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Background Pregnant women with inflammatory bowel diseases (IBD) are prone to adverse pregnancy outcomes. This study aimed to assess pregnancy outcomes and disease management for pregnant patients with IBD treated at a multi-disciplinary IBD- maternal-fetal medicine (MFM) clinic. Methods This retrospective cohort study included consecutive pregnant patients with IBD having a singleton gestation who attended the IBD-MFM clinic at the Rabin Medical Center between 2012 and 2019. We assessed disease activity and flare management at conception and through pregnancy for the IBD cohort. Pregnancy outcomes of interest included: adverse neonatal and obstetrical outcome and mode of delivery. We also assessed three integrative outcomes: a favorable and a poor pregnancy outcome and an unfavorable maternal outcome. The IBD pregnant cohort was compared with a cohort of non-IBD pregnant women who gave birth at the same shift (1:5-10 control). Multivariable logistic regression was used for risk assessment. Results 141 IBD pregnant patients and 1119 non-IBD pregnant women were included. Mean maternal age 32[±4] years. IBD patients had a higher rate of nulliparity (70% [50/141] vs. 30% [340/1119], p Conclusion In this IBD-pregnant cohort followed at a multi-disciplinary IBD- MFM clinic, outcomes were encouraging and comparable with the non-IBD cohort. A diagnosis of IBD was not associated with pregnancy or maternal outcomes.

Background Obesity [body mass index (BMI) ≥30 kg/m2 ] prevalence in patients with inflammatory bowel diseases (IBD) ranges between 15-40%. Dual-energy x-ray absorptiometry (DEXA) is the gold standard for body composition evaluation. Patients with ulcerative colitis (UC) who undergo total proctocolectomy and pouch surgery may develop small bowel inflammation (pouchitis) resembling Crohn's disease (CD). We aimed to assess body composition of patients with UC-pouch and potential risk factors for high adiposity. Methods Patients with UC-pouch ages 18-50 were recruited. Adipose tissue was assessed by DEXA (increased adipose tissue defined as > 26% male, >31% female), sarcopenia- assessed by hand-grip (defined as Results Recruited patients: 30: male/female 14/16; median age 45 (IQR 31-51.7) years; median BMI 23.2 (IQR 21-26.5); median pouch age 17 (IQR 10-25) years. One patient was obese (BMI ≥ 30 kg/m2) and seven-overweight (BMI 25-29.9 kg/m2). Median fat percentage 34.7 (IQR 30.1-39.7); 23/30 (76.6%) had increased adipose tissue. 14/30 (46%) patients were defined as normal weight obesity- normal BMI with increased adipose tissue. In univariate analysis comparing males to females, age and I-MEDAS score were comparable. Females were less physically active (p=0.028), had lower BMI (p=0.043), and higher rates of elevated adipose tissue (p=0.002). In multivariate analysis adherence to the Mediterranean diet was associated with lower adipose tissue regardless of sex and BMI (p Conclusion Patients with UC-pouch are at risk for "Normal-weight obesity", an uprising health concern, having increased adipose tissue regardless of BMI and sarcopenia. Adherence to the Mediterranean diet is inversely associated with increased adiposity, and may be used to modify adiposity in patients with UC after pouch surgery, irrespectively of BMI.

Background The orally administered small molecule drug pan-Jak inhibitor tofacitinib (TFB) appears to be effective in the treatment of ulcerative colitis (UC), however, available real world studies are limited by the cohort size. In addition, TFB may also be efficacious in patients with acute severe colitis (ASUC) as a rescue therapy. We aimed to conduct an international cohort study, to investigate the efficacy and safety of TFB in patients with moderate to severe colitis and ASUC. Methods This was a retrospective, international multi-centre, cohort study including 23 tertiary referral centres. UC patients with at least 6 weeks of TFB treatment were included. Physicians categorized the indication as rescue therapy (RT) and chronic activity (CA). Baseline demographic and clinical data, clinical/endoscopic activity indexes, laboratory parameters (including CRP, faecal calprotectin, liver enzymes, lipids, iron homeostasis), adverse events, and hospitalization/colectomy rates were collected at w0, w2-6, w8-14, w22-30 and w48-56 intervals. Steroid-free remission, colectomy rates, primary non-response (PNR) and loss-of response (LOR) rates, and safety was studied. Results A total of 391 UC patients (mean age: 39.2±14.1 years, male/female ratio 208/183; mean follow-up period 33.7±18.1 weeks) were included. 107 patients (27.4%) received TFB as a rescue therapy. Most of the patients received it as a third line treatment (37.4%). Steroid-free remission (SFR) rates were 21.3% (RT: 25.0%, CA: 22.3%) at w14, and 40.1% (RT: 32.5%, CA: 42.2%) at w52. In total, baseline pMayo (OR: 0.856; p=0.007) was negatively associated with w12 SFR, while line of treatment (OR: 0.749; p=0.047) and age (OR: 1.022; p=0.038) influenced the w52 SFR in the CA group. The w12 colectomy rate was 5.1%, and no difference was observed between groups (RT: 8.5%; CA: 3.8%), however, w52 colectomy rate was higher in the RT group (19.2% compared to 5.9%; p Conclusion TFB is effective in both moderate to severe UC, and in patients with ASUC as a rescue therapy. TFB treatment resulted in high rates of SFR and mucosal healing in short- and long term even after anti-TNF and vedolizumab failure. Higher baseline disease activity and number of previous biological therapies negatively influenced efficacy. Serious adverse events were rare.

