Question

John D'Souza is an 83-year-old who BIBA from the GP suffering a pre-syncopal episode while being examined. He presented with increasing malaise and painful and swollen knee. He has a history of rheumatoid arthritis since he was 18 years old. On examination he has:

Right knee very, swollen, hot, red and painful (pain score on movement 8/10 on NPRS)

limited range of motion of right knee

temperature 38.7degrees Celsius

respiratory rate 22bpm

blood pressure 90/50mmHg

Heart rate 120bpm

deformities of the proximal interphalangeal joints and metacarpophalangeal joints and wrists on both hands

A provisional diagnosis of septic arthritis of the Right knee is made.

Explain the pathogenesis causing the clinical manifestations with which Mr D'Souza presented.

I NEED 1000 WORDS FOR PATHOGENESIS.

Answer 1

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease whose hallmark feature is a persistent symmetric polyarthritis (synovitis) that affects the hands and feet. It involves the joint lined with a synovial membrane, however extra-articular involvement of organs such as the skin, heart, lungs, and eyes can be significant.

RA is theorized to develop when a genetically susceptible individual experiences an external trigger (eg, cigarette smoking, infection, or trauma) that triggers an autoimmune reaction.

Signs and symptoms of RA may include the following:

• Persistent symmetric polyarthritis (synovitis) of hands and feet (hallmark feature)

• Progressive articular deterioration

• Extra-articular involvement

• Difficulty performing activities of daily living (ADLs)

• Constitutional symptoms

Histopathology

a.) Synovium

The synovium, in normal joints, is a thin delicate lining that serves several important functions. The synovium serves as an important source of nutrients for cartilage since cartilage itself is avascular. In addition, synovial cells synthesize joint lubricants such as hyaluronic acid, as well as collagens and fibronectin that constitute the structural framework of the synovial interstitium.

1. Synovial lining or intimal layer: Normally, this layer is only 1-3 cells thick. In RA, this lining is greatly hypertrophied (8-10 cells thick). Primary cell populations in this layer are fibroblasts and macrophages.

2. Subintimal area of synovium: This is where the synovial blood vessels are located; this area normally has very few cells. In RA, however, the subintimal area is heavily infiltrated with inflammatory cells, including T and B lymphocytes, macrophages, mast cells, and mononuclear cells that differentiate into multinucleated osteoclasts. The intense cellular infiltrate is accompanied by new blood vessel growth (angiogenesis). In RA, the hypertrophied synovium (also called pannus) invades and erodes contiguous cartilage and bone. As such, it can be thought of as a tumor-like tissue, although mitotic figures are rare and, of course, metastasis does not occur.

Increase in synovial fluid leads to Swollen joint.

b.) Cartilage

Composed primarily of type II collagen and proteoglycans, this is normally a very resilient tissue that absorbs considerable impact and stress. In RA, its integrity, resilience and water content are all impaired. This appears to be due to elaboration of proteolytic enzymes (collagenase, stromelysin) both by synovial lining cells and by chondrocytes themselves. Cytokines including IL1 and TNF drive the generation of reactive oxygen and nitrogen species and while increasing chondrocyte catabolic pathways and matrix destruction, also inhibit new cartilage formation. Polymorphonuclear leukocytes in the synovial fluid may also contribute to this degradative process.

c.) Bone

Composed primarily of type I collagen, bony destruction is a characteristic of RA. This process is primarily driven by the activation of osteoclasts. Osteoclasts differentiate under the influence of cytokines especially the interaction of RANK with its ligand. The expression of these are driven by cytokines including TNF and IL1, as well as other cytokines including IL-17. There may also be a contribution to bony destruction from mediators derived from activated synovial cells.

Due to the bony destruction and release of Various cytokines there is Redness and Tenderness in the Joint.

d.) Synovial Cavity

The synovial cavity is normally only a “potential” space with 1-2ml of highly viscous (due to hyaluronic acid) fluid with few cells. In RA, large collections of fluid (“effusions”) occur which are, in effect, filtrates of plasma (and, therefore, exudative – i.e., high protein content). The synovial fluid is highly inflammatory. However, unlike the rheumatoid synovial tissue in which the infiltrating cells are lymphocytes and macrophages but not neutrophils, in synovial fluid the predominant cell is the neutrophil.

e.) Genetic Susceptibilities

There is an association of RA with class II major histocompatability (MHC) antigens, specifically the shared epitope found in HLA-DR4.   Class II MHC on the surface of an antigen presenting cell interacts with a T cell receptor in the context of a specific antigen, usually a small peptide sequence from a protein. A sequence of amino acid residues with highly conserved sequence and charge characteristics within the hypervariable region of HLA-DR4 remains the largest genetic risk factor described for RA, estimated to contribute approximately 30% of the genetic risk for the disease.