Review article: The medical treatment of Crohn's perianal fistulas

Perianal fistulas are a frequent manifestation of Crohn's disease. The correct application of the newer diagnostic and therapeutic agents for treating perianal Crohn's disease are beginning to be better defined. In general, a combined medical and surgical approach is preferred. The perianal disease process should first be fully delineated with endoscopy and either MRI or EUS before treatment is begun. Patients are then stratified into one of three groups: simple fistulas and no proctitis; simple fistulas and concomitant proctitis; and complex fistulas. Patients with simple fistulas and no proctitis can be treated medically with a combination of antibiotics and an immunosuppressive agent (azathioprine or mercaptopurine). Patients with simple fistulas and concomitant proctitis should have infliximab added to their treatment plan. Complex fistulas require surgical intervention first prior to medical treatment. A combination of antibiotics, immunosuppressive therapy and infliximab are then initiated to facilitate fistula healing.     

Review article: The medical management of Crohn's disease

The choice of medical therapies for Crohn's disease continues to grow. Although our understanding of the mechanisms of the disease is incomplete, increasing knowledge of the pathogenesis of inflammation in general and Crohn's disease in particular allows targeting of therapies at various points in the immunoinflammatory cascade. In addition, the division of Crohn's disease into subtypes by location, aggressiveness, and the presence or absence of perianal and fistulizing disease allows the tailoring of medical therapy to the individual patient. For those patients with moderate to severe symptoms or frequent flares of disease activity, and those who have required surgical resection, maintenance therapy can substantially reduce the rate of recurrence. Despite these advances, available medical therapies for Crohn's disease remain imperfect, as evidenced by their sometimes substantial toxicities and the continued frequent need for surgery.     

Review article: treatment of perianal fistulizing Crohn's disease

Fistulizing Crohn's disease can involve the bowel, but is more commonly seen in the perianal region. In acute perianal Crohn's disease, perianal lesions are manifestations of disease activity and are frequently treated concomitantly with bowel lesions. Spontaneous resolution occurs in up to 50% of patients. Fistulae are secondary lesions that may progress to destruction of the sphincter apparatus necessitating proctectomy after years of suffering. The control of sepsis is the first objective. The drainage of abscesses and the placement of setons are essential steps in treatment. Disease severity can be readily assessed by examination under anaesthesia and by magnetic resonance imaging. Endoscopic ultrasonography is sensitive, but is hampered by the necessary introduction of a large instrument into an often narrowed anorectum. Antibiotics, especially metronidazole and ciprofloxacin, are useful short-term therapies to decrease or stop drainage, but relapse is immediate on discontinuation. Immunosuppression with azathioprine (2.5 mg/kg per day) or mercaptopurine (1.5 mg/kg per day) is effective, but slow and often incomplete. The management of perianal fistulizing disease resistant to standard treatment has greatly improved with the introduction of the anti-tumour necrosis factor-alpha antibody, infliximab. The complete arrest of the drainage of fistulae is obtained in 46% of patients 10 weeks after the administration of 5-10 mg/kg of infliximab at weeks 0, 2 and 6 and, on average, lasts for 12 weeks. A treatment algorithm for fistulizing Crohn's disease must therefore involve the early and optimal use of immunosuppression and of infliximab. Medical and surgical co-operation is also critical to achieve the best possible outcome.     

Review article: medical treatment of active Crohn's disease

Crohn's disease, a heterogeneous inflammatory process that can affect various sites in the gut, presents an ongoing management challenge for the clinician. The treatment of active disease and complications is one of the main goals in the therapy of this disease. New therapies are aimed at delivering the active compounds to the diseased site, reduction or suppression of enteral flora and modulation of more focal targets within the immune response. The use of antibiotics in the therapy of Crohn's disease is gaining popularity, on the grounds that intestinal bacteria may play a role in the pathogenesis of Crohn's disease lesions. Metronidazole is one of the most widely used antibiotics, especially in the treatment of perianal disease. Corticosteroids are the mainstays of medical treatment in active Crohn's disease and induce the remission of symptoms in about 60-80% of patients. The use of immunosuppressive agents, such as cyclosporine and methotrexate, in patients with active disease resistant to standard therapy has gained acceptance in recent years. With new therapies the outlook for patients with Crohn's disease is more optimistic than it has been for a long time.     

