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Published in: Clinical Rheumatology 12/2016

01-12-2016 | Original Article

Optimizing therapy in inflammatory arthritis: prediction of relapse after tapering or stopping treatment for rheumatoid arthritis patients achieving clinical and radiological remission

Authors: Y. El Miedany, M. El Gaafary, S. Youssef, I. Ahmed, Sami Bahlas, M. Hegazi, A. Nasr

Published in: Clinical Rheumatology | Issue 12/2016

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Abstract

This study aims to assess clinical, lab/immunological or imaging (joint ultrasonography) markers able to predict disease relapse in RA patients in sustained remission when tapering or stopping their treatment. One hundred fifty-seven RA patients in clinical remission (DAS-28 <2.6 for >6 months), receiving treatment with sDMARDs and bDMARD therapy, were randomly allocated into any of five groups: Group 1: continue full dose DMARDs and taper biologic therapy by 50 % (31 patients); Group 2: taper both DMARDs and biologic therapy dose by 50 % (32 patients); Group 3: taper DMARDs by 50 % and stop biologic therapy (31 patients); Group 4: stop both DMARDs and biologic therapy (31 patients); Group 5: continue medications without change (31 patients). Forty joints were assessed ultrasonographically (DAS-28 joints + ankles + metatarsophalangeal joints) and prospectively monitored for 12 months. The primary endpoint was sustained remission for 12 months. Patients were considered as having a relapse when the DAS-28 score was >3.2 and anti-rheumatic treatment was escalated. The frequency of relapse was 41.9 % in Group 1, 59.3 % in Group 2, 67.7 % in Group 3, 77.4 % in Group 4 and 6.5 % in Group 5. Relapse rates were significantly higher in patients whose ultrasound scores raised within 3 months of stopping their medications (P < 0.001 for both GS and PD scores). Cox regression identified ACPA positivity (at baseline) and progression of functional disability (at 2 months) as predictors for relapse. Tapering therapy is feasible in RA patients. Tailored dynamic approach is advised. Joint ultrasonographic assessment, ACPA positivity and worsening functional disability predicted relapse within a short term after discontinuation of the treatment. RA patients whose DAS-28 score was <2 were more likely to remain in remission.
Literature
1.
go back to reference Aga AB, Lie E, Uhlig T et al (2015) Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000–2010. Ann Rheum Dis 74:381–388CrossRefPubMed Aga AB, Lie E, Uhlig T et al (2015) Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000–2010. Ann Rheum Dis 74:381–388CrossRefPubMed
2.
go back to reference Tanaka Y, Hirata S, Kubo S et al (2013) Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis:1–7. doi:10.1136/annrheumdis-2013-204016 Tanaka Y, Hirata S, Kubo S et al (2013) Discontinuation of adalimumab after achieving remission in patients with established rheumatoid arthritis: 1-year outcome of the HONOR study. Ann Rheum Dis:1–7. doi:10.​1136/​annrheumdis-2013-204016
3.
go back to reference Tanaka Y, Takeuchi T, Mimori T et al (2010) RRR study investigators. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis 69:1286–1291CrossRefPubMedPubMedCentral Tanaka Y, Takeuchi T, Mimori T et al (2010) RRR study investigators. Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study. Ann Rheum Dis 69:1286–1291CrossRefPubMedPubMedCentral
4.
go back to reference Nagy G, van Vollenhoven R (2015) Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Research & Therapy 17:181CrossRef Nagy G, van Vollenhoven R (2015) Sustained biologic-free and drug-free remission in rheumatoid arthritis, where are we now? Arthritis Research & Therapy 17:181CrossRef
5.
go back to reference Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG et al (2008) An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 58:2958–2967CrossRefPubMed Brown AK, Conaghan PG, Karim Z, Quinn MA, Ikeda K, Peterfy CG et al (2008) An explanation for the apparent dissociation between clinical remission and continued structural deterioration in rheumatoid arthritis. Arthritis Rheum 58:2958–2967CrossRefPubMed
6.
go back to reference Rech J, Hueber A, Finzel S, Englbrecht M et al (2015) Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis 1–7. doi:10.1136/annrheumdis-2015-207900. Rech J, Hueber A, Finzel S, Englbrecht M et al (2015) Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment. Ann Rheum Dis 1–7. doi:10.​1136/​annrheumdis-2015-207900.
