CCL20 and IL22 Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis: A Randomized Clinical Trial - PubMed (original) (raw)
Randomized Controlled Trial
CCL20 and IL22 Messenger RNA Expression After Adalimumab vs Methotrexate Treatment of Psoriasis: A Randomized Clinical Trial
Ari M Goldminz et al. JAMA Dermatol. 2015 Aug.
Abstract
Importance: Methotrexate is a first-line systemic agent for treating of psoriasis, although its onset of effects is slower and overall it is less effective than tumor necrosis factor blockers.
Objective: To differentiate the response of psoriatic disease to adalimumab and methotrexate sodium.
Design, setting, and participants: Single-center, randomized, assessor-blind, 2-arm clinical trial of 30 patients from the outpatient dermatology center of Tufts Medical Center, enrolled from August 18, 2009, to October 11, 2011. Patients aged 18 to 85 years with chronic plaque-type psoriasis, a minimum Physician Global Assessment score of 3 (higher scores indicate more severe disease), and a psoriatic plaque of at least 2 cm were randomized in a 1:1 fashion to receive subcutaneous adalimumab or oral methotrexate. Skin biopsy specimens obtained at baseline and weeks 1, 2, 4, and 16 were given a histologic grade by blinded assessors to evaluate treatment response. Analyses were conducted from April 16, 2013, to January 5, 2015.
Interventions: A 16-week course of subcutaneous adalimumab (40 mg every 2 weeks after a loading dose) or low-dosage oral methotrexate sodium (7.5-25 mg/wk).
Main outcomes and measures: Changes in genomic, immunohistochemical, and messenger RNA (mRNA) profiles.
Results: Methotrexate responders experienced significant downregulation of helper T-cell-related (T(H)1, T(H)17, and T(H)22) mRNA expression compared with methotrexate nonresponders. Comparisons among adalimumab-treated patients were limited by the number of nonresponders (n = 1). Between adalimumab and methotrexate responders, we found no significant differences in gene expression at any study point or in the expression of T-cell-related mRNA at week 16. Adalimumab responders demonstrated early downregulation of chemokine (C-C motif) ligand 20 (CCL20) mRNA (mean [SE] at week 2, -1.83 [0.52], P < .001; week 16, -3.55 [0.54], P < .001) compared with late downregulation for methotrexate responders (week 2, 0.02 [0.51], P = .96; week 16, -2.96 [0.51], P < .001). Similar differences were observed with interleukin 22 (IL22) mRNA showing early downregulation for adalimumab responders (week 2, -3.17 [1.00], P < .001; week 16, -3.58 [1.00], P < .001) compared with late downregulation for methotrexate responders (week 2, -0.44 [0.68], P = .64; week 16, -5.14 [0.68], P < .001). Analysis of variance findings for key mRNA and immunohistochemical marker expression over the study course were significant only for CCL20 (P = .03) and IL22 (P = .006) mRNA comparing adalimumab and methotrexate responders.
Conclusions and relevance: Methotrexate is an immunomodulator with effects on helper T-cell signaling in psoriasis. Similar genomic and immunohistochemical response signatures and levels of mRNA downregulation at study completion among adalimumab and methotrexate responders suggest a disease-driven instead of therapeutic-driven pathway regulation. Adalimumab and methotrexate responses are differentiated by patterns of normalization of CCL20 and IL22 mRNA expression and may explain the varied onset and degree of clinical responses by each treatment.
Trial registration: clinicaltrials.gov Identifier: NCT00932113.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Krueger is a consultant for Janssen, Lilly, and Pfizer and has grant agreements with Amgen, Janssen, Lilly, Merck, and Pfizer. Dr Gottlieb has consulting/ advisory board agreements with AbbVie, Actelion, Akros, Amgen, Astellas, Beiersdorf, Bristol-Myers Squibb, Canfite, Catabasis, Celgene, Coronado, CSL Behring, Dermipsor, Ltd, GlaxoSmithKline, Incyte, Janssen, Karyopharm, Lilly, Novartis, Novo Nordisk, Pfizer, TEVA, UCB, Vertex, Dusa, and Xenoport and receives research/educational grants (paid to Tufts Medical Center) from AbbVie, Amgen, Celgene, Coronado, Janssen, Levia, Lilly, Novartis, Merck, and Pfizer. No other disclosures were reported.
Additional Contributions: Biljana Bazdar-Vinovrski, MS, PharmD, acted as the study pharmacist. No financial compensation was given for these services.
Figures
Figure 1
CONSORT Flow Diagram
Figure 2. Changes in Genomic Data by Disease Response and Treatment Arm
A, gg plot showing variance stabilization (log2) transformation of gene expression for psoriasis transcriptome (PS) genes (1295 probes/1047 genes) among patients who responded to adalimumab treatment (responders), patients who did not respond to adalimumab treatment (nonresponders), methotrexate sodium–treated responders, and methotrexate nonresponders at week (W) 1, 2, 4, and 16 compared with baseline expression in nonlesional skin (NLS). B, Heat map representing expression of PS genes for methotrexate nonresponders, methotrexate responders, adalimumab nonresponders, and adalimumab responders with fold change (FCH) of greater than 1.5 for baseline lesional and nonlesional skin (LS and NLS, respectively) samples and samples at weeks 1, 2, 4, and 16.Wi indicates expression at any given week (weeki).
Figure 3. Changes in Select Messenger RNA (mRNA) Expression by Disease Response and Treatment Arm
Variance stabilization (log2) transformation fold change (FCH) expression of mRNA for patients who responded (responders) and did not respond (nonresponders) to study treatments. Data points indicate mean; error bars, 95%CI. Chemokine (C-C motif) ligand 20 (CCL20), interleukin 22 (IL22), IL17A, and interferon-γ (IFNG) mRNA expression at baseline are compared for baseline lesional and nonlesional skin (LS and NLS, respectively), and week (W) 1, 2, 4, and 16 for methotrexate sodium (left column) and adalimumab (right column). a P < .001. b P < .01. c P value for responders vs nonresponders, W16-LS. d P < .05.
