Immunologic Research

, Volume 66, Issue 1, pp 120–140 | Cite as

Autoimmune/inflammatory syndrome induced by adjuvants—ASIA—related to biomaterials: analysis of 45 cases and comprehensive review of the literature

  • Jaume Alijotas-Reig
  • Enrique Esteve-Valverde
  • Natalia Gil-Aliberas
  • Victor Garcia-Gimenez
Original Article


Systemic autoimmune or granulomatous disorders related to biomaterials of human use have rarely been described. The aim of this study was to report cases of autoimmune/inflammatory syndrome induced by adjuvants (ASIA) related to biomaterial injections and prostheses, mainly silicone, hyaluronic acid, acrylamides and methacrylate compounds in a Spanish patient cohort. This study is a retrospective analysis of clinical, laboratory, histopathological and follow-up data of 45 cases of patients suffering from late-onset, non-infectious inflammatory/autoimmune disorders related to bioimplants. Late onset was defined as 3 months or more post injection. Data were obtained through a further non-systematic but comprehensive review of the literature. Forty-five cases of late-onset adverse reactions related to biomaterial injections or prostheses were reviewed. All cases had systemic complaints that could be categorised as ASIA. In all but four patients, inflammatory features at the implantation site preceded distant or systemic manifestations. Abnormal blood tests were common. Localised inflammatory nodules and panniculitis in 40/45 (88.88%) evolved into a variety of disorders, viz., primary biliary cirrhosis, Sjögren’s syndrome, sarcoidosis, human adjuvant disease, vasculitis, inflammatory bowel syndrome and inflammatory polyradiculopathy. Five (11.11%) cases presented primarily with systemic autoimmune disorders. Biomaterials and prostheses can provoke late-onset systemic autoimmune disorders fulfilling ASIA criteria, or present primarily local/regional inflammatory reactions that may eventually evolve into systemic autoimmune and/or granulomatous disorders which fall under ASIA.


Adjuvant Adverse reactions ASIA Autoimmune diseases Bioimplants Dermal fillers Granulomatosis 





