Animal models of rheumatoid arthritis

Animal models of arthritis are used to study pathogenesis of disease and to evaluate potential anti-arthritic drugs for clinical use. Therefore morphological similarities to human disease and capacity of the model to predict efficacy in humans are important criteria in model selection. Animal models of rheumatoid arthritis (RA) with a proven track record of predictability for efficacy in humans include: rat adjuvant arthritis, rat type II collagen arthritis, mouse type II collagen arthritis and antigen-induced arthritis in several species. Agents currently in clinical use (or trials) that are active in these models include: corticosteroids, methotrexate, nonsteroidal anti-inflammatory drugs, cyclosporin A, leflunomide interleukin-1 receptor antagonist (IL-1ra) and soluble TNF receptors. For some of these agents, the models also predict that toxicities seen at higher doses for prolonged dosing periods would preclude dosing in humans at levels that might provide disease modifying effects. Data, conduct and features of the various models of these commonly utilized models of RA as well as some transgenic mouse models and less commonly utilized rodent models will be discussed with emphasis on their similarities to human disease.     

Genetic determination of rheumatoid arthritis

The study on the nature of genetic determination of the definite rheumatoid arthritis (RA) and its forms was carried out, based on the material comprising clinical data on 189 probands and their 1st and 2nd degree relatives (713 subjects) which is contained in the computer Family Data Bank at the Department of Epidemiology and Genetics of this institute. The heritability coefficient "in narrow sense" (80%) obtained within the framework of the multifactorial threshold model confirmed once more important role of genetic factors in the appearance of the disease. The study of genetic heterogeneity within the framework of the Ch. Smith's and T. Reich's models failed to reveal any independent genetically RA forms. An assumption of the essential role of the genes localized in the X chromosome, based on diverse susceptibility of sexes, received no conformation. It has been shown that the RA distribution in the population and families may well be described by means of a variant of the single autosomal two-allele locus model with incomplete and differentiated for two sexes penetrance. The model parameters obtained, a particular penetrance of the mutant homozygote in both sexes equalling 100%, and penetrance of the normal homozygote equalling 0 in men and reaching 0 (0.028%) in women testify to a very essential influence of the major gene on determination of RA.     

Rodent models of rheumatoid arthritis

The study of rheumatoid arthritis is greatly facilitated by animal models that enable investigation of a complex system involving inflammation, immunological tolerance, and autoimmunity. Although the models cover several species and pathogenetic mechanisms and can be classified as induced or spontaneous, all converge on arthritis. However, because each model features a different mechanism driving disease expression, the merits of each should be evaluated carefully in making the appropriate choice for the scientific question to be addressed. In addition, because the incidence and kinetics of disease vary by model, careful thought should be given to protocol design to minimize animal use.     

Association of MHC and rheumatoid arthritis: HLA polymorphisms in phenotypic variants of rheumatoid arthritis

Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.     

Angiogenesis in rheumatoid arthritis

There is much evidence that rheumatoid arthritis is closely linked to angiogenesis. Important angiogenic mediators have been demonstrated in synovium and tenosynovium of rheumatoid joints. VEGF (Vascular Endothelial Growth Factor), expressed in response to soluble mediators such as cytokines and growth factors and its receptors are the best characterized system in the angiogenesis regulation of rheumatoid joints. Moreover, other angiogenic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor beta (TGF-beta), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-15, IL-18, angiogenin, platelet activating factor (PAF), angiopoietin, soluble adhesion molecules, endothelial mediator (endoglin) play an important role in angiogenesis in rheumatoid arthritis. On the other hand, endostatin, thrombospondin-1 and -2 are angiogenic inhibitors in rheumatoid arthritis. The persistence of inflammation in rheumatoid joints is a consequence of an imbalance between these inducers and inhibitors of angiogenesis.     

Macrophages in rheumatoid arthritis

In rheumatoid arthritis (RA) tissue macrophages release growth factors, matrix metalloproteinases, cytokines, and chemokines. While in normal joints there is a balance between proinflammatory and anti-inflammatory cytokines, an imbalance between these inducers and inhibitors of inflammation occurs in RA, where macrophages are responsible for inducing inflammation, matrix destruction and angiogenesis.     

Association of MHC and rheumatoid arthritis. HLA polymorphisms in phenotypic variants of rheumatoid arthritis

Genes in the human leukocyte antigen (HLA) region remain the most powerful disease risk genes in rheumatoid arthritis (RA). Several allelic variants of HLA-DRB1 genes have been associated with RA, supporting a role for T-cell receptor-HLA-antigen interactions in the pathologic process. Disease-associated HLA-DRB1 alleles are similar but not identical and certain allelic variants are preferentially enriched in patient populations with defined clinical characteristics. Also, a gene dosing effect of HLA-DRB1 alleles has been suggested by the accumulation of patients with two RA-associated alleles, especially in patient subsets with a severe disease course. Therefore, polymorphisms in HLA genes are being explored as tools to dissect the clinical heterogeneity of the rheumatoid syndrome. Besides HLA polymorphisms, other risk genes will be helpful in defining genotypic profiles correlating with disease phenotypes. One such phenotype is the type of synovial lesion generated by the patient. HLA genes in conjunction with other genetic determinants may predispose patients to a certain pathway of synovial inflammation. Also, patients may or may not develop extraarticular manifestations, which are critical in determining morbidity and mortality. HLA genes, complemented by other RA risk genes, are likely involved in shaping the T-cell repertoire, including the emergence of an unusual T-cell population characterized by the potential of vascular injury, such as seen in extraarticular RA.     

Physiotherapy in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic and painful clinical condition that leads to progressive joint damage, disability, deterioration in quality of life, and shortened life expectancy. Even mild inflammation may result in irreversible damage and permanent disability. The clinical course according to symptoms may be either intermittent or progressive in patients with RA. In most patients, the clinical course is progressive, and structural damage develops in the first 2 years. The aim of RA management is to achieve pain relief and prevent joint damage and functional loss. Physiotherapy and rehabilitation applications significantly augment medical therapy by improving the management of RA and reducing handicaps in daily living for patients with RA. In this review, the application of physiotherapy modalities is examined, including the use of cold/heat applications, electrical stimulation, and hydrotherapy. Rehabilitation treatment techniques for patients with RA such as joint protection strategies, massage, exercise, and patient education are also presented.