Gastro-intestinal autoimmunity: preclinical experiences and successful therapy of fistulizing bowel diseases and gut Graft versus host disease by mesenchymal stromal cells

Mesenchymal stromal cells (MSC) are multipotent adult stem cells with the potential to regenerate tissue damage and inhibit inflammation and fibrosis in parallel. As they are non-immunogenic, MSC can be safely auto- and allotransplanted and consequently represent a therapeutic option for refractory connective tissue diseases and fistulizing colitis like Crohn’s disease. Actually, there are more than 200 registered clinical trial sites for evaluating MSC therapy, 22 are on autoimmune diseases and 27 are actually recruiting bowel disease’ patients. More than 1,500 patients with bowel diseases like Crohn’s disease were treated in clinical trials by local as well as systemic MSC therapy. Phase I and II trials on fistula documented the feasibility and safety of MSC therapy, and a significant superiority compared to fibrin glue in fistulizing bowel diseases was demonstrated. Autologous as well as allogeneic use of Bone marrow as well as of adipose tissue-derived MSC are feasible. In refractory Graft versus host disease, especially in refractory gut Graft versus host diseases, encouraging results were reported using MSC. Systemic MSC therapy of refractory irradiation-induced colitis was safe and effective on pain, diarrhea, hemorrhage, inflammation and fistulization accompanied by modulation of the lymphocyte subsets toward an increase in T regulatory cells and a decrease in activated effector T cells. Mesenchymal stem cells represent a safe therapy for patients with refractory inflammatory bowel diseases.     

Stem cell treatment for Crohn’s disease

While stem cell-based treatments have been established as a clinical standard of care for some conditions, such as hematopoietic stem cell transplants for cancer, the scope of potential stem cell-based therapies has expanded in recent years due to advances in stem cell research, paving the way for the increasing utilization of stem cell therapies in severe immune-mediated diseases including inflammatory bowel diseases (IBDs) and, in particular, Crohn’s disease. Both hematopoietic stem cells and mesenchymal (stromal) stem cells are considered to be of potential therapeutic benefit in immune-mediated conditions. A growing body of experimental and clinical evidence shows that hematopoietic stem cell transplant induces long-lasting remission in a majority of patients with active severe Crohn’s disease refractory to drug treatments, and the differential effect of potent immunosuppression and immune reconstitution in this setting is under evaluation. Mesenchymal stem cells have been shown to exert immunomodulatory action on various types of immune-mediated diseases, and in experimental models of IBD, but evaluation of the potential efficacy of this therapy in IBD is still in the early stages.     

Budesonide in the treatment of inflammatory bowel disease

Inflammatory bowel disease, including Crohn’s disease and ulcerative colitis, features recurrent episodes of inflammation of the GI tract. The treatment of inflammatory bowel disease is aimed at breaking the cycle of relapsing and remitting inflammation by inducing and maintaining remission. Systemically active conventional corticosteroids have long played a role in the induction of remission in both Crohn’s disease and ulcerative colitis, however, their long-term use can lead to adverse systemic effects. Budesonide, a synthetic steroid, has potent local anti-inflammatory effects and limited systemic bioavailability making it an appealing therapeutic option. Ulcerative colitis with predominantly distal disease may be treated with topical budesonide, however, novel oral controlled-release formulations have also been developed to allow for treatment of the entire colon. This article summarizes the use of budesonide in the management of inflammatory bowel disease.     

The histopathological approach to inflammatory bowel disease: a practice guide

Inflammatory bowel diseases (IBDs) are lifelong disorders predominantly present in developed countries. In their pathogenesis, an interaction between genetic and environmental factors is involved. This practice guide, prepared on behalf of the European Society of Pathology and the European Crohn’s and Colitis Organisation, intends to provide a thorough basis for the histological evaluation of resection specimens and biopsy samples from patients with ulcerative colitis or Crohn’s disease. Histopathologically, these diseases are characterised by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the cell types present, but these features frequently overlap. If a definitive diagnosis is not possible, the term indeterminate colitis is used for resection specimens and the term inflammatory bowel disease unclassified for biopsies. Activity of disease is reflected by neutrophil granulocyte infiltration and epithelial damage. The evolution of the histological features that are useful for diagnosis is time- and disease-activity dependent: early disease and long-standing disease show different microscopic aspects. Likewise, the histopathology of childhood-onset IBD is distinctly different from adult-onset IBD. In the differential diagnosis of severe colitis refractory to immunosuppressive therapy, reactivation of latent cytomegalovirus (CMV) infection should be considered and CMV should be tested for in all patients. Finally, patients with longstanding IBD have an increased risk for the development of adenocarcinoma. Dysplasia is the universally used marker of an increased cancer risk, but inter-observer agreement is poor for the categories low-grade dysplasia and indefinite for dysplasia. A diagnosis of dysplasia should not be made by a single pathologist but needs to be confirmed by a pathologist with expertise in gastrointestinal pathology.     

