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.     

Are we giving azathioprine too late？ The case for early immunomodulation in inflammatory bowel disease

Inflammatory bowel disease （IBD） includes two entities, Crohn＇s disease and ulcerative colitis. Both are chronic conditions with frequent complications and surgical procedures and a great impact on patient＇s quality of life. The thiopurine antimetabolites azathioprine and 6-mercaptopurine are widely used in IBD patients. Current indications include maintenance therapy, steroid-dependant disease, fistula closure, prevention of infliximab immunogenicity and prevention of Crohn＇s disease recurrence. Surprisingly, the wide use of immunosuppressants in the last decades has not decreased the need of surgery, probably because these treatments are introduced at too late stages in disease course. An earlier use of immunossupressants is now advocated by some authors. The rational includes： （1） failure to modify IBD natural history of present therapeutic approach, （2） demonstration that azathioprine can induce mucosal healing, a relevant prognostic factor for Crohn＇s disease and ulcerative colitis, and （3） demonstration that early immunossupression has a very positive impact on pediatric, recently diagnosed Crohn＇s disease patients. We are now awaiting the results of new studies, to clarify the contribution of azathioprine, as compared to infliximab （SONIC Study）, and to demonstrate the usefulness of azathioprine in recently diagnosed adult Crohn＇s disease patients （AZTEC study）.     

Emerging treatments for complex perianal fistula in Crohn＇s disease

Complex perianal fistulas have a negative impact on the quality of life of sufferers and should be treated. Correct diagnosis, characterization and classification of the fistulas are essential to optimize treatment. Nevertheless, in the case of patients whose fistulas are associated with Crohn＇s disease, complete closure is particularly difficult to achieve. Systemic medical treatments （antibiotics, thiopurines and other immunomodulatory agents, and, more recently, anti-tumor necrosis factor-α agents such as infliximab） have been tried with varying degrees of success. Combined medical （including infliximab） and less aggressive surgical therapy （drainage and seton placement） offer the best outcomes in complex Crohn＇s fistulas while more aggressive surgical procedures such as fistulotomy or fistulectomy may increase the risk of incontinence. This review will focus on emerging novel treatments for perianal disease in Crohn＇s patients. These include locally applied infliximab or tacrolimus, fistula plugs, instillation of fibrin glue and the use of adult expanded adipose-derived stem cell injection. More welldesigned controlled studies are required to confirm the effectiveness of these emerging treatments.     

Portopulmonary hypertension in liver transplant candidates

Pulmonary vascular disorders including portopulmonary hypertension(PoPHT) are among the common complications of liver disease and are prognostically significant. Survival is very low without medical treatment and liver transplantation. With advances in medical therapy for elevated pulmonary artery pressure(PAP) and liver transplant surgery, survival of patients with Po PHT and advanced liver disease is significantly improved. Because of the prognostic significance of Po PHT and the limited donor pool, a comprehensive preoperative cardio-pulmonary assessment is of great importance in cirrhotic patients prior to transplant surgery. Therefore, a detailed transthoracic Doppler echocardiographic examination must be an essential component of this evaluation. Patients with mild Po PHT can safely undergo liver transplant surgery. In cases of moderate to severe Po PHT, right heart catheterization(RHC) should be performed. In patients with moderate to severe Po PHT on RHC(mean PAP 35-45 mm Hg), vasodilator therapy should be attempted. Liver transplantation should be encouraged in cases that demonstrate a positive response. Bridging therapy with specific pulmonary arterial hypertension treatment agents should be considered until the transplant surgery and should be continued during the peri- and post-operative periods as needed.     

