Advances in medical therapy for Crohn’s disease

Therapeutic research in Crohn’s disease has been intensified in recent years. This has led to many novel approaches and insights into the mechanism of action of ‘classic’ drugs. Antibiotics remain valuable but do not offer benefit when used in addition to corticosteroids. Immunomodulators remain the cornerstone for maintenance therapy, although certain corticosteroid-dependent patients can be switched to maintenance therapy with topical steroids. Azathioprine and 6-mercaptopurine remain efficient beyond 4 years in patients with relapses and elevated C-reactive protein in spite of this therapy. Infliximab has shown efficiency in maintenance of active and fistulizing Crohn’s disease. In addition, ‘automatic reinfusion’ was found to be superior to ‘on-demand’ treatment. Infusion reactions and loss of response, most often caused by antibodies against infliximab, can be prevented with immunomodulators and corticosteroid infusions before dosing. Such alternative anti-tumor necrosis factor agents as adalimumab or CDP-870 may be less immunogenic. Other biologic agents, such as the anti-integrin monoclonal antibody natalizumab, were shown to be effective in maintaining remission and somewhat less so in induction of remission. Finally, much attention is being paid to alteration of the luminal flora with probiotics and helminth ova. Extracorporeal apheresis and even stem cell transplantation were found to be effective in isolated patients, but these therapies warrant further prospective and controlled investigation.     

The long-term outcome of anti-TNF alpha therapy in perianal Crohn’s disease

Background

The aim of the present study was to evaluate the long-term outcomes of anti-tumour necrosis factor alpha therapy in perianal Crohn’s disease and identify factors predicting response to treatment.

Methods

Data from hospital clinical records and coding databases were retrospectively reviewed from a tertiary care hospital in Christchurch, New Zealand. The study included 75 adult patients with perianal Crohn’s disease commenced on anti-tumour necrosis factor alpha therapy from January 2000 to December 2012. Response to treatment was determined from records relating to clinical evaluation, magnetic resonance imaging follow-up and whether further surgical intervention was required.

Results

73% (55) of all patients and 38 of the 57 (67%) patients with perianal fistulas responded to anti-tumour necrosis factor alpha therapy. Patients with complex fistulas were less likely to improve as compared to patients without fistulising disease. Five of the 57 (13%) patients with perianal fistulas demonstrated complete healing on clinical evaluation; however, magnetic resonance imaging confirmed complete healing in only two. Patients that had taken antibiotics and those that had previously required abscess drainage were less likely to respond to treatment [relative risk (RR) = 0.707 and 0.615, respectively; p = 0.03, p = 0.0001]. Responders were less likely to require follow-up surgery (RR = 0.658, p = 0.014) including ileostomy or proctectomy.

Conclusions

Although anti-tumour necrosis factor alpha tends to improve symptoms of perianal Crohn’s disease, in the long term, it rarely achieves complete healing. Perianal fistulising disease, a history of perianal abscess and antibiotic treatment are predictors of poor response to therapy.

     

Management of perianal Crohn’s disease

Opinion statement Perianal manifestations of Crohn’s disease usually coexist with active inflammation of other primary sites of the disease. Although treatment of active proximal disease may sometimes alleviate perianal symptoms, it is reasonable to separately treat symptomatic perianal disease. The diversity of perianal manifestations in Crohn’s disease mandates a tailored, individualized approach in every case. Medical therapy is the best treatment option for hemorrhoids and anal fissures. The medical management of patients with perianal Crohn’s disease includes the use of systemic antibiotics, immunosuppressive agents, and infliximab. Infliximab is now recognized as a very efficacious agent for treating fistulizing Crohn’s disease, including perianal fistulae. It may also reduce the need for surgical intervention in specific cases. Abscesses and fistulae are treated by control of sepsis, resolution of inflammation and optimal preservation of continence, and quality of life. Abscesses require surgical drainage that may need to be prolonged to achieve complete healing. Fistulae may be treated medically, especially in cases of concurrent proctitis. Refractory fistulae may require surgical treatment including an occasional need for fecal diversion or proctectomy. The role of new treatment options such as natalizumab and CDP571 is evolving and requires further investigation.     

Clinical updates on perianal fistulas in Crohn’s disease

Introduction: Perianal fistulizing disease is an aggressive and debilitating phenotype of Crohn’s disease (CD), representing a significant therapeutic challenge. New work has led to advancement in epidemiology and long-term outcomes of perianal disease. The range of therapeutic options continues to expand, including new biologic agents, biosimilars, and stem cell therapy.

