patients exhibited moderate-severe endoscopic inflammation. By the end of induction, 5-aminosalicylic acid administration orally, topically or both resulted in clinical remission rates of 48%, 48%, and 73%, respectively. The rates of treatment escalation to biologics at 1, 3, and 5 years were 10%, 22%, and 43%, respectively. In multivariate analysis, the PUCAI score at diagnosis was significantly associated with initiation of systemic steroids, or biologics, and subsequent acute severe colitis events and inflammatory bowel disease-associated admission, with a score ≥35 providing an increased risk for poor outcomes. By the end of follow-up, 3.1% of patients underwent colectomy. Patients with UP that experienced proximal disease progression during follow-up [48%] had significantly higher rates of a caecal patch at diagnosis and higher PUCAI score by the end of induction, compared to those without progression. CONCLUSION: Paediatric patients with UP exhibit high rates of treatment escalation and proximal disease extension.

Novel mutations in TTC37 associated with tricho-hepato-enteric syndrome.

The Tricho-Hepato-Enteric (THE) syndrome is an autosomal recessive condition marked by early and intractable diarrhea, hair abnormalities, and immune defects. Mutations in TTC37, which encodes the putative protein Thespin, have recently been associated with THE syndrome. In this article, we extend the pattern of TTC37 mutations by the description of 11 novel mutations in 9 patients with a typical THE syndrome. The mutations were spread along the gene sequence, none of themrecurrent. Different types of mutation were observed: frameshift mutations, splice-site altering mutations, or missense mutations, most of them leading to the creation of a premature stop codon. Concurrently, we investigated the pattern of TTC37 expression in a panel of normal human tissues and showed that this gene is widely expressed, with high levels in vascular tissues, lymph node, pituitary, lung, and intestine. In contrast, TTC37 is not expressed in the liver, an organ that is not consistently affected in THE syndrome. Last, we suggested a model for the putative structure of the unknown Thespin protein.