Intestinal Behet’s disease appearing during treatment with adalimumab in a patient with ankylosing spondylitis

Behet’s disease(BD)is a chronic inflammatory disease affecting multiple organ systems,such as the skin,joints,blood vessels,central nervous system,and gastrointestinal tract.Intestinal BD is characterized by intestinal ulcerations and gastrointestinal symptoms.The medical treatment of intestinal BD includes corticosteroids and immunosupressants.There have been several reports of tumor necrosis factor-α (TNF-α)blockers being successful in treatment of refractory intestinal BD.Here,we report on a patient who was diagnosed with intestinal BD despite treatment with the fully humanized TNF-α blocker(adalimumab)for underlying ankylosing spondylitis.This patient achieved clinical remission and complete mucosal healing through the addition of a steroid and azathioprine to the adalimumab regimen.     

Prolonged small vessel vasculitis with colon mucosal inflammation as first manifestations of Behet’s disease

Behet’s disease is a chronic, relapsing, systemic vasculitis of unknown aetiology. Patients present manifestations of gastrointestinal complications, including mouth lesions, small and large intestinal lesions, and vascular lesions in the abdomen. In some cases, the intestinal ulcers of patients with Behet’s disease are indistinguishable from those of Crohn’s disease, tuberculosis, vasculitis and other diseases. In this article, we present a case of atypical Behet’s disease with a complicated medical history and multisystem damage, for the purpose of better management of this disease.     

Beh et’s disease complicated by multiple aseptic abscesses of the liver and spleen

Aseptic abscesses are an emergent entity and have been described in inflammatory bowel disease,especially in Crohn’s disease,and in other diseases.However,aseptic abscesses associated with Beh et’s disease are extremely rare.We report a Japanese male diagnosed with an incomplete type of Beh et’s disease who developed multiple aseptic abscesses of the spleen and liver.In 2002,the spleen abscesses were accompanied by paroxysmal oral aphthous ulcers and erythema nodosum.As the patient’s response to antibiotic treatment was inadequate,a splenectomy was performed.Severe inflammatory cell infiltration,largely of polymorphonuclear neutrophils,was observed without evidence of bacterial or fungal growth.Although the patient had no history of ocular symptoms or genital ulcers,a diagnosis of incomplete Beh et’s disease was made according to the Japanese diagnostic criteria because of the presence of paroxysmal arthritis and epididymitis since 2002.In 2005,multiple liver abscesses developed with right hypochondrial pain and seemed to be attributed to Beh et’s disease because the abscesses yielded negative results during a microbiologic investigation and failed to go into remission under antibiotic therapy.Oral prednisone(15 mg/d) was started in May 2006,and the abscesses dramatically disappeared 4 wk after treatment.Although the patient had a relapse of the liver abscesses in association with the tapering of prednisone,the augmentation of prednisone dosage yielded a response.The abscesses of the liver and spleen were strongly suggested to be attributed to Beh et’s disease.Clinician should be aware of the existence of aseptic abscesses as uncommon manifestations of Beh et’s disease.     

Similarities and differences between Behet's disease and Crohn's disease

Behet's disease(BD) is a chronic inflammatory condition with multisystem involvement. Approximately 10%-15% of patients present with gastrointestinal involvement. Involved sites and the endoscopic view usually resemble Crohn's disease(CD). In addition to intestinal involvement, oral mucosa, the eyes, skin, and joints are commonly affected. No pathognomonic laboratory test is available for the diagnosis of either disease. Management approaches are also similar in various aspects. Differentiating BD from CD is highly challenging. In this article, the similarities and differences between BD and CD in terms of epidemiology, etiopathogenesis, clinical and imaging findings, and histopathological and therapeutic approaches are reviewed.     

Optimization of the treatment with immunosuppressants and biologics in inflammatory bowel disease

