Selective effect of infliximab on the inflammatory component of a colonic stricture in Crohn’s disease

Although infliximab has been shown to improve the clinical course of Crohns disease, its effect on intestinal strictures is controversial. We describe the case of a woman with steroid-resistant colonic Crohns disease presenting with intermittent obstruction because of a tight stricture in the splenic flexure. Compared with uninvolved areas, biopsies showed intense edema and inflammatory cell infiltration and immunohistochemistry revealed an excess of TNF-. Her symptoms responded promptly (CDAI went from 444 to 168) to an infliximab infusion (10 mg kg^–1 BW), which also had a dramatic effect on the stricture, now presenting radiologically as a moderate residual, apparently fibrotic, narrowing of the lumen. Endoscopy and histology confirmed the resolution of inflammation and TNF- virtually disappeared. The patient refused additional infusions and after a few months the disease recurred with features identical to the pre-treatment phase. She then opted for surgery. Histology of the resected strictured colon revealed edema, inflammation, and fibrosis, with TNF- back to pre-treatment levels. This case indicates that, in the colon, infliximab specifically relieves the TNF--mediated inflammatory component of the stricture while having no effect on fibrosis and suggests that the response to infliximab treatment may depend on the nature of the, stricture itself.     

Time of infliximab therapy initiation and dose escalation in Crohn’s disease

AIM:To determine if early initiation of anti-tumor necrosis factor therapy affects the need for dose escalation.METHODS:This was a retrospective review of patients receiving infliximab therapy for Crohn’s disease(CD)at two outpatient gastroenterology clinics during July2009 to October 2010.All patients included in the study were biologic agent na?ve and had moderate to severe CD(Harvey Bradshaw index>8).Patients were divided into groups based on length of time between diagnosis to therapy initiation and concurrent immunosuppressant therapy.Kaplan-Meier survival analysis was used to compare the time to dose escalation for the four groups.RESULTS:There were 68 patients,51% female and 49% male,with an average age at diagnosis of 24.7±11.9 years.The average age at infliximab initiation was 34.8±14.8 years.Of the 68 patients,19%initiated inflixiamb within 2 years of diagnosis,and 51%had concurrent immunosuppressant therapy at the time of therapy initiation.Fifty percent of patients required dose escalation and the median time from therapy initiation to dose escalation was 10 mo(interquartile range:5.3-14.8).There was a statistically significant higher probability of requiring dose esclataion in patients who initiated biologic therapy within 2 years of diagnosis,without concurrent immunosuppressant therapy(P<0.01).CONCLUSION:Those who receive infliximab within 2years of CD diagnosis require more intense immunosuppressant therapy than those who received infliximab later.     

Effect of infliximab on small bowel stenoses in patients with Crohn＇s disease

AIM： To assess prospectively small bowel stenoses in Crohn＇s disease （CD） patients treated with infliximab using Small Intestine Contrast Ultrasonography （SICUS）. METHODS： Twenty patients （M 12, age, 42.7 ± 11.8 years）, 15 of whom showed obstructive symptoms indicating the presence of small bowel stenosis, and 5 without stenosis, were treated with infliximab （5 mg/kg at wk 0, 2, 6 and 5 mg/kg every 8 wk thereafter） for steroid refractoriness, fistulizing disease, or to avoid high-risk surgery. SICUS was performed at the induction phase and at regular time intervals during the followup period of 34.7 ± 16.1 mo （range 7-58）. Small bowel stenoses were detected by SICUS, endoscopy and MRI. RESULTS： In no case was progression of stenoses or the appearance of new ones seen. Of the 15 patients with stenosis, 5 stopped treatment after the induction phase （2 for no response, 3 for drug intolerance, one of whom showed complete regression of one stenosis）. Among the remaining 10 patients, a complete regression of 8 stenoses （1 stenosis in 5 patients and 3 stenoses in one patient） was observed after 6-22 infliximab infusions. CONCLUSION： In patients with CD treated with infliximab we observed： （a） No progression of small bowel stenosis and no appearance of new ones, （b） Complete regression of 1/22 stenosis after the induction phase and of 8/15 （53.3%） stenosis after 6-22 infusions during maintenance therapy.     

