AS
General
the prototypical form of seronegative SpAs. It is a chronic inflammatory disease of the SIJ
and spine that may be associated with a variety of extraspinal lesions involving the eye,
bowel and heart. New bone formation is a hallmark of the disease, which distinguishes SpA
from other types of inflammatory arthritis such as RA.
Back pain: acute <1month, chronic >3months. Up to 25% of the population suffer from
chronic back pain, incidence of IBP is 5% and of them 20% is due to AS. AS is the cause of
≈1% of chronic back pain.
Inflammatory back pain definition (ASAS)
(mnemonic: iPAIN), in a chronic (>3 months) back pain:
i) insidious onset
ii) Pain at night
iii) Age at onset < 40yrs
iv) Improvement with exercise
v) No improvement with rest
Red flags for back pain
Fever (spondylodiscitis)
Use of GCs (vertebral fracture)
Absence of femoral pulses (abdominal aneurysm rupture)
Neurologic manifestations (cauda equina, hernia)
History of neoplasm (metastasis)
Weight loss (malignancy)
Risk or evidence of osteoporosis
Onset <30yrs or >50yrs
IVDU (spondylodiscitis)
Categories
SpAs: axial and peripheral. Axial: AS (=r-axSpA), nr-axSpA (2009 division), early axSpA=
duration of axial symptoms ≤2yrs (spinal/buttock pain or morning stiffness), considered by a
rheumatologist as related to axSpA.
Epidemiology
SpAs occurs in 0.3-2% and is at least as frequent as RA. AS is the most common of all SpAs.
Prevalence (επιπολασμός) 0.5-1% (whites), 6% (Haida natives, Canada). HLA-B27 is more
common in Northern Europeans and is rare in Africans and Australian Aboriginals. Incidence
(επίπτωση): 7/100.000. Men/women: 2-3:1 (r-axSpA), 1:1 (nr-axSpA), women have miler
disease, less ankylosis. Male gender predisposes to structural damage (ankylosis). Young
adulthood, seldom appears before 16-18yrs, average onset 26yrs, rare >40yrs, usually
<45yrs. Monozygotic twins: 63%, 1st-degree relatives: 8%.
Association with IBD
- 5-15% of AS have full-blown IBD, up to 60% have subclinical colitis.
- In IBD peripheral SpA is more common (13%) than AS (3%) and SpA is more common in
patients with Crohn than UC.
Criteria
, X-ray (modified New York criteria)
Grade 0: normal.
Grade 1: suspicious changes.
Grade 2: minimal abnormality: small localized areas with erosion or sclerosis, without joint
width alteration (normal joint space = 2mm).
Grade 3: unequivocal abnormality: moderate/advanced erosions, sclerosis,
widening/narrowing, partial ankylosis.
Grade 4: severe abnormality: total ankylosis.
Causes
HLA-B27 is present in >90% of AS, as well as 50-75% of other forms of SpAs. B27
positivity is neither necessary nor sufficient. Only 5-15% of the general population is HLA-
B27 (+) and among them <5% develop SpA, but up to 20% if there’s a positive family history
of SpA. The overall contribution of HLA-B27 to AS heritability is only 20%. Over 30 HLA-B27
, subtypes but only few associated for AS. Most of these subtypes only differ by a few amino
acids, but these differences may be sufficient to alter the peptide binding properties of the
molecule. Variations related to amino acid differences in B pocket of the antigen binding
cleft alter the nature of the peptides presented by them. HLA-B27 itself can be presented by
HLA-II as an autoantigen and could be recognized by CD4+. It is expressed ubiquitously but
abundantly in APCs and present self-proteins but when infected, foreign ones as well. Only
two subtypes, HLA-B27*06 and *09, are considered not to be associated with SpA. People
with HLA-B27 have different gut microbiota.
Structure: it consists of two components, a heavy a-chain and a light
invariable β2-microglobulin chain. What differentiates it from other HLA-B molecules is that
its a-chain contains a free cysteine at position 67 through which disulfide bonds create
stable homodimers, without involving the light chain. On the other hand, the free light chain
can be released by HLA-B27 and deposited in synovial tissue, stimulating inflammation in
this area, or can interact with receptors on inflammatory cells (CD4+, NK cells, monocytes).
Synthesis: after being synthesized as free heavy chains, HLA-B27 is linked
and folded with β2m and an antigenic peptide, followed by transport to the cell surface as a
trimolecular complex. Must be properly packaged and folded in the ER under guidance of
chaperones (calreticulin and tapasin). It has predisposition to misfold and create dimers/
multimers maybe because of Cys residues at sites 67 and 101. These defective HLA-B27
proteins continually gather in the ER, initiate autophagy and trigger the IL-23/17 pathway.
Also, these misfolded molecules can interfere with ER function, leading to ER stress and UPR
triggering, which further activates the IL-23/17 pathway.
