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Clinical Rheumatology

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10.01.2019 | Review Article

A Bayesian mixed treatment comparison of efficacy of biologics and small molecules in early rheumatoid arthritis

verfasst von: Vincenzo Venerito, Giuseppe Lopalco, Fabio Cacciapaglia, Marco Fornaro, Florenzo Iannone

Erschienen in: Clinical Rheumatology | Ausgabe 5/2019

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Abstract

The current paradigm in the management of rheumatoid arthritis (RA) is to treat patients in the early stage of the disease (ERA). Previous meta-analysis-based mixed treatment comparisons (MTCs), aimed to identify the most effective drugs in ERA, are biased by the wide “window” of early definition, ranging from 6 months to 2 years. The aim of this study was to estimate through a Bayesian Network Meta-Analysis which biologics or small molecules are more likely to achieve a 1-year good clinical response in ERA patients with disease duration < 1 year. According to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, randomized controlled trials (RCTs) of biologic agents and small molecules in combination with MTX to treat patients affected with ERA lasting < 1 year were searched through MEDLINE, EMBASE, Cochrane Library, and Clinicaltrials.gov between 1990 and September 2017. The outcome of interest was the achievement of American College of Rheumatology (ACR) 50 and ACR 70 response at 1 year. WinBUGS 1.4 software (MRC Biostatistics Unit, Cambridge, UK) was used to perform the analyses, using a fixed effect model. Fourteen studies were included in the analysis. Tofacitinib (64.83%) followed by Etanercept (23.26%) were the drugs with the highest probability of achieving ACR50 response. Rituximab showed the highest probability of inducing ACR70 response (52.81%) followed by Etanercept (26.85%). This is the first MTC involving only RCTs on ERA patients with disease duration < 1 year. Tofacitinib and rituximab were the drugs ranked first in inducing 1-year ACR50 and ACR70 response, respectively.

Nur mit Berechtigung zugänglich

Kvien TK (2004) Epidemiology and burden of illness of rheumatoid arthritis. Pharmacoeconomics 22(2 Suppl 1):1–12CrossRefPubMed

Kvien TK, Uhlig T (2005) Quality of life in rheumatoid arthritis. Scand J Rheumatol 34(5):333–341. https://doi.org/10.1080/03009740500327727 CrossRefPubMed

Navarro-Millan I, Curtis JR (2013) Newest clinical trial results with antitumor necrosis factor and nonantitumor necrosis factor biologics for rheumatoid arthritis. Curr Opin Rheumatol 25(3):384–390. https://doi.org/10.1097/BOR.0b013e32835fc62e CrossRefPubMedPubMedCentral

Raza K, Filer A (2015) The therapeutic window of opportunity in rheumatoid arthritis: does it ever close? Ann Rheum Dis 74(5):793–794. https://doi.org/10.1136/annrheumdis-2014-206993 CrossRefPubMed

Epis OM, Giacomelli L, Deidda S, Bruschi E (2013) Tight control applied to the biological therapy of rheumatoid arthritis. Autoimmun Rev 12(8):839–841. https://doi.org/10.1016/j.autrev.2012.11.010 CrossRefPubMed

Zeidler H (2012) The need to better classify and diagnose early and very early rheumatoid arthritis. J Rheumatol 39(2):212–217. https://doi.org/10.3899/jrheum.110967 CrossRefPubMed

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, Mease P, Menard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat E, Symmons D, Tak PP, Upchurch KS, Vencovsky J, Wolfe F, Hawker G (2010) 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 69(9):1580–1588. https://doi.org/10.1136/ard.2010.138461 CrossRefPubMed

Smolen JS, Aletaha D, McInnes IB (2016) Rheumatoid arthritis. Lancet 388(10055):2023–2038. https://doi.org/10.1016/S0140-6736(16)30173-8 CrossRefPubMed

Atzeni F, Benucci M, Salli S, Bongiovanni S, Boccassini L, Sarzi-Puttini P (2013) Different effects of biological drugs in rheumatoid arthritis. Autoimmun Rev 12(5):575–579. https://doi.org/10.1016/j.autrev.2012.10.020 CrossRefPubMed

10.

Bortoluzzi A, Furini F, Generali E, Silvagni E, Luciano N, Scire CA (2018) One year in review 2018: novelties in the treatment of rheumatoid arthritis. Clin Exp Rheumatol 36(3):347–361PubMed

11.

