Spondyloarthropathies Ori Elkayam M D Tel Aviv Medical Center Spondyloarthropathies  Ankylosing spondylitis  Psoriatic arthritis  Reactive arthritis  Entheropathic ar by hilen

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      Ori Elkayam M.D

   Tel Aviv Medical Center

 Ankylosing  spondylitis
 Psoriatic arthritis
 Reactive arthritis
 Entheropathic arthritis
Spondyloarthropathies (1)

 Inflammatory   spinal pain or synovitis
  mainly in the lower limbs
 One or more of the following:

                   European Spondyloarthropathy Study
                  Group Criteria for Spondyloarthropathy
     Spondyloarthropathy (2)
 Positive  family history
 Inflammatory bowel disease
 Urethritis, cervicitis or acute diarrhea
  within one month before arthritis
 Buttock pain alternating between right and
  left gluteal areas
 Enthesopathy
 Sacroiliitis

 Inflammationat the sites of attachment of
 tendons, fascia, ligament or joint capsule
 to bone
 Lateral  malleoli and head of fibula
 Tendon of quadriceps tendon to patella
 Muscle attachments to greater and lesser
  trochanter,iliac crests, ischial tuberosities,
 Insertions on the humeral medial and
  lateral epicondyles
 Insertions of flexor carpi radialis
 Achilles tendon etc
   Common pathophysiology
 Genetic   factors – HLA-B27 related and
 Enthesopathy seems to be the primary
 Increased incidence of histologic evidence
  of inflammatory lesion in ileocolonoscopy
Low Back Pain
            Low Back Pain
 The  most frequent disorder of mankind
  after the common cold
 Between 65% and 80% of the world's
  population develop back pain at some
  point during their lives.
 Over 50% of all patients with back pain
  improve after 1 week, while more than
  90% are better at 8 weeks
        Mechanical Back Pain
 90%   of patients with back pain have a
  'mechanical' reason
 Secondary to overuse of a normal
  anatomic structure, to trauma or to
  deformity of an anatomic structure.
 The remaining 10% of adults with back
  pain have the symptom as a manifestation
  of a systemic illness
      Inflammatory back pain
 Onset  before age 40
 Insidious onset
 Persistence for at least 3 months
 Associated with morning stiffness
 Improvement with exercise
                Case 1
A   30 year old man
 Back pain since age 25
 Irradiation to both legs
 Operation for herniated disc L5-S1
 No improvement
 Referral to rheumatologist
                 Case 1
 Inflammatory    Back Pain
 Arthritis of the left hip
 Bilateral sacroiliitis
 Involvement of the left hip
 Diagnosis of Ankylosing Spondylitis
 Treatment and left total hip replacement.
Ankylosing spondylitis
       Ankylosing spondylitis
“Marie-Strumpell   disease” “Von Bechterew disease”

               Ankylos: bent, fusion

            Spondylos: vertebral disc
    Prevalence & Incidence

 Prevalence  : from 67.7/100000 to
 Incidence : 7.3 per 100,000 person-years
 More common in males
 Familial predominance
      Genetics and ankylosing

 Strong  association with HLA-B27
 Prevalence of AS – associated with wild
  world distribution of HLA-B27
 90-98% of patients with AS are HLA-B27
 Only 1-2% of HLA-B27 positive adults may
  develop AS
               HLA B 27
 HLA-B27    encompasses 40 different alleles
  encoding 40 different proteins
 HLA-B27O5 –most widespread
 HLA-B27 contributes only part of the
  genetic risks
    Genetic factors involved in AS
   ARTS1 gene (26%)
   IL23R (9%)
   HLA-class II
   Low molecular proteasome
   Polymorphisms of TNFα
   Major histocompatibility complex class II –MICA
   Genes encoding IL-1RA,IL-6,IL-10,CYP2D6
      Environmental factors

 Transgenic   B27 mice maintained in germ
  free condition do not develop AS
 MHCI related to pedptide (microbial)
Clinical features
      Inflammatory back pain

