Rheumatoid Arthritis Flashcards
What is the hallmark of RA?
Persistent inflammatory Synovitis that usually involves peripheral joints in a symmetrical distribution. This synovitis has a propensity to erode cartilage and bone as well as reduce joint integrity.
T or F: the course of RA is variable and is likely influenced by genetics and environmental factors with some patients experiencing only mild oligoarticular disease with minimal joint damage while other patients have progressive arthritis that can result if not appropriately treated to marked functional impairment.
True.
Is any one ethnic or age group predisposed to RA?
• if so who?
RA is distributed worldwide across all ethnic groups with a peak incidence ranging from the mid 30s to 50s.
What are your chances of getting RA as you get older?
• who gets RA most commonly?
• what is the disease prevalence?
RA is most common in females (30-50) with an increased incidence with age. This disease is about 1/100 in the U.S.
T or F: RA is a disease of increased morbidity, but not increased mortality.
False, RA is associated with increased mortality - the mortality rates are about 2x as high as the general population
Which HLA type has the greatest association with RA?
• is there any increased risk if you are homozygous for this HLA type?
HLA-DRB1 or HLA-DR4 is associated with RA. People who have 2 copies have increased risk of getting the disease and the disease they get is typically more severe.
what is HLA-DR4 and what is the role of HLA-DR4 in the pathogensis of RA?
• 4 important points
HLA-DR4 is an MHC type II protein that binds and presents peptide it is known that HLA-DR4 1binds arthritogenic peptides (like type II collagen epitopes) and presents them to T-cells or it may 2present sequences that mimic arthritogenic peptides. There may also be 3direct interaction between DR4 shared epitope and the T cell receptor. 4Thymus should select against these T-cells, but it doesn’t.
What is the role of genetics and environment on development of RA?
• what environmental factors are important in the pathogenesis of RA?
- Genetic Risk Factor (HLA-DR4) are 60%
2. 40% is environment
***Smoking is a huge environmental risk factor. Its known to induce the formation of a PAD4 (protein-arginine deaminase) enzyme that turns arginine to citrulline (a non-endogenous molecule) this leads to the formation of citrullinated peptides that our immune system recognizes as foreign.
***Gengivits is also known to upregulate PAD4
What is Rheumatoid Factor?
Rheumatoid Factor = antibodies directed aginst the Fc portion of IgG (typically this is IgM but could also be IgG or IgA)
Is Rheumatoid Factor specific to RA?
NOOO, RhF is upregulated in a number of diseases (Sjorgren, Mixed CT, cyroglobulinemia, SLE, Polymyositis, Dermatomyositis).
• Its also present at low levels in the normal population
In what Non-autoimmune disorders is RhF often seen in?
- Chronic Infection - Bacterial Endocarditis
- Hepatitis B/C
- Pulmonary Fibrosis, Sarcoidosis
- Malignancy (B-cell lymphomas)
- Primary Biliary Cirrhosis
What is the most specific antibody you can look for in a patient with RA?
• what is another besides RhF ?
Anti-CCP (cyclic citrullinated peptide) antibodies are the most specific
• ANAs may be seen
Do all people that present with Rheumatoid Arthritis + ANAs have Rheupus?
No, a small portion does, BUT the majority have a milder form of RA
Is there ever evidence of autoimmunity in RA patients before they present with the disease?
Yes, people may have evidence of autoimmunity years before their RA kicks in
T or F: autoanitbodies in RA are specific only to joint antigens
FALSE, they can recognize BOTH joint antigens like type II collagen AND systemic antigens like glucose phosphate isomerase
Note: Antibodies generated in RA may locally activate complement leading to decreased C4, C5, and increased C5a
How does the prognosis for RA differ for people with the seronegative form?
People with seronegative RA tend to experience a more rapid/aggressive disease course and DO NOT respond as well to treatment
What lymphocytes are implicated in the pathogenesis of RA?
• if you biopsied the synovium what cytokines released specifically from these cells would you find and would you find a lot of them?
CD4+ TH1 and TH17 cells are all implicated in the pathogenesis of RA, but if you biopsy the synovium is has relatively little of any of the IFN-gamma or IL-17 secreted from these cells
NOTE: REGULATORY T-cell function that suppresses activation of other T cells may be low in RA synovium
What is the real contribution of T cell to synovial inflammation thought to stem from?
T cell contribution to Synovial inflammation is though to occur through antigen indepedent mechanisms that just involves direct Cell-cell contact with macrophages
If T cell cytokines aren’t high in the synovium, then what cytokines are?
• what are these cytokines?
Macrophage and Fibroblast cytokines are high in the synovium these include:
• IL-1
• TNF-alpha
• IL-6
• IL-15
• IL-18
• GM-CSF
• IL-33
Anti-inflammtory cytokines such ______________ are produced by the __________.
• is production of these enough to hold back inflammation?
Anti-inflammtory cytokines such IL-1Ra and IL-10 are produced by the SYNOVIUM but this NOT ENOUGH to overcome RA inflammation.
What is the number 1 KEY cytokine secreted by macrohpages in RA?
• what does this cytokine do that causes inflammation?
TNF-alpha = key Cytokine => this is secreted by T cells to activate macrophages. Activated Macrophage in turn secrete More TNF-alpha as well as IL-6 and IL-1.
TNF-alpha then acts to increase IL-8, IL-6, and IL-1.
- *• IL-8** works to recruit neutrophils to contribute to inflammation
- *• IL-1** (OAF - osteoclasts activating factor) activates osteoclasts causing OSTEOPENIA in these joints
- *• IL-6** - PGE2 and Fever?