Many placebo controlled trials and meta-analyses evaluated the efficacy of different drugs for the treatment of inflammatory bowel disease(IBD),including immunosuppressants and biologics.Their use is indicated in moderate to severe disease in non responders to corticosteroids and in steroid-dependent patients,as induction and maintainance treatment.Infliximab,as well as cyclosporine,is considered a second line therapy in the case of severe ulcerative colitis,or non-responders to intravenous corticosteroids.An adequate dosage and duration of therapy with thiopurines should be reached before evaluating their efficacy.Methotrexate is a valid option in patients with Crohn’s disease but its use is confined to patients who are intolerant or non-responders to thiopurines.Evidence for the use of methotrexate in ulcerative colitis is insufficient.The use of thalidomide and mycophenolate mofetil is not recommended in patients with inflammatory bowel disease,these treatments could be considered in case of failure of all other therapeutic options.In patients with moderately active ulcerative colitis,refractory to thiopurines,the use of tacrolimus is considered an alternative to biologics.An increase of the dose or a decrease in the interval of administration of biologic treatment could be useful in the presence of an incomplete clinical response.In the case of primary failure of an anti-tumor necrosis factor alpha a switch to another one should be considered.Data on the efficacy of combination therapy are up to now insufficient to consider this strategy in all IBD patients.The final outcome of the treatment should be considered the clinical remission,with mucosa healing,and not the clinical response.The evaluation of serum concentration of thiopurine methyl transferase activity,thiopurine metabolites,biologic serum levels and antibiologic antibodies could be useful for the management of the treatment but it has not been routinely applied in clinical practice.The evidence of high risk development of lymphoma and cutaneous malignancies should be considered in patients treated with immunosuppressants and biologics for a long period.     

Inflammatory pathways of importance for management of inflammatory bowel disease

Inflammatory bowel disease(IBD)is a group of chronic disorders of the gastrointestinal tract comprising Crohn’s disease(CD)and ulcerative colitis(UC).Their etiologies are unknown,but they are characterised by an imbalanced production of pro-inflammatory mediators,e.g.,tumor necrosis factor(TNF)-α,as well as increased recruitment of leukocytes to the site of inflammation.Advantages in understanding the role of the inflammatory pathways in IBD and an inadequate response to conventional therapy in a large portion of patients,has over the last two decades lead to new therapies which includes the TNF inhibitors(TNFi),designed to target and neutralise the effect of TNF-α.TNFi have shown to be efficient in treating moderate to severe CD and UC.However,convenient alternative therapeutics targeting other immune pathways are needed for patients with IBD refractory to conventional therapy including TNFi.Indeed,several therapeutics are currently under development,and have shown success in clinical trials.These include antibodies targeting and neutralising interleukin-12/23,small pharmacologic Janus kinase inhibitors designed to block intracellular signaling of several pro-inflammatory cytokines,antibodies targeting integrins,and small anti-adhesion molecules that block adhesion between leukocytes and the intestinal vascular endothelium,reducing their infiltration into the inflamed mucosa.In this review we have elucidated the major signaling pathways of clinical importance for IBD therapy and highlighted the new promising therapies available.As stated in this paper several new treatment options are under development for the treatment of CD and UC,however,no drug fits all patients.Hence,optimisations of treatment regimens are warranted for the benefit of the patients either through biomarker establishment or other rationales to maximise the effect of the broad range of mode-of-actions of the present and future drugs in IBD.     

Liver transplantation for Wilson disease

The aim of this paper is to review the current status of liver transplantation (LT) for Wilson disease (WD), focusing on indications and controversies, especially in patients with neuropsychiatric disease, and on identification of acute liver failure (ALF) cases related to WD. LT remains the treatment of choice for patients with ALF, as initial presentation of WD or when anti-copper agents are stopped, and for patients with chronic liver disease progressed to cirrhosis, unresponsive to chelating medications or not timely treated with copper chelating agents. The indication for LT in WD remains highly debated in patients with progressive neurological deterioration and failure to improve with appropriate medical treatment. In case of Wilsonian ALF, early identification is key as mortality is 100% without emergency LT. As many of the copper metabolism parameters are believed to be less reliable in ALF, simple biochemical tests have been proposed for diagnosis of acute WD with good sensitivity and specificity. LT corrects copper metabolism and complications resulting from WD with excellent 1 and 5 year survival. Living related liver transplantation represents an alternative to deceased donor LT with excellent long-term survival, without disease recurrence. Future options mayinclude hepatocyte transplantation and gene therapy. Although both of these have shown promising results in animal models of WD, prospective human studies are much needed to demonstrate their long-term beneficial effects and their potential to replace the need for medical therapy and LT in patients with WD.     

Inflammatory bowel disease course in Crohn’s disease: Is the natural history changing?

