Infliximab use in luminal Crohn's disease

Infliximab has been available in the United States and Europe for more than 6 years, and its use has revolutionized the care of patients who have CD. It is used effectively for both the induction and maintenance of remission in patients who have CD and is efficacious in patients who have steroid-dependent/refractory CD and those who have fistulizing CD. Clinical trials and practice have shown infliximab to be safe, effective, and generally well tolerated. The ACCENT I and ACCENT II trials defined the best dosing and schedule regimens for its administration. With up to 30% of patients not responding to infliximab therapy, much attention has been devoted to identifying risk factors that could allow optimization of response rates. Parsi and colleagues and Arnott and colleagues demonstrated that nonsmoking and the concurrent use of immunomodulators are predictors of response to infliximab. Research has also focused on identifying biologic and immunologic markers that may correlate with response to infliximab. To date, N0D2/CARD15, anti-Saccharomyces cerevisiae antibody (ASCA), and antineutrophil cytoplasmic antibody (ANCA) have not been shown to be predictive of outcome with infliximab treatment for CD. Gene polymorphisms also are being studies with the hope that knowing the patient's genotype may help predict the course or severity of the disease, including the presence of extraintestinal manifestations, response to treatments, and susceptibility to toxicities. No single variable, however, has been consistently demonstrated to be a predictor of response to infliximab. The formation of ATIs in a small number of patients creates a clinical dilemma. ATIs have been associated with an attenuated response or loss of response to the medication over time and the development of both acute and delayed infusion reactions that occasionally are severe enough to lead to discontinuation of the medication. In such patients physicians are often left to ponder what therapy to try next. Adalimumab, a fully human monoclonal antibody used for treating rheumatologic conditions, has been investigated as an alternate treatment for patients who have CD who, after initially responding to infliximab, experience intolerance or loss of efficacy. Two studies have examined the use of adalimumab in patients who have active CD who had lost response to or developed intolerance to infliximab. In both these studies adalimumab was well tolerated and seemed to be a clinically beneficial option for such patients. Confirmation of these findings with ongoing randomized, double-blind, placebo-controlled trials is needed, however. The limits of conventional treatment for CD can be seen as a positive evolutionary force favoring the development and use of advanced therapies. The acceptance of antimetabolites began with data published a quarter-century ago and became robust in the past 5 to 10 years. Biologic therapy has become the standard of care at a far faster rate. The success seen with infliximab has broadened the acceptance of biologic therapy among professional peers, patients, and pharmaceutical developers. The lessons learned in the years since infliximab's arrival show the importance of long-term data in revealing important toxicities and best practices for maintenance. Tempered by this experience, the short cycle from concept to drug production possible with biologic therapies should bring even more advanced treatments to patients quickly while investigators work to find a cure.     

Moxibustion combined with acupuncture increases tight junction protein expression in Crohn's disease patients

