Positioning biologic therapy for Crohn’s disease and ulcerative colitis

Over the past decade, the introduction of biologic agents such as tumor necrosis factor-α and α4 integrin leukocyte adhesion molecule inhibitors has provided new and effective treatment options for patients with inflammatory bowel disease (IBD). Recent debates have centered on where biologics should be positioned within the current treatment strategy so as to maximize efficacy while balancing risk. This review highlights the current position biologics hold relative to conventional therapies within the current “step-up” treatment strategy. It also critically appraises emerging data, testing the hypothesis that positioning biologics early in the IBD treatment algorithm (“top-down” strategy) results in superior outcomes compared with the current step-up strategy, in which biologics are used only in patients failing conventional therapies or who are steroid dependent.     

Successful treatment by azacitidine therapy of intestinal Behçet’s disease associated with myelodysplastic syndrome

Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal hematopoietic stem cell diseases. It has been reported that several autoimmune diseases are associated with MDS. Recently, the co-occurrence of MDS with trisomy 8 and rare disorders of the immune system, such as Behçet’s disease (BD), has been described. Prognosis in the older-onset group of MDS-associated BD is unfavorable. Here, we report a case of MDS-associated intestinal BD treated successfully by azacitidine therapy. A 59-year-old Japanese male suffering from recurrent high fever, melena, and oral and genital ulcerations was diagnosed with MDS with trisomy 8 and intestinal BD by endoscopic and bone marrow examinations. Immunosuppressive therapies, including infliximab, were ineffective. Due to his severe emphysema, the patient was considered ineligible for stem cell transplantation, and azacitidine therapy was initiated. With the exception of fever, the symptoms of intestinal BD improved, and severe malnutrition and anemia were ameliorated. Fluorescence in situ hybridization analyses of the bone marrow before the eighth cycle revealed that the trisomy 8 had not decreased. To our knowledge, this is the first report of azacitidine therapy for MDS-associated BD. We suggest that azacitidine may control intestinal BD by mechanisms other than those responsible for its effect in MDS.     

Systemic sclerosis-rheumatoid arthritis overlap syndrome complicated with Sweet’s syndrome

Clinical Rheumatology - Herein, we report a case of a 34-year-old woman with systemic sclerosis (SSc)-rheumatoid arthritis (RA) overlap syndrome (OS) complicated with Sweet’s syndrome. OS has...     

Advances in biologic therapy for ulcerative colitis and Crohn’s disease

The medical management of inflammatory bowel disease (IBD) has changed considerably since the advent of biologic treatments. In this review we offer a critical evaluation of controlled studies with biologic agents for the management of both Crohn’s disease (CD) and ulcerative colitis (UC). Biologics under evaluation or approved for UC that are discussed include monoclonal antibodies to tumor necrosis factor ([TNF]) infrliximab), inhibitors of adhesion molecules (MLN02 and alicaforsen), anti-CD3 antibodies (visilizumab), and anti-interleukin (IL)-2 receptor antibodies (daclizumab). Biologics under evaluation or approved for CD that are reviewed include three monoclonal antibodies to TNF (infliximab, adalimumab, and certolizumab pegol), monoclonal antibodies against IL-12, interferon-γ, and IL-6 receptors, inhibitors of adhesion molecules (natalizumab, alicaforsen), and growth factors. Only the chimeric monoclonal anti-TNF antibody infliximab is currently available worldwide. The potency of this agent in moderate-to-severe UC and CD has been one of the most important advances in the care of IBD in the past decade.     

Postoperative management of ulcerative colitis and crohn’s disease

Approximately 10% to 30% of patients with ulcerative colitis and up to 70% of patients with Crohn’s disease will undergo surgery at some point during their lifetime. Although patients with ulcerative colitis are considered "cured" by surgery, patients who have undergone an ileal pouch anal anastomosis may develop pouchitis, cuffitis, pouch irritability, or even Crohn’s disease. Various therapies have shown success, including probiotics, in the prevention of pouchitis onset or relapse. Crohn’s disease historically recurs following surgery; prophylaxis against disease recurrence has been attempted with a variety of agents, with variable success. Innovative therapies holding promise for the future treatment or prevention of these conditions are under exploration.     