Autoimmune disease: is it a disorder of the microenvironment?

Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease that involves several vital organs including the cardiovascular system, joints, and kidneys. The pathology is characterized by accumulation of autoreactive lymphocytes that attack the patients' own tissues, secretion of autoantibodies and deposition of immune complexes in vital organs. Chronic widespread inflammation is the hallmark of SLE and the target of current therapy. According to recent theories, intonating immune circuits of inflammatory cytokines and immune cells constitute highly specialized targets for SLE therapy, which nonetheless consists for the most part of anti-inflammatory medications and cytotoxic drugs. For advanced autoimmune disorders, cell therapy aiming at introducing "healthy" stem cells has been promising, keeping in mind that in its current state, stem cell therapy is reserved for the most advanced diseases refractory to traditional therapy. Ongoing studies in our laboratories examined the role of the bone marrow microenvironment, in particular, mesenchymal stem cells (MSCs) in the etiopathogenesis of SLE. Specifically, we are testing the hypothesis that, in human SLE mouse model, marrow MSCs are defective structurally and functionally. Preliminary data indicate that structural and functional defects in MSC population from an autoimmune mouse model for human SLE may contribute to this pathology and consequently present a target for cell therapy.     

S100 proteins in the pathogenesis and diagnosis of inflammatory bowel disease

Crohn’s disease and ulcerative colitis (the inflammatory bowel diseases) are two well characterized conditions featuring inflammation of the gastrointestinal tract. Gut inflammation may be detected, assessed and measured by a variety of methods but their utility varies extensively. Over the past decade, calprotectin, belonging to a family of S100 proteins, has been shown to be a reliable marker of gut inflammation that corresponds to neutrophil migration. In addition, other members of the S100 family have important roles in inflammation and may also be useful markers of gut inflammation. Furthermore, these proteins may have functional roles in gut defense or in the pathogenesis of inflammatory bowel disease.     

Topical immunotherapy for skin disease

The gastrointestinal immune system, innate and adaptive, is continuously exposed to challenges provided by the enteric flora. In most cases, the result of mucosal immune responses is the development of tolerance. Mucosal dendritic cells initiate and regulate local immune responses. Uncontrolled local immune responses are thought to be a major factor in the development of inflammatory bowel disease, such as Crohn’s disease and ulcerative colitis. This review will discuss the function of dendritic cells in the recognition of the enteric flora and their role in the development of intestinal inflammation.     

The combination of fecal calprotectin with ESR,CRP and albumin discriminates more accurately children with Crohn’s disease

PurposeIncreased fecal calprotectin is a sensitive marker of various types of intestinal inflammation. We investigated correlations between high fecal calprotectin concentration and serum inflammatory markers in children with different intestinal diseases with diarrhea with/without blood and/or abdominal pain, to test whether the combination of these markers can differentiate potential patients with inflammatory bowel disease.Materials/methodsThe study included 128 children with high fecal calprotectin concentration (>150ug/g) and symptoms suggesting bowel disorders, hospitalized in the years 2013– 2015. Twenty-six (20%) patients were diagnosed with Crohn’s disease, 55 (43%) with ulcerative colitis, 32 (25%) with intestinal infection and 15 (12%) with food protein induced proctocolitis.ResultsSignificantly increased inflammatory markers were detected in children with inflammatory bowel disease, with a correlation between calprotectin and erythrocyte sedimentation rate – ESR (R = 0.53), mean corpuscular volume – MCV (R=-0.64), red blood cell distribution width (R = 0.56), albumin (R = −0.52), hemoglobin (R = −0.53) only in Crohn’s disease patients. To discriminate Crohn’s disease patients from patients with intestinal infection and patients with food protein induced proctocolitis, AUC analysis was performed. It revealed that considering ESR, CRP and albumin as additional markers to fecal calprotectin significantly improved diagnostic performance (AUC 0.917, p = 0.038).ConclusionsIn children with abdominal pain and/or diarrhea, increased ESR, CRP and decreased albumin combined with a high fecal calprotectin level yields additional diagnostic value in screening potential patients with Crohn’s disease. As far as differentiation of ulcerative colitis is concerned, low additional diagnostic value was found when high fecal calprotectin was combined with albumin.     

