Biological Therapies for Inflammatory Bowel Diseases
ABSTRACT Crohn's disease and ulcerative colitis are chronic disabling inflammatory bowel diseases (IBDs). Although the causes of IBD are unknown, defects in innate and adaptive immune pathways have been identified and biological therapies that target key molecules have been designed. Infliximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody to tumor necrosis factor, dramatically improved treatment of patients with Crohn's disease and ulcerative colitis. Infliximab has achieved treatment goals such as mucosal healing and decreasing the need for hospitalizations and surgeries. Although several anti-tumor necrosis factor therapies have been developed, there is a great need for drugs that target other pathways. Natalizumab, an antibody against the integrin alpha4 subunit, blocks leukocyte adhesion and has reached the clinic in the United States but has not been approved in the European Union; other anti-adhesion molecules currently are under development. Additional approaches under clinical development include therapeutics that target cytokines, such as interleukin-12/23, as well as those that block T-cell signaling. The use of recombinant human proteins, including immunoregulatory cytokines and growth factors, has not been successful so far. The efficacy of each therapy must be shown in carefully designed clinical programs. Biological therapies carry a definite safety risk, so their place in treatment algorithms must be defined carefully.
SourceAvailable from: Jasna Ajduković[Show abstract] [Hide abstract]
ABSTRACT: ackground: The main characteristic of active inflammatory bowel disease (IBD) is the neutrophil infiltration into the intestinal lamina propria, where neutrophils usually do not reside. Selectins are cell surface glycoproteins responsible for binding the leukocytes to vascular cells and their extravasation into the surrounding tissue. They show high affinity to P-selectin glycoprotein ligand-1 (PSGL-1) receptors. PSGL-1 is expressed on the surface of all leukocytes and they mediate the rolling of neutrophils on P-selectin. Soluble PSGL-1 acts competitively with cellular PSGL in many physiological and pathological processes.The aim of our study was to compare serum sPSGL-1 concentration in the blood of patients with ulcerative colitis (UC) and healthy control subjects. Serum concentrations of sPSGL-1 were measured in 20 patients with UC and 20 control subjects. Two-layer immunoenzyme procedure (ELISA) was used. The mean (± standard deviation) serum concentrations of sPSGL-1 in patients with UC and controls were 349.97±75.40 U/mL and 284.39±52.40 U/mL, respectively (p=0.003). In the present study, we showed that patients with UC had significantly higher sPSGL-1 blood values in comparison with healthy subjects. A short-term blockade with anti-PSGL-1 antibodies could block the transport of neutrophils and decrease UC activity. Thus it could possibly be employed in a new therapeutic approach to the treatment of UC (Fig. 1, Ref. 25).Bratislavske lekarske listy 01/2015; 116(3):147-9. · 0.45 Impact Factor
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ABSTRACT: Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal tract associated with an imbalance of the intestinal microbiota. Crohn's disease (CD) and ulcerative colitis (UC) are the most widely known types of IBD and have been the focus of attention due to their increasing incidence. Recent studies have pointed out genes associated with IBD susceptibility that, together with environment factors, may contribute to the outcome of the disease. In ulcerative colitis, there are several therapies available, depending on the stage of the disease. Aminosalicylates, corticosteroids, and cyclosporine are used to treat mild, moderate, and severe disease, respectively. In Crohn's disease, drug choices are dependent on both location and behavior of the disease. Nowadays, advances in treatments for IBD have included biological therapies, based mainly on monoclonal antibodies or fusion proteins, such as anti-TNF drugs. Notwithstanding the high cost involved, these biological therapies show a high index of remission, enabling a significant reduction in cases of surgery and hospitalization. Furthermore, migration inhibitors and new cytokine blockers are also a promising alternative for treating patients with IBD. In this review, an analysis of literature data on biological treatments for IBD is approached, with the main focus on therapies based on emerging recombinant biomolecules.Mediators of Inflammation 03/2015; · 2.42 Impact Factor
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ABSTRACT: Anti-tumor necrosis factor (anti-TNF) agents are widely used to treat patients with moderate-to-severe inflammatory bowel disease (IBD). We aimed to identify the risk factors for adverse skin lesions in patients with IBD receiving anti-TNF agents and assess the effect of concomitant use of azathioprine/6-mercaptopurine (AZA/6 MP). A total of 500 patients (404 with Crohn's disease, 96 with ulcerative colitis) who received anti-TNF agents between June 2002 and July 2013 were identified and retrospectively investigated. We compared 47 patients with IBD with skin lesions with 443 patients with IBD without skin lesions to identify risk factors by univariate and multivariate analysis. The Kaplan-Meier method was used to estimate the cumulative incidence of adverse skin lesions in relation to the concomitant use of AZA/6 MP. Eczematiform eruptions (n = 18, 38%) were the most common skin lesion type, followed by psoriasiform lesions (n = 13, 28%). A response to topical steroids was seen in 70% (33/47) of patients with skin lesions, and anti-TNF agents had to be discontinued in 9% (4/47). Concomitant use of AZA/6 MP decreased the risk of skin lesions in univariate (hazard ratio, 0.452; 95% CI, 0.251-0.814; P = 0.008) and multivariate (hazard ratio, 0.437; 95% CI, 0.242-0.790; P = 0.006) analysis. In addition, the cumulative incidence of adverse skin lesions was lower in patients on concomitant maintenance with AZA/6 MP (P = 0.009) than in those on anti-TNF monotherapy. Concomitant use of AZA/6 MP may decrease the occurrence of adverse skin lesions in patients receiving anti-TNF therapy.Inflammatory Bowel Diseases 04/2015; 21(4):832-9. DOI:10.1097/MIB.0000000000000342 · 5.48 Impact Factor