Deficiency of the Interleukin-36 Receptor Antagonist (DITRA) and Generalized Pustular Psoriasis

  • Arturo DiazEmail author


Deficiency of the interleukin-36 receptor antagonist, DITRA, and generalized pustular psoriasis are life-threatening diseases characterized by a disseminated dermatitis, pustular psoriasis, systemic inflammation with fever, joint pain with swelling, severe liver dysfunction with neutrophilic or sclerosing cholangitis, uveitis, iritis, conjunctivitis, renal dysfunction with oliguric and renal failure, neutrophilic pneumonitis, acute respiratory distress syndrome, electrolyte imbalance, and death by sepsis. DITRA has been linked to loss-of-function recessive mutations in the interleukin-36 receptor antagonist IL23RN locus. The mutations encode for an unstable protein with poor interaction with its receptor allowing for an unopposed effect of IL-36 that results in enhanced production of pro-inflammatory cytokines and systemic inflammation.


Autoinflammatory DITRA IL-36Ra deficiency IL-1 Pustular psoriasis 


  1. 1.
    Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY, Fraitag S, et al. Interleukin-36-receptor antagonist deficiency and generalized pustular psoriasis. N Engl J Med. 2011;365(7):620–8.PubMedGoogle Scholar
  2. 2.
    Parisi R, Symmons DP, Griffiths CE, Ashcroft DM, Identification, Management of P, et al. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2):377–85.PubMedGoogle Scholar
  3. 3.
    Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF. Clinical profile, morbidity, and outcome of adult-onset generalized pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in Johor, Malaysia. Int J Dermatol. 2014;53(6):676–84.PubMedGoogle Scholar
  4. 4.
    de Oliveira ST, Maragno L, Arnone M, Fonseca Takahashi MD, Romiti R. Generalized pustular psoriasis in childhood. Pediatr Dermatol. 2010;27(4):349–54.PubMedGoogle Scholar
  5. 5.
    Zelickson BD, Muller SA. Generalized pustular psoriasis. A review of 63 cases. Arch Dermatol. 1991;127(9):1339–45.PubMedGoogle Scholar
  6. 6.
    Oumeish OY, Parish JL. Impetigo herpetiformis. Clin Dermatol. 2006;24(2):101–4.PubMedGoogle Scholar
  7. 7.
    Sugiura K, Takemoto A, Yamaguchi M, Takahashi H, Shoda Y, Mitsuma T, et al. The majority of generalized pustular psoriasis without psoriasis vulgaris is caused by deficiency of interleukin-36 receptor antagonist. J Invest Dermatol. 2013;133(11):2514–21.PubMedGoogle Scholar
  8. 8.
    Shmidt E, Wetter DA, Ferguson SB, Pittelkow MR. Psoriasis and palmoplantar pustulosis associated with tumor necrosis factor-alpha inhibitors: the Mayo Clinic experience, 1998 to 2010. J Am Acad Dermatol. 2012;67(5):e179–85.PubMedGoogle Scholar
  9. 9.
    Koizumi H, Tokuriki A, Oyama N, Ido H, Sugiura K, Akiyama M, et al. Certolizumab pegol, a pegylated anti-TNF-alpha antagonist, caused de novo-onset palmoplantar pustulosis followed by generalized pustular psoriasis in a patient with rheumatoid arthritis. J Dermatol. 2017;44(6):723–4.PubMedGoogle Scholar
  10. 10.
    Wenk KS, Claros JM, Ehrlich A. Flare of pustular psoriasis after initiating ustekinumab therapy. J Dermatolog Treat. 2012;23(3):212–4.PubMedGoogle Scholar
  11. 11.
    Gregoriou S, Kazakos C, Christofidou E, Kontochristopoulos G, Vakis G, Rigopoulos D. Pustular psoriasis development after initial ustekinumab administration in chronic plaque psoriasis. Eur J Dermatol. 2011;21(1):104–5.PubMedGoogle Scholar
  12. 12.
    Navarini AA, Simpson MA, Borradori L, Yawalkar N, Schlapbach C. Homozygous missense mutation in IL36RN in generalized pustular dermatosis with intraoral involvement compatible with both AGEP and generalized pustular psoriasis. JAMA Dermatol. 2015;151(4):452–3.PubMedGoogle Scholar