Angiotensin-converting enzyme


Antiphospholipid antibodies


Antimitochondrial antibodies


Antinuclear antibodies


Antineutrophil cytoplasmic antibodies


Autoimmune/inflammatory syndrome induced by adjuvants


Autoimmune systemic diseases


Cluster differentiation


C-reactive protein


Epstein-Barr virus


Hyaluronic acid


Human adjuvant disease


Human leukocyte antigen






Major histocompatibility complex


Non-animal stabilised hyaluronic acid


Peripheral blood mononuclear cells




Poly-l-lactic acid


Silicone medical grade


Sjögren’s syndrome


Serum protein electrophoresis


Systemic sclerosis


Toll-like receptors


Tumour necrosis factor-alpha


Undifferentiated connective tissue disease


Author’s contributions

All authors have made substantial contributions to all or some of the following: conception and design of the study, acquisition of data, analysis and interpretation of data (JAR, EEV, NGA, VGG), drafting of the article (JAR), critical revision for important intellectual content (JAR, EEV, NGA) and final approval of the version to be submitted (JAR, EEV, NGA, VGG).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Hanke CW, Rohrich RJ, Busso M, Carruthers A, Carruthers J, Fagien S, et al. Facial soft-tissue fillers: assessing the state of the science conference proceedings report. J Am Acad Dermatol. 2011;64(4 Suppl):S53–65.PubMedCrossRefGoogle Scholar
  2. 2.
    Ellis DA, Makdessian AS, Brown DJ. Survey of future injectables. Facial Plast Surg Clin North Am. 2001;9:405–11.PubMedGoogle Scholar
  3. 3.
    American Society of Plastic Surgery. Statistics of 2010, (2010, Accessed 01 Aug 2011).
  4. 4.
    Frank PJ. Cosmetic symposium: Restylane. The Dermatologic Society of Greater New York,¼3&aui¼sa&aid¼35 (2005, Accessed 2 Feb 2005).
  5. 5.
    Engelman DE, Bradley B, Goldberg DJ. Dermal fillers: complications and informed consent. J Cosmet Laser Ther. 2005;7:29–32.PubMedCrossRefGoogle Scholar
  6. 6.
    Andre P, Lowe NJ, Parc A, Clerici TH, Zimmermann U. Adverse reactions to dermal fillers: a review of European experiences. J Cosmet Laser Ther. 2005;7:171–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Duffy DM. Complications of fillers: overview. Dermatol Surg. 2005;31:1626–33.PubMedCrossRefGoogle Scholar
  8. 8.
    Alijotas-Reig J, Garcia-Gimenez V. Delayed immune-mediated adverse effects related to hyaluronic acid and acrylic hydrogel dermal fillers: clinical findings, long-term follow-up and review of the literature. J Eur Acad Dermatol Venereol. 2008;22:50–61.Google Scholar
  9. 9.
    Alijotas-Reig J, Garcia-Gimenez V, Miró-Mur F, Vilardell-Tarrés M. Delayed immune-mediated adverse effects of poly-alkyl-imide dermal fillers. Arch Dermatol. 2008;144:637–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Bergeret-Galley C. Comparison of resorbable soft tissue fillers. Aesthet Surg J. 2004;24:33–46.PubMedCrossRefGoogle Scholar
  11. 11.
    Alijotas-Reig J, Fernández-Figueras MT, Puig L. Late-onset inflammatory adverse reactions related to soft tissue filler injections. Clin Rev Allergy Immunol. 2013;45:97–108.PubMedCrossRefGoogle Scholar
  12. 12.
    Israeli E, Agmon-Levin N, Blank M, Shoenfeld Y. Adjuvants and autoimmunity. Lupus. 2009;19:1217–25.CrossRefGoogle Scholar
  13. 13.
    Miyoshi K, Miyaoka T, Kobayashi Y, Itakura T, Hihijo K, Higashibara M. Hypergammaglobulinemia by prolonged adjuvanticity in man: disorders developed after augmentation mammoplasty. Ijishimpo. 1964;22:9–14.Google Scholar
  14. 14.
    Miyoshi K, Shiragami H, Yoshida K. Adjuvant disease of man. Clin Immunol (Tokyo). 1973;5:785–94.Google Scholar
  15. 15.
    Alijotas-Reig J, Garcia-Gimenez JV, Llurba E, Vilardell-Tarrés M. Autoimmune/inflammatory syndrome (ASIA) induced by biomaterials injection other than silicone medical grade. Lupus. 2012;21:1326–34.PubMedCrossRefGoogle Scholar
  16. 16.
    Shoenfeld Y, Agmon-Levin N. ‘ASIA’—autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun. 2011;36:4–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Miró-Mur F, Hindié M, Kandhaya-Pillai R, Tobajas V, Schwartz S Jr, Alijotas-Reig J. Medical-grade silicone induces release of proinflammatory cytokines in peripheral blood mononuclear cells without activating T cells. J Biomed Mater Res B Appl Biomater. 2009;90B:510–20.CrossRefGoogle Scholar
  18. 18.
    Alijotas-Reig J, Hindié M, Kandhaya-Pillai R, Miró-Mur F. Bioengineered hyaluronic acid elicited a non-antigenic T cell activation: implications from cosmetic medicine and surgery to nanomedicine. J Biomed Mater Res A. 2010;95A:180–90.CrossRefGoogle Scholar
  19. 19.
    Vera-Lastra O, Medina G, Cruz-Dominguez MP, et al. Human adjuvant disease induced by foreign substances: a new model of ASIA (Shoenfeld’s syndrome). Lupus. 2012;21:128–35.PubMedCrossRefGoogle Scholar
  20. 20.
    Agmon-Levin N, Hughes GRV, Shoenfeld Y. The spectrum of ASIA ‘autoimmune (auto-inflammatory) syndrome induced by adjuvants’. Lupus. 2012;118:20.Google Scholar
  21. 21.
