RA.pdf

Rheumatoid Arthritis (Pathophysiology & Pharmacology) Dr. Fatemeh Saheb. PhD.  Learning Objectives Gain an understanding of the pathophysiology of rheumatoid arthritis (RA). Understand the mechanisms of action, contraindications, adverse effects, and drug interactions of the ant...

Rheumatoid Arthritis (Pathophysiology & Pharmacology) Dr. Fatemeh Saheb. PhD.  Learning Objectives Gain an understanding of the pathophysiology of rheumatoid arthritis (RA). Understand the mechanisms of action, contraindications, adverse effects, and drug interactions of the antirheumatic drugs. Radiological changes in RA? Bone deformity Severe joint deformities due to the destruction of bone and cartilage. Ankylosis Joints are fused (ankylosed) (bone bridging has occurred across the Loading… joint space) result in reduced mobility. What is Rheumatoid Arthritis? It is a common immune-mediated disease in which the activity of immune cells and the resulting pro-inflammatory cytokines lead to chronic inflammation in the joint spaces. This inflammation results in the destruction of bone and cartilage of the joint, and in the later stages, joint fusion (ankylosis) and severe joint deformity occur. Patients typically present with symmetrical polyarthritis, usually involving five or more small joints of the hands and feet. As the disease worsens, larger joints such as the shoulders, elbows, knees, and ankles may also become involved. Signs of morning stiffness of more than 30 minutes. The disease may flare, leading to sudden worsening of symptoms, during which the affected joints become swollen, warm, red, and painful.  Factors affecting Rheumatoid Arthritis Patient Demographics: Diagnosed between the ages of 30 to 70 years, with a prevalence 2 to 3 times higher in women. Genetic Factors: Presence of HLA-DR variant alleles* Environment: Individuals with this genetic predisposition often develop RA when exposed to environmental factors such as cigarette smoke or pathogens (e.g., gut bacteria), which can lead to the modification of self-proteins. One such well-known modification is the citrullination of Type II collagen, where the amino acid arginine is converted into citrulline. *HLA-DR1 and HLA-DR4. Rheumatoid Arthritis- a Battle Against Self-Modified Antigen (Or Autoimmune Disorder) Citrulline, a modified self-antigen, is mistakenly recognized as a foreign antigen, triggering an immune response. This process begins when citrullinated self-antigens are picked up by antigen-presenting cells (APCs) and transported to the lymph nodes. Within the lymph nodes, antigen-presenting cells activate T helper cells. The activated T helper cells then stimulate nearby B cells, causing them to proliferate and differentiate into plasma cells that produce specific autoantibodies against citrulline called (Anti- citrullinated protein antibodies-ACPAs) and other nonspecific autoantibodies called rheumatoid factor (RF) antibodies. Rheumatoid Arthritis- the key players are immune cells and cytokines Many of these T-helper cells migrate through the blood into the synovium. In the synovium activated T cells release interferon-gamma and interleukins (IL-17). These cytokines trigger neighboring immune cells, such as macrophages, as well as synovial fibroblasts, to release proinflammatory cytokines like TNF, IL-1, and IL-6. This contributes to joint inflammation.  Rheumatoid Arthritis- the key players are immune cells and cytokines Anti-citrullinated protein antibodies and rheumatoid factor through the blood into the synovium. ----------------------------------------------------------- Anti-citrullinated protein antibodies bind to citrulline within the joint, and rheumatoid factor binds to IgG, forming immune complexes that activate the complement system. This activation stimulates macrophages to release more cytokines, such as TNF, IL-1, and IL-6, further promoting Loading… chronic inflammation. ----------------------------------------------------- This inflammation is accompanied by angiogenesis, which facilitates the increased trafficking of immune cells (T-helper and monocytes) to the joints and leads to the production of additional proinflammatory cytokines, thereby exacerbating the inflammatory process. Rheumatoid Arthritis As the disease progresses, abnormally proliferating synovial cells cause a "tumor-like growth" called pannus to develop, which erodes bone and cartilage. Additionally, in RA, bone-destructive pathways are activated while bone repair mechanisms are inhibited. As a result, patients develop articular bone loss and systemic osteoporosis. The inflammatory cascade leads to the proliferation of synovial fibroblasts and the formation of pannus, which initiates the destruction of cartilage and bone, ultimately leading to joint space narrowing and, eventually, ankylosis. The treatment aim is to inhibit immune cells activation and reduce release of cytokines Question Which of the following is a typical initial presentation of patients with this