Ultrasound of metacarpophalangeal joints is a sensitive and reliable endpoint for drug therapies in rheumatoid arthritis: results of a randomized, two-center placebo-controlled study
We aimed to investigate the sensitivity and reliability of two-dimensional ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA).
A randomized, double-blind, parallel-group, two-center, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone, 15mg or 7.5mg, each compared to placebo, in consecutive two-week studies; there were 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio, respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were ≥18 years-old with RA disease duration ≥6 months, and had a Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)) ≥3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP).
All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size = 1.17, P = 0.013) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily versus placebo (effect size = 0.61, P = 0.071). A significant treatment effect for DAS28(CRP) was only observed at Day 15 in the prednisone 15 mg group (effect size = 0.95, P = 0.032). However, significant treatment effects at all time points for a variety of ultrasound (US) endpoints were detected with both prednisone doses; the largest observed effect size = 2.33. Combining US endpoints with DAS28(CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of US measures.
Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy.
Clinicaltrials.gov identifier: NCT00746512
- Prevoo ML, van't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL: Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995, 38:44–48. CrossRef
- Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Lightfoot R Jr, Paulus H, Strand V, et al.: American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995, 38:727–735. CrossRef
- Felson DT, Anderson JJ, Lange ML, Wells G, LaValley MP: Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent? Arthritis Rheum 1998, 41:1564–1570.
- Fleming A, Crown JM, Corbett M: Incidence of joint involvement in early rheumatoid arthritis. Rheumatol Rehabil 1976, 15:92–96. CrossRef
- Kane D, Balint PV, Sturrock RD: Ultrasonography is superior to clinical examination in the detection and localization of knee joint effusion in rheumatoid arthritis. J Rheumatol 2003, 30:966–971.
- Naredo E, Bonilla G, Gamero F, Uson J, Carmona L, Laffon A: Assessment of inflammatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with grey scale and power Doppler ultrasonography. Ann Rheum Dis 2005, 64:375–381. CrossRef
- Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M, Klausen T, Ostergaard M: Power Doppler ultrasonography for assessment of synovitis in the metacarpophalangeal joints of patients with rheumatoid arthritis: a comparison with dynamic magnetic resonance imaging. Arthritis Rheum 2001, 44:2018–2023. CrossRef
- Szkudlarek M, Court-Payen M, Strandberg C, Klarlund M, Klausen T, Ostergaard M: Contrast-enhanced power Doppler ultrasonography of the metacarpophalangeal joints in rheumatoid arthritis. Eur Radiol 2003, 13:163–168.
- Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG, Hensor E, Wakefield RJ, O'Connor PJ, Emery P: An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 2008, 58:2958–2967. CrossRef
- Naredo E, Collado P, Cruz A, Palop MJ, Cabero F, Richi P, Carmona L, Crespo M: Longitudinal power Doppler ultrasonographic assessment of joint inflammatory activity in early rheumatoid arthritis: predictive value in disease activity and radiologic progression. Arthritis Rheum 2007, 57:116–124. CrossRef
