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Published in: Trials 1/2017

Open Access 01-12-2017 | Study protocol

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial

Authors: C. I. Busard, S. P. Menting, J. S. van Bezooijen, J. M. van den Reek, B. A. Hutten, E. P. Prens, E. M. de Jong, M. B. van Doorn, P. I. Spuls

Published in: Trials | Issue 1/2017

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Abstract

Background

The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases.

Methods

This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past.

Discussion

OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy.

Trial registration

NTR4499. Registered on 7 April 2014.
Appendix
Available only for authorised users
Footnotes
1
Treatment goals will be achieved if patients reach PASI ≥ 75 or PASI ≥ 50 in combination with DLQI ≤ 5. Treatment goals will not be achieved if PASI < 50 or PASI ≥50 < 75 in combination with DLQI ≥ 5 [42].
 
Literature
1.
Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158(3):558–66.CrossRefPubMed
2.
van den Reek JM, van Luumig PP, Otero ME, Zweegers J, van de Kerkhof PC, Ossenkoppele PM, et al. Satisfaction of treatment with biologics is high in psoriasis: results from the Bio-CAPTURE network. Br J Dermatol. 2014;170(5):1158–65.CrossRefPubMed
3.
Menting SP, van Lumig PP, de Vries AC, van den Reek JM, van der Kleij D, de Jong EM, et al. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up. JAMA Dermatol. 2014;150(2):130–6.CrossRefPubMed
4.
Warren RB, Smith CH, Yiu ZZ, Ashcroft DM, Barker JN, Burden AD, et al. Differential drug survival of biologic therapies for the treatment of psoriasis: a prospective observational cohort study from the British Association of Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2015;135(11):2632–40.CrossRefPubMed
5.
Bito T, Nishikawa R, Hatakeyama M, Kikusawa A, Kanki H, Nagai H, et al. Influence of neutralizing antibodies to adalimumab and infliximab on the treatment of psoriasis. Br J Dermatol. 2014;170(4):922–9.CrossRefPubMed
6.
Prieto-Perez R, Cabaleiro T, Dauden E, Abad-Santos F. Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases. Pharmacogenomics J. 2013;13(4):297–305.CrossRefPubMed
7.
Coto-Segura P, Batalla A, Gonzalez-Fernandez D, Gomez J, Santos-Juanes J, Queiro R, et al. CDKAL1 gene variants affect the anti-TNF response among psoriasis patients. Int Immunopharmacol. 2015;29(2):947–9.CrossRefPubMed
8.
Xu Z, Davis HM, Zhou H. Clinical impact of concomitant immunomodulators on biologic therapy: pharmacokinetics, immunogenicity, efficacy and safety. J Clin Pharmacol. 2015;55 Suppl 3:S60–74.CrossRefPubMed
9.
van Schouwenburg PA, van de Stadt LA, de Jong RN, van Buren EE, Kruithof S, de Groot E, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013;72(1):104–9.CrossRefPubMed
10.
Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460–8.CrossRefPubMed
11.
Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):921–6.CrossRefPubMedPubMedCentral
12.
Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1739–45.CrossRefPubMed
13.
West RL, Zelinkova Z, Wolbink GJ, Kuipers EJ, Stokkers PC, van der Woude CJ. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn's disease. Aliment Pharmacol Ther. 2008;28(9):1122–6.CrossRefPubMed
14.
Zhuang Y, Xu Z, Frederick B, de Vries DE, Ford JA, Keen M, et al. Golimumab pharmacokinetics after repeated subcutaneous and intravenous administrations in patients with rheumatoid arthritis and the effect of concomitant methotrexate: an open-label, randomized study. Clin Ther. 2012;34(1):77–90.CrossRefPubMed
15.
Baert F, Noman M, Vermeire S, Van Assche G, D’ Haens G, Carbonez A, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med. 2003;348(7):601–8.CrossRefPubMed
16.
Pouw MF, Krieckaert CL, Nurmohamed MT, van der Kleij D, Aarden L, Rispens T, et al. Key findings towards optimising adalimumab treatment: the concentration-effect curve. Ann Rheum Dis. 2015;74(3):513–8.CrossRefPubMed
17.
Kuriya B, Arkema EV, Bykerk VP, Keystone EC. Efficacy of initial methotrexate monotherapy versus combination therapy with a biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission. Ann Rheum Dis. 2010;69(7):1298–304.CrossRefPubMed
18.
Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant methotrexate: a pilot study. Clin Ther. 2003;25(6):1700–21.CrossRefPubMed
19.
Busard C, Zweegers J, Limpens J, Langendam M, Spuls PI. Combined use of systemic agents for psoriasis: a systematic review. JAMA Dermatol. 2014;150(11):1213–20.CrossRefPubMed
20.
Hugh J, Van Voorhees AS, Nijhawan RI, Bagel J, Lebwohl M, Blauvelt A, et al. From the Medical Board of the National Psoriasis Foundation: the risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol. 2014;70(1):168–77.CrossRefPubMed
21.
Gottlieb AB, Langley RG, Strober BE, Papp KA, Klekotka P, Creamer K, et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012;167(3):649–57.CrossRefPubMedPubMedCentral