Postprandial response of bone turnover markers in patients with Crohn’s disease

AIM: To investigate the postprandial response of bone turnover markers in patients with Crohn’s disease (CD).METHODS: Fifty nine patients with CD aged 38 ± 14 years, and 45 healthy individuals matched for age and body mass index were included in the study. All participants underwent an oral glucose tolerance test (OGTT) after an overnight fast and serum levels of the bone resorption marker C-terminal crosslinking telopeptide of type I collagen (CTX-I) and the bone formation marker procollagen type I N propeptide were measured. Activity of the disease was assessed by calculation of the Crohn’s disease activity index (CDAI).RESULTS: Serum CTX-I was significantly higher in patients compared to controls (CTX-I: 453 ± 21 pg/mL vs 365 ± 25 pg/mL, P = 0.008), and values were significantly correlated with the activity of the disease (r = 0.435, P = 0.001). Results from OGTT-induced suppression of CTX-I showed two different trends. Patients with more active disease (assessed as CDAI > 150) had a more excessive suppression of CTX-I compared to controls (55% vs 43% P < 0.001), while patients on remission (assessed as CDAI < 150) demonstrated an attenuated CTX-I suppression (30% vs 43% P < 0.001). In line with this, CTX-I suppression after oral glucose load was significantly correlated with the activity of the disease (r = 0.913, P < 0.001).CONCLUSION: The physiological skeletal response of postprandial suppression of bone resorption is maintained in patients with CD and is strongly dependent to the activity of the disease.     

Outcome of continued infliximab therapy in Crohn’s disease patients with response but without remission after one year of infliximab – a retrospective cohort study

Background: Optimal management of Crohn’s disease patients having responded to infliximab but without achieving remission is not well defined. The present study examined if these patients benefit from continued long-term infliximab maintenance therapy.

Method: Retrospective cohort study including all patients treated with infliximab for 1 year until the end of 2017 who have had a response but not reached remission on infliximab. Clinical outcomes were defined by the physicians’ global evaluation, supported by clinical indices and objective markers of disease activity.

Results: In total, 376 Crohn’s disease patients received infliximab. Among these, 76 (20%) were classified as having response but non-remission (RNR) after 1 year of therapy. A great majority (n?=?54; 71%) experienced no additional therapeutic benefit after a further year of infliximab maintenance therapy, thus still having RNR. Nineteen patients (25%) obtained remission during continued infliximab, whereas only 4% (n?=?3) experienced treatment failure. Although infliximab therapy beyond 2 years (follow-up median 35 months, IQR: 23–55) was accompanied by a higher proportion attaining remission (40%), nearly half (46%) still failed to improve. Among patients who had discontinued infliximab while having RNR (n?=?21), half (n?=?11) experienced disease flare within five months (median 22 weeks, IQR: 12–31).

Conclusion: Most patients (71%) had no additional therapeutic benefit after an additional year of infliximab therapy, and after a median maintenance infliximab treatment period of 3 years, half still failed to improve further. Considering the importance of achieving complete remission, these patients appear to have an unmet medical need.     

Interaction of the major inflammatory bowel disease susceptibility alleles in Crohn’s disease patients

AIM:To investigate the interaction of interleukin-23 receptor(IL23R)(rs1004819 and rs2201841),autophagy-related 16-like 1(ATG16L1)(rs2241880), caspase recruitment domain-containing protein 15 (CARD15)genes,and IBD5 locus in Crohn‘s disease(CD) patients. METHODS:A total of 315 unrelated subjects with CD and 314 healthy controls were genotyped.Interactions and specific genotype combinations of a total of eight variants were tested.The variants of IBD5locus(IGR2198a_1 rs11739135 and IGR2096a_1 rs12521868),CARD...     

C-reactive protein is an indicator of serum infliximab level in predicting loss of response in patients with Crohn’s disease

Background

The ability of serum infliximab level to predict clinical outcome in infliximab therapy in Crohn’s disease is unclear. Here, we aimed to clarify the correlation between the timing of loss of response (LOR) to treatment and a decrease in serum infliximab level, and, in addition, to identify an indicator of infliximab level.

