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Do Conventional Methods Give Us What We Need?

A View of the Future, Understanding Disease Progression Through Imaging Mikkel Østergaard Copenhagen University Hospitals at Hvidovre and Herlev, Copenhagen, Denmark. Baseline. 9 months later. X-ray at month 9. -Gd. +Gd. -Gd. +Gd. STIR. Do Conventional Methods Give Us What We Need?. -Gd.

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Do Conventional Methods Give Us What We Need?

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  1. A View of the Future, Understanding Disease Progression Through ImagingMikkel ØstergaardCopenhagen University Hospitals at Hvidovre and Herlev, Copenhagen, Denmark

  2. Baseline 9 months later X-ray at month 9 -Gd +Gd -Gd +Gd STIR Do Conventional Methods Give Us What We Need? -Gd +Gd -Gd +Gd STIR Østergaard, et al. Ann Rheum Dis 2005; 64: 1503-1506

  3. Background • Clinical and biochemical aspects are important in the evaluation of: • Disease activity • Risk of progressive joint destruction • But patients may progress even if in clinical remission • e.g. ’Premier’ early RA trial (Breedveld et al Arthritis Rheum 2006;54:26-37): X-ray progression in 53% of MTX-alone patients achieving DAS28<2.6 • Can modern imaging help us better understand disease progression?

  4. Key point 1:Bone Marrow Oedema • Can only be visualised by MRI • Represents inflammatory infiltrates in the bone marrow (“osteitis”)1-2 • Is a strong independent predictor of subsequent radiographic progression in early RA3-6 1. Jimenez-Boj et al. Arthritis Rheum 2007; 56:1118-11242. McQueen et al. Ann Rheum Dis 2007 (Published online) 3.McQueen et al. Ann Rheum Dis 1999; 58:156-1634.McQueen et al. Arthritis Rheum 2003; 48:1814-18275. Lindegaard et al. Ann Rheum Dis 2006; 65:1208-12126. Haavardsholm et al (abstract). Ann Rheum Dis 2007; 66, Suppl. II:94

  5. Key point 2:Predicting Progression in RA Patients in Clinical Remission by MRI • MRI and US find synovitis in the majority of patients with clinical remission1 • In patients with clinical remission, MRI synovitis was the best predictor of subsequent erosive progression on conventional radiography2 1. Brown, et al. Arthritis Rheum 2006;54:3761-3773; 2. Brown, et al. (abstract). Arthritis Rheum 2006;54:L4

  6. Key point 3:MRI More Sensitive for Erosive Progression Than the Sharp/van der Heijde Radiographic Method • In established RA, MRI RAMRIS scoring1 of unilateral wrist and MCP joints was more sensitive to change than Sharp/van der Heijde radiographic scoring of bilateral hands, wrists and forefeet2 • In a randomised controlled trial of 24 early RA patients, MRI of MCP joints demonstrated a significant lower erosion progression rate in the anti-TNF than the placebo group, while the Sharp/van der Heijde method showed only a trend3 1. Østergaard, et al. J Rheumatol 2003;30:1385-1386 2.Ejbjerg, et al. Arthritis Rheum 2005;52:2300-2306 3.Quinn, et al. Arthritis Rheum 2005;52:27-35

  7. MRI bone marrow oedema reflects histological osteitis Jimenez-Boj, et al. Arthritis Rheum 2007;56:1118-1124 McQueen, et al. Ann Rheum Dis 2007 (published online) 1A: Bone Oedema Reflects Histological Osteitis

  8. Jimenez-Boj, et al. Arthritis Rheum 2007;56:1118-1124 ABSTRACT Objective.To investigate the pathologic nature of features termed “bone erosion” and “bone marrow edema” (also called “osteitis”) on magnetic resonance imaging (MRI) scans of joints affected by rheumatoid arthritis (RA) Methods.RA patients scheduled for joint replacement surgery (metacarpophalangeal or proximal interphalangeal joints) underwent MRI on the day before surgery. The presence and localization of bone erosions and bone marrow edema as evidenced by MRI (MRI bone erosions and MRI bone marrow edema) were documented in each joint (n =12 joints). After surgery, sequential sections from throughout the whole joint were analyzed histologically for bone marrow changes, and these results were correlated with the MRI findings