Present Status and Perspectives of Stem Cell-Based Therapies for Gastrointestinal Diseases

In recent years the interest in stem cell-based therapies for gastrointestinal injury has been increasing continuously. From the clinical point of view, transplantation of bone marrow derived stem cells may represent an alternative therapy for gastrointestinal injury, such as radioactive injury, inflammatory bowel disease, and other refractory gastrointestinal tract injury. There were several reports indicated that bone marrow derived stem cells located in the injured gastrointestinal tract and contributed to its regeneration by differentiating into functional epithelia cells or infusing with the gastrointestinal stem cells. Although the concept of cell-based therapy for various diseases of the gastrointestinal is widely accepted, the practical approach in humans remains difficult. Here we discussed the recent published data on clinical and experimental bone marrow stem cell transplantation and the possible role of stem cells in gastrointestinal tissue repair.     

Stem cell therapy for the treatment of parasitic infections: is it far away?

Stem cell therapy is an interventional treatment that introduces new cells into damaged tissues, which help in treating many diseases and injuries. It has been proved that stem cell therapy is effective for the treatment of cancers, diabetes mellitus, Parkinson’s disease, Huntington’s disease, cardiovascular diseases, neurological disorders, and many other diseases. Recently, stem cell therapy has been introduced to treat parasitic infections. The culture supernatant of mesenchymal stem cells (MSCs) is found to inhibit activation and proliferation of macrophages induced by the soluble egg antigen of Schistosoma japonicum, and MSC treatment relieves S. japonicum-induced liver injury and fibrosis in mouse models. In addition, transplantation of MSCs into naïve mice is able to confer host resistance against malaria, and MSCs are reported to play an important role in host protective immune responses against malaria by modulating regulatory T cells. In mouse models of Chagas disease, bone marrow mononuclear cell has been shown effective in reducing inflammation and fibrosis in mice infected with Trypanosoma cruzi, and transplantation of the bone marrow mononuclear cells prevents and reverses the right ventricular dilatation induced by T. cruzi infection in mice. Preliminary clinical trials demonstrate that transplantation of bone marrow derived-cells may become an important therapeutic modality in the management of end-stage heart diseases associated with Chagas disease. Based on these exciting results, it is considered by stating that it is firmly believed that, within the next few years, we will be able to find the best animal models and the appropriate stem cell type, stem cell number, injection route, and disease state that will result in possible benefits for the patients with parasitic infections, and stem cell therapy, although at an initial stage currently, will become a real therapeutic option for parasitic diseases.     

Review of Saccharomyces boulardii as a treatment option in IBD

Abstract

Context: Review of the yeast Saccharomyces boulardii as a treatment option for the inflammatory bowel diseases (IBD) ulcerative colitis and Crohn’s disease.

Objective: IBD is caused by an inappropriate immune response to gut microbiota. Treatment options could therefore be prebiotics, probiotics, antibiotics and/or fecal transplant. In this review, we have looked at the evidence for the yeast S. boulardii as a treatment option.

Material and methods: Searches in PubMed and the Cochrane Library with the MeSH words ‘Saccharomyces boulardii AND IBD’, ‘Saccharomyces boulardii AND Inflammatory Bowel Disease’, ‘Saccharomyces boulardii AND ulcerative colitis’ and ‘Saccharomyces boulardii AND Crohn’s disease’ gave total a total of 80 articles. After exclusions because of irrelevance, articles in other languages and some articles that were not available, 16 articles were included in this review.

Results: Three of the clinical trials showed a positive effect of S. boulardii in IBD patients (two Crohn’s disease, one ulcerative colitis), while there was one trial that didn’t prove any effect (Crohn’s disease). Included Animal trials and cell assays describes different anti-inflammatory mechanisms of S. boulardii supporting a possible effect when treating IBD patients.

Discussion: The number of studies of S. boulardii as treatment for IBD is limited. Furthermore, the existing trials have small populations and short duration.

Conclusion: We do not have enough evidence to prove the effect of S. boulardii in IBD. Saccharomyces boulardii is, however, a plausible treatment option in the future, but more placebo-controlled clinical studies on both patients with ulcerative colitis and Crohn’s disease are needed.     

