Guideline review: Biologics recommendations in the ECCO guidelines on therapeutics in Crohn's disease: medical treatment

In 2019, the European Crohn’s and Colitis Organisation released guidelines for the medical management of Crohn’s disease, concerning the induction of remission, the maintenance of remission and the treatment of fistulising perianal disease. This review summarises the key recommendations regarding the use of biologics in these settings.     

Factors affecting splanchnic haemodynamics in Crohn's disease: a prospective controlled study using Doppler ultrasound

Background—Current knowledge on splanchnichaemodynamics in Crohn's disease is limited.
Aims—To investigate which features of Crohn'sdisease affect splanchnic haemodynamics, and to establish whetherportal vein (PV) and superior mesenteric artery (SMA) blood supplyreflects clinical or biochemical activity of Crohn's disease.
Methods—Seventy nine patients with Crohn'sdisease and 40 controls were evaluated by Doppler ultrasound (US). Themean velocity of PV and SMA flow, the volume of blood flow of the PVand SMA, and the resistance index of SMA were studied. A series ofclinical, biochemical, and US variables including Crohn's diseaseactivity index, serum C reactive protein concentrations, diseaseduration and its anatomical location, smoking habits, abdominalcomplications, and current medical therapy, as well as the maximumbowel wall thickness as measured by US, were determined. The relationbetween PV and SMA blood flow and these variables was assessed byunivariate and multivariate analysis.
Results—Patients with Crohn's disease hadsignificantly higher PV and SMA flow and a lower SMA resistance indexthan controls. Stepwise multiple regression analysis identified bowelwall thickness and location of the disease as the main predictivevariables of both PV and SMA blood flow variation, accounting for 36%and 45% of their variability, respectively. No relation was foundbetween splanchnic haemodynamics and disease activity.
Conclusion—A hyperdynamic mesenteric circulationdoes exist in Crohn's disease; however splanchnic blood flow does notreflect the clinical or biochemical activity of the disease, but seems to be linked more to other Crohn's disease characteristics, such asmaximum bowel thickness and anatomical location.

Keywords:Crohn's disease; Doppler ultrasound; splanchnicblood flow

     

Postoperative outcome of Crohn's disease in 30 children

Background—Thirty children operated on forCrohn's disease (CD) were reviewed (1975-1994). The aim of the studywas to assess their postoperative outcome.
Patients—19 boys and 11 girls, aged 15.3 (2) years(range 11.3-20) at surgery were studied.
Results—Surgical indications were acutecomplications of CD and chronic intestinal illness. Six months aftersurgery, 11 of 12 patients had been weaned off steroids, and 22 of 23 patients were weaned off nutritional support; 17 patients withoutrecurrrence had a mean (SD) weight gain of 2.1 (8) kg and a height gainof 3.36 (3) cm. During 3.1 (2.7) years follow up, 12 patients (40%) had a recurrence of the disease after 19.4 (14) months (means (SD)):supra-anastomotic recurrence (six), severe perianal disease (two), andchronic illness (four). Six of 14 patients who were treated withmesalazine (13) or azathioprine (one) had recurrences. Thepostoperative recurrence rate was 50% at two years.
Conclusion—Surgical treatment modifies theimmediate outcome of severe or complicated CD, but does not preventrecurrence, despite localised resection or prophylactic postoperativetreatment. Extension of the disease before surgery seems to be a majorrisk factor for postoperative recurrence in children.

Keywords:Crohn's disease; surgery; children

     

Granulomatous pulmonary disease in a child: an unusual presentation of Crohn's disease

Crohn's disease (CD) is a chronic inflammatory disorder of the bowel which may be associated with an extensive list of extraintestinal manifestations involving almost every organ system. The most common organs involved are the eyes, skin, joints, and liver. Symptomatic bronchopulmonary disorders have been reported only rarely in pediatric CD. We report on an 11-year-old child who had a recurrent cough and increasing dyspnea with exercise for 8 months before developing any gastrointestinal symptoms. He was demonstrated to have granulomatous inflammation of the lung, as well as of the gastrointestinal tract. Similarities between CD and sarcoidosis are discussed.     

