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bones & connective tissue > Rheumatoid Arthritis > Flashcards

Rheumatoid Arthritis Flashcards

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
Q

What do Antibodies detect in RA?

A

They recognize not the specific protein but a post-translational modification to arginine that happens in numerous proteins

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26
Q

What factors increase the risk of ACPA-RA?

A
  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.
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27
Q

How does the current idea about RA of pathogenesis of RA differ from old ideas?

A

Original old model –> T cell targets joint because of mis-recognition resulting in autoimmunity and damage. New Model –> ACPA induction immune complex deposition.

28
Q

What important questions would you ask in a patient history?

A

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
Q

How does Osteoarthritis usually present?

A
  • 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
Q

Describe the Onset of RA?

A

Abrupt to insidious; +PMR variant

31
Q

What are typical symptoms?

A

Symmetric joint stiffness/pain improving with exercise, worsening with rest, morning worst. hands feel weak/clumsy

32
Q

What are the usual sites affected by RA?

A

MCPs, PIPs, Wrists/MTPs

33
Q

What constitutional symptoms accompany RA?

A

Fatigue

34
Q

What is histological findings correlate with what is found on physical exam of RA?

A
  • Destruction is centered in synovium, destroying all around it.
  • On histology, you see a lot of inflammation underneath the synovium
35
Q

What would make you suspect OA?

A

If you see DIP involvement?

36
Q

What data exists on the physical exam?

A

Lateral MCP or MTP squeeze. Scored 1-4 for each limb

37
Q

What do you need to know of physical exam?

A

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
Q

What sensitivity and specificity is present on physical exam on squeezing hands?

A 
1-87% (58%)
2-81% (68%)
3-67% (84%)
4-51% (89%)
sensitivity (specificity)
39
Q

What is the use of the tuck and claw test?

A

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
Q

What is the importance of the ACPA test?

A

ACPA does not disappear with remission.
Tightly connected to the shared epitope and RF.
Good for their specificity and prediction of poor outcomes.

41
Q

Why is ACPA best serologic marker for RA?

A

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
Q

Do you need testing to make the diagnosis of RA?

A

No, focus on the hands –> pain, joint deformities plus the tuck and claw test.

43
Q

What are the main principles in management of RA?

A
  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
Q

What are some choices of DMARDs?

A 
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
Q

Describe the importance of peptide restriction of autoantibody formation.

A

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
Q

Describe the cytokines that are important in RA pathogenesis?

A

TNF and IL-6

47
Q

When we treat RA, what are we trying to prevent?

A

Prevent destruction or erosion of the joint.

48
Q

What are the pathological findings in RA?

A
  1. inflammation or synovium with increase in phagocytosis and synovial cell proliferation.
  2. The synovium slowly turns into lymphoid tissue
  3. Joint destruction
49
Q

What is involved in the pathological step of step 1: inflammation of synovium?

A

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
Q

What are some lifestyle changes you can make that can have a good effect on RA?

A

Stopping smoking and weight loss have good benefit

51
Q

Extra-articular RA predominantly occurs in?

A

Seropositive RA

Remember, Smokers with RA can be seronegative

52
Q

Mechanisms of extra-articular

A
  1. immune complex deposition leading to vascular compromise or inflammation
  2. synovial compression or surrounding structures (e.g. nerves)
  3. unknown: ILD
53
Q

RA mechanism pathology step 2: Synovium slowly turns into lymphoid tissue

A

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
Q

Things we worry about in Extra-articular RA?

A
  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
Q

2010 ACR/EULAR classification criteria for diagnosing RA?

A

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
Q

What rheumatoid arthritis?

A

Chronic systemic autoimmune disease.

57
Q

What is the epidemiology of RA?

A

Onset typically 30-50yrs, occurs 3 times more often in women than men

58
Q

What is the typical presentation of RA?

A

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
Q

How does presentation of osteoarthritis differ from RA?

A

OA pain is aggravated by use and worsens as the day progresses.
OA involved PIP and DIP joints but spares the MCP

60
Q

What is the consequence of involvement of the hands?

A

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
Q

What is the result of chronic autoimmune destruction?

A
  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
Q

What are labs found in RA patients?

A
  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
Q

First line therapy for RA?

A
  1. NSAIDs

2. DMARDS - sulfasalazine, MTX, hydroxychloroquine

64
Q

Second line therapy for RA?

A

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
Q

What are some side effects of TNF-alpha inhibitors?

A
  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

bones & connective tissue (19 decks)

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