Gene Delivery Approaches for Mesenchymal Stem Cell Therapy: Strategies to Increase Efficiency and Specificity

A significant number of clinical trials have been undertaken to explore the use of mesenchymal stem cells (MSCs) for the treatment of several diseases such as Crohn’s disease, diabetes, bone defects, myocardial infarction, stroke etc., Due to their efficiency in homing to the tissue injury sites, their differentiation potential, the capability to secrete a large amount of trophic factors and their immunomodulatory effects, MSCs are becoming increasingly popular and expected to be one of the promising therapeutic approaches. However, challenges associated with the isolation of pure MSC populations, their culture and expansion, specific phenotypic characterization, multi-potential differentiation and challenges of efficient transplantation limit their usage. The current strategies of cell-based therapies emphasize introducing beneficial genes, which will improve the therapeutic ability of MSCs and have better homing efficiency. The continuous improvement in gene transfer technologies has broad implications in stem cell biology. Although viral vectors are efficient vehicles for gene delivery, construction of viral vectors with desired genes, their safety and immunogenicity limit their use in clinical applications. We review current gene delivery approaches, including viral and plasmid vectors, for transfecting MSC with beneficial genes. The review also discusses the use of a few emerging technologies that could be used to improve the transfer/induction of desirable genes for cell therapy.     

Adalimumab: A Review of Its Use in the Treatment of Patients with Ulcerative Colitis

Adalimumab is a fully human, recombinant, monoclonal IgG1 antibody specific for the cytokine tumor necrosis factor-α. It is approved for the treatment of patients with inflammatory diseases, including adults with moderately to severely active ulcerative colitis who are refractory to, or intolerant of, corticosteroids and/or immunomodulators. In two well-designed 8- and 52-week clinical trials in patients with moderately to severely active ulcerative colitis despite treatment with corticosteroids and/or immunomodulators, subcutaneous adalimumab (160 mg, week 0; 80 mg, week 2; 40 mg every other week starting at week 4) was more effective than placebo for inducing and maintaining clinical remission. A statistically significant effect size (albeit <10 %) over placebo for the remission per Mayo score (primary endpoint) was observed with adalimumab at 8 weeks in both trials and at 52 weeks in one trial. Compared with placebo, adalimumab was associated with reductions in hospitalizations and improvements in other secondary endpoints, including clinical response, mucosal healing, corticosteroid-sparing, and health-related quality of life measures. Additionally, an early response to adalimumab was shown to be predictive of long-term efficacy. Adalimumab was generally well tolerated, compared with placebo, during clinical trials in patients with ulcerative colitis; the adverse event profile was similar to that in patients with Crohn’s disease or other approved indications. Adalimumab provides a new treatment option for patients with moderately to severely active ulcerative colitis who are refractory to, or intolerant of, corticosteroids and/or immunomodulators.     

Nutrigenomics and inflammatory bowel diseases

The field of nutrigenomics recognizes gene–diet interactions, with regard to both the impact of genetic variation on nutrient requirements, and conversely nutrient regulation of the expression of genes. Crohn’s disease and ulcerative colitis are inflammatory bowel diseases for which twin studies reveal genetic susceptibility that is impacted by diet and environment. Apparently contradictory data on the role of diet in inflammatory bowel disease would be entirely explainable if genetic variability determined dietary requirements and intolerances. Considering Crohn’s disease, we recognize three major classes of genes. The first of these involves bacterial recognition through pattern recognition receptors and autophagy genes, while the second act through secondary immune response, and the third concern epithelial barrier integrity. Despite genetic overlap with CD, the first two groups of genes appear to be less important in ulcerative colitis, while other genes, particularly those involved in barrier function, gain prominence. Case–control studies suggest that these different genetic groups reflect distinct dietary requirements. Such studies suggest nutrigenomic approaches to maintaining disease remission at present, and preventing disease development in the future.     

MiR-17 modulates osteogenic differentiation through a coherent feed-forward loop in mesenchymal stem cells isolated from periodontal ligaments of patients with periodontitis