  9. MRI Bone Oedema Reflects Histological Osteitis McQueen, et al. Ann Rheum Dis 2007 (published online)

  10. MRI bone marrow oedema reflects histological osteitis1-2 Relevance: The histopathological correlate of MRI bone oedema is now explained Bone oedema (”osteitis”) is a potential measure of the earliest bone involvement in RA 1A: Conclusion:Bone Oedema Reflects Histological Osteitis • 1.Jimenez-Boj et al. Arthritis Rheum 2007;56:1118-1124 • 2.McQueen et al. Ann Rheum Dis (published online)

  11. MRI bone marrow oedema is a strong predictor of progression in structural joint damage Early publications: McQueen and others Lindegaard et al. Ann Rheum Dis 2006;9:1208-1212 Haavardsholm, et al. Ann Rheum Dis 2007;66 (Suppl. II):94 Hetland, et al. unpublished data 1B:Bone Oedema Predictor of Joint Damage

  12. MRI-Detected Bone Marrow Oedema is a Predictor of Subsequent Radiographic Progression in Early RA • 84 consecutive RA patients with a disease duration < 1 year • Treated according to best clinical practice (mainly DMARDs) • Multivariate logistic regression model including possible predictors of radiographic progression: baseline RAMRIS synovitis, erosion and bone marrow oedema, MRI tenosynovitis, baseline vdHSS, DAS28, anti-CCP status, ESR and CRP as well as gender and age) • Dependent variable: Progression in Sharp vd Heijde X-ray score baseline to 1-year follow-up Haavardsholm et al. Ann Rheum Dis 2007;66(Suppl. II):94

  13. MRI Bone Oedema Is The Strongest Predictor Of Subsequent Radiographic Progression In Early RA • 89 early RA patients (duration < ½ y), participating in a double-blind, placebo-controlled RCT • Baseline • clinical/biochemical disease activity measures • MRI of the non-dominant wrist and MCP-joints (OMERACT RAMRIS) • Sharp/vdHeijde X-ray score • anti-CCP, IgM RF, age, gender, treatment arm • Multiple regression analysis with stepwise backward selection: • delta Total Sharp/vdHeijde Score (TSS) from 0 to 2 years as the dependent variable Hetland et al. (unpublished)

  14. MRI bone marrow oedema is a strong predictor of progression in structural joint damage1-3 Relevance: MRI may be used for identifying patients most likely to progress (in trials and practice) 1B: ConclusionBone Oedema Predictor of Joint Damage 1. Lindegaard et al. Ann Rheum Dis 2006;65:1208-1212 2. Haavardsholm et al. Ann Rheum Dis 2007;66 (Suppl. II):94 3. Hetland et al. (Unpublished)

  15. MRI synovitis is present in patients in clinical remission Brown et al. Arthritis Rheum 2006;54:3761-73 Subclinical MRI-synovitis predicts erosive progression Brown et al. ACR 2006, late breaking poster L4 2 Clinical Remission: MRI Predicts Progression

  16. Design • Methods • 107 RA patients receiving DMARD (+17 controls) • judged by their rheumatologist to be in remission • clinical, laboratory, functional, and QoL assessments • 1.5T MRI and US • Definitions of remission: 4 different • Physician-determined remission (clinical judgment) • ACR criteria for remission • DAS28 criteria for remission (DAS28<2.6) • Complete clinical remission (asymptomatic patients, no objective findings of disease activity on examination, as indicated by the absence of painful, tender, and swollen joints on formal metrology) Brown et al. Arthritis Rheum 2006;54:3761-3773

