Guidelines in Rheumatology

1
Guidelines in Rheumatology

• The Diagnosis and Management of Ankylosing
  Spondylitis

2
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 positive AS and HLA-B27 positive
Western European Whites 8 90
African Americans 2 to 4 48
3
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

4
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

5
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

6
Advances in MedicineHope 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

7
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

8
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
9
Modified New York Criteria for the Diagnosis of AS

• Clinical Criteria
• Low back pain, gt 3 months, improved by exercise,
  not relieved by rest
• Limitation of lumbar spine motion, sagittal and
  frontal planes
• Limitation of chest expansion relative to normal
  values for age and sex

• Radiologic Criteria
• Sacroiliitis grade ? 2 bilaterally or grade 3 4
  unilaterally
• Grading
• Definite AS if radiologic criterion present plus
  at least one clinical criteria
• Probable AS if
• Three clinical criterion
• Radiologic criterion present, but no signs or
  symptoms satisfy clinical criteria

10
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
11
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

12
Bath Ankylosing Spondylitis Disease Activity
Index (BASDAI)

• A self-administered instrument (using 10-cm
  horizontal visual analog scales) that comprises 6
  questionsOver 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?

13
ASsessment in Ankylosing Spondylitis (ASAS)

• ASAS 20 An improvement of gt 20 and absolute
  improvement of gt 10 units on a 0100 scale in gt 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 BASDAIs last
  two VAS concerning morning stiffness intensity
  and duration)
• Absence of deterioration in the potential
  remaining domain
• (deterioration is defined as gt 20 worsening)

14
Introduction of Anti-TNF Agents for the
Treatment of Ankylosing Spondylitis

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

15
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

16
Pathogenesis of Joint Destruction
Increased Inflammation
Proinflammatory cytokines Chemokines
Macrophages
Increased Cell Infiltration
Adhesion molecules
Endothelium
ArticularCartilage Degradation
TNF
Metalloproteinase synthesis
Synoviocytes
Bone Erosions
Osteoclast progenitors
RANKL expression
17
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 gt 4 cm at two times, 1 month apart
• Physician Global Assessment ? 2 on Likert Scale
• Treatment Failures
• All types AS lack of response/intolerability gt
  2 NSAIDs for ? 3 months
• Patients with peripheral arthritis lack of
  response/intolerability to gt 1 DMARD,
  sulfasalazine preferred

18
Contraindications for Anti-TNF Therapy

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

19
Monitoring and Discontinuing Treatment With
Anti-TNF Agents

• ASAS core set of outcome parameters to monitor
  patients
• Physical function, pain, spinal mobility,
  patients 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 gt 1

20
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

21
Etanercept Vs. InfliximabPharmacologic
Characteristics
Etanercept Infliximab
Mechanism of TNF inhibition Decoy receptor for TNF Binds to TNF and inhibits it from binding with TNF receptor
Terminal half-life 4.25 /- 1.25 days (mean/- SD) 8 to 9.5 days (median values)
In vitro lysis of cells expressing transmembrane TNF No Yes
Mode of administration Subcutaneous IV infusion (over 2 to 3 hours)
22
Etanercept vs InfliximabClinical Differences

• Etanercept
• Approved by FDA for treatment of psoriatic
  arthritis, rheumatoid arthritis, juvenile
  rheumatoid arthritis, and AS
• Infliximab
• Approved by FDA for treatment of Crohns 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

23
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

24
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

25
Etanercept Adverse Events
Events in gt 5 of Patients Placebo (n139) Etanercept (n138)
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
Plt.0001 Plt.050 Plt.020
26
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

27
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 (Plt.0001)
• Van den Bosch
• Significant improvement with infliximab compared
  with placebo on patient and physician global
  assessments of disease activity (Plt.001)

28
Infliximab for the Treatment of AS Clinical
Trials (cont)

• Stone, et al.
• Improvement of gt 60 at week 6 and gt 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

Plt.001, all parameters except CRP, P.01
29
Infliximab Adverse Events
Events in gt 5 of Patients Placebo (n81) Infliximab (n430)
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
Approximation based on all clinical studies
30
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

31
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

32
AS Treatment AlgorithmPatients with Axial AS

• Initiate physical therapy plan with long-
• term exercise program to accompany
• pharmacologic intervention
• Emphasize posture, range of motion, and
  strengthening

• NSAIDs or Selective COX-2 inhibitors
• Efficacy and safety comparable between
  non-selective agents
• Selective COX-2 efficacy comparable, better
  safety profile, higher cost that non-selective
  NSAIDs
• Failure of at least two different
  NSAIDs/selective COX-2 inhibitors
• 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
• Contraindicated in patients with infections,
  tuberculosis, multiple sclerosis, lupus,
  malignancy, and pregnancy/lactation

• Alternative Options
• Pamidronate
• Thalidomide

Only biologic approved for treatment of AS in US
and Europe Approved in Europe only for treatment
of AS This treatment algorithm contains unlabeled
use of infliximab, pamidronate and thalidomide.
33
AS Treatment AlgorithmPatients with
Predominantly Symptomatic Peripheral Arthritis

• Initiate physical therapy plan with long-
• term exercise program to accompany
• pharmacologic intervention
• Emphasize posture, range of motion, and
  strengthening

• NSAIDs or Selective COX-2 inhibitors
• Efficacy and safety comparable between
  non-selective agents
• Selective COX-2 efficacy comparable, better
  safety profile, higher cost that non-selective
  NSAIDs
• Failure of at least two different
  NSAIDs/selective COX-2 inhibitors
• 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
• Contraindicated in patients with infections,
  tuberculosis, multiple sclerosis, lupus,
  malignancy, and pregnancy/lactation

• Alternative Options
• Pamidronate
• Thalidomide

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