BL 03-04-14 8-9AM SPONDYLO-Janson_Hirsh Flashcards
Axial arthropathies- characteristics
Group of diseases characterized by:
- axial arthritis (spine, sacroiliac joints)
- peripheral arthritis
- enthesitis (inflammation of ligamentous-osseous junctions)
- mucocutaneous lesions (skin rash, conjunctivitis)
Genetic association of axial arthropathies
ssociated w/ HLA class I marker HLA-B27
Types of axial arthropathies
- Ankylosing spondylitis (AS)
- Reactive arthritis
- Psoriatic arthritis,
- Arthro-pathies associated w/ regional enteritis (Crohn’s disease) and ulcerative colitis
- Undifferentiated spondyloarthropathies
Pathogenesis of axial arthropathies
- exact pathogenesis uncertain
- strong association w/ HLA-B27 antigen
- –> suggests unknown infectious organism triggering abnormal immune response in genetically susceptible individual
Ankylosing spondylitis - Demographics
- Affects males > females (7:3 ratio)
- Onset occurs btwn 16-40 yo, rarely younger or older
- Caucasians affected more than other racial groups
Ankylosing spondylitis - Clinical history/manifestations
- All patients have inflammatory back pain
- ~25% have peripheral arthritis (usually hips, shoulders = i.e., joints close to spine)
- Frequently affects synchondroses (unlike RA)
Inflammatory back pain in Ankylosing spondylitis
Characterized by:
- Insidious onset >3 months
- Prolonged morning stiffness (>30-60 min)
- Improvement w/ exercise
- No neurologic sequelae
Synchondroses involvement in Ankylosing spondylitis
= areas of cartilaginous union w/ bone
- includes manubriosternal joint, costovertebral joints, and pubic ramis
- such involvement is NOT seen in RA
Ankylosing spondylitis - Physcial exam of the back
- SI joint tenderness
- Global loss of spine ROM
- Late in disease, may find back deformities & reduced chest expansion
Extraarticular manifestations of Ankylosing spondylitis
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
Laboratories in Ankylosing spondylitis
- Elevated ESR
- negative rheumatoid factor (RF)
- negative ANA (serologically negative)
Radiographs in Ankylosing spondylitis
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%)
Reactive arthritis - Demographics
- Affects males > females (5-10:1 ratio)
- Onset from childhood to age 40-50
- Caucasians affected more than other racial groups
Reactive arthritis - Clinical history
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
Infectious Diarrhea & Urethritis in reactive arthritis, due to…
Diarrhea due to
- shigella
- salmonella
- yersinia
- campylo-bacter
Urethritis due to chlamydia
Reactive arthritis - Physical exam findings
- Peripheral & Axial arthritis
- Enthesopathy
- Extraarticular manifestations
Reactive arthritis - Physical exam of Peripheral arthritis
- Asymmetric, oligoarticular, predominately lower extremity arthritis - knees & ankles most common
- Dactylitis (20-50%) - diffusely swollen toes (sausage digit) due mainly to tendon inflammation
Reactive arthritis - Physical exam of Axial (back) arthritis
- Up to 25% will develop persistent inflammatory back disease similar to AS
Reactive arthritis - Physical exam of Enthesopathy
Achilles tendinitis and/or plantar fasciitis (20%)
Reactive arthritis - Extraarticular manifestations
- 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
Reiter’s syndrome
Former term for reactive arthritis combined with urethritis, inflammatory eye disease, & mucocutaneous lesions
Laboratories in Reactive Arthritis
- Elevated ESR
- negative RF
- negative ANA
Radiographs in Reactive Arthritis
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
Colitic arthropathies
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
Psoriatic arthritis
- Up to 10% of pts w/ psoriasis develop peripheral and/or axial arthritis
- Skin disease severity does not correlate w/ arthritis severity
Inflammatory peripheral psoriatic arthritis
- predominantly involves upper extremities, esp. DIP, PIP, & MCP joints
- usually in asymmetric pattern
- Dactylitis of fingers can occur
Axial psoriatic arthritis
- resembles axial arthritis seen in reactive arthritis
- occurs in 5-10% of psoriatic arthritis patients
Epidemiology of Ankylosing spondlytis
- 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
Epidemiology of other axial arthropathies (reactive, psoriatic, colitic spondylitis)
Also associated w/HLA-B27
Reactive arthitis = 60-90%
Colitic spondylitis (not peripheral arthritis) - 50%
Psoriasis vulgaris spondylitis (not peripheral) - 50%
Genetics + Environmental triggers in spondyloarthropathies
- 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
Primary & Unique Pathological site of Axial arthropathies
= enthesis
= ligamentous, tendinous,& fibrous structures as they insert into bone (Achilles tendon, annulus fibrosis, plantar fascia, joint capsules)
Enthesitis
