Rheumatoid Arthritis Flashcards
What is RA?
1) Autoimmune disease
2) multifactorial
3) chronic systemic
4) inflammatory disease mostly affect peripheral small joint in a symmetrical manner
What are the unique changes in joints of RA patients?
1- Radial deviation of the wrists
2- Ulnar deviation of the fingers
3- Swan neck deformity: hyperextension of PIP and flexion of DIP joints
4- Boutonnier deformity: flexion of PIP and extension of DIP joints
RA is characterized by what?
Proliferative synovitis > Pannus that causes: 1- Destruction of articular cartilage 2- Ankylosis (fusion) of joint 3- Joint deformity & disability
What are SF findings in RA?
1) Gross: Yellow white
2) WBC count: 2000-100,000 cells / mm3
3) Neutrophils: >50% of the total count.
4) Crystals : absent
Population affected in RA
Females , 30-50 years of age
What are the manifestations of RA?
1) Articular manifestations:
- Changes in joints
2) Extra-articular manifestations: circulating immune complexes
- Changes in skin
- Changes in blood vessels
- Changes in other tissues and organs
Describe stiffness in RA
As a result of overnight rest of the joint this will result in deposition of water in the periarticular area > edema > as a result of movement after waking up the accumulated fluid overnight will go back into vessels which is known as Reverse Third Spacing & this will improve the morning stiffness
Human Leukocyte Antigens involved in RA
HLA-DR4/DR1
What triggers RA?
Smoking
Genetics
RA autoantibodies (RF & ACPA) are against which antigens?
Citrullinated proteins (Autoantigens)
What is citrullination and what is the process called?
Normal physiologic process. A “post-translational modification” of A.A arginine to neutral citrulline which alters the structure of a protein
Explain Citrullination in RA
In RA, patients shows an exaggerated response to citrullinated proteins as foreign bodies
What does citrullination mean to the cell?
A process related with apoptosis & terminal differentiation of cells
What proteins that are normally citrullinated?
- Keratin
- Basic myelin protein of CNS
- Triton hyaline of hair follicle
Citrullination is catalyzed by which enzyme?
calcium-dependent enzyme PAD
In RA, PAD can be secreted by which cells?
granulocyte & macrophage
ACPA occurs as a result of an abnormal antibody response to a range of citrullinated proteins which are?
- Fibrin
- Vimentin
- Fibronectin
- Epstein-Barr Nuclear Antigen 1
- α-enolase
- Type II collage
- Histones
When there is immune complex deposition, it is what kind of necrosis?
Fibrinoid necrosis
What are the pathologic joint changes in RA?
1) Chronic synovitis (proliferative synovitis)
2) Pannus formation
3) Fibrous and bony ankylosis (joint fusion)
4) Development of Joint deformities
Discuss joint pathology in RA & what happens as a result
1) Synovium is 1/2 layer in thickness. In RA there is proliferation of the synovium > proliferative synovitis > more inflammation > Lymphocytes, Plasma cells, Mast cells & eventually Neutrophils & Macrophages in the synovial membrane.
2) This proliferation of the synovium leads to loss of space & can’t grow anymore & the only way to be accumulated in small joints is to twist and turn on itself creating a finger-like projection > Pannus
3) Also there will be influx of inflammatory cells to the site of action & will be organized in a pseudo-lymphoid follicles.
4) RANKL on surface of CD4+ T cells will get detached under the effect of MMPs > activate osteoclasts > resorb subchondral bone > bony erosion
Result:
1) Due to many layers of the synovial membrane the synovial fluid will be blocked from the articular cartilage leading to death of Chondrocytes
2) M1 Macrophages that promotes inflammation will be dominant than the anti-inflammatory M2 macrophages. So, ratio will be high > activating the osteoclasts > Osteoclastogenesis
What is the source of Nutritional supply to the articular cartilage?
Synovial Fluid
What does pannus lead to?
1) It extends over the articular surface and causes erosion of : Articular cartilage and Subarticular bone
2) Undergoes fibrosis and calcification to cause
fibrous ankylosis which ossifies > bony ankylosis (joint fusion)
What cause Joint deformities?
Due to destruction of tendons, ligaments and joint capsule
What is the cause of Fatigue, Weight loss, Low-grade fever in RA?
Due to release of IL-1 and TNF from macrophages (in the joint) into circulation
What Changes in SKIN of RA patient?
Rheumatoid nodules (most common lesion)
What are Rheumatoid nodules & how do they look?
- Fibrinoid necrosis, surrounded by epithelioid/palisading histiocytes, plasma cells and lymphocytes
- Firm, nontender and round to oval
Where are Rheumatoid nodule located?
forearm elbow lungs spleen heart
What is an associated condition with RA?
Sjogren’s syndrome
What is Sjogren’s syndrome?
Autoimmune destruction of lacrimal and minor salivary glands
What are the Clinical findings of Sjogren’s syndrome?
- Keratoconjunctivitis Sicca
- Xerostomia
What is RF?
An IgM auto-antibody that targets the Fc portion of IgG
State Laboratory Findings in RA
Elevated ESR
Positive rheumatoid factor (70%)
ACPA (high specificity, 97%)
What are the radiographic findings in RA?
- Erosions at articular surface
- Narrow joint space
- Fusion of joints (ankylosis)
- Joint deformity
Explain Pathogenesis of RA briefly
Autoimmune reaction results in:
1) Activation of CD4+ T cells
2) Release of chemical mediators (IL-1 and TNF)
3) Formation of autoantibodies (RF and ACPA)
These cause joint changes and extraarticular manifestations
Detailed Explaination of RA Pathogenesis
1) Injury > Influx of CD4 T cells/macrophages into synovial tissue > Local stimulation of B cells to produce IgM autoantibodies directed against Fc receptor of IgG (RF) and against citrullinated antibodies
2) Formation of immune-complexes that activate the complement system > Production of C5a > Chemotaxis of neutrophils into joint space > Neutrophils produce acute inflammation of synovial tissue causing > Joint injury
3) Phagocytosis of immune-complexes produces Ragocytes > Release of inflammatory mediators by macrophages (IL-1, TNF alpha) > Induce synovial cells to release inflammatory mediators that destroy connective tissue, cartilage and bone > Chronically inflammed synovial tissue begins to proliferate (forms a pannus)
4) Pannus obstructs diffusion of SF to the hyaline cartilage
5) RANK L is released from CD4+ T cells and activate the osteoclasts > Destruction of joint from within, from above and from below
6) Pannus undergo fibrosis > contracture of the joint.
7) Then dystrophic calcification will result in fusion of the joint (ankylosis)