Background Low bone mineral density (BMD) is prevalent in patients with inflammatory bowel diseases (IBD), specifically Crohn's disease (CD) due to multiple factors including active inflammation, use of corticosteroids, surgeries and nutritional deficiencies. Patients with ulcerative colitis (UC) who undergo total proctocolectomy and pouch surgery may develop small bowel inflammation (pouchitis) resembling CD. Data regarding their BMD are scarce. We assessed low BMD rates and risk factors in these patientsץ Methods Patients with UC-pouch ages 18-50 without BMD assessment in the past 5 years were recruited. BMD was assessed by dual-energy x-ray absorptiometry (DEXA). Clinical data, biochemical and inflammatory markers were detected and dietary patterns were assessed using validated questionnaires. Results Patients recruited-30: male/female 14/16; Median age 45 (IQR 31-51.7) years; median BMI 23.2 (IQR 21-26.5); median IBD duration 23 (IQR 15-30) years; median pouch age 17 (IQR 10-25) years. Low BMD detected in 16/30 (53.3%): 6/30 (20%) osteoporosis,10/30 (33.3%) osteopenia. Low L1-L4 T-scores correlated with younger age, lower BMI and shorter disease duration (p= 0.001; p= 0.001; p= 0.023, respectively). In univariate analysis patients with low and normal BMD were comparable in age, gender, BMI, smoking, past and current medical treatment. In multivariate analysis younger age and lower BMI remained significant (age SE= 0.22, β 0.422 p=0.043, BMI SE=0.06, β=0.531 p=0.006) independently of sex, years since IBD diagnosis, and smoking. Dietary patterns were comparable (p=0.715). Conclusion Abnormally low BMD was prevalent in over half of patients with UC-Pouch. Interestingly younger age and lower BMI were risk factors for low spinal BMD. Dietary patterns did not account for the findings. BMD should be routinely assessed in patients with UC-pouch and intervention to correct abnormally low BMD should be planned.

Background Recently, the European Crohn’s and Colitis Organisation (ECCO) Consensus on Quality-of-Care (QoC) Standards proposed essential criteria on the structure of units who manage patients with inflammatory bowel disease (IBD)1. The E-QUALITY taskforce investigated whether there is a gap between the given recommendations and the real-world structure of IBD units across ECCO-affiliated countries. Methods The E-QUALITY task force developed a web survey accessible to all institutions affiliated to ECCO across Europe. Each institution was invited by email to participate. Only one delegate per institution was requested to respond to the 48 questions listed in the web questionnaire. A descriptive analysis was done. Results Data were collected from September 2022 to December 2022. One-hundred nineteen institutions from 24 countries responded (Figure 1). Characteristics of the institutions are shown in Figure 2. Overall, 80 (67%) institutions identified their hospital as an IBD Unit, 75 (63%) had identified IBD sub-specialists (4 on average per hospital), 66 (55%) had a dedicated IBD nurse, 69 (58%) had an IBD surgeon, and 92 (77%) had a referral pathway for complex IBD surgery. In 81 (68%) institutions there was a regular MDT discussion of IBD cases. The multidisciplinary team (MDT) included at least one pathologist in 80 (67%) institutions, a radiologist in 86 (72%), a dietitian in 69 (58%), and a stoma specialist in 79 (66%). In 107 (90%) institutions, timely access to another sub-specialist (i.e., dermatologist, rheumatologist) was provided. Paediatric-to-adult transition clinics were available in 66 (55%) institutions. In 77 (64%) institutions, departmental IBD management guidelines were reported however, only 56 (47%) developed and applied quality indicators. Almost all institutions (113, 95%) provide direct contact to patients, mainly by telephone and email, and 105 (88%) provide remote follow-up to their IBD patients. In 111 (93%) institutions, there were facilities to administer intravenous therapies, 103 (86%) had an integrated hospital emergency department, 107 (90%) had inpatient admission rights, and 86 (82%) defined a pathway for early recognition of flares. Collaboration with patients’ associations was present in 99 (83%) of institutions, and a patient database was available in 88 (74%). Lack of dedicated funds, protected time and shortage of personnel were regarded as the three main challenges to achieving and maintaining QoC. Conclusion Our survey has revealed that the structure of IBD units across Europe seems to be consistent with the ECCO standards, although some gaps still exist. ECCO will improve programs and initiatives to help institutions provide standard QoC across countries. References: 1. Fiorino G, Lytras T, Younge L, et al. Quality of care standards in inflammatory bowel diseases: A european crohn's and colitis organisation [ecco] position paper. Journal of Crohn's & colitis 2020;14:1037-48.

Background Whether fecal calprotectin (FC) and quality of life (QoL) questionnaires reflect change in disease activity in patients with a J-pouch is unknown. Methods Patients with UC following ileal pouch-anal anastomosis developing acute pouchitis were prospectively recruited to a clinical trial at the Rabin Medical Center in Israel, a major referral center for patients with a J-pouch. Consecutive patients with acute pouchitis were diagnosed clinically by the treating physician in a patient with compatible clinical symptoms. Patients were treated with a 2-week course of antibiotics – either metronidazole and ciprofloxacin or metronidazole and doxycycline. Full PDAI, including clinical, endoscopic, and histologic evaluation, was performed at baseline and following 2 weeks of antibiotic therapy. Patients had comprehensive laboratory tests, including fecal calprotectin (FC) measurements at both time points. Patients also filled out QoL questionnaires (short inflammatory bowel disease questionnaire - SIBDQ, inflammatory bowel disease [IBD] disk) at both time points. Outcomes of interest included the responsiveness of FC and QoL questionnaires to change in pouch disease activity according to the PDAI. Paired analyses were performed to compare results between the 2-time points. Results Twenty patients were enrolled in a prospective clinical trial. At enrollment, the median age was 36 years IQR [27-56], females 12 (60%). The median interval from the ileostomy closure was 7 years IQR [2-17]. Median PDAI score: 9 IQR [8-11.5], median FC: 661 ug/g IQR [425-1261], median C-reactive protein: 1.1 mg/dl IQR [0.5-1.8] and median hemoglobin: 13.2 g/dl IQR [12.1-14.1]. Following 14 days of antibiotic treatment, there was a significant decrease in the total PDAI, which decreased from a median of 9 IQR[8-11.5] to 6 IQR[2.5-7],(p=0.007). This difference was mainly related to a significant reduction in both the clinical (p=0.01) and endoscopic subscores (p=0.001) but not the histologic subscore (p=0.1). FC was responsive to this change in PDAI and correlated with the change in endoscopic findings; it decreased significantly between the 2-time points from a median of 661 ug/g IQR[425-1261] to 294 ug/g IQR[113-418] (p=0.02). Both quality of life questionnaires (SIBDQ, IBD disk) improved significantly following antibiotic therapy: The median SIBDQ increased from 44 to 50 (p=0.02), and the median IBD disk score decreased from 59 to 31 (p=0.01) Figure 2 Panel B and C respectively. Conclusion FC is a sensitive and rapidly responsive biomarker of pouch disease activity, and we encourage its use when managing patients with pouchitis. Likewise, the SIBDQ and IBD disk accurately reflect change in QoL associated with change in disease state in patients with a pouch

