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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. Natural History of AS.

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Guidelines in Rheumatology

The Diagnosis and Management of Ankylosing Spondylitis


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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


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Natural History of AS Spondylitis (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 Spondylitis (AS)

  • 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 Recently Spondylitis (AS)

  • 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: Spondylitis (AS)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 Spondylitis (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 Spondylitis (AS)


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Modified New York Criteria for the Diagnosis of AS Spondylitis (AS)

  • 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

  • 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


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Disease Activity Assessment Spondylitis (AS)

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) Spondylitis (AS)

  • 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) Spondylitis (AS)

  • 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) Spondylitis (AS)

  • 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 Spondylitis (AS)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 Cytokine

Increased

Inflammation

­ Proinflammatory cytokines

­ Chemokines

Macrophages

Increased Cell Infiltration

­ Adhesion molecules

Endothelium

ArticularCartilage

Degradation

TNF

­ Metalloproteinase synthesis

Synoviocytes

Bone Erosions

Osteoclast

progenitors

­ RANKL expression


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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 Appropriate Patients for Anti-TNF TherapyAnti-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 Appropriate Patients for Anti-TNF Therapy

  • 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 Agents Appropriate Patients for Anti-TNF Therapy

  • 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: Appropriate Patients for Anti-TNF TherapyPharmacologic Characteristics


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Etanercept vs Infliximab: Appropriate Patients for Anti-TNF TherapyClinical 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 Trials Appropriate Patients for Anti-TNF Therapy

  • 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 Appropriate Patients for Anti-TNF Therapy(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 Appropriate Patients for Anti-TNF Therapy

*P<.0001; †P<.050; ‡P<.020


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Etanercept: Adverse Events Appropriate Patients for Anti-TNF Therapy(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 Appropriate Patients for Anti-TNF Therapy

  • 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 Appropriate Patients for Anti-TNF Therapy(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 Events Appropriate Patients for Anti-TNF Therapy

* Approximation based on all clinical studies


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Infliximab: Adverse Events Appropriate Patients for Anti-TNF Therapy(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 Appropriate Patients for Anti-TNF Therapy

  • 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: Appropriate Patients for Anti-TNF TherapyPatients 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 long-

term 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

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


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AS Treatment Algorithm: Appropriate Patients for Anti-TNF TherapyPatients 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.


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