Successful treatment with intravenous immunoglobulin of severe thrombocytopenia complicated in primary Sjögren’s syndrome

Sjogren’s syndrome (SS) is a systemic autoimmune disease characterized by xerophthalmia, xerostomia and extraglandular manifestations. Anemia, leukopenia, thrombocytopenia and lymphoproliferative disorders, including lymphoma are well-known extraglandular, hematological complications of SS. We report here a rare case of patient with primary SS who developed pancytopenia with severe thrombocytopenia as an initial manifestation and successfully treated with IV immunoglobulin (IVIG). The present case suggests that pancytopenia with severe thrombocytopenia can be a difficult-to-treat abnormality, and initial manifestation of primary SS and IVIG might be an effective treatment for severe thrombocytopenia refractory to high-dose steroid in primary SS.     

Suppression of interleukin-1β- and tumor necrosis factor-·-induced inflammatory responses by leukocytapheresis therapy in patients with ulcerative colitis

Background To elucidate the molecular mechanisms involved in the therapeutic effects of leukocytapheresis (LCAP), we investigated the alterations in the cytokine responses of peripheral blood mononuclear cells (PBMCs) before and after LCAP therapy in ulcerative colitis (UC) patients.Methods Twelve patients with UC who did not respond to steroid therapy were enrolled. Nine patients responded to LCAP therapy, but 3 patients did not show clinical improvement. PBMCs were isolated from peripheral venous blood obtained within 5min before and after the first and second session of LCAP treatment. Cells were stimulated with interleukin (IL)-1 and tumor necrosis factor (TNF)- for 24h, and the levels of secreted IL-8 and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA).Results LCAP induced a significant decrease in peripheral lymphocyte, monocyte, and platelet counts. IL-1- and TNF--induced IL-8 and IL-6 secretion was significantly decreased after the first and second LCAP treatments. These responses were associated with inhibitory effects on nuclear factor (NF)-B DNA-binding activity.Conclusions LCAP downregulates the IL-1- and TNF--induced inflammatory responses in PBMCs isolated from UC patients. The induction of hyporesponsiveness to proinflammatory cytokines may be an important factor mediating the clinical effects of LCAP in UC patients.     

Complete remission of Sweet’s syndrome after azacytidine treatment for concomitant myelodysplastic syndrome

Sweet’s syndrome is a rare condition with potentially disabling implications, characterized by painful skin lesions due to neutrophilic dermal infiltration and systemic inflammatory symptoms. A significant proportion of cases is malignancy associated. Hematologic neoplasms, particularly acute myeloid leukemia and myelodysplastic syndromes, are the most commonly associated malignant conditions. Here, we describe the first case of clinical remission of refractory Sweet’s syndrome following hypomethylating therapy with azacytidine in a patient with myelodysplastic syndrome who concurrently obtained a complete hematologic response.     

Sweet’s syndrome with arthritis and vasculitis

Acute febrile neutrophilic dermatosis or Sweets syndrome is a rare disease. We describe a patient with oligoarthritis, increased liver enzymes and vasculitis. One year later the patient is free of symptoms. Diseases mimicking Sweets syndrome have been excluded.An erratum to this article can be found at     

Medical therapies for ulcerative colitis and crohn’s disease

This review focuses on data reported in the last year on medical treatment of Crohn’s disease and ulcerative colitis. In Crohn's disease, a broad range of cytokine-based therapies are currently being tested. Although all are very exciting, the anti-tumor-necrosis-factor (TNF) approach remains the most effective, with infliximab (a chimeric monoclonal antibody directed against TNF) being the most active agent. With repeated infusions every 8 weeks, remission is induced and can be maintained even in refractory patients with no major apparent side effects. Thalidomide, an oral agent with anti-TNF effects, shows promise in noncontrolled experience. Important new data on azathioprine/ 6-mercaptopurine (6-MP) and its metabolites are also helpful. Methotrexate can induce remissions in 6-MP-allergic or refractory Crohn's patients and has now shown efficacy as a maintenance agent. Beneficial effects are also reported for a variety of new agents: mycophenolate mofetil, tacrolimus (FK506), growth hormone, and granulocyte colony-stimulating factor (G-CSF). Important observations in ulcerative colitis (UC) over the past year include evidence of a protective effect of 5-aminosalicylic acid (5-ASA) with respect to colorectal cancer, negative results from a study for heparin monotherapy, and results from a comparison of mycophenolate mofetil versus azathioprine as maintenance therapy. Epidemiologically, the negative association between appendectomy and UC was corroborated in a meta-analysis, suggesting an immunologic role for this organ. Finally, in chronic pouchitis, probiotic therapy was found to maintain remissions very significantly.     

