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...     

Long-term outcome of infliximab combined with surgery for perianal fistulizing Crohn’s disease

AIM:To evaluate the efficacy and long-term outcome of infliximab combined with surgery to treat perianal fistulizing Crohn’s disease(CD).METHODS:The work was performed as a prospective study.All patients received infliximab combined withsurgery to treat perianal fistulizing CD,which was followed by an immunosuppressive agent as maintenance therapy.RESULTS:A total of 28 patients with perianal fistulizing CD were included.At week 30,89.3%(25/28)of the patients were clinically cured with an average healing time of 31.4 d.The CD activity index decreased to70.07±77.54 from 205.47±111.13(P0.01)after infliximab treatment.The perianal CD activity index was decreased to 0.93±2.08 from 8.54±4.89(P0.01).C-reactive protein,erythrocyte sedimentation rate,platelets,and neutrophils all decreased significantly compared with the pretreatment levels(P0.01).Magnetic resonance imaging results for 16 patients after therapy showed that one patient had a persistent presacral-rectal fistula and another still had a cavity without clinical symptoms at follow-up.After a median follow-up of 26.4 mo(range:14-41 mo),96.4%(27/28)of the patients had a clinical cure.CONCLUSION:Infliximab combined with surgery is effective and safe in the treatment of perianal fistulizing CD,and this treatment was associated with better longterm outcomes.     

Ustekinumab for the treatment of Crohn’s disease

Introduction: Ustekinumab is a human monoclonal antibody directed against the shared p40 subunit of interleukins 12 and 23. Ustekinumab is currently approved for the treatment of psoriatic arthritis (PsA) and moderate to severe plaque psoriasis, and is being evaluated in Crohn’s disease (CD).

Areas covered: The first evidence supporting the efficacy of ustekinumab in the treatment of moderate to severe CD was published in 2008. Results from subsequent phase II and phase III randomized controlled trials (RCTs) have shown promising data on the clinical efficacy of induction and remission of moderate to severe CD. These data and the safety profile of ustekinumab will be reviewed.

Expert commentary: As a significant proportion of individuals with CD have ongoing symptoms and inflammation despite existing therapies, there is a clinical need for new agents like ustekinumab directed at different targets on the inflammatory pathway. Looking forward, more studies are needed to evaluate dosing escalation or de-escalation in addition to timing of therapy switches. In addition, further data is required to gauge the comparative effectiveness of ustekinumab to the biologic agents that are currently used in the treatment of CD.     

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.     

Local injection of infliximab in severe fistulating perianal Crohn’s disease: an open uncontrolled study

Background  

Perianal fistulas are frequent complications of Crohn’s disease. Intravenous infliximab can control perianal disease and promote perianal fistula closure. Perifistular infliximab injections have been proposed for patients who are intolerant or unresponsive to intravenous therapy. The aim of this study was to assess the long-term efficacy of surgical treatment combined with local infliximab therapy.     

Prevention of recurrence after surgery for Crohn’s disease: Efficacy of infliximab

After surgery for Crohn’s disease (CD), early endoscopic lesions are frequently observed despite no symptomatic recurrence. The severity of lesions found at postoperative endoscopy is reported to be a strong predictive factor for future clinical recurrence. If endoscopic lesions in the early postoperative period can be reduced with medications, symptomatic recurrence will likely be delayed and decreased. Before the introduction of biologic therapies, various medications were used for the maintenance of clinical remission after surgery; however, few demonstrated consistent efficacy. Infliximab is a recombinant anti-tumor necrosis factor-α antibody. Although infliximab is one of the most effective medications in the management of CD, its efficacy for early endoscopic lesions after surgery has not yet been assessed. The author and colleagues recently conducted a prospective study in order to investigate the impact of infliximab on early endoscopic lesions after resection for CD. We found that infliximab therapy showed clear suppressive effects on clinical and endoscopic disease activity in patients with early endoscopic lesions after resection.     

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.     

Efficacy of early treatment with infliximab in pediatric Crohn’s disease

AIM: To investigate the effectiveness of early infliximab use for induction and maintenance therapy in pediatric Crohn’s disease. METHODS: We performed a retrospective chart review of 36 patients with Crohn’s disease. Ten patients (group A) were treated with mesalamine after induction therapy with oral prednisolone, and 13 patients (group B) were treated with azathioprine after induction therapy with oral prednisolone. Thirteen patients (group C) received infliximab and azathioprine for induction and mainte...     

