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Guidelines in Rheumatology arthritis

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					    Guidelines in Rheumatology

    The Diagnosis and Management of
    Ankylosing Spondylitis




1
    Genetic Predisposition for Development
    of Ankylosing Spondylitis (AS)

    • AS and HLA-B27 – strong association
    • Ethnic and racial variability in presence and
      expression of HLA-B27

                          HLA-B27    AS and HLA-
                          positive   B27 positive
      Western European    8%         90%
      Whites
      African Americans   2% to 4%   48%


2
    Natural History of AS

    • Highly variable
    • Early stages: spontaneous remissions and
      exacerbations
    • Spectrum of severity
      – Mild with limited sacroiliac or lumbar joint
        involvement to severe, debilitating disease
    • “Pre-spondylitic” phase – unrecognized period
      of progressive structural damage over a
      5-to-10-year period
      – Average delay in diagnosis is 8.9 years

3
    Burden of Illness

    • Functional disability
    • Potential complications
    • Quality-of-life issues
      – Pain, stiffness, fatigue, sleep problems
    • Healthcare costs = $6720 annually
      – 75% indirect medical costs
         • Missed workdays
         • Limited-activity days



4
    Obstacles to Desirable Outcomes in
    AS Until Recently

    • Diagnostic and classification limitations
    • Lack of universally accepted instruments to
      assess AS
    • Until recently, limited treatment options
       – NSAIDs, COX-2 inhibitors, DMARDs
          • Mostly symptomatic relief only
          • Minimal impact on natural course of disease




5
    Advances in Medicine:
    Hope for Patients With AS

    • Increased understanding of pathophysiologic
      processes
    • Advent of Anti-TNF agents
    • International meetings by ASAS (ASsessment in
      AS working group) to address need for universal
      standards
    • Development of ASAS guidelines
      – US modifications to the ASAS International
        Guidelines to meet realities of clinical practice in the
        United States
6
    Pathogenesis of AS

    • Incompletely understood, but knowledge
      increasing
    • Interaction between HLA-B27 and T-cell
      response
    • Increased concentration of T-cells,
      macrophages, and proinflammatory cytokines
      – Role of TNF
    • Inflammatory reactions  produce hallmarks
      of disease
7
    Clinical Features of AS


    Skeletal       Axial arthritis (eg, sacroiliitis and spondylitis)
                   Arthritis of „girdle joints‟ (hips and shoulders)
                   Peripheral arthritis uncommon
                   Others: enthesitis, osteoporosis, vertebral,
                   fractures, spondylodiscitis, pseudoarthrosis
    Extraskeletal Acute anterior uveitis
                   Cardiovascular involvement
                   Pulmonary involvement
                   Cauda equina syndrome
                   Enteric mucosal lesions
                   Amyloidosis, miscellaneous
8
    Modified New York Criteria for the
    Diagnosis of AS
    • Clinical Criteria          • Radiologic Criteria
      – Low back pain, > 3         – Sacroiliitis grade  2
        months, improved by          bilaterally or grade 3 – 4
        exercise, not relieved       unilaterally
        by rest                  • Grading
      – Limitation of lumbar       – Definite AS if radiologic
        spine motion, sagittal       criterion present plus at least
        and frontal planes           one clinical criteria
      – Limitation of chest        – Probable AS if:
        expansion relative to
        normal values for age         • Three clinical criterion
        and sex                       • Radiologic criterion
                                        present, but no signs or
                                        symptoms satisfy clinical
                                        criteria
9
     Disease Activity Assessment


          Index                                         Metric
         BASFI              Disability level
       BASDAI               Disease activity level
     ASAS - IC Composite sum of disease activity


     BASFI = Bath Ankylosing Spondylitis Functional Index
     BASDAI = Bath Ankylosing Spondylitis Disease Activity Index
     ASAS - IC = ASsessment in Ankylosing Spondylitis Improvement Criteria


10
     Bath Ankylosing Spondylitis
     Functional Index (BASFI)
     • Visual analog scale (VAS) – 10 cm
     • Mean score of 10 questions
     • Questions level of functional disability, including:
        –   Ability to bend at the waist and perform tasks
        –   Looking over your shoulder without turning your body
        –   Standing unsupported for 10 minutes without discomfort
        –   Rising from a seated position without the use of an aid
        –   Exercising and performing strenuous activity
        –   Performing daily activities of living
        –   Climbing 12 to 15 steps without aid


