Overlap syndrome of seronegative primary biliary cholangitis and small duct primary sclerosing cholangitis: a first case report and literature review.

Primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) are distinct liver diseases. Cases combining PBC and PSC, are extremely rare. Here, we present a case of a 39-year-old woman with a history of colonic Crohn's disease treated with azathioprine. Discontinuation of the medication was prompted by abnormal liver function tests, but subsequent evaluations revealed persistent liver injury. Extensive diagnostic investigations, including imaging, serological tests, and liver biopsy, were conducted leading to a diagnosis of PBC-PSC overlap syndrome based on the presence of concentric lamellar fibrosis and chronic non-suppurative destructive cholangitis. The patient responded well to ursodeoxycholic acid treatment. This case emphasizes the importance of recognizing and diagnosing rare overlap syndromes, particularly those involving PBC and PSC, to ensure appropriate management and improve patient outcomes.

No Correlation between Anti-drug Antibodies and Therapeutic Response in Tunisian Patients with Chronic Inflammatory Diseases Treated by TNF Blockers.

INTRODUCTION: Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. METHODS: A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). RESULTS: 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. CONCLUSION: In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.

Toxicity profile of thiopurines in inflammatory bowel disease: a retrospective cohort analysis.

BACKGROUND: Thiopurines have proven efficacy in inflammatory bowel disease. However, their use is limited by adverse effects in a subset of patients. AIMS: The present study aimed to evaluate toxicity profile and identify clinical predictive factors of thiopurine adverse effects in inflammatory bowel disease patients. METHODS: A retrospective longitudinal study was conducted among inflammatory bowel disease patients treated with thiopurines. Multiple logistic regression was used to identify risk factors for thiopurine adverse effects. RESULTS: A total of  210 patients were enrolled in the study. Mean age at disease onset was 29.8±11.4 years.  One hundred sixty-nine (169) patients had Crohn's disease, 29 had ulcerative colitis and 12 had indeterminate colitis. During a median follow-up of 28.5 ± 20 months, 56 patients (26.6%) had thiopurine-related adverse effects including digestive intolerance (n=14; 6.6%), immunoallergic reactions (n=8; 3.8%), myelotoxicity (n=25; 11.9%) and hepatotoxicity (n=8; 3.8%). Treatment withdrawal was reported in 19 patients (9%).  The only independent predictive factor for thiopurine adverse effects found in this study was steroid-dependence (OR= 3.96; 95% CI: 1.07- 14.53; p= 0.038). CONCLUSIONS: Almost a quarter of inflammatory bowel disease patients treated with thiopurines developed adverse effects. These adverse effects lead to drug withdrawal in almost 9% of patients either as monotherapy or as in combination with biologic therapies.  Steroid-dependent patients were significantly at higher risk for thiopurine-related toxicity.

Complex perianal fistulas in Crohn's disease: An anti-TNF α based medico-surgical treatment with magnetic imaging assessment.

BACKGROUND: Anti-TNFα associated to seton drainage has a central role in the treatment of complex perineal Crohn's fistulas (PAF). A precise treatment protocol is lacking. AIMS: to evaluate the results of this combined treatment and identify predictive factors of response. METHODS: It was a retrospective study which included all patients with complex PAF treated with Anti-TNFα. RESULTS: We included 49 patients, mean age of 31.6 years. 17 patients had an active rectal involvement. 35 patients had azathioprin. After the induction, 43 patients had a clinical response. Maintenance therapy was started in 45 cases. After a median of 19 months of Anti-TNFα, 24 patients had a clinical remission (with radiological remission in 20), 17 a partial clinical response, and 4 were in failure. After clinico-radiologic remission setons were removed in all patients, 46% of patients who stopped Anti-TNFα treatment after clinico-radiologic remission relapsed. Absence of rectal involvement and Clinical remission after induction were the independent predictive factors of achieving a clinical remission under maintenance therapy with Anti-TNFα (p=0.016) and clinico-radiological remission (p=0.028). CONCLUSION: An Anti-TNFα based treatment combined with long term loose seton drainage have contributed to the high rates of both clinical and radiological responses in this study. Obtaining a "deep" clinico-radiological remission should be the target of the treatment. Stopping the Anti-TNFα should be avoided even after obtaining such response.

The relationship between coagulation disorders and the risk of bleeding in cirrhotic patients.

