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Rheumatoid Arthritis Flashcards

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1
Q

What is the best serologic test for rheumatoid arthritis?

A

ACPA (Anti-citrullinated protein antibody)

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2
Q

What does ACPA target?

A

citrullination of arginine - post translational modification

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3
Q

How does it compare to R-factor?

A

Same sensitivity but more specific because ACPA is only seen in RA.

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4
Q

Why is RF not specific?

A

Seen in other autoimmune diseases - both nonRA and non-rheumatic diseases like hepatitis, TB, endocarditis and chronic lung disease.

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5
Q

Why is ACPA predictive of the presence of a shared epitope?

A

RA will manifest some extra articular symptoms because the auto antibodies will target other tissues that share the same epitope.

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6
Q

What is the prognosis of seropositive (ACPA) RA patients?

A

They have worse outcomes and undergo disease progression, while seronegatives usually remit or never develop full blown RA.

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7
Q

What is the difference in seropositive findings in early, established and refractory RA?

A

Early (with less than 6months of symptoms): 50-50 on serum positivity. Established RA (2yrs of Sx) 75-25. Refractory RA 85-15.
A patients with severe RA is almost definitely seropositive.

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8
Q

What are the two variants of RA?

A

Articular disease (women>men 4:1, synovial inflammation, seropositive and seronegative, strong HLA-DR4 linkage) and Extra-articular disease (men>women, primarily immune complex mediated, RF dependent)

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9
Q

What is the beginning of the natural history of RA?

A

tolerance broken-ACPA receptor (adaptive immune response with B cells making high affinity antibodies to ACPA)

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10
Q

What is the overall natural history?

A

Tolerance broken –> Amplification –> Joint targeting –> tissue injury

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11
Q

How does the amplification vary with age?

A

Young and start making ACPA antibodies –> transition to having clinic disease is much shorter than if you are older.

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12
Q

Characteristics of Early RA?

A

Less than 6 months Sx, 50-50 seropositivity
Cannot tell the difference unless there are interstitial crackles in lungs and nodules –> only occur if you have a positive blood test.

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13
Q

What are the two findings specific for seropositive?

A

crackles in lungs and nodules –> only occur if you have a positive blood test.

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14
Q

Most common cause of death in RA patients?

A

heart disease –> chronic inflammation may be the major diver of atherosclerosis in HD

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15
Q

What is established and Refractory RA?

A

Established = have disease for up to 2 years. Half of the seronegatives remit, never to recur.
Refractory: 80-85% seropositive and 15-20% seronegative.

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16
Q

What if the average age of onset of RA?

A

About 50years. Present in about 0.1-1% of the world’s population. More common northern european because of the genetics of where the 5amino acids are found.

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17
Q

How does extra-articular disease compare between seropositives and seronegatives?

A

Morbidity, mortality,, extra-articular disease is more in positives than negatives.

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18
Q

Why is HLA 2 associated with autoimmune diseases?

A 
HLA2 interacts with CD4+ cells.
But class 2 is not that involved in the progression of the disease.
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19
Q

What confers the risk for RA?

A

5 amino acids in HLA-DR4 beta chain.

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20
Q

What do the 5 amino acids on the HLR-beta chain do?

A

Forms a complex on which B2 microglobulin can bind. Everyone has the same alpha chain. We have different beta chains.

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21
Q

What is the twin concordance?

A

10-30%

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22
Q

How are Psoriatic and Ankylosing, Reactive Arthritis difference from RA?

A

Disease driven by CD8+ T-cells which have HLA-a,B,C and beta 2 microglobulin

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23
Q

What are HLA classes A, B, C not associated with?

A

Increase risk of rheumatoid arthritis.
HLA-B27 –> protects you from infection. Decreased risk of developing AIDS after HIV infection and; risk of neonatal transmission of HIV.

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24
Q

What enzyme citrullinates?