 Onset  before age 40
 Insidious onset
 Persistence for at least 3 months
 Associated with morning stiffness
 Improvement with exercise
 Costosternal   junctions producing chest
 Spinous processes, iliac crests, greater
  trochanters, ischial tuberosities, tibial
 Heels – achilles tendinitis, plantar fasciitis
Plantar fasciitis
             Peripheral joints
 Girdle   joints – hips and shoulders (35%)
 Knees
  Extraskeletal manifestations
 Constitutionalsymptoms
 Acute anterior uveitis
 Cardiovascular disease
 Pulmonary disease
 Neurologic involvement
 Renal involvement
 Anterior
 Acute and unilateral
 Red and painful eye
 Photophobia, lacrimation
 Attacks usually subside in 4-8 weeks
 Without sequelae
 More common in HLA-B27 positive
 May  be clinically silent although clinically
 Ascending aortitis
 Aortic valve incompetence
 Conduction abnormalities
 Cardiomegaly
 Pericarditis
         Pulmonary disease
 Progressive   fibrosis of the upper lobes
 Eventual secondary colonization with
 Impaired pulmonary ventilation due to
  involvement of thoracic joints
 Restrictive lung disease
      Neurologic involvement
 Fracture,   instability or compression of
 Atlanto-axial subluxation
 Ossification of the posterior longitudinal
  ligament resulting in compressive
 Cauda equina synd :lumbosacral roots,
  pain , sensory loss, urinary&bowel
        Renal involvement

 Immunoglobulin  A (IgA) nephropathy
 Secondary amyloidosis
 High incidence of prostatitis
       Physical examination
 Evidence   of sacroiliitis
 Expansion of the lumbar spine –Schober
 Chest expansion < below 5 cm
 Enthesitis
 Posture –forward sloop of the neck,
  stiffness of the spine , loss of lumbar
  lordosis, thoracic kyphosis
Normal pelvis
Elbow enthesopathy
Enthesopathy of heels
     Radiographic and imaging
 Sacroiliitis
 Whiskering   at enthesis (calcaneous,
  ischial tuberosities, femoral trochanters)
 Squaring of vertebrae
 Syndesmophytes
 Spinal osteoporosis
 Hip, shoulder
        Laboratory tests

 HLA-B27
Criteria of ankylosing spondylitis
 Low  back pain of at least 3 months
  duration improved by exercise, not
  relieved by rest
 Limitation of lumbar spine in sagittal and
  frontal planes
 Reduced chest expansion
 Bilateral sacroiliitis, grade2-4
 Unilateral sacroiliitis, grade3-4
     Definite ankylosing spondylitis
        Unilateral grade 3 or 4 or

           Bilateral grade 2-4 sacroiliitis
           and any clinical criterion

        Probable ankylosing spondylitis
a. The three clinical criteria are present
b. The radiologic criteria is present without clinical criteria
Conventional Medical treatment for

      Physiotherapy
      NSAIDs
      Sulfasalazine–peripheral arthritis, acute
       phase response
      Methotrexate
      Corticosteroids (p.o, IA, IV)
      Pamidronate
      Anti-TNF α therapies
                          Dougados M, Ann Rheum Dis 2002;61:40iii-50
Key Actions Attributed to TNFa

         Etanercept                                     Infliximab
                     SS                          (Binding site for TNF)

               SS                              Human (IgG1)



 C H3   C H2

Fc region of         Extracellular domain of
human IgG1          human p75 TNF receptor                                

              TNF INHIBITION WITH ENBREL                              ®
Etanercept: soluble receptor of TNFα
                              ENBREL Inhibits Activation
                               of Cell-Surface Receptors
                                                                   ENBREL has been designed to
                                                                   complement the body’s natural
                                                                   inhibition of TNF 1


 Reference: 1. Data on file, Immunex Corporation, Seattle, Wash.
                 Side effects

 Good tolerability
 The most frequent was injection site reaction
 Infection in 35% and headache 17 %

   Post marketing : severe infections including TB
    and fatalities, demyelinative disorders,
    lymphoma, rare cases of pancytopenia including
    aplastic anemia,vasculitis, drug induced lupus
          REMICADE® (infliximab)

     Hypersensitivity  reactions
     Sepsis, pneumocystosis, histoplasmosis,
      and listeriosis have been reported
     Rare cases of lymphoma, demyelinating
      diseases and drug induced lupus
     Increased incidence of TB

