Rheumatoid arthritis (RA) is a chronic autoimmune disease, clinically characterized by chronic synovitis, serological abnormalities, acute-phase reactants, and symptoms like pain or stiffness, leading to a score ≥ 6 of 10 as established by the 2010 classification criteria of the American college of rheumatology and European league against rheumatism . The prevalence in developed countries rages between 0,5 – 1,1% with an incidence of 0,02 to 0,07 per 1000 . In spite of newer molecular and cellular understanding of RA the pathophysiological pathways and etiology of disease is not already understood in detail . Impact of RA seems to be highly associated with genetic susceptibility, environmental factors and changes in mesenchymal tissue. As genetic factors association with human leukocyte antigen-DRB1 allels, the so called shared epitope could be verified. Those patients were positive for autoantibodies, the IgM and IgG rheumatoid factors, as well as antibodies against citrullinated peptids (ACPA), identified as directly acting against the Fc fragment of human IgG . Most dominant environmental factors are smoking, age and gender (male / female ratio 1/3) . Local Tissue consists of four major types of cells involved in rheumatoid synovial inflammation, the fibroblast-like cells, macrophage like cells as well lymphocytes (T and B Cells). Most insights indicate that RA starts in the joints with enhanced cytokine production by macrophage- and fibroblast-like synoviocytes. These cytokines activate pathways of the adaptive immune system especially targeting T-cell subsets and regulatory T-cells, leading to macrophages, chondrocytes and osteoclasts driven tissue damage . However, the increasing age of patients is highly associated with the contract of RA and edentulism. Moreover, the growing evidence suggests an association between periodontal disease and systemic diseases such as rheumatoid arthritis . Therefore, patients suffering from RA, show characteristics that confirm to lots of patients daily locating our hospital. Since the paradigm shift in RA therapy no longer the reduction of symptoms by the use of analgetics or anti-inflammatory drugs (NSAIDs) is the overarching principle. Actually treatment of disease is dominated by an aggressive and early use of disease modifying anti-rheumatic drugs as recommended by the ACR and EULAR . Therefore, the availability of new therapies in rheumatoid arthritis, especially the admission of newer antirheumatic drugs increases remarkably during the last decades . DMARDs are a heterogeneous group of agents, whose diverse mechanisms of action are not already understood. The most often and usually first time administered DMARD is methotrexate. MTX was primary used at high dosages (100-1000mg) in oncology as anti-neoplastic agent. First data of low dose MTX use in RA Therapy go back to the 1960s. In the following years doses ranged from 2,5-25 mg once weekly, administered orally, intravenously or even subcutaneously . Actually it is still the anchor drug in RA Therapy, with mean dosage of 7,5 mg once weekly, whereas latest reports of the ACR and EULAR recommend higher dosages. However, the precise understanding of antirheumatic action in spite of antineoplastic action remains uncertain. It is known that high concentrations of MTX as a folic acid antagonist, inhibits the de novo purine and pyrimidine synthesis. Intracellular, a part of MTX undergoes polyglutamination (MTXglu). Both, MTX and MTXglu inhibit the dihydrofolate reductase (DHFR), thymidylat synthase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, which leads to accumulation of extracellular adenosine by devious inhibition of AMP deaminase and primary derived from adenine nucleotides. This extracellular adenosine accumulation has been found out to mediate the anti-inflammatory effect of MTX [11–13]. Adverse reactions of MTX are well documented in literature, even if it is often described as generally well tolerated and to possess a superior safety profile [14, 15]. In fact, side effects of DMARDs are discussed controversially. It is already recognized that high dose MTX therapy causes osteoporosis in predisposed patients . Just rare data exist concerning metabolic changes impairing osteogenic pathways affected by low dose MTX therapy. However, one of the most important tissues, which is routinely affected by maxillofacial surgery in the context of fractures, orthognathic surgery, implantology or temporo-mandibular joint diseases is the jaw bone and therefore bone metabolism with its bone forming osteoblasts. This emphasizes the demand of a detailed knowledge of disease specific metabolic changes and pathogenesis, as well as potential side effects and adverse events of disease modifying antirheumatic drugs affecting cranio-maxillofacial surgery. Especially neurological, phylogenetic and metabolic specifics of the cranio-maxillofacial region amplify this request.
Therefore we investigate the proliferation, mitochondrial metabolism and differentiation of primary bovine osteoblasts on clinically relevant concentrations of MTX, to determine potential side effects and risks of low dose methotrexate on the osseous structures of the oral cavity and facial region.