RA Pathophysiology - Postlethwaite/Gupta Flashcards
RA defined as? Hit me with them buzzwords
Chronic systemic autoimmune disease most associated with joint inflammation
Joints commonly involved in RA? distribution of these joint involvement?
peripheral joints in a symmetrical distribution
Epidemiology of RA:
Geographic Distribution?
Age range?
Prevalence in North America?
Prevalence/Age relationship?
Genetic role?
Sex?
Lifespan?
Mr. Worldwide distribution
30-50 years old
1% Prevalence in NA
Prevalence increases with age
Genetic predisposition and familial aggregation confirmed
Women 3x more common than men
Increased mortality, Women - decreases lifespan by 10 years, Men - by 4 years
RA only affects joints, right?
No, multi system means multi system, not just joints
What genetic marker is RA MOST associated with? What other genetic polymorphism is associated with RA?
- HLA-DR4 (aka HLA-DRB1) - 30% genetic risk
- PTPN22 - 5% genetic risk
Describe the role of HLA-DR4 in the pathogenesis of RA?
Antigen presenting cells have HLA-DR4 on them. They will present Type II collagen (the antigen in this case) to auto reactive T cells. As a result, these auto reactive T cells attack the body’s own collagen.
What are rheumatoid factors? In RA, what is the most common rheumatoid factor?
Rheumatoid factors = antibodies directed against the Fc portion of IgG
Usually IgM type, IgG and IgA have been described
What 2 other antibodies are associated with RA?
Anti-CCP antibody, Antinuclear antibodies (ANA)
Describe the relationship b/t evidence of autoimmunity and RA?
Evidence of autoimmunity can be present in RA many years before the onset of clinical arthritis
In RA, autoantibodies can recognize what 2 types of antigens? (vague question)
Autoantibodies can recognize JOINT antigens, such as type II collagen, or SYSTEMIC antigens, such as glucose phosphate isomerase
Complement involvement in inflammation seen in RA? What complements are involved
- Autoantibodies (such as RF) + IgG = immune complexes (IC).
- IC activate complement system, producing C3a and C5a, pulls neutrophils & leukocytes into the joint space, leading to inflammation.
- Rheumatic joint will also have decreased CH50, C3, and C4
Low or high levels of T cell cytokines are present in RA synovium? What T cell cytokines are present? Whats their role?
Low levels of cytokines
IFN-gamma and IL-17 are produced, can activate macrophages within the synovium
Regulatory T cell and its relationship with RA?
Low levels of regulatory T cells (FOXP3, CD24) in RA synovium, not enough to down regulate T cell cytokines.
What cells/cytokines are abundant in the RA synovium? (vague question…i know)
Macrophage and fibroblast cytokines
What cytokines are associated with macrophages and fibroblasts? Whats their role
IL-1, TNFalpha, IL-6, & IL-8 are the big ones.
Others include IL-15, IL-18, GM-CSF, and IL-33.
These cytokines recruit inflammatory cells into the synovial joint, causing further inflammation and pannus formation (that eats into cartilage).
What 2 anti-inflammatory cytokines are associated with RA? Are they effective?
IL-1 receptor antagonists & IL-10 are produced in rheumatoid synovium; however, too few to suppress pro inflammatory cytokines.
Does RA cause destruction of the bone?
Yes
Walk me through how RA starts to destroy bone as well.
- Following the cytokine storm (IL-1, IL-6, IL-8, TNF-alpha), pannus formation starts in the periphery of synovium
- Pannus eventually starts eating into cartilage (chondrocytes)
- Osteoclasts get stimulated, causing bone resorption
- Fibroblasts and macrophages produce MMPS that further erode bone.
What prostaglandin is seen in RA synovial fluid during inflammation? Role?
PGE2 and leukotrienes too. cause vasodilatation and pain of joint.
NSAIDs are great at attacking this
Anti CCPs produced by what cells? What are they predictive of in RA?
- Produced by synovial tissue B cells (can be detected in synovial fluid)
- Predictors of more aggressive RA marked by bone and cartilage destruction
What are some systemic features of RA? What is a fact you should know about all these features?
Fatigue, anorexia, weight loss, weakness, generalized aching and stiffness, low grade fever
- can appear before disease has been diagnosed, and are commonly worse with disease flares
Does RA migrate to other joints?
No, usually involves a joint (symmetrically) and stays there
Features of morning stiffness (…of the joint) in RA?