    Colafrancesco S, Perricone C, Priori R, Valesini G, Shoenfeld Y. Sjögren’s syndrome: another facet of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). J Autoimmun. 2014;51:10–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Alijotas-Reig J. Human adjuvant-related syndrome or autoimmune/inflammatory syndrome induced by adjuvants. Where have we come from? Where are we going? A proposal for new diagnostic criteria. Lupus. 2015;24:1012–8.PubMedCrossRefGoogle Scholar
  23. 23.
    James DG, Williams WJ. Sarcoidosis and other granulomatous disorders. In: Smith LLH, editor. Major problems in internal medicine, vol 24. Philadelphia: W.B. Saunders Co. p. 1–254.Google Scholar
  24. 24.
    Zimmermann US, Clerici TJ. The histological aspects of fillers complications. Semin Cutan Med Surg. 2004;23:241–50.PubMedCrossRefGoogle Scholar
  25. 25.
    Christensen L, Breiting V, Janssen M, Vuust J, Hogdall E. Adverse reactions to injectable soft tissue permanent fillers. Aesthet Plast Surg. 2005;29:34–48.CrossRefGoogle Scholar
  26. 26.
    Christen U, von Herrath G. Infections and autoimmunity. Good or bad? J Immunol. 2005;174:7481–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Rose NR. Autoimmunity, infection and adjuvants. Lupus. 2010;19:354–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:1526–33.PubMedCrossRefGoogle Scholar
  29. 29.
    Kadouch JA, Vos W, Nijhuis EW, Hoekzema R. Granulomatous foreign-body reactions to permanent fillers: detection of CD123+ plasmacytoid dendritic cells. Am J Dermatopathol. 2015;37:107–14.PubMedCrossRefGoogle Scholar
  30. 30.
    Basko-Plluska JL, Thyssen JP, Schalock PC. Cutaneous and systemic hypersensitivity reactions to metallic implants. Dermatitis. 2011;22:65–79.PubMedGoogle Scholar
  31. 31.
    Disegi JA, Eschbach L. Stainless steel in bone surgery. Int J Care Injured. 2003;31(Suppl 4):2–6.Google Scholar
  32. 32.
    Daifuku M, Nishi K, Okamoto T, Sugahara T. Activation of J774.1 murine macrophages by lactate dehydrogenase. Cytotechnology. 2014;66:937–43.PubMedCrossRefGoogle Scholar
  33. 33.
    Sanchez O, Dominguez C, Vilches A, Llurba E, Alijotas-Reig J. Study of biomaterial-induced macrophage activation, cell-mediated immune response and molecular oxidative damage in patients with dermal bioimplants. Immunobiology. 2012;217:44–53.PubMedCrossRefGoogle Scholar
  34. 34.
    Christensen L. Normal and pathologic tissue reactions to soft tissue gel fillers. Dermatol Surg. 2007;33(Suppl 2):S168–75.PubMedGoogle Scholar
  35. 35.
    Lemperle G, Morhenn V, Charrier U. Human histology and persistence of various injectable filler substances for soft tissue augmentation. Aesthet Plast Surg. 2003;27:354–66.CrossRefGoogle Scholar
  36. 36.
    Requena L, Requena C, Christensen L, Zimmermann US, Kutzner H, Cerroni L. Adverse reactions to injectable soft tissue fillers. J Am Acad Dermatol. 2011;64:1–34.PubMedCrossRefGoogle Scholar
  37. 37.
    Alijotas-Reig J, Fernández-Figueras MT, Puig L. Inflammatory, immune-mediated adverse reactions related to soft tissue dermal fillers. Semin Arthritis Rheum. 2013;43:241–58.PubMedCrossRefGoogle Scholar
  38. 38.
    Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, et al. FK-506, a novel immunossupressant isolated from a Streptomyces, I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987;40:1249–55.CrossRefGoogle Scholar
  39. 39.
    Baumgart DC, Pintoff JP, Sturm A, Wiedenmann B, Dignass AU. Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease: a long term follow-up. Am J Gastroenterol. 2006;101:1048–56.PubMedCrossRefGoogle Scholar
  40. 40.
    Yoon KH. Eficacy and cytokine modulating effects of tacrolimus in systemic lupus erythematosus: a review. J Biomed Biotechnol. 2010.Google Scholar
  41. 41.
    Liu J, Farmer J, Lane W, Friedman J, Weissman I, Schreiber S. Calcineurin is a common target of cyclophilin-cyclosporin A and FK506 complexes. Cell. 1991;66:807–11.PubMedCrossRefGoogle Scholar
  42. 42.
    Roitt I, Brostoff J, Male D, editors. Inmunologia. Barcelona: Gower Medical Publishing Ltd; 1986.Google Scholar
  43. 43.
    Alijotas-Reig J, Garcia-Gimenez V, Miró-Mur F, Vilardell-Tarrés M. Delayed immune-mediated adverse effects related to polyacrylamide dermal fillers: clinical findings, management, and follow-up. Dermatol Surg. 2009;35:360–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Alijotas-Reig J. Recurrent urticarial vasculitis related to non-animal hyaluronic acid skin filler injection. Dermatol Surg. 2008;35:1–4.Google Scholar
  45. 45.
    Mullins RJ, Richards C, Walker T. Allergic reactions to oral, surgical and topical bovine collagen. Anaphilactic risk for surgeons. Aust NZJ Opthalmol. 1996;4:257–60.CrossRefGoogle Scholar
  46. 46.
    Mackern-Oberti JP, Jara EL, Riedel CA, Kalergis AM. Hormonal modulation of dendritic cells differentiation, maturation and function: implications for the initiation and progress of systemic autoimmunity. Arch Immunol Ther Exp. 2017;65:123–36.CrossRefGoogle Scholar
  47. 47.