Chronic inflammatory diseases, such as rheumatoid arthritis and periodontitis, are the most common causes of bone tissue destruction. Recently, human periodontal ligament tissue-derived mesenchymal stem cells (PDLSCs), a population of multipotent stem cells, have been used to reconstruct tissues destroyed by chronic inflammation. However, the impact of the local inflammatory microenvironment on tissue-specific stem cells and the mechanisms controlling the effects of the local inflammatory environment remain poorly understood. In this study, we found that the multidifferentiation potential of mesenchymal stem cells (MSCs) isolated from periodontitis-affected periodontal ligament tissue (P-PDLSCs) was significantly lower than that of MSCs isolated from healthy human periodontal ligament tissue (H-PDLSCs). Inflammation in the microenvironment resulted in an inhibition of miR-17 levels, and a perturbation in the expression of miR-17 partly reversed the differentiation potential of PDLSCs in this microenvironment. Furthermore, inflammation in the microenvironment promoted the expression of Smad ubiquitin regulatory factor one (Smurf1), an important negative regulator of MSC osteogenic differentiation. Western blotting and 3' untranslated regions (3'-UTR) reporter assays confirmed that Smurf1 is a direct target of miR-17 in PDLSCs. Our data demonstrate that excessive inflammatory cytokine levels, miR-17, and Smurf1 were all involved in a coherent feed-forward loop. In this circuit, inflammatory cytokines led to direct activation of Smurf1 and downregulation of miR-17, thereby increasing degradation of Smurf1-mediated osteoblast-specific factors. The elucidation of the molecular mechanisms governing MSC osteogenic differentiation in a chronic inflammatory microenvironment could provide us with a better knowledge of chronic inflammatory disorder and improve stem cell-mediated inflammatory bone disease therapy.     

Reappraisal of antibodies against Saccharomyces cerevisiae (ASCA) as persistent biomarkers in quiescent Crohn’s disease

A clear correlation exists between microbiota and the dysregulation of the immune response in Inflammatory Bowel Diseases (IBD), which comprise Crohn’s disease (CD) and ulcerative colitis (UC). These unbalanced reactions also involve humoral responses, with antibodies against Saccharomyces cerevisiae. Thus, here we aimed to quantify IgA and IgG specific to S. cerevisiae (ASCA) in quiescent CD and UC, to correlate the production of these antibodies with patient’s inflammatory response and disease clinical presentation. Twenty-nine subjects (16?CD and 13 UC) and 45 healthy controls were enrolled in this study and had plasma samples tested for ASCA and cytokines (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α), besides clinical evaluation. IBD patients had increase IgA and IgG ASCA, especially those with colonic (L2) and fistulizing (B3) CD. Similarly, patients who dropped out the treatment had augmented ASCA, while IgG was reduced in those receiving sulfasalazine treatment. Furthermore, the quiescent CD patients had elevated IL-6 on plasma, especially in the absence of treatment, together with increased counter regulatory response of IL-10. There was a positive correlation between IgA and IgG on CD but not UC, as well as between IgA and TNF in total IBD patients. In addition, the levels of IgG x TNF, IgA x IL-10 and IgG x IL-10 were also correlated in CD, indicating that ASCA production may be influenced by the inflammatory response. Finally, we concluded that ASCA could be pointed as relevant biomarker of CD presentation and residual inflammation, even in clinical remission patients.     

A Consensus Statement Addressing Mesenchymal Stem Cell Transplantation for Multiple Sclerosis: It’s Time!

Multiple sclerosis is a neurodegenerative disease of the central nervous system that is characterized by inflammation, demyelination with associated accumulation of myelin debris, oligodendrocyte and axonal loss. Current therapeutic interventions for multiple sclerosis predominantly modulate the immune system and reduce the inflammatory insult by general, non-specific mechanisms but have little effect on the neurodegenerative component of the disease. Predictably, the overall long-term impact of treatment is limited since the neurodegenerative component of the disease, which can be the dominant process in some patients, determines permanent disability. Mesenchymal stem cells, which are endowed with potent immune regulatory and neuroprotective properties, have recently emerged as promising cellular vehicles for the treatment of MS. Preclinical evaluation in experimental models of MS have shown that MSCs are efficacious in suppressing clinical disease. Mechanisms that may underlie these effects predominantly involve the secretion of immunomodulatory and neurotrophic growth factors, which collectively act to limit CNS inflammation, stimulate neurogenesis, protect axons and promote remyelination. As a logical progression to clinical utility, the safety of these cells have been initially assessed in hematological, cardiac and inflammatory diseases. Importantly, transplantation with autologous or allogeneic MSCs has been well tolerated by patients with few significant adverse effects. On the basis of these results, new, multicentre clinical trials have been launched to assess the safety and efficacy of MSCs for inflammatory MS. It thus comes as no surprise that the coalescence of an international group of experts have convened to generate a consensus guide for the transplantation of autologous bone marrow-derived MSC which, in time, may set the foundation for the next generation of therapies for the treatment of MS patients.     

