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Unit 3 B&L > BL 03-04-14 8-9AM SPONDYLO-Janson_Hirsh > Flashcards

BL 03-04-14 8-9AM SPONDYLO-Janson_Hirsh Flashcards

1
Q

Axial arthropathies- characteristics

A

Group of diseases characterized by:

  • axial arthritis (spine, sacroiliac joints)
  • peripheral arthritis
  • enthesitis (inflammation of ligamentous-osseous junctions)
  • mucocutaneous lesions (skin rash, conjunctivitis)
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2
Q

Genetic association of axial arthropathies

A

ssociated w/ HLA class I marker HLA-B27

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3
Q

Types of axial arthropathies

A
  • Ankylosing spondylitis (AS)
  • Reactive arthritis
  • Psoriatic arthritis,
  • Arthro-pathies associated w/ regional enteritis (Crohn’s disease) and ulcerative colitis
  • Undifferentiated spondyloarthropathies
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4
Q

Pathogenesis of axial arthropathies

A
  • exact pathogenesis uncertain
  • strong association w/ HLA-B27 antigen
  • –> suggests unknown infectious organism triggering abnormal immune response in genetically susceptible individual
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5
Q

Ankylosing spondylitis - Demographics

A
  • Affects males > females (7:3 ratio)
  • Onset occurs btwn 16-40 yo, rarely younger or older
  • Caucasians affected more than other racial groups
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6
Q

Ankylosing spondylitis - Clinical history/manifestations

A
  • All patients have inflammatory back pain
  • ~25% have peripheral arthritis (usually hips, shoulders = i.e., joints close to spine)
  • Frequently affects synchondroses (unlike RA)
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7
Q

Inflammatory back pain in Ankylosing spondylitis

A

Characterized by:

  • Insidious onset >3 months
  • Prolonged morning stiffness (>30-60 min)
  • Improvement w/ exercise
  • No neurologic sequelae
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8
Q

Synchondroses involvement in Ankylosing spondylitis

A

= areas of cartilaginous union w/ bone

  • includes manubriosternal joint, costovertebral joints, and pubic ramis
  • such involvement is NOT seen in RA
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9
Q

Ankylosing spondylitis - Physcial exam of the back

A
  • SI joint tenderness
  • Global loss of spine ROM
  • Late in disease, may find back deformities & reduced chest expansion
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10
Q

Extraarticular manifestations of Ankylosing spondylitis

A

1) Acute anterior uveitis - 25%
2) Osteoporosis-19-62%
3) Microscopic colitis- 22-69%, Crohn’s-like lesions 7%
4) Pulmonary apical fibrosis - 2%
5) Cardiovascular disease w/ aortitis, aortic insufficiency, & heart block - 10%
6) Cauda equina syndrome - rare
7) Amyloidosis-rare

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11
Q

Laboratories in Ankylosing spondylitis

A
  • Elevated ESR
  • negative rheumatoid factor (RF)
  • negative ANA (serologically negative)
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12
Q

Radiographs in Ankylosing spondylitis

A

Sacroiliitis - 100% of AS pts by 45 yo
- bone erosion & sclerosis (+/- bony fusion)

Radiographic spondylitis in over 66% of AS pts
= w/ thin marginal syndesmophytes

Complete spinal fusion (bamboo spine) in 10%

Peripheral joints –> inflammatory hip disease, which can lead to bony fusion (20-25%)

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13
Q

Reactive arthritis - Demographics

A
  • Affects males > females (5-10:1 ratio)
  • Onset from childhood to age 40-50
  • Caucasians affected more than other racial groups
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14
Q

Reactive arthritis - Clinical history

A

Hx of infectious diarrhea or urethritis precedes onset of arthritis by 2-4 weeks

Abrupt onset of inflammatory peripheral arthritis, typically lower extremities

May also have inflammatory back pain symptoms and/or extraar-ticular manifestations

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15
Q

Infectious Diarrhea & Urethritis in reactive arthritis, due to…

A

Diarrhea due to

  • shigella
  • salmonella
  • yersinia
  • campylo-bacter

Urethritis due to chlamydia

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16
Q

Reactive arthritis - Physical exam findings

A
  • Peripheral & Axial arthritis
  • Enthesopathy
  • Extraarticular manifestations
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17
Q

Reactive arthritis - Physical exam of Peripheral arthritis

A
  • Asymmetric, oligoarticular, predominately lower extremity arthritis - knees & ankles most common
  • Dactylitis (20-50%) - diffusely swollen toes (sausage digit) due mainly to tendon inflammation
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18
Q

Reactive arthritis - Physical exam of Axial (back) arthritis

A
  • Up to 25% will develop persistent inflammatory back disease similar to AS
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19
Q

Reactive arthritis - Physical exam of Enthesopathy

A

Achilles tendinitis and/or plantar fasciitis (20%)

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20
Q

Reactive arthritis - Extraarticular manifestations

A
  1. Inflammatory eye disease
    - conjunctivitis (50%)
    - acute anterior uveitis (20%)

2) Mucocutaneous lesions (20%)
- painless oral ulcers
- balanitis
- keratoderma blennorrhagicum

3) Aortitis & cardiac conduction defects - rare

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21
Q

Reiter’s syndrome

A

Former term for reactive arthritis combined with urethritis, inflammatory eye disease, & mucocutaneous lesions

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22
Q

Laboratories in Reactive Arthritis

A
  • Elevated ESR
  • negative RF
  • negative ANA
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23
Q

Radiographs in Reactive Arthritis

A

Peripheral joint radiographs

  • erosive changes of feet > ankles/knees
  • hips usually spared

SI joint & spine

  • abnormal in 25%
  • changes similar to AS although sacroiliitis tends to be asymmetric & syndesmophytes tend to be larger & non-marginal (jug handles)

Enthesis insertion sites (heels, etc.)
- can show erosions & calcification

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24
Q

Colitic arthropathies

A

Inflammatory peripheral arthritis occuring in 10-20% of pts w/ inflammatory bowel disease
- OFTEN follows activity of bowel disease

Axial arthritis involving sacroiliac joints & spine occurs in 5% of pts

  • resembles AS
  • does NOT follow activity of bowel disease
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25
Q

Psoriatic arthritis

A
  • Up to 10% of pts w/ psoriasis develop peripheral and/or axial arthritis
  • Skin disease severity does not correlate w/ arthritis severity
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26
Q

Inflammatory peripheral psoriatic arthritis

A
  • predominantly involves upper extremities, esp. DIP, PIP, & MCP joints
  • usually in asymmetric pattern
  • Dactylitis of fingers can occur
27
Q

Axial psoriatic arthritis

A
  • resembles axial arthritis seen in reactive arthritis

- occurs in 5-10% of psoriatic arthritis patients

28
Q

Epidemiology of Ankylosing spondlytis

A
  • relationship between major histocompatibility antigen HLA-B27 & ankylosing spondylitis is the strongest of all associations between class I HLA & disease
  • Over 90% of Caucasian AS pts are HLA-B27 positive
  • The estimated frequency of AS in general population is 0.1% to 0.2%
  • Chance of developing AS is ~1-2% if you are HLA-B27 positive
  • Chance increases to 10-20% if a 1st- degree relative has AS
  • Identical twins have a concordance rate of up to 60%
  • Hence, these diseases tend to run in families
29
Q

Epidemiology of other axial arthropathies (reactive, psoriatic, colitic spondylitis)

A

Also associated w/HLA-B27
Reactive arthitis = 60-90%
Colitic spondylitis (not peripheral arthritis) - 50%
Psoriasis vulgaris spondylitis (not peripheral) - 50%

30
Q

Genetics + Environmental triggers in spondyloarthropathies

A
  • Not all ppl who possess HLA-B27 develop a spondyloarthropathy
  • So, though that genetically susceptible individual develops disease when exposed to environmental trigger
  • Bacteria such as salmonella, shigella, yersinia, campylobacter, & chlamydia induce reactive arthritis in 20% of B27 positive individuals
  • Trigger for ankylosing spondylitis is unknown although normal bowel bacteria has been proposed
31
Q

Primary & Unique Pathological site of Axial arthropathies

A

= enthesis
= ligamentous, tendinous,& fibrous structures as they insert into bone (Achilles tendon, annulus fibrosis, plantar fascia, joint capsules)

32
Q

Enthesitis

A

= inflammation of the enthesis, the ligamentous, tendinous,& fibrous structures as they insert into bone (Achilles tendon, annulus fibrosis, plantar fascia, joint capsules)

33
Q

Pathology of Axial Arthropathies

A
  • inflammation starts in enthesis & may also occur in the synovium lining the joint
  • Unlike in RA, synovial pannus is not seen
  • calcification of entheses & joints may occur via TGF-beta, bone morphogenic proteins (BMP), and WNT family of proteins
34
Q

Inflammatory infiltrate content in Axial Arthropathies

A
  • inflammatory infiltrate consists mainly of macrophages, T cells (CD4+ & CD8+), and cytokines (TNF-alpha, IL-17, and TGF-beta)
35
Q

Calcification of entheses/joints

A
  • TGF-beta, bone morphogenic proteins (BMP), and the WNT family of proteins may contribute to development of calcification at sites of entheses & occasionally in joints (SI joints or hips)
  • Inhibitors of TNF (can suppress inflammatory response & symptoms of AS) unfortunately do not stop progression of calcification & syndesmophyte formation
36
Q

Pathophysiology of axial arthropathies

A

Human B27 and Beta-2 microglobulin genes introduced into rats

  • -> spontaneously developed inflammatory disease involving GI tract, peripheral & vertebral joints, male genital tract, skin, nails and heart
  • This pattern of disease bears striking resemblance to human B27-related axial arthropathies
  • –> gives credence to hypothesis that HLA-B27 is directly involved in disease process
  • Exact immunologic mechanism not clearly elucidated
  • However, disease manifestations don’t develop in these B27 transgenic rats if they are raised in sterile environments, suggesting an environmental trigger is also important
37
Q

Ankylosing spondylitis (AS) - Genetics in Pathophysiology

A
  • Caucasians w/ HLA-B27 gene have relative risk of developing AS which is 50-100x more than an HLA-B27 negative person
  • Based on GWAS, genetics accounts for 90% of risk for developing AS
  • Only 40% of this genetic risk is due to HLA-B27
  • Estimated that several other genes may contribute (helps explain why only 1-2% of HLA-B27 positive individuals actually get AS during their lifetime)
38
Q

Other genes associated w/ increased risk of AS:

A
  • ER aminopeptidase 1 (ERAP1)
  • IL-23 receptor (IL23R)
  • IL-1 receptor type II (IL-1R2)
  • Anthrax toxin receptor 2 (ANTXR2)
  • two loci not encoding gene sequences (gene deserts)
  • RUNX3
  • IL12B
  • TNF pathway-associated genes
39
Q

Ankylosing spondylitis (AS) - Environmental trigger in Pathophysiology

A
  • Trigger unknown but felt to be common to all pts
  • Reasonable candidate is normal bowel bacteria.
  • –> Most pts w/AS have asymptomatic microscopic colitis that could allow bowel bacterial antigens to breach mucosal immune system
40
Q

Gut-arthritis connection in Ankylosing spondylitis (AS)

A

Bacterial antigens from gut could drain through veno-lymphatic plexus (Batson’s plexus) into area of sacroiliac joints & spine

  • –> these Ags could disseminate or be transported by monocytes to joints which lack a vascular basement membrane or to entheses
  • –> Bacterial antigens that reach joints/entheses are taken up by APCs through Toll-like receptors
  • –> APCs w/ these bacterial fragments can stimulate adaptive immune system —> inflammation
41
Q

The different AS + HLA-B27 theories

A

Arthritogenic peptide hypothesis
Molecular mimicry
Free heavy chain hypothesis
Unfolded protein hypothesis

42
Q

AS + HLA-B27 theories: Arthritogenic peptide hypothesis

A
  • Arthritogenic response might involve specific microbial peptides that bind to HLA-B27
  • presented in unique manner to CD8+ (cytotoxic) T cells
  • –> disease
43
Q

AS + HLA-B27 theories: Molecular mimicry

A
  • Induction of autoreactivity to self-antigens might develop as result of “molecular mimicry” btwwn sequences or epitopes on infecting organism or Ag & a portion of HLA-B27 molecule or other self-peptides
44
Q

AS + HLA-B27 theories: Free heavy chain hypothesis

A
  • HLA-B27 heavy chains can form stable homodimers w/ no associated β-2 microglobulin on the cell surface
  • –> can trigger direct activation of NK cells though recognition via killer cell Ig-like receptors (KIR)
45
Q

AS + HLA-B27 theories: Unfolded protein hypothesis

A
  • HLA-B27 has a propensity to misfold in the ER
  • –> unfolded protein stress response

Results in release of inflammatory cytokines such as IL-23
—> can activate proinflammatory Th 17 cells

Notably, ER aminopeptidase 1 (ERAP-1) is involved in the trimming of peptides for loading MHC molecules (ie HLA-B27) into ER

  • Abnormal loading may contribute to misfolding
  • ERAP-1 & IL-23 polymorphisms both contribute to the genetic risk of developing AS
46
Q

Inflammation, autoimmunity, and calcification in Pathogenesis of Ankylosing spondylitis (AS)

A

Final common pathway proposed :

Inflammation —> cartilage injury w/ release of cartilage components such as aggrecan

  • T cells have been demonstrated in joints & entheses of AS patients to react to aggrecan
  • Thus, aggrecan may cause an autoimmune response resulting in more inflammation

Release of cytokines such as TNF-α & IL-17 can cause inflammation & erosions

TGF-β, bone morphogenic proteins (BMP), & WNT family of proteins can lead to calcifications of joints and entheses.

47
Q

Reactive arthritis - pathogenesis

A
  • better understood than AS

- Genetics + Environmental antigens + Immune response

48
Q

Reactive arthritis - Environmental triggers in pathogenesis

A
  • Chlamydia causing urethral infections
  • Salmonella, yersinia, shigella and campylobacter causing intestinal infections
  • Only certain bacterial subtypes can induce reactive arthritis
49
Q

Reactive arthritis - Transport of environmental triggers to joints

A

Each of the above bacterial environmental triggers are transported to joints inside monocytes
—> Chlamydia reach joint & remain alive but latent —> Yersinia, salmonella, & shigella reach joint but are dead or in fragments of bacterial lipopolysaccharides

50
Q

Reactive arthritis - Genetics in pathogenesis

A
  • HLA-B27 is neither necessary nor sufficient to cause a reactive arthritis
  • Majority of HLA-B27 + individuals never develop disease whereas HLA-B27 negative individuals can develop disease
  • Other genes must contribute to the risk.
51
Q

Theories of how HLA-B27 predisposes to reactive arthritis

A

= similar to those of AS

1) Molecular mimicry
- Shigella & Chlamydia Ags resemble HLA-B27
2) Arthritogenic peptide hypothesis
3) HLA-B27 free heavy chain theory
4) HLA-B27 unfolded protein hypothesis

52
Q

Reactive arthritis: Immune response to bacterial antigens in joints after interaction w/HLA-B27 molecule

A
  • Both CD4 & CD8 T cells participate in immune response resulting in synovitis & other clinical manifestations

Cytokine profile of T cells and macrophages / monocytes involved in synovitis show…
- low Th-1 cytokine (IFNgamma) response
- elevated Th-2 cytokine (IL-4, IL-10) response
—> May contribute to bacterial persistence.
This abnormal cytokine pattern may be partly genetically determined.

53
Q

Responsible Bacterial antigenic epitope in Reactive Arthritis

A
  • Bacterial antigenic epitope which T cells are responding to in reactive arthritis is unknown
  • Bacterial heat shock protein 60 (hsp 60) is a leading candidate
54
Q

Pathogenesis of other spondyloarthropathies

A

= less well understood
= felt to be similar to AS & reactive arthritis
- Bacterial triggers, however, are unknown

55
Q

HLA-B27 test for spondyloarthropathy

A
  • Prevalence of HLA-B27 in Caucasian population is 6-9%
  • Number of patients w/ HLA-B27 developing a spondyloarthropathy is small
  • –> Positive predictive value of HLA-B27 test is exceedingly low
  • Much more useful is close attention to clinical manifestations of the disease entities

Used most often when diagnostic challenge is difficult
–> increase/decrease probability that spondyloarthropathy is the Dx, but can’t rule in/out

56
Q

Treatment of AS - Lifestyle

A
  • specific back exercises & good posture
  • sleep w/ either no pillow or a small pillow
  • Smoking avoidance (can lose chest wall function secondary to disease process)
57
Q

Treatment of AS - Drugs

A
  • NSAIDs are usually 1st drugs used (esp. indole derivatives such as indomethacin or tolmetin)
  • Steroid injections into peripheral joints may help
  • Sulfasalazine useful in some peripheral arthritis, to bowel inflammation in AS & IBD, leading to improvement in peripheral arthritis
58
Q

Treatment of refractory peripheral arthritis (in AS, reactive arthritis, psoriatic arthritis)

A

Methotrexate

59
Q

Treatment of chlamydial-induced reactive arthritis

A

Tetracycline early in course may ameliorate it

—> eradicate persisting latent organisms causing ongoing inflammation

60
Q

Treatment of Established arthritis

A

3 month course of tetracycline or erythromycin may be beneficial, although usually it is not.

61
Q

Treatment of Reactive Arthritis secondary to enteric pathogens (Shigella, Salmonella, etc.)

A

It is unclear if a 3-month course of antibiotics (quinolone) is beneficial, although usually it is not

62
Q

Treatment for pts w/ sacroiliitis, spondylitis, peripheral arthritis, and/or enthesitis who failed standard therapy

A

Anti-TNF biologic agents have been very effective

- Unfortunately, DO NOT stop progression of bony erosions or formation of syndesmophytes

63
Q

Seronegative spondyloarthropathies share the clinical features of:

A
  1. Sacroiliitis and spondylitis.
  2. Enthesitis (hallmark of the disease)
  3. Peripheral arthritis tends to involve large joints in an asymmetric distribution.
  4. Mucocutaneous lesions & ophthalmologic disease are characteristic & common.
  5. Genitourinary & GI involvement is common (often infections of these mucosal surfaces trigger reactive arthritis)
  6. Association w/ HLA-B27 causes disease to run w/in families.
  7. Negative RF and ANA
64
Q

Pathogenesis of seronegative spondyloarthropathies

A 
UNKNOWN
Environmental trigger 
HLA-B27 
T cells 
Abnormal cytokine response ---> persistence of bacterial products in the joint (Th-2 profile)

Unit 3 B&L (18 decks)

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