Rheumatoid arthritis serum proteins

Gutteridge, J.M.C. (1986). Antioxidant properties of the proteins caeruloplasmin, albumin and transferrin. A study of their activity in serum and synovial fluid fiom patients with rheumatoid arthritis. Biochim. Biophys. Acta 869, 119-127. 

Enbrel is a product now approved for medical use that is based upon this strategy. The product is an engineered hybrid protein consisting of the extracellular domain of the TNF p75 receptor fused directly to the Fc (constant) region of human IgG (see Box 13.2 for a discussion of antibody structure) The product is expressed in a CHO cell line from which it is excreted as a dimeric soluble protein of approximately 150 kDa. After purification and excipient addition (mannitol, sucrose and trometamol), the product is freeze-dried. It is indicated for the treatment of rheumatoid arthritis and is usually administered as a twice-weekly s.c. injection of 25 mg product reconstituted in WFI. Enbrel functions as a competitive inhibitor of TNF, a major pro-inflammatory cytokine. Binding of TNF to Enbrel prevents it from binding to its true cell surface receptors. The antibody Fc component of the hybrid protein confers an extended serum half-life on the product, increasing it by fivefold relative to the soluble TNF receptor portion alone. 

Pfizer s tenidap (CP-66,248) (157), another enolic compound, was also more potent (500-fold) toward CO over 5-LO inhibition in human ISN (0.032 /iM and 18 /iM, respectively) [379-381]. Efficacy in rheumatoid arthritis clinical trials has been reported [380,382] in patients, serum levels of acute phase proteins and synovial fluid levels of IL-1 were reduced by tenidap, in contrast to the lack of this effect with NSAIDs. Besides CO/5-LO inhibition, a variety of in vitro activities have been reported, including a number of effects on monocyte functions and differentiation [379], inhibition of neutrophil degranulation [382], inhibition of the activation of neutrophil collagenase [383], inhibition of leukocyte-endothelial cell adhesion [384], and inhibition of LTB4-induced neutrophil chemotaxis [385]. Al-... 

The compound is a drug for the treatment of rheumatoid arthritis. The mode of transport of this drug in the body involves the exchange of thiomalate ligands in vivo and the binding of Au(I) to -SH and S—S units of proteins, such as blood serum albumin. 

Liao, H., Wu, J., Kuhn, E., Chin, W, Chang, B., Jones, M.D., O Neil, S., Clauser, K.R., Karl, J., Hasler, F., Roubenoff, R., Zolg, W. and Guild, B.C. (2004) Use of Mass Spectrometry to Identify Protein Biomarkers of Disease Severity in the Synovial Fluid and Serum of Patients with Rheumatoid Arthritis. Arthritis Rheum, 50, 3792-3803. 

Adalimumab is a completely human IgGi approved for use in rheumatoid arthritis. Like the other anti-TNF- biologicals, adalimumab blocks the interaction of TNF- with TNF receptors on cell surfaces it does not bind TNF-3. Pharmacodynamic studies showed that administration of adalimumab reduced levels of C-reactive protein, erythrocyte sedimentation rate, serum IL-6, and matrix metalloproteinases MMP-1 and MMP-3. In vitro, adalimumab lyses cells expressing TNF- in the presence of complement. Patients may self-administer single doses of the antibody subcutaneously, every other week. Adalimumab has a serum half-life of 2 weeks, which is increased by 29-44% in patients who are also taking methotrexate. 

Serum IL-6 levels are usually very low or not measurable prior to middle age. However, subsequent IL-6 dysregulation results in increased production such that it is readily measurable in older persons even in the absence of inflammation. It has been suggested that dysregulation of IL-6 gene expression may be related to increased autoantibody production and the presence of benign paraproteinemia, both of which are commonly present in the elderly (Rl). Moreover, increased IL-6 levels may be responsible for the age-associated development of malignant B-cell tumors. In addition, Ershler (E4) noted that increased IL-6 has been associated with alteration of amyloid precursor protein, as is present in Alzheimer s disease, and stimulation of postmenopausal bone resorption. IL-6 has also been implicated in multiple myeloma, lymphoma, rheumatoid arthritis, Castleman s disease, and cardiac myxoma (E4). 

Liao H, et al. Use of mass spectrometry to identify protein biomarkers of disease severity in the synovial fluid and serum of patients with rheumatoid arthritis. Arthritis Rheum. 2004 50 3792-3803. 

In a prospective study of renal disease in 235 patients with early rheumatoid arthritis, persistent proteinuria and a raised serum creatinine concentration were predominantly related to drugs, including penicillamine and other DMARDs, whereas isolated hematuria was more directly associated with the activity of the disease process (205). Risk factors for drug-induced proteinuria were raised C-reactive protein, raised erythrocyte sedimentation rate, and age over 50 years. 

Inflammation is a local protective response to infection or injury whereby cells and proteins in the blood enter to remove the pathogens and repair the damaged tissue. Edema, redness, pain, and heat are the four cardinal symptoms of inflammation. Extent of reactions is determined by inflammatory mechanisms mediated by serum protein or cellular systems. Serum protein systems include complement, coagulation, fibrinolysis, and kinin cellular systems include PMN cells, mast cells, platelets, eosinophils, lymphocytes, macrophages, and reticuloendothelial system. Insufficient responses result in immunodeficiency leading to cancer and infections excessive responses are the cause of a number of chronic diseases like diabetes, cardiovascular disease, rheumatoid arthritis, multiple sclerosis, and Alzheimer s disease (Tracey, 2002). 

Recognized in 1961 (KIO), these are now well described (B18) and mimic the syndrome of mixed cryoglobulinemia (see 6.13). Skin lesions in this condition are raised, painful, and edematous with or without necrosis. Biopsy always reveals arteritis with a mononuclear and neutro-phile infiltrate. There is in most cases a preceding history of rheumatoid arthritis, Sjogren s syndrome, syphilis, sarcoidosis or other hyperimmune states, and this will dominate the clinical findings. Rarely the protein interactions build up to a level presenting as a viscosity syndrome so that this group can overlap with 7.7.1 unless the serum is carefully examined. 

Two types of soluble binding protein have been described, nonspecific serum proteins and cytokine-specific soluble receptor proteins. The major nonspecific serum protein capable of binding cytokines appears to be a2-macroglobuIin (B57, B58, Mil). A number of soluble cytokine inhibitors related to the relevant receptor have been described. The soluble form of the IL-2R a chain has been found in the serum of apparently normal individuals and is increased in the serum of individuals with inflammatory diseases such as rheumatoid arthritis (W31). Similar molecules have been described for IL-1, IL-6, IFNy, and IL-7 (F7, N14, S62). The mechanism of release has not been properly established but appears to require proteolytic cleavage of the membrane-bound receptor. Soluble inhibitors for two other cytokines, IL-4 and TNF, appear to be derived by alternative RNA splicing sites that give rise to receptors lacking a transmembrane sequence and that are secreted (M50, S22). 

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