7.
go back to reference Freeston JE, Wakefield RJ, Conaghan PG, Hensor EM, Stewart SP, Emery PA (2010) Diagnostic algorithm for persistence of very early inflammatory arthritis: the utility of power Doppler ultrasound when added to conventional assessment tools. Ann Rheum Dis 69:417–419CrossRefPubMed Freeston JE, Wakefield RJ, Conaghan PG, Hensor EM, Stewart SP, Emery PA (2010) Diagnostic algorithm for persistence of very early inflammatory arthritis: the utility of power Doppler ultrasound when added to conventional assessment tools. Ann Rheum Dis 69:417–419CrossRefPubMed
8.
go back to reference Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P et al (2011) Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very early synovitis. Ann Rheum Dis 70:500–507CrossRefPubMed Filer A, de Pablo P, Allen G, Nightingale P, Jordan A, Jobanputra P et al (2011) Utility of ultrasound joint counts in the prediction of rheumatoid arthritis in patients with very early synovitis. Ann Rheum Dis 70:500–507CrossRefPubMed
9.
go back to reference Nakagomi D, Ikeda K, Okubo A, Iwamoto T, Sanayama Y, Takahashi K et al (2013) Ultrasound can improve the accuracy of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis to predict the requirement for methotrexate treatment. Arthritis Rheum 65:890–898CrossRefPubMed Nakagomi D, Ikeda K, Okubo A, Iwamoto T, Sanayama Y, Takahashi K et al (2013) Ultrasound can improve the accuracy of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis to predict the requirement for methotrexate treatment. Arthritis Rheum 65:890–898CrossRefPubMed
10.
go back to reference Naredo E, Moller I, Cruz A, Carmona L, Garrido J (2008) Power Doppler ultrasonographic monitoring of response to anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Arthritis Rheum 58:2248–2256CrossRefPubMed Naredo E, Moller I, Cruz A, Carmona L, Garrido J (2008) Power Doppler ultrasonographic monitoring of response to anti-tumor necrosis factor therapy in patients with rheumatoid arthritis. Arthritis Rheum 58:2248–2256CrossRefPubMed
11.
go back to reference Wakefield RJ, D’Agostino MA, Naredo E, Buch MH, Iagnocco A, Terslev L et al (2012) After treat-to-target: can a targeted ultrasound initiative improve RA outcomes? Ann Rheum Dis 71:799–803CrossRefPubMed Wakefield RJ, D’Agostino MA, Naredo E, Buch MH, Iagnocco A, Terslev L et al (2012) After treat-to-target: can a targeted ultrasound initiative improve RA outcomes? Ann Rheum Dis 71:799–803CrossRefPubMed
12.
go back to reference Ikeda K, Nakagomi D, Sanayama Y, Yamagata M, Okubo A, Iwamoto T et al (2013) Correlation of radiographic progression with the cumulative activity of synovitis estimated by power Doppler ultrasound in rheumatoid arthritis: difference between patients treated with methotrexate and those treated with biological agents. J Rheumatol 40:1967–1976CrossRefPubMed Ikeda K, Nakagomi D, Sanayama Y, Yamagata M, Okubo A, Iwamoto T et al (2013) Correlation of radiographic progression with the cumulative activity of synovitis estimated by power Doppler ultrasound in rheumatoid arthritis: difference between patients treated with methotrexate and those treated with biological agents. J Rheumatol 40:1967–1976CrossRefPubMed
13.
