Ankylosing Spondylitis

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Ankylosing Spondylitis

• Swanthri De Silva M.D
• Rheumatology, Allergy and Immunology

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• Introduction
• Clinical manifestations
• HLA B27
• Pathology
• MRI in diagnosis of AS
• Pathogenesis and animal models of AS
• Treatment of AS
• Prognosis

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Introduction

• The spondyloarthropathies are a heterogeneous
  group of diseases characterized by enthesial and
  synovial involvement of both axial and peripheral
  skeleton
• Entities belonging to this concept are
• Ankylosing spondylitis most typical form
• Reactive arthritis
• Psoriatic arthritis
• Undifferentiated spondyloarthritis
• Arthritis associated with inflammatory bowel
  disease
• Arthritis associated with acute anterior uveitis

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• Primary pathological sites
• Entheses sites of bony insertion of ligaments
  and tendons
• Axial skeleton
• Sacroiliac joints
• Non articular structures gut, skin, eye and
  aortic valve

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• Spinal fusion is the clinical and pathological
  hallmark
• Bony fusion of the sacroiliac joints, spinal
  apophyseal joints and intervetebral disk spaces
  progresses slowly over time

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• Not associated with rheumatoid factor hence
  sero-negative spondyloarthropathy
• Shows a strong association with HLA B27 an allele
  of the major histocompatibility complex

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Introduction - cont

• The spondyloarthropathies have an estimated
  prevalence of between 0.6 to 1.9
• .Both men and women are affected with an overall
  male predominance. MF 31
• In a study among residents of Rochester
  Minnesota, the overall prevalence of AS was
  129/100,000.(1)
• In a second study from the Mayo clinic an
  overall incidence rate of 7.3 per 100,000 person
  years was reported. (2)

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• The prevalence varies depending upon the ethnic
  group and the prevalence of HLA-B27.
• Spondyloarthropathy is common in Eskimos and
  Inuit persons HLA B 27 is seen in 25 to 40
• Rare in Japanese persons who have a very low lt1
  prevalence of HLA B 27

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Introduction - cont

• The prevalence of SpA among all patients
  presenting to a primary care physician with
  chronic low back pain is very low lt 5.
• If the chronic back pain has inflammatory
  features then the probability of AS/SpA increases
  to 14.
• The additional presence of the following clinical
  features increases the probability further
• History of acute anterior uveitis
• Family history of SpA
• Impaired spinal mobility or diminished chest
  expansion
• Presence of enthesitis with resultant tenderness
  over the SI joints, the spine, heels iliac crest
  and anterior chest

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Clinical Manifestations

• The modified New York criteria for AS
• Low back pain of at least 3 months duration that
  improves with exercise and is not relieved by
  rest
• Limited lumbar spinal motion in sagittal and
  frontal planes
• Chest expansion decreased relative to normal
  values for sex and age
• Bilateral or unilateral sacroiliitis seen on X-ray

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Ankylosing Spondylitis X-Ray Changes
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Clinical Manifestations of AS

• Hip involvement can be an early sign and denotes
  a poorer prognosis
• Acute anterior uveitis Uveitis is the most
  common extraarticular complication of AS,
  occurring in 25 to 40 percent of patients - acute
  unilateral pain, photophobia, and blurring of
  vision

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• Spinal complications of AS
• Fracture of ankylosed spines on mild trauma
• Atlantoaxial-axial subluxation spontaneous
• Cauda equina syndrome - lumbosacral nerve root
  damage caused by arachnoiditis.
• Osteopororsis

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Cardiac disease in AS

• Heart disease is a well recognized complication
  of AS.
• The most characteristic lesions are aortic
  incompetence and conduction defects, however four
  different anatomic sites in the heart can be
  involved
• Aortic root
• Conduction system
• Myocardium
• Pericardium

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Cardiac - cont

• Aortitis focal destruction of muscular and
  elastic structures of media, and thickening of
  intima and adventitia similar to syphylitic
  aortitis
• Aortitis may extend below the aortic root to the
  base of the mitral valve leading to mitral valve
  disease

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Cardiac - cont

• Aortic valve disease described as fibrotic,
  thickened and retracted cusps with rolled edges
  leading to aortic insufficiency over time
• Prevalence of aortic incompetence increases with
  age, disease duration and presence of peripheral
  arthritis
• 5 with dz duration lt 15yrs
• 10 with dz duration gt 30yrs

