Severe Refractory Crohn's Disease Research Articles

S3204 Patient With Severe Refractory Crohn's Disease Achieved Remission on Golimumab With Guselkumab for Psoriasiform Rash and Delivered Healthy Term Infant

S3204 Patient With Severe Refractory Crohn's Disease Achieved Remission on Golimumab With Guselkumab for Psoriasiform Rash and Delivered Healthy Term Infant

P022 Autologous hematopoietic stem cell transplantation in refractory Crohn's disease: series case report in a Brazilian tertiary center

BACKGROUND: Crohn's disease (CD) is a chronic inflammatory and relapsing disease that can affect any segment of the gastrointestinal tract causing intestinal and extra-intestinal manifestations. A significant percentage of these patients suffer an aggressive disease course, refractory to pharmacological therapy and most of them are not favorable to surgical treatment, besides not being a curative procedure. Recent analysis of autologous haematopoietic stem cell transplantation (HSCT) showed a high rate of clinical and endoscopic remission after 1 year in these patients. METHODS: In 2015 our hospital developed a partnership protocol with ministry of health to submit adult patients from many cities of Brazil, with refractory CD to perform HSCT as an optional treatment. The follow up period of this protocol was only 6 months. We analyzed the 6 patients from this protocol to assess the efficacy and safety of autologous HSCT for refractory CD. RESULTS: Five men and 1 woman, between 43y and 19y (median age 38y), corporal index mass 20 Kg/m2 (18–25), with refractory CD, median course of illness 14y (5–23 years), all negative for X-linked inhibitor apoptosis protein (XIAP). Two patients were non-structuring non-penetrating, but only one hadn't had previous surgery. Five patients had 2–3 previous intestinal surgeries, and one had ileostomy, 2 had tuberculosis, one had multiple sclerosis, one had epilepsy and depression and one had pancreatitis as comorbities before HSCT. One patient had reactivation of tuberculosis and was treated during 6 months before the HSCT. All patients used thiopurines, metotrexate and more than one immunobiological therapies (IFX, ADA, VEDO), steroids, antibiotics, and aminosalicylates. All the 6 patients completed the mobilization, conditioning and transplantation phases, during a median time of hospitalization of 35 days (21–58d). We had no transplant related mortality. All patients had infectious complications during mobilization which included febrile neutropenia, anemia and life-threatening complications as KPC, Staphylococcus aureus infecction, and sepsis caused by E. coli. Among non-infectious complications all had mucositis, and red cell transfusion was required in all patient. The 6 months follow up of protocol all patients reached clinical and endoscopic remission and were steroid and immunosuppressive free remission. Most of them related viral infections. Only the youngest patient answered the SF36, IBDQ and PedsQL4.0 questionnaire pre and post HSCT, with improvement of health-related quality of life in all domains. Although the project last 6m, actually all patients are alive and the longest post HSCT time is 2y 9m. Only one patient restarted ADA as monotherapy (1y11m post HSCT). CONCLUSION: Due to its high complexity, risk of infections and death we consider that autologous HSCT should be an option of treatment only for patients with severe refractory CD.

Cyclophosphamide Pulse Therapy in Severe Refractory Crohn's Disease: A Retrospective Multicenter Case Series

Background and Aims: In Crohn's disease (CD) patients still remain refractory to current regimens, including biologicals. Previous data from small single-center studies indicated cyclophosphamide pulse therapy (CPT) to be effective for induction of remission at least in steroid-refractory cases. The aim of the present study was to study the efficacy and safety of CPT in mainly tumor necrosis factor (TNF)-refractory complicated CD patients. Methods: Patients with refractory CD undergoing CPT were identified in 13 centers of the German IBD Study Group and retrospectively registered. In total, 41 patients (12 male, 29 female, median age 36 years, range 18-72 years) were included for analysis. Seventy-eight percent of these had previously been treated with thiopurines and 90% had previously received anti-TNF antibodies. Former steroid treatment was found throughout the cohort. Results: Patients received a median number of 5 (1-13) pulses every 28 (13-54) days in a period of 120 (12-411) days. A median dose of 766 (600-1,200) mg and a median cumulative dose of 4,500 (750-9,750) mg was given. A clinical response (reduction in the Harvey-Bradshaw Index [HBI] ≥2 points) was found in 68% of the patients and clinical remission (HBI <5 points) in 32%. Steroids could be reduced from 31 to 12 mg per day over all patients. Side effects were recorded in 71% (n = 29) of the patients. Three patients terminated CPT due to side effects. No patient died. Conclusion: Our data point to CPT as a therapeutic alternative for induction of remission in patients with severe refractory courses of CD including TNF antagonists. CPT might serve as bridging for maintenance treatment.

