Rheumatoid Arthritis

• Rheumatoid arthritis lecture objectives:

  • Assess the severity and pattern of rheumatoid arthritis to select appropriate therapeutic options
  • Understand the roles of anti-inflammatories in symptomatic management of rheumatoid arthritis
  • Discuss the role of disease-modifying drugs including small molecules and biologics in rheumatoid arthritis
• Decreased survival in RA:

  • Mortality is increased twofold, resulting in a decreased lifespan of 7 to 10 years
  • Main causes of death are heart attacks and strokes
  • Treatment reduces the risk, but RA patients still have a higher mortality rate compared to the general population
• Inflammation:

  • Complex, highly regulated set of interactions between cells, soluble mediators, and tissues
  • Essential defense mechanism in response to irritation or injury
  • Failure of resolution can lead to chronic inflammation, persistent pain, and tissue damage
• RA risk factors:

  • Sex: Women are more likely than men to develop RA
  • Age: Risk increases with older age, but can occur at any age
  • Family history, genetics, smoking, hormones, and obesity are also risk factors
• RA pathogenesis:

  • Environmental factors, epigenetic modifications, susceptibility genes contribute to RA onset
  • Loss of tolerance, autoantibodies, secondary lymphoid tissue, immune cells play roles in RA pathogenesis
  • Clinical phases include synovitis, structural damage, and feedback loops
• Post-translational modifications and autoantibodies in RA:

  • Citrullination and carbamylation processes in RA
  • Citrullination linked to increased immunogenicity and arthritogenicity
  • Presence of citrullinated proteins and PAD4 enzyme in joints correlate with disease severity
• Roles of anti-inflammatories in symptomatic management:

  • NSAIDs mechanism of action, benefits, limitations, common types, side effects, and monitoring
  • Glucocorticoids in RA management: short-term and long-term roles, mechanisms, usage strategies, side effects
• Inflammation resolution:

  • Importance of resolving inflammation to limit damage
  • Involves removal of pro-inflammatory mediators, neutrophil apoptosis, release of pro-resolving mediators, and transformation of M1 to M2 macrophages
  • Failure of resolution leads to chronic inflammation
• Treatment protocol for rheumatoid arthritis:

  • Symptomatic treatment for immediate pain relief using NSAIDs
  • NSAIDs inhibit cyclooxygenase and prostaglandin production, but do not slow disease progression
  • Illustration of varying degrees of COX enzyme inhibition by different NSAIDs
• Disease-modifying anti-rheumatic drugs (DMARDs):

  • Small molecules like hydroxychloroquine, leflunomide, methotrexate, minocycline, sulfasalazine, cyclosporine A, tofacitinib
• Disease-modifying anti-rheumatic drugs (DMARDs) can be classified into Small Molecules and Biologicals
• Small Molecules include Hydroxychloroquine, Leflunomide, Methotrexate, Minocycline, Sulfasalazine, Cyclosporine A, and Tofacitinib
• Biologicals include Abatacept, Rituximab, Tocilizumab, Anakinra, Adalimumab, Etanercept, Infliximab, Certolizumab pegol, and Golimumab
• Early use of DMARDs recommends starting with Monotherapy, ideally with Methotrexate
• If Methotrexate is not effective, other conventional DMARDs such as leflunomide, hydroxychloroquine, and sulfasalazine may be used, either alone or in combination
• Methotrexate acts by interfering with dihydrofolate reductase necessary for DNA synthesis, inhibiting replication of all cells including B and T-cells
• Methotrexate toxicity can include hepatotoxicity, pulmonary damage, myelosuppression, gastrointestinal problems, stomatitis, infection, and alopecia
• Sulfasalazine is reduced by the bacterial enzyme azoreductase to sulfapyridine and 5-aminosalicylic acid in the bowel
• Leflunomide inhibits B- and T-cells replication by inhibiting dihydroorotate dehydrogenase (DHODH) essential for de novo pyrimidine synthesis
• Hydroxychloroquine, an anti-malarial medication, is useful for the treatment of inflammatory arthritis
• Biologic Disease-Modifying Antirheumatic Drugs (DMARDs) block specific parts of the immune system, unlike conventional DMARDs which suppress the overall immune system
• Tumour necrosis factor superfamily and receptors play a key role in the immune response, with TNF-α being a key pro-inflammatory cytokine
• Anti-TNF agents like Adalimumab, Etanercept, Infliximab, Certolizumab pegol, and Golimumab are used for the treatment of autoimmune diseases
• Rituximab is a monoclonal antibody that targets CD20, leading to B cell depletion through various mechanisms
• If biologics are not effective, targeted synthetic DMARDs like Janus kinase inhibitors can be considered
• Intravenous immunoglobulin (IVIG) is used as an antibody replacement therapy and immunomodulator in autoimmune or inflammatory diseases