Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Paradoxical psoriasiform reactions to anti-TNFα drugs are associated with genetic polymorphisms in patients with psoriasis

The Pharmacogenomics Journal volume 16, pages 336–340 (2016)Cite this article

Subjects

Abstract

Paradoxical psoriasiform reactions to anti-tumor necrosis factor α (TNFα) agents have been described. We aimed to study the association between these reactions and polymorphisms in genes previously associated with psoriasis or other autoimmune diseases. A total of 161 patients with plaque-type psoriasis treated with anti-TNFα drugs were genotyped for 173 single-nucleotide polymorphisms (SNPs) using the Illumina Veracode genotyping platform. Among the 161 patients, 25 patients developed a paradoxical psoriasiform reaction consisting of a change in morphology, mostly to guttate psoriasis (88%). These lesions developed 9.20±13.52 months after initiating treatment, mainly with etanercept (72%). Psoriasis type and a Psoriasis Area and Severity Index (PASI) 75 response to treatment were not associated with lesions. Multivariate logistic regression revealed that five SNPs (rs11209026 in IL23R, rs10782001 in FBXL19, rs3087243 in CTLA4, rs651630 in SLC12A8 and rs1800453 in TAP1) were associated with paradoxical reactions. This is the first study to show an association between genetic polymorphisms and paradoxical reactions in patients with psoriasis treated with anti-TNFα drugs.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM . Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol 2013; 133: 377–385.

    Article  CAS  PubMed  Google Scholar 

  2. Severs GA, Lawlor TH, Purcell SM, Adler DJ, Thompson R . Cutaneous adverse reaction to infliximab: report of psoriasis developing in 3 patients. Cutis 2007; 80: 231–237.

    PubMed  Google Scholar 

  3. Passarini B, Infusino SD, Barbieri E, Varotti E, Gionchetti P, Rizzello F et al. Cutaneous manifestations in inflammatory bowel diseases: eight cases of psoriasis induced by anti-tumor-necrosis-factor antibody therapy. Dermatology 2007; 215: 295–300.

    Article  CAS  PubMed  Google Scholar 

  4. Collamer AN, Guerrero KT, Henning JS, Battafarano DF . Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: a literature review and potential mechanisms of action. Arthritis Rheum. 2008; 59: 996–1001.

    Article  CAS  PubMed  Google Scholar 

  5. Rongioletti F, Burlando M, Parodi A . Adverse effects of biological agents in the treatment of psoriasis. Am J Clin Dermatol 2010; 11: 35–37.

    Article  PubMed  Google Scholar 

  6. López-Robles A, Queiro R, Alperi M, Alonso S, Riestra JL, Ballina J . Psoriasis and psoriasiform lesions induced by TNFα antagonists: the experience of a tertiary care hospital from northern Spain. Rheumatol Int 2012; 32: 3779–3783.

    Article  PubMed  Google Scholar 

  7. Denadai R, Teixeira FV, Steinwurz F, Romiti R, Saad-Hossne R . Induction or exacerbation of psoriatic lesions during anti-TNF-α therapy for inflammatory bowel disease: a systematic literature review based on 222 cases. J Crohns Colitis 2013; 7: 517–524.

    Article  PubMed  Google Scholar 

  8. Navarro R, Daudén E . Clinical management of paradoxical psoriasiform reactions during TNF-α therapy. Actas Dermosifiliogr 2014; 105: 752–761.

    Article  CAS  PubMed  Google Scholar 

  9. Wollina U, Hansel G, Koch A, Schonlebe J, Kostler E, Haroske G . Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients. Am J Clin Dermatol 2008; 9: 1–14.

    Article  PubMed  Google Scholar 

  10. Ko JM, Gottlieb AB, Kerbleski JF . Induction and exacerbation of psoriasis with TNF-blockade therapy: a review and analysis of 127 cases. J Dermatolog Treat 2009; 20: 100–108.

    Article  CAS  PubMed  Google Scholar 

  11. Collamer AN, Battafarano DF . Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: Clinical features and possible immunopathogenesis. Semin Arthritis Rheum 2010; 40: 233–240.