INTRODUCTION AND OBJECTIVES: For long, bleeding in cirrhotic patients has been associated with acquired coagulation disorders. The aim of our study was to investigate the impact of acquired coagulation disorders on bleeding risk in cirrhotic patients. MATERIALS AND METHODS: Blood samples were collected from 51 cirrhotic patients with (H+) or without (H-) bleeding events and 50 controls matched by age and sex. Thrombin generation was assessed as endogenous thrombin potential (ETP). Hemostatic balance was assessed by means of ratios of pro- to anticoagulant factors and by ETP ratio with/without protein C (PC) activator (ETP ratio). RESULTS: Bleeding events occurred in 9 patients (17.6%). Compared with controls, VIII/anticoagulant factors, VII/PC and XII/PC were significantly higher in (H+) patients. No significant difference as regards all ratios across patient groups was detected. ETP ratio was significantly higher in (H+) patients than in controls (p=0.017). However, there was no significant difference between patient groups as regards ETP ratio. CONCLUSION: Hemostatic balance is shifted toward a hypercoagulability state even in cirrhotic patients who experienced bleeding. These findings provide evidence against traditional concept of hemostasis-related bleeding tendency in cirrhotic patients.

Haemostatic balance in cirrhosis.

Despite the prolongation of coagulation tests, recent studies reported an increased frequency of thromboembolic events in patients with cirrhosis. The aim of this study was to evaluate the haemostatic balance in cirrhotic patients through assessing the variation of pro- and anticoagulant factors and evaluating the in-vitro thrombin generation in patients with cirrhosis and in healthy patients. Fifty-one cirrhotic patients with or without thromboembolic events and 50 controls matched by age and sex were enrolled. Procoagulant (factors VII, II, V, VIII, and XII) and inhibitor (protein C, protein S and antithrombin) factor activities were determined. Thrombin generation was measured as endogenous thrombin potential (ETP). Haemostatic balance was assessed by means of both procoagulant to inhibitor coagulation factor ratios and ETP with to without protein C activation ratios. There were 24 males and 27 females. The mean age was 57.8 years [16-91 years]. Pro and anticoagulant factors were significantly lower in patients than in controls (P < 0.001) except for factor VIII and protein S. In fact factor VIII level was significantly higher in patients than in controls and protein S levels were not significantly different between patients and controls. Almost all the pro to anticoagulant factor ratios were higher in cirrhotics than in controls, especially the factor VIII to protein C ratios which increased significantly from Child Pugh A to C (P < 0.001), the ratio of ETP with to without protein C activator was higher in patients than in controls, but did not reach a significant level (0.8 vs. 0.52) There was no statistically significant difference between Child classes. When comparing patients with history of thrombosis (n = 7) to those matched by age and sex and without history of thrombosis (n = 14), the ratios were not statistically different between the two groups. Haemostatic changes in cirrhosis tend to rebalance the haemostatic system. This state often results in a hypercoagulable state attested by increased pro- to anticoagulant factor ratios and a normal thrombin generation.

Radiation exposure in Crohn's disease patients.

Introudction Crohn's disease (CD) is a lifelong condition. Multiple imaging investigations are often performed during follow-up. This could cause overexposure to radiation. The aim of our study was to determine mean radiation dose in patients  with  at least a 5-year course of CD and to determine possible risk factors associated with exposure to high doses of radiation. Methods We conducted a retrospective study including patients whose CD was diagnosed between 1998 and 2005. Epidemiologic features of patients, characteristics of the disease,  types of imaging investigations that were performed during follow-up and cumulative radiation effective dose were determined. Risk factors associated with exposure to high doses of radiation were then determined. Results One hundred sixty seven patients were included.  There were 92 males (55.1%) and 75 females (44.9%) with mean age at dianosis of 31.4±12.3years. Global radiation dose was 18.8±18.9 mSv. Twenty seven patients (16,2%) were exposed to more than  35 mSv and 4 patients (2.4%) had an exposure  of more than  75 mSv. Use of Infliximab, age at disease onset ≤ 24 years old and number of flares ≥ 8  were independent risk factors of radiation exposure more than 35 mSv with adjusted Odds ratios (OR) : 2.5 [2.1- 5.3]; 1.6 [1.2- 4.7] and 3.2 [2.1- 7.8] respectively. Similarly,  use of Infliximab and number of flares ≥ 8  were independent risk factors of radiation exposure more than 75 mSv with adjusted OR : 4.3 [2.8-9.5] and 7 [3.2-11.2] respectively. Conclusion Radiation risk seems to be increased with severe course of  CD. Both referring physicians and radiologists have the responsibility to minimise radiation exposure. Entero-magnetic resonance imaging (Entero-MRI)  may reduce this risk.

Changes of Crohn's disease phenotype over time.