Methods

The study used data from a previous clinical study of infliximab for Crohn’s disease, in which infliximab was initially given at 0, 2, 6 weeks at 5 mg/kg, and then at 8-week intervals to 62 week-10 responders. Of these 62, here we analysed data from 57 in whom Crohn’s disease activity index and serum infliximab level were evaluated at week 14.

Results

Twelve patients showed a clinical response despite an infliximab level <1 μg/mL at week 14; of these, 8 (67 %) experienced LOR by week 54. A decrease in infliximab level preceded LOR in 6 (75 %). In receiver operating characteristic curve analysis, C-reactive protein (CRP) showed better performance in detecting an infliximab level <1 μg/mL. Infliximab level was <1 μg/mL in 60–80 % of patients with CRP >0.5 mg/dL. Time to LOR (median: 22.0 weeks) was significantly longer than that to a decrease in infliximab level to <1 μg/mL (14.0 weeks, p < 0.05) or to an increase in CRP to >0.5 mg/dL (14.0 weeks, p < 0.01).

Conclusions

A decrease in serum infliximab level preceded LOR, and was easily detected by an increase in CRP. The CRP may be an indicator of serum infliximab level in predicting LOR.     

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

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

Hyperhomocysteinemia in patients with Crohn’s disease

Background

Thromboembolic complications have been reported in patients with Crohn’s disease. Among the contributing factors, hyperhomocysteinemia has been described, although controversial data exist. The aim of our study was to assess the incidence of hyperhomocysteinemia in a nonselected group of patients with Crohn’s disease and to determine whether it might represent a risk marker for thrombosis in such patients.

Methods

Fifty consecutive patients were recruited, and clinical and laboratory variables were compared between those without and those with hyperhomocysteinemia. In the latter, gene mutations in N5-N10-methyltetrahydrofolate reductase were searched for, and clinical and laboratory variables were related to hyperhomocysteinemia. The presence/absence of thrombotic episodes in both groups was determined.

Results

Both groups had similar clinically active disease, with higher C-reactive protein values found in those with hyperhomocysteinemia. Hyperhomocysteinemia was found in 46 % of patients. Of these, 74 % had moderate, 13 % intermediate, and 13 % severe increase in serum homocysteine levels. No relationship was found between homocysteine levels, and age, vitamin B12 levels, folic acid levels, Crohn’s Disease Activity Index score, and CRP values. Gene mutations were found in 5 (22 %) patients, 2 homozygotes and 3 heterozygotes. None of the patients with or without hyperhomocysteinemia had episodes of venous or arterial thrombosis, or stroke.

Conclusions

Hyperhomocysteinemia is frequent in patients with Crohn’s disease, and it could be a cofactor for the pathogenesis of thrombotic episodes.     

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

BACKGROUND:

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

OBJECTIVE:

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

METHODS:

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

RESULTS:

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

CONCLUSION:

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

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...     

Acute coronary syndrome after infliximab therapy in a patient with Crohn’s disease

INTRODUCTION Serious adverse events (infections, malignancies, serum sickness, lupus syndrome) that need hospitalization have been reported with a divergent frequency of 6%-18.9% for patients with inflammatory bowel disease (IBD) treated with infliximab[1…     

The impact of disease activity of Crohn’s disease during pregnancy on fetal growth

Although it is known that women with inflammatory bowel disease have an increased risk of adverse outcome of pregnancy, the relationship between disease activity during pregnancy and the adverse outcome is not well known. A 29-year-old woman with Crohn’s disease presented with flare-up at the end of the first trimester. Although the disease had been rendered inactive by maintenance infusion of infliximab, the drug was discontinued at the time of conception because of the patient’s fear of the adverse effects of infliximab. Because retardation of fetal growth was observed at the flare-up, we re-started infliximab therapy. As disease activity reduced with therapy, the retardation of fetal growth subsequently improved. The patient finally delivered a newborn of 2550 g in weight and no adverse outcome was noted. The case supports the notion that disease activity is a risk factor for adverse outcome in pregnancy and that infliximab may be safely used in pregnancy.     