 ASAS consensus statement for the use of
anti-TNF agents in patients with ankylosing
    A  diagnosis of definitive ankylosing
    Active disease for at least four weeks:
         - Bath ankylosing spondylitis disease
     activity index (BASDAI) of > or =4
         - Expert opinion based on clinical
     Failure of at least two NSAIDs, 3 month
     Failure of SZPin patients with peripheral
            Case history (2)
A  22 year old man
 A 5 month history of recurrent low back
  pain and stiffness
 An attack of anterior uveitis 5 months ago
 Episodes of pain in his shoulders
 Clinical examination : severe restriction of
  forward and lateral flexions, tenderness
  over SIJ
          Case History (2)
 Normocytic, normochromic anemia
 Increased ESR OF 40 mm/h
 Increased sclerosis of the SIJ
 HLA-B27 positive
 Treated with NSAIDS and physiotherapy
 Salazopyrine
 Anti-TNFα therapy
 Diagnostic problems of Case 1
 Low back pain
 A detailed history and clinical examination
  is mandatory
 Presence of sacroiliitis
 HLA-B27?
Psoriatic arthritis
          Case History (3)
A   25 year old woman
 5 years history of psoriasis
 Oligoarthritis involving the knee and ankle
 Increased ESR, negative RF
 Treated with NSAIDS and intra-articular
  corticosteroid injections
 Polyarticular course
 Methotrexate
         Historical background
 1882   : Bourdillon – first study on psoriatic
 1956 : Wright – first definition of psoriatic
  arthritis as “an inflammatory arthritis
  associated with psoriasis usually with an
  absence of rheumatoid factor in the
 1970 : Wright and Moll : clinical
  classification of psoriatic arthritis

 7-42%  of patients with psoriasis
 Estimated prevalence of 1 %
 Annual incidence of 6.1 per 100000
 Mild predominance in males

 Familial
 HLA-B13, 17,38,Cw6, DR4 and DR7
 HLA-B27 related to axial involvement
        Immunologic factors
 Imbalance   of T cell activity
 Increased proliferative activity of
  fibroblasts and synovia
 Activated T cells in both skin and joints
 Inflammatory mediators : TNF,
  IL,prostaglandins, leukotrienes
Skin lesions
Link between skin and joint disease
 Skin   involvement precedes arthritis in 70
 Simultaneous onset in 15%
 Psoriatic arthritis sine psoriasis in 10-15%
 Loose correlation between joint and skin
 Different genetic background
 Increased nail involvement
        Moll and Wright clinical
 Arthritis of the distal interphalangeal joints
 Arthritis mutilans
 Symmetric polyarthritis (28-78)
 Asymmetric oligoarthritis (16-53%)
 Spondyloarthropathy (20-40%)
DIP involvement
Psoriatic arthritis is an enthesitis

 DIP joint disease
 Spinal inflammation
 Dactylitis-sausage finger
Sausage finger
 Extra-articular features of psoriatic

 Psoriatic   skin lesions
 Iritis
 Mouth  ulcers
 Urethritis
  Radiological features of PsA
 Lack of juxta-articular osteopenia
 Pencil-in cup change
 Ankylosis
 Periostal reaction
 Asymmetric sacroiliitis
 Coarse syndesmophytes
Erosive psoriatic arthritis
  Prognosis of psoriatic arthritis
 Increased risk of progression in patients
  who present with > 5 swollen joints
 HLA-B27 + DR-7, B-39, DQw3- bad
  prognostic signs
 Hla-b22 - protective
 Increased risk of death
                     CASPAR criteria
     Inflammatory musculoskeletal disease (joint, spine, or
                 With 3 or more of the following:
1. Current psoriasis

   2. Personal history of psoriasis (if current psoriasis not present)
3. Family history of psoriasis (if personal history of psoriasis or
current psoriasis is not present)
4. Psoriatic nail dystrophy
5. A negative test for rheumatoid factor
6. Current dactylitis
7. History of dactylitis (if current dactylitis is not present)

