Pathophysiology
Summary
Rheumatoid arthritis (RA) is an inflammatory arthritis characterized by systemic inflammation that involves that characteristically involves the joints but also affects the heart, lungs, and blood vessels. The HLADRB1-gene harbors RA-susceptibility alleles: individuals with specific variations in this gene have an increased risk of developing RA, especially when exposed to environmental triggers such as smoking or viral/bacterial infections that can trigger molecular mimicry.
At the molecular level, citrullination of proteins plays a central role in the pathogenesis of RA. Macrophage-mediated citrullination relies on the enzyme peptidylarginine deaminase, found in macrophages, pathogens, and synovial tissue. Peptidylarginine deaminase converts arginine residues from environmental antigens into citrulline. This citrullinated protein that is then presented to CD4+ T-helper cell, sparking the release inflammatory cytokines. Anti-cyclic citrullinated peptide antibodies (ACPA) are formed in response to these citrullinated proteins, and are specific to RA. Additionally, rheumatoid factor, an IgM antibody, is produced, binding to the Fc region of IgG. Large complexes formed by the rheumatoid factor can deposit in tissues, activating the complement system and causing inflammation via a type III hypersensitivity reaction.
Rheumatoid arthritis is marked by pathological changes to the synovium, including hypertrophy, immune cell infiltration, and angiogenesis. Chronic synovitis leads to synovial pannus formation, characterized by hyperplasia and granulation tissue within joints. Subsequently, proteases are produced due to active joint inflammation, leading to the degradation of articular cartilage. Marginal erosions can arise due to pannus invasion and osteoclast activity. Over time, chronic pannus formation and fibrosis can cause joints to become stiff and near-fused, a condition termed fibrous ankylosis.
Clinically, RA manifests as symmetric pain & inflammation, predominantly affecting the metacarpophalangeal and proximal interphalangeal joints of the 2nd & 3rd digits, as well as the base of the thumb. Additional sites include the cervical spine, elbows, shoulders, knees, ankles, & feet. In contrast to osteoarthritis, RA symptoms are worse in the morning. The pain & stiffness typically lasts longer than 1 hour and improves with activity.
RA can cause various specific deformities. In the fingers, ’swan neck’ deformity, caused by fixed flexion at the DIP and fixed extension at the PIP joints, and ’boutonniere’ deformities, caused by fixed extension of the DIP and fixed flexion of the PIP joints, and ulnar deviation of the fingers are classical findings. Involvement of the cervical spine can induce cervical instability, leading to subluxation, potential spinal injury, and vertebral artery damage. Ultimately, fusion of the cervical vertebral facets results in a rigid, immobile neck.
The systemic inflammation in RA causes various symptoms, including constitutional symptoms like fever, malaise, & weight loss, as well as conditions like interstitial lung disease, pericarditis, vasculitis, and anemia of chronic inflammation. A severe form or RA known as Felty’s syndrome can cause splenomegaly and a decreased granulocyte count, manifesting as neutropenia. Dermatologically, rheumatoid nodules composed granulation tissue can form. Prolonged systemic inflammation can also trigger AA (secondary) amyloidosis. Characteristic laboratory findings in RA include elevated ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein), both markers systemic inflammation.
Lesson Outline
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FAQs
The HLADRB1-gene contains specific alleles that increase the risk of rheumatoid arthritis (RA). These genetic variations predispose individuals to RA, making them more susceptible to environmental factors, such as smoking or infection, that can initiate the development of RA. These multifactorial risk factors highlight the complex interplay between genetics and environmental factors in the development of RA.
Citrullination is a key process in the development of rheumatoid arthritis. It involves the conversion of arginine residues in environmental antigens to citrulline by macrophages. This citrullinated protein is then presented to CD4+ T-helper cells, sparking an immune response. This leads to systemic inflammation, the central component of the clinical manifestations of RA.
Anti-cyclic citrullinated peptide antibodies (ACPA) are specific to rheumatoid arthritis and form in response to citrullinated proteins in the body. When ACPA binds to these proteins, it initiates an inflammatory response. This inflammation contributes to the joint damage and other clinical manifestations seen in RA. The presence of ACPA is a significant marker, highlighting the body's immune response against modified proteins and its role in RA's progression.
Rheumatoid arthritis induces notable pathological alterations in the synovium, the lining that protects the joints. In RA, the synovium thickens and becomes infiltrated with immune cells, leading to increased blood vessel formation, known as angiogenesis. This results in chronic synovitis, or persistent inflammation of the synovium. Over time, this inflammation gives rise to synovial pannus, a granulation tissue that invades and erodes the joint's articular cartilage, leading to the bone damage commonly seen in RA patients.
The systemic inflammation in RA causes various symptoms, including constitutional symptoms fever, malaise, and weight loss. The consequences of this systemic inflammation can also manifest as conditions like pericarditis, vasculitis, and interstitial lung disease. A severe form or RA known as Felty’s syndrome can cause splenomegaly and a decreased granulocyte count, manifesting as neutropenia.
