Refractory Crohn's Disease Research Articles

The insulin-like growth factor (IGF) system and its relation to infliximab treatment in adult patients with Crohn's disease

Objective. Metabolic bone disease (MBD) and muscle wasting (MW) are serious complications in adult patients suffering from inflammatory bowel disease. These complications may be caused by alterations in the insulin-like growth factor (IGF) system. The aim of the present study was to assess changes in the IGF system in patients with active Crohn's disease (CD) before and during infliximab treatment. Material and methods. We studied 13 patients with therapy refractory CD, treated with infliximab (5 mg/kg body-weight) at baseline and after 2 weeks. The IGF system and markers of inflammation were examined at baseline, on days 2–5 and after 1, 4, and 8 weeks. Ten healthy age- and gender-matched persons served as controls. Results. Total IGF-I and IGF binding protein (IGFBP)-3 levels were reduced by 36% (p<0.05) and 27% (p<0.001), respectively, compared with those of controls, and normalized during the study period. Free IGF-I levels were reduced by 46% (p<0.05) compared with those of controls and remained suppressed. IGFBP-2 levels were increased at baseline by a factor 2.3 compared to controls (p<0.01) with partial normalization at the end of the study period. The Crohn's disease Activity Index, the Harvey Bradshaw Index, C-reactive protein, orosomucoid and albumin reached normal levels during infliximab treatment. Conclusions. Treatment with infliximab normalized circulating levels of total IGF-I and IGFBP-3, and partially normalized IGFBP-2, whereas free IGF-I remained suppressed. We suggest that the changes in the IGF system may be part of the catabolic state in active CD and may have an association with MBD and MW.

Do anti-tumor necrosis factors induce response and remission in patients with acute refractory Crohn's disease? A systematic meta-analysis of controlled clinical trials

To determine whether anti-tumor necrosis factors induce clinical response and remission in patients with Crohn's disease, PUBMED, OVID, and SCOPUS databases were searched for studies investigated the efficacy of anti-tumor necrosis factors on CD. Data were collected from 1966 to 2005 (up to 31 December). Types of outcome investigated were response (decrease in CDAI score ≥70 points) and remission (CDAI score ≤150 points) 2 and 4 weeks after drug administration. The criteria for inclusion of studies in this analysis were exposure of patients with CD to any therapeutic dosage of any anti-tumor necrosis factors (infliximab, cetrolizumab, CDP870, CDP571, etanercept, onarcept).The results showed that anti-tumor necrosis factors have improved only clinical response 2 weeks after administration of these drugs statistically, but their effects on clinical remission after 2 weeks and response and remission after 4 weeks have not been significant. It seems that anti-tumor necrosis factors are not effective for induction of response and remission in patients with Crohn's disease.

Is Stem Cell Transplantation the Way Forward for Refractory Crohn's Disease?

Is Stem Cell Transplantation the Way Forward for Refractory Crohn's Disease?

Dopamine D2 Receptor Polymorphisms in Inflammatory Bowel Disease and the Refractory Response to Treatment

Dopamine and its receptors may be involved in inflammatory reaction. The availability of this molecule depends on its receptors. The DRD2 gene, which codifies for the D2 dopamine receptor, has several polymorphisms. In this study, the DRD2 TaqIA polymorphism, which confers a decreased receptor density, was evaluated in 313 individuals including 220 inflammatory bowel disease patients (143 patients with Crohn's disease and 77 with ulcerative colitis) and in 93 healthy blood donors. The analysis was carried out by PCR-RFLP techniques. The frequencies of A (1) A (1) and A (2) A (2) genotypes were similar among Crohn's disease, ulcerative colitis patients, and health controls. Also, the genotype frequency was similar in different groups of disease localization, behavior, and age of disease onset. However, the Crohn's disease patients carriers of A (2) A (2) genotype showed a lower risk for development refractory Crohn's disease (37 out 65) than A (1) A (1) and A (1) A (2) carriers (28 out of 65) [(OR=0.4, 95% CI 0.21-0.87; p=0.02)]. Our results support an involvement of the dopamine receptor in inflammatory bowel disease and suggest a new potential target for therapy in refractory Crohn's disease patients.