    Yuan K, Wing LY, Lin MT. Pathogenetic roles of angiogenic factors in pyogenic granulomas in pregnancy are modulated by female sex hormones. J Periodontol. 2002;73:701–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Pasternak FR, Fox LP, Engler DE. Silicone granulomas treated with etanercept. Arch Deramtol. 2005;141:13–5.CrossRefGoogle Scholar
  49. 49.
    Gutmann C (2003). Silicone granuloma management: TNF inhibitors may be effective as intervention. Dermatol Times. 75–6.Google Scholar
  50. 50.
    Desai AM, Browning J, Rosen T. Etanercept therapy for silicone granuloma. J Drugs Dermatol. 2006;5:894–6.PubMedGoogle Scholar
  51. 51.
    Rapaport MJ. Silicone granulomas treated with etanercept. Arch Dermatol. 2005;141:1171.PubMedGoogle Scholar
  52. 52.
    Ramos-Casals M, Roberto-Perez-Alvarez D-LC, Cuadrado MJ, Khamashta MA, BIOGEAS Study Group. Autoimmune diseases induced by biological agents: a double-edged sword? Autoimmun Rev. 2010;9:188–93.PubMedCrossRefGoogle Scholar
  53. 53.
    Ramos-Casals M, Brito-Zerón P, Soto MJ, Cuadrado MJ, Khamashta MA. Autoimmune diseases induced by TNF-targeted therapies. Best Pract Res Clin Rheumatol. 2008;22:847–61.PubMedCrossRefGoogle Scholar
  54. 54.
    Rsachi E, Borghi MO, Grossi C, Broggini V, Pierangeli S, Meroni PL. Toll-like receptors: another player in the pathogenesis of the anti-phospholipid syndrome. Lupus. 2008;17:937–42.Google Scholar
  55. 55.
    Chen K, Huang J, Gong W, Iribarren P, Dunlop NM, Wang JM. Toll-like receptors in inflammation, infection and cancer. Int Immunopharmacol. 2007;26:1271–85.CrossRefGoogle Scholar
  56. 56.
    Cavalcante P, Galbardi B, Franzi S, Marcuzzo S, Barzago C, Bonanno S, et al. Increased expression of Toll-like receptors 7 and 9 in myasthenia gravis thymus characterized by active Epstein-Barr virus infection. Immunobiology. 2016;221:516–27.PubMedCrossRefGoogle Scholar
  57. 57.
    Farina A, Peruzzi G, Lacconi V, Lenna S, Quarta S, Rosato E, et al. Epstein-Barr virus lytic infection promotes activation of Toll-like receptor 8 innate immune response in systemic sclerosis monocytes. Arthritis Res Ther. 2017;19:39.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Kool M, Soullié T, van Nimwegen M, Willart MA, Muskens F, Jung S, et al. Alum adjuvant boosts adaptive immunity by inducing uric acid activating inflammatory dendritic cells. J Exp Med. 2008;205:869–82.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Hormung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, et al. Silica crystals and aluminium salts mediate NALP-3 inflammasome activation via phagosomal destabilization. Nat Immunol. 2008;9:847–56.CrossRefGoogle Scholar
  60. 60.
    Vera-Lastra O, Medina G, Cruz-Dominguez MP, Jara LJ, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome): clinical and immunological spectrum. Exp Rev Clin Immunol. 2013;9:361–73.CrossRefGoogle Scholar
  61. 61.
    Balmes JR, Speizer FE. Occupational and environmental lung disease. In: Kasper DL, Fauci AS, Hauser SL, et al., editors. Harrison’s principles of internal medicine. 19th ed. New York: McGraw Hill; 2015. p. 1687–94.Google Scholar
  62. 62.
    Yeter D, Portman MA, Aschner M, Farina M, Chan WCH, Hsieh K-S, et al. Ethnic Kawasaki disease risk associated with blood mercury and cadmium in U.S children. Int J Environ Res Public Health. 2016;13:101. Scholar
  63. 63.
    Krecisz B, Kiec-Swiercznska M, Chomiczewska-Skora D. Allergy to orthopedic metal implants—prospective study. Int J Occup Med Environ Health. 2012;25:463–9.PubMedGoogle Scholar
  64. 64.
    Frigerio E, Piagatto PD, Guzzi G, Altomare G. Metal sensitization in patients with orthopedic implants: a prospective study. Contact Dermatitis. 2011;64:273–4.PubMedCrossRefGoogle Scholar
  65. 65.
    Hallab N, Merrit K, Jacobs JJ. Metal sensitivity in patients with orthopedic implants. J Bone Joint Surg Am. 2001;83:428–36.PubMedCrossRefGoogle Scholar
  66. 66.
    Dietrich K-A, Mazoochian F, Summer B, Reinert M, Ruzicka T, Thomas P. Intolerance reactions to knee arthroplasty in patients with nickel/cobalt allergy and disappearance of symptoms after revision surgery with titanium-based endoprostheses. JDDG. 2009;7:410–3.PubMedGoogle Scholar
  67. 67.
    Stejskal V. Metals as a common trigger of inflammation resulting in non-specific symptoms: diagnosis and treatment. IMAJ. 2014;16:753–8.PubMedGoogle Scholar
  68. 68.
    Stejskal V, Kal B, Ilhan Evcin O, Dundar N, Tezel H, Unal I, et al. An unusual case of immediate hypersensitivity reaction associated with an amalgam restoration. Br Dental J. 2005;10:547–50.Google Scholar
  69. 69.
    Loyo E, Jara LJ, López PD, Puig AC. Autoimmunity in connection with a metal implant: a case of autoimmune/autoinflammatory syndrome induced by adjuvants. Auto Immun Highlights. 2012;4:33–8.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Eitan I, Agmon-Levin N, Blank M, Shoenfeld Y. Adjuvants and immunity. Lupus. 2009;18:1217–25.CrossRefGoogle Scholar
  71. 71.
    Soriano A. The paradigm of ASIA (autoimmune / inflammatry syndrome induced by adjuvants): a concept in evolution. IMAJ. 2014;16:113–4.PubMedGoogle Scholar
  72. 72.