Short-term study of infliximab treatment for Crohn's disease in China

OBJECTIVE: To determine the effectiveness and safety of short‐term treatment of infliximab (IFX) in a group of Chinese patients with active Crohn's disease (CD). METHODS: Patients with established diagnosis of active CD were treated with IFX intravenously with a dose of 5 mg/kg at week 0, 2, 6. Clinical assessments were performed at baseline (week 0) and every week after IFX infusion until 8 weeks after the induction dose. RESULTS: Fourteen patients (nine male, five female) with a mean age of 29.7 years (range from 15 to 65 years) were included in the analysis. The mean subjective scores were decreased from 2.85 ± 0.57 at baseline to 1.3 ± 0.4 at week 14 (P < 0.05). The mean Harvey‐Bradshaw index was 7.9 ± 1.5 at baseline and 2.3 ± 1.0 at week 14. The levels of erythrocyte sedimentation rate, serum C‐reactive protein, total protein (TP) and albumin (ALB) were significantly improved during the 14‐week period. Colonoscopy showed a remarkable improvement. Mild and transient adverse events including skin itching, headache and elevation of serum alanine aminotransferase and aspartate transaminase were each observed in one patient. Severe anemia, leucopenia and thrombocytopenia at week 27 after three infusions of IFX were observed in one patient. CONCLUSIONS: Treatment with three infusions of IFX at a dose of 5 mg/kg was effective for induction of remission for active CD patients who failed to respond to conventional therapies. Study of long‐term efficacy and safety of IFX therapy is warranted for further investigations.     

Behaviour of Crohn's disease according to the Vienna classification: changing pattern over the course of the disease.

BACKGROUND: Crohn's disease is a heterogeneous disorder with both a genetic and environmental aetiology. Clinical classifications of the disease, such as the newly proposed Vienna classification, may help to define subgroups of patients suitable for studying the influence of specific genetic or environmental factors. AIM: To assess the stability over the course of the disease of its location and behaviour, as determined according to the Vienna classification. PATIENTS AND METHODS: The notes of 297 Crohn's disease patients regularly followed up at our institution were carefully reviewed retrospectively. The behaviour and location of the disease according to the Vienna classification were determined at diagnosis and after 1, 3, 5, 10, 15, 20, and 25 years of follow up. The proportions of the different behaviours and locations of the disease were calculated at these time points. A statistical analysis of the evolution of these characteristics over 10 years was performed on a subgroup of 125 patients with at least 10 years of follow up. The influence of age at diagnosis on location and behaviour of the disease was assessed as well as the influence of location on the behaviour of the disease. RESULTS: The location of the disease remained relatively stable over the course of the disease. Although the proportion of patients who had a change in disease location became statistically significant after five years (p=0.01), over 10 years only 15.9% of patients had a change in location (p<0.001). We observed a more rapid and prominent change in disease behaviour, which was already statistically significant after one year (p=0.04). Over 10 years, 45.9% of patients had a change in disease behaviour (p<0.0001). The most prominent change was from non-stricturing non-penetrating disease to either stricturing (27.1%; p<0.0001) or penetrating (29.4%; p<0.0001) disease. Age at diagnosis had no influence on either location or behaviour of disease. Ileal Crohn's disease was more often stricturing, and colonic or ileocolonic Crohn's disease was more often penetrating: this was already the case at diagnosis and became more prominent after 10 years (p<0.05). CONCLUSIONS: Location of Crohn's disease, as defined by the Vienna classification, is a relatively stable phenotype which seems suitable for phenotype-genotype analyses. Behaviour of Crohn's disease according to the Vienna classification varies dramatically over the course of the disease and cannot be used in phenotype-genotype analyses. The potential influence of genes on the behaviour of Crohn's disease should be studied in subgroups of patients defined by their disease behaviour after a fixed duration of disease.     

