Biologies autoimmune diseases

TNF is a pleiotropic cytokine exerting a wide range of cellular responses, that affect biological processes such as lipid metabolism, coagulation, and insulin resistance and the function of endothelial cells. As a major proinflammatory cytokine TNF is also involved in progression of diseases like cancer, Alzheimer, Diabetes type II, cardiovascular, pulmonary or neurological disorders, and many autoimmune diseases. Blocking the action of TNF clearly reduces its inflammatory potential on various autoimmune disorders like Crohn s disease, rheumatoid arthritis (RA), and psoriasis. 

Antimetabolites. This class of drugs includes purine, pyrimidine, and folic acid analogs that have been successfully used to treat various carcinomas, autoimmune diseases, and dermatological disorders such as psoriasis. Because of their structural similarities to normal components of DNA and RNA synthesis, they are capable of competing with the normal macromolecules and alkylating biological nucleophiles. 

With the advent of biological-DMARD combinations with Methotrexate (MTX) a new era of therapy in autoimmune disease is introduced. DMARD-refractory autoimmune diseases are treated with combinations of a biological with MTX with achievement of improvements of ACR 20 and ASAS 20 in the majority of patients. A small minority of around 20% obtains improvements of ACR 70 and ASAS 70. ACR responses are American College of Rheumatology response criteria and ASAS stands for Assessment in Ankylosing Spondylitis. ACR and ASAS 20, 50 or 70 scores are exactly defined improvements of respectively 20%, 50% or 70%. 

The introduction of intravenous DMARD combinations provides a less expensive alternative than the use of biologicals in DMARDs refractory autoimmune disease in developing countries. The regimen of Step-down Bridge Combination of 5 immunosuppressants (SBC-5-IMNs, see below) obtained better results than single biological DMARDs or biological DMARDs in combination with MTX. 

Based on the bio-molecular pathogenesis, novel therapeutic agents have been developed since 1998 for the treatment of DMARDs refractory autoimmune diseases. These biological-DMARDs include infliximab, etanercept, adalimumab, rituximab and abatacept. The biological-DMARDs anti TNF-a were first approved for therapy of refractory RA, followed by Crohn s disease, AS, and PsA. Scores of other biological DMARDs in Phase I, II, and III clinical trials in autoimmune diseases indicate that the number of these biological agents may ultimately become equal to the number of NSAIDs introduced over the last 50 years. 

Rasker JJ. Review of biologic response modifiers efficacy, adverse effects, and safety in various autoimmune diseases. Proceedings book of the 12th APLAR Congress of Rheumatology. Kuala Lumpur (Malaysia) 2006. p. 167-70. 

Azathioprine is a cytotoxic inhibitor of purine synthesis effective for the control of tissue rejection in organ transplantation. It is also used in the treatment of autoimmune diseases. Its biologically active metabolite, mercaptopurine, is an inhibitor of DNA synthesis. Mercaptopurine undergoes further metabolism to the active antitumour and immunosuppressive thioinosinic acid. This inhibits the conversion of purines to the corresponding phosphoribosyl-5 phosphates and hypoxanthine to inosinic acid, leading to inhibition of cell division and this is the mechanism of the immunosuppression by azathioprine and mercaptopurine. Humans are more sensitive than other species to the toxic effects of the thiopurines, in particular those involving the haematopoietic system. The major limiting toxicity of the thiopurines is bone marrow suppression, with leucopenia and thrombocytopenia. Liver toxicity is another common toxic effect. 

Inbred strains could be chosen on the basis of availability, knowledge of strain characteristics and absence of any biological properties which would preclude use of the strain, such as autoimmune disease or cancer. Strains which are genetically dissimilar could be chosen in order to maximise the chance of choosing at least one susceptible strain. For example inbred mouse strains have been classified into seven major families, based on the analysis... 

Because of the instability of peroxynitrite under physiological conditions, the detection of 3-nitrotyrosine (NC>2-Tyr) has become a biochemical marker for the presence of peroxynitrite in pathophysiological processes. The biological significance of tyrosine nitration is a subject of great interest, because extensive evidence supports the formation of nitrotyrosine in vivo in diverse pathological conditions such as heart diseases, chronic inflammation and autoimmune diseases, cancer, Parkinson s disease, Alzheimer s disease, multiple sclerosis, amyotrophic lateral sclerosis, and ischemia-reperfusion injury [11]. 

Lee SJ, Kavanaugh A. Adverse reactions to biologic agents focus on autoimmune disease therapies. J Allergy Clin Immunol 2005 116(4) 900-5. 

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