For cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis Folic acid is needed for the de novo synthesis of the nucleoside thymidine, required for DNA synthesis. Also, folate is needed for purine base synthesis, so all purine synthesis will be inhibited. Methotrexate, therefore, inhibits the synthesis of DNA, RNA, thymidylates, and proteins. Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle
This slide provides an overview of how activated T cells lead to the inflammation and bone destruction that is characteristic of RA. Antigen presenting cells such as dendritic cells present a putative self-peptide to naïve T cells. Two signals are required to activate the T cell, a signal one mediated by MHC-TCR interaction and a co-stimulation signal, which can be mediated by CD80/86 interaction with CD28. The activated T cells produce cytokines such as Interferon-gamma, IL-2 and TNF-alpha. These and more direct cell-cell interactions like those shown on the next slide, lead to the activation of macrophages and B cells, which in turn produce inflammatory cytokines such as IL-1, IL-6 and TNF-alpha. B cells also produce autoantibodies such rheumatoid factor. Activated T cells also produce RANKL which binds to RANK on osteoclasts to activate them to induce bone resorption. Chondrocytes are also induced to produce matrix metallo-proteinases 1 and 3 which cause cartilage degradation. Thus, activated T cells induce a cascade that results in inflammation and destruction in the joint.
IL-6, alone or with other cytokines, interacts with various cells such as T cells, B cells, monocytes and fibroblasts, driving synovial proliferation, inflammation, autoimmunity and destruction of articular structures Serum IL-6 levels are elevated in patients with RA. -Levels may be associated with disease stage, severity of joint destruction and extra-articular manifestations of
Safety of Tocilizumab • Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral and protozoal and other opportunistic pathogens have occurred in patients receiving tocilizumab, and a black box warning is included in the label. The rate of serious infections in the all‐exposure drug treatment group was 4.7 per 100 patient‐years, in the range of other biologic agents. Screening for latent tuberculosis prior to starting therapy is recommended. • Gastrointestinal perforations have been reported in clinical trials, primarily as a complication of diverticulitis, however, the drug is not specifically contraindicated in patients with diverticular disease. • The package insert gives recommendations for monitoring. • Neutropenia and thrombocytopenia have also been reported, though with no specific relationship with infection or bleeding