condition? A) Symmetrical involvement of large joints B) Asymmetrical involvement of small joints C) Symmetrical polyarthritis involving five or more small joints D) Involvement of the spine and pelvis Question Which genetic factor is associated with an increased risk of developing RA? A) HLA-B27 B) HLA-DR variant alleles C) MHC class I D) PTPN22 gene Question Which modification of self-proteins is associated with the autoimmune response in RA? A) Methylation of histones B) Citrullination of Type II collagen C) Phosphorylation of enzymes D) Glycosylation of antibodies Question What role do cytokines like TNF, IL-1, and IL-6 play in RA? A) They reduce inflammation and promote healing. B) They trigger bone repair and cartilage regeneration. C) They promote chronic inflammation and contribute to joint destruction. D) They inhibit immune cell activation. Question Which autoantibodies are commonly formed in rheumatoid arthritis and contribute to inflammation through complement activation? A) ACPAs and rheumatoid factor (RF) B) IgE and allergens C) T-helper cells and plasma cells D) Osteoclasts and fibroblasts Question What is the term used to describe the tumor-like growth in the joints caused by proliferating synovial cells in RA? A) Granuloma B) Pannus C) Osteophyte D) Fibroma Question Which of the following describes a consequence of RA on bone health? A) Increased bone density B) Bone repair and healing C) Articular bone loss and systemic osteoporosis D) Decreased bone turnover cDMARDs Following an RA diagnosis, a cDMARD should be started as soon as possible to delay disease progression. For patients with an inadequate response to monotherapy: 1) A combination of two cDMARDs. 2) Addition of a bDMARD to a cDMARD. 3) Lastly, if the bDMARD is not effective, addition of a JAKi to a cDMARD. (NSAIDs or glucocorticoids can be used for their anti- inflammatory effects if needed.) Methotrexate- (The preferred DMARD!) MOA- (Folic acid antagonist) leads to inhibits cytokine production leading to immunosuppressive and anti-inflammatory effects. Adverse effect- Mucosal ulceration, cytopenias (especially leukopenia), and cirrhosis. Folic acid may be supplemented to improve methotrexate tolerability and reduce gastrointestinal and hepatic adverse effects. Methotrexate TNF biologics These compounds bind to TNF-α and interfere with its activity by blocking its interaction with cell surface receptors. Abatacept Abatacept is a co-stimulation modulator that binds to the CD80/CD86 proteins on antigen-presenting cells, inhibiting their interaction with CD28 on T cells. This prevents full T-cell activation and reduces the inflammatory response. This blockade interrupts the early stages of the pathogenic cascade of RA. Rituximab- B cell depleting agent In RA, B lymphocytes can perpetuate the inflammatory process in the synovium by producing autoantibodies and exacerbating the inflammatory process. Rituximab is a monoclonal antibody directed against the CD20 antigen found on the surface of B lymphocytes. Administration of rituximab results in B-cell depletion. Loading… Tocilizumab Tocilizumab is a recombinant monoclonal antibody that binds to IL-6 receptors and inhibits the activity of the proinflammatory cytokine IL-6. Janus kinases inhibitor (JAKi) These are enzymes located inside immune cells that play a crucial role in transmitting signals from the cell surface to the nucleus. When cytokines bind to receptors on the cell membrane, they trigger JAKs to activate signaling pathways that potentiate immune responses and the resultant local inflammation. ----------------------------------------------------------- JAKi is a synthetic drug taken orally that targets and inhibits Janus kinases. Due to its small size, it can enter cells and block the JAK signaling pathways. By disrupting these pathways, tofacitinib interferes with the communication between cytokines and immune cells, thereby reducing the inflammatory response. Question What is the mechanism of action of abatacept in the treatment of rheumatoid arthritis? A) Inhibits the binding of TNF to its receptor B) Blocks B cell activation C) Modulates T-cell activation by binding to CD80/CD86 on antigen-presenting cells (APCs) D) Inhibits cytokine release from macrophages Question What is the mechanism of action of rituximab in rheumatoid arthritis? A) Depletion of CD20-positive B cells B) Inhibition of TNF-alpha C) Blocking T cell activation D) Inhibition of IL-6 signaling Question What is the primary mechanism of action of anti-TNF agents (e.g., infliximab, adalimumab) in rheumatoid arthritis? A) Inhibit IL-6 signaling B) Neutralize TNF-alpha by binding to it and preventing its interaction with TNF receptors C) Inhibit T cell activation by blocking CD28 D) Induce apoptosis of macrophages Question Which statement correctly represents the mechanism of action of tofacitinib in the treatment of RA? A. TNF inhibitor B. Janus kinase inhibitor C. IL-6 receptor blocker D. Dihydrofolate reductase inhibitor