A girl with severe fistulizing Crohn's disease

We report the case of a girl with a severe perianal fistulizing Crohn's disease who during intravenous infusion of cyclosporine developed headache, general seizures and cortical blindness. Head magnetic resonance imaging showed spread, cortical-subcortical nonenhancing signal changes. Full neurological recovery was achieved in 24 hours. Cyclosporine was stopped and a single dose of infliximab was infused with rapid improvement of the fistula that at 7 months' follow-up is still closed.     

Infliximab in the treatment of Crohn''s disease: Predictors of response in an Italian multicentric open study

BACKGROUND: Almost 20% of patients with active Crohn's disease are refractory to conventional therapy. Infliximab is a treatment of proven efficacy in this group of patients and it is not clear which variables predict a good response. AIMS.: To evaluate the role of infliximab looking at the predictors of response in a large series of patients with Crohn's disease. PATIENTS AND METHODS: Five hundred and seventy-three patients with luminal refractory Crohn's disease (Crohn's Disease Activity Index (CDAI)>220-400) (312 patients) or with fistulising disease (190 patients) or both of them (71 patients) were treated with a dose of 5 mg/kg in 12 Italian referral centres. The primary endpoints of the study were clinical response and clinical remission for luminal refractory and fistulising disease. We evaluated at univariable and multivariable analysis the following variables: number of infusions, sex, age at diagnosis, smoking habit, site of disease, previous surgery, extraintestinal manifestations and concomitant therapies, and type of fistulas. RESULTS: Patients with luminal refractory disease: 322 patients (84.1%) had a clinical response and 228 (59.5%) reached clinical remission. Patients with fistulising disease: 187 patients (72%) had a reduction of 50% of the number of fistulas and in 107 (41%) a total closure of fistulas was observed. For luminal disease, single infusion (OR 0.49, 95% CI 0.28-0.86) and previous surgery (OR 0.53, 95% CI 0.30-0.93) predicted a worse response for fistulising disease. Other fistulas responded worse than perianal fistulas (OR 0.57, 95% CI 0.303-1.097). CONCLUSION: In Crohn's disease infliximab is effective in luminal refractory and in fistulising disease. A single infusion and previous surgery predicted a worse response in luminal disease whereas perianal fistulas predicted a better response than other type of fistulas.     

Treatment of Pyoderma Gangrenosum with Infliximab in Crohn's Disease

Pyoderma gangrenosum (PG) is an ulcerating noninfectious disease of the skin seen in 1 to 5% of patients with inflammatory bowel disease. The pathogenesis of PG has yet to be determined but may be related to abnormal T cell responses and the production of TNF-alpha, a powerful proinflammatory cytokine. Infliximab, a chimeric monoclonal antibody to TNF-alpha, has been approved for the treatment of Crohn's disease. We present four patients with PG treated with Infliximab for fistulizing Crohn's in whom complete healing of PG was achieved. Four patients with active fistulizing Crohn's disease and PG were treated. All patients were females ranging in age from 48 to 60 years, with a mean age of 54 years. Three of four patients had PG lesions located on the lower extremities; one patient had peristomal disease. All patients had at least colonic involvement of their Crohn's. The patients received either a single infusion or a series of three 5 mg/kg Infliximab infusions. All four patients demonstrated rapid healing of PG within 4 weeks of the first infusion of Infliximab. PG healing followed improvement in bowel disease. Complete resolution without recurrence was noted in all patients. Rapid resolution of PG was noted in four female patients with fistulizing Crohn's disease treated with Infliximab. Healing was complete, without recurrence. The anti-TNF-alpha properties of Infliximab suggest that healing may be mediated by the drug's effect on cytokine pathways, perhaps by blunted T cell activation early in the inflammatory cascade. We suggest an independent effect of Infliximab on PG.     

Early or late guided missile in the treatment of Crohn''s disease?

Over the last few years, much light has been shed on the pathogenesis of Crohn's disease. Further knowledge in this field has provided a firm basis not only in the understanding of current treatment but also for the development of new therapeutic strategies. Aim of these new agents is primarily to selectively interact with the key processes of intestinal inflammation. At present, only anti-tumour necrosis factor-alpha antibodies namely infliximab, is licensed for clinical practice but it is feasible to foresee that, in the near future, a larger range of these agents will become available.