Crohn’s disease(CD)is a multifactorial potentially debilitating disease.It has a variable disease course,but the majority of patients eventually develop penetrating or stricturing complications leading to repeated surgeries and disability.Studies on the natural history of CD provide invaluable data on its course and clinical predictors,and may help to identify patient subsets based on clinical phenotype.Most data are available from referral centers,however these outcomes may be different from those in population-based cohorts.New data suggest the possibility of a change in the natural history in Crohn’s disease,with an increasing percentage of patients diagnosed with inflammatory disease behavior.Hospitalization rates remain high,while surgery rates seem to have decreased in the last decade.In addition,mortality rates still exceed that of the general population.The impact of changes in treatment strategy,including increased,earlier use of immunosuppressives,biological therapy,and patient monitoring on the natural history of the disease are still conflictive.In this review article,the authors summarize the available evidence on the natural history,current trends,and predictive factors for evaluating the disease course of CD.     

Clostridium difficile and inflammatory bowel disease: Role in pathogenesis and implications in treatment

Clostridium difficile(C.difficile)is the leading cause of antibiotic associated colitis and nosocomial diarrhea.Patients with inflammatory bowel disease(IBD)are at increased risk of developing C.difficile infection(CDI),have worse outcomes of CDI-including higher rates of colectomy and death,and experience higher rates of recurrence.However,it is still not clear whether C.difficile is a cause of IBD or a consequence of the inflammatory state in the intestinal environment.The burden of CDI has increased dramatically over the past decade,with severe outbreaks described in many countries,which have been attributed to a new and more virulent strain.A parallel rise in the incidence of CDI has been noted in patients with IBD.IBD patients with CDI tend be younger,have less prior antibiotic exposure,and most cases of CDI in these patients represent outpatient acquired infections.The clinical presentation of CDI in these patients can be unique-including diversion colitis,enteritis and pouchitis,and typical findings on colonoscopy are often absent.Due to the high prevalence of CDI in patients hospitalized with an IBD exacerbation,and the prognostic implications of CDI in these patients,it is recommended to test all IBD patients hospitalized with a disease flare for C.difficile.Treatment includes general measures such as supportive care and infection control measures.Antibiotic therapy with either oral metronidazole,vancomycin,or the novel antibiotic-fidaxomicin,should be initiated as soon as possible.Fecal macrobiota transplantation constitutes another optional treatment for severe/recurrent CDI.The aim of this paper is to review recent data on CDI in IBD:role in pathogenesis,diagnostic methods,optional treatments,and outcomes of these patients.     

Endoscopic and radiographic features of gastrointestinal involvement in vasculitis

Vasculitis is an inflammation of vessel walls,followed by alteration of the blood flow and damage to the dependent organ.Vasculitis can cause local or diffuse pathologic changes in the gastrointestinal (GI) tract.The variety of GI lesions includes ulcer,submucosal edema,hemorrhage,paralytic ileus,mesenteric ischemia,bowel obstruction,and life-threatening perforation.The endoscopic and radiographic features of GI involvement in vasculitisare reviewed with the emphasis on small-vessel vasculitis by presenting our typicalcases,including Churg-Strauss syndrome,HenochSch nlein purpura,systemic lupus erythematosus,and Beh et’s disease.Important endoscopic features are ischemic enterocolitis and ulcer.Characteristic computed tomographic findings include bowel wall thickening with the target sign and engorgement of mesenteric vessels with comb sign.Knowledge of endoscopic and radiographic GI manifestations can help make an early diagnosis and establish treatment strategy.     

Colonic perforation in Behet’s syndrome

A 17-year-old gentleman was admitted to our hospital for headache, the differential diagnosis of which included Behet’s syndrome (BS). He developed an acute abdomen and was found to have air under the diaphragm on erect chest X-ray. Subsequent laparotomy revealed multiple perforations throughout the colon. This report describes an unusual complication of Behcets syndrome occurring at the time of presentation and a review of the current literature of reported cases.     

Are we giving biologics too late？ The case for early late use

Corticosteroids and immunomodulators have been the mainstay therapies for Crohn＇s disease. Corticosteroids are highly effective to control symptoms in the shortterm, but they are not effective in maintaining remission, they heal the mucosa in a reduced proportion of cases, and long-time exposure is associated with an increased risk of infections and mortality. Immunomodulators, azathioprine and methotrexate, heal the mucosa in a higher proportion of patients that corticosteroids but their onset of action is slow and they benefit less than half of patients with Crohn＇s disease. In the last decade, medical therapy for Crohn＇s disease has experienced a remarkable change due to the introduction of biologic therapy, and particularly the use of anti-tumour necrosis factor-alpha agents. Infliximab, adalimumab, and certolizumab pegol have demonstrated efficacy for induction and maintenance of remission in active Crohn＇s disease. These agents have raised the bar for what is a suitable symptomatic response in Crohn＇s disease and modification of the natural history of the disease has become a major goal in the treatment of Crohn＇s disease. There are several data in the literature that suggest that early use of biologic therapy and achievement of mucosal healing contribute to disease course modification. However, many questions on early biological therapy for Crohn＇s disease remain still unanswered.     