  17. Results • Irrespective of which clinical remission criteria: • the majority of patients continued to have evidence of active inflammation on US/MRI Brown, et al. Arthritis Rheum 2006;54:3761-3773

  18. MRI Predicts Erosive Progression in RA Patients in Clinical Remission • METHODS: • 107 RA patients on DMARD therapy judged to be in remission • assessed using the ACR and DAS28 remission criteria • clinical, laboratory, functional and quality of life assessments, over a 12-month period • standard radiography of hands and feet • hand and wrist with 1.5 Tesla MRI and US at baseline and 12 months, using standardized and validated acquisition and scoring techniques Brown, et al. ACR 2006, late breaking abstract L4

  19. MRI Predicts Erosive Progression in RA Patients in Clinical Remission • Erosion progression during 1 year: • X-ray: 30%; MRI: 46% and US 41% • Prediction of progression: • Multiple logistic regression model, the baseline factor which best predicted a worsening of radiographic erosion score in any joint over 12 months was MRI synovitis in more than two joints (OR 8.454, p = 0.009) Brown, et al. ACR 2006, late breaking abstract L4

  20. MRI synovitis is present in patients in clinical remission1 Subclinical MRI-synovitis predicts erosive progression2 2: Conclusion Clinical Remission: MRI Predicts Progression 1. Brown et al. Arthritis Rheum 2006;54:3761-3773 2. Brown, et al. ACR 2006, late breaking abstract L4

  21. MRI is more sensitive to change in structural joint damage than X-ray Ejbjerg et al. Arthritis Rheum 2005; 52: 691-6 Quinn et al Arthritis Rheum 2005;52:27-35 Ejbjerg et al., presented at ACR 2005, poster 204 3More Sensitive to Change in Damage

  22. X-ray Sharp/van der Heijde MRI Few joint approach p<0.001 NS p<0.001 MRI Many joint approach Sensitivity to Change – Erosive ProgressionNo of patients with progression on X-ray and MRI (1 y follow-up) Raw data Ejbjerg et al. Arthritis Rheum 2005;52:691-696

  23. X-ray Sharp/van der Heijde MRI Few joint approach p<0.05 NS p<0.05 MRI Many joint approach Sensitivity to Change – Erosive ProgressionNo of patients with progression on X-ray and MRI (1 y follow-up) SDD corrected data Ejbjerg et al. Arthritis Rheum 2005;52:691-696

  24. Sensitivity to Change – 1 y Follow-up 90 Early RA Patients • MRI of unilateral MCP and wrist joints, corrected for SDD, shows significantly more erosive progressors • Than X-ray of both wrists and hands(Larsen score) (chi-square, p<0.05) Ejbjerg et al. ACR 2005, poster 204

  25. Inflix Plac Early RA RCT Using MRI • 24 early (< 2 months) RA patients receiving MTX + placebo or MTX + infliximab • MRI of MCP joints demonstrated a significantly lower erosion progression rate in MTX + infliximab group • X-ray of both hands, wrists and forefeet (Sharp/vdHeijde):no statistically significant difference • MRI discriminated better than X-ray between active and placebo therapy 20 Number of erosive sites 10 0 4 14 54 Time (weeks) Quinn et al. Arthritis Rheum 2005;52:27-35

  26. MRI is more sensitive to change in structural joint damage than X-ray1-3 Relevance: To trials:Shorter or smaller trials needed to find difference between treatment arms To practice: More sensitive determination of whether the goal of ”no structural progression” is met 3: Conclusion: More Sensitive to Change in Damage • 1. Ejbjerg et al. Arthritis Rheum 2005;52:691-6 • 2. Quinn et al. Arthritis Rheum 2005;52:27-35 • 3. Ejbjerg et al. ACR 2005, poster 204

  27. Conclusion • MRI is more sensitive to change in bone erosion than X-ray • MRI bone oedema reflects osteitis • MRI findings predict erosive progression, e.g. in patients in clinical remission Modern imaging provides knowledge that helps us better understand disease progression

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