Monozygotic twins with Crohn's disease and ulcerative colitis: a unique case report

Background—A large number of monozygotic anddizygotic twin pairs with inflammatory bowel disease have beenreported. To date no twin pair has developed phenotypically discordantinflammatory bowel disease. This case report is the first documentedoccurrence of discordant inflammatory bowel disease occurring inmonozygotic twins.
Case report—Twenty two year old identical maletwins presented within three months of each other with inflammatorybowel disease that proved to be discordant in overall disease type,disease distribution, clinical course, and histopathological findings. Twin 1 developed a severe pancolitis necessitating total colectomy while twin 2 developed a predominantly distal patchy colitis with frequent granulomas, controlled by aminosalicylates. Twin 1 was antineutrophil cytoplasmic antibody (ANCA) negative at the time oftesting while twin 2 (Crohn's disease) was ANCA positive.Significantly, the twins possessed the HLA type DR3-DR52-DQ2 previouslyassociated with extensive colitis.
Conclusion—This case report confirms the importantrole played by genetic factors in the development of inflammatory bowel disease. It also highlights the crucial role of undeterminedenvironmental agents in dictating disease expression and phenotype.

Keywords:monozygotic twins; ulcerative colitis; Crohn'sdisease; inflammatory bowel disease

     

Incidence of Crohn's disease in Stockholm County 1955-1989

Aim—To evaluate the incidence of Crohn'sdisease in Stockholm County between 1955 and 1989.
Methods—A cohort of 1936 patients withCrohn's disease was retrospectively assembled. Incidence rates andchanges in disease distribution were assessed.
Results—The mean increase inincidence was 15% (95% confidence intervals 12% to 18%) per fiveyear period with a mean annual incidence rate at 4.6/10⁵during the last two decades. The mean incidence for the entire studyperiod was similar for men and women. The mean age at diagnosis increased from 25 years in 1960-64 to 32 years in 1985-89, partly because of an increasing proportion of patients aged at least 60 yearsat diagnosis. The proportion of patients with colonic Crohn's diseaseat the time of diagnosis increased from 15% to 32% (17% difference;95% confidence intervals 12% to 23%) whereas the proportion ofpatients with ileocaecal disease decreased from 58% to 41% (17%difference; 95% confidence intervals 10% to 24%) during the studyperiod. Elderly patients had a higher proportion of small bowel diseaseand a lower proportion of ileocolonic disease compared with the youngerpatients.
Conclusion—The incidence rate ofCrohn's disease in Stockholm has stabilised at 4.6/10⁵ andthe proportion of elderly patients has increased during a 35 yearperiod. Colonic Crohn's disease has increased in frequency with areciprocal decrease in ileocaecal disease.

Keywords:Crohn's disease; inflammatory bowel disease; incidence; epidemiology

     

Usefulness of the capsule endoscopy Crohn's disease activity index in assessing the necessity of early additional treatment in patients with Crohn's disease in clinical remission

The Capsule Endoscopy Crohn''s Disease Activity Index (CECDAI) was recently reported as a new scoring system to evaluate the mucosal lesions of patients with Crohn''s disease (CD). We investigated whether CECDAI is useful for assessing the necessity of early additional treatment in patients with CD in clinical remission.Twenty-one patients with small intestinal CD in clinical remission underwent capsule endoscopy (CE). The CECDAI and Lewis score (LS) were used to evaluate the intestinal lesions. We analyzed the correlations between several biomarkers and CECDAI or LS and examined the changes in therapeutic regimens based on the CECDAI.CE identified intestinal abnormalities in most CD patients in clinical remission: 81.0% and 85.7%, as assessed using CECDAI and LS, respectively. A significant positive correlation was observed between the CDAI and LS (P = .025), as well as between CDAI and CECDAI (P = .014) in these cases. Compared to LS, CECDAI scores were more evenly distributed. No significant correlations were observed between endoscopic scores and serum markers, including CRP, hemoglobin, and albumin levels. Additional treatment was performed significantly more often in patients with moderate-severe disease activity (CECDAI ≥5.8) (P = .012) than in those with normal (CECDAI <3.5) and mild (3.5≤CECDAI<5.8) disease activity. Resection of the small intestine did not affect the small bowel transit time or CE score.CECDAI is useful in evaluating mucosal lesions in small bowel CD patients in clinical remission and helps in assessing the requirement for additional treatment for these patients, including those who undergo intestinal resection.     

