Clinical Rheumatology

, Volume 37, Issue 2, pp 483–493 | Cite as

The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld’s syndrome: descriptive analysis of 300 patients from the international ASIA syndrome registry

  • Abdulla Watad
  • Mariana Quaresma
  • Nicola Luigi Bragazzi
  • Ricard Cervera
  • Jan Willem Cohen Tervaert
  • Howard Amital
  • Yehuda ShoenfeldEmail author
Original Article


The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is a recently identified condition in which the exposure to an adjuvant leads to an aberrant autoimmune response. We aimed to summarize the results obtained from the ASIA syndrome registry up to December 2016, in a descriptive analysis of 300 cases of ASIA syndrome, with a focus on the adjuvants, the clinical manifestations, and the relationship with other autoimmune diseases. A Web-based registry, based on a multicenter international study, collected clinical and laboratory data in a form of a questionnaire applied to patients with ASIA syndrome. Experts in the disease validated all cases independently. A comparison study regarding type of adjuvants and differences in clinical and laboratory findings was performed. Three hundred patients were analyzed. The mean age at disease onset was 37 years, and the mean duration of time latency between adjuvant stimuli and development of autoimmune conditions was 16.8 months, ranging between 3 days to 5 years. Arthralgia, myalgia, and chronic fatigue were the most frequently reported symptoms. Eighty-nine percent of patients were also diagnosed with another defined rheumatic/autoimmune condition. The most frequent autoimmune disease related to ASIA syndrome was undifferentiated connective tissue disease (UCTD). ASIA syndrome is associated with a high incidence of UCTD and positive anti-nuclear antibodies (ANA) test. Clinical and laboratory features differ from the type of adjuvant used. These findings may contribute to an increased awareness of ASIA syndrome and help physicians to identify patients at a greater risk of autoimmune diseases following the exposure to vaccines and other adjuvants. The ASIA syndrome registry provides a useful tool to systematize this rare condition.


Adjuvants ANA Autoantibodies Autoimmune diseases Chronic fatigue syndrome (CFS) Fibromyalgia Silicone Systemic lupus erythematosus Vaccines 


Compliance with ethical standards

Conflict of interest

YS appears in the Special vaccine compensation court in Washington US.


