Supplementary material
Supplementary Table 1. Search strategy in the databases
Supplementary Table 2. Reason for exclusion and the corresponding list of references of fully assessed studies
Supplementary Table 3. List of the published reports of the five included randomized clinical trials
Supplementary Table 4. Assessment of risk of bias with Cochrane Collaboration’s tool
Supplementary Table 5. Effects of withdrawing individual biologics compared to continuing the treatment and quality of the evidence of critical and important outcomes
Supplementary Table 1. Search strategy in the databases
Database / Strategy / ResultsMEDLINE (via PubMed) / (rheumatoid OR "arthritis, rheumatoid"[mesh]) AND (adalimumab OR humira OR "certolizumab pegol" OR cimzia OR etanercept OR enbrel OR golimumab OR simponi OR infliximab OR remicade OR inflectra OR rensima OR rituximab OR mabthera OR rituxan OR abatacept OR orencia OR tocilizumab OR actemra OR "dmard"[tiab] OR "dmards"[tiab] OR "disease modifying antirheumatic drugs"[tiab] OR "antirheumatic agents"[mesh] OR "biological products"[mesh] OR "tnf inhibitors"[tiab] OR "tnf inhibitor"[tiab]) AND ("withholding treatment"[mesh] OR "remission induction"[mesh] OR "remission"[tiab] OR discontinuati*[tiab] or withdraw*[tiab] OR stopping[tiab]) AND ("randomized controlled trial"[pt] OR (("randomized"[tiab] OR "randomised"[tiab]) AND ("controlled"[tiab] AND "trial"[tiab]))) / 451
EMBASE / 'rheumatoid arthritis'/exp AND ('adalimumab'/exp OR 'certolizumab pegol'/exp OR 'etanercept'/exp OR 'golimumab'/exp OR 'infliximab'/exp OR 'rituximab'/exp OR 'abatacept'/exp OR 'tocilizumab'/exp OR 'recombinant interleukin 1 receptor blocking agent'/exp OR 'disease modifying antirheumatic drug'/exp OR 'biological product'/exp) AND ('treatment withdrawal'/exp OR 'drug withdrawal'/exp OR 'remission'/exp) AND 'randomized controlled trial'/exp AND [embase]/lim / 403
CENTRAL / (rheumatoid arthritis) AND (withdrawal OR discontinuation ) AND ("disease modifying antirheumatic drug" OR DMARD OR biological product) / 105
Scopus / TITLE-ABS-KEY((rheumatoid arthritis) AND (adalimumab OR certolizumab pegol OR etanercept OR golimumab OR infliximab OR rituximab OR abatacept OR tocilizumab OR "disease modifying antirheumatic drug" OR biological product) AND (withdrawal OR discontinuation OR remission) AND ("randomized controlled trial" OR "clinical trial")) / 122
WHO ICTRP / withdrawal OR discontinuation [in the Title] AND rheumatoid arthritis [in the Condition] / 16
ACR annual meeting / “biologic”, “withdraw” / 135
EULAR congress / withdraw / 51
Notes:
mRCT, metaRegister of Controlled Trials
CENTRAL, Cochrane Central Register of Controlled Trials
EULAR, European League Against Rheumatism
ACR, American College of Rheumatology
Supplementary Table 2. Reason for exclusion and the corresponding list of references of fully assessed studies
1. van der Kooij SM, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Guler-Yuksel M, Zwinderman AH, Kerstens PJ, van der Lubbe PA, de Beus WM, Grillet BA, Ronday HK, Huizinga TW, Breedveld FC, Dijkmans BA, Allaart CF (2009) 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 (6):914-921. doi:10.1136/ard.2008.092254
2. van den Broek M, Klarenbeek NB, Dirven L, van Schaardenburg D, Hulsmans HM, Kerstens PJ, Huizinga TW, Dijkmans BA, Allaart CF (2011) Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study. Ann Rheum Dis 70 (8):1389-1394. doi:10.1136/ard.2010.147751