Acute pancreatitis and visual impairment after infliximab infusion

We report a case of a 12-year-old boy with refractory Crohn's disease (CD) who developed severe pancreatitis and visual impairment after the first infliximab (IFX) infusion. An antihistamine agent and hydrocortisone were administered before IFX (5mg/kg) infusion. The patient was on azathioprine (AZA - 3mg/kg/day) since 6 months. 36h after IFX infusion he presented severe abdominal pain. Blood tests and ultrasound scan revealed an acute pancreatitis. The child complained also of visual impairment (his right eye 3–4/10, left eye 9/10, normal fundus).

Infliximab as First‐Line Therapy in Severe Pediatric Crohn Disease

Infliximab as First‐Line Therapy in Severe Pediatric Crohn Disease

Clostridium difficile Infection in Patients with Ileal Pouch-Anal Anastomosis (IPAA)

Purpose: The importance of C. difficile infection in patients with IPAA is not known. Methods: Consecutive 115 ulcerative colitis (UC) patients with IPAA were enrolled from our Pouchitis Clinic from May 2005 to March 2006. Pouch aspirate specimens were collected during pouch endoscopy and analyzed for C. difficile toxin A & B by ELISA. 18 clinical variables were assessed. Diagnosis of pouch disorders was based on clinical, endoscopic, radiographic, and histologic assessments. Logistic regression models were constructed to study possible etiology and adverse consequences of C. difficile infection. Results: 21 patients (18.3%) tested positive for C. difficile. 6 C. difficile positive patients (3 refractory pouchitis, 2 Crohn's disease, & 1 irritable pouch syndrome) had repeated endoscopic & lab evaluation after 2– 4 weeks of combined antibiotic therapy (tinidazole + rifaximin or ciprofloxacin). 5 patients with refractory pouchitis or Crohn's disease went into clinical and endoscopic remission corresponding to disappearance of C. difficile. Conclusions: C. difficile infection is prevalent in patients with IPAA, with risk factors being males gender and a pre-operative left colitis. C. difficile infection in this population has no apparent association with previous antimicrobial treatment, but treatment may alter the outcome in these cases.Table: Logistic regression analysis for associated factors in C. difficile infection.

Combining infliximab with long-term methotrexate may be an effective treatment for refractory Crohn's disease,

Combining infliximab with long-term methotrexate may be an effective treatment for refractory Crohn's disease,

Combining infliximab with methotrexate for the induction and maintenance of remission in refractory Crohn??s disease: a controlled pilot study

Immunosuppression of chronic active Crohn's disease resistant or intolerant to purine antimetabolites still remains a clinical challenge. To obtain long-lasting effects with the anti-TNF-alpha antibody infliximab repeated infusions are often required. Methotrexate has been shown to be a moderately effective drug in maintaining remission in Crohn's disease. The aim of the present pilot study was to evaluate the combination of infliximab and methotrexate as therapy for refractory Crohn's disease. Nineteen patients with chronic active Crohn's disease resistant or intolerant to azathioprine were enrolled. Patients received either two infusions of infliximab (5 mg/kg) alone (n=8) or in combination with long-term methotrexate at a dosage of 20 mg/week (n=11) over 48 weeks. Two out of eight patients receiving infliximab monotherapy and four out of 11 patients treated with infliximab and concomitant methotrexate had discontinued study treatment by week 48, solely because of lack of efficacy. Clinical remission at week 48 was observed in five out of seven patients treated with infliximab and methotrexate, but only in two out of six patients receiving infliximab monotherapy. In addition, patients treated with concomitant methotrexate achieved remission earlier (median time 2 versus 18 weeks) and needed fewer steroids (median prednisolone dose 0 versus 11.8 mg). Despite an increased mean number of adverse events per patient in the methotrexate group, the proportions of patients experiencing any adverse events and serious adverse events were similar across treatment groups. The combination of infliximab with long-term methotrexate may be a promising concept in refractory Crohn's disease. Our data prompt larger trials.

