Guidelines in Rheumatology

The Diagnosis and Management of Ankylosing Spondylitis

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 Western European Whites African Americans 8% 2% to 4% AS and HLAB27 positive 90% 48%

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
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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

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

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
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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

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Clinical Features of AS
Axial arthritis (eg, sacroiliitis and spondylitis) Arthritis of girdle joints (hips and shoulders) Peripheral arthritis uncommon Others: enthesitis, osteoporosis, vertebral, fractures, spondylodiscitis, pseudoarthrosis Cardiovascular involvement Pulmonary involvement Cauda equina syndrome Enteric mucosal lesions Amyloidosis, miscellaneous
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Skeletal

Extraskeletal Acute anterior uveitis

Modified New York Criteria for the Diagnosis of AS

Clinical Criteria
Low back pain, > 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

Disease Activity Assessment

Index BASFI BASDAI Disability level Disease activity level Metric

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

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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

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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?

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ASsessment in Ankylosing Spondylitis (ASAS)

ASAS 20: An improvement of > 20% and absolute improvement of > 10 units on a 0100 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 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-TNF Agents for the Treatment of Ankylosing Spondylitis

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

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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
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Pathogenesis of Joint Destruction

Proinflammatory cytokines Macrophages Chemokines Increased Inflammation

Endothelium

Adhesion molecules

Increased Cell Infiltration

TNF

Synoviocytes Metalloproteinase synthesis

Articular Cartilage Degradation

Osteoclast progenitors
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RANKL expression

Bone Erosions

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

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Contraindications for Anti-TNF Therapy

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

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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 > 1

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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

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Etanercept Vs. Infliximab: Pharmacologic Characteristics

Etanercept Infliximab

Mechanism of TNF inhibition

Decoy receptor Binds to TNF and for TNF inhibits it from binding with TNF receptor

Terminal half-life

4.25 +/- 1.25 days (mean+/- SD)

No

8 to 9.5 days (median values)

Yes

In vitro lysis of cells expressing transmembrane TNF 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 infliximab and 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 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
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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

Placebo % (n=139) 9 17 12 12 4 9 7 7 5 2 7 Etanercept % (n=138) 30* 21 20 14 12 8 11 6 6 6 4

Events in > 5% of Patients Injection site reaction Injection site bruising Upper respiratory infection Headache Accidental injury Diarrhea Rash Rhinitis Abdominal pain Dizziness Flu syndrome
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*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
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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/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)
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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

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*P<.001, all parameters except CRP, P=.01

Infliximab: Adverse Events

Placebo% (n=81) 10* 35 21 19 7 14 12 9 Infliximab% (n=430) 20* 40 29 19 18 14 17 13

Events in > 5% of Patients

Acute infusion reaction Upper respiratory infection Headache Diarrhea Rash Rhinitis Abdominal pain Fatigue

Arthralgia
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* 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

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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 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

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AS Treatment Algorithm: Patients with Axial AS

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 Initiate physical therapy plan with longterm exercise program to accompany pharmacologic intervention Emphasize posture, range of motion, and strengthening

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 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
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 Initiate physical therapy plan with longterm exercise program to accompany pharmacologic intervention Emphasize posture, range of motion, and strengthening

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 33 This treatment algorithm contains unlabeled use of infliximab, pamidronate and thalidomide.