Areas covered: We discuss updates to all aspects of management of perianal disease, with a focus on the last 3 years of published data. Areas considered include new data on epidemiology and prognostication, medical and surgical therapy, and stem cell therapy.

Expert commentary: The presence of perianal disease at CD diagnosis portends a significantly worse disease course. Patients with perianal disease require close monitoring to identify those who are at risk for worsening disease, suboptimal biologic drug levels, and signs of developing neoplasm. With the impending availability of local mesenchymal stem cell therapy, this becomes increasingly important as this therapy, although extremely promising, is thus far only effective in patients without proctitis.     

Optimizing biological therapy in Crohn’s disease

Anti-TNF therapy has revolutionized the treatment of inflammatory bowel diseases, including both Crohn’s disease and ulcerative colitis. However, a significant proportion of patients does not respond to anti-TNF agents or lose response over time. Recently, therapeutic drug monitoring has gained a major role in identifying the mechanism and management of loss of response. The aim of this review article is to summarize the predictors of efficacy and outcomes, the different mechanisms of anti-TNF/biological failure in Crohn’s disease and identify strategies to optimize biological treatment.     

Long-term efficacy of infliximab maintenance therapy for perianal Crohn’s disease

AIM:To assess the long-term efficacy of seton drainage with infliximab maintenance therapy in treatment of stricture for perianal Crohn’s disease(CD). METHODS:Sixty-two patients with perianal CD who required surgical treatment with or without infliximab between September 2000 and April 2010 were identified from our clinic’s database.The activities of the perianal lesions were evaluated using the modified perianal CD activity index(mPDAI)score.The primary endpoint was a clinical response at 12-15 wk after su...     

Imaging of perianal fistulizing Crohn’s disease

Perianal fistula is a complication of Crohn’s disease that carries a high morbidity. It is a channel that develops between the lower rectum, anal canal and perianal or perineal skin. The development of perianal fistulas typically connotes a more aggressive disease phenotype and may warrant escalation of treatment to prevent poor outcomes over time. Based on fistula anatomy, debris can form inside these tracts and cause occlusion, which subsequently leads to abscess formation, fever and malaise. The clinical presentation is often with complaints of pain, continuous rectal drainage of fecal matter as well as malodorous discharge. Considering that the presence of fistulas often indicates refractory and aggressive disease, early identification of its presence is important. Some patients may not have the classic symptoms of fistulizing disease at presentation and others may have significant scarring and/or pain from previous fistulizing episodes, which can make an accurate assessment on physical exam alone problematic. As a result, utilizing diagnostic imaging is the best means of identifying the early signs of perianal fistulas or abscess formation in these patients. Several imaging modalities exist which can be used for diagnosis and management. Endoscopic ultrasound and pelvic MRI are considered the most useful in establishing the diagnosis. However, a combination of multiple imaging modalities and/or examination under anesthesia is probably the most ideal. Incomplete characterization of the fistula tract(s) extent or the presence of abscess carries a high morbidity and far-reaching personal expense for the patient – promoting worsening of the disease.     

Medical therapy of Crohn’s disease

Opinion statement There is no medical or surgical treatment that provides a permanent cure for Crohn’s disease (CD). However, an evolving understanding of the pathogenesis of CD has provided clinicians with a diversity of medical treatment options for the disease. The goal of therapy is to induce and maintain clinical remission. The efficacy of immune-modifying agents such as azathioprine/6-mercaptopurine and infliximab have supported a paradigm shift in CD treatment in which maintenance agents are introduced earlier in the disease course. At the same time, it is imperative to balance the efficacy, safety, and tolerability of medical therapy. Given the variable and relapsing clinical course of CD, the physician and patient should ideally develop an ongoing relationship that allows for individualization of treatment regimens, monitoring of response and side effects, and modification of the therapeutic strategy in the absence of improvement.     

The current therapeutic options for Crohn’s disease: from medical therapy to intestinal transplantation

Introduction: Crohn’s disease (CD) has an annual incidence per 100.000 person-year of 20.2 in North America and 12.7 in Europe, and the purpose of this review is to evaluate its medical management, from diagnosis to transplant. Pharmacologic manipulation with nutritional care aims to achieve and maintain remission, but more than half of patients will undergo an intestinal resection, very often repeated over time. They could experience short bowel syndrome (SBS) requiring total parenteral nutrition (TPN). Intestinal transplantation (ITx) represents an alternative in case of irreversible intestinal failure (IF) with life-threatening TPN complications. Patient survival after ITx is 79%, 53% and 43% at 1, 3 and 5 years respectively, with no differences among ITx for other disorders.