- Naredo E, Moller I, Cruz A, Carmona L, Garrido J: Power Doppler ultrasonographic monitoring of response to anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Arthritis Rheum 2008, 58:2248–2256. CrossRef
- Taylor PC, Steuer A, Gruber J, Cosgrove DO, Blomley MJ, Marsters PA, Wagner CL, McClinton C, Maini RN: Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis. Arthritis Rheum 2004, 50:1107–1116. CrossRef
- Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al.: The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988, 31:315–324. CrossRef
- Koski JM, Saarakkala S, Helle M, Hakulinen U, Heikkinen JO, Hermunen H, Balint P, Bruyn GA, Filippucci E, Grassi W, Iagnocco A, Luosujärvi R, Manger B, De Miguel E, Naredo E, Scheel AK, Schmidt WA, Soini I, Szkudlarek M, Terslev L, Uson J, Vuoristo S, Ziswiler HR: Assessing the intra- and inter-reader reliability of dynamic ultrasound images in power Doppler ultrasonography. Ann Rheum Dis 2006, 65:1658–1660. CrossRef
- Brown AK, Quinn MA, Karim Z, Conaghan PG, Peterfy CG, Hensor E, Wakefield RJ, O'Connor PJ, Emery P: Presence of significant synovitis in rheumatoid arthritis patients with disease-modifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006, 54:3761–3773. CrossRef
- Naredo E, Moller I, Moragues C, de Agustin JJ, Scheel AK, Grassi W, de Miguel E, Backhaus M, Balint P, Bruyn GA, D'Agostino MA, Filippucci E, Iagnocco A, Kane D, Koski JM, Mayordomo L, Schmidt WA, Swen WA, Szkudlarek M, Terslev L, Torp-Pedersen S, Uson J, Wakefield RJ, Werner C, EULAR Working Group for Musculoskeletal Ultrasound: Interobserver reliability in musculoskeletal ultrasonography: results from a "Teach the Teachers" rheumatologist course. Ann Rheum Dis 2006, 65:14–19. CrossRef
- Naredo E, Rodriguez M, Campos C, Rodriguez-Heredia JM, Medina JA, Giner E, Martinez O, Toyos FJ, Ruiz T, Ros I, Pujol M, Miquel X, García L, Aznar JJ, Chamizo E, Páez M, Morales P, Rueda A, Tuneu R, Corominas H, de Agustín JJ, Moragues C, Mínguez D, Willisch A, González-Cruz I, Aragón A, Iglesias G, Armas C, Pablo Valdazo J, Vargas C, et al.: Validity, reproducibility, and responsiveness of a twelve-joint simplified power doppler ultrasonographic assessment of joint inflammation in rheumatoid arthritis. Arthritis Rheum 2008, 59:515–522. CrossRef
- Qvistgaard E, Rogind H, Torp-Pedersen S, Terslev L, Danneskiold-Samsoe B, Bliddal H: Quantitative ultrasonography in rheumatoid arthritis: evaluation of inflammation by Doppler technique. Ann Rheum Dis 2001, 60:690–693. CrossRef
- Rosenberg C, Etchepare F, Fautrel B, Bourgeois P: Diagnosis of synovitis by ultrasonography in RA: a one-year experience is enough for reliability on static images. Joint Bone Spine 2009, 76:35–38. CrossRef
- Ribbens C, Andre B, Marcelis S, Kaye O, Mathy L, Bonnet V, Beckers C, Malaise MG: Rheumatoid hand joint synovitis: gray-scale and power Doppler US quantifications following anti-tumor necrosis factor-alpha treatment: pilot study. Radiology 2003, 229:562–569. CrossRef
- Albrecht K, Grob K, Lange U, Muller-Ladner U, Strunk J: Reliability of different Doppler ultrasound quantification methods and devices in the assessment of therapeutic response in arthritis. Rheumatology (Oxford) 2008, 47:1521–1526. CrossRef
- D'Agostino MA, Maillefert JF, Said-Nahal R, Breban M, Ravaud P, Dougados M: Detection of small joint synovitis by ultrasonography: the learning curve of rheumatologists. Ann Rheum Dis 2004, 63:1284–1287. CrossRef
- Filippucci E, Farina A, Carotti M, Salaffi F, Grassi W: Grey scale and power Doppler sonographic changes induced by intra-articular steroid injection treatment. Ann Rheum Dis 2004, 63:740–743. CrossRef
