7 - Spondyloarthropathies - Classification and Pathogenesis

Question 1

Biblical Leprosy

Answer 1

Spondyloarthritis + Psoriasis

Question 2

Spondyloarthritis (SpA)

Answer 2

A chronic immune-mediated inflammatory disease group with diverse phenotypic manifestations

Question 3

Spondyloarthritis - 4 Domains

Answer 3

Axial skeleton:
Sacroiliitis
Spondylitis

Synovium:
Arthritis

Entheses:
Enthesitis

Extra-articular features:
Psoriasis (skin and nails)
Uveitis
Inflammatory bowel disease

Question 4

Spondyloarthritis - Traditional Clinical Subtype Classification

Answer 4

Ankylosing Spondylitis (ASp)
Reactive Arthritis (ReA)
Juvenile Spondyloarthritis (JSpA)
Enteropathic Arthritis (Ulcerative Colitis, Regional Enteritits)
Psoriatic Arthritis (PsA)
Undifferentiated Spondyloarthritis (USpA)

Question 5

Spondyloarthritis - Pathophys

Answer 5

Inflammatory autoimmune response is granulomatous in nature

Involves T cells (especially CD8 T cells)
Involves Macrophages
Involves NK Cells
Involves Innate T Cells

Does NOT involve B Cells
Does NOT involve autoantibodies
(ANA, RF & ACPA negative)

Consequence: Fibrosis and new bone formation

Some inflammation mediated by IL-17/IL-23 axis and TNF-α

Very strong familial and genetic component:
Certain Class I HLA alleles determine susceptibility and likely specify the ability to bind a target peptide from target antigen

Question 6

Spondyloarthritis - Targets of inflammation - Axial Skeleton

Answer 6

Fibrocartilage of sacroiliac joints
Entheses and ligametns of spine
Synovial Joints and vertebrae

“Corner Inflammatory Lesions” - Anterior spondylitis

MRI has a major role in understanding the inflammation here

T2 Short Tau Inversion Recovery (STIR) is an important type of imaging sequence will reveal axial spondyloarthritis
Gadolinium contrast

Activated T Cells invade the enthesis junction of annulus fibrosis and vertebral body
This triggers a granulation tissue response
Annulus fibers erode and replaced by fibrocartilage
Subperiosteal new bone formation, vertebral squaring
Fibrocartilage ossifies to form syndesmophytes
Inflammation resolves, but progressive cartilagenous and periosteal ossification forms “bamboo spine”

Question 7

Spondyloarthritis - Targets of inflammation - Entheses

Answer 7

Fibrocartilage insertions of ligaments, tendons and fascia in axial and peripheral sites

Lover’s heel:
Calcaneal spurs at plantar fascia and calcaneal tendon
Occurs with Reactive Arthritis, which is venereally transmitted

Infiltration of entheses by activated T Cells
Granulation tissue forms (activated macrophages and fibroblasts)
Bone erosions and heterotropic NEW BONE FORMATION

Question 8

Spondyloarthritis - Targets of inflammation - Synovium

Answer 8

Synovitis of peripheral and axial joints
Pencil-in-cup deformity
Can happen in the Distal Interphalangeal Joint, a joint NEVER associated with Rheumatoid Arthritis

Question 9

Spondyloarthritis - Sacroiliitis

Answer 9

Subchondral regions of the synarthrotic SI joints invaded by activated T cells and granulation tissue

Erosion of cartilage on iliac side
Bone plate blurs
Joint space widens
Reactive sclerosis ensues
Fibrous ankylosis replaced by bone, obliterating the SI joint

Can be symmetric or asymmetric

Asymmetric more common with peripheral ASp

Question 10

Synovitis - Clinical Patterns

Answer 10

Large joints: Monoarticular (asymmetric) or symmetric involvement of hip and knee joints

Small joints:
Asymmetric (1 or 2 PIP joints on one hand)
All of the joints in one ray
Symmetric (similar to RA)

DIP involvement

Asymmetry and pattern of involvement usually distinguish spondylitis from RA

Question 11

Spondyloarthritis Diseases - Genetics

Answer 11

Strong familial aggregation
High monozygotic twin concordance
Genetically complex pattern of inheritance

