Ankylosing spondylitis revisited Time to unveil the myths and correct the misconceptions

Ankylosing spondylitis revisited: Time to unveil the myths and correct the misconceptions Presenter: Dr. Millicent Stone 1 What is Ankylosing Spondylitis? ‘ankylos’ ‘spondylosis ’ ‘itis’ Inflammatory disease of the spine that can lead to stiffening of the back 17th Century: First description • Dr. Bernard O’Connor (1666-1698) Irish physician in France described a ‘Skeleton so straightly and intimately joined and the articulations so uniform and so effaced that they really made one continuous bone’ 19th Century • First clinical descriptions – Vladimir Von Bechterew 1857-1927 – Adolf Stumpell 1853-1926 – Pierre Marie 1853-1940 – X-ray description – Valentin (1899) – Krebs (1934) ‘obliteration of the sacroiliac joints’ Sacroilitis by MRI Normal SI - SE T1 Fused SI - SE T1 Myth #1 ‘AS is just a bit of back pain’ Extra-axial features of AS – Peripheral joints (30% of patients) – Enthesopathy (up to 98%) – Extra-articular manifestations • • • • Bowel Cardiac Renal Lung Important diagnostic issues…. • Which diagnostic criteria to use? modified New York criteria vs European Spondyloarthropathy Study Group criteria • Delay in diagnosis Delay in diagnosis from symptom onset Calin et al J Rheumatol 2002 Myth #2 ‘AS does not occur after the age of 40’ International comparison of annual incidence of AS and SpA Disease Site AS AS SpA SpA Report Year Minnesota 1993 Finland 1997 Massachus 1994 etts Japan 2002 Incidence/100,000 person-years 7.3 6.9 2.0 0.48 Myth #3 ‘The Epidemiology of AS has changed over time’ AS over 50 years in Rochester Carbone et al Arthritis Rheum 1992 International comparison of prevalence of AS and SpA Disease AS AS AS AS AS AS AS AS SpA SpA SpA SpA SpA Race/Site White Minnesota Finland Taiwan Eskimo Japan Japan Germany Lebanon Circumpolar Thailand Germany Japan Report Year 1992 1992 1997 1995 1998 1973 2002 1998 1997 1996 1998 1998 2002 Prevalence (%) 0.2 0.13 0.15 0.19-0.54 0.2 0.04 0.0065 0.86 8 2-3.4 0.12 1.9 0.0095 Myth #4 ‘AS is a rare disease’ Myth #5 ‘AS is a male disease’ Sex bias • Sporadic AS – M>F This has reduced over the years – 10:1 in 1949 2.6:1 in 1993 • Familial AS – M:F=1.8:1 Gender Differences • Age at disease onset – females have later onset for sporadic earlier for familial disease – Females have a greater delay in diagnosis • Family history more likely in females – Transmission of disease • Females more likely to transmit • Disease severity – Less spinal involvement in females Myth #6 ‘AS is a not disabling’ Disability • Functional – Important predictors age, social support lack of back exercise and smoking – Ward et al Arthritis Rheum 2002 • Work – AS patients 3X more likely than the normal population to leave the work force – Boonen et al Ann Rheum Dis 2001 Functional disability in AS and RA by gender AS male (%) RA male (%) AS femal e (%) 44 RA female (%) P Steinbroker functional classification 90% • HLA B27 – Associated with AS Brewerton et al Lancet 1973 – Prevalence depends on ethnic population – Linkage proven Rubin et al Arthritis Rheum 1994 • Non HLA B27 – Genome wide screen Brown et al Arthritis Rheum 1998 Laval et al Am. J Hum Genet 2000 Genome wide scans – Brown et al 1998 • 105 affected sib pairs • Linkage to MHC=LOD 8.2 • moderate linkage: 2p 2q 3p 10q 11p 16 q LOD>1 – Laval et al 2000 • 185 families, 255 sib pairs affected. • significant or suggestive linkage: 1,2,6,9,10,16,19 • MHC contributes only 37% to AS susceptibility Myth #8 ‘HLA B27 is the AS gene’ Who’s looking for the gene(s)? • Oxford, UK • North American Spondylitis Consortium NASC • European Collaborative Group EUROAS Looking beyond B27... • Within the MHC – HLA DRB1, DQ1, DQA1: (NASC) LOD 12.4, 10.4, 8.95 – TNF- promoter polymorphisms (Höhler et al) • Outside the MHC – X chromosome: no association, (Oxford) – NOD2: no association – candidate gene approach Outside the MHC • Candidate gene approach – CYPD6 • association and weak linkage with AS (Oxford) – hANK gene (Toronto) – Interleukin 1 receptor antagonist (IL-1Ra) (Scotland, NASC and Holland) Outside the MHC • Candidate gene approach – CYPD6 weak linkage (Oxford) – hANK gene (Toronto) – IL-1Ra 2 (Scotland, NASC and Holland) The