Functions: presents antigens to CD8+ after adequate tailoring in the ER by
ERAP1/2. HLA-B27 and HLA-B57 are specific alleles associated with better HIV, HBV control!
Additionally, ERAP1 cleaves cytokine receptors such as TNFR1, IL-6R2 and IL-1R2, modulating
their availability on the cell surface.
non-HLA-B27: multiple other HLA alleles influence the risk of developing AS: -B51,
-B40 and -B13 and protective associations with -B*0702 and -B*5701. Of note, HLA-B51 is
the major HLA-B risk allele for Behçet’s, which can also be complicated by sacroiliitis and has
other shared genetic risk factors with AS.
non MHC-I: variations in IL-23R, ERAP1/2, IL-1 family genes. Mutations in ERAP1/2
account for 7% of risk for SpA, being the second risk factor after HLA-B27. The genetic
association of ERAP1 with AS was found only in HLA-B27 (+) individuals, suggesting that
ERAP1 likely interacts with HLA-B27 and contributes to AS development through loss of
function, aberrant processing and defective antigen presentation. ERAP1 is also involved in
the development of JIA, PsO (HLA-C06 [former Cw6]), Behçet (HLA-B51), birdshot
retinopathy (HLA-A29), while ERAP2 is related to IBD and PsO. SNPs in IL-23R and in
downstream signaling molecules (TYK2, JAK2, STAT3) are associated with r-axSpA and IBD.
Gut and microbiome: Campylobacter, Chlamydia, Salmonella, Shigella. The
presence of bacterial products in joints provides a potential link between gut infection and
joint inflammation. Defects in the GI mucosal barriers allowing a systemic immune response
with the activation of IL-23. HLA-B27 transgenic rats failed to develop features of SpA in a
germ-free environment, which changed when commensal bacteria were introduced into the
germ-free models, suggesting possible interactions between HLA-B27 and the microbiome.
Klebsiella pneumoniae acts as an opportunistic pathogen in the normal human gut and it
may be an exacerbating agent in the autoimmune process of AS. Ruminococcus gnavus is an
anaerobic Gram(+) coccus and is a frequent commensal of the gut that has also been
associated with Crohn. Because it is a mucolytic bacterium, it might have the capacity to
generate breakdown in the epithelial integrity of the gut
sex hormones: estradiol levels in patients with active AS are significantly lower.
vit. D deficiency?
General
the prototypical form of seronegative SpAs. It is a chronic inflammatory disease of the SIJ
and spine that may be associated with a variety of extraspinal lesions involving the eye,
bowel and heart. New bone formation is a hallmark of the disease, which distinguishes SpA
from other types of inflammatory arthritis such as RA.
Back pain: acute <1month, chronic >3months. Up to 25% of the population suffer from
chronic back pain, incidence of IBP is 5% and of them 20% is due to AS. AS is the cause of
≈1% of chronic back pain.
Inflammatory back pain definition (ASAS)
(mnemonic: iPAIN), in a chronic (>3 months) back pain:
i) insidious onset
ii) Pain at night
iii) Age at onset < 40yrs
iv) Improvement with exercise
v) No improvement with rest
Red flags for back pain
Fever (spondylodiscitis)
Use of GCs (vertebral fracture)
Absence of femoral pulses (abdominal aneurysm rupture)
Neurologic manifestations (cauda equina, hernia)
History of neoplasm (metastasis)
Weight loss (malignancy)
Risk or evidence of osteoporosis
Onset <30yrs or >50yrs
IVDU (spondylodiscitis)
Categories
SpAs: axial and peripheral. Axial: AS (=r-axSpA), nr-axSpA (2009 division), early axSpA=
duration of axial symptoms ≤2yrs (spinal/buttock pain or morning stiffness), considered by a
rheumatologist as related to axSpA.
Epidemiology
SpAs occurs in 0.3-2% and is at least as frequent as RA. AS is the most common of all SpAs.
Prevalence (επιπολασμός) 0.5-1% (whites), 6% (Haida natives, Canada). HLA-B27 is more
common in Northern Europeans and is rare in Africans and Australian Aboriginals. Incidence
(επίπτωση): 7/100.000. Men/women: 2-3:1 (r-axSpA), 1:1 (nr-axSpA), women have miler
disease, less ankylosis. Male gender predisposes to structural damage (ankylosis). Young
adulthood, seldom appears before 16-18yrs, average onset 26yrs, rare >40yrs, usually
<45yrs. Monozygotic twins: 63%, 1st-degree relatives: 8%.
Association with IBD
- 5-15% of AS have full-blown IBD, up to 60% have subclinical colitis.
- In IBD peripheral SpA is more common (13%) than AS (3%) and SpA is more common in
patients with Crohn than UC.