go back to reference Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G (2011) Clinical and ultrasonographic remission determines different chances of relapse in early and long standing rheumatoid arthritis. Ann Rheum Dis 70:172–175CrossRefPubMed Peluso G, Michelutti A, Bosello S, Gremese E, Tolusso B, Ferraccioli G (2011) Clinical and ultrasonographic remission determines different chances of relapse in early and long standing rheumatoid arthritis. Ann Rheum Dis 70:172–175CrossRefPubMed
14.
go back to reference Saleem B, Keen H, Goeb V, Parmar R, Nizam S, Hensor EM et al (2010) Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 69:1636–1642CrossRefPubMed Saleem B, Keen H, Goeb V, Parmar R, Nizam S, Hensor EM et al (2010) Patients with RA in remission on TNF blockers: when and in whom can TNF blocker therapy be stopped? Ann Rheum Dis 69:1636–1642CrossRefPubMed
15.
go back to reference Aletaha D, Neogi T, Silman AJ et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69:1580–1588CrossRefPubMed Aletaha D, Neogi T, Silman AJ et al (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69:1580–1588CrossRefPubMed
16.
go back to reference Prevoo ML (1995) Van ‘t Hof MA, Kuper HH, et al. 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 38:44–48CrossRefPubMed Prevoo ML (1995) Van ‘t Hof MA, Kuper HH, et al. 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 38:44–48CrossRefPubMed
17.
go back to reference El Miedany Y, El Gaafary M, Youssef S, Palmer D (2010) Incorporating patient reported outcome measures in clinical practice: development and validation of a questionnaire for inflammatory arthritis. Clin Exp Rheumatol 28:734–744PubMed El Miedany Y, El Gaafary M, Youssef S, Palmer D (2010) Incorporating patient reported outcome measures in clinical practice: development and validation of a questionnaire for inflammatory arthritis. Clin Exp Rheumatol 28:734–744PubMed
18.
go back to reference El Miedany YE, Gaafary ME, Ahmed I, Youssef S, Nasr AUS (2015) Guided treat-to-target approach in early RA: implications for uncoupling of disease activity and structural joint damage. Curr Rheumatol Rev 11:18–27CrossRef El Miedany YE, Gaafary ME, Ahmed I, Youssef S, Nasr AUS (2015) Guided treat-to-target approach in early RA: implications for uncoupling of disease activity and structural joint damage. Curr Rheumatol Rev 11:18–27CrossRef
19.
go back to reference Wakefield RJ, Balint PV, Szkudlarek M, Filippucci E, Backhaus M, D’Agostino MA et al (2005) Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol 32:2485–2487PubMed Wakefield RJ, Balint PV, Szkudlarek M, Filippucci E, Backhaus M, D’Agostino MA et al (2005) Musculoskeletal ultrasound including definitions for ultrasonographic pathology. J Rheumatol 32:2485–2487PubMed
20.
go back to reference Smolen J, Keystone E (2012) Future of RA: building on what we know and tailoring treatment. Rheumatology 51:v55v56 Smolen J, Keystone E (2012) Future of RA: building on what we know and tailoring treatment. Rheumatology 51:v55v56
21.
go back to reference El Miedany Y, El Gaafary M, Palmer D, Youssef S (2011) Imaging as an outcome measure in early inflammatory arthritis: monitoring disease activity and patients’ response to therapy using ultrasonography. Arthritis. Rheumatism 63(10):S319 El Miedany Y, El Gaafary M, Palmer D, Youssef S (2011) Imaging as an outcome measure in early inflammatory arthritis: monitoring disease activity and patients’ response to therapy using ultrasonography. Arthritis. Rheumatism 63(10):S319
22.