Vedolizumab in the treatment of Crohn’s disease

Vedolizumab, a recent addition to the therapeutic armamentarium in Crohn’s disease, is promising in efficacy, durability of remission and safety. It is the first gut selective biologic treatment, acting by targeting α4β7-integrin, a receptor expressed on activated lymphocytes and binding to MAdCAM1, a cell adhesion molecule selectively expressed in the circulatory system of the digestive tract, preventing trafficking of lymphocytes to the gut. The pivotal GEMINI studies have demonstrated the efficacy and safety of vedolizumab in achieving clinical response and clinical remission in patients with moderately to severely active CD who are naïve or have previously failed therapy with TNF-antagonists, immunomodulators or dependent on steroids. Vedolizumab had a favorable safety profile and specifically showed no evidence of PML, reactivation of latent TB or hepatitis B. Overall, the number of malignancies in the clinical trials was small; however, long-term exposure was limited. Vedolizumab can be given as a first-line therapy or following treatment failure, and was tolerated as part of combination therapy. More medications with similar and novel therapeutic mechanisms are anticipated in the coming years.     

Outcome of ileal pouch after secondary diagnosis of Crohn’s disease

Ileal-pouch anal anastomosis is sometimes performed inappropriately in Crohn’s disease patients. The aim of this study was to evaluate long-term results in this subset. In 54 ileal-pouch anal anastomoses performed between 1985 and 1997 for CUD the patient was eventually diagnosed as having Crohn’s disease in seven cases. A retrospective review was performed. Definitive diagnosis was established on histopathology, endoscopy, and clinical presentation. The principal outcome factors were pouch failure, reason for failure, and functional results in cases of retained pouch. Patients ranked their quality of life between 1 and 10. We found three failures due to pelvic abscess, anoperineal disease, and anovulvar fistula. The pouch was excised in the latter patient; four patients retained their pouch. Functional results were good in the four (7 year follow-up): 7.25 bowel movements per day, ability to discriminate flatus from feces in three, soiling in one, urgency in one, perianal pad in one, ability to differ bowel movement for 66 min, diet, and antidiarrheal medication all four, pouchitis in one, sexual troubles in one woman, no urinary or obstetric trouble. Quality of life was judged satisfactory by six of the seven patients. Our 13% rate of inadvertent ileal-pouch anal anastomosis is higher than results usually reported. This difference is explained by the diagnostic criteria, whose validity is controversial. Three-stage surgery to decrease inadvertent restorative coloproctectomy is worth considering. Even if results are good when the pouch is functioning, Crohn’s disease remains a contraindication to ileal-pouch anal anastomosis because of its high rate of failure and excision. Accepted: 24 November 1999     

Efficacy and safety of adalimumab for the treatment of Crohn’s disease in adults

Biologic agents offer potentially disease-modifying benefits that address long-term symptom control. Adalimumab was developed to be a fully human monoclonal antibody and an advancement over previously developed biologics. Adalimumab induces and maintains long-term clinical response and remission in patients with moderate-to-severe Crohn’s disease (CD) who had failed to respond to conventional therapy. In addition, adalimumab is effective in patients who cannot tolerate or who have lost response to infliximab therapy. Clinical trials demonstrate that adalimumab reduces the risk of CD-related hospitalization, maintains rapid complete fistula closure and is steroid-sparing, especially when administered early in the course of the disease. Adalimumab is generally well-tolerated by patients with moderate-to-severe CD. Opportunistic infections occurred in approximately 2% of adalimumab-treated patients and malignant neoplasms occurred in approximately 1% of patients, with no differences compared with placebo during the randomized, placebo-controlled portions of the adalimumab trials. This article reviews the efficacy and safety of adalimumab in the treatment of adult patients with CD and discusses the role of adalimumab in the current and future management of CD.     

Review of local injection of anti-TNF for perianal fistulising Crohn’s disease

Background

Perianal fistulising Crohn’s disease (PFCD) affects a third of Crohn’s disease patients and represents a disabling phenotype with poor outcome. The anti-tumour necrosis factor alpha (TNF) therapies have been shown to maintain clinical remission in a third of patients after 1 year of treatment. Maintenance therapy with systematic administration schedules confers greatest benefit, but exposes patients to risks/side effects of continued systemic use and led to consideration of local drug delivery (first described in 2000). In this review, we analyse all published articles on local anti-TNF therapy in the treatment of PFCD.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to systematically search Medline and Embase using the medical subject headings ‘fistula’, ‘anus’, ‘Crohn disease’, ‘infliximab’ and ‘adalimumab’. This was combined with free text searches, e.g. ‘local injection’ and ‘Crohn’s perianal disease’. Studies/abstracts describing local injection treatment with anti-TNF were included in this review.

Results

Six pilot studies including a total of 92 patients were included in this review. Outcomes reported were mostly clinical and included ‘complete/partial response’ to therapy and short-term results varied between 40 and 100%. There were no significant adverse events and the local injections were well tolerated.