Treatment-resistant lingual Crohn's disease disappears after infliximab

Oral manifestations of Crohn's disease (CD) are not uncommon, but they can be difficult to diagnose and treat. We describe a patient with long-standing CD and a lingual ulcer, which we attributed to CD. The oral lesions were unresponsive to conventional therapy such as steroids, mesalamine, and other topical agents. There was an excellent response to infliximab, a chimeric monoclonal antibody to tumor necrosis factor (TNF-α). In the context of this case we discuss the various differential diagnoses. Furthermore, we report on different therapeutic options and their effectiveness. Oral manifestations of CD, which are refractory to systemic steroids and mesalamine, show an excellent response to infliximab.     

Interleukin 10 (Tenovil) in the prevention of postoperative recurrence of Crohn's disease

BACKGROUND AND AIMS: New lesions of Crohn's disease occur early after ileal or ileocolonic resection and ileocolonic anastomosis. We performed a double blind controlled trial to evaluate the safety and tolerance of recombinant human interleukin 10 (IL-10; Tenovil) in subjects operated on for Crohn's disease. We also assessed the effect of Tenovil in preventing endoscopic recurrence 12 weeks after surgery. METHODS: Patients with Crohn's disease who underwent curative ileal or ileocolonic resection and primary anastomosis were randomised within two weeks after surgery to receive subcutaneous Tenovil 4 microg/kg once daily (QD) (n=22) or 8 microg/kg twice weekly (TIW) (n=21), or placebo (QD or TIW) (n=22). An ileocolonoscopy was performed after 12 weeks of treatment. RESULTS: Compliance was excellent. The most frequently observed adverse events were mild and moderate in severity and equally distributed across treatment groups. Thirty seven patients in the pooled Tenovil group and 21 patients in the pooled placebo group were evaluable by endoscopy. At 12 weeks, 11 of 21 patients (52%) in the placebo group had recurrent lesions compared with 17 of 37 patients (46%) in the Tenovil group (ns). The incidence of severe endoscopic recurrence was similar in both groups (9%). CONCLUSION: Tenovil treatment for 12 consecutive weeks in patients with Crohn's disease after intestinal resection was safe and well tolerated. No evidence of prevention of endoscopic recurrence of Crohn's disease by Tenovil was observed.     

Unsatisfactory effect of cyclosporin A treatment in Crohn's disease: a report of five cases

Five patients with chronic continuous Crohn's colitis were treated with peroral Cyclosporin A (CyA) for 3 months in an open, uncontrolled pilot trial. The CyA dose was 10 mg kg-1 d-1 the first month of study, and thereafter 5 mg kg-1 d-1. Three of the patients initially showed some response to the treatment with decreases in the Crohn's disease activity index, but subsequently deteriorated. In one patient the condition was unchanged and another clearly worsened. Increases in serum creatinine levels were noted in three patients, and all of these also had decreased 51Cr-EDTA clearance indicating impaired renal function. Hypertrichosis and hyperaesthesia were also noted as side-effects. This study does not support the use of CyA in the short-term treatment of Crohn's disease in the colon.     

Laparoscopy in Crohn's disease

In Crohn's disease (CD) surgical management, laparoscopic approach offers several theoretical advantages over the open approach. However, the importance of inflammatory lesions associated with CD, and the frequent presence of adhesions from previous surgery have initially questioned its feasibility and safety. In the present review article we will discuss the role of laparoscopic approach for Crohn's disease surgical management, along with its potential benefits as compared to the open approach.     