8. Radiological evidence of juxta-articular new bone formation
         Management of PsA
 Methotrexate
 Sulphasalazine
 Leflunomide
 Azathioprine
 Cyclosporine
 Anti TNFα therapies
 Intra articular injections of corticosteroids
 Efficacy  in PsA 1st demonstrated in 1964.
 Placebo controlled study of 21 patients
  with active skin disease and peripheral
  arthritis – observation 3 months.
 Improvement in skin and joint involvement.
5   controlled studies
 221 patients treated with 2 g/day over 36
  week course. Improvement in tender and
  swollen joints.
 Its actions appears to be confined to
  peripheral arthritis with no benefit in axial
 Rare reports of cutaneous improvement.
      Leflunomide (ARAVA)
A  selective pyrimidine synthesis inhibitor
  that targets activated T cells lacking a
  salvage pathway.
 Randomised double blind, placebo
  controlled study in 188 patients with active
  PsA and active rash.
 After 6 months 59% met primary efficacy.
  Compared with 30% of placebo.
           Other options ?
 Gold
 Cyclosporine  A
 Azathioprine and 6-mercaptopurine
 Antimalarial agents
 Colchicine
Biological treatment of PsA
         Etanercept                                     Infliximab
                     SS                          (Binding site for TNF)

               SS                              Human (IgG1)



 C H3   C H2

Fc region of         Extracellular domain of
human IgG1          human p75 TNF receptor                                

           Why target TNFα
 Increased serum
  levels of TNFα in
 Increased levels of
  TNFα in synovial fluid
  of PsA
                TNF INHIBITION WITH ENBREL                              ®
Etanercept: soluble receptor of TNFα
                                ENBREL Inhibits Activation
                                 of Cell-Surface Receptors
                                                                     ENBREL has been designed to
                                                                     complement the body’s natural
                                                                     inhibition of TNF 1


   Reference: 1. Data on file, Immunex Corporation, Seattle, Wash.
         Etanercept in PsA
       A phase III clinical trial
               (N -205 PsA, active dis.)
 Stratification
  - Etanercept 25 mg twice weekly (n=101)
  as either Etanercept (n=59) or
  Etanercept+MTX (n=42)
  - Placebo (n=104) or either placebo alone
  (n=61) or Placebo +MTX (n=43)

                    Gottlieb A. Ann Rheum Dis 2002;61(Suppl1)
Percentage of patients
    achieving ACR 20




30                                          Etanercept


     1    3         6
                  Gottlieb A. Ann Rheum Dis 2002;61(Suppl1
    Measures of arthritis activity (median
  improvement from baseline to 3 months)

    Measure         Placebo   Etanercept   P value
                     n=104       n= 101
 Phys. Assess.         0          50       <.0001
 Patient assess.       0          33.3     <.0001
  Pain ( VAS)          0          50       <.0001
Morning stiffness     25          68.3     <.0001
   CRP                -6.3        74.2     <.0001
   PASI                 9         46       <.0001
    Infliximab (Remicade)
 Chimeric  monoclonal antibody
 104 , PsA, 5 mg/kg
 O, 2 weeks, 6 weeks, thereafter every
  8 weeks.
 Week 16: ACR 20 of 65% in infliximab-
  treated pts vs 10% in controls
 Impressive improvement in skin
      Adalimumab (Humira)
 Fully human anti-TNF monoclonal
  antibody, SC, 40 mg e.o.w
 315 patients with PsA
 At week 12, ACR 20 in 58% of the
  adalimumab-treated patients vs 14% of
  the placebo-treated patients .
 59% achieved a 75% PASI improvement
  response at 24 weeks
     T cell activators blocking
Alefacept (Amevive)
 Fully human fusion protein binds CD2 on
    memory T cells and blocks interaction with
    LFA-3 on the antigen presenting cells.
Efalizumab (Raptiva)
   Humanised antibody to the CD11 subunit
    of LFA1
             PsA Treatment Guidelines

             Establish Diagnosis of Psoriatic Arthritis

Peripheral    Skin &         Axial Disease         Dactylitis   Enthesitis
Arthritis     Nail

                          NSAID (continous)
                          +/- Corticosteroid inj

                   Reassess Response to
                    Therapy and Toxicity
          PsA Treatment Guidelines
               Severe and moderate PsA           Poor prognosis
   Mild PsA
               (oliygo-polyarthritis?).          PsA

          NSAIDs and/or                Early DMARD
Respond                                (MTX,SZP, LEF)
          IA steroids