Case Report: Combination therapy with granulocyte apheresis and infliximab for refractory Crohn's disease

Journal of Clinical ApheresisVolume 21, Issue 4 p. 249-251 Case Report Case Report: Combination therapy with granulocyte apheresis and infliximab for refractory Crohn's disease P. González Carro, Corresponding Author P. González Carro pesagoca@gmail.com Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainGastroenterology Division, Hospital General La Mancha Centro, Alcazar de San Juan, Spain.Search for more papers by this authorF. Pérez Roldán, F. Pérez Roldán Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorO. Roncero García Escribano, O. Roncero García Escribano Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorR. Lafuente, R. Lafuente Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorM.L. Legaz Huidobro, M.L. Legaz Huidobro Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorA. Amigo Echenagusía, A. Amigo Echenagusía Pathology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this author P. González Carro, Corresponding Author P. González Carro pesagoca@gmail.com Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainGastroenterology Division, Hospital General La Mancha Centro, Alcazar de San Juan, Spain.Search for more papers by this authorF. Pérez Roldán, F. Pérez Roldán Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorO. Roncero García Escribano, O. Roncero García Escribano Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorR. Lafuente, R. Lafuente Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorM.L. Legaz Huidobro, M.L. Legaz Huidobro Gastroenterology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this authorA. Amigo Echenagusía, A. Amigo Echenagusía Pathology Department, Hospital General La Mancha Centro, Alcazar de San Juan, SpainSearch for more papers by this author First published: 10 April 2006 https://doi.org/10.1002/jca.20093Citations: 9AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume21, Issue4December 2006Pages 249-251 RelatedInformation

Autologous Hematopoietic Stem Cell Transplantation in Patients With Refractory Crohn's Disease

Autologous Hematopoietic Stem Cell Transplantation in Patients With Refractory Crohn's Disease

Hematopoietic cell transplantation for Crohn’s disease; is it time?

To review all studies in the literature that have assessed Hematopoietic cell transplantation (HCT) and Crohn's disease (CD) with the ultimate aims of determining if this is a viable treatment option for those with CD. A secondary aim was to review the above literature and determine if the studies shed further light on the mechanisms involved in the pathogenesis of CD. An extensive Medline search was performed on all articles from 1970 to 2005 using the keywords; bone marrow transplant, stem cell, hematopoietic cell, Crohn's disease and inflammatory bowel disease. We identified one case in which a patient developed CD following an allogeneic HCT from a sibling suffering with CD. Evidence for transfer of the genetic predisposition to develop CD was also identified with report of a patient that developed severe CD following an allogeneic HCT. Following HCT it was found that the donor (that had no signs or symptoms of CD) and the recipient had several haplotype mismatches in HLA class III genes in the IBD3 locus including a polymorphism of NOD2/CARD15 that has been associated with CD. Thirty three published cases of patients with CD who underwent either autologous or allogeneic HCT were identified. At the time of publication 29 of these 33 patients were considered to be in remission. The median follow-up time was seven years, and twenty months for allogeneic and autologous HCT respectively. For patients who underwent HCT primarily for treatment of their CD there have been no mortalities related to transplant complications. Overall these preliminary data suggest that both allogeneic and autologous HCT may be effective in inducing remission in refractory CD. This supports the hypothesis that the hematolymphatic cells play a key role in CD and that resetting of the immune system may be a critical approach in the management or cure of CD.

Targeted Drug Delivery for Refractory Hemorrhagic Crohn Disease

Focal gastrointestinal inflammation and hemorrhage is a common problem associated with Crohn disease. The present report describes a case of chronic hemorrhage from an inflamed duodenum that was refractory to all endoscopic and systemic therapies, which was successfully treated with chemoembolization of the pancreaticoduodenal arcade with use of corticosteroids and gelatin sponge. The application of chemoembolization techniques need not be limited to treatment of malignancies.