Herein, the most promising biological agents in the treatment of Crohn's disease are outlined, which patients would benefit from these agents and when they should be administered. Attention is focused on the early (top–down) or late (step-up) use of biological agents, which for their very targeted mechanism of action may be compared to guided missiles.

As yet, early use of biological agents remains to be supported by convincing evidence, nevertheless it may be advocated as first-line therapy for newly diagnosed severe Crohn's disease patients, both adults and children.     

Infliximab for the treatment of pediatric ulcerative colitis

Ulcerative colitis is a chronic, idiopathic, inflammatory disease of the colon and rectum that may be associated with growth failure, nutritional derangements and psychosocial ramifications in affected children. Multiple medical options are available to achieve disease remission; however, some of these medications can have unwanted side effects, especially in younger patients. With increased understanding of the etiology of the disease, newer therapeutic alternatives have arisen in the form of biologic therapies, namely monoclonal antibodies targeted to a specific protein or receptor. Specifically, infliximab, an anti-TNF-α agent, has been shown to be safe and effective for the treatment of moderate-to-severe pediatric ulcerative colitis.     

Infliximab for treatment of steroid-refractory ulcerative colitis

BACKGROUND: Success achieved in two subtypes of Crohn's disease has persuaded a few investigators to experiment the monoclonal anti-tumour necrosis factor antibody infliximab in the treatment of ulcerative colitis. So far, however, the results (achieved in some 30 steroid-refractory patients included in two independent full-papers) indicate a rate of initial response of 50% and of remission of 25%. AIMS: To analyse data of an open trial conducted on consecutive steroid-refractory severely ill patients admitted to our referral Unit. PATIENTS AND METHODS: In 9 months, infliximab was given to 8 patients (4 male, 4 female aged 20-60 years) with uncontrolled ulcerative colitis of whom 6 were non-responders to parenteral steroids. All received the first infliximab dose as an intravenous infusion of 5 mg/kg. RESULTS: Of the 8, 4 (50%) did not respond to the first injection and were submitted to urgent colectomy; the other four responded clinically. Two have maintained clinical remission for 7 months, without the need for steroids; both have received daily azathioprine at 2 mg/kg, and only one has received two further infliximab injections. Of the other two, one received a second injection at week 5, despite this relapsed, and underwent elective colectomy at that time; the other relapsed at 6 months and showed a partial response to a repeat infliximab infusion. Thus, the rate of sustained response is 2/8 (25%) in this study. CONCLUSION: These results, achieved in an open uncontrolled fashion, seem to reflect those of other independent studies. In our opinion, these findings warrant an in-depth reappraisal of the indication to use infliximab as rescue treatment for refractory ulcerative colitis.     

Efficacy of treatment with chimeric monoclonal antibody (Infliximab) to tumor necrosis factor-α for Crohn''s disease in Japan: Evaluation by rapid turnover proteins, and radiologic and endoscopic findings

BACKGROUND: Several studies have reported that the chimeric monoclonal antibody to tumor necrosis factor (TNF)-alpha (Infliximab) is extremely valuable in the treatment of Crohn's disease. The aim of this study was to clarify the efficacy of this treatment in Japanese patients with Crohn's disease. METHODS: A 12-week multicenter, open trial of Infliximab was carried out and involved 25 patients with moderate to severe Crohn's disease who were resistant to conventional treatment. Patients received a single 2-h intravenous infusion of Infliximab at a dose of 1, 3, 5 or 10 mg/kg bodyweight. Clinical evaluation of this treatment response was defined as a reduction in the index of the inflammatory bowel disease (IOIBD) and of the Crohn's disease activity index scores (CDAI), and in serum levels of C-reactive protein (CRP) at 2, 4, 8 and 12 weeks, and as an increase in serum levels of rapid turnover proteins as well as improvement of radiologic and endoscopic findings at 4 weeks. RESULTS: The IOIBD score was reduced after 4 weeks in 66.7% of the group receiving 1 mg/kg Infliximab, 71.4% in the group receiving 3 mg/kg, 80.0% in the group receiving 5 mg/kg, and 85.7% in the group receiving 10 mg/kg. Improvement was better maintained over 12 weeks in the 5 and 10 mg/kg groups compared with the 1 and 3 mg/kg groups. Similar results were obtained for the CDAI scores. Serum levels of rapid turnover proteins significantly increased to within the normal ranges after infusion in all groups. Seven of the 11 (63.6%) patients evaluated showed improvement of radiologic and endoscopic findings. CONCLUSIONS: A single infusion of Infliximab was effective for the treatment of Japanese patients with Crohn's disease. Serum rapid turnover proteins reflected the clinical response to antibody for TNF-alpha well.     

