The autoimmune/inflammatory syndrome induced by adjuvants (ASIA) is an entity that includes different autoimmune conditions observed after exposure to an adjuvant. Patients with undifferentiated connective tissue disease (UCTD) present many signs and symptoms of ASIA, alluding to the idea that an exposure to adjuvants can be a trigger also for UCTD. The aim of this case-control study was to investigate exposure to adjuvants prior to disease onset in patients affected by UCTD. Ninety-two UCTD patients and 92 age- and sex-matched controls with no malignancy, chronic infections, autoimmune disease nor family history of autoimmune diseases were investigated for exposure to adjuvants. An ad hoc-created questionnaire exploring the exposure to vaccinations, foreign materials and environmental and occupational exposures was administered to both cases and controls. Autoantibodies were also analyzed (anti-nuclear, anti-extractable nuclear antigens, anti-double-stranded DNA, anti-cardiolipin, anti-β2 glycoprotein I). UCTD patients displayed a greater exposure to HBV (p = 0.018) and tetanus toxoid (p < 0.001) vaccinations, metal implants (p < 0.001), cigarette smoking (p = 0.006) and pollution due to metallurgic factories and foundries (p = 0.048) as compared to controls. UCTD patients exposed to major ASIA triggers (vaccinations, silicone implants) (n = 49) presented more frequently with chronic fatigue (p < 0.001), general weakness (p = 0.011), irritable bowel syndrome (p = 0.033) and a family history for autoimmunity (p = 0.018) in comparison to non-exposed UCTDs. ASIA and UCTD can be considered as related entities in the “mosaic of autoimmunity”: the genetic predisposition and the environmental exposure to adjuvants elicit a common clinical phenotype characterized by signs and symptoms of systemic autoimmunity.
Adjuvants ASIA syndrome Undifferentiated connective tissue disease Vaccinations Metal implants
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The authors wish to acknowledge the kind collaboration of Dr. Lucia Cretti and Dr. Mirella Marini (Department of Transfusion Medicine, Spedali Civili, Brescia) in the enrollment of healthy blood donors.
Thanks to all the patients and control individuals participating to the study.
Compliance with ethical standards
The study was approved by the local Ethic Committee in Brescia and performed in accordance to the good clinical practice and to the Declaration of Helsinki.
Shoenfeld Y, Agmon-Levin N. ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;36(1):4–8.CrossRefPubMedGoogle Scholar
Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S. The diagnosis and classification of undifferentiated connective tissue diseases. J Autoimmun. 2014;48-49:50–2.CrossRefPubMedGoogle Scholar
Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y. Macrophagic myofaciitis a vaccine (alum) autoimmune-related disease. Clinical reviews in allergy & immunology. 2011;41(2):163–8.CrossRefGoogle Scholar
Ryan AM, Bermingham N, Harrington HJ, Keohane C. Atypical presentation of macrophagic myofasciitis 10 years post vaccination. Neuromuscular disorders : NMD. 2006;16(12):867–9.CrossRefPubMedGoogle Scholar
Balestrieri G, Tincani A, Spatola L, Allegri F, Prati E, Cattaneo R, et al. Anti-beta 2-glycoprotein I antibodies: a marker of antiphospholipid syndrome? Lupus. 1995;4(2):122–30.CrossRefPubMedGoogle Scholar
Tincani A, Allegri F, Sanmarco M, Cinquini M, Taglietti M, Balestrieri G, et al. Anticardiolipin antibody assay: a methodological analysis for a better consensus in routine determinations—a cooperative project of the European Antiphospholipid Forum. Thromb Haemost. 2001;86(2):575–83.PubMedGoogle Scholar
Perricone C, Colafrancesco S, Mazor RD, Soriano A, Agmon-Levin N, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) 2013: unveiling the pathogenic, clinical and diagnostic aspects. J Autoimmun. 2013;47:1–16.CrossRefPubMedGoogle Scholar
Loyo E, Jara LJ, Lopez PD, Puig AC. Autoimmunity in connection with a metal implant: a case of autoimmune/autoinflammatory syndrome induced by adjuvants. Auto- immunity highlights. 2013;4(1):33–8.CrossRefPubMedGoogle Scholar
Stejskal V. Metals as a common trigger of inflammation resulting in non-specific symptoms: diagnosis and treatment. The Israel Medical Association journal : IMAJ. 2014;16(12):753–8.PubMedGoogle Scholar