Infliximab Therapy in 30 Patients With Refractory Pediatric Crohn Disease With and Without Fistulas in The Netherlands

Infliximab Therapy in 30 Patients With Refractory Pediatric Crohn Disease With and Without Fistulas in The Netherlands

Pneumocystis Jirovecii Pneumonia Complicating Treatment With Infliximab

Blockade of TNF-α using tumor necrosis factor-α antibodies is used in the management of a number of chronic inflammatory diseases and is indicated for treatment of refractory Crohn's Disease. We report the development of Peumocystis Jirovecii (Carinii) pneumonia and acute respiratory failure in a patient five weeks after the initiation of infliximab (Remicade®) therapy.

Autologous Hematopoietic Stem Cell Transplantation for Refractory Crohn's Disease, the Summary of Phase I Trial.

Background &AimsCrohn's disease (CD) is an immunologically mediated inflammatory disease of the gastrointestinal tract. In theory, immune ablation followed by autologous hematopoietic stem cell transplantation (HSCT) can induce remission by reconstituting a new immune system.MethodsWe conducted a phase I HSCT study in 17 patients with severe CD. Candidates were less than 60 years old with a Crohn's Disease Activity Index (CDAI) of 250–400 or Craig Crohn's Severity Index (CCSI) of >17 despite conventional therapy including infliximab. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor and CD34+ enriched. The immune ablative conditioning regimen consisted of 200mg/kg cyclophosphamide, and 90mg/kg equine antithymocyte globulin.ResultsThere was no treatment related mortality. The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and disease-related fever, diarrhea, anorexia, nausea, vomiting. The median days for neutrophil and platelet engraftment were 9 (range 7–11) and 9 (range 8–18, three patients never below 20,000), respectively. The median infused CD34+ and CD3+ cell counts were 4.83 x 106/kg (range 1.73–24.88) and 0.56 x 104/kg (range 0.0–3.09), respectively. Initial median CDAI and CCSI were 282 (range 101–358) and 24 (range 18–33). Symptoms and CDAI/CCSI improved quickly and dramatically (figure), and radiographic and colonoscopy findings improved gradually over months to years following HSCT. For patients with >6 months follow up, twelve out of fifteen patients entered sustained remission defined by a CDAI < 150 or reduction of a CCSI >10 after median follow-up of 29 months (range 11–48).ConclusionAutologous HSCT can be performed safely and has a marked durable salutary effect on CD activity. A randomized study {KISS study: C(K)rohn's Immune Suppression vs. Stem Cell Transplant} comparing HSCT to standard therapy is now enrolling patients. [Display omitted]

Low-Dose Oral Methotrexate for Maintaining Crohn??s Disease Remission

Methotrexate has been considered a second-line immunomodulating therapy, behind azathioprine (AZA) or its metabolite 6-mercaptopurine (6-MP), for the treatment of Crohn's disease (CD). Approximately 27% to 50% of patients with refractory CD are intolerant or resistant to AZA or 6-MP. Two well-designed randomized double-blind placebo-controlled trials have demonstrated that low-dose methotrexate (<25 mg/wk), given intramuscularly (IM), is effective in inducing and maintaining remission in CD. In clinical practice, IM injection involves an inconvenience for patients and higher costs. Furthermore, frequent IM injections increase the risk of complications such as peripheral nerve injury, local irritation, pain, bleeding, fibrosis, abscess formation, gangrene, and contractures. Alternatively, subcutaneous (SQ) injection has been advocated because it has been shown to have similar pharmacokinetics to IM injection. However, because of a recent and ongoing national shortage of parenteral methotrexate, patients who were receiving IM methotrexate had to switch to the oral form until the parenteral formulation becomes available. Oral methotrexate has been used with great success in treatment of rheumatoid arthritis and psoriasis for the past 50 years. However, the data on the usage of low-dose oral methotrexate in maintaining CD remission are scanty and controversial. The purpose of this article is to review the mechanism of action, absorption, and the objective evidence in supporting the use of oral methotrexate in maintaining CD remission.