- Freeston JE, Brown AK, Hensor EM, Emery P, Conaghan PG: Extremity magnetic resonance imaging assessment of synovitis (without contrast) in rheumatoid arthritis may be less accurate than power Doppler ultrasound. Ann Rheum Dis 2008, 67:1351. CrossRef
- Scheel AK, Schmidt WA, Hermann KG, Bruyn GA, D'Agostino MA, Grassi W, Iagnocco A, Koski JM, Machold KP, Naredo E, Sattler H, Swen N, Szkudlarek M, Wakefield RJ, Ziswiler HR, Pasewaldt D, Werner C, Backhaus M: Interobserver reliability of rheumatologists performing musculoskeletal ultrasonography: results from a EULAR "Train the trainers" course. Ann Rheum Dis 2005, 64:1043–1049. CrossRef
- Szkudlarek M, Court-Payen M, Jacobsen S, Klarlund M, Thomsen HS, Ostergaard M: Interobserver agreement in ultrasonography of the finger and toe joints in rheumatoid arthritis. Arthritis Rheum 2003, 48:955–962. CrossRef
- Larche MJ, Seymour M, Lim A, Eckersley RJ, Petavy F, Chiesa F, Rioja I, Lukey PT, Binks M, McClinton C, Dolan K, Taylor PC: Quantitative Power Doppler ultrasonography is a sensitive measure of metacarpophalangeal joint synovial vascularity in rheumatoid arthritis and declines significantly following a 2-week course of oral low-dose corticosteroids. J Rheumatol 2010, 37:2493–2501. CrossRef
- Hammer HB, Bolton-King P, Bakkeheim V, Berg TH, Sundt E, Kongtorp AK, Haavardsholm EA: Examination of intra and interrater reliability with a new ultrasonographic reference atlas for scoring of synovitis in patients with rheumatoid arthritis. Ann Rheum Dis 2011, 70:1995–1998. CrossRef
- Mouterde G, Dernis E, Ruyssen-Witrand A, Claudepierre P, Schaeverbeke T, Cantagrel A, Gaudin P, Maillefert JF, Pham T, Saraux A, Tebib J, Wendling D, Fautrel B, Le Loët X: Indications of glucocorticoids in early arthritis and rheumatoid arthritis: recommendations for clinical practice based on data from the literature and expert opinion. Joint Bone Spine 2010, 77:597–603. CrossRef
- Seymour M, Pétavy F, Chiesa F, Perry H, Lukey PT, Binks M, Donatien PD, Freidin AJ, Eckersley RJ, McClinton C, Heath K, Prodanovic S, Radunovic G, Pilipovic N, Damjanov N, Taylor PC: Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa clinical trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis. Clin Exp Rheumatol 2012, 30:254–261.
- Backhaus M, Ohrndorf S, Kellner H, Strunk J, Backhaus TM, Hartung W, Sattler H, Albrecht K, Kaufmann J, Becker K, Sörensen H, Meier L, Burmester GR, Schmidt WA: Evaluation of a novel 7-joint ultrasound score in daily rheumatologic practice: a pilot project. Arthritis Rheum 2009, 61:1194–1201. CrossRef
- Kamishima T, Tanimura K, Henmi M, Narita A, Sakamoto F, Terae S, Shirato H: Power Doppler ultrasound of rheumatoid synovitis: quantification of vascular signal and analysis of interobserver variability. Skeletal Radiol 2009, 38:467–472. CrossRef
- Ultrasound of metacarpophalangeal joints is a sensitive and reliable endpoint for drug therapies in rheumatoid arthritis: results of a randomized, two-center placebo-controlled study
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
Arthritis Research & Therapy
- Online Date
- September 2012
- Online ISSN
- BioMed Central
- Additional Links
- Author Affiliations
- 1. Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford, OX3 7LD, England
- 2. John Vane Science Centre, William Harvey Research Institute, Centre for Experimental Medicine and Rheumatology, Barts and The London School of Medicine, Charterhouse Square, London, EC1M 6BQ, England
- 3. Merck Sharp & Dohme Corp, One Merck Drive, Whitehouse Station, NJ, 08889, USA
- 4. Cytel, Inc, Cambridge, 675 Massachusetts Ave, Massachusetts, 02139, USA