Areas covered: The research discussed medical therapy with nutritional support, evaluating the role of endoscopy, surgery and transplant in CD. A systematic literature review was conducted using the PubMed search engine up to May 31^th, 2017 without restriction of the language. The decision on paper’s eligibility was reached by consensus between the 3 screening authors.

Expert commentary: CD treatment is mainly medical, leaving endoscopy and surgery for a complex course. ITx represents a therapeutic option if TPN complications with IF arise.     

Current therapy of pediatric Crohn’s disease

Inflammatory bowel diseases(IBD), including Crohn's disease(CD) and ulcerative colitis, are chronic relapsing and remitting diseases of the bowel, with an unknown etiology and appear to involve interaction between genetic susceptibility, environmental factors and the immune system. Although our knowledge and understanding of the pathogenesis and causes of IBD have improved significantly, the incidence in the pediatric population is still rising. In the last decade more drugs and treatment option have become available including 5-aminosalicylate,antibiotics, corticosteroids, immunomodulators and biological agents. Before the use of anti-tumor necrosis factor(TNF)-α became available to patients with IBD, the risk for surgery within five years of diagnosis was very high, however, with anti-TNF-α treatment the risk of surgery has decreased significantly. In the pediatric population a remission in disease can be achieved by exclusive enteral nutrition. Exclusive enteral nutrition also has an important role in the improvement of nutritional status and maintained growth. In this review we summarize the current therapeutic treatments in CD. The progress in the treatment options and the development of new drugs has led to optimized tactics for achieving the primary clinical goals of therapy- induction and maintenance of remission while improving the patient's growth and overall well-being.     

Management of perianal fistulas in Crohn’s disease:An upto-date review

Perianal disease is one of the most disabling manifestations of Crohn’s disease.A multidisciplinary approach of gastroenterologist,colorectal surgeon and radiologist is necessary for its management.A correct diagnosis,based on endoscopy,magnetic resonance imaging,endoanal ultrasound and examination under anesthesia,is crucial for perianal fistula treatment.Available medical and surgical therapies are discussedin this review,including new local treatment modalities that are under investigation.     

Nutritional therapy for active Crohn’s disease

Nutritional therapy for active Crohn’s disease （CD） is an underutilised form of treatment in adult patients, though its use is common in the paediatric population. There is evidence that nutritional therapy can effectively induce remission of CD in adult patients. Enteral nutrition therapy is safe and generally well tolerated. Meta-analysis data suggest that corticosteroids are superior to nutritional treatment for induction of remission in active CD. However, the potential side effects of such pharmacotherapy must be taken into consideration. This review examines the evidence for the efficacy of elemental and polymeric diets, and the use of total parenteral nutrition in active CD.     

New horizons in the imaging of perianal Crohn’s disease: transperineal ultrasonography

Introduction: perianal disease, most commonly manifest as fistula or abscess formation, affects up to 40% of patients with crohn’s disease. perianal crohn’s disease is disabling, associated with poor outcomes, and represents a therapeutic challenge for physicians. correct diagnosis and classification of perianal disease is the first crucial step for appropriate multidisciplinary management.

Areas covered: A literature search was performed of the PubMed database using the terms ‘transperineal ultrasonography’, ‘transperineal ultrasound’, ‘perianal disease’, ‘perianal fistula’, ‘perianal abscess’, ‘magnetic resonance’, ‘endoanal ultrasonography’, ‘endoscopic ultrasound’ in combination with ‘Crohn’s disease’. A comprehensive review of the relative advantages and disadvantages of the various methods of evaluation of perianal Crohn’s disease is provided. A particular focus is placed on transperineal ultrasonography, including historical and technical factors, advantages and limitations, and its current role in practice. An algorithm for integration of transperineal ultrasound into the management of perianal Crohn’s disease into clinical practice is proposed, along with future areas research.

Expert commentary: Transperineal ultrasound is a simple, safe, cheap and reliable imaging technique for evaluation of perianal Crohn’s disease, which should be used more frequently in clinical practice.     