Farhat SC, Silva CA, Orione MA, Campos LM, Sallum AM, Braga AL. Air pollution in autoimmune rheumatic diseases: a review. Autoimmun Rev. 2011;11(1):14–21.CrossRefPubMedGoogle Scholar
Webber MP, Moir W, Zeig-Owens R, Glaser MS, Jaber N, Hall C, et al. Nested case-control study of selected systemic autoimmune diseases in world trade center rescue/recovery workers. Arthritis & rheumatology (Hoboken, NJ). 2015;67(5):1369–76.CrossRefGoogle Scholar
Sugiyama D, Nishimura K, Tamaki K, Tsuji G, Nakazawa T, Morinobu A, et al. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann Rheum Dis. 2010;69(1):70–81.CrossRefPubMedGoogle Scholar
van der Helm-van Mil AH, Verpoort KN, le Cessie S, Huizinga TW, de Vries RR, Toes RE. The HLA-DRB1 shared epitope alleles differ in the interaction with smoking and predisposition to antibodies to cyclic citrullinated peptide. Arthritis Rheum. 2007;56(2):425–32.CrossRefPubMedGoogle Scholar
Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum. 1996;39(5):732–5.CrossRefPubMedGoogle Scholar
Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on immunity, inflammation and autoimmunity. J Autoimmun. 2010;34(3):J258–65.CrossRefPubMedGoogle Scholar
Bartunkova J, Kayserova J, Shoenfeld Y. Allergy and autoimmunity: parallels and dissimilarity: the yin and yang of immunopathology. Autoimmun Rev. 2009;8(4):302–8.CrossRefPubMedGoogle Scholar
Akishima S, Matsushita S, Sato F, Hyodo K, Imazuru T, Enomoto Y, et al. Cigarette-smoke-induced vasoconstriction of peripheral arteries: evaluation by synchrotron radiation microangiography. Circulation journal : official journal of the Japanese Circulation Society. 2007;71(3):418–22.CrossRefGoogle Scholar
Blank M, Krause I, Fridkin M, Keller N, Kopolovic J, Goldberg I, et al. Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome. J Clin Invest. 2002;109(6):797–804.CrossRefPubMedPubMedCentralGoogle Scholar
Zivkovic I, Petrusic V, Dimitrijevic R, Stojanovic M, Dimitrijevic L. Adjuvant dependence of APS pathology-related low-affinity antibodies during secondary immune response to tetanus toxoid in BALB/c mice. Immunol Res. 2013;56(1):143–9.CrossRefPubMedGoogle Scholar
Dimitrijevic L, Zivkovic I, Stojanovic M, Petrusic V, Zivancevic-Simonovic S. Vaccine model of antiphospholipid syndrome induced by tetanus vaccine. Lupus. 2012;21(2):195–202.CrossRefPubMedGoogle Scholar
Cruz-Tapias P, Blank M, Anaya JM, Shoenfeld Y. Infections and vaccines in the etiology of antiphospholipid syndrome. Curr Opin Rheumatol. 2012;24(4):389–93.CrossRefPubMedGoogle Scholar
Rasheed A, Lipstein-Kresch E, Kalra J. Undifferentiated connective tissue disease after silicone-gel testicular implantation. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 1995;1(5):310.CrossRefGoogle Scholar
Spiera RF, Gibofsky A, Spiera H. Breast implants and connective-tissue diseases. N Engl J Med. 1994;331(18):1232. author reply 3-4PubMedGoogle Scholar
Spiera H, Spiera RF. Silicone breast implants and connective tissue disease: an overview. The Mount Sinai journal of medicine, New York. 1997;64(6):363–71.PubMedGoogle Scholar
Park AJ, Black RJ, Sarhadi NS, Chetty U, Watson AC. Silicone gel-filled breast implants and connective tissue diseases. Plast Reconstr Surg. 1998;101(2):261–8.CrossRefPubMedGoogle Scholar
Bruzzese V, Zullo A, Hassan C. Connective tissue disease following hepatitis B vaccination. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases. 2013;19(5):280–1.CrossRefGoogle Scholar
Shoenfeld Y, Zandman-Goddard G, Stojanovich L, Cutolo M, Amital H, Levy Y, et al. The mosaic of autoimmunity: hormonal and environmental factors involved in autoimmune diseases—2008. The Israel Medical Association journal : IMAJ. 2008a;10(1):8–12.PubMedGoogle Scholar
Shoenfeld Y, Gilburd B, Abu-Shakra M, Amital H, Barzilai O, Berkun Y, et al. The mosaic of autoimmunity: genetic factors involved in autoimmune diseases—2008. The Israel Medical Association journal : IMAJ. 2008b;10(1):3–7.PubMedGoogle Scholar
Versini M, Aljadeff G, Jeandel PY, Shoenfeld Y. Obesity: an additional piece in the mosaic of autoimmunity. The Israel Medical Association Journal: IMAJ. 2014 Oct;16(10):619–21.PubMedGoogle Scholar