3. Klarenbeek NB, van der Kooij SM, Güler-Yüksel M, van Groenendael JH, Han KH, Kerstens PJ, Huizinga TW, Dijkmans BA, Allaart CF (2011) Discontinuing treatment in patients with rheumatoid arthritis in sustained clinical remission: exploratory analyses from the BeSt study. Ann Rheum Dis 70 (2):315-319. doi:10.1136/ard.2010.136556
4. Fautrel B, Pham T, Alfaiate T, Morel J, Dernis E (2012) Tapering TNF-Blockers in Established Rheumatoid Arthritis Patients in DAS28 Remission: Results of a DAS28-Driven Step-Down Strategy Randomized Controlled Trial. Arthritis Rheum 64 (12)
5. Allaart CF, Lems WF, Huizinga TW (2013) The BeSt way of withdrawing biologic agents. Clin Exp Rheumatol 31 (4 Suppl 78):S14-18
6. Fautrel B, Pham T, Alfaiate T, Gandjbakhch F, Foltz V, Morel J, Dernis E, Gaudin P, Brocq O, Solau-Gervais E, Berthelot JM, Balblanc JC, Mariette X, Tubach F (2015) 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. doi:10.1136/annrheumdis-2014-206696
7. Spacing of TNF-blocker Injections in Rheumatoid Arthritis Study (STRASS). In: ClinicalTrials.gov [Internet]. (2012) National Library of Medicine (US). ttp://clinicaltrials.gov/show/NCT00780793.
8. Haschka J, Englbrecht M, Hueber AJ, Manger B, Kleyer A, Reiser M, Finzel S, Tony HP, Kleinert S, Feuchtenberger M, Fleck M, Manger K, Ochs W, Schmitt-Haendle M, Wendler J, Schuch F, Ronneberger M, Lorenz HM, Nuesslein H, Alten R, Demary W, Henes J, Schett G, Rech J (2015) 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. doi:10.1136/annrheumdis-2014-206439
9. Jobanputra P, Maggs F, Deeming A, Carruthers D, Rankin E, Jordan AC, Faizal A, Goddard C, Pugh M, Bowman SJ, Brailsford S, Nightingale P (2012) A randomised efficacy and discontinuation study of etanercept versus adalimumab (RED SEA) for rheumatoid arthritis: a pragmatic, unblinded, non-inferiority study of first TNF inhibitor use: outcomes over 2 years. BMJ Open 2 (6). doi:10.1136/bmjopen-2012-001395
10. Kameda H, Kurasawa T, Nagasawa H, Amano K, Takeuchi T (2012) The Addition Of Another Disease-Modifying Anti-Rheumatic Drug To Methotrexate In Place Of Infliximab Reduces The Flare Rate During 2 Years After Infliximab Discontinuation In Patients With Rheumatoid Arthritis. Arthritis Rheum 64 (10)
11. Kurasawa T, Nagasawa H, Kishimoto M, Amano K, Takeuchi T, Kameda H (2014) Addition of another disease-modifying anti-rheumatic drug to methotrexate reduces the flare rate within 2 years after infliximab discontinuation in patients with rheumatoid arthritis: an open, randomized, controlled trial. Mod Rheumatol 24 (4):561-566. doi:10.3109/14397595.2013.844886
12. van Herwaarden N, van der Maas A, Minten MJ, van den Hoogen FH, Kievit W, van Vollenhoven RF, Bijlsma JW, van den Bemt BJ, den Broeder AA (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:h1389. doi:10.1136/bmj.h1389
13. Yamanaka H, Nagaoka S, Lee SK, Bae SC, Kasama T, Kobayashi H, Nishioka Y, Ueki Y, Seto Y, Nishinarita M, Tamura N, Kimura N, Saito K, Tomita T, Nawata Y, Suzuki S, Ishigatsubo Y, Munakata Y, Makino Y, Inoue E, Tanaka Y, Takeuchi T (2015) Discontinuation of etanercept after achievement of sustained remission in patients with rheumatoid arthritis who initially had moderate disease activity-results from the ENCOURAGE study, a prospective, international, multicenter randomized study. Mod Rheumatol:1-11. doi:10.3109/14397595.2015.1123349
The study is ongoing
1. Assessing Withdrawal of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis (ARCTIC REWIND). In: ClinicalTrials.gov [Internet]. (2014) National Library of Medicine (US). http://clinicaltrials.gov/show/NCT01881308.