Background The herbal extracts Curcumin and QingDai (QD, Indigo) were previously shown to be effective in mild-moderate and in moderate-severe ulcerative colitis (UC), respectively. We evaluated the efficacy and safety of a combination of curcumin-QingDai (CurQD) in patients with active UC. Methods This was a two parts trial. Part 1 was an open label study of 4 weeks CurQD in patients with active UC, defined by a Simple Clinical Colitis Activity Index (SCCAI) score ≥5 and a modified Mayo endoscopic sub-score≥2. Part 2 was a placebo-controlled trial conducted in two centers in Israel and Greece, that randomized active UC patients at a 2:1 ratio to either enteric-coated CurQD 3gr/day or an identical placebo for eight weeks. The co-primary outcome at week 8 was clinical response (reduction in SCCAI of ≥3 points) and an objective evidence of response (Mayo endoscopic subscore improvement of ≥1 or 50% calprotectin reduction from baseline). Responding patients continued either curcumin or placebo alone for additional 8 weeks as maintenance treatment. Expression of Cyp1A1 in rectal mucosa was assessed as a measure of aryl-hydrocarbon receptor (AhR) pathway activation. Curcumin purity, and indigo and indirubin content in CurQD were confirmed by LC-MS/MS. Results There were 59 patients enrolled in the two study parts. In efficacy analysis of part 1, 7/10 responded including 3/10 who achieved clinical remission. For part 2, 95 patients were screened and 42 were included and randomized (48.8% biologics and/or immuno-modulators experienced, 36.6% biologics-experienced). The co-primary outcome was achieved in 43% and 8% of CurQD and placebo patients, respectively (p=0.033). Clinical response was observed in 85.7% versus 30.7% (p Conclusion In this randomized controlled trial, combination CurQD was found to be effective for inducing remission in active UC patients. Induction of AhR may merit further study as a potential treatment target in active UC

Background Patients with inflammatory bowel diseases (IBD) with an increased risk of developing colorectal carcinoma should undergo periodic surveillance colonoscopies. There is no quality metric for dysplasia detection rate (DDR) in IBD surveillance. We evaluated DDR in a dedicated surveillance program at a tertiary IBD referral center. Methods This cross-sectional study assessed DDR among consecutive patients with quiescent colitis enrolled in our surveillance program. Patients underwent high-definition colonoscopy with dye chromoendoscopy (DCE). A single specialized operator performed the procedures. Advanced dysplasia (AD) was defined as low-grade dysplasia ≥ 10mm, high-grade dysplasia, or colorectal cancer. We evaluated risk factors for dysplasia detection. Results Overall, 119 patients [female: 39.5%; median age: 54 years (IQR 43-66); median disease duration: 20 years (IQR 14-29)] underwent 151 procedures that revealed 206 lesions, of which 40 were dysplastic, and seven were considered AD. Per-procedure and per-lesion DDR were: 20.5%, and 19.4%, respectively. Per-procedure AD detection rate (ADDR) was 4.6%. Per-procedure dysplasia detection was associated with increased age at diagnosis at the index colonoscopy and past dysplasia or indefinite dysplasia, however, on multivariable analysis, only past dysplasia or indefinite dysplasia maintained a significant association (AdjOR 4.84, 95% CI 1.52-15.45, p=0.008). A Kudo pit pattern of II-V had a sensitivity of 92.5% for per-lesion dysplasia detection but a false positive rate of 64.8% (p Conclusion DDR in a dedicated surveillance program in a real-world setting reached 20%. DDR should be considered a quality measure while surveying high-risk patients with IBD.

Background 5-aminosalicylates (5-ASA) are widely used in Crohn's disease (CD) despite guidelines advising otherwise. In this nationwide study, we aimed to assess the outcomes of first-line 5-ASA-maintenance therapy (5-ASA-MT) compared with no-maintenance treatment (no-MT) in patients with newly diagnosed CD. Methods We utilized data from the epi-IIRN cohort, including all patients with CD diagnosed in Israel between 2005-2020. Outcomes included therapeutic failure, hospitalization, surgeries, steroid dependency, escalation to biologics, and 5-ASA-related adverse events. Propensity-score (PS) matching was utilized to compare outcomes in the 5-ASA-MT vs. no-MT groups. Results Of the 19,264 patients diagnosed with CD, 3,027 (16%) received first-line 5-ASA-MT and 5,583 (29%) received no-MT. Both strategies declined over the years; 5-ASA-MT from 21% in 2005 to 11% in 2019 (p Conclusion First-line 5-ASA-monotherapy was not superior to no-MT but associated with a slightly higher rate of adverse events, while both strategies have declined over the years. These findings suggest that a subset of patients with mild CD may be offered a watchful waiting approach.

Background Patency capsule (PC) is a recommended procedure to rule-out small-bowel stenosis before video capsule endoscopy (VCE).We examined future clinical outcomes among patients with failed-PC versus patients in whom PC had passed (passed-PC). Methods A Post-hoc analysis of two prospective cohort studies of adult patients with quiescent small-bowel CD that underwent PC between 2013-2020. The primary composite-outcome was the need for intestinal-surgery or endoscopic-dilation during follow-up in patients with or without failed-PC. Results A total of 191 patients were included (47-failed PC, 144-passed PC, median follow-up 34.12 months). Patients with a failed-PC had higher rates of the primary composite-outcome (21.3% vs. 1.4%, Hazard ratio [HR] 20.4, 95% confidence interval [CI] 4.4-94.1, p Conclusion Clinically-stable CD patients with failed-PC have worse long-term clinical outcomes than those without, independently of CD phenotype. Standalone PC may serve as a novel, safe and affordable prognostic examination to stratify patients with CD for future risk of poor outcomes and potentially guide pre-emptive management decisions.

Background Isolated complicated perianal disease (cPD) might be the sole representation of Crohn’s disease (CD). We aimed to evaluate the impact of small bowel capsule endoscopy (SBCE) as a diagnostic tool for CD in this population. Methods A multicenter, retrospective cohort study from three tertiary centers. Patients with cPD who had a negative workup for CD (Ileocolonoscopy and cross-sectional imaging) and underwent evaluation with SBCE were included. Demographics, biomarkers, and the Lewis inflammatory score (LS) were recorded and analyzed. A LS≥135 was considered a positive SBCE. Results Ninety-one patients were included: 65 males (71.4%), mean age 40 (14) years, median duration of cPD 25.13 months (12.53-66.1). SBCE was positive in 24 patients (26.37%). Median LS was 675 (222-1518). Fecal calprotectin (FC) positively correlated with LS (r=0.81; p Conclusion SBCE was positive in over a quarter of patients with cPD and a negative workup for CD. FC levels correlated with the degree of inflammation defined by the LS. However, the sensitivity of low FC to rule out CD was low. These results suggest that SBCE is an essential diagnostic tool for patients with cPD even after negative workup.