Conclusions

There is paucity of data assessing this treatment modality. Local anti-TNF therapy appears safe, but outcome reporting is heterogeneous, subjective and long-term data are unavailable. Our review suggests a potential role may be in those in whom systemic treatment is contraindicated and calls for standardised reporting of outcomes in this field to enable better data interpretation.

     

Efficacy of infliximab for luminal and fistulizing Crohn’s disease and in ulcerative colitis

Opinion statement Infliximab is arguably the first major advance in therapy for inflammatory bowel disease in more than a quarter of a century. Although it is important to distinguish efficacy from effectiveness, the data from clinical practice mirror those from randomized controlled trials. Infliximab has proven efficacious for luminal manifestations of Crohn’s disease (CD) regardless of location. It also has proven efficacy in the subset of penetrating disease to the skin and perianal area, and it increases rates of steroid-free remission. These benefits are reflected in improved quality of life, with limited data showing that infliximab can decrease rates of hospitalization and CD-related surgery. Infliximab also has proven to be efficacious in patients with ulcerative colitis (UC) and has increased rates of steroid-free remission. Whether infliximab will have an impact on the risk of colorectal cancer in UC and Crohn’s colitis has yet to be determined. The combination of strong evidence from large randomized controlled trials with substantial examination of use in the practice setting has moved biologic therapy with infliximab from novel to mainstream. In this review, the data for the efficacy of infliximab in controlled trials will be discussed in the context of real world effectiveness.     

The diagnosis and treatment of whipple’s disease

Whipple’s disease is a rare, chronic, and systemic infectious disease caused by the ubiquitously occuring bacterium Tropheryma whippelii. For two reasons, the disease represents a good example for documenting the input of modern molecular-based techniques into pathogenetic, diagnostic, and therapeutic concepts in clinical medicine. First, the unidentified and uncultivable causative organism has been characterized by novel molecular-genetic techniques. Second, in contrast to other chronic inflammatory disorders, clinical manifestations of T. whippelii infection seem to be based on reduced T-cell helper type 1 (TH1) activity. These findings have led to an improved pathophysiologic understanding of the disease and to new aspects in treatment strategies that are discussed in this paper.     

Clinical monitoring: infliximab biosimilar CT-P13 in the treatment of Crohn’s disease and ulcerative colitis

Objective: The infliximab biosimilar CT-P13 (Remsima^®, Inflectra^®) was approved in Europe for the treatment of inflammatory bowel disease (IBD) based on extrapolation of data from patients with rheumatic disease. Because there are limited published reports on clinical outcomes for IBD patients treated with CT-P13, we monitored responses to induction treatment with this biosimilar in patients with Crohn’s disease (CD) or ulcerative colitis (UC) in centres across the Czech Republic.

Material and methods: Fifty-two patients with CD (n?=?30) or UC (n?=?22) were treated with 5?mg/kg CT-P13 for up to 14 weeks. Effectiveness of therapy was evaluated with the Crohn’s Disease Activity Index (CDAI) or the Mayo Scoring System (MSS) in patients with CD or UC, respectively, before and after 14 weeks. Additional goals were to evaluate weight changes, serum C-reactive protein (CRP) levels, and complications/adverse events.

Results: In patients with CD, remission (CDAI?<150) was achieved in 50.0% of cases, and partial response (≥70-point decrease in CDAI score from baseline) in the remaining 50.0%. In patients with UC, remission (total score on partial Mayo index?≤2 points) was achieved in 40.9% of cases, partial response (≥2-point decrease in partial Mayo score from baseline) in 54.5%, and no response in 4.5%. There were statistically significant improvements in CDAI, MSS and CRP serum levels after 14 weeks of therapy, and body weight increased. Four adverse events were identified (n?=?1 each): lower-extremity phlebothrombosis, herpes labialis, pneumonia and allergic reaction.

Conclusions: This prospective observational study provides evidence of the effectiveness of CT-P13 in IBD.     

Roles of double-balloon endoscopy in the diagnosis and treatment of Crohn’s disease: a multicenter experience

Background

Double-balloon endoscopy (DBE) examinations are not yet widely accepted as routine procedures for examining the small bowel of patients with Crohn’s disease (CD).

Aim

To evaluate the feasibility and usefulness of DBE for CD in tertiary-care hospitals.

Methods

Between July 2004 and September 2008, 1444 DBE procedures were performed for 704 patients in 6 tertiary-care hospitals. Patient profile, indication, diagnosis and treatment of DBE were evaluated using a multicenter database.