Azathioprine-induced toxoplasma gondii infection in a patient with Crohn's disease with NUDT15 variation: A case report

Introduction:Azathioprine (AZA) has been widely used for the treatment of various immune-related diseases and has become a mainstay in the treatment of inflammatory bowel disease. However, patients with genetic mutations may experience severe adverse events when treated with azathioprine. Most of the previous literature focused on the TPMP gene-related adverse reactions, herein, we report a case of Crohn''s disease patient with nucleoside diphosphate-linked moiety X motif 15 gene (NUDT15) variation and wild-type TPMP gene who developed toxoplasma gondii infection after azathioprine treatment.Patient concerns:A 56-year-old Crohn''s disease patient developed toxoplasma gondii infection within 2 months after the administration of azathioprine; however, he had no relevant high-risk factors.Diagnosis:Subsequent genetic testing revealed that the patient was heterozygous for NUDT15. Therefore, it was reasonable to consider that the patient''s genetic mutation resulted in reduced tolerance to azathioprine, leading to low immunity and eventually toxoplasma infection.Interventions:AZA was then discontinued; after anti-infection, antipyretic and other supportive treatments were administered, the patient''s condition gradually improved.Outcomes:The patient was followed up at 1, 3, and 6 months after discharge; fortunately, he was in good health.Conclusion:We report a case of Crohn''s disease in a patient who developed severe pneumonia caused by toxoplasma gondii infection due to the administration of AZA, with normal TPMP gene but NUDT15 gene mutation. This indicates that NUDT15 variation may contribute to severe adverse events in patients treated with azathioprine, and we suggest that NUDT15 genotype be detected before the use of azathioprine in order to provide personalized therapy and reduce side effects.     

Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn's disease

Background—The relapse rate after steroid inducedremission in Crohn's disease is high.
Aims—To test whether oral pH modified releasebudesonide (3 × 1 mg/day) reduces the relapse rate and to identifypatient subgroups with an increased risk of relapse.
Methods—In a multicentre, randomised, doubleblind study, 179 patients with steroid induced remission of Crohn'sdisease received either 3 × 1 mg budesonide (n=84) or placebo (n=95)for one year. The primary study aim was the maintenance of remission ofCrohn's disease for one year.
Results—Patient characteristics at study entrywere similar for both groups. The relapse rate was 67% (56/84) in thebudesonide group and 65% (62/95) in the placebo group. The relapsecurves in both groups were similar. The mean time to relapse was 93.5days in the budesonide group and 67.0 days in the placebo group. Noprognostic factors allowing prediction of an increased risk for relapseor definition of patient subgroups who derived benefit from low dosebudesonide were found. Drug related side effects were mild and nodifferent between the budesonide and the placebo group.
Conclusion—Oral pH modified release budesonide ata dose of 3 × 1 mg/day is not effective for maintaining steroidinduced remission in Crohn's disease.

Keywords:budesonide; Crohn's disease; maintenance ofremission

     

Genetic analyses of chromosome 12 loci in Crohn's disease

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) includes ulcerative colitis and Crohn's disease, both of which are multifactorial diseases involving the interaction of genetic and environmental factors. A region on chromosome 12 centred around the marker locus D12S83 has previously been associated with IBD predisposition. The aim of the study was to investigate this genetic region in an independent panel of European families affected by Crohn's disease. METHODS: A sample of 95 families with two or more affected relatives and 75 simplex nuclear families were genotyped for 19 microsatellite loci located on chromosome 12. A search for linkage and linkage disequilibrium was performed using non-parametric two point and multipoint analyses with the Analyze and Genehunter packages. RESULTS: No evidence of linkage or linkage disequilibrium was observed for any of the marker loci, including D12S83 (p=0.35 for the two point linkage test). Multipoint linkage analysis also failed to reveal positive linkage on chromosome 12. Power calculations allowed us to reject the hypothesis that the genetic region of chromosome 12 centred on D12S83 contains a susceptibility locus with a relative risk (lambda(s)) equal to or greater than 2.0 in these families. CONCLUSION: Failure to detect linkage or linkage disequilibrium in these families suggests that the chromosome 12 locus previously reported to be associated with genetic predisposition to IBD does not play a role in all European family samples. This observation is compatible with heterogeneity in the genetic basis of susceptibility to the disease and/or exposure to various environmental factors among Caucasian families.     