Background There are sparse data regarding the effectiveness of novel treatment strategies for newly diagnosed patients with Crohn’s disease (CD). Data from clinical trials demonstrate 30–40% remission rates after 1-year. We aim to assess remission rates among newly diagnosed patients with CD in a referral center. Methods A prospective observational cohort study of patients with newly diagnosed CD between 03/2018- 01/2021. Patients were scheduled for semi-annual visits for assessment, data collection, and education by an IBD-oriented gastroenterologist who determined a treatment plan, IBD nurse, and dietitian. Disease activity was determined by Crohn’s disease activity index (CDAI). Clinical remission (CR) at 1-year-period (9–18 months) was defined as: CDAI < 150, no active perianal disease, and steroid-free> 3 months. Biochemical remission: C-reactive protein (CRP) Results Out of 110 enrollees, 77 completed 1-year period: 50.6% female, median age 27 years (22–38), median BMI 22 kg/m2 (20–25), 16.9% smokers. At diagnosis 72.7% had an inflammatory phenotype (B1), and 26% had complex perianal disease, 55.8% had moderate-severe CD (CDAI>220). During the first year after diagnosis 59.7% were treated with a biologic (58.5% anti-TNF, 1.3% ustekinumab, 3.9%>1 biologic), diagnosis-biologic interval 4.3 months (IQR:2.6–7.3), and 9.1% required surgery. At 1-year-period 63.6% achieved CR (comparable CR rates in patients recruited with mild-moderate vs moderate-severe CD:61.8% vs 65.1%, p= 0.814). Biochemical, endoscopic and deep remission rates: 51.9% (40/77), 44.4% (24/54), and 25.9% (14/54), respectively. Significant decrease in clinical and biochemical activity during follow up: median CDAI 233 (IQR:143–286) to 83 (IQR:29–150); median CRP 1.8 mg/dl (IQR:0.4–4.1) to 0.2 (IQR:0.1–1); median FC 714 ug/g (IQR:128–1538) to 114 (IQR:18–355); all p Conclusion In a cohort of patients with newly diagnosed CD treated by a multidisciplinary team, there were favorable 1-year outcomes; specifically, CR demonstrated in >60%.

Background Data regarding sustainability of biologics in ulcerative colitis (UC) are limited. We aimed to assess sustainability of intravenous biologics used to treat UC, infliximab (IFX) and vedolizumab (VDZ), in biologic-naïve and biologic-experienced patients, specifically focusing on their sustainability over time. Methods This retrospective cohort study was conducted at the Rabin Medical Center (RMC), a tertiary referral center for patients with inflammatory bowel diseases. We included patients ≥ 18 years, treated at the RMC IV infusion center between Dec 1st 2017 and May 1st 2021. An extensive medical chart review was performed. Patients’ data were collected from the first to last documentation of treatment or end of follow-up. Drug sustainability was defined as long as cortico-steroid-free, surgical-free treatment was documented. Data collected, included sex, age at UC diagnosis, age at biologic treatment commencement and the interval UC-diagnosis-first biologic, disease extent (proctitis, left-sided or extensive colitis), previous treatment with biologics, and clinical laboratory data. Concomitant therapy was documented as well, specifically immunomodulatory drugs. Results were adjusted to factors associated with disease severity (based on factors including hemoglobin, hematocrit, neutrophil-to-lymphocyte ratio, albumin, C-reactive protein, and total protein), combination therapy and age. Results A total of 217 patients with UC treated with IFX or VDZ were included. Of those, 186 were treatment-(biologic)-naïve. First biologic was IFX in 77 (41.3%) patients and VDZ-in 109 (58.6%). Follow-up continued for up to 300 weeks. Median survival time was 106.5 (82.9–135) weeks for IFX and 265.6 weeks (121.3–273.1) for VDZ (p=0.002, KM survival curve shown in Figure 1). Median survival time was longer for vedolizumab even when adjusting for factors associated with disease severity, combination therapy and age (HR 0.55 95 CI 0.3–0.98, p=0.042). In treatment-experienced patients, IFX and VDZ sustainability was comparable (p=0.593). Conclusion In this -real world, tertiary referral center study, VDZ had significantly longer drug sustainability in treatment-naïve patients with UC compared to IFX. This held true when adjusted for disease severity. Drug sustainability in treatment-experienced patients with UC was comparable. The data support VDZ as the first-line biologic in moderate-to-severe UC.

Background Patients with ulcerative colitis (UC) undergoing total proctocolectomy with ileal pouch anal anastomosis (pouch surgery) may be prone to develop nutritional deficiencies. Here we aimed to evaluate the rates of vitamin deficiencies and their risk factors in these patients. Methods Patients after pouch surgery were consecutively enrolled in a tertiary referral center. Pouch behavior determined clinically (normal pouch; recurrent acute pouchitis; chronic pouchitis; Crohn’s like disease of the pouch), disease activity, inflammatory markers and serum vitamin D, B12 and folic acid levels were repeatedly assessed. Body mass index (BMI) and the use of dietary supplements were recorded at each visit. Results A total of, 136 patients (mean age-, 47.5±16 years, mean BMI-, 24.9±5 Kg/m2, female gender, 58%) underwent, 721 study visits. Average visits/patients:, 5 (range, 1–15); between-visit interval:, 5±4 months. Normal pouch:, 41%, recurrent acute pouchitis, 24%, chronic pouchitis/ Crohn’s like disease of the pouch:, 35%. Vitamin D deficiency ( Conclusion In a longitudinal follow up of patients with UC after pouch surgery, we detected significant vitamin D, B12 and folic acid deficiencies and identified specific risk factors. Insufficient active correction with dietary supplements was noticed. Screening and improved correction of nutritional deficiencies should be a part of the routine pro-active multidisciplinary care of patients after pouch surgery.