    Article  CAS  Google Scholar 

  12. Cullen G, Kroshinsky D, Cheifetz AS, Korzenik JR . Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature. Aliment Pharmacol Ther 2011; 34: 1318–1327.

    Article  CAS  PubMed  Google Scholar 

  13. Verea MM, Del Pozo J, Yebra-Pimentel MT, Porta A, Fonseca E . Psoriasiform eruption induced by infliximab. Ann Pharmacother 2004; 38: 54–57.

    Article  PubMed  Google Scholar 

  14. Sari I, Akar S, Birlik M, Sis B, Onen F, Akkoc N . Anti-tumor necrosis factor-alpha-induced psoriasis. J Rheumatol 2006; 33: 1411–1414.

    PubMed  Google Scholar 

  15. Goiriz R, Dauden E, Perez-Gala S, Guhl G, Garcia-Diez A . Flare and change of psoriasis morphology during the course of treatment with tumour necrosis factor blockers. Clin Exp Dermatol 2007; 32: 176–179.

    Article  CAS  PubMed  Google Scholar 

  16. Conklin LS, Cohen B, Wilson L, Cuffari C, Oliva-Hemker M . Rash induced by anti-tumor necrosis factor agents in an adolescent with Crohn's disease. Nat Rev Gastroenterol Hepatol 2010; 7: 174–147.

    Article  PubMed  Google Scholar 

  17. Tammaro A, Persechino S, Abruzzese C, Narcisi A, Cortesi G, Parisella FR et al. Psoriasiform dermatitis in a non-psoriatic patient treated with adalimumab. Int J Immunopathol Pharmacol 2012; 25: 499–501.

    Article  CAS  PubMed  Google Scholar 

  18. Sfikakis PP, Iliopoulos A, Elezoglou A, Kittas C, Stratigos A . Psoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction. Arthritis Rheum 2005; 52: 2513–2518.

    Article  CAS  PubMed  Google Scholar 

  19. Wendling D, Prati C . Paradoxical effects of anti-TNF-α agents in inflammatory diseases. Expert Rev Clin Immunol 2014; 10: 159–169.

    Article  CAS  PubMed  Google Scholar 

  20. Seneschal J, Milpied B, Vergier B, Lepreux S, Schaeverbeke T, Taïeb A . Cytokine imbalance with increased production of interferon-alpha in psoriasiform eruptions associated with antitumour necrosis factor-alpha treatments. Br J Dermatol 2009; 161: 1081–1088.

    Article  CAS  PubMed  Google Scholar 

  21. Ariza ME, Rivailler P, Glaser R, Chen M, Williams MV . Epstein-Barr virus encoded dUTPase containing exosomes modulate innate and adaptive immune responses in human dendritic cells and peripheral blood mononuclear cells. PLoS One 2013; 8: e69827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Prieto-Pérez R, Solano-López G, Cabaleiro T, Román M, Ochoa D, Talegón M et al. New immune system genetic polymorphisms associated with moderate-to-severe plaque psoriasis: a case-control study. Br J Dermatol. 2015; 172: 1432–1435.

    Article  PubMed  Google Scholar 

  23. Sherlock ME, Walters T, Tabbers MM, Frost K, Zachos M, Muise A et al. Infliximab-induced psoriasis and psoriasiform skin lesions in pediatric Crohn disease and a potential association with IL-23 receptor polymorphisms. J Pediatr Gastroenterol Nutr 2013; 56: 512–518.

    Article  CAS  PubMed  Google Scholar 

  24. 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: 1–10.

    Article  CAS  PubMed  Google Scholar 

  25. Prieto-Pérez 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: 297–305.

    Article  PubMed  Google Scholar 

  26. Cabaleiro T, Roman M, Gallo E, Ochoa D, Tudelilla F, Talegón M et al. Association between psoriasis and polymorphisms in the TNF, IL12B, and IL23R genes in Spanish patients. Eur J Dermatol 2013; 23: 640–645.