2. Cimzia Treatment in Rheumatoid Arthritis: Randomizing to Stop Versus Continue Disease-modifying Anti-rheumatic Drug(s). In: ClinicalTrials.gov [Internet]. (2013) National Library of Medicine (US). http://clinicaltrials.gov/show/NCT01489384.
3. Tapering and withdrawal of Methotrexate (MTX) or Tocilizumab (TCZ), after achievement of RA remission in concomitant use of MTX and TCZ, a randomized control study. (2015) UMIN-CTR Clinical Trial. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&language=E&recptno=R000020368.
The study was terminated prior to patients’ enrolment
1. A Study to Investigate the Ability of GSK706769 to Maintain Clinical Remission After Withdrawal of Enbrel in Rheumatoid Arthritis Patients. In: ClinicalTrials.gov [Internet]. (2012) National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00979771.
Supplementary Table 3. List of the published reports of the included randomized clinical trials
OPTIMA [23] / 1. Smolen JS, Emery P, Fleischmann R, van Vollenhoven RF, Pavelka K, Durez P, Guérette B, Kupper H, Redden L, Arora V, Kavanaugh A (2014) Adjustment of therapy in rheumatoid arthritis on the basis of achievement of stable low disease activity with adalimumab plus methotrexate or methotrexate alone: the randomised controlled OPTIMA trial. Lancet 383 (9914):321-332. doi:10.1016/S0140-6736(13)61751-1
2. Kavanaugh A, Fleischmann RM, Emery P, Kupper H, Redden L, Guerette B, Santra S, Smolen JS (2013) Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis 72 (1):64-71. doi:10.1136/annrheumdis-2011-201247
3. Kavanaugh A, Emery P, Fleischmann R, Van Vollenhoven RF, Pavelka K, Durez P, Guerette B (2012) Withdrawal Of Adalimumab In Early Rheumatoid Arthritis Patients Who Attained Stable Low Disease Activity With Adalimumab Plus Methotrexate: Results Of A Phase 4, Double-Blind, Placebo-Controlled Trial [presentation]. Rheumatology 2012, 1-3 May, Glasgow, United Kingdom.
4. Kavanaugh A, Emery P, Fleischmann R, Van Vollenhoven RF, Pavelka K, Durez P, Guerette B (2011) Withdrawal Of Adalimumab In Early Rheumatoid Arthritis Patients Who Attained Stable Low Disease Activity With Adalimumab Plus Methotrexate: Results Of A Phase 4, Double-Blind, Placebo-Controlled Trial [presentation]. ACR/ARHP Annual Scientific Meeting in Chicago, IL, United States, November 5-9.
PRESERVE [24] / 5. Smolen JS, Nash P, Durez P, Hall S, Ilivanova E, Irazoque-Palazuelos F, Miranda P, Park MC, Pavelka K, Pedersen R, Szumski A, Hammond C, Koenig AS, Vlahos B (2013) Maintenance, reduction, or withdrawal of etanercept after treatment with etanercept and methotrexate in patients with moderate rheumatoid arthritis (PRESERVE): a randomised controlled trial. Lancet 381 (9870):918-929. doi:10.1016/S0140-6736(12)61811-X
6. A Study Comparing Etanercept in Combination With Methotrexate in Subjects With Rheumatoid Arthritis (PRESERVE). In: ClinicalTrials.gov [Internet]. (2015) National Library of Medicine (US). https://clinicaltrials.gov/ct2/show/NCT00565409.