Use of the Crohn＇s disease activity index in clinical trials of biological agents

The Crohn＇s disease activity index （CDAI） has been commonly used to assess the effects of treatment with different agents in Crohn＇s disease （CD）. However, these studies may be compromised, if the results compared to a placebo or standard therapy group （in the absence of a placebo） substantially differ from the expected response. In addition, significant concerns have been raised regarding the reliability and validity of the CDAI. Reproducibility of the CDAI may be limited as significant inter-observer error has been recorded, even if measurements are done by experienced clinicians with expertise in the diagnosis and treatment of CD. Finally, many CDAI endpoints are open to subjective interpretation and have the potential for manipulation. This is worrisome as there is the potential for significant financial gain, if the results of a clinical trial appear to provide a positive result. Physicians caring for patients should be concerned about the positive results in clinical trials that are sponsored by industry, even if the trials involve respected centers and the results appear in highly ranked medical journals.     

Is endoscopic therapy the treatment of choice in all patients with chronic pancreatitis?

Chronic pancreatitis(CP) is a progressive inflammatory disease of the pancreas characterized by destruction of the pancreatic parenchyma with subsequent fibrosis that leads to pancreatic exocrine and endocrine insufficiency.Abdominal pain and local complications(bile duct or duodenal stenosis and pancreatic tumor) secondary to CP are indications for therapy.At the beginning,medical therapy is used.More invasive treatment is recommended for patients with pancreatic duct stones(PDS) and pancreatic obstruction in whom standard medical therapy is not sufficient.Recently,Clarke et al assessed the long-term effectiveness of endoscopic therapy(ET) in CP patients.The authors compared ET with medical treatment.They reported that ET was clinically successful in 50% of patients with symptomatic CP.In this commentary,current CP treatment,including indications for ET and surgery in CP patients,is discussed.Recommendations for endoscopic treatment of CP according to the European Society of Gastrointestinal Endoscopy Clinical Guidelines are reviewed.Different surgical methods used in the treatment of CP patients are also discussed.ET is the most useful in patients with large PDS,pancreatic duct obstruction and dilation.It should be the first-line option because it is less invasive than surgery.Surgery should be the first-line option in patients in whom ET has failed or in those with a pancreatic mass with suspicion of malignancy.ET is a very effective and less invasive procedure,but it cannot be recommended as the treatment of choice in all CP patients.     

Treatment of inflammatory bowel disease： A review of medical therapy

Crohn＇s disease （CD） and ulcerative colitis （UC） are chronic inflammatory diseases of the gastrointestinal tract. While a cure remains elusive, both can be treated with medications that induce and maintain remission. With the recent advent of therapies that inhibit tumor necrosis factor （TNF） alpha the overlap in medical therapies for UC and CD has become greater. Although 5-ASA agents have been a mainstay in the treatment of both CD and UC, the data for their efficacy in patients with CD, particularly as maintenance therapy, are equivocal. Antibiotics may have a limited role in the treatment of colonic CD. Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy; non- systemic steroids such as oral and rectal budesonide for ileal and right-sided CD and distal UC respectively are also effective in mild-moderate disease. 6-mercaptopurine （6-MP） and its prodrug azathioprine are steroid-sparing immunomodulators effective in the maintenance of remission of both CD and UC, while methotrexate may be used in both induction and maintenance of CD. Infliximab and adalimumab are anti-TNF agents approved in the US and Europe for the treatment of Crohn＇s disease, and infliximab is also approved for the treatment of UC.     

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.     

Value of colonoscopy for prediction of prognosis in patients with ulcerative colitis

Ulcerative colitis （UC） is a chronic inflammatory bowel disorder characterized by exacerbations and remissions. Some UC patients remain refractory to conventional medical treatment while, in others, the effectiveness of drugs is limited by side-effects. Recently, cyclosporine and leukocyte removal therapy have been used for refractory UC patients. To predict the efficacy of these therapies is important for appropriate selection of treatment options and for preparation for colectomy. Endoscopy is the cornerstone for diagnosis and evaluation of UC. Endoscopic parameters in patients with severe or refractory UC may predict a clinical response to therapies, such as cyclosporine or leukocyte removal therapy. As for the patients with quiescent UC, relapse of UC is difficult to predict by routine colonoscopy. Even when routine colonoscopy suggests remission and a normal mucosal appearance, microscopic abnormalities may persist and relapse may occur later. To more accurately identify disease activity and to predict exacerbations in UC patients with clinically inactive disease is important for deciding whether medical treatment should be maintained. Magnifying colonoscopy is useful for the evaluation of disease activity and for predicting relapse in patients with UC.     