Review article: the management of severe Crohn's disease

The treatment of severe and active Crohn's disease is currently based on immunosuppression, but also involves the management of nutrition, appropriate selection of patients for surgery, and maintenance of remission in the long term. Corticosteroids remain the drug of the first choice, particularly in the acute setting. However, there is evolving understanding of the role of other immunosuppressants and immune modifiers, as major concerns regarding side-effects and efficacy of steroids in the medium to long-term drive the search for alternatives.     

Review article: the dietary management of Crohn's disease

Enteral feeding has been shown to be as effective as primary therapy for Crohn's disease, but it requires high patient motivation, may be unpalatable and is expensive. However, in adolescents with growth failure and when corticosteroid therapy is contra-indicated or has failed, it may become the treatment of choice. Furthermore, dietary therapy allows circumvention of the adverse side-effects of repeated courses of steroids.
A number of different hypotheses have been proposed to explain the effect of enteral feeds but none has reached universal acceptance. Prospective trials suggest that the exclusion of whole protein is not necessary. Comparison of feeds with differing composition suggests that a low fat content increases efficacy and various explanations have been offered. The reduction of colonic bacterial load may also be important.
Because symptoms of Crohn's disease may be provoked by eating, there is a risk of falsely attributing symptoms to specific foodstuffs. However, in many individuals foods can be identified which affect disease activity, and their exclusion leads to prolongation of disease remission. Dietetic supervision during food testing is important to avoid detrimental effects on nutrient and micronutrient intake.     

Review article: the management of refractory Crohn's disease

Refractoriness to conventional therapy is a common and intriguing problem in Crohn's disease patients. At the present time there is no agreement on its definition and several mechanisms are involved in its determination. Immunosuppressors, such as azathioprine (AZA), 6-mercaptopurine (6MP) and methotrexate (MTX) are effective drugs for controlling the inflammatory process and avoid chronic glucocorticosteroid treatment and its related side-effects. Recently, the introduction of tumour necrosis factor antibodies (infliximab) has dramatically changed the natural history of Crohn's disease and its therapeutic approach. Several studies have determined the efficacy, mechanisms and safety of infliximab. However, this molecular approach has also left several questions unanswered about the mechanisms of refractoriness, possible concomitant treatments and long-term safety and efficacy.     

Review article: medical treatment of moderate to severe Crohn's disease

The treatment for patients with Crohn's disease of moderate to severe activity includes traditional drugs, such as corticosteroids, the primary therapy for these forms of disease, able to induce the remission of symptoms in a high percentage of patients. Because of the side-effects produced by systemic steroids, a new glucocorticoid derivative, budesonide, which acts locally in the mucosa, has recently been introduced with positive results. On the assumption that intestinal bacteria play a role in the causing Crohn's disease symptoms, antibiotics are often used in the treatment of active phases, as an alternative to or in association with steroids. The most widely employed antibiotics are metronidazole and ciprofloxacin. Immunosuppressors, such as azathioprine and 6-mercaptopurine, are useful for the treatment of chronic active disease and for maintaining remission, but they have only a marginal role in the therapy of an acute flare-up of Crohn's disease. Methotrexate acts more rapidly and its use in patients with active disease resistant to standard therapy is of interest. The discovery of biological agents represents a new era in the management of patients. To date, infliximab is the more extensively studied biological therapy in the treatment of Crohn's disease and clinical studies have demonstrated its efficacy in inducing remission of refractory disease.     