PRIZE [25] / 7. Emery P, Hammoudeh M, FitzGerald O, Combe B, Martin-Mola E, Buch MH, Krogulec M, Williams T, Gaylord S, Pedersen R, Bukowski J, Vlahos B (2014) Sustained Remission with Etanercept Tapering in Early Rheumatoid Arthritis N Engl J Med 371 (19):1781-1792
8. Emery P, Hammoudeh M, FitzGerald O, Combe B, Martin Mola E, Bukowski J, Pedersen R, Williams T, Gaylord S, Vlahos B (2013) Assessing Maintenance Of Remission After Withdrawal Of Etanercept Plus Methotrexate, Methotrexate Alone, Or Placebo In Early Rheumatoid Arthritis Patients Who Achieved Remission With Etanercept and Methotrexate: The Prize Study [abstract]. Ann Rheum Dis 72 (Suppl 3):399
9. Emery P, Spieler W, Stopinska-Polaszewska M, Bukowski J, Pedersen R, Williams T, Gaylord S, Vlahos B (2013) Assessing Maintenance of Remission After Withdrawal of Etanercept Plus Methotrexate, Methotrexate Alone, or Placebo in Early Rheumatoid Arthritis Patients Who Achieved Remission With Etanercept and Methotrexate: The PRIZE Study [abstract]. Arthritis & rheumatology (Hoboken, NJ) 65 (Suppl 10):2689. doi:10.1002/art.2013.65.issue-s10
10. Zhang W, Bansback N, Sun H, Pedersen R, Kotak S, Anis AH (2015) Estimating the monetary value of the annual productivity gained in patients with early rheumatoid arthritis receiving etanercept plus methotrexate: interim results from the PRIZE study. RMD open 1 (1):e000042. doi:10.1136/rmdopen-2014-000042
11. Emery P, Wiland P, Dudler J, Ionescu RM, Vlahos B, Bukowski J, Pedersen R, Williams T, Gaylord S, Kotak S (2013) Reduced/Withdrawn dose of etanercept-Methotrexate therapy of early rheumatoid arthrtis has a favorable impact on patient-reported outcomes compared with MTX alone or placebo: the PRIZE study [results]. Ann Rheum Dis 72 (Suppl 3):2. doi:10.1136/annrheumdis-2013-eular.2267
12. Wiland P, Combe B, FitzGerald OM, Tahir H, Gaylord S, Williams T, Pedersen R (2011) Impact of etanercept-methotrexate therapy on patient-reported outcomes in rheumatoid arthritis patients with up to 12 months of symptoms (PRIZE Trial) [abstract]. Arthritis Rheum 65 (Suppl 10):2359
13. Wiland P, Combe B, FitzGerald OM, Tahir H, Gaylord S, Williams T, Pedersen R (2012) Induction of Remission in Patients with up to 12 Months of Moderate-to- Severe Rheumatoid Arthritis Symptoms Treated with Etanercept Plus Methotrexate Over 52 Weeks [abstract]. Arthritis Rheum 64 (Suppl 10):2549
14. Emery P, Hamoudeh M, FitzGerald O, Combe B, Gaylord S, Williams T, Bukowski J, Pedersen R, Koenig A, Vlahos B (2012) Induction of Remission in Patients with up to 12 Months of Moderate-to-Severe Rheumatoid Arthritis Symptoms Treated with Etanercept Plus Methotrexate Over 52 Weeks. [abstract]. Arthritis & rheumatology (Hoboken, NJ) 64 (Suppl 10):2549. doi:10.1002/art.40280
15. Study Evaluating Etanercept Plus Methotrexate in Early Rheumatoid Arthritis (PRIZE). In: ClinicalTrials.gov [Internet]. (2013) National Library of Medicine (US). https://www.clinicaltrials.gov/ct2/show/NCT00913458.