Evolution of clinical behaviour in Crohn''s disease: predictive factors of penetrating complications

BACKGROUND AND AIMS: Crohn's disease is a heterogeneous entity. The Vienna Classification defines three different clinical patterns: 'non-stricturing, non-penetrating', 'stricturing' and 'penetrating'. Aim of this study was to assess the change in clinical behaviour over time and to evaluate whether an evolution towards penetrating complications can be predicted. METHODS: A total of 139 patients with non-penetrating behaviour at the time of diagnosis were included. The mean follow-up was 4.84 years (range 1-23.2 years). The clinical behaviour, according to the Vienna Criteria, was assessed at the diagnosis and at the end of follow up. Statistical analysis was performed by means of the Kaplan-Meier method and standard logistic regression analysis. RESULTS: The cumulative probability of a change in clinical behaviour was 22, 38 and 63% at 3, 6 and 12 years, respectively, and the cumulative probability of developing penetrating complications was 22, 33 and 55% at 3, 6 and 12 years, respectively. Young age at diagnosis (<40 years) and a stricturing behaviour are independent risk factors of developing major penetrating complications (internal fistula, mass or abscess): OR=6.0, 95% CI 1.1-30.5; OR=4.0, 95% CI 1.5-10.9, respectively, but not perianal disease. CONCLUSIONS: The behavioural classification of Crohn's disease is a dynamic model in which each status should be considered as not fixed but evolutive. Perianal disease should be considered a distinct pattern of penetrating behaviour.     

Effect of concurrent elemental diet on infliximab treatment for Crohn's disease

BACKGROUND: Infliximab and elemental diet (ED) have been shown to be effective in the management of Crohn's disease. However, few experiences have been reported regarding their combination therapy. The aim of the present study was to investigate the efficacy and safety of infliximab in Japanese patients, the first such study in Asia, as well as the effect of concomitant ED. METHODS: One hundred and ten consecutive patients receiving infliximab were followed up to week 16 after the last infusion, and clinical response and primary outcome were collected. A response was defined as a reduction in Harvey-Bradshaw Index for inflammatory disease and closure of fistula in fistulizing disease. RESULTS: Out of 75 inflammatory and 35 fistulizing disease patients, 68 (90.7%) and 25 (71.4%) responded at week 4, and 38 (50.7%) and 14 (40.0%) continued to respond until week 16, respectively. Interestingly, inflammatory disease patients with concurrent ED had a significantly higher response rate at week 16 (68.4%) than those without ED (32.4%, P = 0.0026). The effects of ED were independent of the usage of azathioprine and smoking habit. CONCLUSIONS: Infliximab was clinically useful in the treatment of Crohn's disease in Japanese patients as well as in those in Western countries. The efficacy of concurrent ED was suggestive and should be confirmed in a randomized controlled study.     

英夫利西单抗治疗重症和(或)难治性神经白塞病的疗效及安全性

目的探讨英夫利西单抗(infliximab,IFX)治疗重症和(或)难治性神经白塞病(neuro-Behcet’disease,NBD)的疗效和安全性。方法回顾性分析2016年1月至2019年12月在北京协和医院接受IFX治疗的10例重症和(或)难治性NBD患者的临床资料。结果 10例患者均为实质受累NBD,8例为多发病灶,6例同时并发脑干、大脑半球受累,起病时Rankin评分(4.1±0.88),且伴发活动性眼炎和肠道溃疡各1例。应用IFX联合激素和免疫抑制剂治疗中位疗程6(1, 40)月,9例患者治疗有效,神经系统症状改善,Rankin评分降至(2.7±1.34)分(P=0.000 5),且4例(40%)患者影像学病变较前减轻。IFX治疗后炎症指标较治疗前显著下降,中位血沉由16(10, 70)mm/h下降至5(1, 13)mm/h(P=0.007),中位C反应蛋白由7.53(1.86, 60)mg/L降至1.35(0.51, 5.0)mg/L(P=0.005)。此外,患者口腔、外阴溃疡、皮肤病变、关节炎、葡萄膜炎、肠道溃疡均明显改善。中位随访时间13(4, 40)月,1例完全缓解,8例部分缓解,糖皮质激素使用剂量较前显著减少,泼尼松由(60.0±21.73)mg降至(21.25±14.78)mg(P=0.000 2)。结论 IFX联合传统治疗可有效治疗重症和(或)难治性NBD。     