Lasts AT LEAST 30 minutes, and may persist for several hours
As compared to OA that would only last for AT MOST 20-30 minutes
Since this is a inflammatory disease, what superficial skin findings would you observe around an RA joint? (Cant spoon feed this one any better)
Swelling, warmth, and erythema around joint
Synovial fluid of RA will have what 3 features
- exudative yellow fluid
- Increased # WBCs
- Decreased viscosity (b/c hyaluronic acid is destroyed)
Joint involvement: Symmetrical or asymmetrical? Most characteristic pattern of joint involvement?
Symmetrical
wrist and proximal hand joint involvement
What joint(s) are not involved in RA (distinguishing it from OA)
No DIP involvement
No lumbar spine involvement
What joint in the head is involved in RA?
temporomandibular joint
RA patient starts complaining of neck pain. Why? Is this an early or later stage of RA? Risks associated?
- Cervical spine involved. C1 “slips” relative to C2.
- Damage usually occurs after several years of disease
- Risk of spinal cord compression (sensory loss to sudden death)
4 hand deformities associated in RA? Name them and what bones associated with.
Wrist: Volar subluxation with radial ward rotation
MCP joints: Ulnar deviation
PIP and DIP joints: Swan neck and Boutonniere deformities
List common sites of extra-articular involvement seen with RA?
Skin, eyes, mouth, CV, Lungs, Neurologic
What skin probs are seen in RA?
- Rheumatoid nodules
- Vasculitis
What eye/mouth probs are see in RA?
- Keratoconjunctivitis sicca - “dry eyes”
- Xerostomia - “dry mouth”
- Episcleritis and scleritis
What lung probs are seen in RA? Which is “HUGEEEE”
- Interstitial fibrosis
- Pulmonary nodules
- Pleuritis with Pleural Effusion (Mr. Monotone said these are HUGEEEE)
What cardiac probs are seen in RA?
- Pericarditis (common but largely asymptomatic)
- Valve nodules
What neurologic probs are seen in RA?
- Cervical myelopathy
- Compressive peripheral neuropathy (carpal tunnel, ulnar tunnel)
Immune complexes of RA manifest as chronic ____?
polyarticular arthritis
Path question. Except for the acute stage, what cells are not generally present in RA? What cells are?
Acute stage - Neutrophils + mononuclear cells
Chronic - mononuclear cells (plasma cells and lymphocytes)
If you see neutrophils, what stage of RA are you in?
Acute stage. I just said this.
Path. Earliest changes of RA include? Proliferation of what cells?
hyperemia of synovium with proliferation of synovial lining cells with infiltration by plasma cells and lymphocytes
Path. Describe synovial villi.
Hyperplastic synovial villi eroding and replacing cartilage at the joint margin
Path. Following synovial villi hypertrophy, what characteristic cells develop (think similar to lymph nodes)
- Multinucleated giant cells underlying the synovial lining begin to develop
- Eventual formation of germinal centers
Path. In synovium, after multinucleated cells/germinal centers develop, what gets deposited?
Fibrin deposition and fibrinoid change
Necrosis can be present as well.
Path. What is a pannus?
Pannus occurs when synovial inflammatory and granulation tissue adjacent to the margin of the joint begins to cover and adhere to the cartilage as a membrane
- The articular cartilage under the pannus undergoes degradation and disappears, beginning at the joint margin and extending centrally
What characteristic feature regarding joint mobility is different between OA and RA?
Fibrous ankylosis (fusion) of the joint occurs in RA (after pannus formation and destruction by MMPs/osteoclasts,etc)
OA - is NOT associated with ankylosis of the joint
Path. Most common extra-articular manifestation of RA? What organ? Where in the organ?
Rheumatoid nodules (found in 25% of RA patients)
Skin
usually over bony prominence, like the elbow
Path. Histologically describe a rheumatoid nodule?
Granulomatous lesion consisting of:
- a central zone of collagen necrosis and fibrinoid change
- Middle zone of epitheliod cells and macrophages
- Outer zone of granulation tissue infiltrated by lymphocytes, plasma cells and macrophages
Triad seen in Felty’s Syndrome?
RA
Palpable Splenomegaly
Manifestations of hypersplenism (such as leukopenia)
Fun fact. Splenomegaly and its relation to a blood component?
Platelets will get sequestered in the spleen. Large ass spleen = platelets in between