22.
Zachariae C, Mork NJ, Reunala T, Lorentzen H, Falk E, Karvonen SL, et al. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy. Acta Derm Venereol. 2008;88(5):495–501.CrossRefPubMed
23.
Dalaker M, Bonesronning JH. Long-term maintenance treatment of moderate-to-severe plaque psoriasis with infliximab in combination with methotrexate or azathioprine in a retrospective cohort. J Eur Acad Dermatol Venereol. 2009;23(3):277–82.CrossRefPubMed
24.
van den Reek JM, van Lumig PP, Kievit W, Zweegers J, van de Kerkhof PC, Seyger MM, et al. Effectiveness of adalimumab dose escalation, combination therapy of adalimumab with methotrexate, or both in patients with psoriasis in daily practice. J Dermatolog Treat. 2013;24(5):361–8.CrossRefPubMed
25.
Driessen RJ, van de Kerkhof PC, de Jong EM. Etanercept combined with methotrexate for high-need psoriasis. Br J Dermatol. 2008;159(2):460–3.CrossRefPubMed
26.
van Bezooijen JS, Prens EP, Pradeepti MS, Atiqi R, Schreurs MW, Koch BC, et al. Combining biologics with methotrexate in psoriasis: a systematic review. Br J Dermatol. 2015;172(6):1676–80.CrossRefPubMed
27.
Gallo E, Cabaleiro T, Roman M, Solano-Lopez G, Abad-Santos F, Garcia-Diez A, et al. The relationship between tumour necrosis factor (TNF)-alpha promoter and IL12B/IL-23R genes polymorphisms and the efficacy of anti-TNF-alpha therapy in psoriasis: a case–control study. Br J Dermatol. 2013;169(4):819–29.CrossRefPubMed
28.
Koder S, Repnik K, Ferkolj I, Pernat C, Skok P, Weersma RK, et al. Genetic polymorphism in ATG16L1 gene influences the response to adalimumab in Crohn's disease patients. Pharmacogenomics. 2015;16(3):191–204.CrossRefPubMed
29.
Davila-Fajardo CL, van der Straaten T, Baak-Pablo R, Medarde Caballero C, Cabeza Barrera J, Huizinga TW, et al. FcGR genetic polymorphisms and the response to adalimumab in patients with rheumatoid arthritis. Pharmacogenomics. 2015;16(4):373–81.CrossRefPubMed
30.
Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point Investigator's Global Assessment (IGA) scale: a modified tool for evaluating plaque psoriasis severity in clinical trials. J Dermatolog Treat. 2015;26(1):23–31.CrossRefPubMed
31.
Menting SP, van den Reek JM, Baerveldt EM, de Jong EM, Prens EP, Lecluse LL, et al. The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis in a clinical-practice setting. Br J Dermatol. 2015;173(3):855–7.CrossRefPubMed
32.
Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012;71(11):1914–5.CrossRefPubMed
33.
Zhang J, Xie F, Delzell E, Yun H, Lewis JD, Haynes K, et al. Impact of biologic agents with and without concomitant methotrexate and at reduced doses in older rheumatoid arthritis patients. Arthritis Care Res. 2015;67(5):624–32.CrossRef
34.
Fagerli KM, Lie E, van der Heijde D, Heiberg MS, Lexberg AS, Rodevand E, et al. The role of methotrexate co-medication in TNF-inhibitor treatment in patients with psoriatic arthritis: results from 440 patients included in the NOR-DMARD study. Ann Rheum Dis. 2014;73(1):132–7.CrossRefPubMed
35.
Heiberg MS, Koldingsnes W, Mikkelsen K, Rodevand E, Kaufmann C, Mowinckel P, et al. The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study. Arthritis Rheum. 2008;59(2):234–40.CrossRefPubMed
36.
Kristensen LE, Gulfe A, Saxne T, Geborek P. Efficacy and tolerability of anti-tumour necrosis factor therapy in psoriatic arthritis patients: results from the South Swedish Arthritis Treatment Group register. Ann Rheum Dis. 2008;67(3):364–9.CrossRefPubMed
37.
38.
Nielsen OH, Bjerrum JT, Herfarth H, Rogler G. Recent advances using immunomodulators for inflammatory bowel disease. J Clin Pharmacol. 2013;53(6):575–88.CrossRefPubMed
39.
Shen DD, Azarnoff DL. Clinical pharmacokinetics of methotrexate. Clin Pharmacokinet. 1978;3(1):1–13.CrossRefPubMed
40.
Menting SP, Dekker PM, Limpens J, Hooft L, Spuls PI. Methotrexate dosing regimen for plaque-type psoriasis: a systematic review of the use of test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and folic acid supplementation. Acta dermato-venereologica. 2015.
41.
Vogelzang EH, Pouw MF, Nurmohamed M, Kneepkens EL, Rispens T, Wolbink GJ, et al. Adalimumab trough concentrations in patients with rheumatoid arthritis and psoriatic arthritis treated with concomitant disease-modifying antirheumatic drugs. Ann Rheum Dis. 2015;74(2):474–5.CrossRefPubMed
42.
Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, Nast A, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303(1):1–10.CrossRefPubMed
Metadata
Title
Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial
Authors
C. I. Busard
S. P. Menting
J. S. van Bezooijen
J. M. van den Reek
B. A. Hutten
E. P. Prens
E. M. de Jong
M. B. van Doorn
P. I. Spuls
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Trials / Issue 1/2017
Electronic ISSN: 1745-6215
DOI
https://doi.org/10.1186/s13063-017-1777-y

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