AIM:To investigate the effect of herb-partitioned moxibustion combined with acupuncture on the expression of intestinal epithelial tight junction(TJ) proteins.METHODS:Sixty patients diagnosed with mild to moderate Crohn’s disease(CD)were allocated into the herb-partitioned moxibustion combined with acupuncture(HMA)group(n=30)or the mesalazine(MESA)group(n=30)using a parallel control method.There were 2 sets of acupoints used alternately for HMA treatment.The following points were included in Set A:ST25(Tianshu),RN6(Qihai),and RN9(Shuifen)for herb-partitioned moxibustion and ST36(Zusanli),ST37(Shangjuxu),LI11(Quchi),and LI4(Hegu)for acupuncture.The points for Set B included BL23(Shenshu)and BL25(Dachangshu)for herb-partitioned moxibustion and EX-B2 of T6-T1(Jiajixue)fo r acupuncture.The patients received the same treatment6 times a week for 12 consecutive weeks.The MESA group received 1 g of mesalazine enteric coated tablets4 times daily for 12 consecutive weeks.Intestinaltissues were stained and examined to compare the morphological and ultrastructural changes before and after the treatment session.Immunohistochemistry and in situ hybridization assays were used to detect the expression of intestinal epithelial TJ proteins zonula occludens-1(ZO-1),occludin,and claudin-1.The m RNA levels were also evaluated.RESULTS:After the treatment,both herb-partitioned moxibustion combined with acupuncture and mesalazine improved intestinal morphology and ultrastructure of CD patients;the patients treated with HMA showed better improvement.HMA significantly increased the expression of ZO-1(P=0.000),occludin(P=0.021),and claudin-1(P=0.016).MESA significantly increased the expression of ZO-1(P=0.016)and occludin(P=0.026).However,there was no significant increase in the expression of claudin-1(P=0.935).There was no statistically significant difference between the two groups for the expression of occludin and claudin-1(P0.05).The HMA group showed a significant improvement in ZO-1 expression compared to the MESA group(2333.34±352.51 vs 2160.38±307.08,P=0.047).HMA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.017),and claudin-1 m RNA(P=0.017).MESA significantly increased the expression of ZO-1 m RNA(P=0.000),occludin m RNA(P=0.042),and claudin-1 m RNA(P=0.041).There was no statistically significant difference between the two groups in the expression of occludin and claudin-1 m RNA(P0.05).However,the HMA group showed a significant improvement in ZO-1 m RNA expression compared with the MESA group(2378.17±308.77 vs 2200.56±281.88,P=0.023).CONCLUSION:HMA can repair intestinal epithelial barrier lesions and relieve inflammation by upregulating the expression of TJ proteins and their m RNAs.     

Crohn's disease of the distal ileum.

A clinical and statistical analysis has been undertaken in a consecutive series of 227 patients with Crohn's disease involving the distal ileum under long-term review between 1944 and 1978. We have determined the long-term prognosis, cumulative reoperation rates after each resection, mortality rates, and their causes. Actuarial analysis has shown that the reoperation rates are similar after first, second, and third resections. There was no evidence that additional operations increase the risk of yet more resections. Reoperation rates were very little influenced by the age at diagnosis of the underlying Crohn's disease. A short interval from diagnosis of Crohn's disease to the first resection tended to increase the reoperation rate in the short term but there was no overall long-term effect. There was a two-fold increase in mortality risk when compared with the general population. Half the deaths were unrelated to the underlying Crohn's disease and, in this group, the incidence and causes were similar to those expected in the general population matched for age, sex, and years at risk. Of the disease related deaths many occurred in the early years of experience. Only four patients in the series have died of Crohn's disease in the last 10 years. One hundred and ninety-three patients are still alive after a mean interval of 16.1 years from the diagnosis of Crohn's disease. Full information is available on 185, of whom 161 are well and symptom free. Seven have minor problems, while 17 are unwell (nine with radiological evidence of recurrent disease).     

Abnormal small intestinal permeability to sugars in patients with Crohn's disease of the terminal ileum and colon

The absorption of lactulose and mannitol in 20 patients with Crohn's disease limited to the ileum or colon was studied, and lactulose/mannitol excretion ratios were calculated. The results were compared to those from 16 normal controls and 6 patients with ulcerative colitis. The 13 patients with ileal Crohn's disease had significantly higher lactulose/mannitol excretion ratios than the controls (p less than 0.01) or ulcerative colitics (p less than 0.01). Similarly, the 7 patients with Crohn's disease limited to the colon had significantly higher excretion ratios than the controls (p less than 0.01) or ulcerative colitics (p less than 0.01). The results provide support for the concept that Crohn's disease may be more extensive than is apparent macroscopically.     

Hypertonic saline increases tight junction permeability in airway epithelium.