                          Adequate therapeutic          Respond
                          trial of 2 DMARD

                          Anti TNF α
           Case history (4)
A   37 year old man- positive family of
 Synovitis in the knee and swelling of the
  calf and lower thigh
 Resolved with steroid injection in the knee
 6 year later, a similar episode+ sausage
  finger of the right great toe
 11 years later, synovitis of the knee, ankle
  , toe and psoriasis
  Clinical clues to the diagnosis of
  Psoriatic arthritis sine Psoriasis
 Positivefamily history of psoriasis
 Sausage digits
 Asymmetric, oligoarticular involvement
 DIP involvement
 Waxing and waning course with frequent
 Absent RF
 Absence of rheumatoid nodules
Reactive arthritis
                  Case 5
A  20 year old soldier
 High fever with bloody diarrhea
 Two weeks later, arthritis of the right knee
 Joint aspiration: inflammatory sterile fluid
 Resolution after 3 months
              Reiter syndrome

 Arthritis
 Nongonococcal    urethritis
 Conjunctivitis
           Reactive arthritis
 An  acute arthritis developing soon after an
  infection elsewhere
 Different from septic arthritis although
  component of the infective organism may
  be present
 Increased frequency of HLA-B27
 Increased association with HIV
           Role of bacteria
 Chlamydia   trachomatis
 Shigella flexneri
 Salmonella typhimurium
 Yersinia enterocolitica
 Yersinia pseudotuberculosis
 Campylobacter jejuni
 Mycoplasma
Pathogenesis of Reactive
           Clinical features
 Symptoms   1-3 weeks after the inciting
 Mild constitutional symptoms
 Joint stiffness, inflammatory low back pain
 Oligoarthritis
 Predominant involvement of lower limbs-
  knees, ankles, feet
 Enthesitis
    Extra-articular manifestations (1)
   Urethritis
   Meatal erythema and edema – balanitis circinata
   Keratoderma blennorhagica
   Oral ulcers
   Erythema nodosum (yersinia)
   Conjunctivitis, uveitis
   Increased gut involvement
  Extra articular manifestations

 Conjunctivitis,uveitis
 Increased gut involvement
 Conduction defects
 Aortic regurgitation
Extra articular manifestations
 Laboratory and radiologic findings

 Increased ESR and CRP
 Inflammatory synovial fluid
 Erosions, asymmetric sacroiliitis
 Coarse ossification
      Course and prognosis

 Single episode or recurrent symptomatic
  attacks lasting up to 6 months
 The 10- to 20 year prognosis of
  postdysenteric syndrome better than post-

 Intraarticular
 Sulfasalazine
 Methotrexate
 Controversial effect of antibiotics
Entheropathic arthritis
       Entheropathic arthritis

 Inflammatory  bowel disease
 Bypass arthritis dermatitis syndrome
 Gluten-sensitive entheropathy
 Whipple disease
                Case 6
A  30 year old man
 Crohn at age of 25
 Treatment with Imuran, Remicade
 Clinical remission of Crohn
 Low back Pain
 Pain in the Right hip
 Sacroiliitis , Rt hip arthritis
  Inflammatory bowel diseases

 Peripheral arthritis, seronegative , large
  joints, more frequent in Crohn’s
 Ankylosing spondylitis like – clearly related
  with HLA-B27
 Association between peripheral arthritis
  and gut activity
 Extra intestinal manifestations
 Skin involvement: erythema nodosum,
  pyoderma gangrenosum, erythema
 Aphtous ulcerations
 Liver disease
 Eye inflammation
 Amyloidosis
 Treatthe underlying IBD
 Sulphasalazine
 Methotrexate
 AntiTNFα therapies

 Be   careful with NSAIDS
      Bypass arthritis-dermatitis

 Within1 year of bypass
 Oligoarthritis, sacroiliitis
 Pustular rash
 Erythema nodosum
 Related to BOG
  Gluten sensitive enteropathy

 Asymmetric   oligoarthritis, sacroiliitis
 Often GI asymptomatic
 Anti endomysial Ab, anti gliadin Ab
 Typical intestine biopsy
           Whipple disease
 Due  to tropheryma whippleii
 Seronegative oligoarthritis, sacroiliitis
 Diarrhea
 Cardiac involv-endocarditis,aortic insuff.
 Lymphadenopathy,uveitis, rash
 Prolonged treatment with penicillin or

 Synovitis
 Acne
 Palmo-plantar   pustulosis
 Hyperostosis
 Osteitis

 Musculoskeletal  complains related to the
  anterior chest wall
 Synovial involvement
 Skin involvement
Bull’s Head
hyperostosis: chest (CT
The rheumatologist

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