Impact of medical therapy on patients with Crohn’s disease requiring surgical resection

AIM: To evaluate the impact of medical therapy on Crohn’s disease patients undergoing their first surgical resection.METHODS: We retrospectively evaluated all patients with Crohn’s disease undergoing their first surgical resection between years 1995 to 2000 and 2005 to 2010 at a tertiary academic hospital (St. Paul’s Hospital, Vancouver, Canada). Patients were identified from hospital administrative database using the International Classification of Diseases 9 codes. Patients’ hospital and available outpatient clinic records were independently reviewed and pertinent data were extracted. We explored relationships among time from disease diagnosis to surgery, patient phenotypes, medication usage, length of small bowel resected, surgical complications, and duration of hospital stay.RESULTS: Total of 199 patients were included; 85 from years 1995 to 2000 (cohort A) and 114 from years 2005 to 2010 (cohort B). Compared to cohort A, cohort B had more patients on immunomodulators (cohort A vs cohort B: 21.4% vs 56.1%, P < 0.0001) and less patients on 5-aminosalysilic acid (53.6% vs 29.8%, P = 0.001). There was a shift from inflammatory to stricturing and penetrating phenotypes (B1/B2/B3 38.8% vs 12.3%, 31.8% vs 45.6%, 29.4% vs 42.1%, P < 0.0001). Both groups had similar median time to surgery. Within cohort B, 38 patients (33.3%) received anti-tumor necrosis factor (TNF) agent. No patient in cohort A was exposed to anti-TNF agent. Compared to patients not on anti-TNF agent, ones exposed were younger at diagnosis (anti-TNF vs without anti-TNF: A1/A2/A3 39.5% vs 11.8%, 50% vs 73.7%, 10.5% vs 14.5%, P = 0.003) and had longer median time to surgery (90 mo vs 48 mo, P = 0.02). Combination therapy further extended median time to surgery. Using time-dependent multivariate Cox proportional hazard model, patients who were treated with anti-TNF agents had a significantly higher risk to surgery (adjusted hazard ratio 3.57, 95%CI: 1.98-6.44, P < 0.0001) compared to those without while controlling for gender, disease phenotype, smoking status, and immunomodulator use.CONCLUSION: Significant changes in patient phenotypes and medication exposures were observed between the two surgical cohorts separated by a decade.     

Long-term response rates to infliximab therapy for Crohn’s disease in an outpatient cohort

BACKGROUND:

Infliximab’s efficacy in the induction and maintenance of remission in luminal Crohn’s disease has been confirmed by randomized, controlled trials. Less clearly described are long-term outcomes in the clinical practice setting since the establishment of regularly scheduled, every eight-week maintenance infliximab infusions. Existing reports describing clinical practice outcomes are limited by short durations of follow-up or by the use of episodic dosing, or focus on safety data rather than clinical outcomes.

OBJECTIVE:

To examine induction and maintenance responses to infliximab in an outpatient inflammatory bowel disease clinic.

METHODS:

A retrospective chart review was performed. Clinical outcomes were infliximab induction and maintenance responses, defined as the ability to stop and remain off corticosteroids while not requiring additional therapy for active disease.

RESULTS:

One hundred thirty-three patients were identified with records sufficiently detailed to be analyzed. Of these, 117 patients (88%) demonstrated a clinical response to induction; 104 of 117 (89%) were on concomitant immunosuppressive therapy; 80 of 104 on azathioprine/6-mercaptopurine (77%); and 24 of 104 on methotrexate (23%). The mean duration of clinical response was 94 weeks (95% CI 78.8 to 109.2). The proportion of patients who maintained response at 30 weeks was 83.2%, at 54 weeks was 63.6% and at 108 weeks was 44.9%. Adverse events occurred for 15 of 117 patients (12.8%), consisting of nine infusion reactions, four serum sickness-like reactions, one rash and one infection.

CONCLUSION:

Patients treated with infliximab therapy for luminal Crohn’s disease in our outpatient clinic achieved excellent induction and maintenance of response rates, confirming the real-life efficacy of maintenance infliximab established in clinical trials.     

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.     

Advances in biologic therapy for ulcerative colitis and Crohn’s disease

The medical management of inflammatory bowel disease (IBD) has changed considerably since the advent of biologic treatments. In this review we offer a critical evaluation of controlled studies with biologic agents for the management of both Crohn’s disease (CD) and ulcerative colitis (UC). Biologics under evaluation or approved for UC that are discussed include monoclonal antibodies to tumor necrosis factor ([TNF]) infrliximab), inhibitors of adhesion molecules (MLN02 and alicaforsen), anti-CD3 antibodies (visilizumab), and anti-interleukin (IL)-2 receptor antibodies (daclizumab). Biologics under evaluation or approved for CD that are reviewed include three monoclonal antibodies to TNF (infliximab, adalimumab, and certolizumab pegol), monoclonal antibodies against IL-12, interferon-γ, and IL-6 receptors, inhibitors of adhesion molecules (natalizumab, alicaforsen), and growth factors. Only the chimeric monoclonal anti-TNF antibody infliximab is currently available worldwide. The potency of this agent in moderate-to-severe UC and CD has been one of the most important advances in the care of IBD in the past decade.