Recent insights into the molecular pathogenesis of Crohn's disease: a review of emerging therapeutic targets.

Chronic inflammatory bowel diseases (IBDs) are a subject of great interest in gastroenterology, due to a pathological mechanism that is difficult to explain and an optimal therapeutic approach still undiscovered. Crohn’s disease (CD) is one of the main entities in IBD, characterized by clinical polymorphism and great variability in the treatment response. Modern theories on the pathogenesis of CD have proven that gut microbiome and environmental factors lead to an abnormal immune response in a genetically predisposed patient. Genome-wide association studies in patients with CD worldwide revealed several genetic mutations that increase the risk of IBD and that predispose to a more severe course of disease. Gut microbiota is considered a compulsory and an essential part in the pathogenesis of CD. Intestinal dysmicrobism with excessive amounts of different bacterial strains can be found in all patients with IBD. The discovery of Escherichia coli entero-invasive on resection pieces in patients with CD now increases the likelihood of antimicrobial or vaccine-type treatments. Recent studies targeting intestinal immunology and its molecular activation pathways provide new possibilities for therapeutics. In addition to antitumor necrosis factor molecules, which were a breakthrough in IBD, improving mucosal healing and resection-free survival rate, other classes of therapeutic agents come to focus. Leukocyte adhesion inhibitors block the leukocyte homing mechanism and prevent cellular immune response. In addition to anti-integrin antibodies, chemokine receptor antagonists and SMAD7 antisense oligonucleotides have shown encouraging results in clinical trials. Micro-RNAs have demonstrated their role as disease biomarkers but it could also become useful for the treatment of IBD. Moreover, cellular therapy is another therapeutic approach under development, aimed for severe refractory CD. Other experimental treatments include intravenous immunoglobulins, exclusive enteral nutrition, and granulocyte colony-stimulating factors.

Tirofiban-Induced Thrombocytopenia Occurring with Crohn's Disease.

A 69-year-old man, with severe refractory Crohn's disease, presented with acute coronary syndrome that required angioplasty. He developed severe tirofiban-induced thrombocytopenia (TIT) heralded by type I allergic reaction that required steroids and a combination of antihistamine H1 and antihistamine H2 for symptomatic management. The thrombocytopenia spontaneously resolved uneventfully in 48 hours thereafter. This case report suggests a possible association between TIT and inflammatory bowel disease. Therefore, strict monitoring of the platelet count is required in patients who develop allergic reactions to tirofiban.

Therapy with stem cells in inflammatory bowel disease

Inflammatory bowel disease (IBD) affects a part of the young population and has a strong impact upon quality of life. The underlying etiology is not known, and the existing treatments are not curative. Furthermore, a significant percentage of patients are refractory to therapy. In recent years there have been great advances in our knowledge of stem cells and their therapeutic applications. In this context, autologous hematopoietic stem cell transplantation (HSCT) has been used in application to severe refractory Crohn's disease (CD), with encouraging results. Allogenic HSCT would correct the genetic defects of the immune system, but is currently not accepted for the treatment of IBD because of its considerable risks. Mesenchymal stem cells (MSCs) have immune regulatory and regenerative properties, and low immunogenicity (both autologous and allogenic MSCs). Based on these properties, MSCs have been used via the systemic route in IBD with promising results, though it is still too soon to draw firm conclusions. Their local administration in perianal CD is the field where most progress has been made in recent years, with encouraging results. The next few years will be decisive for defining the role of such therapy in the management of IBD.

