Ankylosing spondylitis pathogenesis

1. Dr. Naeem Jagani

3. These are a group of clinical disorders that
share certain clinical features ,a predilection
to cause inflammation at enthesis and have
an association with HLA-B27 allele.
These include: 1) Ankylosing spodylitis
2) Reactive arthritis (Reiter’s
syndrome)
3) Psoriatic arthritis & spondylitis

4) Enteropathic S & A ( IBD )
5) Juvenile onset SA
6) Undifferentiated SA

4. The estimated prevalence is 0.2% to 1.2%
Among adults with chronic low back pain:
prevalence is about 5%

5. Greek: “ankylos” = bent
“spondylos” = spinal vertebra
Chronic inflammatory disease of axial
skeleton causing back pain and progressive
stiffness
Periph jts & extra- articular tissue may also
be involved
Peak age 20-30 years
Three times more prevalent in men

6. Strong link between AS and HLA-B27
Gene on Chr 6; therefore autosomal
transmission
Relative Risk if 1st degree relative with AS:
16 to 94
Twin studies concordance of AS: 63% for
identical twins
90% of risk estimated to be genetic
Only small percentage of HLA-B27 individuals
in population suffer from a SpA (3-8% of
Americans HLA-B27 positive), suggesting that
other genetic and environmental factors may
play a role

7. AS and HLA-B27 – strong association
Ethnic and racial variability in presence and
expression of HLA-B27
7
HLA-B27
positive
AS and HLA-
B27 positive
Western European
Whites
8% 90%
African Americans2% to 4%48%

8. Major histocompatability complex (MHC) class I allele
(antigen presenting cells)
Presents peptides from intracellular
pathogens( arthritogenic peptide) for recognition by
T-cell receptors of CD8+ T cells (recognise epitope)
(Autoimmunity to cartilage proteoglycan aggrecan);
sharing of Pg epitopespossible explanation for
pathological sites of AS
Pathogenic link between HLA-B27 and AS elusive
despite association of over 30 years
HLA B271) may function @ level of thymus by
allowing selection of arthritogenic T cells
2) peptide binding cleft of HLA B27 mol.
That is able to bind a unique arthritis causing peptide
3)Molecular mimicry theory
4) Receptor theory(peptide well presented
by B27)

9. Characterized by chronic inflammation
and progressive ankylosis
Commonly accepted that inflammation is
driving force for structural damage in AS
Current research shows that tumor
necrosis factor (TNF) is important
cytokine contributing to inflammation in
AS.

10. Hallmark of
structural
abnormality in AS is
bony ankylosis.
No molecular
explanation for
ankylosis.

11. Stimulation of endothelial cells to express adhesion
molecules
Recruitment of white blood cells in inflamed
synovium and skin
Induction of inflammatory cytokine production
(e.g., IL-1, IL-6)
Stimulation of synovial cells to release
collagenases
Induction of bone and cartilage resorption
Stimulation of fibroblast proliferation
11

12. 12
Bone
Erosions
Macrophages
Endothelium
Synoviocytes
­ Proinflammatory cytokines
­ Chemokines
­ Adhesion molecules
­ Metalloproteinase synthesis
Articular
Cartilage
Degradation
Increased Cell
Infiltration
Increased
Inflammation
Osteoclast
progenitors
­ RANKL expression
TNF

13. Poorly documented in literature
Variable severity of symptoms and radiographic progression
Slow speed of disease progression
Until recently, lack of validated outcome measure
No motivation to study AS until Anti-TNFs arrived on scene
Average age of onset: 25 years
Mean time between diagnosis and onset of
symptoms: 8.6 years
Average age of retirement 39.4 years
Mean disease duration at retirement: 10.8 years
AS cause of work cessation: 96%
.

14. Inflammatory back pain
Onset before age 40 years
Insidious onset
Improvement with exercise
No improvement with rest
Pain at night (with improvement upon arising)
Patient has a 25% probability of having ankylosing spondylitis if
four of five of the above symptoms are present, assuming a 5%
prevalence of AS among patients with chronic low back pain.
.

15. Chronic & progressive form of seronegative
arthritis with axial skeleton predominance
Affects 0.1-0.2% of the population
90-95% of patients are HLA-B27 positive
7% of general population is positive, only 1% of
positives will develop ankylosing spondylitis
Male:female 4-10:1

16. Starts with sacroiliac joints
begins with sclerosis, eventually get ankylosis
Progresses to include facet joints, spine, iliac
crest, ischial tuberosity, greater trochanter,
hips, patella, calcaneus, glenohumeral joints
peripheral joint involvement in 30%

17. Enthesopathy - calcification & ossification of
ligaments, tendons, joint capsules at
insertion into bone
Erosion of subligamentous bone due to
inflammatory response
Marrow oedema
Fusion of interspinous ligament
Dagger sign

19.  IN SPINE : inflammatory granulation tissue @ junctn of
annulus fibrosus of disc cartilage & margin of vertebral
bone, the outer annular fibres erode & eventually replaced
by bone forming bony ‘syndesmophytes’ which grow by
enchondral ossification bridging adjacent vertebral
bodies BAMBOO spine
Resorption of vertebral endplates(@ disk margin)
‘squaring of vertebrae’…….also diffuse osteoporosis
Soft tissue findings are new bone formation in outer layers
of annulus fibrosis as well as chronic synovitis and capsular
fibrosis
Peripheral Jts : Synovial hyperplasia, lymphoid infiltration
& pannus but lacks the exuberant synovial villi, fibrin
deposits & plasma cell accumulations of RA. Central
cartilagenous erosions caused by proliferation of
subchondral granulation tissue are common in AS but rare
in RA.

21. Patients usually present with low back pain
and stiffness, which improves with activity
Decreased range of motion in lumbar spine
Thoraco-cervical kyphosis (late)
One-third of patients will have acute,
unilateral uveitis

22. Pseudoarthrosis (Anderson lesion), cervical
spine fracture, C1-C2 subluxation, cauda
equina syndrome
Peripheral joint ankylosis
Restrictive lung disease, upper lobe fibrosis
Aortic root dilation (20%) & murmur (2%)