Clinicopathological features and outcomes of patients with gastric cancer:A single-center experience

AIM:To evaluate the location,histopathology,stages,and treatment of gastric cancer and to conduct survival analysis on prognostic factors.METHODS:Patients diagnosed with of stomach cancer in our clinic between 2000 and 2011,with follow-up or a treatment decision,were evaluated retrospectively.They were followed up by no treatment,adjuvant therapy,or metastatic therapy.We excluded from the study any patients whose laboratory records lacked the operating parameters.The type of surgery in patients diagnosed with gastric cancer was total gastrectomy,subtotal gastrectomy or palliative surgery.Patients with indications for adjuvant treatment were treated with adjuvant and/or radio-chemotherapy.Prognostic evaluation was made based on the parameters of the patient,tumor and treatment.RESULTS:In this study,outpatient clinic records of patients with gastric cancer diagnosis were analyzed retrospectively.A total of 796 patients were evaluated(552male,244 female).The median age was 58 years(22-90 years).The median follow-up period was 12 mo(1-276 mo),and median survival time was 12 mo(11.5-12.4 mo).Increased T stage and N stage resulted in a decrease in survival.Other prognostic factors related to the disease were positive surgical margins,lymphovascular invasion,perineural invasion,cardio-esophageal settlement,and the levels of tumor markers in metastatic disease.No prognostic significance of the patient’s age,sex or tumor histopathology was detected.CONCLUSION:The prognostic factors identified in all groups and the proposed treatments according to stage should be applied,and innovations in the new targeted therapies should be followed.     

Treatment of peri-anal fistula in Crohn’s disease

Anal fistulas are a common manifestation of Crohn’s disease(CD). The first manifestation of the disease is often in the peri-anal region, which can occur years before a diagnosis, particularly in CD affecting the colon and rectum. The treatment of peri-anal fistulas is difficult and always multidisciplinary. The European guidelines recommend combined surgical and medical treatment with biologic drugs to achieve best results. Several different surgical techniques are currently em-ployed. However, at the moment, none of these tech-niques appear superior to the others in terms of healing rate. Surgery is always indicated to treat symptomatic, simple, low intersphincteric fistulas refractory to medi-cal therapy and those causing disabling symptoms. Ut-most attention should be paid to correcting the balance between eradication of the fistula and the preservationof fecal continence.     

Minimally invasive approaches for the treatment of inflammatory bowel disease

Despite significant improvements in medical management of inflammatory bowel disease, many of these patients still require surgery at some point in the course of their disease. Their young age and poor general conditions, worsened by the aggressive medical treatments, make minimally invasive approaches particularly enticing to this patient population. However, the typical inflammatory changes that characterize these diseases have hindered wide diffusion of laparoscopy in this setting, currently mostly pursued in high-volume referral centers, despite accumulating evidences in the literature supporting the benefits of minimally invasive surgery. The largest body of evidence currently available for terminal ileal Crohn’s disease shows improved short term outcomes after laparoscopic surgery, with prolonged operative times. For Crohn’s colitis, high quality evidence supporting laparoscopic surgery is lacking. Encouraging preliminary results have been obtained with the adoption of laparoscopic restorative total proctocolectomy for the treatment of ulcerative colitis. A consensus about patients’ selection and the need for staging has not been reached yet. Despite the lack of conclusive evidence, a wave of enthusiasm is pushing towards less invasive strategies, to further minimize surgical trauma, with single incision laparoscopic surgery being the most realistic future development.     