Thalidomide Use and Outcomes in Pediatric Patients With Crohn Disease Refractory to Infliximab and Adalimumab

The aim of the study was to evaluate thalidomide as rescue therapy for pediatric patients with severe refractory Crohn disease (CD) who failed to respond to antitumor necrosis factor (TNF) biologic agents. A computerized database was used to identify children with CD who had failed conventional immunosuppression therapy and received thalidomide rescue therapy. Twelve patients, mean age at diagnosis 10 years, were identified. Eight children had disease localized to the ileum and colon and 4 to the gastroduodenal area and colon. Five cases were complicated by strictures and 7 by fistulae. Previous drug therapy included azathioprine/6-mercaptopurine (11/12), methotrexate (7/12), and anti-TNF biologics (12/12). Outcome measures were Harvey-Bradshaw Index, change in prednisone dose, hospitalizations, bowel resections, and incision and drainage procedures. Laboratory evaluations were calculated before and after 1 to 6 months of thalidomide. Mean Harvey-Bradshaw Index score improved from 11.8 to 3.9 (P = 0.0004), mean prednisone dose decreased from 13.9 to 2.3 mg/day (P = 0.001), mean number of hospitalizations decreased from 6.3 to 1.3 (P = 0.002), and erythrocyte sedimentation rate decreased from 35 to 14 mm/h (P = 0.02). The surgery rate pre-thalidomide was 0.031 and on thalidomide was 0.004. Of the 7 patients with fistulae, 5 had complete fistula closure, 1 had partial closure, and 1 showed no improvement. Adverse reactions that resulted in discontinuation of thalidomide are as follows: 42% peripheral neuropathy, 17% worsening of the CD, 8% dizziness, and 8% allergic reaction. All 5 patients who developed peripheral neuropathy had clinical resolution of the neurologic symptoms within 2 to 3 months after stopping thalidomide. Thalidomide is a potentially effective rescue therapy for severe refractory CD in children who fail to respond to anti-TNF medications.

Long-term follow-up of autologous hematopoietic stem cell transplantation for severe refractory Crohn's disease

Background Although new therapeutic strategies have been developed to control Crohn's disease, medical treatment for refractory cases is not able to prevent extensive and/or repeat surgery. Recently, several cases have been reported of successful remission induction in Crohn's disease patients by means of hematopoietic stem cell transplantation (HSCT). Here we report our long-term (4 to 6 years) outcome in three patients. Patients Three patients (two male, one female) with active severe Crohn's disease were planned to undergo autologous HSCT. All patients were intolerant or refractory to conventional therapies, including anti-TNFα antibodies. Patients either refused surgery or surgery was considered not to be a feasible alternative due to the extensive disease involvement of the small intestine. Methods Peripheral blood stem cells were mobilized using a single infusion of cyclophosphamide 4 g/m 2, followed on day 4 by subcutaneous injections with G-CSF 5 μg/kg twice daily until leukapheresis. CD34+ cells were isolated after leukapheresis by magnetic cell sorting. In two of the three patients a second round of stem cell mobilization using G-CSF only was required, either because of low yield or because of insufficient recovery after CD34 selection. Prior to transplantation, immune ablation was achieved using cyclophosphamide 50 mg/kg/day (4 days), antithymocyte globulin 30 mg/kg/day (3 days) and prednisolone 500 mg (3 days). Endoscopy, barium small bowel enteroclysis and MRI enterography were performed. Results All three patients successfully completed stem cell mobilization, and two of them subsequently underwent conditioning and autologous HSCT with CD34+ cell selection. Treatment was well tolerated, with acceptable toxicity. Now, 5 and 6 years post-transplantation, these patients are in remission under treatment. The third patient went into remission after mobilization and therefore she decided not to undergo conditioning and HSCT transplantation. After a successful pregnancy she relapsed two years later. Since then, she suffers from refractory Crohn's disease for which we are now reconsidering conditioning and transplantation. Conclusion Autologous HSCT appears to be safe and can be an alternative strategy for Crohn's disease patients with severe and therapy resistant disease.