Successful treatment of osteomalacia caused by renal tubular acidosis associated with Sjögren’s syndrome

A 62-year-old woman was diagnosed with severe osteomalacia caused by renal tubular acidosis associated with Sjögren’s syndrome. She was treated with sodium bicarbonate, risedronate, alfacalcidol, and prednisolone (1 mg/kg). By 24 months, renal tubular acidosis was improved and the bone density had normalized. Here we report the successful amelioration of bone lesions through a multidisciplinary approach that improved renal tubular acidosis, with a special focus on treatment of the underlying inflammatory disorder with glucocorticoids.     

Clinical monitoring: infliximab biosimilar CT-P13 in the treatment of Crohn’s disease and ulcerative colitis

Objective: The infliximab biosimilar CT-P13 (Remsima^®, Inflectra^®) was approved in Europe for the treatment of inflammatory bowel disease (IBD) based on extrapolation of data from patients with rheumatic disease. Because there are limited published reports on clinical outcomes for IBD patients treated with CT-P13, we monitored responses to induction treatment with this biosimilar in patients with Crohn’s disease (CD) or ulcerative colitis (UC) in centres across the Czech Republic.

Material and methods: Fifty-two patients with CD (n?=?30) or UC (n?=?22) were treated with 5?mg/kg CT-P13 for up to 14 weeks. Effectiveness of therapy was evaluated with the Crohn’s Disease Activity Index (CDAI) or the Mayo Scoring System (MSS) in patients with CD or UC, respectively, before and after 14 weeks. Additional goals were to evaluate weight changes, serum C-reactive protein (CRP) levels, and complications/adverse events.

Results: In patients with CD, remission (CDAI?<150) was achieved in 50.0% of cases, and partial response (≥70-point decrease in CDAI score from baseline) in the remaining 50.0%. In patients with UC, remission (total score on partial Mayo index?≤2 points) was achieved in 40.9% of cases, partial response (≥2-point decrease in partial Mayo score from baseline) in 54.5%, and no response in 4.5%. There were statistically significant improvements in CDAI, MSS and CRP serum levels after 14 weeks of therapy, and body weight increased. Four adverse events were identified (n?=?1 each): lower-extremity phlebothrombosis, herpes labialis, pneumonia and allergic reaction.

Conclusions: This prospective observational study provides evidence of the effectiveness of CT-P13 in IBD.     

Multicentric Castleman’s disease complicated by tumor lysis syndrome

We report a case of Castlemans disease that developed tumor lysis syndrome spontaneously and after systemic chemotherapy. A 44-year-old male patient was admitted with a 2-week history of abdominal distension accompanied by dyspnea. Physical examination revealed multiple lymph node enlargements. After admission, spontaneous hemoperitoneum developed and he underwent exploratory laparotomy, with the removal of the ruptured spleen. Pathologic review of the splenic tissue and excised lymph node gave the diagnosis of multicentric Castlemans disease. He experienced two episodes of tumor lysis syndrome, initially spontaneous and then chemotherapy related, which needed vigorous management including hemodialysis and intensive fluid therapies. To our knowledge, this is the first reported case of Castlemans disease complicated by tumor lysis syndrome. This suggests that the possibility of tumor lysis syndrome should be considered when treating Castlemans disease with a large disease burden.     