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Cardiac - cont

• A wide variety of conduction disturbances have
  been described
• 1st, 2nd, 3rd, degree Av block
• Bundle branch block and fascicular block
• Prevalence of AV block increases with duration of
  disease ( 3 if lt 5yrs duration and 8.5 if gt
  30yrs duration) and almost doubles if peripheral
  joints are affected
• In a population of 223 men with permanent
  pacemakers 15(7) fulfilled Dx criteria for AS

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HLA B27

• HLA B27 an allele of the major histocompatibility
  complex shows a strong association with AS and
  related spondyloarthropathies
• Disease Prevalence of B27
• AS 90
• ReA 40-80
• Psoriatic 40-50
• Enteropathic 35-75
• Anterior uveitis 50
• Undifferentiated SpA 70

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HLA B27 - cont

• The prevalence of HLA B27 differs significantly
  among the different ethnic groups
• Eskimo and Inuit persons prevalence of HLA B27
  is 25-40 and prevalence of SpA is also high
• SpA are relatively rare among Japanese persons
  who have a very low prevalence lt1 of HLA B27
• HLA B27 is present in 8 of healthy white persons
  of Western European extraction
• ( 75 80 of HLA B27 positive persons do not
  develop any disease that can be related to this
  genetic trait
• The reason for the penetrance of HLA B27
  associated disease of 20-25 is unknown)

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HLA B27 - cont

• The clinical usefulness or predictive value of a
  positive test will be highest in those groups in
  which HLA B27 has a low general prevalence but
  still shows a strong association with AS
• Japanese HLA B27 present in lt1 of general
  population, but , gt85 in people with AS
• Eskimos HLA B 27 present in 25 40 of general
  population and gt 90 in people with AS
• African American HLA B27 present in 2-4 of
  general population, but seen in only 50 of AS
  patients

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HLA B27 - cont

• HLA B27 is a family of at least 25 different
  alleles - 2701 to 2725
• The two major subtypes observed in white persons
  2705 and 2702 are clearly associated with
  AS/SpA
• 2704 seen in Chinese/Japanese is also associated
  with disease
• However 2706 in southeast Asia seems not to be
  associated with AS/SpA

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HLA B27 - cont

• Although HLA B27 is the major gene involved in
  susceptibility to AS it is thought to operate in
  combination with other genes in determining
  disease susceptibility
• HLA B27 is also thought to have little role in
  determining disease severity, only susceptibility
• Other candidate genes include IL1 and ILrA gene
  family on Ch 2q, genes encoding for LMP and TAP
  molecules involved in processing and presentation
  of antigen by MHC class 1.

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HLA B27 - cont

• HLA B 27 test as an aid to diagnosis
• In a patient with clinical findings suggestive
  of AS but who has normal or equivocal X-rays. HLA
  B 27 testing can be useful.
• In such a patient with a pretest probability of
  50. A positive result increases the probability
  to 80-90, while a negative result will markedly
  drop that down to 2, assuming the patient is
  white.
• HLA B27 does not help to distinguish between the
  SpA and is not useful as a screening test

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Pathology

• The primary pathologic sites include
• The enthesis- two types
• Fibrous enthesis
• Fibrocartilage enthesis - 4 consecutive zones
• Tendon, uncalcified and calcified fibrocartilage,
  bone
• The SI joints and axial skeleton
• Peripheral joints
• Non articular structures gut, skin, eye, aortic
  valve

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Pathology- cont

• The initial inflammatory lesion in the spine in
  AS is thought to be at the region where the disc,
  the anterior ligament and the edge of the
  vertebral body meet.
• Spondylitis anterior or Romanus lesion
• Spondylodiscitis is referred to as the Andersson
  lesion

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Pathology - cont

• Histopathology of 12 cases of AS was studied by 5
  bx and 7 autopsy of the SI joint (AR 43, Sep
  2000)
• Earliest changes identified
• Hypertrophy of synovium
• Marginal erosion of cartilage
• Subchondral myxoid (granulation tissue) bone
  marrow

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Pathology - cont

• Biopsy of 5 SI joints in pts with active disease,
  with disease duration 4 to 5 yrs showed a
  predominance of T cells and macrophages
• Braun J, AR 1995 April38 (4) 499-505
• Bollow M, Ann rhem dis 2000 feb 59 (2) 135 40

