ankylosing spondilitis

7/29/2019 ankylosing spondilitis

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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

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ankylosing spondilitis