Background - Crohn's disease is a clinically heterogeneous condition. Our aim was to identify the phenotype evolution of Crohn's disease over time according to the Montreal Classification and to precise predictive factors of the need for immunosuppressant treatment or surgery. Methods - We included Crohn's disease patients who were followed up for at least 5 years. We excluded patients who were lost to follow up before five. Patients were classified according to the Montreal classification for phenotype at diagnosis and five years later. The evolution of phenotype over time and the need for surgery, immunosuppressive or immunomodulatory drugs were evaluated. Results - One hundred twenty consecutive patients were recruited: 70 males and 50 females. At diagnosis, 68% of patients belong to A2 as determined by the Montreal classification. Disease was most often localized in the colon. The disease location in Crohn's disease remains relatively stable over time, with 93.4% of patients showing no change in disease location. Crohn's disease phenotype changed during follow up, with an increase in stricturing and penetrating phenotypes from 6% to 11% after 5 years. The only predictive factor of phenotype change was the small bowel involvement (OR=3.7 [1.2-7.6]). During follow-up, 82% of patients have presented a severe disease as attested by the use of immunosuppressive drugs or surgery. The factors associated with the disease severity were: small bowel involvement (L1), the stricturing (B2) and penetrating (B3) phenotypes and perineal lesions (OR=17.3 [8.4-19.7]; 12 [7.6-17.2]; 3[1.7-8.3] and 2.8 [2.2-5.1] respectively), without association with age, sex or smoking habits. Conclusion - Crohn's disease evolves over time: inflammatory diseases progress to more aggressive stricturing and penetrating phenotypes. The ileal location, the stricturing and penetrating forms and perineal lesions were predictive of surgery and immunosuppressant or immunomodulatory treatment.

[Nocturnal gastroesophageal reflux. About a pH metric series]. / Le reflux gastro-oesophagien acide nocturne pathologique. A propos d'une série pHmétrique.

BACKGROUND: Nocturnal gastroesophageal reflux has been shown to be associated with the more severe forms of gastroesophageal reflux disease (GERD), particularly with extraesophageal manifestations as well as complications of mucosal damage. AIM: To determine the frequency of nocturnal gastro esophageal reflux disease on 24-hour esophageal pH monitoring in patients with digestives or extra-digestives symptoms and to evaluate the clinical and pHmetric characteristics of nocturnal reflux in these patients. METHODS: We conducted a retrospective study based on results of 24- hour esophageal pH monitoring during a 11-year period in patients with or without digestive symptoms of gastroesophageal reflux disease. The nocturnal gastroesophgeal reflux was defined. RESULTS: We studied 696 patients (299 men, 397 women; mean age: 34.05 years). Gastroesophageal reflux was found in 350 patients (50%). Nocturnal reflux was observed in 240 patients (34.3%), mostly in association with pathological reflux in the total period (223 cases). Compared to the diurnal period, the nocturnal period was characterized by fewer number of reflux episodes (21.9±27.4 vs 67.4±5.,1 ; p<0.0001), more longer duration of reflux episodes (24.4±37.9 minutes vs 13.9± 17.5 minutes ; p<0.001), and a lower symptomatic correlation (26% vs 45% ; p=0.0005). CONCLUSION: Nocturnal reflux is associated with overall reflux on the 24 hour examination. Nocturnal period is characterized by longer reflux episodes, less number of reflux episodes and less symptomatic correlation.

Stem cell transplantation as rescue therapy for refractory Crohn's disease: a sytematic review.

BACKGROUND: Crohn's disease is a chronic relapsing- remitting affection. It has a strong immunologic component which represent the target of standard therapies including immunosppressants and biological therapies. However, many patients remain refracory or intolerant to these therapies. AIM: The aim of this review is to determine the effects of stem cell transplantation in patients with refractory Crohn's disease. METHODS: Systematic review of observational studies, clinical trials and case reports that focused on the effectiveness and safety of stem cell transplantation in patients with refractory Crohn's disease. RESULTS: Hematopoietic stem cell transplantation seems to be efficient in maintaining clinical and endoscopic remission in patients with Crohn's disease refractory or intolerant to current therapies. However, it has been associated to high morbidity and mortality due to chemotherapy. Mesenchymal stem cell transplantation could induce remission in patients with fistulising refractory Crohns disease with no severe side effects. Its impact on luminal Crohns disease is still controversial. CONCLUSION: Stem cell transplantation seems to hold promising in patients with refractory Crohn's disease. However, because of the high morbidity and mortality related to chemotherapy, hematopoietic stem cell transplantation should be used as last resort to control this disease. Effectiveness of mesenchymal stem cell transplantation in luminal Crohn's disease has yet to be proven.

[Epithelial cell in intestinal homeostasis and inflammatory bowel diseases]. / Rôle de la cellule épithéliale dans l'homéostasie intestinale et les maladies inflammatoires chroniques de l'intestin.