T or F: the pannus actually is partially responsible for eating away the joint capsule.
True, the pannus eats into cartilage
What will you see in joint effusions in an RA patient?
Neutrophils and Mononuclear cells
Do immune complexes play any role in RA?
YES, Rheumatoid Factor and Anticitrullinated protein antibodies can fix complement leading to generation of chemotrattractants (C5a).
What is the main driver of inflammation in RA?
Synovium/Pannus and synovial fluid
Is CRP typically elevated in patients with RA?
Yes
Are APCAs (anti-cyclic citrullinated peptide antibodies) predictive of individuals that will progress to RA?
Yes, indivduals who present with undifferentiated inflammatory arthritis are more likely to progress to RA
T or F: the presence of ACPAs are often present in UNaffected relatives of patients with RA
True 20% of unaffected 1st degree relatives and 10% of distant relatives have APCAs without disease. This could be due to proximity to relatives that smoke.
Does the presence of ACPAs change the prognosis of a patient with suspected RA?
Yes, people with APCAs typically have a more aggressive disease course with more intense bone and cartilage destruction
**Describe the onset of RA**
Patients often experience fatigue, anorexia, weight loss, weaknes, generalized aching and stiffness, and low grade fever (IL-6) at disease onset which occurs over weeks to months. It’s important to note that joint involvment may only be intermittent at onset. Typically on one or a few LARGE joints are involved at onset. These symptoms often get worse with flare-ups.
Is joint involvment migratory in RA?
No, it usually stays in the same joints but may be intermittent at disease onset before developing into a full time polyarthritis.
Differentiate morning stiffness in inflammatory joint diseases vs. non-inflammatory diseases such as osteoarthritis.
In RA and inflammatory arthritis:
• joint stiffness lasts at least 30 minutes and may persist for several hours (because this is inflammatory you often see swelling, warmth, and erythema around the joint)
In non-inflammatory arthritis:
• Joint stiffness is brief and may only last 5-15 minutes
What will the color, cellularity, and viscosity be like in synovial fluid from an RA joint?
Exudate is typically yellow with elevated number of WBCs and reduced viscosity. (due to less hyaluronic acid)
While the PATTERN joint involvement in RA starts off as patchy and may only involve a few large scattered joints like the knees and hips, this pattern differs in established disease. How so?
RA Pattern:
• SYMMETRICAL joint involvement is typical
• WRIST AND PROXIMAL HAND JOINTS (MCPs and PIPs) is the MOST CHARACTERISTIC patten
• Other joints like shoulder, knees, hips, etc also will become involved.
Why should you ask your RA patient if they have a headache at the base of their skull?
• what risks are associated with not asking this question?
- After several years of disease C1 and C2 vertebra which have a SYNOVIUM may fuse.
- Spinal cord compression could cause sensory loss or sudden death
What are some of the consequences of chronic inflammation on the joint cavity?
Other than presence of inflammation, why might the muscles of someone with RA atrophy?
What deformities occur in RA as a result of muscular traction?
What complication of RA is shown here?
Swan neck deformity
Where do flexion contractures typically occur?
Larger Peripheral Joints like the knee, hip, and elbow
Notice the loss of the styloid in A and the reduced joint space in all the picture. In E the acetabulum is bulging into the pelvis, this can be painful as well as debilitating.
Where are Rheumatoid Nodules usually located?
• are these present in the majority of patients?
Rheumatoid Nodules are usually on EXTENSOR surfaces like the Olecranon or Proximal Ulna, but they can also occur on pleura, meninges, or ears.
How does vasculitis in RA present?
RA vasculitis is typically characterized by small vessel inflammatino palpable purpura or skin ulceration
Palpable Pupura
• do these blanch?
NO- palpable purpura do not blanch
What eye and mouth involvment do we see in RA?
Sjorgren’s-like symptoms
• Keratoconjunctivitis sicca (dry eyes) may result from lymphocytes infiltrating lacrimal glands
• Xerostomia (dry mouth) may be caused by lymphocytic infiltration of salivary glands
In severe cases Episcleritis or Scleritis may occur causing scleral erosion
What cardiac and respiratory involement is often present in RA?
What Neurologic Complications are associated with RA?
What does normal synovium look like?
What features do you expect to see in the synovium in the early stages of RA?
- Hyperemia
- Proliferation of the Synovial Lining Cells
- Infiltration of Plasma Cells and Lymphocytes
Compare these top images to the norm on bottom
Describe what causes the following in this synovium shown:
• The cinnamon color
• Pulmp Papillae
• White Nodules
Cinnamon color is the result of posthemorrhagic hemosiderin deposits
Plump papillae are from the cellular overgrowth of the synovium and lymphoid infiltration
White nodules are fibrin from exudation in inflammed tissue
What is this?
What is shown here?
Multinucleated Giant cells underlying synovial surface in RA
What do you expect to see in this effusion (synovial fluid aspirate) from RA?
Neutrophils and mononuclear infiltrate
What is this?
RHEUMATOID NODULES
What is shown here?
What is shown here?
A pannus overlaying cartilage
Bones may fuse via fibrous ankylosis with the pannus as a linker or the pannus may destroy so much bone that a new bone to bone connection is made at the loss of a joint (bony ankylosis). Which is shown here?
Fibrous Ankylosis
what are the 3 zones of a rheumatoid nodule?
- Central zone = collagen necrosis and fibrinoid change
2. Middle zone - epitheliod cells and macrophage
3. Outer zone - granulation tissue infiltrated by lymphocytes, plasma cells, and macrophages
What’s this?
Rheumatoid Nodule
