Rheumatoid Arthritis: Etiology and Pathogenesis

• Rheumatoid arthritis (RA) is a chronic inflammatory disorder, mainly affecting joints, but potentially involving other organ systems like skin and lungs.
• "Rheumatoid" originates from "rheumatism," broadly referring to musculoskeletal illnesses.

Etiology and Epidemiology of RA

• RA's origin is unknown, but cellular and humoral immune response abnormalities lead to autoantibody development.
• Autoantibodies against post-translationally modified proteins such as citrullination, carbamylation, and acetylation can cause T and B cells to migrate into joint synovium.
• Genetic factors, mainly HLA DRB1 and tumor necrosis factor alleles, contribute to RA susceptibility, explaining about 50% of the genetic impact.

Pathogenesis of RA

• Intense innate immune system activation occurs, with highly activated cells in affected tissues.
• Synovial hyperplasia, a hallmark of RA, significantly contributes to forming an invasive pannus.
• RA is characterized by inflammation, joint pain, swelling, cartilage/bone destruction, and inflammatory cytokines.
• The stage is dominated by macrophages and fibroblasts, which are RA activated cells, which dominates the degenerative process.
• Factors like IL-6 and TNF alpha deregulate the balance between cartilage and bone matrix formation/degradation within joints.

Healthy Joint Anatomy

• A healthy joint consists of two bones covered with articular cartilage, which acts as a protective cushion.
• Synovial joints connect two bones via a fibrous joint capsule, continuous with the periosteum.
• The fibrous capsule is lined with the synovial membrane, which produces synovial fluid and removes debris.
• Synovial fluid, a viscous liquid, lubricates the joint; the synovial membrane and articular cartilage form the inner lining of the joint space.

RA as an Autoimmune Process

• RA is an autoimmune process typically triggered by a genetic-environmental interaction.
• Those with genes for immune proteins like HLA Dr one and HLA Dr four might develop RA after exposure to environmental factors, such as cigarette smoke or a specific pathogen like gut bacteria.
• Environmental factors can modify self-antigens, such as IgG antibodies, type II collagen, or Vimentin.
• Type II collagen and vimentin can undergo citrullination, where arginine is converted to citrulline.
• Due to susceptibility genes (HLA Dr one and HLA Dr four), immune cells may mistake these altered proteins as foreign antigens.
• Antigen-presenting cells carry these antigens to lymph nodes, activating CD4 T helper cells.
• T helper cells stimulate B cells to proliferate and differentiate into plasma cells, producing autoantibodies against self-antigens.

Inflammatory Processes in RA

• T helper cells and antibodies enter circulation and reach the joints.
• T cells secrete cytokines like interferon-gamma and interleukin-17 to recruit more inflammatory cells (e.g., macrophages) into the joint space.
• Macrophages also produce inflammatory cytokines like TNF alpha, interleukin-1, and interleukin-6, which stimulate synovial cells to proliferate.
• Increased synovial and immune cells create a pannus, a swollen synovial membrane with granulation tissue.
• Over time, the pannus damages cartilage and other soft tissues and erodes bone via proteases secreted by activated synovial cells.
• Inflammatory cytokines increase RANKL on T cells, which binds RANK on osteoclasts to break down bone.

Antibody Involvement and Complement Activation

• Rheumatoid factor (RF) is an IgM antibody targeting the constant region of altered IgG antibodies.
• Anti-cyclic citrullinated peptide antibody (CCP) targets citrullinated proteins.
• These antibodies form immune complexes, accumulate in synovial fluid, and activate the complement system, promoting inflammation and injury. Chronic inflammation induces angiogenesis around the joint, attracting more inflammatory cells.

Systemic Effects of RA

• Inflammatory cytokines escape into the bloodstream, affecting multiple organ systems (extra-articular problems).
• IL-1 and IL-6 act as pyrogens in the brain, inducing fever; in skeletal muscle, they promote protein breakdown.
• In the skin and visceral organs, they lead to rheumatoid nodules, collections of macrophages and lymphocytes with central necrosis.
• Vessel walls get inflamed, resulting in vasculitis and atheromatous plaques in response to inflammatory cytokines.
• The liver produces high amounts of hepcidin, decreasing serum iron levels by inhibiting its absorption.
• In the lung, interstitial fibroblasts get activated, causing fibrotic tissue and impaired gas exchange. Pleural cavities can become inflamed with fluid accumulation (pleural effusion).

Joint Involvement and Deformities

• Rheumatoid Arthritis typically involves multiple joints symmetrically.
• Small joints of the hands are commonly affected.
• As the disease worsens, it can start to affect large joints.
• During flares, affected joints get extremely swollen warm and painful.
• Over time, joints become stiff, especially in the morning or after inactivity.
• People with rheumatoid arthritis may develop specific deformities, usually of the metacarpal phalangeal joints of the hand, such as ulna deviation of fingers.
• Deformities are also common in the interphalangeal joints, such as the so called pecuniary or buttonhole conformity.
• Another finger deformity is the swan neck deformity, which is the opposite.
• In the knee, a one-way valve can form with fluid filling the Seminoles Bursa.
• Extra articular manifestations, organ specific manifestations include rheumatoid nodules or firm bumps of tissue, and these are most commonly found in the skin, around pressure points such as the elbows.
• There's also an increased risk of atherosclerosis, and therefore heart attack or stroke; also anemia, interstitial lung fibrosis, and pleural effusions.