Macrophage Subset Expressing CD169 in Peritoneal Cavity-Regulated Mucosal Inflammation Together with Lower Levels of CCL22

Crohn’s disease (CD) and ulcerative colitis (UC) are the most widely known types of inflammatory bowel diseases (IBD) and have been paid more attention due to their increasing incidence and a substantial increase in the risk of colorectal cancer (CRC). However, the phenotype and, more importantly, the function in the regulation of mucosal inflammation by different macrophages are poorly understood, even though macrophages constitute a major subset of intestinal myeloid cells. The results firstly showed that the subset of peritoneal CD11b⁺CD169⁺ macrophages increased and CCL22 expression level decreased significantly during the DSS-induced colitis. DSS-induced colitis was alleviated in CD169-DTR mice at least partially due to the deletion CD169⁺ macrophages. Moreover, the CCL22 expression level in peritoneal macrophages from CD169-DTR mice was much higher than that from WT mice with DSS-induced colitis. And, the cell-sorting result revealed that CD11b⁺CD169⁺ macrophage cells did not express CCL22 dominantly. Further experiment in vivo demonstrated that treatment with recombinant murine CCL22 (rmCCL22) ameliorated the clinical symptoms of DSS-induced colitis. All these data indicated that macrophage subset of CD11b⁺CD169⁺ from peritoneal cavity played critical role probably together with low levels of CCL22 in DSS-induced colitis.     

Infliximab Biosimilar (CT-P13; Infliximab-dyyb): A Review in Autoimmune Inflammatory Diseases

Infliximab biosimilar (CT-P13/infliximab-dyyb; Remsima^®, Inflectra^®) is approved in several countries for use in all indications for which reference infliximab (Remicade^®) is approved, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis, psoriasis, Crohn’s disease, and ulcerative colitis. Clinical data contributing to the EU approval of infliximab biosimilar were obtained from two pivotal double-blind clinical trials in patients with AS (PLANETAS) or RA (PLANETRA). Infliximab biosimilar demonstrated equivalence to reference infliximab in terms of its pharmacokinetic profile in patients with AS, patients with RA, and in healthy volunteers, and in terms of its efficacy in patients with RA. Clinical response rates in patients with RA or AS were maintained over the longer term (up to 102 weeks). In addition, the efficacy of infliximab biosimilar in patients with RA or Crohn’s disease and ulcerative colitis [i.e. inflammatory bowel disease (IBD)] has been demonstrated in the real-world setting. Infliximab biosimilar was generally well tolerated, with a tolerability profile similar to that of reference infliximab. Switching from reference infliximab to infliximab biosimilar had no detrimental effect on efficacy, safety, or immunogenicity compared with continuous infliximab biosimilar therapy, according to the extensions of PLANETAS and PLANETRA, and real-world data in IBD. Current evidence therefore suggests that infliximab biosimilar is a useful alternative to reference infliximab in patients with autoimmune inflammatory diseases.     

Spotlight on Infliximab in Crohn Disease and Rheumatoid Arthritis

Infliximab (Remicade) is a chimeric monoclonal antibody against tumor necrosis factor (TNF)-alpha that has shown efficacy in Crohn disease and rheumatoid arthritis with a disease-modifying activity and rapid onset of action. It is administered intravenously, generally in a schedule with initial infusions at 0, 2, and 6 weeks, followed by administration once every 8 weeks. Infliximab is effective in the treatment of patients with moderately to severely active Crohn disease with an inadequate response to other treatment options or those with fistulizing disease. In combination with methotrexate, infliximab reduced signs and symptoms and delayed disease progression in patients with active, methotrexate-refractory rheumatoid arthritis and in those with early disease. The drug was generally well tolerated. Recrudescence of tuberculosis infection and worsening of heart failure and demyelinating disease are among some of the concerns with anti-TNFalpha therapy, requiring cautious use of these agents in high-risk patients. Current data suggest that infliximab may be cost effective, especially when long-term clinical outcomes and burden of the diseases are taken into account. More robust, prospective pharmacoeconomic studies are required to better ascertain the cost effectiveness of infliximab. Direct head-to-head comparative trials of infliximab with other biological agents are not yet available and would be helpful in determining with greater certainty the place of infliximab in the management of these diseases. Nonetheless, infliximab, like other biological agents, is a valuable treatment option in patients with moderately to severely active Crohn disease (including fistulizing disease) or rheumatoid arthritis (including early disease).