    Gherardi RK, Coquet M, Cherin P, Belec L, Moretto P, Dreyfus PA, et al. Macrophagic myofascitis lesions assess long-term persistence of vaccine-derived alumunium hydroxide in muscles. Brain. 2001;124(Pt9):1821–31.PubMedCrossRefGoogle Scholar
  73. 73.
    Israeli E. Gulf War syndrome as a part of the autoimmune (autoinflammatory) syndrome induced by adjuvant (ASIA). Lupus. 2012;21:190–4.PubMedCrossRefGoogle Scholar
  74. 74.
    Tabuenca JM. Toxic-allergic syndrome caused by ingestion of rapeseed oil denatured with aniline. Lancet. 1981;ii:567–8.CrossRefGoogle Scholar
  75. 75.
    Antó JM, Taylor AJ, Moya C. Outbreak of organising pneumonia in textile printing sprayers. Collaborative Group for the Study of Toxicity in Textile Aerographic Factories. Lancet. 1994;344:498–502.PubMedCrossRefGoogle Scholar
  76. 76.
    Norback D. An update on sick building syndrome. Curr Opin Allergy Clin Immunol. 2009;9:55–9.PubMedCrossRefGoogle Scholar
  77. 77.
    Israel E, Pardo A. The sick building syndrome as a part of the autoimmune (auto-inflammatory) syndrome induced by adjuvants. Mod Rheumatol. 2011;21:235–9.CrossRefGoogle Scholar
  78. 78.
    Mosca M, Neri R, Bonbardieri S. Undifferentiated connective tissue diseases (UCTD): a review of the literature and a proposal for preliminary classification criteria. Clin Exp Rheumatol. 1999;17:585–9.Google Scholar
  79. 79.
    Mosca M, Baldini C, Bombardieri S. Undifferentiated connective tissue diseases in 2004. Clin Exp Rheumatol. 2004;22(3 Suppl 33):S14–8.PubMedGoogle Scholar
  80. 80.
    Amador-Patarroyo MJ, Arbelaez JG, Mantilla RD, Rodriguez-Rodriguez A, Cardenas-Roldan J, Pineda-Tamayo R, et al. Sjogren’s síndrome at the crossroad of polyautoimmunity. J Autoimmun. 2012;39:199–205.PubMedCrossRefGoogle Scholar
  81. 81.
    Peri Y, Agmon-Levin N, Theodor E, Shoenfeld Y. Sjogren’s syndrome, the old and the new. Best Pract Res Clin Rheumatol. 2012;26:105–17.PubMedCrossRefGoogle Scholar
  82. 82.
    Meroni PL. Autoimmune/inflammatry syndrome induced by adjuvants (ASIA): old truths and new syndrome? J Autoimmun. 2011;36:1–3.PubMedCrossRefGoogle Scholar
  83. 83.
    Watad A, Quaresma M, Brown S, Cohen Tervaert JW, Rodríguez-Pint I, et al. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld's syndrome)—an update. Lupus. 2017;26:675–81.PubMedCrossRefGoogle Scholar
  84. 84.
    Wolfe F, Anderson J. Silicone filled breast implants and the risk of fibromyalgia and rheumatoid arthritis. J Rheumatol. 1999;26:2025–8.PubMedGoogle Scholar
  85. 85.
    van Nunen SA, Gatenby PA, Basten A. Post-mammoplasty connective tissue diseases. Arthritis Rheum. 1982;25:694–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Lidar M, Agmon-Levin N, Langevitz P, Shoenfeld Y. Silicone and scleroderma revisited. Lupus. 2012;21:121–7.PubMedCrossRefGoogle Scholar
  87. 87.
    Kumagai Y, Abe C, Shiokawa Y. Scleroderma after cosmetic surgery. Arthritis Rheum. 1979;22:532–7.PubMedCrossRefGoogle Scholar
  88. 88.
    Spiera RF, Gibofsky A, Spiera H. Silicone gel filled breast implants and connective tissue disease: an overview. J Rheumatol. 1994;21:239–45.PubMedGoogle Scholar
  89. 89.
    Garcia MI, Alijotas-Reig J, Mitjavila F, Boliart Y, Vidaller A. Esclerodermia tras implantes mamarios de silicona: a propósito de tres casos. Rev Esp Reumatol. 1997;24:215–9.Google Scholar
  90. 90.
    Whorton D, Wong O. Scleroderma and silicone breast implants. West J Med. 1997;167:159–65.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Bridges AJ, Conley C, Wang G, Burns DE, Vasey FB. A clinical and immunologic evaluation of women with silicone breast implants and symptoms of rheumatic disease. Ann Intern Med. 1993;118:929–37.PubMedCrossRefGoogle Scholar
  92. 92.
    Houpt KR, Sontheimer RD. Autoimmune connective tissue diseases and connective tissue-related illnesses after silicone gel augmentation. J Am Acad Dermatol. 1994;31:626–42.PubMedCrossRefGoogle Scholar
  93. 93.
    Selva-O'Callaghan A, Tura JM, Grau-Junyent JM, Labrador-Horrillo M, Solans-Laque R, Vilardell-Tarrés M. Silicone gel filled breast implants and dermatomyositis. Clin Exp Rheumatol. 2004;22:376.PubMedGoogle Scholar
  94. 94.
    Kivity S, Katz M, Langevitz P, Eshed I, Olchovski D, Barzilai A. Autoimmune syndrome induced by adjuvants (ASIA) in the Middle East: morphea following silicone implantation. Lupus. 2012;21:136–9.PubMedCrossRefGoogle Scholar
  95. 95.
    Agmon-Levin N, Shoenfeld Y. Chronic fatigue syndrome with autoantibodies—the result of an augmented adjuvant effect of hepatitis-B vaccine and silicone implant. Autoimmun Rev. 2008;8:52–5.CrossRefGoogle Scholar
  96. 96.
    Cohen Tervaert JW, Kappel RM. Silicone implant incompatibility syndrome: a frequent cause of ASIA (Shoenfeld’s syndrome). Immunol Res. 2013;56:293–8.PubMedCrossRefGoogle Scholar
  97. 97.
    Goren I, Segal G, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) evolution after silicone implants. Who is at risk? Clin Rheumatol. 2015;34:1661–6.PubMedCrossRefGoogle Scholar
  98. 98.
    Jara LJ, Garcia-Collinot G, Medina G, Cruz-Dominguez MP, Vera-lastra O, Carranza-Muleiro RA, et al (2016). Severe manifestations of autoinmune síndrome induced by adjuvants (Shoenfeld’s syndrome). Imunol Res.