Criteria
, X-ray (modified New York criteria)
Grade 0: normal.
Grade 1: suspicious changes.
Grade 2: minimal abnormality: small localized areas with erosion or sclerosis, without joint
width alteration (normal joint space = 2mm).
Grade 3: unequivocal abnormality: moderate/advanced erosions, sclerosis,
widening/narrowing, partial ankylosis.
Grade 4: severe abnormality: total ankylosis.
Causes
HLA-B27 is present in >90% of AS, as well as 50-75% of other forms of SpAs. B27
positivity is neither necessary nor sufficient. Only 5-15% of the general population is HLA-
B27 (+) and among them <5% develop SpA, but up to 20% if there’s a positive family history
of SpA. The overall contribution of HLA-B27 to AS heritability is only 20%. Over 30 HLA-B27
, subtypes but only few associated for AS. Most of these subtypes only differ by a few amino
acids, but these differences may be sufficient to alter the peptide binding properties of the
molecule. Variations related to amino acid differences in B pocket of the antigen binding
cleft alter the nature of the peptides presented by them. HLA-B27 itself can be presented by
HLA-II as an autoantigen and could be recognized by CD4+. It is expressed ubiquitously but
abundantly in APCs and present self-proteins but when infected, foreign ones as well. Only
two subtypes, HLA-B27*06 and *09, are considered not to be associated with SpA. People
with HLA-B27 have different gut microbiota.
Structure: it consists of two components, a heavy a-chain and a light
invariable β2-microglobulin chain. What differentiates it from other HLA-B molecules is that
its a-chain contains a free cysteine at position 67 through which disulfide bonds create
stable homodimers, without involving the light chain. On the other hand, the free light chain
can be released by HLA-B27 and deposited in synovial tissue, stimulating inflammation in
this area, or can interact with receptors on inflammatory cells (CD4+, NK cells, monocytes).
Synthesis: after being synthesized as free heavy chains, HLA-B27 is linked
and folded with β2m and an antigenic peptide, followed by transport to the cell surface as a
trimolecular complex. Must be properly packaged and folded in the ER under guidance of
chaperones (calreticulin and tapasin). It has predisposition to misfold and create dimers/
multimers maybe because of Cys residues at sites 67 and 101. These defective HLA-B27
proteins continually gather in the ER, initiate autophagy and trigger the IL-23/17 pathway.
Also, these misfolded molecules can interfere with ER function, leading to ER stress and UPR
triggering, which further activates the IL-23/17 pathway.
Functions: presents antigens to CD8+ after adequate tailoring in the ER by
ERAP1/2. HLA-B27 and HLA-B57 are specific alleles associated with better HIV, HBV control!
Additionally, ERAP1 cleaves cytokine receptors such as TNFR1, IL-6R2 and IL-1R2, modulating
their availability on the cell surface.
non-HLA-B27: multiple other HLA alleles influence the risk of developing AS: -B51,
-B40 and -B13 and protective associations with -B*0702 and -B*5701. Of note, HLA-B51 is
the major HLA-B risk allele for Behçet’s, which can also be complicated by sacroiliitis and has
other shared genetic risk factors with AS.
non MHC-I: variations in IL-23R, ERAP1/2, IL-1 family genes. Mutations in ERAP1/2
account for 7% of risk for SpA, being the second risk factor after HLA-B27. The genetic
association of ERAP1 with AS was found only in HLA-B27 (+) individuals, suggesting that
ERAP1 likely interacts with HLA-B27 and contributes to AS development through loss of
function, aberrant processing and defective antigen presentation. ERAP1 is also involved in
the development of JIA, PsO (HLA-C06 [former Cw6]), Behçet (HLA-B51), birdshot
retinopathy (HLA-A29), while ERAP2 is related to IBD and PsO. SNPs in IL-23R and in
downstream signaling molecules (TYK2, JAK2, STAT3) are associated with r-axSpA and IBD.
Gut and microbiome: Campylobacter, Chlamydia, Salmonella, Shigella. The
presence of bacterial products in joints provides a potential link between gut infection and
joint inflammation. Defects in the GI mucosal barriers allowing a systemic immune response
with the activation of IL-23. HLA-B27 transgenic rats failed to develop features of SpA in a
germ-free environment, which changed when commensal bacteria were introduced into the
germ-free models, suggesting possible interactions between HLA-B27 and the microbiome.
Klebsiella pneumoniae acts as an opportunistic pathogen in the normal human gut and it
may be an exacerbating agent in the autoimmune process of AS. Ruminococcus gnavus is an
anaerobic Gram(+) coccus and is a frequent commensal of the gut that has also been
associated with Crohn. Because it is a mucolytic bacterium, it might have the capacity to
generate breakdown in the epithelial integrity of the gut
sex hormones: estradiol levels in patients with active AS are significantly lower.
vit. D deficiency?