Similar articles
- Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial.
Papp K, Thaçi D, Marcoux D, Weibel L, Philipp S, Ghislain PD, Landells I, Hoeger P, Kotkin C, Unnebrink K, Seyger M, Williams D. Papp K, et al. Lancet. 2017 Jul 1;390(10089):40-49. doi: 10.1016/S0140-6736(17)31189-3. Epub 2017 May 4. Lancet. 2017. PMID: 28478975 Clinical Trial. - A Phase 2 Trial of Guselkumab versus Adalimumab for Plaque Psoriasis.
Gordon KB, Duffin KC, Bissonnette R, Prinz JC, Wasfi Y, Li S, Shen YK, Szapary P, Randazzo B, Reich K. Gordon KB, et al. N Engl J Med. 2015 Jul 9;373(2):136-44. doi: 10.1056/NEJMoa1501646. N Engl J Med. 2015. PMID: 26154787 Clinical Trial. - Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis.
Revicki D, Willian MK, Saurat JH, Papp KA, Ortonne JP, Sexton C, Camez A. Revicki D, et al. Br J Dermatol. 2008 Mar;158(3):549-57. doi: 10.1111/j.1365-2133.2007.08236.x. Epub 2007 Nov 28. Br J Dermatol. 2008. PMID: 18047521 Clinical Trial. - Cost effectiveness of biologic therapies for plaque psoriasis.
Ahn CS, Gustafson CJ, Sandoval LF, Davis SA, Feldman SR. Ahn CS, et al. Am J Clin Dermatol. 2013 Aug;14(4):315-26. doi: 10.1007/s40257-013-0030-z. Am J Clin Dermatol. 2013. PMID: 23696234 Review. - Adalimumab: in plaque psoriasis.
Croom KF, McCormack PL. Croom KF, et al. Am J Clin Dermatol. 2009;10(1):43-50. doi: 10.2165/0128071-200910010-00008. Am J Clin Dermatol. 2009. PMID: 19170412 Review.
Cited by
- Comparison of adalimumab with methotrexate for psoriasis: A meta-analysis of randomized controlled studies.
Yang X, Liu Y. Yang X, et al. Medicine (Baltimore). 2024 Aug 9;103(32):e37216. doi: 10.1097/MD.0000000000037216. Medicine (Baltimore). 2024. PMID: 39121282 Free PMC article. - Short-, Mid-, and Long-Term Efficacy of Deucravacitinib Versus Biologics and Nonbiologics for Plaque Psoriasis: A Network Meta-Analysis.
Armstrong AW, Warren RB, Zhong Y, Zhuo J, Cichewicz A, Kadambi A, Junqueira D, Westley T, Kisa R, Daamen C, Augustin M. Armstrong AW, et al. Dermatol Ther (Heidelb). 2023 Nov;13(11):2839-2857. doi: 10.1007/s13555-023-01034-7. Epub 2023 Oct 6. Dermatol Ther (Heidelb). 2023. PMID: 37801281 Free PMC article. - The influence of adalimumab treatment on the systemic gene expression in patients with psoriatic arthritis - preliminary report.
Krawczyk A, Strzałka-Mrozik B, Wcisło-Dziadecka D, Kimsa-Dudek M, Kruszniewska-Rajs C, Gola J. Krawczyk A, et al. Arch Med Sci. 2021 Mar 26;19(4):1080-1091. doi: 10.5114/aoms/113027. eCollection 2023. Arch Med Sci. 2021. PMID: 37560743 Free PMC article. - IL-22RA2 Is a SMAD7 Target Mediating the Alleviation of Dermatitis and Psoriatic Phenotypes in Mice.
Ke Y, Li BZ, Nguyen K, Wang D, Wang S, Young CD, Wang XJ. Ke Y, et al. J Invest Dermatol. 2023 Nov;143(11):2243-2254.e10. doi: 10.1016/j.jid.2023.04.029. Epub 2023 May 19. J Invest Dermatol. 2023. PMID: 37211203 Free PMC article. - Pharmaco-Omics in Psoriasis: Paving the Way towards Personalized Medicine.
Antonatos C, Asmenoudi P, Panoutsopoulou M, Vasilopoulos Y. Antonatos C, et al. Int J Mol Sci. 2023 Apr 11;24(8):7090. doi: 10.3390/ijms24087090. Int J Mol Sci. 2023. PMID: 37108251 Free PMC article. Review.
References
- Saurat JH, Stingl G, Dubertret L, et al. CHAMPION Study Investigators. 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):558–566. - PubMed
- Nast A, Sporbeck B, Rosumeck S, et al. Which antipsoriatic drug has the fastest onset of action? systematic review on the rapidity of the onset of action. J Invest Dermatol. 2013;133(8):1963–1970. - PubMed
- Spuls PI, Lecluse LL, Poulsen ML, Bos JD, Stern RS, Nijsten T. How good are clinical severity and outcome measures for psoriasis? quantitative evaluation in a systematic review. J Invest Dermatol. 2010;130(4):933–943. - PubMed
- Orr M, Liu P. Sample size estimation while controlling false discovery rate for microarray experiments using the ssize.fdr package. R J. 2009;1:47–53.
- Liu P, Hwang JT. Quick calculation for sample size while controlling false discovery rate with application to microarray analysis. Bioinformatics. 2007;23(6):739–746. - PubMed
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous