BL-SPONDYLO Flashcards
The primary and unique pathologic site in spondyloarthropathies is the
Enthesis
Enthesis
The enthesis is the connective tissue between tendon or ligament and bone
Spondyloarthropathy genetic association:
HLA-B27
bacterial subtypes can induce reactive arthritis. These include all of the following
Chlamydia
Salmonella
Yersinia
Shigella
clinical manifestations of spondyloarthropathies
Anterior uveitis
Dactylitis
Keratoderma blennorrhagicum
Sacroiliitis
Laboratory studies characteristic of seronegative spondyloarthropathies are
Negative rheumatoid factor (RF) and negative anti-nuclear antibodies (ANA)
Seronegative spondyloarthropathies share the clinical features of (7)
Sacroiliitis and spondylitis.
Enthesitis which is the hallmark of the disease.
Peripheral arthritis tends to involve large joints in an asymmetric distribution.
Mucocutaneous lesions and ophthalmologic disease are characteristic and common.
GU and GI is common.
Association with HLA-B27
- rheumatoid factor and antinuclear antibodies.
pathogenesis of the seronegative spondyloarthropathies is unknown, may be due to
The HLA-B27 transgenic rat has provided valuable insight into the pathophysiology of the axial arthropathies.
An environmental trigger is probably necessary for the diseases to develop.
HLA-B27 is important in the pathogenesis.
T cells are critical to the pathogenesis.
Cytokine response may be abnormal allowing for persistence of bacterial
products in the joint
Therapy is based on our understanding of the pathogenesis
Sulfasalazine is used to decrease bowel inflammation in AS and inflammatory bowel disease which leads to improvement in peripheral arthritis.
Tetracycline is used in reactive arthritis due to Chlamydia to eradicate persisting latent organisms causing ongoing inflammation.
Anti-TNF biologic agents are used for severe and resistant cases because excess amounts of TNF-α has been demonstrated in the joints and entheses, and drive the inflammation. Anti-IL-17 therapies may hold promise.
Sacroiliitis and spondylitis.
Enthesitis which is the hallmark of the disease.
Peripheral arthritis tends to involve large joints in an asymmetric distribution.
Mucocutaneous lesions and ophthalmologic disease are characteristic and common.
GU and GI is common.
Association with HLA-B27
- rheumatoid factor and antinuclear antibodies.
Seronegative spondyloarthropathies shared features
The HLA-B27 transgenic rat has provided valuable insight into the pathophysiology of the axial arthropathies.
An environmental trigger is probably necessary for the diseases to develop.
HLA-B27 is important in the pathogenesis.
T cells are critical to the pathogenesis.
Cytokine response may be abnormal allowing for persistence of bacterial
products in the joint
pathogenesis of the seronegative spondyloarthropathies is unknown
Possible correlates
______is used to decrease bowel inflammation in AS and inflammatory bowel disease which leads to improvement in peripheral arthritis.
Sulfasalazine
Tetracycline is used in reactive arthritis due to _____ to eradicate persisting latent organisms causing ongoing inflammation.
Chlamydia
Anti-TNF biologic agents are used for severe and resistant cases because excess amounts of ______has been demonstrated in the joints and entheses, and drive the inflammation. Anti-IL-17 therapies may hold promise.
TNF-α
Can you diagnosis gout with uric acid?
No, not this alone at least
Does AS have stiffness in the prolonged morning?
Yes!
Movement helps
Lumbosacral spine - both sacroiliac joint spaces are completely obliterated. There is also obliteration of the posterior elements in the distal lumbar area and bridging or “bambooing of the spine”. Chest x-ray - “squaring-off of the mid-portion of the thoracic vertebrae but no significant syndesmophyte formation.
Diagnosis?
Ankylosing spondylitis
is mechanical back pain episodic?
yes (comes and goes)
it also usually does not have morning stiffness
HLA-B27 is ______necessary nor sufficient to cause a reactive arthritis. Clearly, the majority of HLA-B27 positive individuals never develop disease whereas HLA-B27 negative individuals can develop disease.
neither
HLA-B27 theories
Arthritogenic peptide hypothesis
Molecular mimicry
Free heavy chain hypothesis
Unfolded protein hypothesis
The arthritogenic response might involve specific microbial peptides that bind to HLA-B27 and then are presented in a unique manner to CD8+ (cytotoxic) T cells resulting in disease.
Arthritogenic peptide hypothesis
HLA-B27 theories
The induction of autoreactivity to self-antigens might develop as a result of “molecular mimicry” between sequences or epitopes on the infecting organism or antigen and a portion of the HLA-B27 molecule or other self-peptides.
Molecular mimicry:
HLA-B27 theories
Joints in AS vs RA?
AS: axial joints
RA: peripheral small joints
HLA-B27 heavy chains can form stable homodimers with no associated β-2 microglobulin on the cell surface. These ho-modimers can trigger direct activation of natural killer (NK) cells though recognition via killer cell immunoglobulin-like re-ceptors (KIR).
Free heavy chain hypothesis
HLA-B27 theories
Abnormal loading may contribute to misfolding of HLA-B27 resulting in an unfolded protein stress response and IL-23 production. ERAP-1 and IL-23 polymorphisms both contribute to the genetic risk of deveoping AS.
Unfolded protein hypothesis
HLA-B27 theories
____% of people have AS
0.1%
1.0% of ____ people develop AS
HLA-B27
1/1000 people with this gene get the disease
10% of HLA-B27 people with____develop AS
FDR with AS
10% of ____ people are HLA-B27
white folks
____% of AS pts are HLA-B27
90%
would you test HLA-B27 to determine AS?
No, because so many people have the gene w/o disease
1/1000 people with this gene get the disease
spondyloarthropathy diseases
AS- bilateral psoriasis colitis- bilateral reactive arthritis undifferentiated
Gut-arthritis connection
Bacterial antigens from the gut could drain through the veno-lymphatic plexus (Batson’s plexus) into the area of the sacroiliac joints and spine.
These antigens could disseminate or be transported by monocytes to joints which lack a vascular basement membrane or to entheses.
unilateral spondyloarthropathy diseases
psoriasis
reactive arthritis
undifferentiated
Bacterial antigens that reach joints/entheses are taken up by antigen presenting cells through _______. Antigen presenting cells with these bacterial fragments can stimulate the adaptive immune system leading to inflammation.
(Gut-arthritis connection)
Toll-like receptors
Ankylosing spondylitis
Demographics
Affects males > females (7:3 ratio)
Onset occurs between 16 and 40 years old, rarely younger or older
Caucasians affected more than other racial groups.
two broad theroies for HLAB27
1- CD8 T cells
(mimicary, Arthritogenic peptide hypothesis)
2- Autoinflamitory
(unfolded, heavy chain)
IL-23*
interleukin-23 receptor
IL-23 which can activate proinflammatory Th 17 cells.
(Unfolded protein hypothesis)
ERAP-1*
endoplasmic reticulum aminopeptidase 1
involved in the trimming of peptides for loading MHC mole-cules (ie HLA-B27) into the endoplasmic reticulum. Abnormal loading may contribute to misfolding
Ankylosing spondylitis Rx:
NSAIDs
helps inhibit bone deformities
anti-tnf drugs help with inflammation
“Rat bite” erosion on x-ray is likely
Gout
Dactylitis
not in RA
is in AS
inflammation of an entire digit (a finger or toe), and can be painful.
in AS inflammation factors _____ causing deformity
ARE NOT
in RA, they are