go back to reference Iwamoto T, Ideda K, Hosokawa J, Yamagata M (2014) Prediction of relapse after discontinuation of biologic agents by ultrasonographic assessment in patients with rheumatoid arthritis in clinical remission: high predictive values of total Gray-Scale and Power Doppler Scores that represent residual synovial inflammation before discontinuation. Arthritis Care Res 66(10):1576–1581CrossRef Iwamoto T, Ideda K, Hosokawa J, Yamagata M (2014) Prediction of relapse after discontinuation of biologic agents by ultrasonographic assessment in patients with rheumatoid arthritis in clinical remission: high predictive values of total Gray-Scale and Power Doppler Scores that represent residual synovial inflammation before discontinuation. Arthritis Care Res 66(10):1576–1581CrossRef
23.
go back to reference Lamers-Karnebeek F, Jacobs H, Fransen J, Luime J, Riel P et al (2013) The post-US study: can ultrasonography predict flare inpatients with RA and persistent low disease activity in whom the TNF inhibitor (TNFi) is stopped? Preliminary results of an ongoing study. Ann Rheum Dis 72(Suppl3):214 Lamers-Karnebeek F, Jacobs H, Fransen J, Luime J, Riel P et al (2013) The post-US study: can ultrasonography predict flare inpatients with RA and persistent low disease activity in whom the TNF inhibitor (TNFi) is stopped? Preliminary results of an ongoing study. Ann Rheum Dis 72(Suppl3):214
24.
go back to reference Lamers-Karnebeek F, Jansen T, van Riel P, Luime J, Jacobs J (2015) Ultrasonography as predictor for flare in rheumatoid arthritis patients with low disease activity: nine month results from post-US- study. Ann Rheum Dis 74(Suppl2):140 Lamers-Karnebeek F, Jansen T, van Riel P, Luime J, Jacobs J (2015) Ultrasonography as predictor for flare in rheumatoid arthritis patients with low disease activity: nine month results from post-US- study. Ann Rheum Dis 74(Suppl2):140
25.
go back to reference Lamers-Karnebeek F, Luime J, van Riel P, Jacobs J, Jansen T (2016) Prediction of flare after stopping TNF-inhibitor by baseline ultrasonography and patient characteristics in rheumatoid arthritis patients with low disease activity: 12-month results. Ann Rheum Dis 75(Suppl2):125 Lamers-Karnebeek F, Luime J, van Riel P, Jacobs J, Jansen T (2016) Prediction of flare after stopping TNF-inhibitor by baseline ultrasonography and patient characteristics in rheumatoid arthritis patients with low disease activity: 12-month results. Ann Rheum Dis 75(Suppl2):125
26.
go back to reference Hirata S, Saito K, Kubo S et al (2013) Discontinuation of adalimumab after attaining disease activity score 28-erythrocyte sedimentation rate remission in patients with rheumatoid arthritis (HONOR study): an observational study. Arthritis Res Ther 15:R135CrossRefPubMedPubMedCentral Hirata S, Saito K, Kubo S et al (2013) Discontinuation of adalimumab after attaining disease activity score 28-erythrocyte sedimentation rate remission in patients with rheumatoid arthritis (HONOR study): an observational study. Arthritis Res Ther 15:R135CrossRefPubMedPubMedCentral
27.
go back to reference Haschka J, Englbrecht M, Hueber A et al (2016) Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis 75:45–51CrossRefPubMed Haschka J, Englbrecht M, Hueber A et al (2016) Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis 75:45–51CrossRefPubMed
28.
go back to reference El Miedany Y, El Gaafary M, Sayed S, Ahmed I, Nasr A, Palmer D (2014) Functional disability: a parameter fit to be a biomarker for inflammatory arthritis. Ann Rheum Dis El Miedany Y, El Gaafary M, Sayed S, Ahmed I, Nasr A, Palmer D (2014) Functional disability: a parameter fit to be a biomarker for inflammatory arthritis. Ann Rheum Dis
29.