A

Peptidylarginine deiminase (PADI)

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25
What do Antibodies detect in RA?
They recognize not the specific protein but a post-translational modification to arginine that happens in numerous proteins
26
What factors increase the risk of ACPA-RA?
1. Smoking - 5 fold relative risk increase. This is why people think it starts in the lung because it starts with the chronic bronchitis that starts with smoking. 2. Female gender: men rare under 45, have to have more genetic and environmental triggers RF, SE and ACPA+ and smoking history. Females will not have it between menarche and menopause.
27
How does the current idea about RA of pathogenesis of RA differ from old ideas?
Original old model --> T cell targets joint because of mis-recognition resulting in autoimmunity and damage. New Model --> ACPA induction immune complex deposition.
28
What important questions would you ask in a patient history?
Prior history and family history. Location of the pain. Character of the painful area=stiff, better or worse with use, tempo of onset. Onset=worse in the morning/evening; any night pain? Is it one or more joints? Is it symmetric? Does the joint complaint limit function? Are there global, constitutional sx?
29
How does Osteoarthritis usually present?
- OA of hands begins typically in dips, progressing to pips, sometimes, but usually not with swelling. - Strong family hx, 80-90% have affected mother. 15% concordance in sons. - Predicts OA in first CMC joint, which can present first.
30
Describe the Onset of RA?
Abrupt to insidious; +PMR variant
31
What are typical symptoms?
Symmetric joint stiffness/pain improving with exercise, worsening with rest, morning worst. hands feel weak/clumsy
32
What are the usual sites affected by RA?
MCPs, PIPs, Wrists/MTPs
33
What constitutional symptoms accompany RA?
Fatigue
34
What is histological findings correlate with what is found on physical exam of RA?
- Destruction is centered in synovium, destroying all around it. - On histology, you see a lot of inflammation underneath the synovium
35
What would make you suspect OA?
If you see DIP involvement?
36
What data exists on the physical exam?
Lateral MCP or MTP squeeze. Scored 1-4 for each limb
37
What do you need to know of physical exam?
Since hands are targeted by RA, be aware of: 1) A wince when you shake hands 2) inability to oppose distal pulp space to base of digit (claw maneuver) ... indicates mcp, pip or flexor tendon inflammation.
38
What sensitivity and specificity is present on physical exam on squeezing hands?
``` 1-87% (58%) 2-81% (68%) 3-67% (84%) 4-51% (89%) sensitivity (specificity) ```
39
What is the use of the tuck and claw test?
Tuck and claw test --> if you can do it, you cannot have RA. This is not specific when you have OA. The classic RA does not have pain when they make a fist.
40
What is the importance of the ACPA test?
ACPA does not disappear with remission. Tightly connected to the shared epitope and RF. Good for their specificity and prediction of poor outcomes.
41
Why is ACPA best serologic marker for RA?
Stable, predictor of bad outcomes, marker for shared epitopes, sensitivity equal to RF, high correlation with RF, higher specificity that RF, positive at diagnosis or earlier.
42
Do you need testing to make the diagnosis of RA?
No, focus on the hands --> pain, joint deformities plus the tuck and claw test.
43
What are the main principles in management of RA?
1. early aggressive therapy = better because damage occurs early - worst in the first year. 2. any DMARD (disease modifying anti-rheumatic drug) in first year is better than placebo 3. early intervention with a single DMARD is as good as late intervention with multiple drugs
44
What are some choices of DMARDs?
``` Prednisone Hydroxychloroquine (not if patient has eye disease) MTX (not if drinker, trying to conceive) Lefluonomide/SSZ/Tofacitinib TNF, IL-6R (cytokine antagonists) Rituximab (anti-CD20) CTLA-4 Ig --> Early use MTX typical + NSAID and Aspirin ```
45
Describe the importance of peptide restriction of autoantibody formation.
ACPA confer a risk for RA - How do you make ACPA Antibodies --> If you have the HLA-DRB1 selectively have citrullinated proteins preferred binding. So those immune cells recognizing that more. Also happens in other disease like those involving orexin etc.
46