Careful patient selection may improve response rates to infliximab in inflammatory bowel disease

BACKGROUND AND AIM: The use of infliximab in the treatment of Crohn's disease (CD) is acceptable and appears to be effective in ulcerative colitis (UC). Careful patient selection, resulting in infliximab only for truly refractory inflammatory bowel disease (IBD), may improve its efficacy. The present study aimed to determine if careful patient selection improved infliximab efficacy in IBD. Methods: CD or UC/IBD unclassified patients (Montreal classification) were considered for infliximab treatment only after failure of disease control with conventional therapies and confirmation of active disease. Patients with purely luminal IBD received a single infliximab dose. Patients with fistulizing disease (with or without luminal disease) received infliximab at 0, 2 and 6 weeks. Changes to Harvey Bradshaw (HBI) for inflammatory CD and Colitis Activity Index (CAI) for UC/IBDU were used to determine the response and remission rates. In fistulizing CD, a remission was sustained cessation of drainage and resolution of the fistula. Response was correlated to inflammatory marker levels. RESULTS: Seventy IBD patients were treated. In CD, 85.2% (46/54) had active luminal and 40.7% (22/54) had fistulizing disease. In luminal CD, at 8 weeks a single infliximab dose induced remission in 75% (24/32) of patients compared to 92.9% (13/14) after infliximab at 0, 2 and 6 weeks. Fistulizing disease responded in 77.2% (17/22) and remitted in 50% (11/22) of patients at 8 weeks. In UC/IBDU, 75% (12/16) responded and 43.8% (7/16) of patients were in remission at 8 weeks. CONCLUSION: Careful patient selection may improve infliximab's efficacy and clinical remission appears greater after induction with three infliximab doses in CD. Clinical efficacy is suggested for UC/IBDU.     

Nonsurgical treatment of abdominal or pelvic abscess in consecutive patients with Crohn''s disease

BACKGROUNDS: There is little agreement about the efficacy of nonsurgical treatment for abscess associated with Crohn's disease. Furthermore, there is no study on characteristics of abscess or patient that nonsurgical treatment could be worth trying as initial treatment. AIMS: To evaluate the outcome of nonsurgical treatment in Crohn's disease-related abscess and identify factor leading to failure of nonsurgical treatment of this complication. PATIENTS: Twenty-four patients, who consecutively admitted for Crohn's disease-related abscess to our institution during a 7-year period, underwent nonsurgical treatment as initial therapy. METHODS: Outcome data such as recurrence and intractability, and clinical features were retrospectively analysed. Univariate analysis with patient-related factors and abscess-related factors was performed for risk factor identification. RESULTS: Median follow-up period was 47.5 months. Of the eligible patients, 19 patients were treated medically and 5 patients underwent percutaneous catheter drainage with medical treatment. Overall success rate of nonsurgical treatment in our centre was 66.7%. The cumulative recurrence rate at 7 months was 12.5%. All recurrences occurred within 7 months from complete resolution on follow-up imaging. Univariate analysis showed that the significant factors which lead to failure of nonsurgical treatment were presence of associated fistula and concurrent steroid use (P=0.019 and P=0.019, respectively). CONCLUSION: Nonsurgical treatment can be considered as initial treatment modality for the Crohn's disease-related abscess without concurrent steroid therapy or relevant fistula.     

Dysphagia in Crohn''s disease: a diagnostic challenge

Dysphagia is a rare manifestation in a patient with Crohn's disease. We report on the case of a patient with long-standing Crohn's disease who developed progressive dysphagia over 3 years. Endoscopy showed minimal distal oesophagitis with non-specific histological findings. Further investigation with cinematography, barium swallow and manometry established an achalasia-like motility disorder. Biopsies obtained from the oesophagus were non-specific. Balloon dilatation was performed. Initial success was followed by recurrent dysphagia. At repeat endoscopy, an oesophageal fistula was detected. An attempt at conservative medical management failed and oesophagectomy was successfully performed. Pathology results of the resected specimen confirmed the suspected diagnosis of oesophageal Crohn's disease. Even if achalasia is suspected in a Crohn's patient, it should be taken into consideration that the motility disorder could be the result of a transmural inflammation with or without fibrosis caused by Crohn's disease.     