Review article: medical treatment of mild to moderately active Crohn's disease

Crohn's disease is a chronic, debilitating subset of inflammatory bowel diseases, which may affect any part of the gastrointestinal tract. The most common sites of inflammation are the terminal ileum and/or the colon. Fistulous disease is present in up to 20% of patients, particularly in those having rectal involvement. The aetiology of Crohn's disease still remains obscure, therefore medical therapy is directed towards symptomatic relief in active disease and relapse prevention in the long-term setting. Contemporary Crohn's disease management comprises individual treatment depending mainly on Crohn's disease localization in the gastrointestinal tract and the disease severity. The mainstay of current medical treatment for mild to moderately active stages of Crohn's disease includes aminosalicylates, antibiotics, glucococorticosteroids and immunomodulators. Biologics such as anti TNF-compounds and anti-integrins are being introduced.     

Review article: surgical, neo-adjuvant and adjuvant management strategies in biliary tract cancer

Aliment Pharmacol Ther 2011; 34: 1063–1078

Summary

Background The majority of patients with cholangiocarcinoma present with advanced, irresectable tumours associated with poor prognosis. The incidence and mortality rates associated with cholangiocarcinoma continue to rise, mandating the development of novel strategies for early detection, improved resection and treatment of residual lesions. Aim To review the current evidence base for surgical, adjuvant and neo‐adjuvant techniques in the management of cholangiocarcinoma. Methods A search strategy incorporating PubMed/Medline search engines and utilising the key words biliary tract carcinoma; cholangiocarcinoma; management; surgery; chemotherapy; radiotherapy; photodynamic therapy; and radiofrequency ablation, in various combinations, was employed. Results Data on neo‐adjuvant and adjuvant techniques remain limited, and much of the literature concerns palliation of inoperable disease. The only opportunity for long‐term survival remains surgical resection with negative pathological margins or liver transplantation, both of which remain possible in only a minority of selected patients. Neo‐adjuvant and adjuvant techniques currently provide only limited success in improving survival. Conclusions The development of novel strategies and treatment techniques is crucial. However, the shortage of randomised controlled trials is compounded by the low feasibility of conducting adequately powered trials in liver surgery, due to the large sample sizes that are required.     

Review article: maintenance treatment of Crohn's disease

The aetiology of Crohn's disease is unknown and therefore no curative treatments are available for the disease. The natural history of Crohn's disease is characterized by recurrent flare-ups of symptoms. Several drug treatments are effective in inducing clinical remission. However, no drug treatments are available in order to prevent clinical relapses, although several drug regimens may delay clinical flare-ups. Crohn's disease treatment for maintaining clinical remission needs to be tailored in relation to specific characteristics of each patient. The frequency of clinical relapse indeed shows marked variations in subgroups of patients, as the likelyhood of relapse is higher in patients in clinical remission for less than 6 months. Treatment strategies for maintaining remission may therefore differ among inactive patients. In chronically active, steroid-dependent or steroid-refractory Crohn's disease patients immunomodulatory drugs (azathioprine 2-2.5 mg/kg by mouth, 6-mercaptopurine 1-1.5 mg/kg by mouth, or methotrexate 15-25 mg/i.m./week) should be added to oral mesalazine (2.4 g/day), while in long-term inactive Crohn's disease patients mesalazine alone may be effective in delaying relapse. Recently, treatment with anti-tumour necrosis factor-alpha monoclonal antibodies (Infliximab or CDP571) has shown efficacy in delaying relapse in responsive patients. One other issue which needs to be considered before selecting drug treatments for maintaining remission in Crohn's disease, is that Crohn's disease activity is currently assessed on the basis of standard clinical scores which may not appropriately reflect the biological activity of the disease. Clinical remission as defined by standardized scores may include heterogeneous subgroups of patients showing different endoscopic and histological activity or persistence of activated immunocompetent cells within the gut. Several sub-clinical markers of relapse have indeed been reported in quiescent Crohn's disease, although their usefulness in clinical practice in currently uncertain.     