  13. 13.
    Borges-Costa J, Silva R, Goncalves L, Filipe P, Soares de Almeida L, Marques Gomes M. Clinical and laboratory features in acute generalized pustular psoriasis: a retrospective study of 34 patients. Am J Clin Dermatol. 2011;12(4):271–6.PubMedGoogle Scholar
  14. 14.
    Viguier M, Allez M, Zagdanski AM, Bertheau P, de Kerviler E, Rybojad M, et al. High frequency of cholestasis in generalized pustular psoriasis: Evidence for neutrophilic involvement of the biliary tract. Hepatology. 2004;40(2):452–8.PubMedGoogle Scholar
  15. 15.
    Setta-Kaffetzi N, Navarini AA, Patel VM, Pullabhatla V, Pink AE, Choon SE, et al. Rare pathogenic variants in IL36RN underlie a spectrum of psoriasis-associated pustular phenotypes. J Invest Dermatol. 2013;133(5):1366–9.PubMedGoogle Scholar
  16. 16.
    Korber A, Mossner R, Renner R, Sticht H, Wilsmann-Theis D, Schulz P, et al. Mutations in IL36RN in patients with generalized pustular psoriasis. J Invest Dermatol. 2013;133(11):2634–7.PubMedGoogle Scholar
  17. 17.
    Abbas O, Itani S, Ghosn S, Kibbi AG, Fidawi G, Farooq M, et al. Acrodermatitis continua of Hallopeau is a clinical phenotype of DITRA: evidence that it is a variant of pustular psoriasis. Dermatology. 2013;226(1):28–31.PubMedGoogle Scholar
  18. 18.
    Takahashi T, Fujimoto N, Kabuto M, Nakanishi T, Tanaka T. Mutation analysis of IL36RN gene in Japanese patients with palmoplantar pustulosis. J Dermatol. 2017;44(1):80–3.PubMedGoogle Scholar
  19. 19.
    Sugiura K, Shoda Y, Akiyama M. Generalized pustular psoriasis triggered by amoxicillin in monozygotic twins with compound heterozygous IL36RN mutations: comment on the article by Navarini et al. J Invest Dermatol. 2014;134(2):578–9.PubMedGoogle Scholar
  20. 20.
    Navarini AA, Valeyrie-Allanore L, Setta-Kaffetzi N, Barker JN, Capon F, Creamer D, et al. Rare variations in IL36RN in severe adverse drug reactions manifesting as acute generalized exanthematous pustulosis. J Invest Dermatol. 2013;133(7):1904–7.PubMedGoogle Scholar
  21. 21.
    Capon F. IL36RN mutations in generalized pustular psoriasis: just the tip of the iceberg? J Invest Dermatol. 2013;133(11):2503–4.PubMedGoogle Scholar
  22. 22.
    Jordan CT, Cao L, Roberson ED, Duan S, Helms CA, Nair RP, et al. Rare and common variants in CARD14, encoding an epidermal regulator of NF-kappaB, in psoriasis. Am J Hum Genet. 2012;90(5):796–808.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Ammar M, Jordan CT, Cao L, Lim E, Bouchlaka Souissi C, Jrad A, et al. CARD14 alterations in Tunisian patients with psoriasis and further characterization in European cohorts. Br J Dermatol. 2016;174(2):330–7.PubMedGoogle Scholar
  24. 24.
    Setta-Kaffetzi N, Simpson MA, Navarini AA, Patel VM, Lu HC, Allen MH, et al. AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. Am J Hum Genet. 2014;94(5):790–7.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Debets R, Timans JC, Homey B, Zurawski S, Sana TR, Lo S, et al. Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an antagonist and agonist of NF-kappa B activation through the orphan IL-1 receptor-related protein 2. J Immunol. 2001;167(3):1440–6.PubMedGoogle Scholar
  26. 26.
    Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE. Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-1RAcP to activate the pathway leading to NF-kappaB and MAPKs. J Biol Chem. 2004;279(14):13677–88.PubMedGoogle Scholar
  27. 27.
    Kumar S, McDonnell PC, Lehr R, Tierney L, Tzimas MN, Griswold DE, et al. Identification and initial characterization of four novel members of the interleukin-1 family. J Biol Chem. 2000;275(14):10308–14.PubMedGoogle Scholar