    CAS  PubMed  Google Scholar 

  27. Cohen JD, Bournerias I, Buffard V, Paufler A, Chevalier X, Bagot M et al. Psoriasis induced by tumor necrosis factor-alpha antagonist therapy: a case series. J Rheumatol 2007; 34: 380–385.

    CAS  PubMed  Google Scholar 

  28. Harrison MJ, Dixon WG, Watson KD, King Y, Groves R, Hyrich KL et al. Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Ann Rheum Dis 2009; 68: 209–215.

    Article  CAS  PubMed  Google Scholar 

  29. Nguyen K, Vleugels RA, Velez NF, Merola JF, Qureshi AA . Psoriasiform reactions to anti-tumor necrosis factor α therapy. J Clin Rheumatol 2013; 19: 377–381.

    Article  PubMed  Google Scholar 

  30. Afzali A, Wheat CL, Hu JK, Olerud JE, Lee SD . The association of psoriasiform rash with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease: a single academic center case series. J Crohns Colitis 2014; 8: 480–488.

    Article  PubMed  Google Scholar 

  31. Tillack C, Ehmann LM, Friedrich M, Laubender RP, Papay P, Vogelsang H et al. Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment. Gut 2014; 63: 567–577.

    Article  CAS  PubMed  Google Scholar 

  32. Barthel C, Biedermann L, Frei P, Vavricka SR, Kündig T, Fried M et al. Induction or exacerbation of psoriasis in patients with Crohn's disease under treatment with anti-TNF antibodies. Digestion 2014; 89: 209–215.

    Article  CAS  PubMed  Google Scholar 

  33. Shale M, Ghosh S . Learning the lessons of antitumour necrosis factor therapy-associated psoriasis. Can J Gastroenterol 2009; 23: 674–676.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Włodarczyk M, Sobolewska A, Wójcik B, Loga K, Fichna J, Wiśniewska-Jarosińska M . Correlations between skin lesions induced by anti-tumor necrosis factor-α and selected cytokines in Crohn's disease patients. World J Gastroenterol 2014; 20: 7019–7026.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Taylor C, Burns D, Wiselka M . Extensive psoriasis induced by interferon alpha treatment for chronic hepatitis C. Postgrad Med J 2000; 76: 365–367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Eriksen KW, Lovato P, Skov L, Krejsgaard T, Kaltoft K, Geisler C et al. Increased sensitivity to interferonalpha in psoriatic T cells. J Invest Dermatol 2005; 125: 936–944.

    Article  CAS  PubMed  Google Scholar 

  37. Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005; 202: 135–143.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nestle FO, Kaplan DH, Barker J . Psorasis. N Engl J Med 2009; 361: 496–509.

    Article  CAS  Google Scholar 

  39. Grinblat B, Scheinberg M . The enigmatic development of psoriasis and psoriasiform lesions during anti-TNF therapy: a review. Semin Arthritis Rheum 2008; 37: 251–255.

    Article  PubMed  Google Scholar 

  40. Di Meglio P, Di Cesare A, Laggner U, Chu CC, Napolitano L, Villanova F et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 2011; 6: e17160.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Stuart PE, Nair RP, Ellinghaus E, Ding J, Tejasvi T, Gudjonsson JE et al. Genome-wide association analysis identifies three psoriasis susceptibility loci. Nat Genet 2010; 42: 1000–1004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rahman P, Elder JT . Genetics of psoriasis and psoriatic arthritis: a report from the GRAPPA 2010 annual meeting. J Rheumatol 2012; 39: 431–433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhao J, Wei J, Mialki RK, Mallampalli DF, Chen BB, Coon T et al. F-box protein FBXL19-mediated ubiquitination and degradation of the receptor for IL-33 limits pulmonary inflammation. Nat Immunol 2012; 13: 651–658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wei J, Mialki RK, Dong S, Khoo A, Mallampalli RK, Zhao Y et al. A new mechanism of RhoA ubiquitination and degradation: roles of SCF(FBXL19) E3 ligase and Erk2. Biochim Biophys Acta 2013; 1833: 2757–2764.