Use of exclusive enteral nutrition in adults with Crohn’s disease: A review

Exclusive enteral nutrition(EEN)is well-established as a first line therapy instead of corticosteroid(CS)therapy to treat active Crohn’s disease(CD)in children.It also has been shown to have benefits over and above induction of disease remission in paediatric populations.However,other than in Japanese populations,this intervention is not routinely utilised in adults.To investigate potential reasons for variation in response between adult studies of EEN and CS therapy.The Ovid database was searched over a 6-mo period.Articles directly comparing EEN and CS therapy in adults were included.Eleven articles were identified.EEN therapy remission rates varied considerably.Poor compliance with EEN therapy due to unpalatable formula was an issue in half of the studies.Remission rates of studies that only included patients with previously untreated/new CD were higher than studies including patients with both existing and new disease.There was limited evidence to determine if disease location,duration of disease or age of diagnosis affected EEN therapy outcomes.There is some evidence to support the use of EEN as a treatment option for a select group of adults,namely those motivated to adhere to an EEN regimen and possibly those newly diagnosed with CD.In addition,the use of more palatable formulas could improve treatment compliance.     

Use of thiopurines in inflammatory bowel disease

The use of thiopurines as immunosuppression for the treatment of refractory or chronic active inflammatory bowel disease is established for both Crohn’s disease and ulcerative colitis.Nevertheless,many questions remain concerning the optimal treatment regimens of azathioprine,6-mercaptopurine and thioguanine.We will briefly summarize dose recommendations,indications for thiopurine therapy and side effects which are relevant in clinical practice.We discuss some currently debated topics,including the combination of azathioprine and allopurinol,switching of thiopurine therapy in case of side effects,the use of azathioprine in pregnancy,the infection risk using thiopurines and the evidence when to stop thiopurines.Excellent reviews have been published on the thiopurine metabolic pathway which will not be discussed here in detail.     

Treating inflammatory bowel disease by adsorptive leucocytapheresis:A desire to treat without drugs

Ulcerative colitis and Crohn’s disease are the major phenotypes of the idiopathic inflammatory bowel disease(IBD),which afflicts millions of individuals throughout the world with debilitating symptoms,impairing function and quality of life.Current medications are aimed at reducing the symptoms or suppressing exacerbations.However,patients require life-long medications,and this can lead to drug dependency,loss of response together with adverse side effects.Indeed,drug side effects become additional morbidity factor in many patients on long-term medications.Nonetheless,the efficacy of anti-tumour necrosis factors(TNF)-αbiologics has validated the role of inflammatory cytokines notably TNF-αin the exacerbation of IBD.However,inflammatory cytokines are released by patients’own cellular elements including myeloid lineage leucocytes,which in patients with IBD are elevated with activation behaviour and prolonged survival.Accordingly,these leucocytes appear logical targets of therapy and can be depleted by adsorptive granulocyte/monocyte apheresis(GMA)with an Adacolumn.Based on this background,recently GMA has been applied to treat patients with IBD in Japan and in the European Union countries.Efficacy rates have been impressive as well as disappointing.In fact the clinical response to GMA seems to define the patients’disease course,response to medications,duration of active disease,and severity at entry.The best responders have been first episode cases(up to 100%)followed by steroid nave and patients with a short duration of active disease prior to GMA.Patients with deep ulcers together with extensive loss of the mucosal tissue and cases with a long duration of IBD refractory to existing medications are not likely to benefit from GMA.It is clinically interesting that patients who respond to GMA have a good long-term disease course by avoiding drugs including corticosteroids in the early stage of their IBD.Additionally,GMA is very much favoured by patients for its good safety profile.GMA in 21st century reminds us of phlebotomy as a major medical practice at the time of Hippocrates.However,in patients with IBD,there is a scope for removing from the body the sources of proinflammatory cytokines and achieve disease remission.The bottom line is that by introducing GMA at an early stage following the onset of IBD or before patients develop extensive mucosal damage and become refractory to medications,many patients should respond to GMA and avoid pharmacologics.This should fulfill the desire to treat without drugs.     