Topical Therapy for Severe Refractory Crohn's Disease of the Vulva in a Prepubertal Female

Background: Crohn's disease is a gastrointestinal autoimmune disorder associated with extraintestinal manifestations sometimes extending to the vulva. Crohn's disease of the vulva is an uncommon occurrence in children and usually responds well to systemic therapy. However, the management of Crohn's is limited by the patient's ability to tolerate systemic therapy. We report a case of refractory vulvar Crohn's disease.

P103 - Mesenchymal stem cells administered via novel selective mesenteric artery cannulation for the treatment of severe refractory Crohn's disease

P103 - Mesenchymal stem cells administered via novel selective mesenteric artery cannulation for the treatment of severe refractory Crohn's disease

Recent advances in the management of Crohn's disease

In the last 10 years many advances have been achieved in the treatment of patients with Crohn's disease, particularly in the field of biological agents. Infliximab, a tumour necrosis factor alpha antagonist, has been recently added to the therapeutic armamentarium for Crohn's disease and has greatly improved our treatment options. Infliximab has demonstrated efficacy in the induction and maintenance of remission in luminal and fistulizing Crohn's disease both in adults and children. However, the potential development of autoantibodies and the risk of serious adverse events limit the possibility of a wider use of infliximab. Searching for less immunogenicity and higher effectiveness in the last years a number of biological agents have been developed. Adalimumab, a fully human monoclonal antibody anti tumour necrosis factor alpha, has resulted effective and safe in patients with Crohn's disease, both naïve and refractory to infliximab, presenting also the advantage of subcutaneous way of administration. Natalizumab also showed promising results in terms of efficacy but its safety is still under investigation. To date no particular advances have been recently appeared in the literature concerning conventional immunosuppressive drugs. Surgery remains a valid resort for refractory patients. Autologous stem cell transplantation represents a new hope as rescue treatment for patients with severe refractory Crohn's disease.

Promising new agents for the treatment of inflammatory bowel disorders.

A groundswell of therapeutic modalities is presently sweeping through the field of inflammatory bowel disease (IBD), revolutionising the treatment and management of these disorders. At the forefront of newer agents are biological therapies, also referred to as 'biologics'. These include infliximab (cA2), CDP 571, rhIL-10, ICAM-1 antisense oligonucleotide (ISIS 2302) and opreleukin (rhIL-11). Among these, infliximab and CDP 571 are perhaps the most promising, particularly in Crohn's disease. Both are anti-TNF alpha monoclonal antibody formulations with proven efficacy at doses of 5 mg/kg for inducing remission in patients with moderate to severe refractory Crohn's disease. Infliximab is beneficial in the treatment of fistulous Crohn's disease as well. Anti-inflammatory cytokines such as rhIL-10 and opreleukin (rhIL-11) in early reports appear efficacious in Crohn's disease but not in ulcerative colitis. Budesonide, a second generation glucocorticoid, in an oral controlled ileal release capsule, is an attractive alternative to prednisone for treating active Crohn's disease of the distal ileum and proximal colon. Also available as an enema, budesonide's efficacy approximates that of prednisolone for inducing remission in active distal ulcerative colitis. Postoperative recurrences of Crohn's disease are a common clinical scenario. Recently, mesalazine, metronidazole and mercaptopurine have been re-evaluated in the postoperative setting. In the largest postoperative prophylaxis trial, mercaptopurine was superior to both placebo and mesalazine in preventing clinical, endoscopic and radiographic relapses. Finally, miscellaneous therapies such as transdermal nicotine, nicotine tartrate enemas and topical lidocaine used in pilot studies for ulcerative colitis have shown promise. Case reports of thalidomide and tacrolimus (FK 506) have reported beneficial effects in treating complicated, refractory Crohn's disease.