Crohn's disease (CD) and ulcerative colitis (UC) are the principal inflammatory bowel diseases (IBD) which physiopathology is currently poorly elucidated. During these diseases, the participation of the epithelial cell in the installation and the perpetuation of the intestinal inflammation is now clearly implicated. In fact, the intestinal epithelium located at the interface between the internal environment and the intestinal luminal, is key to the homeostatic regulation of the intestinal barrier. This barrier can schematically be regarded as being three barriers in one: a physical, chemical and immune barrier. The barrier function of epithelial cell can be altered by various mechanisms as occurs in IBD. The goal of this article is to review the literature on the role of the epithelial cell in intestinal homeostasis and its implication in the IBD.

[Is there any interest to dose the azathioprine's metabolites during inflammatory bowel diseases?]. / Y a-t-il intérêt à doser les métabolites de l'azathioprine chez les malades ayant une maladie inflammatoire chronique de l'intestin ?

OBJECTIVE: The objective of our work is to search if there is a relation between azathioprine's metabolites (6-thioguanines nucleotides and 6-methyl mercaptopurines) and clinical efficacy and adverse effects of azathioprine in inflammatory bowel disease population. METHOD: We included patients with Crohn's disease or ulcerative colitis (UC) treated by azathioprine for a duration more than 1 year. Each patient had a dosage of azathioprine metabolites. RESULTS: We included 43 Crohn's disease patients and 7 UC. Azathioprine was indicated for steroid dependancy in 23 cases, to prevent post-operative recurrence in 10 cases, to maintain clinical remission obtained by medical treatment in 17 patients. A clinical response to azathioprine (obtention of remission, absence of recurrence during the follow up) was observed in 34 patients. CONCLUSION: Our work confirms the relation between the doses of azathioprine metabolites and the myelotoxicity due to this molecule.

[Bone metabolism, biochemical markers of bone resorption and formation processes and interleukine 6 cytokin level during coeliac disease]. / Anomalies du métabolisme osseux et résultats des marqueurs biochimiques du remodelage osseux et de l'interleukine 6 au cours de la maladie coeliaque.

BACKGROUND: Celiac disease (CD) is characterized by a malabsorption syndrom. The bone anomalies are one of the principal complications of this disease. The osteoporosis frequency is high: 3.4% among patients having with CD versus 0.2% in the general population. AIM: To study the bone mineral density during the CD, to compare it to a control group and to determine the anomalies of biochemical markers of bone turn over and level of interleukin 6 cytokin (IL6) in these patients. METHODS: All patients with CD have a measurement of bone mineral density by dual-energy x-ray absorptiometry (DXA), a biological exam with dosing calcemia, vitamin D, parathormone (PTH), the osteoblastic bone formation markers (serum osteocalcin, ALP phosphates alkaline), bone osteoclastic activity (C Télopeptide: CTX) and of the IL6. RESULTS: 42 patients were included, with a median age of 33.6 years. 52. 8% of the patients had a low level of D vitamine associated to a high level of PTH. An osteoporosis was noted in 21.5% of patients. No case of osteoporosis was detected in the control group. The mean level of the CTX, ostéocalcine and the IL6 was higher among patients having an osteoporosis or ostéopenia compared to patients with normal bone (p = 0,017). The factors associated with an bone loss (osteopenia or osteoporosis) were: an age > 30 years, a weight <50 kg, a level of ALP phosphates alkaline > 90 UI/ml, an hypo albuminemia < 40 g/l and a level of CTX higher than 1.2. CONCLUSION: Our study confirms the impact of the CD on the bone mineral statute. The relative risk to have an osteopenia or an osteoporosis was 5 in our series. The measurement of the osseous mineral density would be indicated among patients having a CD.

[Not Available]. / Y a-t-il intérêt à doser les métabolites de l'azathioprine chez les malades ayant une maladie inflammatoire chronique de l'intestin?

OBJECTIVE: The objective of our work is to search if there is a relation between azathioprine's metabolites (6-thioguanines nucleotides and 6-methyl mercaptopurines) and clinical efficacy and adverse effects of azathioprine in inflammatory bowel disease population. METHOD: We included patients with Crohn's disease or ulcerative colitis (UC) treated by azathioprine for a duration more than 1year. Each patient had a dosage of azathioprine metabolites. RESULTS: We included 43 Crohn's disease patients and 7 UC. Azathioprine was indicated for steroid dependancy in 23 cases, to prevent post-operative recurrence in 10 cases, to maintain clinical remission obtained by medical treatment in 17 patients. A clinical response to azathioprine (obtention of remission, absence of recurrence during the follow up) was observed in 34 patients. CONCLUSION: Our work confirms the relation between the doses of azathioprine metabolites and the myelotoxicity due to this molecule.