By: Prof. Dr. Seyed Saeid Zamanieh Shahri, MD and Prof. Dr. Sonia Sayyedalhosseini, MD
Synovial Inflammation: The normal synovium is a thin layer lining the inner surface of the joint. In rheumatoid arthritis, immune cells infiltrate this tissue, resulting in synovial thickening.
Macrophages, synovial fibroblasts, lymphocytes, and dendritic cells produce substantial amounts of pro-inflammatory cytokines. Among the most important are:
• TNF-α
• IL-6
• IL-1
• IL-17
• GM-CSF
Pannus Formation: As a consequence of chronic inflammation, the synovial tissue gradually becomes highly cellular and invasive, forming a structure known as the pannus.
The pannus expands over the cartilage and, through the secretion of tissue-degrading enzymes, contributes to the erosion of cartilage and subchondral bone.
Bone Destruction: Activation of osteoclasts plays a major role in bone destruction. Increased expression of certain molecular mediators stimulates osteoclast differentiation and enhances bone resorption.
Role of the Complement System: Activation of the complement system increases vascular permeability, promotes recruitment of inflammatory cells, and intensifies joint inflammation.
Metabolic Alterations: Activated synovial cells alter their energy metabolism, resulting in increased glucose consumption and lactate production. These metabolic changes create a local environment that supports the persistence of inflammation.
Causes of Rheumatoid Arthritis: No single cause of rheumatoid arthritis has been established. Rather, the disease results from the interaction of multiple factors.
Genetic Factors: The strongest genetic associations involve genes within the human leukocyte antigen (HLA)-DRB region.
left000 In addition, genes involved in lymphocyte regulation, immune-signaling pathways, and cytokine production contribute to increased susceptibility to the disease.
Environmental Factors: Studies have shown that certain environmental exposures may initiate or promote autoimmune responses. These include:
• Tobacco smoking
• Air pollution
• Exposure to silica dust
• Certain microbial infections
Protein Citrullination: One important event in disease development is the chemical modification of certain endogenous proteins, in which arginine is converted to citrulline. This structural alteration may cause the modified protein to be recognized by the immune system as a foreign antigen.
Hormonal Factors
Differences in disease prevalence between women and men have suggested a potential role for sex hormones. Hormonal changes may influence the regulation of immune responses.
Epigenetic Factors: Epigenetic alterations—including DNA methylation, histone modifications, and regulation by non-coding RNAs—also contribute to the activation or suppression of genes involved in inflammatory processes.
Risk Factors: Multiple factors have been associated with an increased likelihood of developing rheumatoid arthritis. Important examples include:
• Female sex
• Middle age
• Family history of rheumatoid arthritis
• Certain HLA genetic variants
• Tobacco smoking
• Obesity
• Prolonged exposure to industrial pollutants
• Certain other autoimmune diseases
• Alterations in the oral and intestinal microbiome
In recent years, the role of disturbances in the composition of the microbiome has received considerable attention as a potential factor influencing the initiation of abnormal immune responses.
Signs and Symptoms
The severity of symptoms varies considerably among patients and may fluctuate over time.
Articular Symptoms
Common joint manifestations include:
• Joint pain
• Joint swelling
• Increased joint warmth
• Restricted range of motion
• Prolonged morning stiffness
Joint involvement is typically symmetrical.
Commonly Affected Joints
The joints most frequently affected include the finger joints, wrists, metatarsophalangeal joints, and ankles. However, the knees, shoulders, elbows, and other joints may also become involved.
To be continued…