Describe the cytokines that are important in RA pathogenesis?
TNF and IL-6
47
When we treat RA, what are we trying to prevent?
Prevent destruction or erosion of the joint.
48
What are the pathological findings in RA?
1. inflammation or synovium with increase in phagocytosis and synovial cell proliferation. 2. The synovium slowly turns into lymphoid tissue 3. Joint destruction
49
What is involved in the pathological step of step 1: inflammation of synovium?
Inflammation of Synovium --> this process continues even after CD4 cells are destroyed e.g. AIDS suggesting a circulating agent like ACPA that fixes complement
50
What are some lifestyle changes you can make that can have a good effect on RA?
Stopping smoking and weight loss have good benefit
51
Extra-articular RA predominantly occurs in?
Seropositive RA | Remember, Smokers with RA can be seronegative
52
Mechanisms of extra-articular
1. immune complex deposition leading to vascular compromise or inflammation 2. synovial compression or surrounding structures (e.g. nerves) 3. unknown: ILD
53
RA mechanism pathology step 2: Synovium slowly turns into lymphoid tissue
Neovascularization and infiltration by lymphocytes - CD4+ cells, plasma cells along with some macrophages (that produce TNF and IL6). Later stages show replacement of mononuclear cells by PMNs
54
Things we worry about in Extra-articular RA?
1. Rheumatoid Nodules (macrophages or monocytes with necrosis in the middle) 2. ILD - nodules often subpleural. Associated with effusions with low glucose. Mechanism of fibrosis is unknown. Nodules can rupture and cause a pleural effusion. 3. carpal tunnel syndrome: synovial compression of surrounding structures like nerves 4. loss of ligamentous integrity - atlantoaxial subluxation nor incredibly rare
55
2010 ACR/EULAR classification criteria for diagnosing RA?
High titer ACPA, Symptom duration great than 6 weeks, Acute phase reactants like ESR, and the number of swollen and tender joints. A score greater than or equal to 6 --> RA
56
What rheumatoid arthritis?
Chronic systemic autoimmune disease.
57
What is the epidemiology of RA?
Onset typically 30-50yrs, occurs 3 times more often in women than men
58
What is the typical presentation of RA?
Patients typically present with: 1. Morning stiffness which improves as the day progresses 2. symmetric involvement of the small joints of the hands 3. Systemic signs and symptoms: fever, fatigue, malaise, pleuritis, anorexia, pericarditis. Affects MCP and PIP but spares DIP
59
How does presentation of osteoarthritis differ from RA?
OA pain is aggravated by use and worsens as the day progresses. OA involved PIP and DIP joints but spares the MCP
60
What is the consequence of involvement of the hands?
Causes: 1. Ulnar deviation of the fingers 2. Bouteniere deformity: extension of PIP and flexion of DIP 3. Swan neck deformity: flexion of PIP and extension of PIP 4. Z-thumb deformity: thumb with fixed flexion and subluxation at the MCP joint, hyperextension of the IP joint
61
What is the result of chronic autoimmune destruction?
1. Synovitis: chronic inflammation of the synovium 2. Formation of a pannus (granulation tissue rich in inflammatory cells and fibroblasts). These release cytokines TNFalpha and IL-6 which trigger cell mediated attack of the cartilage via a type4 hypersensitivity reaction. This leads to reactive fibrosis and ankylosis (joint fusion)
62
What are labs found in RA patients?
1. Positive RF, positive anti-ACPA antibodies, Some may have positive ANCA. 2. Synovial fluid: decreased viscosity, increased WBCs, low C3 3. High ESR and CRP. SPEP shows polyclonal gammopathy due to the high IgG from the chronic inflammation.
63
First line therapy for RA?
1. NSAIDs | 2. DMARDS - sulfasalazine, MTX, hydroxychloroquine
64
Second line therapy for RA?
TNFalpha inhibitors: Etanercept, Infliximab, Leflunomide: inhibits pyrimidine synthesis --> anti-inflammatory and anti-proliferative effects Rituximab - binds CD20 on B-cells targeting them for destruction via ADCC and complement fixation.
65
What are some side effects of TNF-alpha inhibitors?
1. increased susceptibility to infection (fungi, TB, atypical mycobacteria). Therefore contraindicated in patients with underlying infection 2. reactivation of latent TB --> so screen patients with PPD before commencing treatment

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