Asthmatics are known to react to inhaled hyperosmolar solution. Therefore, the effect of hyperosmolar salt solutions on tight junctions of the airway epithelium was investigated by electron microscopy. Rat trachea was perfused with different concentrations of sodium chloride (NaCl) and then fixed from the luminal side with glutaraldehyde to which the electron dense tracer lanthanum chloride had been added. Lanthanum penetrated 3+/-1% of the tight junctions in trachea perfused with 295 mOsm Krebs-Ringer's buffer (KRB). Adding NaCl to the KRB (KRB-NaCl) increased osmolarity of the solution. After perfusion with 589 or 876 mOsm KRB-NaCl, lanthanum was observed in the lateral intercellular spaces in 50+/-11 and 57+/-6%, respectively. The effect of hyperosmolarity was reversible and only 6+/-1% of the tight junctions were penetrated after perfusion with 295 mOsm KRB solution following 589 mOsm KRB-NaCl perfusion. Adding mannitol to the KRB to an osmolarity of 589 mOsm only caused 5+/-1% of the tight junctions to open, even though osmotic effects were observed. Opening the tight junctions with hyperosmolar salt solutions may play a role in exercise-induced asthma. It may also open the prospect for increased penetration of inhaled drugs into the interstitium and the circulation.     

Therapy of mild to moderate luminal Crohn's disease

The management of luminal Crohn's disease, the most common form of initial presentation of the disease, depends on the location and the severity of the lesions. Mild to moderate disease represents a relatively large proportion of patients with a first flare of luminal disease, which may also be associated with perianal disease. As quality of life of these patients correlates with disease activity, adequate therapy is a central goal of the overall patient management. Treatment options include mainly sulfasalazine, budesonide and systemic steroids, while the role of mesalazine and antibiotics remains controversial. The role of biological therapies in mild to moderate disease has not been thoroughly evaluated and will not be discussed here.     

Predictors of response to infliximab in luminal Crohn's disease

AIMS: To identify predictive factors of response to infliximab in luminal Crohn's disease (CD). PATIENTS AND METHODS: All consecutive patients with luminal CD treated with infliximab between October 1999 and March 2003 in Bordeaux's referral centers were included. All had at least 3 months follow-up post infliximab infusion and no prior treatment with infliximab. Response rates were determined 2 and 8 weeks after infusion according to Crohn's Disease Activity Index (CDAI) (remission=CDAI<150 and response=CDAI decrease more than 100). RESULTS: Among 44 patients (33 female; mean age 35 +/- 14 yr.), 39 (88%) had a clinical response 2 weeks after infusion (79% in remission). At week 8, the rate of response was 61.4% and exclusive colonic involvement predicted sustained response to treatment (P=0.03). The probability of remission at 56 weeks was 21.4%. Multivariate analysis demonstrated that the only factor associated with response duration was initiating immunosuppressive (IS) therapy in women (RR=3.61 95%CI[1.25-10.41], P=0.017). CONCLUSION: Exclusive colonic involvement is the only predictive factor of sustained response to infliximab in luminal CD. At the time of infliximab infusion, initiation or modification of IS therapy may favor sustained response, at least in women.     

Antiflagellin antibodies recognize the autoantigens Toll-Like Receptor 5 and Pals 1-associated tight junction protein and induce monocytes activation and increased intestinal permeability in Crohn's disease

Background and objectives. Bacterial flagellin is considered an important antigen in Crohn’s disease (CD) as it activates innate immunity through Toll‐Like Receptor 5 (TLR5) engagement and induces an elevated adaptive immune response. Little is known about the presence of an autoimmune process in CD. We aimed to identify pathogenically relevant autoantigen targets in CD. Methods. We screened a random peptide library with pooled sera of patients with active CD. Transepithelial flux of [3H] mannitol in T84 human intestinal epithelial cell line was used to study the epithelial barrier function. Monocyte activation was evaluated by surface expression of activation markers and by production of pro‐inflammatory cytokines. Gene modulation of T84 cells exposed to antipeptide antibodies was analysed by gene array. Results. We identified a peptide that shares homology with Salmonella typhimurium flagellin and with self‐antigens such as TLR5 and cell junction protein, Pals 1‐associated tight junction protein. The affinity‐purified antipeptide antibodies recognized the self‐antigens and induced increased intestinal epithelial cell permeability. Moreover, the antibodies induced monocyte activation upon binding TLR5. Finally, in cultured intestinal cells (T84) the purified antibodies induced the modulation of clusters of proinflammatory genes similar to the one induced by the engagment of TLR5 by its natural ligand flagellin. Conclusions. Antibodies directed against an immunodominant peptide of flagellin recognize self‐antigens and are functionally active suggesting the presence of an autoimmune process that can both facilitate loss of tolerance to intestinal microflora by increasing cell permeability and amplify the innate immunity involvement through a novel mechanism of TLR5 activation.     