genetics of cytokines in AS • IL-1 gene complex – Association and linkage in population and family studies • TNF- promoter polymorphisms – Controversy surrounds association with AS and functional significance Quick recap… • AS is common, affecting men and women, causing significant disability and is a progressive disease • New insights into the aetiopathogenesis and genetics of the disease may lead to more effective targeted therapy Myth #9 ‘There is no effective treatment for AS’ Rationale for TNF- blockers in AS • TNF- mRNA in inflamed sacroiliac joints • SpA is associated with chronic IBD – TNF- strongly expressed in inflamed gut mucosa • Anti TNF- agents effective in other inflammatory arthropathies TNF- blockers • Infliximab – chimeric IgG1 monoclonal antibody • IV 5mg/kg induction and 8 weekly intervals • Etanercept – 75 kDa IgG1 fusion protein • SC 25mg twice weekly • Both catch soluble TNF- and infliximab binds to cell membrane bound TNF- Uncontrolled studies Study Infliximab Van den Bosch 2000 Brandt et al 2000 Stone et al 2001 Breban 2001 Abstract Maksymowytch 2002 Etanercept Marzo-Ortega Patients Trial duration MRI (weeks) 12 12 22 12 12 12 Yes(6) Yes(10) Yes(3) Yes(10) 21SpA 11 21 50 AS axial 21 10 AS (E) Toronto Experience • 21 AS • infliximab IV 5mg/kg • Active disease – 3 months NSAIDS, at least 2 at max tolerated doses – BASDAI >4 – EMS >30mins – Stone et al J Rheum 2001 Outcomes measures • Primary outcome – >20% improvement in disease activity • Secondary outcomes – ESR, CRP Spinal mobility, MRI • Sequential cytokine analysis – IL-1, TNF-, IL-10, IFN- and TGF- Percentage of patients meeting response criteria at different time points 100 90 80 70 % of patients 60 50 40 30 20 10 0 0 2 6 infusion time points, weeks. 14 Change in disease activity: BASDAI 12 10 basdai scores (0-10) 8 6 4 2 0 0 2 6 14 Assesment time points in weeks SACROILIAC JOINT INFLAMMATION Baseline 2 weeks One year SPINAL INFLAMMATION BASELINE 2 DAYS 2 WEEKS PRE-INFUSION 2 WEEKS POST POST-GD SE T1 Baeten et al Arthritis Rheum 2001 Adverse events • • • • Headaches abnormal LFT minor infections ANA + • TB • demyelination Randomized Controlled Studies in AS Trial Infliximab Braun et al 2002 75 12 16 58 Patients Trial duration Px % Tx % Etanercept Gorman et al 2002 40 16 30 80 Summary • Safe and Efficacious in the short-term – reduction in clinical disease activity, spinal and synovial inflammation • ???? – Long term efficacy and safety – Effect on Structural damage – Effect on early onset disease So…. Should all AS patients be given a trial of biologics?? Why not…. ?? • Biologics are – expensive – potential adverse effects • Not all patients respond Response after one year of therapy • At one year – 18 responders and 4 non responders Stone et al 2003 Discriminating features of responders at one year Responders N=18 Sex M:F Age Disease duration NSAID therapy DMARD therapy Non responders N=4 3:1 40.3  6.5 16  5.7 3 2 5.6  2.2 6 2.2 6.25  4.99 2607  546 p-value 15:3 39.7  8.5 9 7.2 14 7 5.8  1.15 6  2.4 30.72  35.9 4797.8  2793 0.78 0.9 0.08 0.14 0.7 0.39 0.9 0.01 0.006 BASDAI BASFI CRP TNF- Future strategies • Pharmacogenetics • Pharmacokinetics Consensus statement on use of biologics in AS • Ankylosing spondylitis assessment study group • ASAS workshop Berlin 2003 ASAS Consensus • Ankylosing Spondylitis • (usually meet modified New York criteria) • Failed conventional therapy • Active disease • BASDAI > 4 and Physician global (specialist) • Response • at 6-14 weeks • BASDAI >50% improvement &>2 units and Physician global • Infusions every 6-8 weeks The way forward ….. • Identification of patients most likely to respond • Identification of patients most likely to develop adverse events • Development of new therapies that target TNF- Cumulative frequency plot of % of patients by gender and age who have symptoms of AS and who are diagnosed with AS Population Individual patient Survival of the fittest…….? Carbone et al Arthritis Rheum 1992 Improvement in pain 3 2.5 pain score 2 1.5 1 0.5 0 0 2 6 spinal pain total body pain 14 Assessment time points weeks total body pain spinal pain TNF- blockers • Infliximab – IV 5mg/kg induction and 8 weekly intervals • Etanercept – SC 25mg/twice weekly • Humira