Fecal Lactoferrin: A New Parameter to Monitor Infliximab Therapy

The glycoprotein lactoferrin is found in many body fluids but also in the granules of neutrophilic granulocytes. Fecal lactoferrin levels increase quickly with the influx of leukocytes into the intestinal lumen during inflammation. This biomarker has recently been shown to be a sensitive and specific marker of disease activity in chronic inflammatory bowel disease. Our aim was the determination of fecal lactoferrin as a marker of intestinal inflammation and therapeutic response following infliximab therapy in pediatric patients with Crohn's disease (CD). A total of five patients (ages 10-15 years) with severe Crohn's disease as defined by the Pediatric Crohn's Disease Activity Index (PCDAI) was enrolled in the study. The fecal lactoferrin levels were determined before and after therapy with infliximab by a quantitative lactoferrin ELISA (IBD-SCAN; TechLab, Inc.). Of the five patients on infliximab therapy, three received a single infusion and the remaining two underwent a regime with three maintenance infusions. All five patients responded to infliximab clinically after the first infusion, and in all patients, fecal lactoferrin levels significantly and rapidly decreased from elevated to near baseline in parallel to clinical assessment and the PCDAI. The reduction in fecal lactoferrin at days 7-10 was 93.43 +/- 4.49%, in comparison with the level before infliximab therapy, and correlated with a mean decrease in the PCDAI from 48.50 to 14.0. For the patients followed during multiple infusions, one remained with mild disease and the other reached remission (subjective and PCDAI). Fecal lactoferrin is a sensitive and specific biomarker representing intestinal inflammation and response to therapy in pediatric patients with Crohn's disease. It may be a helpful noninvasive diagnostic tool for monitoring therapeutic efficiency in pediatric IBD patients. Future studies are needed to further establish the relationship between endoscopic changes and the level of fecal lactoferrin as well as the possible role of lactoferrin as being an early and preclinical indicator of relapse.     

Oral nutritional supplementation is effective in the maintenance of remission in Crohn''s disease

Background. Enteral feeding with either elemental or polymeric diets is an established primary therapy for active Crohn's disease. However, the role of supplementing normal food with elemental diet in the long-term management of Crohn's disease has hitherto not been explored.

Patients and methods. A series of 39 consecutive patients with Crohn's disease in clinical remission were studied. Of these, 21 patients (Group 1) received oral nutritional supplementation, taken in addition to their normal diet. Their outcome (relapse rate, Crohn's disease activity index, inflammatory markers) was compared with that of 18 patients (Group 2), who were maintained on a normal unrestricted diet over an observation period of 12 months.

Results. A total of 17 patients (81%) tolerated the nutritional supplementation. On an intention-to-treat basis, 10 patients (48%) remained in remission for 12 months, compared to 4/18 (22%) patients in Group 2, p<0.0003. Their Crohn's disease activity index and CRP remained stable while their weight and body mass index improved during the period of nutrition therapy. Seven patients in Group 1 and 14 in Group 2 relapsed at a mean of 7.4±0.9 and 6.2±0.4 months, respectively. The response to nutrition supplement was independent of age, sex, disease duration or location. Four patients (1945) were intolerant to enteral feeding.

Conclusions. Nutritional supplementation is safe, well tolerated and effective in the long-term management of patients with quiescent Crohn's disease.     

Heartburn and multiple-site foregut perforations as primary manifestation of Crohn''s disease

SUMMARY: Crohn's disease may affect any segment of the digestive tract, more commonly the distal ileum, colon and/or perianal region. There is an increasing number of reports dealing with foregut Crohn's disease. We present the case of a patient with a history of heartburn and multiple spontaneous perforations of the esophagus, duodenum and jejunum as a primary manifestation of Crohn's disease who required emergency surgical and endoscopic procedures. Early detection of Crohn's disease may decrease the incidence of acute life-threatening complications provided that appropriate medical treatment is administered and a multidisciplinary approach is offered to these patients.