    Article  CAS  PubMed  Google Scholar 

  45. Repnik K, Potocnik U . CTLA4 CT60 single-nucleotide polymorphism is associated with Slovenian inflammatory bowel disease patients and regulates expression of CTLA4 isoforms. DNA Cell Biol 2010; 29: 603–610.

    Article  CAS  PubMed  Google Scholar 

  46. Chambers CA, Allison JP . CTLA-4—the costimulatory molecule that doesn’t: regulation of T-cell responses by inhibition. Cold Spring Harb Symp Quant Biol 1999; 64: 303–312.

    Article  CAS  PubMed  Google Scholar 

  47. Read S, Greenwald R, Izcue A, Robinson N, Mandelbrot D, Francisco L et al. Blockade of CTLA-4 on CD4+CD25+ regulatory T cells abrogates their function in vivo. J Immunol 2006; 177: 4376–4383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sakaguchi S, Sakaguchi N, Shimizu J, Yamazaki S, Sakihama T, Itoh M et al. Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev 2001; 182: 18–32.

    Article  CAS  PubMed  Google Scholar 

  49. Ursini F, Naty S, Russo E, Grembiale RD . Abatacept in psoriatic arthritis: case report and short review. J Pharmacol Pharmacother 2013; 4: S29–S32.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hewett D, Samuelsson L, Polding J, Enlund F, Smart D, Cantone K et al. Identification of a psoriasis susceptibility candidate gene by linkage disequilibrium mapping with a localized single nucleotide polymorphism map. Genomics 2002; 79: 305–314.

    Article  CAS  PubMed  Google Scholar 

  51. Vasku A, Bienertova-Vasku J, Izakovicova-Holla L, Pavkova Goldbergova M, Kozacikova Z, Splichal Z et al. Polymorphisms in HLA-related genes and psoriasis heredity in patients with psoriasis. Int J Dermatol 2013; 52: 960–965.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was partially funded by Fondo de Investigación Sanitaria (PI10-01740), Fundación Teófilo Hernando and Fundación Salud 2000. We are grateful to Mr Thomas O’Boyle for editorial assistance. This study would not have been possible without the cooperation of the patients.

Author information

Author notes

  1. T Cabaleiro and R Prieto-Pérez: These authors contributed equally to this work.

  2. F Abad-Santos and E Daudén: These authors contributed equally to this work.

Authors and Affiliations

  1. Clinical Pharmacology Service, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain

    T Cabaleiro, R Prieto-Pérez, M Román, D Ochoa & F Abad-Santos

  2. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

    T Cabaleiro & F Abad-Santos

  3. Dermatology Service, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain

    R Navarro, G Solano & E Daudén

Authors
  1. T Cabaleiro
    View author publications

    Search author on:PubMed Google Scholar

  2. R Prieto-Pérez
    View author publications

    Search author on:PubMed Google Scholar

  3. R Navarro
    View author publications

    Search author on:PubMed Google Scholar

  4. G Solano
    View author publications

    Search author on:PubMed Google Scholar

  5. M Román
    View author publications

    Search author on:PubMed Google Scholar

  6. D Ochoa
    View author publications

    Search author on:PubMed Google Scholar

  7. F Abad-Santos
    View author publications

    Search author on:PubMed Google Scholar

  8. E Daudén
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to F Abad-Santos.

Ethics declarations

Competing interests

E Daudén has conflict of interest (advisory board member, consultant, grants, research support, participation in clinical trials, honoraria for speaking and research support) with the following pharmaceutical companies: AbbVie (Abbott), Amgen, Janssen-Cilag, Leo Pharma, Novartis, Pfizer, MSD and Celgene. F Abad-Santos and D Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Faes, Farmalíder, Ferrer, GlaxoSmithKline, Janssen-Cilag, Kern, Normon, Servier, Teva and Zambon. The remaining authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cabaleiro, T., Prieto-Pérez, R., Navarro, R. et al. Paradoxical psoriasiform reactions to anti-TNFα drugs are associated with genetic polymorphisms in patients with psoriasis. Pharmacogenomics J 16, 336–340 (2016). https://doi.org/10.1038/tpj.2015.53

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/tpj.2015.53

This article is cited by

Search

Advanced search

Quick links