  99. 99.
    Maijers MC, de Blok CJM, Niessen FB, van der Veldt AAM, Ritt MJPF, et al. Women with silicone breast implant and unexplained systemic symptoms: a descriptive cohort study. Netherlands J Med. 2013;71:534–40.Google Scholar
  100. 100.
    Contant CM, Swaak AJ, Obdeijin AI, van der Holt B, Tjong Joe WAi R, et al. A prospective study on silicone breast implants and the silicone-related symptoms complex. Clin Rheumatol. 2002;21:215–9.PubMedCrossRefGoogle Scholar
  101. 101.
    Shoaib BO, Pattern BM, Calkjins DS. Adjuvant breast disease: an evaluation of 100 symptomatic women with breast implants or silicone fluid injections. Keio Med J. 1994;43:79–87.CrossRefGoogle Scholar
  102. 102.
    Shoaib BO, Patten BM. Human adjuvant disease: presentation as a multiple sclerosis-like syndrome. South Med J. 1996;89:179–88.PubMedCrossRefGoogle Scholar
  103. 103.
    Cuellar ML, Gluck O, Molina JF, Gutierrez S, Garcia C, Espinoza R. Silicone breast implant-associated musculoskeletal manifestations. Clin Rheumatol. 1995;14:667–72.PubMedCrossRefGoogle Scholar
  104. 104.
    Gaubitz M, Jackish C, Domschke W, Heindel W, Pfeiderer B. Silicone breast implants: correlation between implant ruptures, magnetic resonance spectroscopically estimated silicone presence in the liver, antibody status and clinical symptoms. Rheumatology (Oxford). 2001;41:129–35.CrossRefGoogle Scholar
  105. 105.
    Giltay EG, Bernelot Moens HJ, Riley AH, Tan RG. Silicone breast prostheses and rheumatic symptoms: a retrospective follow up study. Ann Rheum Dis. 1994;53:194–6.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Vasey FB, Havice DL, Bocanegra TS, Seleznick MJ, Bridgeford PH, Martinez-Osuna P, et al. Clinical findings in symptomatic women with silicone breast implants. Semin Arthritis Rheum. 1994;24(suppl 1):22–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Freundlinch B, Altman C, Snadorfi N, Greenberg M, Tomaszewski J. A profile of symptomatic patients with silicone breast implants: a Sjögren-like syndrome. Semin Arthritis Rheum. 1994;24(suppl 1):44–53.CrossRefGoogle Scholar
  108. 108.
    Solomon G. Clinical and laboratory profile of symptomatic women with silicone breast implants. Semin Arthritis Rheum. 1994;24(Suppl 1):29–37.PubMedCrossRefGoogle Scholar
  109. 109.
    De Jong WH, Goldhoorn CA, Kallewaard M, Geertsma RE, Van Loveren H, Bijilsma JW, et al. Study to determine the presence of antipolymer antibodies in a group of Dutch women with a silicone breast implants. Clin Exp Rheumatol. 2002;20:151–60.PubMedGoogle Scholar
  110. 110.
    Vermeulen RC, Scholte HR. Rupture of silicone gel breast implants and symptoms of pain and fatigue. J Rheumatol. 2003;30:2263–7.PubMedGoogle Scholar
  111. 111.
    Wells KE, Roberts C, Daniels SM, Kearney RE, Cox CE. Psychological and rheumatic symptoms of women requesting silicone breast implants removal. Ann Plast Surg. 1995;34:572–7.PubMedCrossRefGoogle Scholar
  112. 112.
    Peters W, Smith D, Fornasier V, Lugowski S, Ibañez D. An outcome analysis of 100 women after explantation silicone gel breast implants. Ann Plast Surg. 1997;39:9–19.PubMedCrossRefGoogle Scholar
  113. 113.
    Pineda JC, Díaz JC, Agualimpia A, Gracía JF. Autoimmune/inflammatory síndrome induced by adjuvants causing myositis and pulmonary fibrosis. IMAJ. 2016;18:720–1.Google Scholar
  114. 114.
    Colafrancesco S, Perricone C, Shoenfeld Y. Autoimmune/inflammatory syndrome induced by adjuvants and Sjögren syndrome. IMAJ. 2016;18:150–4.PubMedGoogle Scholar
  115. 115.
    David PR, Dagan A, Colaris M, de Boer M, Cohen Tervaert JW. Churg-Strauss syndrome: singulair or silicone (or both?). IMAJ. 2016;18:168–70.PubMedGoogle Scholar
  116. 116.
    Bindoli S, Dagan A, Torres-Ruiz JJ, Perricone C, Bizjak M, Doria A, et al. Sarcoidosis and autoimmunity: from genetic background to environmental factors. IMAJ. 2016;18:197–202.PubMedGoogle Scholar
  117. 117.
    Esposito S, Prada E, Mastrolia MV, Tarantino G, Codeca C, Rigante D. Autoimmune/inflammatory syndrome induced by adjuvants (ASIA): clues and pitfalls in the pediatric background. Immunol Res. 2014;60:366–75.PubMedCrossRefGoogle Scholar
  118. 118.
    Colaris MJL, de Boer M, van der Hulst RR, Cohen Tervaert JW. Two hundred cases of ASIA syndrome following silicone implants: a comparative study of 30 years and a review of current literature. Immunol Res. 2017;65:120–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Cohen Tervaert JW, Colaris MJ, van der Hulst RR (2017). Silicone breast implants and autoimmune rheumatic diseases: myth or reality. Curr Opin Rheumatol.
  120. 120.
    Sanchez-Guerrero J, Colditz GA, Karlson EW, Hunter DJ, Speizer FE, Liang MH. Silicone breast implants and the risk of connective tissue diseases and symptoms. N Engl J Med. 1995;332:1666–70.PubMedCrossRefGoogle Scholar
  121. 121.
    Gabriel SE, O’Fallon WM, Kurland LT, Beard CM, Wooda JE, Melton LJ. Risk of connective tissue diseases and other disorders after silicone breast implantation. N Engl J Med. 1994;330:1697–702.PubMedCrossRefGoogle Scholar