go back to reference El Miedany Y, Youssef S, Mehanna A, El Gaafary M (2007) Development of a scoring system for assessment of outcome of early undifferentiated inflammatory synovitis. Joint Bone Spine 75(2):155–162CrossRefPubMed El Miedany Y, Youssef S, Mehanna A, El Gaafary M (2007) Development of a scoring system for assessment of outcome of early undifferentiated inflammatory synovitis. Joint Bone Spine 75(2):155–162CrossRefPubMed
30.
go back to reference van der Woude D, Young A, Jayakumar K et al (2009) Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum 60:2262–2271CrossRefPubMed van der Woude D, Young A, Jayakumar K et al (2009) Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum 60:2262–2271CrossRefPubMed
31.
go back to reference Klarenbeek NB, van der Kooij SM, Guler-Yuksel M et al (2011) Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study. Ann Rheum Dis 70:315–319CrossRefPubMed Klarenbeek NB, van der Kooij SM, Guler-Yuksel M et al (2011) Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study. Ann Rheum Dis 70:315–319CrossRefPubMed
32.
go back to reference van der Kooij SM, Goekoop-Ruiterman YP (2009) De Vries-Bouwstra JK, et al. drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis 68:914–921CrossRefPubMed van der Kooij SM, Goekoop-Ruiterman YP (2009) De Vries-Bouwstra JK, et al. drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis 68:914–921CrossRefPubMed
33.
go back to reference Smolen JS, Landewe R, Breedveld FC et al (2014) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 73:492–509CrossRefPubMed Smolen JS, Landewe R, Breedveld FC et al (2014) EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 73:492–509CrossRefPubMed
34.
go back to reference Fautrel B, Pham T, Alfaiate T et al (2016) Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: spacing of TNF-blocker injections in Rheumatoid Arthritis Study. Ann Rheum Dis 75:59–67CrossRefPubMed Fautrel B, Pham T, Alfaiate T et al (2016) Step-down strategy of spacing TNF-blocker injections for established rheumatoid arthritis in remission: results of the multicentre non-inferiority randomised open-label controlled trial (STRASS: spacing of TNF-blocker injections in Rheumatoid Arthritis Study. Ann Rheum Dis 75:59–67CrossRefPubMed
35.
go back to reference van Vollenhoven RF, Østergaard M, Leirisalo-Repo M et al (2016) Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis 75:52–58CrossRefPubMed van Vollenhoven RF, Østergaard M, Leirisalo-Repo M et al (2016) Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis 75:52–58CrossRefPubMed
36.
go back to reference van Herwaarden N, van der Maas A, Minten MJ et al (2015) Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 350:h1389CrossRefPubMedPubMedCentral van Herwaarden N, van der Maas A, Minten MJ et al (2015) Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial. BMJ 350:h1389CrossRefPubMedPubMedCentral
37.
go back to reference Moghadam M, Vonkeman H, ten Klooster P, Tekstra J et al (2016) Stopping tumor necrosis factor inhibitor treatment in patients with established rheumatoid arthritis in remission or with stable low disease activity. Arthritis Rheumatology 68:1810–1817CrossRef Moghadam M, Vonkeman H, ten Klooster P, Tekstra J et al (2016) Stopping tumor necrosis factor inhibitor treatment in patients with established rheumatoid arthritis in remission or with stable low disease activity. Arthritis Rheumatology 68:1810–1817CrossRef
Metadata
Title
Optimizing therapy in inflammatory arthritis: prediction of relapse after tapering or stopping treatment for rheumatoid arthritis patients achieving clinical and radiological remission
Authors
Y. El Miedany
M. El Gaafary
S. Youssef
I. Ahmed
Sami Bahlas
M. Hegazi
A. Nasr
Publication date
01-12-2016
Publisher
Springer London
Published in
Clinical Rheumatology / Issue 12/2016
Print ISSN: 0770-3198
Electronic ISSN: 1434-9949
DOI
https://doi.org/10.1007/s10067-016-3413-8

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