Results

DBE examinations were most frequently performed in 75 patients with CD, corresponding to 10.5% of all the patients examined by DBE. Fifty patients were diagnosed with CD before DBE, while DBE was performed for the diagnosis of 25 new CD patients. Small bowel lesions were often detected even when the terminal ileum was not involved. In the 75 patients, 21 patients were asymptomatic at the time of DBE examinations. Active inflammatory lesions were detected in 51.2% of the CD patients, and were even detected in 33.3% of the asymptomatic CD patients. The treatment was altered in 53.3% of the CD patients after the DBE evaluation. No severe complications were experienced.

Conclusions

DBE procedures can be safely performed in patients with CD and should be considered for the precise evaluation of and to determine the treatment strategy for CD.

     

Use of antibiotics in the treatment of Crohn’s disease

Many data coming from animal models and clinical observations support an involvement of intestinal microbiota in the pathogenesis of Crohn’s disease(CD). It is hypothesized in fact,that the development of chronic intestinal inflammation is caused by an abnormal immune response to normal flora in genetically susceptible hosts.The involvement of bacteria in CD inflammation has provided the rationale for including antibiotics in the therapeutic armamentarium.However, randomized controlled trials have failed to demonstrate an efficacy of these drugs in patients with active uncomplicated CD,even if a subgroup of patients with colonic location seems to get benefit from antibiotics. Nitroimidazole compounds have been shown to be efficacious in decreasing CD recurrence rates in operated patients,and the use of metronidazole and ciprofloxacin is recommended in perianal disease.However,the appearance of systemic side effects limits antibiotic long-term employment necessary for treating a chronic relapsing disease.Rifaximin,characterized by an excellent safety profile,has provided promising results in inducing remission of CD.     

Need for infliximab dose intensification in Crohn’s disease and ulcerative colitis

AIM: To compare the need for infliximab dose intensification in two cohorts of patients with Crohn’s disease (CD) or ulcerative colitis (UC).METHODS: Single centre, uncontrolled, observational study. Consecutive patients with CD and UC who responded to infliximab induction doses were included. Data collected in a prospectively maintained database were retrospectively analysed. Differences in the rates of dose intensification per patient-month and the intensification-free survival time were compared. We also evaluated the interval between the first infliximab induction dose and the first infliximab escalated dose. The weight-adjusted infliximab administration costs were also calculated.RESULTS: Fifty nine patients with CD and 38 patients with UC were enrolled. The rate of intensification per patient-month was 3.9% for UC and 1.4% for CD (P = 0.005). The median time from baseline to intensification was significantly shorter in UC compared to CD [6.6 mo (IQR: 4.2-9.5 mo) vs 10.7 mo (IQR: 8.9-11.7 mo), P = 0.005]. In the survival analysis, the cumulative probability of avoiding infliximab dose intensification was significantly higher in CD (P = 0.002). In the multivariate analysis, disease (UC vs CD) was the only factor significantly associated with dose intensification. The infiximab administration costs during the first year were significantly higher for UC compared to CD (mean ± SD 234.9 ± 53.3 Euros/kg vs 212.3 ± 15.1 Euros/kg, P = 0.03).CONCLUSION: The rate of infliximab dose intensification per patient-month is significantly higher in UC patients. The infliximab administration costs are also significantly higher in patients with UC.     

Sexual function and quality of life after surgical treatment for anal fistulas in Crohn’s disease

Background

The aim of this study was to assess sexual function and quality of life (QoL) in patients after surgery for perianal Crohn’s disease.

Methods

Eighty-eight consecutive patients with perianal Crohn’s disease, operated on at the Medical University of Vienna, completed a self-administered questionnaire including the International Index of Erectile Function (IIEF), Female Sexual Function Index (FSFI), Short Form-12 Health Survey (SF-12), and the Inflammatory Bowel Disease Questionnaire (IBDQ). Patients with a current stoma were excluded from further analysis. The median follow-up time was 104 months (range 3–186 months). Healthy subjects served as controls for each case and were matched by age (±6 years) and gender. Forty-seven (68 %) female and 22 male patients with a median age of 46.5 years (range 18–64 years) were analyzed. Eleven (16 %) patients had simple and 58 (84 %) complex anal fistulas.

Results

The median SF-12 physical health score of the patients was significantly lower (47.9 (range 25.5–57.2)) than that of the controls (54.3 (range 34.6–61.8); p = 0.03). Not surprisingly, the median total sore of the IBDQ of the controls was significantly better than that of the patients (controls: 188.5 (range 125–206.5), patients: 157 (range 60–199.5); p < 0.0001). Analysis with the multiple logistic regression test showed that type of operation, >1 perianal fistula opening, and active Crohn’s disease were independent risk factors for a worse IBDQ (p = 0.03, p = 0.015 and p < 0.0001). Interestingly, the median FSFI and IIEF score were not found to be significant different in any domain.

Conclusions

QoL but not sexual function is significantly influenced by surgery for perianal Crohn’s disease.