Why interleukin-10 supplementation does not work in Crohn’s disease patients

Inflammatory bowel diseases (IBD) such as Crohn’s disease (CD) or ulcerative colitis are chronic intestina disorders, which are on the increase in "Westernised" countries. IBD can be caused by both genetic and environmental factors. Interleukin-10 (IL-10) is an immunoregulatory cytokine that has been identified as being involved in several diseases including IBD. Studies have shown that polymorphisms in the promoter region reduce serum levels of IL-10 and this reduction has been associated with some forms of IBD. Mouse models have shown promising results with IL-10 supplementation, as such IL-10 supplementation has been touted as being a possible alternative treatment for CD in humans. Clinical trials have shown that recombinant human IL-10 is safe and well tolerated up to a dose o 8 μg/kg. However, to date, the results of the clinica trials have been disappointing. Although CD activity was reduced as measured by the CD activity index IL-10 supplementation did not result in significantly reduced remission rates or clinical improvements when compared to placebo. This review discusses why IL-10supplementation is not effective in CD patients currently and what can be addressed to potentially make IL-10 supplementation a more viable treatment option in the future. Based on the current research we conclude that IL-10 supplementation is not a one size fits all treatment and if the correct population of patients is chosen then IL-10 supplementation could be of benefit.     

Role of capsule endoscopy in inflammatory bowel disease

Videocapsule endoscopy(VCE) has revolutionized our ability to visualize the small bowel mucosa. This modality is a valuable tool for the diagnosis of obscure small bowel Crohn’s disease(CD), and can also be used for monitoring of disease activity in patients with established small-bowel CD, detection of complications such as obscure bleeding and neoplasms, evaluation of response to anti-inflammatory treatment and postoperative recurrence following small bowel resection. VCE could also be an important tool in the management of patients with unclassified inflammatory bowel disease, potentially resulting in reclassification of these patients as having CD. Reports on postoperative monitoring and evaluation of patients with ileal pouch-anal anastomosis who have developed pouchitis have recenty been published. Monitoring of colonic inflammatory activity in patients with ulcerative colitis using the recently developed colonic capsule has also been reported. Capsule endoscopy is associated with an excellent safety profile. Although retention risk is increased in patients with small bowel CD, this risk can be significanty decreased by a routine utilization of a dissolvable patency capsule preceding the ingestion of the diagnostic capsule. This paper contains an overview of the current and future clinical applications of capsule endoscopy in inflammatory bowel disease.     

Adalimumab-induced interstitial pneumonia in a patient with Crohn’s disease

There are several reports of anti-tumor necrosis factor(TNF)-induced lung disease,especially in patients with rheumatologic diseases.Adalimumab is an antiTNF drug used to induce and maintain remission in patients with immune-mediated diseases,such as Crohn’s disease.Although pulmonary disorders could be an extra-intestinal manifestation of inflammatory bowel disease,biologic therapy could also be a cause of lung injury.Only few cases of adalimumab-induced lung toxicity have been reported,and the majority of them were in patients with rheumatologic diseases.Lung injury secondary to anti-TNF therapy should,after ruling out other etiologies,be considered in patients who have a temporal association between the onset of respiratory symptoms and the exposure to these drugs.A compatible pattern in the biopsy and the clinical improvement after discontinuation of the anti-TNF drug would strongly support the diagnosis.     

Gastroesophageal reflux disease and severe obesity: Fundoplication or bariatric surgery?

Increases in the prevalence of obesity and gastroesophageal reflux disease (GERD) have paralleled one another over the past decade, which suggests the possibility of a linkage between these two processes. In both instances, surgical therapy is recognized as the most effective treatment for severe, refractory disease. Current surgical therapies for severe obesity include (in descending frequency) Roux-en-Y gastric bypass, adjustable gastric banding, sleeve gastrectomy, and biliopancreatic diversion with duodenal switch, while fundoplication remains the mainstay for the treatment of severe GERD. In several large series, however, the outcomes and durability of fundoplication in the setting of severe obesity are not as good as those in patients who are not severely obese. As such, bariatric surgery has been suggested as a potential alternative treatment for these patients. This article reviews current concepts in the putative pathophysiological mechanisms by which obesity contributes to gastroesophageal reflux and their implications with regards to surgical therapy for GERD in the setting of severe obesity.