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MRI in diagnosis of AS

• Assessment of structural change in AS is
  essential for diagnosis and management.
• However in the early phase of disease
  conventional radiographs are often too
  insensitive to show disease.
• Active spinal and SI joint inflammation can be
  demonstrated by MRI using either
• Fat saturation STIR technique
• Contrast enhanced MRI

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MRI - cont

• STIR Short-Tau-inversion-recovery sequence. The
  STIR sequence nullifies the signal from fat,
  hence normal fatty bone marrow appears dark, and
  contrast between areas with high concentration of
  free water (inflammation, edema, tumor) and
  normal tissue is greatly enhanced

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MRI - cont

• 20 patients with recent onset knee effusion were
  evaluated with MRI, 10 with SpA
• 2 significant findings in patients with SpA
• Focal soft tissue edema outside the joint capsule
  adjacent to entheseal insertions
• Subchondral bone marrow edema, maximal adjacent
  to entheseal insertion
• ( AR 41 (4) April 1998 694- 700 )

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MRI to assess response to therapy

• 10 SpA pts with active inflammatory back pain and
  peripheral involvement were treated with
  etanercept for 6 months, MRI scans were done at
  baseline and 6 months
• SI joints
• At base line 3pts asymptomatic had normal MRI, 6
  pts with symptoms had subchondral edema
• At f/U improvement in 60 of lesions

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MRI - cont

• Spine
• Base line 9 pts had 22 active lesions
• Romanus lesion anterior spondylitis 11
• End plate edema 4
• Spinous process edema 3
• All spinal lesions improved following treatment
  and 17 lesions disappeared completely
• Peripheral joints
• Hip joint synovitis and enthesitis at psoas
  insertion
• Knee joint- subchondral edema in tibial plateau
• F/U improvement in enthesitis and synovitis

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Animal models

• Rats transgenic for HLA B27 and human ?²
  microglobulin
• Immunization of BALB/C mice with cartilage
  proteoglycan
• Endogenous ?² microglobulin deficient HLA B27
  transgenic mice with and without human ?²m
• White footed mice expressing a truncated form of
  the TNF ? gene ( Pe- TNF? transgene)
• Murine progressive ankylosis mice homozygous
  for the gene ank/ank

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HLA B27/human ?² transgenic rats

• Develop a spontaneous inflammatory disorder that
  resembles SpA
• Axial and peripheral joint arthritis
• Changes in tail skin and distal aspects of digits
• Hyperkeratosis and dystrophy of nails
• Heart inflammation in AV and myocardium
• Diarrhea frequent voluminous watery stools
• Orchitis and epididymitis
• Neuro cerebellar ataxia and muscular
  dyskinesia
• Do not develop spontaneous anterior uveitis

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HLA B27/human ?² transgenic rats - cont

• Only some transgenic rat lines are affected
• A correlation has been found between
  susceptibility to disease and the number of
  copies of the B27 gene integrated in to the rat
  genome
• Gut and joint inflammation are suppressed if rats
  are raised in a germ free environment, and
  exposure to normal flora is sufficient to induce
  disease
• Disease can be transferred to non transgenic rats
  by bone marrow engraftment, indicating that
  expression of B27 in epithelial cells in not
  important but T cell, APC ( DC) expression of B27
  is critical for disease induction

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BALB/C mice

• Intraperitoneal injection of human fetal
  cartilage proteoglycan ( from which the
  chondroitin sulfate chain has been removed) into
  female BALB/C mice induces a chronic erosive
  polyarthritis and spondylitis in all mice that
  progresses to ankylosis
• The development of disease is closely associated
  with the development of autoimmunity to native
  mouse cartilage proteoglycan
• A strong humoral and cellular response develops
  that cross reacts with native mouse proteoglycan

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Pathogenesis

• What is the role of HLA B27 in the development of
  disease
• Is HLA B27 an - auto antigen or antigen
  presenting molecule
• There are primarily two opposing theories
• Trimolecular mimicry hypothesis
• Arthritogenic peptide (antigen) presentation
  hypothesis

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Trimolecular mimicry

• Immunization of Lewis rats with HLA B27 peptides,
  B27 PA and B2702 PA, and a peptide from
  cytokeratin ( expressed in synovial membranes,
  eyes and gut) independently induced an
  inflammatory response in joints spine and eyes
  resembling the symptoms of AS
• HLA B27 has a unique structural feature which
  leads to its increased mis-folding and
  degradation and presentation as a peptide
• T cells that react with these peptides then also
  cross react with joint peptides such as
  cytokeratin
• Stimulation of these T cells with a foreign Ag
  (Chlamydial peptide) that also recognizes the T
  cell receptor may lead to activation of these T
  cells and initiation of disease