Enterolithiasis-associated ileus in Crohn's disease

Stasis of the flow of the intestinal contents, ingested material and unfavorable composition of the chylus can lead to the formation of enteroliths inside the bowel. Enterolithiasis represents a rare disorder of the gastrointestinal tract that can be associated with intermittent abdominal pain or more serious complications such as bleeding or obstruction. Enterolithiasis in Crohn’s disease represents an extremely rare condition and usually occurs only in patients with a long symptomatic history of Crohn’s disease. We report an unusual case of enterolithiasis-related intestinal obstruction in a young male patient with Crohn’s disease (A2L3B1 Montreal Classification for Crohn’s disease 2005) undergoing emergency laparotomy and ileocoecal resection. In addition, we present an overview of the relevant characteristics of enterolithiasis on the basis of the corresponding literature.     

Therapeutic strategies in Crohn’s disease in an emergency surgical setting

Crohn’s disease (CD) remains a chronic, incurable disorder that presents unique challenges to the surgeon. Multiple factors must be considered to allow development of an appropriate treatment plan. Medical therapy often precedes or complements the surgical management. The indications for operative management of CD include acute and chronic disease complications and failed medical therapy. Elective surgery comes into play when patients are refractory to medical treatment if they have an obstructive phenotype. Toxic colitis, acute obstruction, perforation, acute abscess, or massive hemorrhage represent indications for emergency surgery. These patients are generally in critical conditions and present with intra-abdominal sepsis and a preoperative status of immunosuppression and malnutrition that exposes them to a higher risk of complications and mortality. A multidisciplinary team including surgeons, gastroenterologists, radiologists, nutritional support services, and enterostomal therapists are required for optimal patient care and decision making. Management of each emergency should be individualized based on patient age, disease type and duration, and patient goals of care. Moreover, the recurrent nature of disease mandates that we continue searching for innovative medical therapies and operative techniques that reduce the need to repeat surgical operations. In this review, we aimed to discuss the acute complications of CD and their treatment.     

Crohn’s and colitis in children and adolescents

Crohn’s disease and ulcerative colitis can be grouped as the inflammatory bowel diseases (IBD). These conditions have become increasingly common in recent years, including in children and young people. Although much is known about aspects of the pathogenesis of these diseases, the precise aetiology is not yet understood, and there remains no cure. Recent data has illustrated the importance of a number of genes-several of these are important in the onset of IBD in early life, including in infancy. Pain, diarrhoea and weight loss are typical symptoms of paediatric Crohn’s disease whereas bloody diarrhoea is more typical of colitis in children. However, atypical symptoms may occur in both conditions: these include isolated impairment of linear growth or presentation with extra-intestinal manifestations such as erythema nodosum. Growth and nutrition are commonly compromised at diagnosis in both Crohn’s disease and colitis. Consideration of possible IBD and completion of appropriate investigations are essential to ensure prompt diagnosis, thereby avoiding the consequences of diagnostic delay. Patterns of disease including location and progression of IBD in childhood differ substantially from adult-onset disease. Various treatment options are available for children and adolescents with IBD. Exclusive enteral nutrition plays a central role in the induction of remission of active Crohn’s disease. Medical and surgical therapies need to considered within the context of a growing and developing child. The overall management of these chronic conditions in children should include multi-disciplinary expertise, with focus upon maintaining control of gut inflammation, optimising nutrition, growth and quality of life, whilst preventing disease or treatment-related complications.     

Canadian Association of Gastroenterology Clinical Practice Guidelines: The use of tumour necrosis factor-alpha antagonist therapy in Crohn’s disease

BACKGROUND:

Guidelines regarding the use of infliximab in Crohn’s disease were previously published by the Canadian Association of Gastroenterology in 2004. However, recent clinical findings and drug developments warrant a review and update of these guidelines.