  28. 28.
    Blumberg H, Dinh H, Dean C Jr, Trueblood ES, Bailey K, Shows D, et al. IL-1RL2 and its ligands contribute to the cytokine network in psoriasis. J Immunol. 2010;185(7):4354–62.PubMedGoogle Scholar
  29. 29.
    Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, et al. Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J Exp Med. 2007;204(11):2603–14.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Tauber M, Bal E, Pei XY, Madrange M, Khelil A, Sahel H, et al. IL36RN mutations affect protein expression and function: a basis for genotype-phenotype correlation in pustular diseases. J Invest Dermatol. 2016;136(9):1811–9.PubMedGoogle Scholar
  31. 31.
    Robinson A, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Bebo BF Jr, et al. Treatment of pustular psoriasis: from the Medical Board of the National Psoriasis Foundation. J Am Acad Dermatol. 2012;67(2):279–88.PubMedGoogle Scholar
  32. 32.
    Ozawa A, Ohkido M, Haruki Y, Kobayashi H, Ohkawara A, Ohno Y, et al. Treatments of generalized pustular psoriasis: a multicenter study in Japan. J Dermatol. 1999;26(3):141–9.PubMedGoogle Scholar
  33. 33.
    Viguier M, Aubin F, Delaporte E, Pages C, Paul C, Beylot-Barry M, et al. Efficacy and safety of tumor necrosis factor inhibitors in acute generalized pustular psoriasis. Arch Dermatol. 2012;148(12):1423–5.PubMedGoogle Scholar
  34. 34.
    Cordoro KM, Ucmak D, Hitraya-Low M, Rosenblum MD, Liao W. Response to Interleukin (IL)-17 Inhibition in an Adolescent With Severe Manifestations of IL-36 Receptor Antagonist Deficiency (DITRA). JAMA Dermatol. 2017;153(1):106–8.PubMedGoogle Scholar
  35. 35.
    Carrier Y, Ma HL, Ramon HE, Napierata L, Small C, O'Toole M, et al. Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis. J Invest Dermatol. 2011;131(12):2428–37.PubMedGoogle Scholar
  36. 36.
    Bonekamp N, Caorsi R, Viglizzo GM, Graaf M, Minoia F, Grossi A, et al. High-dose ustekinumab for severe childhood deficiency of interleukin-36 receptor antagonist (DITRA). Ann Rheum Dis. 2018;77:1241–3.PubMedGoogle Scholar
  37. 37.
    Arakawa A, Ruzicka T, Prinz JC. Therapeutic efficacy of interleukin 12/interleukin 23 blockade in generalized pustular psoriasis regardless of IL36RN mutation status. JAMA Dermatol. 2016;152(7):825–8.PubMedGoogle Scholar
  38. 38.
    Tortola L, Rosenwald E, Abel B, Blumberg H, Schafer M, Coyle AJ, et al. Psoriasiform dermatitis is driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest. 2012;122(11):3965–76.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Huffmeier U, Watzold M, Mohr J, Schon MP, Mossner R. Successful therapy with anakinra in a patient with generalized pustular psoriasis carrying IL36RN mutations. Br J Dermatol. 2014;170(1):202–4.PubMedGoogle Scholar
  40. 40.
    Rossi-Semerano L, Piram M, Chiaverini C, De Ricaud D, Smahi A, Kone-Paut I. First clinical description of an infant with interleukin-36-receptor antagonist deficiency successfully treated with anakinra. Pediatrics. 2013;132(4):e1043–7.PubMedGoogle Scholar
  41. 41.
    Tominaga C, Yamamoto M, Imai Y, Yamanishi K. A case of old age-onset generalized pustular psoriasis with a deficiency of IL-36RN (DITRA) treated by granulocyte and monocyte apheresis. Case Rep Dermatol. 2015;7(1):29–35.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Shibata A, Sugiura K, Furuta Y, Mukumoto Y, Kaminuma O, Akiyama M. Toll-like receptor 4 antagonist TAK-242 inhibits autoinflammatory symptoms in DITRA. J Autoimmun. 2017;80:28–38.PubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of RheumatologyBeth Israel Deaconess Medical Center, Harvard Medical SchoolBostonUSA

Personalised recommendations