  122. 122.
    Hochberg MC, White B, Steen V, Medsger TA, Weisman M, Wigley FM. The association of augmentation mammoplasty with systemic sclerosis: preliminary results from a case-control study. Arthritis Rheum. 1993;36(suppl):S71.Google Scholar
  123. 123.
    Hennekens CH, Lee IM, Cook NR, Hebert PR, Karlson EW, LaMotte F, et al. Self-reported breast implants and connective-tissue diseases in female health professionals. A retrospective cohort study. JAMA. 1996;275:616–21.PubMedCrossRefGoogle Scholar
  124. 124.
    Nyrén O, Yin L, Josefsson S, McLaughlin JK, Blot WJ, Engqvist M, et al. Risk of connective tissue disease and related disorders among women with breast implants: a nation-wide retrospective cohort study in Sweden. BMJ. 1998;316:417–22.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Janoswky EC, Kupper LL, Hulka BS. Meta-analyses of the relation between silicone breasts implants and the risk of connective-tissue diseases. N Engl J Med. 2000;342:781–90.CrossRefGoogle Scholar
  126. 126.
    Rongioletti F. Exogenous cutaneous deposits with special consideration to skin reactions to soft tossue fillers. In: Rongioletti F, Smoller BR, editors. Clinical and pathological aspects of skin diseases in endocrine, metabolic, nutritional and deposition diseases. New York: Springer; 2010. p. 181–9.CrossRefGoogle Scholar
  127. 127.
    Alijotas-Reig J, Garcia-Gimenez V, Vilardell-Tarres M. Late-onset immune-mediated adverse effects after poly-L-lactic acid injection in non-HIV patients: clinical findings and long-term follow-up. Dermatology. 2009;219:303–8.PubMedCrossRefGoogle Scholar
  128. 128.
    Rosner M, Rossner F, Bachmann F, Wiest L, Rzany B. Risk of severe adverse reactions to an injectable filler based on a fixed combination on hydroxylethylmethacrylate and ethylmethycrylate with hyaluronic acid. Dermatol Surg. 2009;35(Suppl 1):367–74.CrossRefGoogle Scholar
  129. 129.
    Bachmann F, Erdmann R, Hartmann V, Becker-Wegerich P, Wiest L, Rzany B. Adverse reactions caused by consecutive injections of different fillers in the same facial region: risk assessment based on the results from the Injectable Filler Safety study. J Eur Acad Dermatol Venereol. 2011;25:907–12.Google Scholar
  130. 130.
    Ashutosh K, Mangalam AK, Taneja V, David CS. HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile. J Immunol. 2013;190:513–8.CrossRefGoogle Scholar
  131. 131.
    Gough SCL, Simmonds MJ. The HLA region and autoimmune disease: associations and mechanisms of action. Curr Genomics. 2007;8:453–65.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Miyadera H, Tokunaga K. Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism. J Human Gen. 2015;60:697–702.CrossRefGoogle Scholar
  133. 133.
    Hofmann S, Franke A, Fisher A, Jacobs G, Nothnagel M, Gaede KI, et al. Genome-wide association study identifies ANX-A11 as a new susceptibility locus for sarcoidosis. Nat Genet. 2008;40:1103–6. Erratum in: Nat Genet. 2009;41:504PubMedCrossRefGoogle Scholar
  134. 134.
    De Boulle K. Management of complications after implantation of fillers. J Cosmet Dermatol. 2004;3:2–15.PubMedCrossRefGoogle Scholar
  135. 135.
    Sanchis-Bielsa JM, Bagán JV, Poveda R, Salvador I. Foreign body granulomatous reactions to cosmetic fillers: a clinical study of 15 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2009;108:237–4.PubMedCrossRefGoogle Scholar
  136. 136.
    Leonhardt JM, Lawrence N, Narins RS. Angioedema acute hypersensitivity reaction to injectable hyaluronic acid. Dermatol Surg. 2005;31:577–9.PubMedCrossRefGoogle Scholar
  137. 137.
    Lemperle G, Gauthier-Hazan N. Foreign body granulomas after all injectable dermal fillers: part 2, treatment options. Plast Reconstr Surg. 2009;123:1864–73.PubMedCrossRefGoogle Scholar
  138. 138.
    Antonovic D, Callen J. Development of sarcoidosis in cosmetic tattoos. Arch Dermatol. 2005;141:869–72.Google Scholar
  139. 139.
    Vedamurthy M. Soft tissue augmentation—use of hyaluronic acid as dermal filler. Indian J Dermatol Venereol Leprol. 2004;70:383–7.PubMedGoogle Scholar
  140. 140.
    Sclafani AP, Fagien S. Treatment of injectable soft tissue filler complications. Dermatol Surg. 2009;35:1672–80.PubMedCrossRefGoogle Scholar
  141. 141.
    Tsai TF, Yeh TY. Allopurinol in dermatology. Am J Clin Dermatol. 2010;11:225–32.PubMedCrossRefGoogle Scholar
  142. 142.
    Reisemberger EM, Landthaler M, Wiest I, Schröder J, Stolz W. Foreign body granulomascaused by polymethtylmethacrylate microspheres: successful treatment with allopurinol. Arch Dermatol. 2003;139:17–20.CrossRefGoogle Scholar
  143. 143.
    Redondo P, Del Olmo J, Alberola I. In situ and distant foreign body granulomas caused by silicone. Treatment with allopurinol. Br J Dermatol. 2005;152:1064–5.PubMedCrossRefGoogle Scholar
  144. 144.
    Ficcara G, Mosqueda-Taylor A, Carlos R. Silicone granuloma of the facial tisúes: a report of seven cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;94:65–73.CrossRefGoogle Scholar
  145. 145.