Gut luminal neutrophil migration is influenced by the anatomical site of Crohn's disease

BACKGROUND: Clinical differences between small- and large-bowel Crohn's disease have been demonstrated. Neutrophil migration and degranulation are important effector mechanisms in gut damage. Granulocyte elastase, a neutrophil-bound enzyme, interleukin 8 and 1beta can be detected in whole-gut lavage fluid. We aimed to assess differences between large- and small-bowel Crohn's disease. METHODS: A total of 167 patients with active inflammatory bowel disease (118 Crohn's disease, 49 ulcerative colitis) underwent whole-gut lavage with a polyethylene glycol electrolyte solution. Granulocyte elastase was assayed using an enzyme substrate reaction, IL-8 and IL-1beta by ELISA. RESULTS: Twenty-seven of 36 patients with isolated colonic Crohn's disease had detectable granulocyte elastase (median 0.259 pKat/l, range < 0.039-2.742 microKat/l), whereas 3 of 15 with small-bowel involvement alone had detectable granulocyte elastase (median < 0.039 microKat/l, range < 0.039-0.266 microKat/l; P < 0.0001). Granulocyte elastase levels were significantly higher in patients with ileocolonic disease and post-ileocaecal resection compared with small-bowel disease alone. IL-8 (P< 0.0001) and IL-1beta (P < 0.04) levels differed between colonic and ileal distributions. No variations were seen in ulcerative colitis. CONCLUSIONS: Neutrophil migration to the gut lumen in Crohn's disease is a feature of colonic disease irrespective of associated ileal lesions. This suggests that bacterial-derived chemo-attractants may play a role. High levels of IL-8 in colonic disease are consistent with this hypothesis.     

Ingested toothpick fistula of the ileum mimicking Crohn's disease

Foreign body ingestion is an accidental or an intentional event, with most of the ingested foreign bodies passing spontaneously through the gastrointestinal tract without incidents. About 10-20% of them, especially long and sharp objects like toothpicks, will fail to pass through the entire gastrointestinal tract and may cause symptoms. Toothpick injury of the gastrointestinal tract is often associated with considerable morbidity and mortality. The complications that can be caused by toothpick ingestion are obstruction, perforation, hemorrhage, fistula formation, small bowel inflammation, sepsis and even death. Diagnosis of toothpick injury can be difficult as there are no specific physical findings or laboratory examinations which may aid the diagnosis and even imaging studies are of little help as wooden toothpicks are radiolucent. We report a rare case of incidental toothpick ingestion which caused an ileum fistula and mimicked Crohn's disease.     

Acute toxic dilatation limited to the ileum in Crohn's disease

Two patients are presented with a previously undescribed grave complication of Crohn's disease, which we have termed toxic dilatation of the ileum because of its resemblance both clinically and radiographically to toxic dilatation of the colon. This entity is characterized clinically by the rapid onset of marked toxicity, fever and severe abdominal distention with pain, tenderness and diarrhea, occurring during the course of Crohn's disease. Radiographically, these patients showed severe ulceration, edema and marked dilatation, limited to the ileum in the absence of any similar alterations in the colon, distal mechanical obstruction, electrolyte disturbance or other obvious precipitating cause. Prompt and vigorous treatment with small bowel intubation, high doses of parenteral steroids and antibiotics, plus appropriate fluid and electrolyte therapy, produced clinical and radiographic improvement with restoration of the small bowel to its former state in both instances.     