Gilbert’s syndrome and antiviral therapy of hepatitis C

Treatment of chronic hepatitis C with type I interferons and ribavirin can be associated with exacerbation of hepatitis and sometimes liver decompensation. We report two patients with chronic hepatitis C virus infection who experienced a severe increase of bilirubin levels of up to 17 times upper the limit of normal value in the absence of deterioration of hepatic function during therapy with pegylated-interferon and ribavirin. A genetic disposition for Gilbert’s syndrome explained the adverse events and permitted a continuation of therapy leading to a sustained clearance of chronic hepatitis C infection. Since one patient jaundiced already during a lead-in treatment period with ribavirin monotherapy we suggest that hyperbilirubinaemia during combination therapy is primarily caused by ribavirin rather than by effects of interferon alpha on UDP-glucuronosyltransferase activities. Of note, both patients recovered from their initial unconjugated hyperbilirubinemia despite continuation of ribavirin therapy, which indicates that compensatory mechanisms leading to a normalization of UGT1A1 activity are likely.     

Efficacy of infliximab for luminal and fistulizing Crohn’s disease and in ulcerative colitis

Opinion statement Infliximab is arguably the first major advance in therapy for inflammatory bowel disease in more than a quarter of a century. Although it is important to distinguish efficacy from effectiveness, the data from clinical practice mirror those from randomized controlled trials. Infliximab has proven efficacious for luminal manifestations of Crohn’s disease (CD) regardless of location. It also has proven efficacy in the subset of penetrating disease to the skin and perianal area, and it increases rates of steroid-free remission. These benefits are reflected in improved quality of life, with limited data showing that infliximab can decrease rates of hospitalization and CD-related surgery. Infliximab also has proven to be efficacious in patients with ulcerative colitis (UC) and has increased rates of steroid-free remission. Whether infliximab will have an impact on the risk of colorectal cancer in UC and Crohn’s colitis has yet to be determined. The combination of strong evidence from large randomized controlled trials with substantial examination of use in the practice setting has moved biologic therapy with infliximab from novel to mainstream. In this review, the data for the efficacy of infliximab in controlled trials will be discussed in the context of real world effectiveness.     

Frequency and prognostic role of mucosal healing in patients with Crohn’s disease and ulcerative colitis after one-year of biological therapy

AIM:To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn’s disease(CD)and ulcerative colitis(UC).METHODS:The data from 41 patients with CD and 22 patients with UC were assessed.Twenty-four CD patients received infliximab,and 17 received adalimumab.The endoscopic severity of CD was quantified with the simplified endoscopic activity score for Crohn’s disease in CD and with the Mayo endoscopic subscore in UC.RESULTS:Mucosal healing was achieved in 23 CD and7 UC patients.Biological therapy had to be restarted in78%of patients achieving complete mucosal healing with CD and in 100%of patients with UC.Neither clinical remission nor mucosal healing was associated with the time to restarting the biological therapy in either CD or UC.CONCLUSION:Mucosal healing did not predict sustained clinical remission in patients in whom the biological therapies had been stopped.     

Successful use of infliximab in the treatment of Reiter’s syndrome: a case report and discussion

Reiter’s syndrome is one of the reactive forms of seronegative spondyloarthropathies. Various therapies used in the management of Reiter’s syndrome are nonsteroidal antiinflammatory drugs (NSAIDs), antibiotics, and disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine (SSZ) or methotrexate (MTX). There is only one case report of successful treatment of Reiter’s syndrome with tumor necrosis factor-α (TNF-α) blockers in human immunodeficiency virus (HIV) patient (Gaylis N, 2003, J Rheumatol 30(2):407–411 Feb). We hereby report a case of Reiter’s syndrome treated successfully with infliximab, an anti-TNF-α chimeric monoclonal antibody. A 28-year-old white male presented with painful swelling of right elbow and ankle joints, urethritis. and lesions involving skin of soles of feet and penis. Detailed work-up of sexually transmitted diseases (STDs), HIV, and systemic etiology were negative. Despite aggressive treatment with antibiotics, NSAIDS, prednisone, and MTX for 3 months, he had persistent synovitis and worsening of skin lesions. He was then treated with infliximab 200 mg intravenously at weeks 0, 2, 6, and 14 weeks which resulted in complete resolution of arthritis and skin lesions within 6 weeks of infliximab therapy.