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Arthritogenic peptide

• This model suggests that HLA B27 has a key role
  in initiating an immune response by binding small
  antigenic peptides (from disease inducing
  environmental antigens) and presenting them to
  CD8 T cells
• These T cells then cross react with self antigen
  peptides
• The cartilage proteoglycans versican and aggrecan
  are being studied as potential self antigen.
• The source of disease inducing arthritogenic Ag
  is being investigated microbial origin

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Treatment

• Medical
• NSAIDs
• DMARDs
• TNF ? blockers
• Surgical

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NSAIDs

• A quick effect on pain, morning stiffness and
  functional disability is usually seen after
  initiation of NSAIDs
• Although short term efficacy is observed, long
  term efficacy was not established.
• A recent study demonstrated that continuous use
  of NSAIDs reduced radiographic progression of
  disease

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DMARDs

• In contrast to R.A few studies have been
  performed on the treatment of patients with AS
  with disease modifying anti-rheumatic drugs, and
  none of which have proved clearly effective in
  axial disease
• SLZ may be beneficial in the treatment of the
  peripheral arthritis associated AS
• MTX/ARAVA studies have shown success of these
  drugs in the treatment of psoriatic arthritis,
  but there is no data to suggest any impact on
  axial disease in AS
• Oral CS or SI joint injections have not proven to
  be effective

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TNF ? blockers

• The new TNF ? blockers have been proven highly
  effective in improving the spinal and extra
  spinal manifestations of SpA

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Infliximab

• Braun, Lancet 2002 359 1187-93
• German multicenter placebo controlled trial of 70
  pts with active AS
• Txed with infliximab 5mg/kg at wks 0,2,6 and
  observed until week 12
• 53 had regression of disease activity of at
  least 50 of fatigue, spinal pain, morning
  stiffness, enthesial pain and joint pain
• One year open extension F/U 5mg/kg q 6weeks f/U
  for 54 weeks the same magnitude of improvement
  was sustained
• Significant adverse effects
• Systemic TB (1)
• Poly arthritis with high ANA (3) and skin lupus
  (1)
• Mild luekopenia (1)
• Increased LFT (1)
• Infusion reactions (2)

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Infliximab

• Makysmowych, J Rheumatol 200229959
• Prospective observational inception cohort of pts
  with NSAIDs refractory AS- 21pts
• Infliximab 3mg/kg at 0,2,6 wks and Q 2m
• At 14 wks significant improvement in BASDAI and
  BASFAI, maintained at one year
• AE- Septic OM (1), Severe hypersensitivity (1)
• 5 pts ANA ve at base line no change with Tx

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Infliximab

• Optimal dose
• 5mg/kg every 6 weeks
• OR
• 3mg/kg every 8 weeks
• ( limited data )

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Etanercept

• Gorman JD. NEJM 2002, 346 1349
• Randomized double blind placebo controlled 4
  month study with 6 month open label extension
• 40 pts with AS tx with etanercept 25mg SQ 2/wk
• Primary end point 20 improvement in morning
  stiffness, spinal pain, swollen joint count,
  global assessment of disease activity and
  function
• Etanercept group 80 achieved primary end point
  and results seen as early as one month

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Etanercept - cont

• AE
• Self limited injection site reactions
• 2 neuro events in one pt tinnitus and increase
  muscle fasciculation ( increase from a
  pre-existing condition )
• No change in ANA
• Infection rate similar to placebo
• Measures which did not improve
• - modified schobers index
• - Occiput to wall measurement
• - Fatigue severity scale

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Indications for Surgical treatment

• Unstable injuries
• Presence of neurological deficits
• Painful spinal deformity
• Functionally/cosmetically unacceptable deformitis
• Minimally invasive techniques of corrective
  osteotomy

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Prognosis

• 5-7 yr lapse prior to diagnosis
• Most damage occurs first 10 yrs of disease
• Factors predictive of more severe disease
• Onset lt 16yrs
• Hip arthritis / Oligoarthritis
• Poor response to NSAIDs
• Sausage like digits
• Limitation of lumbarspine
• ESR gt 30

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• Cessation of work occurred at a mean disease
  duration of 16yrs
• Overall mortality 1.5 times higher than expected
• Cause of death
• 40 cardiovascular
• 18 renal amyloidosis

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Questions?