Background Endoscopic post-operative recurrence (ePOR) is common following ileocecal resection (ICR) in patients with Crohn’s disease (CD), reaching up to, 70% at, 1-year. In clinical trials, prophylaxis with anti-TNF therapies demonstrated a decrease in ePOR to around, 20% at, 1-year. Here we aimed to compare the effectiveness of vedolizumab (VDZ) and ustekinumab (UST) to anti-TNFs for preventing ePOR after curative ICR in adults with CD in a real-world setting. Methods This was a retrospective multicenter study, assessing patients with CD >17years who underwent ICR between, 2015–2019, started prophylaxis within six months of surgery, and underwent an ileocolonoscopy ≥ four months after prophylaxis. ePOR (Rutgeerts score ≥ i2 or colonic-segmental-SES-CD≥6) was assessed at, 12, 24, 36-months periods post-surgery. Multivariate logistic regression was used to assess risk factors for ePOR, and IPTW was performed to compare the effectiveness between agents. Results Included, 297 patients [53.9% males, age-at-diagnosis, 24(19–32) years (median;IQR), age-at-ICR, 34(26–43)years (median;IQR), 18.5% current-smokers]. Of these, 17.2% had previous-ICR, 8.1% were biologic naïve, 65.7% anti-TNF experienced, and, 28.6% exposed to, 2 biologics. Overall, 224, 39 and, 34 patients received respectively anti-TNFs, VDZ or UST for prevention of POR. Patients on VDZ and UST were more likely to be biologic experienced or post previous-ICR. ePOR rates for the entire cohort, anti-TNF, VDZ and UST were:, 41.8%, 40.2%, 33%, and, 61.8% at, 12-months, 49.0%, 46.5%, 44.4%, and, 72.4% at, 24- months, and, 48.6%, 47.9%, 44.0% and, 62.5% at, 36-months, respectively. Risk factors for ePOR: past infliximab (Adj.OR =1.73 [95% CI:, 1.01–2.97], p=0.045) or adalimumab (Adj.OR = 2.32 [95% CI:, 1.35–4.01], p=0.002), and technical aspects of anastomosis. After controlling for the disparities between groups by the IPTW method risk of ePOR at, 12-months was comparable between patients on anti-TNFs vs VDZ or anti-TNFs vs UST. However, comparison between VDZ vs UST groups revealed that patients on UST were at a higher risk for ePOR at, 12-months (OR=3.75 [95% CI:, 1.33–10.6]), p=0.012. Conclusion Prevention of ePOR was successful in ~60% of patients at, 12-months period. Patients on prophylaxis VDZ or UST consisted of a distinct, more refractory group with higher rates of ePOR. Post-operative treatment with UST or VDZ resulted in a similar risk of ePOR when compared to post-operative prophylaxis with anti-TNF after controlling for disease severity.

Background The prevalence of inflammatory bowel diseases (IBD) is high in women of childbearing age. Maintaining remission from conception to delivery is associated with improved pregnancy outcomes, and continued drug therapy throughout pregnancy is often needed. Data regarding pregnancy outcomes in patients with IBD treated with ustekinumab (UST) are limited. We aimed to assess maternal, pregnancy, and neonatal outcomes in patients with IBD treated with ustekinumab (UST). Methods In a multicenter, prospective, cohort study, women with IBD treated with UST during conception and pregnancy were recruited between 2019–2021. Outcomes were compared between patients treated with: UST, anti-tumor necrosis factor (TNF)-a, and non-UST,non anti-TNF therapy (thiopurines or mesalazine) or no therapy. UST treated patients were matched to controls in a 1:2 ratio according to age, BMI, and number of previous pregnancies. Newborns were followed up-to 12 months. Results Pregnant patients recruited: 129, 27-UST; 52- anti-TNF; 30-non-UST, non anti-TNF 20- no therapy (the latter 50=conventional control group). The vast majority (96.9%) had Crohn’s disease (CD). Patients treated with UST compared to those treated with anti-TNF or conventional therapy, showed a trend towards longer disease duration (11 vs 7 vs 6 years, respectively, p=0.06), higher proportion of smokers (30.8% vs 5.9% vs 0%, respectively, p Among UST-treated patients, pregnancy outcomes included: two spontaneous abortions, 4% of of preterm labor and low birth weight, one congenital anomaly (tetralogy of Fallot) (4%), and 42% cesarean section. Maternal outcomes, specifically obstetric complications and hospitalizations, pregnancy, and neonatal outcomes were comparable between treatment groups. Rates of newborn 1st-year infections, hospitalizations, and developmental delay were also comparable. Conclusion Pregnant patients with IBD treated with UST comprise a highly refractory group, with high rates of disease activity at conception. Their pregnancy and neonatal outcomes were favorable, and comparable to those in patients treated with anti-TNF or conventional therapy.

Background Advanced endoscopic technologies led to significant progress in the definition of endoscopic remission of ulcerative colitis (UC), and correlate better with histological changes, compared to standard endoscopy. However, whilst studies have assessed the diagnostic accuracy of endoscope technologies individually, there is current limited data comparing between technologies. As such, we aimed to compare the correlations between endoscopy and histology disease activity scores across endoscope technologies Methods We searched PubMed and Embase in January 2021 for eligible studies reporting the correlation between endoscopy and histology activity scores in UC. Studies were grouped by endoscope technology as standard-definition white light (SD-WLE), high-definition white light (HD-WLE), or electronic virtual chromoendoscopy (VCE), and comparisons made between these groups Results A total of N=27 studies were identified, of which N=12 were included in a meta-analysis of correlations between endoscopic and histological activity scores. Combining these returned a pooled correlation coefficient (rho) for the SD-WLE group of 0.61, which did not differ significantly from HD-WLE (rho: 0.79, p=0.140) or VCE (rho: 0.70, p=0.471) [Fig 1a]. In addition, N=4 studies reported the accuracy of endoscopic activity scores on WLE and VCE to diagnose histological remission. Pooling these found significantly higher accuracy for VCE, compared to WLE (risk ratio: 1.13, 95% CI: 1.07–1.19, p Conclusion Activity scores assessed using endoscopy are strongly correlated with activity on histology. VCE appears to have better accuracy for the diagnosis of histological remission in UC, compared to WLE.