Review article: Crohn's disease: monitoring disease activity

A global measurement of Crohn's disease activity, comprising clinical, endoscopic, biochemical and pathological features is not available yet and perhaps is unobtainable. In this review we analyse the most used and validated clinical indices (Crohn's Disease Activity Index [CDAI], Perianal Disease Activity Index [PDAI], fistula drainage assessment), quality of life scores (Inflammatory Bowel Disease Questionnaire [IBDQ]), sub-clinical markers (C-reactive protein, faecal calprotectin, intestinal permeability) and endoscopic indices (Crohn's Disease Endoscopic Index of Severity [CDEIS]/Simple Endoscopic Score for Crohn's Disease [SES-CD], Rutgeeerts' score for postsurgical recurrence). We also review the main advantages and disadvantages of each of these scoring systems. All these indices are rather complex and time-consuming, therefore their use is limited to clinical trials. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision-making.     

Review article: Crohn's disease--the role of nutritional therapy

Maintenance of adequate nutrition is of obvious importance in the management of patients with Crohn's disease. Exclusive parenteral nutrition can achieve high rates of remission, but this is not usually necessary since exclusive elemental and polymeric enteral regimes can yield similarly good results. Comparison of exclusive enteral formula feeding with steroid treatment favours steroids only because compliance is less complete for the restrictive nutritional regimes, and formula feeds should always be the first choice in the growing child with active Crohn's disease. It is probable that the nature of the lipid provided in Crohn's diets is clinically important, and there is some evidence that the n-3 fatty acids are beneficial. Continuation of nutritional supplements once remission has been obtained appears valuable even when malnutrition is not a major consideration.     

Review article: monitoring the activity of Crohn's disease

Crohn's disease is characterized by a chronic inflammation of the intestine of unknown aetiology. One of the main problems when treating patients with Crohn's disease, is the identification of patients undergoing early clinical relapse, for timely treatment and the possible prevention of complications. No sub-clinical markers are currently available that predict relapse during remission. Several parameters have been proposed for this purpose. Although none have proven useful, growing evidence suggests a possible benefit in the clinical management of Crohn's disease. Among these, we may identify: clinical behaviour, the characteristics of the host, clinical activity, markers of intestinal inflammation and markers of immune activation. In particular, the possible relationship between cytokine pattern and the clinical behaviour of Crohn's disease has been addressed. Overall, these observations suggest that mucosal immune activation is a feature of Crohn's disease, and may persist in the form of activated immunocompetent cells during remission. On the basis of this evidence, studies are currently investigating whether the down-regulation of immune activation markers is associated with clinical remission in Crohn's disease. It has been shown that higher mucosal levels of TNF-alpha and an increased state of activation of lamina propria mononuclear cells in patients with inactive Crohn's disease, are significantly associated with an earlier clinical relapse of the disease. These observations suggest that a persistent local immune activation during remission may represent a marker of early clinical relapse of Crohn's disease.     

Review article: the optimal medical management of acute severe ulcerative colitis

Aliment Pharmacol Ther 2010; 32: 615–627

Summary

Background Management of acute severe ulcerative colitis (UC) is a clinical challenge, with a mortality rate of approximately 1–2%. The traditional management with intravenous corticosteroids has been modified by introduction of ciclosporin and more recently, infliximab. Aim To provide a detailed and comprehensive review of the medical management of acute severe UC. Methods PubMed and recent conference abstracts were searched for articles relating to treatment of acute severe UC. Results Two‐thirds of patients respond to intravenous steroids in the short term. In those who fail steroids, low‐dose intravenous ciclosporin at 2 mg/kg/day is effective. Approximately 75% and 50% of patients treated with ciclosporin avoid colectomy in the short and long‐terms, respectively. Long‐term outcome of ciclosporin therapy is improved by introduction of azathioprine on discharge from hospital, together with oral ciclosporin as a bridging therapy. Controlled data show that infliximab is effective as rescue therapy for acute severe UC and the effect appears to be durable, although longer‐term follow‐up data are needed. Conclusions Both ciclosporin and infliximab have demonstrated efficacy as rescue medical therapies in patients with acute severe UC, but surgery needs to be considered if there is failure to improve or clinical deterioration.