OBJECTIVE:

To review and update Canadian guidelines regarding the use of tumour necrosis factor-alpha antibody therapy in both luminal and fistulizing Crohn’s disease.

METHODS:

A consensus group of 25 voting participants developed a series of recommendation statements that addressed pertinent clinical questions and gaps in existing knowledge. An iterative voting and feedback process was used in advance of the consensus meeting in conjunction with a systematic literature review to refine the voting statements. These statements were brought to a formal consensus meeting held in Montreal, Quebec (March 2008), wherein each statement underwent discussion, reformulation, voting and subsequent revision until group consensus was obtained (at least 80% agreement).

OUTCOME:

The 47 voting statements addressed three themes: induction therapy, maintenance therapy and safety issues. As a result of the iterative process, 23 statements achieved consensus and were submitted for publication.

CONCLUSION:

In the past five years, tumour necrosis factor-alpha antagonist therapy has become a cornerstone in the management of moderate-to-severe Crohn’s disease refractory to conventional treatment algorithms. The evidentiary base supporting the use of these drugs in Crohn’s disease is substantial and strengthened by results from long-term clinical and molecular studies. However, significant gaps in knowledge exist, particularly with regard to treatment failure. Confidence in the safety of these drugs is increasing, provided that therapy is administered in a clinical setting in which potential complications can be readily recognized and treated.     

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.     

Tracheobronchial nodules and pulmonary infiltrates in a patient with Crohn's disease

Crohn’s disease is a granulomatous systemic disorder of unknown etiology. Obvious pulmonary involvement is exceptional. Tracheal involvement in Crohn’s disease is even more unusual, only a few cases have been reported to date. We herein report a rare case of tracheobronchial nodules and pulmonary infiltrates in both lungs as a complication of Crohn’s disease. A 42-year-old man underwent pancolectomy for multiple broken colon caused by Crohn’s disease. Forty days later pulmonary symptoms and radiologic abnormalities were noted. A search for bacterial (including mycobacteria) and fungal in the repeated sputum proved negative. The treatment consisted of intravenous antimicrobials for one month, but there was no improvement in pyrexia or cough and radiologic abnormalities. Fibreoptic bronchoscopy (FOB) was performed and revealed nodes in the trachea and the right upper lobe opening. Histopathology of tracheobronchial nodules and bronchial mucosa biopsy specimen both showed granulomatous inflammation with proliferation of capillaries and inflammatory cells. Oral steroid and salicylazosulfapyridine were commenced and led to marked improvement in symptoms and an almost complete resolution of his chest radiograph. Repeated FOB showed that nodes in the trachea disappeared and the ones in the right upper lobe opening diminished obviously. Crohn’s disease can be associated with several respiratory manifestations. The form of tracheal and bronchopulmonary involvement in Crohn’s disease is rare and responded well to steroids.     

Successful use of adalimumab for treating fistulizing Crohn＇s disease with pyoderma gangrenosum： Two birds with one stone

Crohn＇s disease （CD） is a chronic relapsing and remitting autoinflammatory disorder of the gastrointestinal tract that has many intestinal and extraintestinal complications. The purpose of treatment is long-term remission, reduction of complications, and improvement of patients＇ quality of life. In many cases, this can be quite challenging and it is necessary to have a well thought out management strategy. We present the case of a 38-year-old woman with fistulizing CD that manifested as diffuse abdominal pain and bloody diarrhea accompanied by arthralgia. In addition, there were ulcerative lesions surrounded by cutaneous inflammation and erythema on her extremities, indicative of pyoderma gangrenosum. The patient was treated with high doses of parenteral methylprednisolone without any improvement and was started on adalimumab. A positive response to adalimumab therapy was observed： after 2 mo of therapy, the ulcerative skin lesion healed completely and the enterogastric fistula was closed affcer 5 mo adalimumab treatment. Adalimumab might be a suitable initial as well as maintenance therapy in patients with complicated CD.