Background Patients with ulcerative colitis (UC) after total proctocolectomy and ileal pouch-anal anastomosis (IPAA) may develop chronic pouchitis or Crohn’s like disease of the pouch (CLDP). These patients may need treatment with biologic therapies. Data regarding treatment persistence as well as clinical, biochemical, endoscopic, and histologic remission rates are lacking Methods Patients after IPAA were followed prospectively at a dedicated pouch clinic. Patients with CP or CLDP who were antibiotic/steroid-refractory or dependent, had antibiotics/steroids side effects or had extraintestinal manifestations were treated with biologics. Clinical, endoscopic, histologic, and laboratory data were extracted from medical records at the last follow-up. Patient’s quality of life (QoL) was assessed by visual analog scale (VAS), with scores of, 0–100 (higher=better QoL). Time to biologic therapy discontinuation was measured for all patients; patients were censored if still on biologic therapy at the time of the last follow-up. Biochemical remission was defined as C-reactive protein (CRP) Results The prospective cohort constituted, 130 patients. Females:, 73 (56%). Before IPAA, most (70%) patients had pancolitis, 95% received steroids and mesalamine, and, 37% - biologic therapies. Median follow-up after ileostomy closure:, 16 years. Biologic therapy was started in, 28 patients (22%) due to CP or CLDP. The first line biologic for all, 28 patients was anti-TNF’s and, 9 patients received more than one line of biologics. Median time to commencing biologics:, 130 months. Median first-line biologic drug persistence:, 222 weeks. Among patients treated with biologic therapy, at the last clinic visit, median CRP was, 0.58 mg/dl, median FC:, 255ug/g, median HB:, 12.46 mg/dl, and median albumin was, 4.5 mg/dl.Median PDAI endoscopic and histologic scores were, 2; median VAS rating was, 80. Biologic remission criteria were fulfilled by, 43% of patients (N-12). An additional, 43% (N-12) were also in endoscopic remission with an endoscopic PDAI subscore of, 2 or below, and an additional, 29% of patients (N-8) were in histologic remission with a histologic PDAI score of, 0 or 1. Conclusion Biologics reintroduction after IPAA was relatively common, albeit after a very long interval. Biologic therapy was effective, with a sizable proportion of patients in biochemical, endoscopic, and histologic remission. Likewise, drug persistence was long. We suggest that early initiation of biologic therapy in certain patients may be prudent.

SETTING: This study was conducted among tuberculosis (TB) patients in a highly endemic Thai province.OBJECTIVE: To evaluate the association between different Mycobacterium tuberculosis lineages and clinical characteristics, especially mortality.DESIGN: We enrolled 1,304 TB patients registered from 2002–2011 with culture isolates whose lineages were identified by specific regions of deletion. Data on mortality within 1 year of follow-up were extracted from the registration system and hospital records. Mortality-associated risk factors, including bacterial lineages, as independent variables were analysed using Cox regression models.RESULTS: Of 1,304 isolates, 521 (40.0%) and 582 (44.6%) belonged to Indo-Oceanic and East-Asian lineages, respectively. Indo-Oceanic strains significantly increased the mortality risk compared with East-Asian strains (adjusted hazard ratio [aHR] 1.42, 95%CI 1.02–1.99) or modern lineages (aHR 1.49, 95%CI 1.08–2.06) in the 172 patients who died within 1 year after TB diagnosis. The former also caused significantly higher mortality than modern lineages among patients who died within 6 months after TB diagnosis (aHR 1.62, 95%CI 1.12–2.35). No significant association was found between drug resistance and death.CONCLUSION: In Thailand, the Indo-Oceanic lineage of M. tuberculosis increased mortality risk compared with modern lineages or the East-Asian lineage, the latter being considered highly virulent in previous studies.

Background The reported prevalence of low bone mineral density (BMD) in patients with inflammatory bowel diseases (IBD) varies between 20–50%. The multiple contributing factors include inflammation,use of corticosteroids, life style and diet.Patients with ulcerative colitis (UC) undergoing proctocolectomy with ilealpouch-anal anastomosis (IPAA) commonly develop pouchitis-de novo inflammation in previously normal small bowel, which may resemble Crohn’s disease (CD). We aimed to assess rate of low BMD in patients with a pouch and rate of DXA performance. Methods Patients after IPAA due to UC were prospectively followed; Questionnaires regarding demographic, disease course, surgery, diet and blood tests were collected biannually. BMD was assessed by dual-energy x-ray absorptiometry(DXA).All medical records were reviewed for DXA performance within the last five years, if not found-patients were contacted and submitted the results. Low BMD was defined as T score < -1. Results Out of 146 prospectively followed patients, data regarding DXA was available for 114; 70 (61%) women. Median age 46 (IQR 38–67), median age at UC diagnosis 21 years (IQR 15.7–29.5), median pouch age 16 years (IQR 8.5–22.5). DXA scans were performed in 41/114 patients (36%), low BMD was noted in 68.3 %: osteopenia- 16 (39%), osteoporosis: 12 (29.3%). Patients performing DXA scan were older: 54 (IQR 42–64) vs. 45 years (IQR 31–54) (p=0.012), and were diagnosed with UC at younger age: 23 (IQR 17–29) vs. 19 years (IQR 14–26) (p=0.018). Smoking, UC duration prior to IPAA, indication for surgery, pouch age and pouchitis were comparable between patients who performed and did not perform DXA scans. In patients with low BMD- current smoking rates were higher compared to those with normal BMD:4 (14.3%) vs. 0 (p=0.008),respectively. Vitamin D levels in patients with low and normal BMD were comparable:22.8 (IQR 17.5–26) vs. 20 (IQR 16.8–21.8)ng/ml (p=0.158), respectively. Vitamin D supplementation was comparable as well [38% vs. 60% (p=0.16)]. No differences in micronutrients consumption between the groups were noticed. Conclusion In a prospective cohort of patients after IPAA due to UC, approximately 36% performed DXA scans and the majority of them had low BMD, with smoking as a potential risk modifier. Due to high rates of low BMD in this population multidisciplinary advice and follow up should be provided to address the low performance of DXA scans and the abnormalities in BMD.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since vendredi 4 novembre 2016