  1. 1.
    Shoenfeld Y, Agmon-Levin N (2011) ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36(1):4–8. doi: 10.1016/j.jaut.2010.07.003 CrossRefPubMedGoogle Scholar
  2. 2.
    Meroni PL (2011) Autoimmune or auto-inflammatory syndrome induced by adjuvants (ASIA): old truths and a new syndrome? J Autoimmun 36(1):1–3. doi: 10.1016/j.jaut.2010.10.004 CrossRefPubMedGoogle Scholar
  3. 3.
    Agmon-Levin N, Hughes GR, Shoenfeld Y (2012) The spectrum of ASIA: ‘autoimmune (auto-inflammatory) syndrome induced by Adjuvants’. Lupus 21(2):118–120. doi: 10.1177/0961203311429316 CrossRefPubMedGoogle Scholar
  4. 4.
    Watad A, Quaresma M, Brown S, Cohen Tervaert JW, Rodriguez-Pint I, Cervera R, Perricone C, Shoenfeld Y (2017) Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome)—an update. Lupus 26(7):675–681. doi: 10.1177/0961203316686406 CrossRefPubMedGoogle Scholar
  5. 5.
    Agmon-Levin N, Arango MT, Kivity S, Katzav A, Gilburd B, Blank M, Tomer N, Volkov A, Barshack I, Chapman J, Shoenfeld Y (2014) Immunization with hepatitis B vaccine accelerates SLE-like disease in a murine model. J Autoimmun 54:21–32. doi: 10.1016/j.jaut.2014.06.006 CrossRefPubMedGoogle Scholar
  6. 6.
    Ruiz JT, Lujan L, Blank M, Shoenfeld Y (2017) Adjuvants- and vaccines-induced autoimmunity: animal models. Immunol Res 65(1):55–65. doi: 10.1007/s12026-016-8819-5 CrossRefPubMedGoogle Scholar
  7. 7.
    Cruz-Tapias P, Agmon-Levin N, Israeli E, Anaya JM, Shoenfeld Y (2013) Autoimmune (auto-inflammatory) syndrome induced by adjuvants (ASIA)—animal models as a proof of concept. Curr Med Chem 20(32):4030–4036CrossRefPubMedGoogle Scholar
  8. 8.
    Watad A, Azrielant S, Bragazzi NL, Sharif K, David P, Katz I, Aljadeff G, Quaresma M, Tanay G, Adawi M, Amital H, Shoenfeld Y (2017) Seasonality and autoimmune diseases: the contribution of the four seasons to the mosaic of autoimmunity. J Autoimmun. doi: 10.1016/j.jaut.2017.06.001
  9. 9.
    Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y (2009) Adjuvants and autoimmunity. Lupus 18(13):1217–1225. doi: 10.1177/0961203309345724 CrossRefPubMedGoogle Scholar
  10. 10.
    Guimaraes LE, Baker B, Perricone C, Shoenfeld Y (2015) Vaccines, adjuvants and autoimmunity. Pharmacol Res 100:190–209. doi: 10.1016/j.phrs.2015.08.003 CrossRefPubMedGoogle Scholar
  11. 11.
    Jara LJ, Garcia-Collinot G, Medina G, Cruz-Dominguez MDP, Vera-Lastra O, Carranza-Muleiro RA, Saavedra MA (2017) Severe manifestations of autoimmune syndrome induced by adjuvants (Shoenfeld’s syndrome). Immunol Res 65(1):8–16. doi: 10.1007/s12026-016-8811-0 CrossRefPubMedGoogle Scholar
  12. 12.
    Arango MT, Perricone C, Kivity S, Cipriano E, Ceccarelli F, Valesini G, Shoenfeld Y (2017) HLA-DRB1 the notorious gene in the mosaic of autoimmunity. Immunol Res 65(1):82–98. doi: 10.1007/s12026-016-8817-7 CrossRefPubMedGoogle Scholar
  13. 13.
    Hawkes D, Benhamu J, Sidwell T, Miles R, Dunlop RA (2015) Revisiting adverse reactions to vaccines: a critical appraisal of autoimmune syndrome induced by adjuvants (ASIA). J Autoimmun 59:77–84. doi: 10.1016/j.jaut.2015.02.005 CrossRefPubMedGoogle Scholar
  14. 14.
    Schulz KF, Grimes DA (2002) Sample size slippages in randomised trials: exclusions and the lost and wayward. Lancet (London, England) 359(9308):781–785. doi: 10.1016/s0140-6736(02)07882-0 CrossRefGoogle Scholar
  15. 15.
    Auerbach DM, Darrow WW, Jaffe HW, Curran JW (1984) Cluster of cases of the acquired immune deficiency syndrome. Patients linked by sexual contact. Am J Med 76(3):487–492CrossRefPubMedGoogle Scholar
  16. 16.
    Rodriguez-Pinto I, Moitinho M, Santacreu I, Shoenfeld Y, Erkan D, Espinosa G, Cervera R (2016) Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of 500 patients from the International CAPS Registry. Autoimmun Rev 15(12):1120–1124. doi: 10.1016/j.autrev.2016.09.010 CrossRefPubMedGoogle Scholar
  17. 17.
    Dahan S, Shoenfeld Y (2017) Letter to the editor—HPV vaccine and autoimmunity incidence of new-onset autoimmune disease in girls and women with pre-existing autoimmune disease after quadrivalent human papillomavirus vaccination: a cohort study. J Intern Med 281(3):313–315. doi: 10.1111/joim.12575 CrossRefPubMedGoogle Scholar
  18. 18.
    Colaris MJL, de Boer M, van der Hulst RR, Cohen Tervaert JW (2017) Two hundreds cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature. Immunol Res 65(1):120–128. doi: 10.1007/s12026-016-8821-y CrossRefPubMedGoogle Scholar
  19. 19.
    Inbar R, Weiss R, Tomljenovic L, Arango MT, Deri Y, Shaw CA, Chapman J, Blank M, Shoenfeld Y (2017) Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil. Immunol Res 65(1):136–149. doi: 10.1007/s12026-016-8826-6 CrossRefPubMedGoogle Scholar
  20. 20.
    Katzav A, Kivity S, Blank M, Shoenfeld Y, Chapman J (2012) Adjuvant immunization induces high levels of pathogenic antiphospholipid antibodies in genetically prone mice: another facet of the ASIA syndrome. Lupus 21(2):210–216. doi: 10.1177/0961203311429550 CrossRefPubMedGoogle Scholar
  21. 21.
    Colafrancesco S, Perricone C, Shoenfeld Y (2016) Autoimmune/inflammatory syndrome induced by adjuvants and Sjogren’s syndrome. Israel Med Assoc J : IMAJ 18(3–4):150–153Google Scholar
  22. 22.
    Scanzi F, Andreoli L, Martinelli M, Taraborelli M, Cavazzana I, Carabellese N, Ottaviani R, Allegri F, Franceschini F, Agmon-Levin N, Shoenfeld Y, Tincani A (2017) Are the autoimmune/inflammatory syndrome induced by adjuvants (ASIA) and the undifferentiated connective tissue disease (UCTD) related to each other? A case-control study of environmental exposures. Immunol Res 65(1):150–156. doi: 10.1007/s12026-017-8912-4 CrossRefPubMedGoogle Scholar
  23. 23.
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, Harley JB (2003) Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 349(16):1526–1533. doi: 10.1056/NEJMoa021933 CrossRefPubMedGoogle Scholar
  24. 24.
    van Assen S, Agmon-Levin N, Elkayam O, Cervera R, Doran MF, Dougados M, Emery P, Geborek P, Ioannidis JP, Jayne DR, Kallenberg CG, Muller-Ladner U, Shoenfeld Y, Stojanovich L, Valesini G, Wulffraat NM, Bijl M (2011) EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis 70(3):414–422. doi: 10.1136/ard.2010.137216 CrossRefPubMedGoogle Scholar
  25. 25.
    Schelke LW, van den Elzen HJ, Canninga M, Neumann MH (2009) Complications after treatment with polyalkylimide. Dermatologic surgery: official publication for American Society for Dermatologic Surgery [et al] 35 Suppl 2:1625-1628. doi: 10.1111/j.1524-4725.2009.01340.x

Copyright information

© International League of Associations for Rheumatology (ILAR) 2017

Authors and Affiliations

  1. 1.Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center (Affiliated to Tel-Aviv University)Tel-HashomerIsrael
  2. 2.Sackler Faculty of MedicineTel-Aviv UniversityTel-AvivIsrael
  3. 3.Department of Medicine A, Centro Hospitalar do PortoPortoPortugal
  4. 4.School of Public Health, Department of Health Sciences (DISSAL)University of GenoaGenoaItaly
  5. 5.Department of Autoimmune Diseases, Hospital ClínicBarcelonaSpain
  6. 6.Clinical and Experimental Immunology, Reinaert ClinicMaastrichtThe Netherlands
  7. 7.Laura Schwarz-Kipp Chair for Research of Autoimmune DiseasesTel-Aviv UniversityTel-AvivIsrael

Personalised recommendations