Intestinal cancer in patients with Crohn’s disease

Background Surveillance of intestinal cancer in Crohn’s disease (CD) has often been advocated. To date, no clear evidence exists whether CD patients are at special risk for intestinal cancer. An increased incidence of small bowel adenocarcinoma is suggested. However, recent figures also suggest an increased risk of CD associated colorectal cancer. We report our experience with 10 cases of CD complicated by intestinal adenocarcinoma. Materials and methods Our institutional database included 330 patients treated for CD between 1988–2005. Data of patients that developed carcinoma within Crohn’s lesions of either small or large bowel were analyzed. Results Ten patients were diagnosed with CD complicated by carcinoma. In nine patients, cancer was present in the colorectum and in one, in Crohn’s ileitis. Tumors were in conjunction with fistulae in three and developed within strictures in five patients. Mean age at the time of diagnosis of CD was 43 years. Mean duration of CD until diagnosis of cancer was 14 years. Only five patients were diagnosed for cancer preoperatively. Staging revealed advanced tumors in almost all patients. Mean survival after surgery was 29 months (2–149 months). Conclusions Cancer risk in CD and especially in Crohn’s colitis may still be underestimated. Delayed diagnosis resulted in a poor prognosis. The value of colonoscopy as surveillance tool is questioned by the fact that in our patients, carcinoma was diagnosed in some patients preoperatively by routine colonoscopy. Therefore, additional markers should be identified to detect CD patients at risk.     

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...     

The role of ABO blood groups in Crohn’s disease and in monitoring response to infliximab treatment

BackgroundThe variation in ABO blood groups is reported to be associated with multiple diseases. Infliximab (IFX) has been widely used in the treatment of Crohn’s disease (CD). We aim to investigate the distribution of ABO blood groups in Chinese patients with CD and to explore its impact on response to IFX.ResultsIn 293 patients with CD, most patients (40.6%) had blood type O (119/293). The odds ratio (OR) of CD in blood type O patients was 1.06 (95%CI: 0.6–1.86; p=0.84) compared to all other blood types. Among those CD patients, 107 patients received IFX treatment. One year after the first course of IFX, a significant association was found between the overall ABO system and outcomes of IFX treatment (p<0.001). CD patients with blood type AB (OR=4.42, 95% CI: 1.04–18.76; p=0.044) were more likely to achieve mucosal healing, while CD patients with blood type A had a high risk of losing response (OR=0.38, 95% CI: 0.15–0.96; p=0.040).DiscussionABO blood groups are not associated with prevalence of CD. Patients with blood type AB had a better response to IFX while those with blood type A appeared to have a risk of losing response to IFX.     

Effectiveness and tolerability of repeated treatment with infliximab in patients with Crohn’s disease: a retrospective data analysis in Germany

Aim The aim was to evaluate the efficacy and safety of repeated treatment with infliximab in patients with chronic active Crohns disease under routine conditions in clinics and private practices.Methods Patients with active Crohns disease were treated with a total of 567 infusions (420 re-infusions) of infliximab. The treatment schedule was at the discretion of the treating physician. Efficacy and tolerability were documented by a standardized questionnaire.Results There were indications for therapy in 46% of patients with chronic active disease, fistulas in 15% and combined symptoms in 38%. The mean disease duration was 9.4 years. At the beginning of therapy, 76% of patients were on corticosteroids, 67% received 5-aminosalicylates and 48% azathioprine. The average dose of infliximab administered was 300 mg; the mean interval between individual infusions was 8.7 weeks. Following treatment with infliximab, steroids could be withdrawn in 47% and reduced in 33% of patients, whereas the dosage of 5-aminosalicylates and azathioprine mostly remained unchanged. The efficacy and tolerability of infliximab were judged by the physicians as being very good or good in 73.4 and 88.4% of patients respectively. Further treatment with the anti-TNF antibody was planned for 61% of patients. Improvement of Crohns Disease Activity Index (CDAI), white blood cell (WBC) and C-reactive protein (CRP) levels was noted in almost all patients.Conclusion Infliximab used in an individually adapted regimen induced a significant clinical response in the majority of patients with refractory and fistulating Crohns disease. In nearly 80% of patients corticosteroids could be withdrawn or reduced and the majority of patients were on azathioprine at the end of follow-up procedures.     