11
     Bath Ankylosing Spondylitis
     Disease Activity Index (BASDAI)
     • A self-administered instrument (using 10-cm horizontal
       visual analog scales) that comprises 6 questions:

       Over the last one week, how would you
       describe the overall level of:
        –   Fatigue/tiredness
        –   AS spinal (back, neck) or hip pain
        –   Pain/swelling in joints other than above
        –   Level of discomfort from tender areas
        –   Morning stiffness from the time you awake
        –   How long does morning stiffness last?


12
     ASsessment in Ankylosing
     Spondylitis (ASAS)

     • ASAS 20: An improvement of > 20% and absolute
       improvement of > 10 units on a 0–100 scale in > 3 of the
       following 4 domains:
        – Patient global assessment (by VAS global assessment)
        – Pain assessment (the average of VAS total and nocturnal
          pain scores)
        – Function (represented by BASFI)
        – Inflammation (the average of the BASDAI‟s last two VAS
          concerning morning stiffness intensity and duration)
     • Absence of deterioration in the potential remaining domain
        – (deterioration is defined as > 20% worsening)


13
     Introduction of Anti-TNF
     Agents for the Treatment of
     Ankylosing Spondylitis

     US Modifications of the ASAS
     International Guidelines for Use of
     Anti-TNF Agents




14
     Tumor Necrosis Factor: Functions
     of the Proinflammatory Cytokine

     • Stimulation of endothelial cells to express adhesion
       molecules
     • Recruitment of white blood cells in inflamed
       synovium and skin
     • Induction of inflammatory cytokine production
       (e.g., IL-1, IL-6)
     • Stimulation of synovial cells to release
       collagenases
     • Induction of bone and cartilage resorption
     • Stimulation of fibroblast proliferation

15
     Pathogenesis of Joint Destruction

                      Proinflammatory cytokines        Increased
         Macrophages  Chemokines                     Inflammation


                                                      Increased Cell
         Endothelium  Adhesion molecules
                                                        Infiltration


                                                        Articular
TNF                                                     Cartilage
         Synoviocytes  Metalloproteinase synthesis    Degradation


         Osteoclast                                      Bone
                         RANKL expression              Erosions
         progenitors

16
     US Modifications of the ASAS
     International Guidelines: Appropriate
     Patients for Anti-TNF Therapy
     • Definitive AS according to Modified New York Criteria
     • Active disease for  4 weeks
        – BASDAI > 4 cm at two times, 1 month apart
        – Physician Global Assessment  2 on Likert Scale
     • Treatment Failures
        – All types AS – lack of response/intolerability > 2 NSAIDs
          for  3 months
        – Patients with peripheral arthritis – lack of
          response/intolerability to > 1 DMARD, sulfasalazine preferred



17
     Contraindications for
     Anti-TNF Therapy

     •   Current or recurrent infections
     •   Tuberculosis
     •   Multiple sclerosis
     •   Lupus
     •   Malignancy
     •   Pregnant or lactating




18
     Monitoring and Discontinuing
     Treatment With Anti-TNF Agents

     • ASAS core set of outcome parameters to
       monitor patients
       – Physical function, pain, spinal mobility, patient‟s
         global assessment, stiffness, peripheral joints and
         entheses, acute phase reactant, fatigue
     • Assess at 6 to 8 weeks and discontinue
       patients who do not meet response criteria
       – BASDAI: Reduction of  2 units and
       – Physician Global Assessment > 1


19
     Anti-TNF Agents

     • Etanercept
       – Approved in the United States and Europe for
         treatment of AS
       – Dose: 50 mg SC per week as two 25 mg injections
         administered on same day or 3 to 4 days apart
     • Infliximab
       – Approved in Europe for treatment of AS
       – Dose: 5 mg/kg IV at week 0, 2, and 6 and every 6
         to 8 weeks thereafter