Practical application of anti-TNF therapy for luminal Crohn's disease

Anti-tumor necrosis factor (TNF) therapy to treat inflammatory bowel disease has been available for more than a decade. Although extensive data on the outcome of anti-TNF therapy from individual clinical trials and patient cohorts are available, integrated guidance on the best use of such therapy to achieve optimal clinical outcomes when managing patients with luminal Crohn's disease is lacking. This review combines published data to establish practical strategies for anti-TNF therapy with respect to effective and safe timing of introduction, use of concurrent immunosuppressive therapy, dose escalation, managing relapse, changing drugs, pregnancy and breast feeding, and stopping drug treatment.     

Treatment of luminal and fistulizing Crohn's disease with infliximab

Infliximab is a novel biologic agent developed from recombinant technology now used widely in the treatment of Crohn's disease. It is effective in inducing and maintaining response in patients with moderate to severe luminal and fistulizing disease refractory to conventional therapy. Infliximab has also been shown to have a steroid-sparing effect. Although safe and generally well tolerated, the drug carries side effects that clinicians need to be able to recognize and to manage properly. Studies are underway to determine the best strategies to avoid antibodies to infliximab and to refine use of the agent.     

Clinical trials in luminal Crohn's disease: A historical perspective

It goes back to 1932 when Dr. Burrill Bernard Crohn and co-workers published their landmark paper, describing regional ileitis as a disease entity. However, clinical trial research has been developing rather slowly in luminal Crohn's disease. It took until the early seventies before the first randomized clinical trial was set up by the National Co-operative Crohn's Disease Study (NCCDS) group. Although the efforts of this group triggered a first wave of clinical trials in Crohn's disease, the lack of guidelines for conducting a clinical trial in this research area resulted in a variety of study designs and much criticism. Besides having a rather small sample size and a short follow-up time, they were often characterized by vague and subjective assessment of disease activity and treatment response.Following the advent of a new and very potent drug class in the late nineties, the anti-TNF agents, investigators started to re-think their study protocols and the first guidelines were set up by the regulatory authorities.Over the last 15 years, clinical trials in luminal Crohn's disease have been evolving significantly. Inclusion criteria have been shifting from clinical scores such as Crohn's Disease Activity Index (CDAI) to more objective disease activity parameters such as biomarkers (C-reactive protein and faecal calprotectin) and endoscopic lesions. Primary endpoints have been developing from clinical response to corticosteroid-free remission and more ambitious end-points such as mucosal healing.In this paper, we will give a historical overview on clinical trials in luminal Crohn's disease, before and within the biologic era, and provide insight into how they have shaped our current understanding of trial designs in Crohn's disease.     

Focal segmental ischemia of the terminal ileum mimicking Crohn's disease

The clinical, radiographic, and pathologic features of focal segmental ischemia are similar to Crohn's disease. We report a patient with focal segmental ischemia mimicking Crohn's disease and discuss the histologic distinction between the two entities. Ischemia must be considered when "Crohn's-like" lesions are encountered in elderly patients.     

Predictors of response to Infliximab in children with luminal Crohn's disease

ObjectiveA significant proportion of patients with initial response to Inflximab (IFX), subsequently lose response (LOR). Multicentre paediatric studies report LOR in 33% to 50% with 3–5 year follow-up. Our retrospective study examined durability of response and predictors of LOR.MethodsFrom our IBD database of 185 children with CD, 65 received IFX maintenance therapy for luminal or fistulising Crohn's disease between January, 2006 and April, 2013. 47 with luminal CD ≥ 1 year follow-up after commencing IFX were included. We evaluated variables associated with response and describe outcomes on those remaining on IFX at four time points; before IFX, after induction, at 1 year and at the last follow-up. Response was divided into sustained primary, recovered, durable (combined sustained primary and recovered) and complete LOR (discontinuation from LOR or intolerance).ResultsOverall, 28/47 (60%) children sustained primary response over a median duration of 2.83 years (1.6–4.4, IQR). 19/47 (40%) developed LOR (including 2 intolerant) at a median of 11 months (9–19, IQR). Of 17 with LOR, 7 were successfully re-induced giving durable response (35/47, 74%); 6 failed dose intensification needing surgery (n = 2), second anti-TNF (n = 2) or both (n = 2). 4 had surgery without dose intensification.LOR was associated with low BMI at diagnosis, lower height Z scores prior to induction, elevated CRP following induction (p = 0.007) and failure to use concomitant IM (p = 0.02).ConclusionThe cumulative probability of durable response to IFX in luminal CD was 83%, 74% and 70% after 1, 2, and 3 years on IFX maintenance therapy.     

