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Guidelines in RheumatologyGuidelines in Rheumatology

The Diagnosis and Management of Ankylosing Spondylitis

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Genetic Predisposition for Development of Ankylosing Spondylitis (AS)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%

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Natural History of ASNatural 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 IllnessBurden 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 in AS Until RecentlyObstacles 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

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Advances in Medicine:Hope for Patients With ASAdvances 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 ASPathogenesis 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 ASClinical 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 the Diagnosis of ASModified 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

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Disease Activity AssessmentDisease 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 IndexASAS - IC = ASsessment in Ankylosing Spondylitis Improvement Criteria

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Bath Ankylosing Spondylitis Functional Index (BASFI)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)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)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)

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

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 CytokineTumor 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 Pathogenesis of Joint Destruction

Bone Erosions

Macrophages

Endothelium

Synoviocytes

Proinflammatory cytokines Chemokines

Adhesion molecules

Metalloproteinase synthesis

ArticularCartilage

Degradation

Increased Cell Infiltration

Increased Inflammation

Osteoclast progenitors

RANKL expression

TNF

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US Modifications of the ASAS International Guidelines: Appropriate Patients for Anti-TNF Therapy

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 TherapyContraindications 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 AgentsMonitoring 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

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Anti-TNF AgentsAnti-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 CharacteristicsEtanercept Vs. Infliximab:Pharmacologic 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)

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Etanercept vs Infliximab:Clinical DifferencesEtanercept 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

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Etanercept for the Treatment of AS: Clinical TrialsEtanercept 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)

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 EventsEtanercept: Adverse Events

Events in > 5% of Patients

Placebo %(n=139)

Etanercept % (n=138)

Injection site reaction 9 30*Injection site bruising 17 21Upper respiratory infection 12 20†

Headache 12 14

Accidental injury 4 12‡

Diarrhea 9 8

Rash 7 11Rhinitis 7 6Abdominal pain 5 6Dizziness 2 6Flu syndrome 7 4

*P<.0001; †P<.050; ‡P<.020

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Etanercept: Adverse Events (cont)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 TrialsInfliximab 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)

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

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Infliximab: Adverse EventsInfliximab: Adverse Events

Events in > 5% of Patients

Placebo% (n=81)

Infliximab% (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

* Approximation based on all clinical studies

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Infliximab: Adverse Events (cont)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: SummaryAnti-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 ASAS 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 weeks

thereafter†

• 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, higher

cost 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

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 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 weeks

thereafter†

• 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, higher

cost that non-selective NSAIDs

Failure of at least two different NSAIDs/selective COX-2 inhibitorsfor minimum of 3 months