Anti-tuberculosis drug-induced liver injury (AT-DILI) is one of the most common forms of drug-induced liver injury (DILI) in high tuberculosis (TB) burden countries. Among anti-tuberculosis drugs, isoniazid is the main cause of hepatotoxicity in patients with AT-DILI.To investigate the association of AT-DILI with N-acetyltransferase 2 (NAT2) genotype status in Thai TB patients.We enrolled 53 patients diagnosed with AT-DILI and 85 patients who tolerated anti-tuberculosis treatment as controls. Acetylator status was determined based on the inferred NAT2 haplotypes from four common single-nucleotide polymorphisms (SNPs) in Thais using Sanger sequencing.Phenotype frequencies of the NAT2 acetylator in AT-DILI patients were respectively 71.7%, 22.6% and 5.7% for slow, intermediate and rapid acetylators. Among slow, intermediate, and rapid acetylators in treatment tolerant controls, phenotype frequencies were respectively 22.4%, 62.4% and 15.3%. Slow NAT2 acetylators demonstrated a significant association with risk of AT-DILI. The odds ratio of comparing slow NAT2 acetylator in DILI patients and tolerance was 8.80 (95%CI 4.01-19.31, P = 1.53 × 10Slow acetylator status in the NAT2 genotype is a significant risk factor for DILI in Thai patients with TB. This evidence provides confirmatory data in support of the role of NAT2 in AT-DILI in the Thai population.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since mercredi 20 juillet 2016

Background The treatment of Irritable bowel syndrome (IBS) is still challenging. Partially hydrolyzed guar gum (PHGG) is a known prebiotic fiber. To assess the effects of PHGG on clinical symptoms of IBS patients in a prospective randomized double blind placebo-controlled study. Methods Suitable IBS patients were recruited into an 18-week-long study (2 weeks of run-in, 12 weeks of treatment and 4 weeks of follow-up). They were blindly randomized to receive 6 gr of PHGG or placebo. Treatment efficacy was evaluated by the Francis Severity IBS score, the IBS quality-of-life scores and scored parameters of weekly journal of symptoms. Deltas of changes between the final and baseline scores were compared between two groups. Results Of 121 patients who underwent randomization, 108 patients (49 in the PHGG group and 59 in the placebo group) had all the data needed for intention-to-treat analysis. A 12-week administration of PHGG led to a significant improvement of journal bloating score in the PHGG group versus placebo (−4.1±13.4 versus −1.2±11.9, P=0.03), as well as in bloating+gasses score (−4.3±10.4 versus −1.12±10.5, P = 0.035). The effect lasted for at least 4 weeks after the last PHGG administration. PHGG had no effect on other journal reported IBS symptoms or on Severity and Quality of life scores. There were no significant side effects associated with PHGG ingestion. The rate of dropouts was significantly higher among patients in the placebo group compared with the PHGG group (49.15% versus 22.45%, respectively, P = 0.01). Conclusions The results of this study support the administration of 6 g/day PHGG for IBS patients with bloating. Trial registration NCT01779765

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since lundi 8 aout 2016

The presence of receptor for chicken parathyroid hormone-related peptide (cPTHrP) in the cortical cells of the adrenal gland of the hen was demonstrated by radioligand binding assays. When the cortical cells were incubated in vitro with chicken adrenocorticotropic hormone (cACTH) in the presence of cPTHrP, greater production of corticosterone was observed than when incubated with cACTH alone. The results suggest that PTHrP may act directly on the adrenocortical cells via its receptor binding and increase the response to ACTH for corticosterone secretion in the hen.

A major upgrade of the Silicon Vertex Detector (SVD 2.0) of the Belle experiment at the KEKB factory was installed along with new front-end and back-end electronics systems during the summer shutdown period in 2003 to cope with higher particle rates, improve the track resolution and meet the increasing requirements of radiation tolerance. The SVD 2.0 detector modules are read out by VA1TA chips which provide “fast or” (hit) signals that are combined by the back-end FADCTF modules to coarse, but immediate level 0 track trigger signals at rates of several tens of a kHz. Moreover, the digitized detector signals are compared to threshold lookup tables in the FADCTFs to pass on hit information on a single strip basis to the subsequent level 1.5 trigger system, which reduces the rate below the kHz range. Both FADCTF and level 1.5 electronics make use of parallel real-time processing in Field Programmable Gate Arrays (FPGAs), while further data acquisition and event building is done by PC farms running Linux. The new readout system hardware is described and the first results obtained with cosmics are shown.

We have developed a new data acquisition system (DAQ) utilizing PC farms for the upgraded silicon vertex detector (SVD2) in the Belle experiment at the KEKB factory. The SVD upgrade will increase the number of readout channels by about 50% to 110592. The maximum trigger rate is also expected to rise to 1.0kHz due to the increasing beam intensity from KEKB. To manage the increased dataflow, we have constructed the DAQ system with twelve Linux PCs, each of which is directly connected to three flash AD converter boards through PCI data I/O boards. The advantages of using the PCs include the ease of software maintenance, market availability of hardware when replacements are needed, scalability and much improved processing speed. In order to decrease the data transfer load to the data storage system, we have developed data sparsification algorithms that calculate pedestal and noise, find particle hit channels and thus reduce the data down to 5% of the original volume. We have measured the data processing speed of the system at various read-out channel occupancy levels. The system is able to process data at a 1.3kHz trigger rate with 5% occupancy and will thus be able to handle the anticipated 1.0kHz trigger rate.

During the summer shutdown of 2003, the new silicon vertex detector SVD2 was installed in Belle at the KEKB factory and started to take data in October 2003. It provides important improvements in the tracking capabilities and adds new trigger functionality. In addition, a new hardware trigger Level 1.5 was designed and installed that takes advantage of the digitized SVD hit data. The improvement in the Belle trigger system will be important to deal with the increasing luminosity and higher beam currents of the KEKB factory.

We have searched for neutrinoless τ lepton decays into three charged leptons using an 87.1fb-1 data sample collected with the Belle detector at the KEKB e+e- collider. Since the number of signal candidate events is compatible with that expected from the background, we set 90% confidence level upper limits on the branching fractions in the range (1.9-3.5)×10-7 for various decay modes τ -→l-l+l- where l represents e or μ. © 2004 Published by Elsevier B.V.