Infliximab as a bridge to remission maintained by antimetabolite therapy in Crohn's disease: A retrospective study

BackgroundInfliximab withdrawal in patients with Crohn's disease on concomitant antimetabolite therapy is considered to be superior if obtained after a maintenance therapy period compared to induction alone.MethodsWe retrospectively analyzed the outcome of Crohn's disease patients treated with infliximab and an antimetabolite after infliximab was withdrawn using induction alone or induction plus at least 1-year of maintenance therapy. The time to relapse was analyzed using univariate and multivariate analyses. The model was adjusted according to the period of infliximab withdrawal.ResultsA total of 92 patients were included, 54 in the induction alone group. The patient characteristics were identical in the two groups except for the period of infliximab withdrawal. After a median follow-up period of 47.1 (interquartile range = 4.4–110.2) months, 66 patients (72%) experienced a relapse. After a year-adjustment, no significant difference was observed between the two groups. Based on year-adjusted multivariate analysis, the risk factors for relapse were active smoking, previous antimetabolite failure, and perianal disease. After relapse, 53 patients (80%) were retreated with infliximab. After infliximab retreatment, clinical remission was observed in 47 patients (89%) at weeks 8–10.ConclusionIn Crohn's disease patients, the probability of relapse on antimetabolite therapy after infliximab withdrawal was not superior after a 1-year scheduled maintenance therapy as compared with an induction alone.     

Olsalazine is not superior to placebo in maintaining remission of inactive Crohn's colitis and ileocolitis: a double blind, parallel, randomised, multicentre study

BACKGROUND AND AIMS: The benefit of 5-aminosalicylic acid therapy for maintenance of remission in Crohn's disease is controversial. The primary aim of this study was to evaluate the prophylactic properties of olsalazine in comparison with placebo for maintenance of remission in quiescent Crohn's colitis and/or ileocolitis. METHODS: In this randomised, double blind, parallel group study of olsalazine versus placebo, 328 patients with quiescent Crohn's colitis and/or ileocolitis were recruited. Treatment consisted of olsalazine 2.0 g daily or placebo for 52 weeks. The primary end point of efficacy was relapse, as defined by the Crohn's disease activity index (CDAI) and by clinical relapse. Laboratory and clinical disease activity indicators were also measured. Safety analysis consisted of documentation of adverse events and laboratory values. RESULTS: No differences in the frequency of termination due to relapse or time to termination due to relapse were noted between the two treatment groups (olsalazine 48.5% v placebo 45%) for either colitis or ileocolitis. The failure rate, defined as not completing the study, was significantly higher in olsalazine treated patients compared with placebo treated patients for the overall population (colitis and/or ileocolitis: olsalazine 65.4% v 53.9%; p=0.038). Similar failure rates were seen for patients with colitis. A significantly higher percentage of olsalazine treated patients experienced adverse gastrointestinal events. Drug attributed adverse events were reported more frequently in the olsalazine treated group with gastrointestinal symptoms being causally related to olsalazine treatment (olsalazine 40.7% v placebo 26.9%; p=0.010). Back pain was reported significantly more often by the placebo treated group. However, serious medical events did not differ between the two groups. Adverse events led to more early withdrawals in the olsalazine treated group than in the placebo treated group; thus average time in the study for patients in the olsalazine treatment group was significantly shorter than that of patients in the placebo group. CONCLUSIONS: Patients treated with olsalazine were more likely to terminate their participation in the trial than those taking placebo. This difference was not related to relapse of disease, as measured by CDAI and clinical measures, but rather was due to the development of intolerable adverse medical events of a non-serious nature related to the gastrointestinal tract. The gastrointestinal related events in the olsalazine treated group may be due to the difference in gastrointestinal status at baseline which favoured the placebo treatment group.