20
     Etanercept Vs. Infliximab:
     Pharmacologic Characteristics

                                    Etanercept           Infliximab

     Mechanism of TNF          “Decoy” receptor Binds to TNF and
     inhibition                for TNF          inhibits it from binding
                                                with TNF receptor
     Terminal half-life        4.25 +/- 1.25      8 to 9.5 days
                               days               (median values)
                               (mean+/- SD)
     In vitro lysis of cells   No                 Yes
     expressing
     transmembrane TNF
     Mode of administration    Subcutaneous       IV infusion
                                                  (over 2 to 3 hours)

21
     Etanercept vs Infliximab:
     Clinical Differences

     • Etanercept
        – Approved by FDA for treatment of psoriatic arthritis,
          rheumatoid arthritis, juvenile rheumatoid arthritis, and AS
     • Infliximab
        – Approved by FDA for treatment of Crohn‟s disease and
          rheumatoid arthritis
     • Safety
        – Tuberculosis and histoplasmosis
           • Post-marketing reports and FDA surveillance database
             indicate disproportionate association between infliximab
             and risk of such (opportunistic) infections

22
     Etanercept for the Treatment of AS:
     Clinical Trials
     • Marzo-Ortega, et al.
        – Significant improvement in all clinical and functional
          parameters with etanercept treatment
        – 86% MRI-detected entheseal lesions regressed completely
          or improved
     • Marzo-Ortega, et al.
        – Mean hip and spine BMD increased with 24 weeks‟
          etanercept treatment
     • Gorman, et al.
        – 80% etanercept-treated patients, 30% placebo-treated
          patients achieved ASAS 20 at 4 months
        – 6-month extension: 83%, 80%, 60% achieved ASAS 20,
          ASAS 50, ASAS 70, respectively
           • 95% of patients treated only with etanercept (not placebo)
              over 10 months achieved ASAS 20
23
     Etanercept for the Treatment of AS:
     Clinical Trials (cont)

     • Brandt, et al.
        – 57% etanercept-treated patients and 6% placebo-treated
          patients improved at least 50% on BASDAI
        – 56% in placebo group improved following switch to etanercept
        – Improvements ceased once etanercept therapy was discontinued
     • Davis, et al.
        – 57% etanercept-treated patients and 22% placebo-treated
          patients achieved ASAS 20 at 24 weeks




24
     Etanercept: Adverse Events

                                    Placebo %   Etanercept %
      Events in > 5% of Patients     (n=139)       (n=138)
      Injection site reaction            9           30*
      Injection site bruising           17           21
      Upper respiratory infection       12           20†
      Headache                          12           14
      Accidental injury                  4           12‡
      Diarrhea                         9            8
      Rash                             7            11
      Rhinitis                         7            6
      Abdominal pain                   5            6
      Dizziness                        2            6
      Flu syndrome                     7            4

25   *P<.0001; †P<.050; ‡P<.020
     Etanercept: Adverse Events (cont)

     • Serious infections and sepsis
        – Mainly in patients with underlying illness or receiving
          immunosuppressive therapy
     • CNS demyelinating disorders
        – Causal relationship unclear
        – Use with caution or avoid use in patients with transverse myelitis,
          optic neuritis, multiple sclerosis
     • Pancytopenia
        – Causal relationship unclear
        – Use with caution in patients with history of hematologic abnormalities
     • Autoantibody formation
       – Discontinue if lupus-like symptoms are observed
     • Heart failure
        – Carefully monitor if prescribed to patients with heart failure
26
     Infliximab for the Treatment of AS:
     Clinical Trials

     • Brandt, et al.
        –  50% improvement on outcome variables (ie, BASDAI,
          BASFI, pain on VAS, BASMI, QOL (SF-36) with 5 mg/kg
          dose of infliximab;  15% improvement with 3 mg/kg dose
     • Braun
        – 53% of infliximab-treated patients and 9% placebo-treated
          patients experienced regression of disease activity of  50%
        – Function and quality of life significantly improved with
          infliximab treatment (P<.0001)
     • Van den Bosch
        – Significant improvement with infliximab compared with
          placebo on patient and physician global assessments of
          disease activity (P<.001)

27
     Infliximab for the Treatment of AS:
     Clinical Trials (cont)

     • Stone, et al.
         – Improvement of > 60% at week 6 and > 75% at week 14
           observed in BASDAI, BASFI, patient global assessment,
           physician global assessment, spinal pain and total body pain,
           and HAQ
         – Improvement on MRI scans
     • Maksymowych, et al.
         – Significant improvement* on BASDAI; significant mean
           reduction in BASFI, BASGI, ESR, and CRP at week 14
         – Efficacy sustained at 1 year