Susceptibility associated with certain Class I MHC alleles:
HLA-B*27

Question 12

Spondyloarthritis Diseases Associated with HLA-B*27

Answer 12

Ankylosing Spondylitis - 95%
Reiter’s Syndrome (Reactive Arthritis) - 60 to 70%
Psoriatic Arthritis - 15 to 20%
Ethnically matched controls - 3 to 8%

Question 13

Inflammatory Back Pain

Answer 13

Due to the initial inflammation of:
Enthesitis
Spondylitis
Sacroiliitis

Question 14

Assessment of Spondyloarthritis (ASAS) Criteria

Answer 14

4 out of 5 needed:

Insidious onset
Pain at night (with improvement on getting up)
Age of onset 3 mo) dull deep buttock or low back pain
Poorly localized, does not follow nerve root
Alternating buttock pain
Stiffness/pain in the morning (>30 min) awakens from sleep

Question 15

Ankylosing Spondylitis (Axial Spondyloarthritis) - ASp

Answer 15

Widespread spondylitis and sacroiliitis
Male:Female = 3 - 10:1
Culminates in bony ankylosis of spine
Onset age 10 - 35 with inflammatory back pain
Hip, shoulder, knee arthritis in ~30%
95% of those affected are HLA-B27
Disease prevalence follows circumpolar distribution of HLA-B27
Affects ~5% of HLA-B*27 individuals
No evidence of triggering by microorganisms

Question 16

Course of Axial Spondyloarthritis

Answer 16

Inflammatory back pain and tenderness
Worsens and ascends over months to years
Increasing stiffness
Loss of mobility
Ultimately results in spinal ankylosis

Postural changes: Loss of lumbar lordosis
Buttock atrophy and kyphosis
Chest expansion compromised
C-Spine ventroflexion
Peripheral joints, notably hips develop flexion contractures of anxylosis, compensatory knee flexion

Inflammatory back pain
Peripheral arthritis (~30%) and peripheral enthesopathy (~30%) dominate the early phase, then bony ankylosis predominates the later phase

Question 17

Axial Spondylitis - Systemic Involvement

Answer 17

Acute Anterior Uveitis (25%)
May occur at any time (syncheae and glaucoma)

Apical pulmonary fibrosis, often with cavitation (

Question 18

1984 New York Criteria for Ankylosing Spondylitis (Still used)

Answer 18

Radiological: Sacroiliitis Grade 2 bilaterally
OR
Grade 3- 4 unilaterally on conventional X Ray

PLUS

Clinical (need at least 1):
Low back pain and stiffness for more than 3 months which improves with exercise but is not relieved with rest
Limitation of motion of the lumbar spine in both sagittal and frontal planes
Limitation of chest expansion relative to normal values corrected for age and sex

Question 19

Problems with the 1984 New York Criteria

Answer 19

Radiographic sacroiliitis is a LATE manifestation, so diagnosis only comes after 6 - 8 years of back pain.

MRI and PET should be used now

HLA-B*27 was not included, even though we now know that it is present in 95% of cases, and just 5% of controls
Inflammatory back pain’s definition is not inclusive

Question 20

B*27:06 (Southeast Asia)

B*27:09 (Sardinia)

Answer 20

Alleles NOT associated with ankylosing spondylitis

They don’t have an aspartate at position 116 in the P9 binding pocket

Question 21

Endoplasmic Reticulum Aminopeptidase - ERAP1

Answer 21

Involved in the final processing steps of trimming peptides to optimal size for MHC-I binding (~9 amino acids long)

Polymorphisms are associated with HLA-B*27 + ankylosing spondylitis

Supports loading of HLA-B*27 molecules

Question 22

3 hypotheses about something (poorly explained)

Answer 22

Folding of B27

Presenting of peptide antigenic something something

Question 23

Treatment

Answer 23

High does NSAIDs (80% experience symptomatic relief)
Physical therapy - Not bike riding, but swimming. Resist the posture that the disease will pull you into.

TNF inhibitors block symptoms, but symptoms return when you stop. Also doesn’t cause radiographic changes.

RA treatments don’t work

Secukinumab (anti-IL-17) works for a 60% improvement in ASAS20
Ustekinumab leads to MRI improvement