Outcome of Infliximab Therapy in Children with Refractory Crohnʼs Disease

Purpose: Crohn's disease (CD) is a chronic inflammatory bowel disorder that can affect children and adults. Treatments include anti-inflammatory and immunomodulator drugs. Due to the potential side effects of impaired growth and osteoporosis due to chronic corticosteroid therapy, steroid-sparing agents are often utilized for treatment of refractory CD. Inflimixab, a monoclonal antibody to TNFα has been increasingly used for treatment of CD refractory to treatment with other medications. Methods: The medical records of pediatric patients with Crohn's disease treated with infliximab were reviewed. Demographic characteristics, concomitant medication use, Pediatric Crohn's Disease Activity Index (PCDAI), and the presence/absence of extraintestinal manifestations were analyzed. All patients received induction therapy with intravenous infliximab 5 mg/kg over 2 hours at 0, 2, and 6 weeks. Treatment efficacy was determined by the change in PCDAI, where < 10 is in remission and >30 is moderate to severe disease. Results: The medical records of fifteen patients, age 13.8 ± 2.8 yr, x ± SD, range 8–18 yr, 40% male) with CD who were treated with infliximab were reviewed. There were 9 patients with inflammatory disease and 6 with fistulizing disease with a distribution of 12 with ileocolonic, 2 ileal, and 1 jejunal disease. Concomitant medications at baseline included antibiotics (n = 13), azathioprine (n = 11), 5-aminosalicylates (5-ASA, n = 10), methotrexate (n = 2), and nonsteroidal anti-inflammatory drugs (n = 5). The PCDAI score significantly decreased after infliximab therapy (40.1 ± 13.3 vs. 10.9 ± 8.2, pre- and post- infliximab, respectively, p = 0.0000025). The PCDAI score decreased in all patients and 10 of 15 patients were in remission as defined by a PCDAI of ≤ 10. Corticosteroids were used an average of 11.5 months prior to infliximab therapy and were able to be discontinued in 13 of 15 patients. Eleven patients continue to receive infliximab every 8 weeks for maintenance therapy (duration of therapy 26.7 ± 8.7 months, range 15 – 44 mo.) while infliximab was discontinued in 4 patients after fistula closure was achieved. Four patients underwent surgery (2 for fistulae, 2 for resection). Conclusions: Infliximab significantly reduced the PCDAI and improved symptoms of CD in children with refractory disease. Infliximab can be effective therapy for pediatric patients with refractory Crohn's disease.

Adalimumab, a Novel Anti‐Tumor Necrosis Factor‐α Antibody in a Child with Refractory Crohn's Disease

Adalimumab, a Novel Anti‐Tumor Necrosis Factor‐α Antibody in a Child with Refractory Crohn's Disease

Methotrexate for Crohn??s disease: experience in a district general hospital

Controlled trials have demonstrated the efficacy of methotrexate (MTX) in the induction and maintenance of remission in patients with luminal Crohn's disease, but its use outside of specialist centres remains limited. We present a case series of 24 patients treated with parenteral MTX in a district general hospital. Patients received an induction course of 25 mg weekly for 16 weeks, followed by maintenance doses of 15 mg weekly. Nineteen patients achieved remission during the induction period. Of these, 10 were maintained in remission for more than 12 months. In total, there were six relapses within 1 year and five drug withdrawals due to side effects during the observation period. Of the six relapses, three required surgical intervention (with two of these re-starting methotrexate postoperatively) and three were recommenced on maintenance MTX after a short period at an increased dose. Our results are similar to outcomes achieved in large, randomized, controlled trials and indicate that MTX can be used safely and effectively for the treatment of refractory Crohn's disease in the district general hospital setting.