Singh JA, Hossain A, Tanjong Ghogomu E, Mudano AS, Maxwell LJ, Buchbinder R, Lopez-Olivo MA, Suarez-Almazor ME, Tugwell P, Wells GA (2017) Biologics or tofacitinib for people with rheumatoid arthritis unsuccessfully treated with biologics: a systematic review and network meta-analysis. Cochrane Database Syst Rev 3:CD012591. https://doi.org/10.1002/14651858.CD012591 CrossRefPubMed

12.

Singh JA, Hossain A, Tanjong Ghogomu E, Kotb A, Christensen R, Mudano AS, Maxwell LJ, Shah NP, Tugwell P, Wells GA (2016) Biologics or tofacitinib for rheumatoid arthritis in incomplete responders to methotrexate or other traditional disease-modifying anti-rheumatic drugs: a systematic review and network meta-analysis. Cochrane Database Syst Rev 5:CD012183. https://doi.org/10.1002/14651858.CD012183 CrossRef

13.

Singh JA, Hossain A, Mudano AS, Tanjong Ghogomu E, Suarez-Almazor ME, Buchbinder R, Maxwell LJ, Tugwell P, Wells GA (2017) Biologics or tofacitinib for people with rheumatoid arthritis naive to methotrexate: a systematic review and network meta-analysis. Cochrane Database Syst Rev 5:CD012657. https://doi.org/10.1002/14651858.CD012657 CrossRefPubMed

14.

Migliore A, Bizzi E, Petrella L, Bruzzese V, Cassol M, Integlia D (2016) The challenge of treating early-stage rheumatoid arthritis: the contribution of mixed treatment comparison to choosing appropriate biologic agents. BioDrugs 30(2):105–115. https://doi.org/10.1007/s40259-016-0164-7 CrossRefPubMed

15.

Albert DA (2015) Are all biologics the same? Optimal treatment strategies for patients with early rheumatoid arthritis: systematic review and indirect pairwise meta-analysis. J Clin Rheumatol 21(8):398–404. https://doi.org/10.1097/RHU.0000000000000272 CrossRefPubMed

16.

Song F, Altman DG, Glenny AM, Deeks JJ (2003) Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 326(7387):472. https://doi.org/10.1136/bmj.326.7387.472 CrossRefPubMedPubMedCentral

17.

Coleman CI, Phung OJ, Cappelleri JC, Baker WL, Kluger J, White CM, Sobieraj DM (2012) In: Use of mixed treatment comparisons in systematic reviews. AHRQ methods for effective health care. Rockville (MD)

18.

Barhamain AS, Magliah RF, Shaheen MH, Munassar SF, Falemban AM, Alshareef MM, Almoallim HM (2017) The journey of rheumatoid arthritis patients: a review of reported lag times from the onset of symptoms. Open Access Rheumatol 9:139–150. https://doi.org/10.2147/OARRR.S138830 CrossRefPubMedPubMedCentral

19.

Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, Group P-P (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1. https://doi.org/10.1186/2046-4053-4-1 CrossRefPubMedPubMedCentral

20.

Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31(3):315–324CrossRefPubMed

21.

Gøtzsche PC (2000) Why we need a broad perspective on meta-analysis: it may be crucially important for patients. 321(7261):585–586. https://doi.org/10.1136/bmj.321.7261.585

22.

Durez P, Malghem J, Nzeusseu Toukap A, Depresseux G, Lauwerys BR, Westhovens R, Luyten FP, Corluy L, Houssiau FA, Verschueren P (2007) Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum 56(12):3919–3927. https://doi.org/10.1002/art.23055 CrossRefPubMed

23.

Quinn MA, Conaghan PG, O'Connor PJ, Karim Z, Greenstein A, Brown A, Brown C, Fraser A, Jarret S, Emery P (2005) Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 52(1):27–35. https://doi.org/10.1002/art.20712 CrossRefPubMed

24.

St Clair EW, van der Heijde DM, Smolen JS, Maini RN, Bathon JM, Emery P, Keystone E, Schiff M, Kalden JR, Wang B, Dewoody K, Weiss R, Baker D, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study G (2004) Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 50(11):3432–3443. https://doi.org/10.1002/art.20568 CrossRefPubMed

25.

Breedveld FC, Weisman MH, Kavanaugh AF, Cohen SB, Pavelka K, van Vollenhoven R, Sharp J, Perez JL, Spencer-Green GT (2006) The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 54(1):26–37. https://doi.org/10.1002/art.21519 CrossRefPubMed

26.

