Guidelines in Rheumatology

Guidelines in Rheumatology The Diagnosis and Management of Ankylosing Spondylitis 1 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% 2 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 3 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 4 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 5 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 6 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 7 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 Skeletal Extraskeletal Acute anterior uveitis Cardiovascular involvement Pulmonary involvement Cauda equina syndrome Enteric mucosal lesions Amyloidosis, miscellaneous 8 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 9 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 10 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 11 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? 12 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) 13 Introduction of Anti-TNF Agents for the Treatment of Ankylosing Spondylitis US Modifications of the ASAS International Guidelines for Use of Anti-TNF Agents 14 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 15 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 16  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 17 Contraindications for Anti-TNF Therapy • • • • • • Current or recurrent infections Tuberculosis Multiple sclerosis Lupus Malignancy Pregnant or lactating 18 Monitoring 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 19 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 20 Etanercept Vs. Infliximab: Pharmacologic Characteristics Etanercept Infliximab Mechanism of TNF inhibition Terminal half-life “Decoy” receptor Binds to TNF and for TNF inhibits it from binding with TNF receptor 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) 21 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 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 22 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 23 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 24 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 25 *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 26 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) 27 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 28 *P<.001, all parameters except CRP, P=.01 Infliximab: Adverse Events Placebo% (n=81) 10* Infliximab% (n=430) 20* Events in > 5% of Patients Acute infusion reaction Upper respiratory infection Headache Diarrhea Rash 35 21 19 7 40 29 19 18 Rhinitis Abdominal pain Fatigue Arthralgia 29 14 12 9 7 14 17 13 13 * 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 30 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 31 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.