Rheumatoid arthritis pathophysiology

Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with which genetic factors, environmental factors, and microorganisms contribute, resulting in the inflammation and destruction of the synovial membrane. These factors lead to citrullination or post-translational modifications, resulting in the production of altered peptides. The altered peptides bind to MHC protein with shared epitopes which further leads to antigen presentation to T-cells. T-cells further stimulate B-cells and cytokines which results in cartilage damage. Mutation of human leukocyte antigen (HLA) genes on chromosome 6 is involved in pathogenesis of rheumatoid arthritis. Various conditions associated with RA include vasculitis, uveitis, scleritis, peripheral ulcerative keratitis, interstitial fibrosis, pulmonary nodules, bronchiolitis obliterans, organizing pneumonia, venous thromboembolism, pericarditis, myocarditis, congestive heart failure, atrial fibrillation, sjogren’s syndrome, and felty’s syndrome.

Rheumatoid arthritis is mediated by the combination of a predisposing genotype along with genetic factors, environmental factors, and microorganisms, resulting in the inflammation and destruction of the synovial membrane.

Various factors involved are:

Environmental factors:

• Environmental factors lead to repeated activation of innate immunity at mucosal surfaces.

• Smoking effects the genes to increase susceptibility up to 20 to 40 fold.
  • Smoking causes increased expression of peptidyl arginine deiminase (PAD) in alveolar macrophages.
  • Peptidyl arginine deiminase converts arginine to citrulline, the process is known as citrullination, in the airway which further creates neoantigens that can be recognized by the adaptive immune system.^[1][2]

Genetic factors:

• Genetics factors such as human leukocyte antigen (HLA)-DR.
• These genes are involved in inducing immune response, matrix regulation, and inflammation.^[3]

Microrganisms:

• In periodontal disease, P. gingivalis is commonly found, it also expresses peptidyl arginine deiminases.
• This can lead to citrullination and thereby promotes anti-citrullinated protein antibodies (ACPA)
• A. actinomycetemcomitans produces a toxin that increases calcium influx into neutrophils which further leads to citrullination of peptides and promotes APCA.

• All the above factors lead to citrullination or post-translational modifications.
• The altered peptides bind to MHC protein with shared epitopes which further leads to antigen presentation to T-cells.
• T cells further stimulate B cells to produce a range of antibodies that recognize self-proteins, including rheumatoid factors and anti-citrullinated protein antibodies (ACPAs).
• Fibroblast-like synoviocytes, antigen presenting cells (APCs), and macrophages are activated locally and produce various inflammatory factors.
• The autoimmune response causes synovial inflammation resulting in immune complex formation and complement activation, leading to an increase in cytokine production and synovial vascular leakage.
• Cytokines lead to bone and cartilage destruction.

• The development of rheumatoid arthritis is the result of mutation of human leukocyte antigen (HLA) genes on chromosome 6.^[4][5]

Conditions associated with rheumatoid arthritis include:^[6][7]

• Osteopenia
• Myositis
• Vasculitis
• Uveitis
• Scleritis
• Peripheral ulcerative keratitis
• Interstitial fibrosis
• Pulmonary nodules
• Bronchiolitis obliterans
• Organizing pneumonia
• Venous thromboembolism
• Pericarditis
• Myocarditis
• Congestive heart failure
• Atrial fibrillation
• Sjogren’s syndrome
• Felty’s syndrome

On gross pathology of rheumatoid arthritis the following features may be noticed:^[8]

• Irregular surface, seen due to synovial hyperplasia.
• Subchondral cysts, usually present at the later stage of the disease.

On microscopic histopathological analysis:^[9][10]

• The earliest finding is the formation of the new synovial blood vessels.
• Hypertrophy of synovial lining layer and infiltration of mononuclear cells may be observed.
• Chronic inflammation with lymphocytic infiltration may be seen.
• There is pannus formation which consists of fibrovascular tissue or granulation tissue.

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