      *P<.001, all parameters except CRP, P=.01
28
     Infliximab: Adverse Events

                                                     Placebo%   Infliximab%
     Events in > 5% of Patients                        (n=81)     (n=430)
     Acute infusion reaction                           10*         20*
     Upper respiratory infection                        35          40
     Headache                                           21          29
     Diarrhea                                           19          19
     Rash                                               7           18
     Rhinitis                                           14          14
     Abdominal pain                                     12          17
     Fatigue                                            9           13
     Arthralgia                                         7           13

29   * Approximation based on all clinical studies
     Infliximab: Adverse Events (cont)

     • Serious infections and sepsis
        – Cases in patients on concomitant immunosuppressive therapy
     • Neurologic events
        – Use with caution in patients with pre-existing CNS
          demyelinating or seizure disorders
     • Autoantibody formation
        – Discontinue if lupus-like symptoms are observed
     • Heart failure
        – Consider other treatment options in patients with heart failure
        – Closely monitor patients if infliximab is administered




30
     Anti-TNF Agents: Summary

     • Anti-TNF agents target underlying inflammatory process
        – Alter disease progression
        – Provide symptomatic relief
     • Recommended treatment after trial of chronic daily
       NSAIDs, physical therapy, and regular exercise
     • Good safety and tolerability profiles
     • Long-term data needed
     • Implement treatment guidelines to ensure proper
       treatment given to appropriate patients
        – Treatment algorithm presented on next two slides


31
    AS Treatment Algorithm:
    Patients with Axial AS
               NSAIDs or Selective COX-2 inhibitors
                                                                                 Initiate physical therapy plan with long-
   • Efficacy and safety comparable between non-selective agents                 term exercise program to accompany
   • Selective COX-2 efficacy comparable, better safety profile, higher          pharmacologic intervention
     cost that non-selective NSAIDs                                              • Emphasize posture, range of motion,
   Failure of at least two different NSAIDs/selective COX-2 inhibitors             and strengthening
   for minimum of 3 months




                           Anti-TNF agents
   • Etanercept 50 mg SC per week as two 25 mg injections in the
     same day or 3-4 days apart*
   • Infliximab 5 mg/kg at 0, 2, and 6 weeks and every 6 to 8 weeks
     thereafter†
                                                                                   Alternative Options
   • Contraindicated in patients with infections, tuberculosis,                      • Pamidronate
     multiple sclerosis, lupus, malignancy, and pregnancy/lactation                  • Thalidomide


   *Only biologic approved for treatment of AS in US and Europe
   †Approved in Europe only for treatment of AS
32
   This treatment algorithm contains unlabeled use of infliximab, pamidronate and thalidomide.
AS Treatment Algorithm:
Patients with Predominantly Symptomatic Peripheral Arthritis


               NSAIDs or Selective COX-2 inhibitors
                                                                                 Initiate physical therapy plan with long-
   • Efficacy and safety comparable between non-selective agents                 term exercise program to accompany
   • Selective COX-2 efficacy comparable, better safety profile, higher          pharmacologic intervention
     cost that non-selective NSAIDs                                              • Emphasize posture, range of motion,
   Failure of at least two different NSAIDs/selective COX-2 inhibitors             and strengthening
   for minimum of 3 months

                             DMARDs
                     • Preferably sulfasalazine

                           Anti-TNF agents
   • Etanercept 50 mg SC per week as two 25 mg injections in the
     same day or 3-4 days apart*
   • Infliximab 5 mg/kg at 0, 2, and 6 weeks and every 6 to 8 weeks
     thereafter†
                                                                                   Alternative Options
   • Contraindicated in patients with infections, tuberculosis,                      • Pamidronate
     multiple sclerosis, lupus, malignancy, and pregnancy/lactation                  • Thalidomide


   * Only biologic approved for treatment of AS in US and Europe
   †Approved in Europe only for treatment of AS
33
   This treatment algorithm contains unlabeled use of infliximab, pamidronate and thalidomide.

				
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