Ileocolic resection for acute presentation of Crohn's disease of the ileum

PURPOSE: Traditional therapy for patients with terminal ileitis found at laparotomy for appendicitis has been to perform appendectomy when the cecum is normal and to leave the diseased ileum in place. METHODS: To determine the role of ileocolic resection in the setting of acute ileitis, records of 1,421 patients with Crohn's disease seen from 1986 to 1994 were retrospectively reviewed. RESULTS: Crohn's disease was found at laparotomy for presumed appendicitis in 36 patients (2.5 percent). Ten patients underwent ileocolic resection, 23 had appendectomy, and 3 had exploratory laparotomy alone. One patient whose appendix was removed also had ileocecal bypass. Of the 36 patients, 20 were women and 16 were men. Mean age at operation was 24 (range, 11–61) years, and mean follow-up time was 14 (range, 0.1–49) years. After initial ileocolic resection, five patients (50 percent) required no further resection, with a mean follow-up time of 12.4 (range, 4–19) years. None required more than three ileocolic resections, with a mean follow-up time of 18.1 (range, 4–49) years. Of 26 patients treated traditionally, 24 (92 percent) required ileocolic resection for intractability or complications of Crohn's disease. Thirty-eight percent required resection within one year and 65 percent within three years (intractability, 8; obstruction, 3; fistula, 4; and perforation, 2). Of 24 patients who subsequently underwent resection, only 6 (25 percent) required further small-bowel resection for Crohn's disease, with a mean follow-up time of 13 (range, 0.1–34) years. CONCLUSION: The majority of patients found to have Crohn's disease at laparotomy for appendicitis required early ileocolic resection. Therefore, the traditional dictum of nonoperative therapy for these patients may not be in their best long-term interest and merits re-evaluation.Read at the meeting of The American Society of Colon and Rectal Surgeons, Montreal, Quebec, Canada, May 7 to 12, 1995.     

Why does Crohn's disease usually occur in terminal ileum?

Crohn's disease can affect any part of the gastrointestinal tract, but terminal ileum is the most frequent localization. The reason why Crohn's disease is primarily located in the distal part of the ileum remains unexplained.In this article it has been attempted to provide a compelling explanation why Crohn's disease usually occurs in terminal ileum. Recent data indicate that some individuals are genetically predisposed to develop ileal Crohn's disease. Two genetic alterations, the polymorphism of Caspase Associated Recruitment Domain (CARD15) and Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 (CEACM6), favour the colonization of terminal ileum by entero adherent-invasive Escherichia coli (AIEC). The adhesion of these bacteria to epithelial intestinal cells depends on Carcinoembryonic Antigen-related Cell Adhesion Molecule 6 expression in ileal epithelial cells and on the reduced ileal defensins expressed in a CARD15 dependent manner. Genetic defects in Authophagy-related 16-like gene (ATG16L1) and Immunity-related Guanosine Triphospatase (IRGM) recently found in ileal CD patients lead to a reduction of bacterial killing by macrophages and consequent continuous immunological upstimulation, cytokine secretion, chronic inflammation of the ileum and tissue injury. On the basis of all these data Crohn's disease of the ileum seems to be a subset of the disease mainly genetically determined.