Bejarano V, Quinn M, Conaghan PG, Reece R, Keenan AM, Walker D, Gough A, Green M, McGonagle D, Adebajo A, Jarrett S, Doherty S, Hordon L, Melsom R, Unnebrink K, Kupper H, Emery P, Yorkshire Early Arthritis Register C (2008) Effect of the early use of the anti-tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis. Arthritis Rheum 59(10):1467–1474. https://doi.org/10.1002/art.24106 CrossRefPubMed

27.

Emery P, Breedveld FC, Hall S, Durez P, Chang DJ, Robertson D, Singh A, Pedersen RD, Koenig AS, Freundlich B (2008) Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet 372(9636):375–382. https://doi.org/10.1016/S0140-6736(08)61000-4 CrossRefPubMed

28.

Emery P, Bingham CO 3rd, Burmester GR, Bykerk VP, Furst DE, Mariette X, van der Heijde D, van Vollenhoven R, Arendt C, Mountian I, Purcaru O, Tatla D, VanLunen B, Weinblatt ME (2017) Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naive patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study. Ann Rheum Dis 76(1):96–104. https://doi.org/10.1136/annrheumdis-2015-209057 CrossRefPubMed

29.

Bijlsma JWJ, Welsing PMJ, Woodworth TG, Middelink LM, Petho-Schramm A, Bernasconi C, Borm MEA, Wortel CH, Ter Borg EJ, Jahangier ZN, van der Laan WH, Bruyn GAW, Baudoin P, Wijngaarden S, Vos P, Bos R, Starmans MJF, Griep EN, Griep-Wentink JRM, Allaart CF, Heurkens AHM, Teitsma XM, Tekstra J, Marijnissen ACA, Lafeber FPJ, Jacobs JWG (2016) Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 388(10042):343–355. https://doi.org/10.1016/S0140-6736(16)30363-4 CrossRefPubMed

30.

Burmester GR, Rigby WF, van Vollenhoven RF, Kay J, Rubbert-Roth A, Blanco R, Kadva A, Dimonaco S (2017) Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial. Ann Rheum Dis 76(7):1279–1284. https://doi.org/10.1136/annrheumdis-2016-210561 CrossRefPubMed

31.

Westhovens R, Robles M, Ximenes AC, Nayiager S, Wollenhaupt J, Durez P, Gomez-Reino J, Grassi W, Haraoui B, Shergy W, Park SH, Genant H, Peterfy C, Becker JC, Covucci A, Helfrick R, Bathon J (2009) Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 68(12):1870–1877. https://doi.org/10.1136/ard.2008.101121 CrossRefPubMed

32.

Emery P, Burmester GR, Bykerk VP, Combe BG, Furst DE, Barre E, Karyekar CS, Wong DA, Huizinga TW (2015) Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period. Ann Rheum Dis 74(1):19–26. https://doi.org/10.1136/annrheumdis-2014-206106 CrossRefPubMed

33.

Conaghan PG, Ostergaard M, Bowes MA, Wu C, Fuerst T, van der Heijde D, Irazoque-Palazuelos F, Soto-Raices O, Hrycaj P, Xie Z, Zhang R, Wyman BT, Bradley JD, Soma K, Wilkinson B (2016) Comparing the effects of tofacitinib, methotrexate and the combination, on bone marrow oedema, synovitis and bone erosion in methotrexate-naive, early active rheumatoid arthritis: results of an exploratory randomised MRI study incorporating semiquantitative and quantitative techniques. Ann Rheum Dis 75(6):1024–1033. https://doi.org/10.1136/annrheumdis-2015-208267 CrossRefPubMed

34.

Tak PP, Rigby WF, Rubbert-Roth A, Peterfy CG, van Vollenhoven RF, Stohl W, Hessey E, Chen A, Tyrrell H, Shaw TM, Investigators I (2011) Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis 70(1):39–46. https://doi.org/10.1136/ard.2010.137703 CrossRefPubMed

35.

Schiff M, Weinblatt ME, Valente R, van der Heijde D, Citera G, Elegbe A, Maldonado M, Fleischmann R (2014) Head-to-head comparison of subcutaneous abatacept versus adalimumab for rheumatoid arthritis: two-year efficacy and safety findings from AMPLE trial. Ann Rheum Dis 73(1):86–94. https://doi.org/10.1136/annrheumdis-2013-203843 CrossRefPubMed

36.

Detert J, Bastian H, Listing J, Weiss A, Wassenberg S, Liebhaber A, Rockwitz K, Alten R, Kruger K, Rau R, Simon C, Gremmelsbacher E, Braun T, Marsmann B, Hohne-Zimmer V, Egerer K, Buttgereit F, Burmester GR (2013) Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naive patients with early rheumatoid arthritis: HIT HARD, an investigator-initiated study. Ann Rheum Dis 72(6):844–850. https://doi.org/10.1136/annrheumdis-2012-201612 CrossRefPubMed

37.

