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Guidelines in Rheumatology
The Diagnosis and Management ofAnkylosing Spondylitis
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Genetic Predisposition for Developmentof Ankylosing Spondylitis (AS)
AS and HLA-B27 strong association
Ethnic and racial variability in presence and
expression of HLA-B27
HLA-B27positive
AS and HLA-B27 positive
Western EuropeanWhites
8% 90%
African Americans 2% to 4% 48%
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Natural History of AS
Highly variable
Early stages: spontaneous remissions andexacerbations
Spectrum of severity Mild with limited sacroiliac or lumbar joint
involvement to severe, debilitating disease
Pre-spondylitic phase unrecognized periodof progressive structural damage over a5-to-10-year period Average delay in diagnosis is 8.9 years
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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
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Obstacles to Desirable Outcomes inAS 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
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Advances in Medicine:Hope for Patients With AS
Increased understanding of pathophysiologicprocesses
Advent of Anti-TNF agents International meetings by ASAS (ASsessment in
AS working group) to address need for universalstandards
Development of ASAS guidelines US modifications to the ASAS International
Guidelines to meet realities of clinical practice in theUnited States
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Pathogenesis of AS
Incompletely understood, but knowledgeincreasing
Interaction between HLA-B27 and T-cellresponse
Increased concentration of T-cells,macrophages, and proinflammatory cytokines
Role of TNF
Inflammatory reactions produce hallmarksof disease
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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
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Modified New York Criteria for theDiagnosis of AS
Clinical Criteria Low back pain, > 3
months, improved byexercise, not relieved
by rest Limitation of lumbar
spine motion, sagittaland frontal planes
Limitation of chestexpansion relative tonormal values for ageand sex
Radiologic Criteria Sacroiliitis grade 2
bilaterally or grade 3 4unilaterally
Grading Definite AS if radiologic
criterion present plus at leastone clinical criteria
Probable AS if: Three clinical criterion
Radiologic criterionpresent, but no signs orsymptoms satisfy clinical
criteria
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Disease Activity Assessment
Index Metric
BASFI Disability level
BASDAI Disease activity level
ASAS - IC Composite sum of disease activity
BASFI = Bath Ankylosing Spondylitis Functional IndexBASDAI = Bath Ankylosing Spondylitis Disease Activity Index
ASAS - IC = ASsessment in Ankylosing Spondylitis Improvement Criteria
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Bath Ankylosing SpondylitisFunctional 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
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Bath Ankylosing SpondylitisDisease Activity Index (BASDAI)
A self-administered instrument (using 10-cm horizontalvisual analog scales) that comprises 6 questions:
Over the last one week, how would youdescribe 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?
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ASsessment in AnkylosingSpondylitis (ASAS)
ASAS 20: An improvement of > 20% and absoluteimprovement of > 10 units on a 0100 scale in > 3 of thefollowing 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 > 20% worsening)
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Introduction of Anti-TNFAgents for the Treatment ofAnkylosing Spondylitis
US Modifications of the ASASInternational Guidelines for Use of
Anti-TNF Agents
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Tumor Necrosis Factor: Functionsof the Proinflammatory Cytokine
Stimulation of endothelial cells to express adhesionmolecules
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
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Pathogenesis of Joint Destruction
BoneErosions
Macrophages
Endothelium
Synoviocytes
Proinflammatory cytokines
Chemokines
Adhesion molecules
Metalloproteinase synthesis
ArticularCartilage
Degradation
Increased CellInfiltration
IncreasedInflammation
Osteoclastprogenitors
RANKL expression
TNF
S f f S S
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US Modifications of the ASASInternational Guidelines: AppropriatePatients 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 NSAIDsfor 3 months
Patients with peripheral arthritis lack ofresponse/intolerability to > 1 DMARD, sulfasalazine preferred
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Contraindications forAnti-TNF Therapy
Current or recurrent infections
Tuberculosis
Multiple sclerosis Lupus
Malignancy
Pregnant or lactating
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Monitoring and DiscontinuingTreatment With Anti-TNF Agents
ASAS core set of outcome parameters tomonitor patients
Physical function, pain, spinal mobility, patients
global assessment, stiffness, peripheral joints andentheses, 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
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Anti-TNF Agents
Etanercept
Approved in the United States and Europe fortreatment of AS
Dose: 50 mg SC per week as two 25 mg injectionsadministered 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
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Etanercept Vs. Infliximab:Pharmacologic Characteristics
Etanercept Infliximab
Mechanism of TNFinhibition
Decoy receptor
for TNFBinds to TNF andinhibits it from binding
with TNF receptorTerminal half-life 4.25 +/- 1.25
days(mean+/- SD)
8 to 9.5 days(median values)
In vitro lysis of cells
expressingtransmembrane TNF
No Yes
Mode of administration Subcutaneous IV infusion(over 2 to 3 hours)
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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 Crohns disease and
rheumatoid arthritis
Safety
Tuberculosis and histoplasmosis Post-marketing reports and FDA surveillance database
indicate disproportionate association between infliximaband risk of such (opportunistic) infections
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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 weeksetanercept 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
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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
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Etanercept: Adverse Events
Events in > 5% of Patients
Placebo %
(n=139)
Etanercept %
(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
*P
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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
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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/kgdose 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 withinfliximab treatment (P
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Infliximab: Adverse Events
Events in > 5% of Patients
Placebo%
(n=81)
Infliximab%
(n=430)
Acute infusion reaction 10* 20*
Upper respiratory infection 35 40Headache 21 29
Diarrhea 19 19
Rash 7 18
Rhinitis 14 14Abdominal pain 12 17
Fatigue 9 13
Arthralgia 7 13
* Approximation based on all clinical studies
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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 CNSdemyelinating 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
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Anti-TNF Agents: Summary
Anti-TNF agents target underlying inflammatory process Alter disease progression
Provide symptomatic relief
Recommended treatment after trial of chronic dailyNSAIDs, physical therapy, and regular exercise
Good safety and tolerability profiles
Long-term data needed
Implement treatment guidelines to ensure propertreatment given to appropriate patients Treatment algorithm presented on next two slides
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AS Treatment Algorithm:Patients with Axial AS
Alternative Options Pamidronate
Thalidomide
*Only biologic approved for treatment of AS in US and Europe
Approved in Europe only for treatment of ASThis treatment algorithm contains unlabeled use of infliximab, pamidronate and thalidomide.
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 weeksthereafter
Contraindicated in patients with infections, tuberculosis,multiple sclerosis, lupus, malignancy, and pregnancy/lactation
Initiate physical therapy plan with long-term exercise program to accompanypharmacologic 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, highercost that non-selective NSAIDs
Failure of at least two different NSAIDs/selective COX-2 inhibitorsfor minimum of 3 months
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AS Treatment Algorithm:Patients with Predominantly Symptomatic Peripheral Arthritis
Alternative Options Pamidronate
Thalidomide
* Only biologic approved for treatment of AS in US and Europe
Approved in Europe only for treatment of AS
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 weeksthereafter
Contraindicated in patients with infections, tuberculosis,multiple sclerosis, lupus, malignancy, and pregnancy/lactation
DMARDs
Preferably sulfasalazine
Initiate physical therapy plan with long-term exercise program to accompanypharmacologic 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, highercost that non-selective NSAIDs
Failure of at least two different NSAIDs/selective COX-2 inhibitorsfor minimum of 3 months