Impact of enteral nutrition on energy metabolism in patients with Crohn’s disease

AIM: To investigate the impact of enteral nutrition(EN) on the body composition and metabolism in patientswith Crohn's disease(CD). METHODS: Sixty-one patients diagnosed with CD were enrolled in this study. They were given only EN(enteral nutritional suspension, TPF, non-elemental diet) support for 4 wk, without any treatment with corticosteroids, immunosuppressive drugs, infliximab or by surgical operation. Body composition statistics such as weight, body mass index, skeletal muscle mass(SMM), fat mass, protein mass and inflammation indexes such as C-reactive protein(CRP), erythrocyte sedimentation rate(ESR) and CD activity index(CDAI) were recorded before and after EN support. RESULTS: The 61 patients were divided into three groups according to CDAI before and after EN support: A(active phase into remission via EN, n = 21), B(remained in active phase before and after EN, n = 19) and C(in remission before and after EN, n = 21). Patients in group A had a significant increase in SMM(22.11 ± 4.77 kg vs 23.23 ± 4.49 kg, P = 0.044), protein mass(8.01 ± 1.57 kg vs 8.44 ± 1.45 kg, P = 0.019) and decrease in resting energy expenditure(REE) per kilogram(27.42 ± 5.01 kcal/kg per day vs 22.62 ± 5.45 kcal/kg per day, P 0.05). There was no significant difference between predicted and measured REE in active CD patients according to the HarrisBenedict equation. There was no linear correlation between the measured REE and CRP, ESR or CDAI in active CD patients. CONCLUSION: EN could decrease the hypermetabolism in active CD patients by reducing the inflammatory response.     

The effect of infliximab on extraintestinal manifestations of Crohn’s disease

Objective The purpose of this open pilot study was to assess prospectively the effect of infliximab on extraintestinal manifestations in patients with active Crohns disease refractory to conventional treatment.Patients and methods Twenty-two consecutive patients with Crohns disease and one with ulcerative colitis presenting at least one of the known extraintestinal manifestations of Crohns disease participated in the study. All the patients had Crohns disease activity index (CAI) scores above 2. Each patient received an intravenous infusion of infliximab at a dosage of 5 mg/kg. A thorough questionnaire was used reviewing the extraintestinal manifestations of Crohns disease such as erythema nodosum, pyoderma gangrenosum, eye lesions, arthritis or arthralgia, sacroiliitis or inflammatory back pain, hepatic disease, hematologic manifestations (megaloblastic, iron deficiency or hemolytic anemia, thrombocytosis), thrombosis, and nephrolithiasis. Musculoskeletal complaints were evaluated using the parameters intensity of pain, duration of morning stiffness (in minutes), presence of inflammatory back pain, Schobers test of the lumbar region, chest expansion, and distance from occiput to wall. The clinical assessment was performed on the day of the infusion and 2 weeks later.Results Eleven out of 23 patients had arthralgia of inflammatory nature, three others had evidence of active synovitis on physical examination, and 11 reported inflammatory back pain. Four patients suffered from protracted pyoderma gangrenosum; three had resistant aphthous stomatitis. Eleven patients had more than one extraintestinal manifestation. All four with pyoderma gangrenosum demonstrated significant improvement of their ulcers after one course of infliximab, with complete resolution of the skin lesions in three of them after repeated infusions of infliximab. Aphthous stomatitis completely responded in all patients after a single infusion. Seven out of 11 patients with arthralgia and seven out of 11 with inflammatory back pain/sacroiliitis experienced benefit after treatment with infliximab and reported at least partial clinical improvement in duration of morning stiffness, tender joint count, and visual analogue scale for pain. Only one of three patients with frank arthritis demonstrated clear improvement, and two others failed to respond to infliximab treatment.Conclusion These preliminary results are encouraging and suggest a promising role of infliximab in the treatment of extraintestinal symptoms of Crohns disease.