If oesophageal carcinoma is detected in the superficial stage, the prognosis is better than for advanced oesophageal carcinoma. But the factors which predict the prognosis and treatment policy remain unclear. Matrix metalloproteinase-7 (MMP-7) and matrix metalloproteinase-9 (MMP-9) have been reported to have close associations with tumour invasion and metastasis. In this study, we retrospectively studied the relations between MMP-7 and MMP-9 expression in immunohistochemistry, clinicopathologic factors, and prognosis in 55 superficial oesophageal carcinomas. MMP-7 and MMP-9 expression occurred in 23.6% and 47.3% of the patients, respectively. MMP-7 expression was significantly correlated with the presence of nodal metastasis (P=0.004). MMP-9 expression was significantly correlated with the depth of tumour invasion (P=0.004), lymphatic permeation (P=0.001), nodal metastasis (P=0.049), and pathologic differentiation grade (P=0.003). By the log-rank test, MMP-7 expression and MMP-9 expression on the invasive front were related to the prognosis. In multivariate analysis, MMP-9 expression on the invasive front was an independent prognostic indicator. The combined expression of MMP-7 and MMP-9 may be a good marker for the degree of malignancy of oesophageal cancer and for the presence of lymphatic metastasis.

We report on a study of $\bar{B^{0}} \to D^{(*) 0} \pi^+ \pi^-$ decays using 29.1 fb$^{-1}$ of $e^{+}e^{-}$ annihilation data recorded at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB storage ring. Making no assumptions about the intermediate mechanism, the branching fractions for $\bar{B}^0 \to D^0 \pi^+ \pi^-$ and $\bar{B}^0 \to D^{* 0} \pi^+ \pi^-$ are determined to be $(8.0 \pm 0.6 \pm 1.5) \times 10^{-4} $ and $ (6.2 \pm 1.2 \pm 1.8) \times 10^{-4}$ respectively. An analysis of $\bar{B^{0}} \to D^{0} \pi^+ \pi^-$ candidates yields to the first observation of the color-suppressed hadronic decay $\bar{B}^0 \to D^0 \rho^0$ with the branching fraction $(2.9 \pm 1.0 \pm 0.4) \times 10^{-4}$. We measure the ratio of branching fractions ${\mathcal B}(\bar{B^0} \to D^0 \rho^0) / {\mathcal B}(\bar{B^0} \to D^0 \omega)$ = 1.6 $\pm$ 0.8.

We present measurements of CP-violating parameters in $B^0(\bar{B}{}^0) \to \eta^\prime K_S^0$ and $B^{\pm} \to \eta' K^{\pm}$ decays based on a 41.8 fb$^{-1}$ data sample collected at the $\Upsilon(4S)$ resonance with the Belle detector at the KEKB asymmetric-energy $e^{+} e^{-}$ collider. We fully reconstruct one neutral $B$ meson as a $B^0(\bar{B}{}^0) \to \eta^\prime K_S^0$ CP eigenstate and identify the flavor of the accompanying $B$ from its decay products. From the distribution of time intervals between pairs of $B$ meson decay points, we obtain the CP-violating asymmetry parameters ${\mathcal S}_{\eta^\prime K_S^0} = 0.28\pm0.55(stat)^{+0.07}_{-0.08}(syst)$, and ${\mathcal A}_{\eta^\prime K_S^0} = 0.13\pm0.32(stat)^{+0.09}_{-0.06}(syst)$. We also reconstruct charged $B^{\pm} \to \eta^\prime K^{\pm}$ decays and determine a direct-CP violating asymmetry value of ${\mathcal A}_{\eta^\prime K^\pm}=(-1.5\pm7.0(stat)\pm0.9(syst))%$.

The B -> D^{(*)} K^- K^{(*)0} decays have been observed for the first time. The branching fractions of the B -> D^{(*)} K^- K^{(*)0} decay modes are measured. Significant signals are found for the B -> D^{(*)} K^- K^{*0} and B^- -> D^0 K^- K^0_S decay modes. The invariant mass and polarization distributions for the K^-K^{*0} and K^-K^0_S subsystems have been studied. For the K^-K^{*0} sybsystem these distributions agree well with those expected for two-body B -> D^{(*)} a_1^-(1260) decays, with a_1^-(1260) -> K^- K^{*0}. The analysis was done using 29.4 fb^{-1} of data collected with the Belle detector at the e^+ e^- asymmetric collider KEKB.

This paper describes a study of B meson decays to the pseudoscalar-vector final state \rho\pi using 31.9\times 10^6 B\bar{B} events collected with the Belle detector at KEKB. The branching fractions B(B^+ \to \rho^0\pi^+) = (8.0^{+2.3+0.7}_{-2.0-0.7}) \times 10^{-6} and B(B^0 -> \rho^{+-} \pi^{-+}) = (20.8^{+6.0+2.8}_{-6.3-3.1}) \times 10^{-6} are obtained. In addition, a 90% confidence level upper limit of B(B^0 \to \rho^0\pi^0) < 5.3 \times 10^{-6}is reported.

The production of the \chi_{c2} charmonium state in two-photon collisions has been measured with the Belle detector at the KEKB e^+e^- collider. A clear signal for \chi_{c2} --> \gamma J/\psi, J/\psi --> l^+l^- is observed in a 32.6fb^{-1} data sample accumulated at center-of-mass energies near 10.6GeV, and the product of its two-photon decay width and branching fraction is determined to be \Gamma_{\gamma\gamma}(\chi_{c2})B(\chi_{c2} --> \gamma J/\psi) B(J/\psi --> l^+l^-)= 13.5 +/- 1.3(stat.) +/- 1.1(syst.)eV., Comment: 16 pages, 5 figures, to be submitted to Phys. Lett. B

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since jeudi 4 juin 2015

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since mardi 21 octobre 2014

Although primary pulmonary hypertension (PPH) is considered to be an idiopathic condition, it has been postulated that autoimmunity may play a role in the pathogenesis of the disease. This argument has been based on frequent coexisting clinical and serological rheumatic findings. Moreover, approximately in a third of the patients with PPH, and antinuclear factor can be detected. Pulmonary hypertension may appear as a secondary complication to various autoimmune conditions. In light of these findings we examined sera derived from 40 patients diagnosed as having PPH for the presence of 18 different autoantibodies by the ELISA and immunofluorescent techniques. Of the 40 patients, 62.4% had circulating autoantibodies and 47.5% presented with multiantibody responses. Autoantibodies most commonly observed were antinuclear (42.5%), anti-ssDNA (25%) and antithyroglobulin (30%) antibodies. These results may imply that in a subgroup of patients with PPH the disease may be ascribed to an immune dysregulation or alternatively that autoantibodies accompany the disease progression as an epiphenomenon.