    Park CS, Cho JH, Kang JM, Kim BK, Han MA. Levocetrizine has anti-inflammatory effects against Toll-like receptor (TLR)3 through the inhibition of Toll-IL-1 receptor (TIR)-domain-containing adapter inducing IFN-beta (TRIF) and receptor-interacting protein (RIP). Auris Nasus Larynx. 2011;38:474–9.PubMedCrossRefGoogle Scholar
  146. 146.
    Duranti F, Salti G, Bovani B, Calandri M, Rosati M. Injectable hyaluronic acid gel for soft tissue augmentation. Dermatol Surg. 1998;24:1317–25.PubMedGoogle Scholar
  147. 147.
    Alam M, Dover JS. Management of complications and sequelae with temporary injectable fillers. Plast Reconstr Surg. 2007;120(Suppl 120):98S–105.PubMedCrossRefGoogle Scholar
  148. 148.
    Christensen LH. Host tissue interaction, fate, and risks of degradable and nondegradable gel fillers. Dermatol Surg. 2009;35(Suppl 2):1612–9.PubMedCrossRefGoogle Scholar
  149. 149.
    Sánchez-Carpintero I, Candelas D, Ruiz-Rodríguez R. Dermal fillers: types, indications, and complications. Actas Dermosifiliogr. 2010;101:381–93.PubMedCrossRefGoogle Scholar
  150. 150.
    Senet P, Bachelez H, Ollivaud L, Vignon-Pennamen D, Dubertret L. Minocycline for the treatment of cutaneous silicone granulomas. Br J Dermatol. 1999;140:985–7.PubMedCrossRefGoogle Scholar
  151. 151.
    Fernández-Aceñero MJ, Zamora E, Borbujo J. Granulomatous foreign body reaction against hyaluronic acid: report of a case after lip augmentation. Dermatol Surg. 2003;29:1225–6.PubMedCrossRefGoogle Scholar
  152. 152.
    Nichols BJ, Carpenter J, Hribar KP, Go J, Rice DH. Acute parotitis after injection of poly-L-lactic acid for malar augmentation: a case report and review of relevant anatomy. Dermatol Surg. 2011;37:381–6.PubMedCrossRefGoogle Scholar
  153. 153.
    Duffy DM. Complications of fillers: overview. Dermatol Surg. 2005;31:1226–33.Google Scholar
  154. 154.
    Alijotas-Reig J, Gracía-Gimenez V, Vilardell-Tarrés M. Tacrolimus in the treatment of chronic and refractory late-onset immune-mediated adverse effects related to silicone injections. Dermatol Surg. 2012;38:38–47.PubMedCrossRefGoogle Scholar
  155. 155.
    Lloret P, España A, Leache A, Bauzá A, Fernández-Galar M, Idoate MA, et al. Successful treatment of granulomatous reactions secondary to injection of esthetic implants. Dermatol Surg. 2005;31:486–90.PubMedCrossRefGoogle Scholar
  156. 156.
    Lemperle G, Rullan PP, Gauthier-Hazan N. Avoiding and treating dermal filler complications. Plast Reconstr Surg. 2006;118(S3):92S–107S.PubMedCrossRefGoogle Scholar
  157. 157.
    Sperling B, Bachmann F, Hartmann V, Erdmann R, Wiest L, Rzany B. The current state of treatment of adverse reactions to injectable fillers. Dermatol Surg. 2010;36:1895–904.PubMedCrossRefGoogle Scholar
  158. 158.
    Broder KW, Cohen SR. An overview of permanent and semipermanent fillers. Plast Reconstr Surg. 2006;118(Suppl):7S–14S.PubMedCrossRefGoogle Scholar
  159. 159.
    Hirsch R, Stier M. Complications of soft tissue augmentation. J Drugs Dermatol. 2008;7:841–5.PubMedGoogle Scholar
  160. 160.
    Melmed EP. A review of explantation in 240 symptomatic women: a description of explantation and capsulectomy with reconstruction using a periareolar technique. Plast Reconstr Surg. 1998;101:1364–73.PubMedCrossRefGoogle Scholar
  161. 161.
    de Boer M, Colaris M, van der Hulst RRWJ, Cohen Tervaert JW. Is explantation of silicone breast implants useful in patients with complaints? Immunol Res. 2017;65:25–36.PubMedCrossRefGoogle Scholar
  162. 162.
    Hruza GJ, Ammirati LT. Granuloma faciale treated with 595-nm pulsed dye laser. Dermatol Surg. 2011;37:1060–1.PubMedCrossRefGoogle Scholar
  163. 163.
    Pohl L, Karsai S, Raulin C. Recurrent pyogenic granulomas. Treatment at difficult anatomic sites with the pulsed Nd: YAG laser (1064-nm). Hautarz. 2011;62:46–50.CrossRefGoogle Scholar
  164. 164.
    Cassuto D, Marangoni O, De Santis G, Christensen L. Advanced laser techniques for filler-induced complications. Dermatol Surg. 2009;35(Suppl 2):1689–95.PubMedCrossRefGoogle Scholar
  165. 165.
    Cassuto D, Pignatti M, Pacchioni L, Boscaini G, Spaggiari A, De Santis G. Management of complications caused by permanent filers in the face: a treatment algorithm. Plast Reconstr Surg. 2016;138:215e–27e.PubMedCrossRefGoogle Scholar
  166. 166.
    Paradisi A, Ricci F, Sbano P. Drug-resistant granuloma faciale: treatment with carbon dioxide-GaAs laser. Dermatol Ther. 2016;29:317–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Jaume Alijotas-Reig
    • 1
    • 2
  • Enrique Esteve-Valverde
    • 3
  • Natalia Gil-Aliberas
    • 3
  • Victor Garcia-Gimenez
    • 4
    • 5
  1. 1.Systemic Autoimmune Diseases Unit, Department of Internal Medicine-1Vall d’Hebron University HospitalBarcelonaSpain
  2. 2.Department of Medicine, Faculty of MedicineUniversitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Department of Internal MedicineAlthaia Network Health, ManresaBarcelonaSpain
  4. 4.Europe Medical CentreBarcelonaSpain
  5. 5.Spanish Society of Cosmetic Medicine & SurgeryBarcelonaSpain

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