= inflammation of the enthesis, the ligamentous, tendinous,& fibrous structures as they insert into bone (Achilles tendon, annulus fibrosis, plantar fascia, joint capsules)
Pathology of Axial Arthropathies
- 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
Inflammatory infiltrate content in Axial Arthropathies
- inflammatory infiltrate consists mainly of macrophages, T cells (CD4+ & CD8+), and cytokines (TNF-alpha, IL-17, and TGF-beta)
Calcification of entheses/joints
- 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
Pathophysiology of axial arthropathies
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
Ankylosing spondylitis (AS) - Genetics in Pathophysiology
- 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)
Other genes associated w/ increased risk of AS:
- 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
Ankylosing spondylitis (AS) - Environmental trigger in Pathophysiology
- 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
Gut-arthritis connection in Ankylosing spondylitis (AS)
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
The different AS + HLA-B27 theories
Arthritogenic peptide hypothesis
Molecular mimicry
Free heavy chain hypothesis
Unfolded protein hypothesis
AS + HLA-B27 theories: Arthritogenic peptide hypothesis
- Arthritogenic response might involve specific microbial peptides that bind to HLA-B27
- presented in unique manner to CD8+ (cytotoxic) T cells
- –> disease
AS + HLA-B27 theories: Molecular mimicry
- 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
AS + HLA-B27 theories: Free heavy chain hypothesis
- 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)
AS + HLA-B27 theories: Unfolded protein hypothesis
- 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
Inflammation, autoimmunity, and calcification in Pathogenesis of Ankylosing spondylitis (AS)
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.
Reactive arthritis - pathogenesis
- better understood than AS
- Genetics + Environmental antigens + Immune response
Reactive arthritis - Environmental triggers in pathogenesis
- Chlamydia causing urethral infections
- Salmonella, yersinia, shigella and campylobacter causing intestinal infections
- Only certain bacterial subtypes can induce reactive arthritis
Reactive arthritis - Transport of environmental triggers to joints
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
Reactive arthritis - Genetics in pathogenesis
- 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.
Theories of how HLA-B27 predisposes to reactive arthritis
= 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
Reactive arthritis: Immune response to bacterial antigens in joints after interaction w/HLA-B27 molecule
- 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.
Responsible Bacterial antigenic epitope in Reactive Arthritis
- 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
Pathogenesis of other spondyloarthropathies
= less well understood
= felt to be similar to AS & reactive arthritis
- Bacterial triggers, however, are unknown
HLA-B27 test for spondyloarthropathy
- 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
Treatment of AS - Lifestyle
- 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)
Treatment of AS - Drugs
- 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
Treatment of refractory peripheral arthritis (in AS, reactive arthritis, psoriatic arthritis)
Methotrexate
Treatment of chlamydial-induced reactive arthritis
Tetracycline early in course may ameliorate it
—> eradicate persisting latent organisms causing ongoing inflammation
Treatment of Established arthritis
3 month course of tetracycline or erythromycin may be beneficial, although usually it is not.
Treatment of Reactive Arthritis secondary to enteric pathogens (Shigella, Salmonella, etc.)
It is unclear if a 3-month course of antibiotics (quinolone) is beneficial, although usually it is not
Treatment for pts w/ sacroiliitis, spondylitis, peripheral arthritis, and/or enthesitis who failed standard therapy
Anti-TNF biologic agents have been very effective
- Unfortunately, DO NOT stop progression of bony erosions or formation of syndesmophytes
Seronegative spondyloarthropathies share the clinical features of:
- Sacroiliitis and spondylitis.
- Enthesitis (hallmark of the disease)
- Peripheral arthritis tends to involve large joints in an asymmetric distribution.
- Mucocutaneous lesions & ophthalmologic disease are characteristic & common.
- Genitourinary & GI involvement is common (often infections of these mucosal surfaces trigger reactive arthritis)
- Association w/ HLA-B27 causes disease to run w/in families.
- Negative RF and ANA
Pathogenesis of seronegative spondyloarthropathies
UNKNOWN Environmental trigger HLA-B27 T cells Abnormal cytokine response ---> persistence of bacterial products in the joint (Th-2 profile)