DOSERA [26] / 16. van Vollenhoven RF, Ostergaard M, Leirisalo-Repo M, Uhlig T, Jansson M, Larsson E, Brock F, Franck-Larsson K (2016) Full dose, reduced dose or discontinuation of etanercept in rheumatoid arthritis. Ann Rheum Dis 75 (1):52-58. doi:10.1136/annrheumdis-2014-205726
17. Study Comparing The Effect On Disease Activity When Reducing Or Discontinuing Etanercept In Subjects With RA (DOSERA). In: ClinicalTrials.gov [Internet]. (2013) National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00858780.
18. Vollenhoven RV, Østergaard M, Leirisalo-Repo M, Uhlig T, Jansson M, Klackenberg A, Hutchinson K, Franck-Larsson K (2012) In rheumatoid arthritis patients with stable low disease activity on methotrexate plus etanercept, continuation of etanercept 50 mg weekly or 25 mg weekly are both clinically superior to discontinuation: results from a randomized, 3-armed, double-blind clinical trial [abstract]. Paper presented at the 2012 ACR/ARHP Annual Meeting Late-Breaking Abstract, Washington, DC.
19. Østergaard M, Leirisalo-Repo M, Uhlig T, Jansson M, Larsson E, Brock F, Van Vollenhoven RF (2013) In Rheumatoid Arthritis Patients With Stable Low Disease Activity On Methotrexate Plus Etanercept, Continuation Of Etanercept Is Superior Both Clinically And Radiographically To Discontinuation: Results From A Randomized, 3-Armed, Double-Blind Clinical Trial. [abstract]. Arthritis & rheumatology (Hoboken, NJ) 65 (Suppl 10):2379. doi:10.1002/art.2013.65.issue-s10
ADMIRE [27] / 20. Chatzidionysiou K, Turesson C, Teleman A, Knight A, Lindqvist E, Larsson P, Coster L, Forslind K, van Vollenhoven R, Heimburger M (2016) A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission. RMD open 2 (1):e000133. doi:10.1136/rmdopen-2015-000133
21. A Pilot Study of the Feasibility of Discontinuation of Adalimumab in Stable Rheumatoid Arthritis Patients in Clinical Remission (ADMIRE). In: ClinicalTrials.gov [Internet]. (2013) National Library of Medicine (US). http://clinicaltrials.gov/show/NCT00808509.
22. Chatzidionysiou K, Turesson C, Teleman A, Knight A, Lindqvist E, Larsson P, Coster L, Rydberg B, van Vollenhoven RF, Heimburger M (2012) A Multicenter, Randomized, Controlled, Open-Label Pilot Study of the Feasibility of Discontinuation of Adalimumab in Rheumatoid Arthritis Patients in Stable Clinical Remission [abstract]. Arthritis Rheum 64 (S10):S336-S336A Pilot Study of the Feasibility of Discontinuation of Adalimumab in Stable Rheumatoid Arthritis Patients in Clinical Remission (ADMIRE). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2013; Available from: http://clinicaltrials.gov/show/NCT00808509.
POET [28] / 1. Moghadam MG, Vonkeman HE, Ten Klooster PM, Tekstra J, van Schaardenburg D, Starmans-Kool M, Brouwer E, Bos R, Lems WF, Colin EM, Allaart CF, Meek IL, Landewe R, Bernelot Moens HJ, van Riel PL, van de Laar MA, Jansen TL (2016) Stopping Tumor Necrosis Factor-inhibitors in Patients with Established Rheumatoid Arthritis in Remission or Stable Low Disease Activity: A Pragmatic Randomized Multicenter Open-Label Controlled Trial. Arthritis & rheumatology (Hoboken, NJ). doi:10.1002/art.39626
Supplementary Table 4. Assessment of risk of bias with Cochrane Collaboration’s tool