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. https://doi.org/10.1136/annrheumdis-2011-201247 CrossRefPubMed

38.

Emery P, Fleischmann RM, Moreland LW, Hsia EC, Strusberg I, Durez P, Nash P, Amante EJ, Churchill M, Park W, Pons-Estel BA, Doyle MK, Visvanathan S, Xu W, Rahman MU (2009) Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis. Arthritis Rheum 60(8):2272–2283. https://doi.org/10.1002/art.24638 CrossRefPubMed

39.

Soubrier M, Puechal X, Sibilia J, Mariette X, Meyer O, Combe B, Flipo RM, Mulleman D, Berenbaum F, Zarnitsky C, Schaeverbeke T, Fardellone P, Dougados M (2009) Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford) 48(11):1429–1434. https://doi.org/10.1093/rheumatology/kep261 CrossRef

40.

Strand V, Lee EB, Fleischmann R, Alten RE, Koncz T, Zwillich SH, Gruben D, Wilkinson B, Krishnaswami S, Wallenstein G (2016) Tofacitinib versus methotrexate in rheumatoid arthritis: patient-reported outcomes from the randomised phase III ORAL start trial. RMD Open 2(2):e000308. https://doi.org/10.1136/rmdopen-2016-000308 CrossRefPubMedPubMedCentral

41.

Fleischmann R, Mysler E, Hall S, Kivitz AJ, Moots RJ, Luo Z, DeMasi R, Soma K, Zhang R, Takiya L, Tatulych S, Mojcik C, Krishnaswami S, Menon S, Smolen JS, investigators OS (2017) Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL strategy): a phase 3b/4, double-blind, head-to-head, randomised controlled trial. Lancet 390(10093):457–468. https://doi.org/10.1016/S0140-6736(17)31618-5 CrossRefPubMed

42.

Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, Zerbini CA, Gurbuz S, Dickson C, de Bono S, Schlichting D, Beattie S, Kuo WL, Rooney T, Macias W, Takeuchi T (2017) Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 69(3):506–517. https://doi.org/10.1002/art.39953 CrossRefPubMedPubMedCentral

43.

Nam JL, Villeneuve E, Hensor EM, Wakefield RJ, Conaghan PG, Green MJ, Gough A, Quinn M, Reece R, Cox SR, Buch MH, van der Heijde DM, Emery P (2014) A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial. Ann Rheum Dis 73(6):1027–1036. https://doi.org/10.1136/annrheumdis-2013-204882 CrossRefPubMed

44.

Combe B, Landewe R, Daien CI, Hua C, Aletaha D, Alvaro-Gracia JM, Bakkers M, Brodin N, Burmester GR, Codreanu C, Conway R, Dougados M, Emery P, Ferraccioli G, Fonseca J, Raza K, Silva-Fernandez L, Smolen JS, Skingle D, Szekanecz Z, Kvien TK, van der Helm-van Mil A, van Vollenhoven R (2017) 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis 76(6):948–959. https://doi.org/10.1136/annrheumdis-2016-210602 CrossRefPubMed

45.

Teitsma XM, Jacobs JWG, Welsing PMJ, de Jong PHP, Hazes JMW, Weel A, Petho-Schramm A, Borm MEA, van Laar JM, Lafeber F, Bijlsma JWJ (2018) Inadequate response to treat-to-target methotrexate therapy in patients with new-onset rheumatoid arthritis: development and validation of clinical predictors. Ann Rheum Dis 77(9):1261–1267. https://doi.org/10.1136/annrheumdis-2018-213035 CrossRefPubMed

46.

Modena V, Bianchi G, Roccatello D (2013) Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: an achievable target? Autoimmun Rev 12(8):835–838. https://doi.org/10.1016/j.autrev.2012.11.009 CrossRefPubMed

Titel: A Bayesian mixed treatment comparison of efficacy of biologics and small molecules in early rheumatoid arthritis
verfasst von: Vincenzo Venerito
Giuseppe Lopalco
Fabio Cacciapaglia
Marco Fornaro
Florenzo Iannone
Publikationsdatum: 10.01.2019
Verlag: Springer London
Erschienen in: Clinical Rheumatology / Ausgabe 5/2019
Print ISSN: 0770-3198
Elektronische ISSN: 1434-9949
DOI: https://doi.org/10.1007/s10067-018-04406-z

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