- Case Report
- Open Access
Autoimmunity in connection with a metal implant: a case of autoimmune/autoinflammatory syndrome induced by adjuvants
© Springer-Verlag Italia 2012
- Received: 1 July 2012
- Accepted: 26 November 2012
- Published: 15 December 2012
Autoimmune/autoinflammatory syndrome induced by adjuvants (ASIA) has been recently proposed by Shoenfeld and Agmon-Levin as a new entity that comprises several conditions: the macrophagic-myofasciitis syndrome, the Gulf War syndrome, silicosis and post-vaccination phenomena, autoimmunity related to infectious fragments, hormones, aluminum, silicone, squalene oil, and pristane. We report the case of a 23-year-old woman who developed serial episodes of high fever, extreme fatigue, transient thrombocytopenia, multiple cervical adenopathies, hepatosplenomegaly, anemia, neutropenia, severe proteinuria and urine sediment abnormalities, elevated serum ferritin levels, and transient low positive antinuclear antibodies 1 year after she had a nickel–titanium chin implant for cosmetic reasons. The clinical picture simulated a variety of probable diseases: systemic lupus erythematosus, Kikuchi–Fujimoto syndrome, adult onset Still’s disease, antiphospholipid syndrome, and hemophagocytic syndrome, among others, so she underwent an extensive medical investigation including two lymph node biopsies. She received treatment accordingly with steroids, methotrexate, and mofetil mycophenolate, with initial improvement of her symptoms, which recurred every time the dose was reduced. Two and a half years later the patient decided to retire the chin implant and afterwards all her systemic symptoms have disappeared. She remains in good health, without recurrence of any symptom and off medications until today. Albeit this patient fulfills proposed major ASIA criteria, to our knowledge it would be the first description of systemic features of autoinflammation in connection with a metal implant.
- Adult onset Still’s disease
- Lupus-like syndrome
- ASIA syndrome
- Metal hypersensitivity
Autoimmune (autoinflammatory) syndrome induced by adjuvants (ASIA) denotes a complex of signs and symptoms that suggest a ‘‘direct link between injection of foreign matter and ‘autoimmune’-like syndromes’’ [1–3].
Adjuvants have been widely used in medicine as a tool to increase desired immune responses against certain microbes, i.e., vaccination. However, these substances can also increase the immune responses elicited to undesired levels, as vaccines can induce autoantibodies and manifestations of arthritis, encephalitis, and even vasculitis . The risks factors are unknown.
In the last decade, there has been a concern about possible allergic (hypersensitivity) reactions to foreign materials implanted in the body. The most common form of metal hypersensitivity is contact dermatitis due to nickel , which has led the Northern European countries to regulate consumer nickel exposure. Consumer items intended to be in direct and prolonged contact with the skin are not allowed to release more than 0.5 μg nickel/cm2/week . However, the metal use in oral, cardiovascular, orthopedic, and now cosmetic devices continues to increase over time, with little control at all.
We report the case of a young female who developed severe systemic autoinflammatory manifestations 1 year after a cosmetic nickel–titanium chin implant, all of which resolved after the implant was retired.
While in Argentina as an Odontology student in November 2006, a 23-year-old female started with high fever, extreme fatigue, cervical adenopathies, and transient thrombocytopenia. At the time she was diagnosed with dengue fever; a lymph node biopsy reported ‘reactive hyperplasia’ only.
She also presented splenomegaly and urine sediment alterations with protein and granular cylinders, which were attributed to the fever.
As a child, she suffered repeated respiratory allergic reactions and several bouts of allergic asthma. Her mother related an episode of cutaneous hypersensitivity to an oral anti-inflammatory drug (fixed pigmented erythema apparently against diclofenac). At the age of 19, the patient underwent eye surgery for myopic correction and an abdominal liposuction. Approximately, 1 year before all symptoms began in Argentina, she had a nickel–titanium chin implant for cosmetic reasons.
First visit and treatment
Further workup on presentation
C reactive protein
1:40 with a speckled pattern
aCL-IgG, IgM, IgA
B-2-glycoprotein IgG, IgM, IgA
Protein 3+; granular cylinders 2+
Protein 3+; granular and hyaline cylinders
Protein urine test (24 h)
0–0.15 mg/24 h
Subsequent analysis determined a negative rheumatoid factor (RF), negative anti-citrullinated peptide antibodies (ACPA) along with negative results in new ANA, anti-Ro, -Sm, and -dsDNA determinations, and normal IgE levels. C3 levels were 135 mg/dL (88–206 mg/dL), while C4 was 16 mg/dL (13–75 mg/dL). All her cultures and bacilloscopies were negative too, as well as a virus panel testing (HIV1/2, hepatitis B and C, cytomegalovirus, Epstein–Barr and herpes simplex 1/2) and serum tests for syphilis. Thorax X-rays were normal but a transthoracic echocardiogram revealed fluid in the pericardium with a 75 % ejection fraction, without evidence of endocarditis. A second lymph node biopsy again reported ‘reactive hyperplasia.’ Other departments (hematology, infectivology) were involved in the evaluation and workup, but there was no definitive diagnosis. We began treatment with intra-venous (IV) methylprednisolone, and she had a rapid good clinical response and eventual remission of symptoms.
Second visit and treatment
Back in Argentina, where she was referred to a rheumatologist, she was diagnosed as adult onset Still’s disease (AOSD) because of elevated ferritin serum levels and started on oral methotrexate 10 mg once a week and decreasing doses of oral steroids. However, she did not feel well and in April 2008 returned to the Dominican Republic with a similar clinical picture as in 2007: fever, myalgia, arthralgia, anemia, and high ferritin (1,500 ng/mL); ANA and anti-dsDNA antibodies were negative, C3 and C4 were normal. She had negative anti-cardiolipin antibodies (IgG, IgM, and IgA). She improved with prednisone 30 mg/day and was switched to subcutaneous methotrexate 20 mg/week.
Alas, her improvement did not last. She presented again in June with anemia, myalgia, arthralgia, ferritin 1,970 ng/ml, and elevated hepatic enzymes for the third time, as a result of lowering the dose of prednisone to 10 mg/day. In September 2008, we withdrew methotrexate due to lack of response and started mofetil mycophenolate 2.0 g/day. Ferritin level dropped to 58 ng/ml and ESR to 9 mm/h. She did well throughout 2009, but was lost to follow-up, returning in January 2010 with severe abdominal pain and acute splenomegaly, high fever, transient cutaneous rash, arthralgia, anemia, massive proteinuria (3,407 mg/24 h) with granular and hyaline cylinders, ferritin 1,270 ng/mL, ESR 50 mm/h, negative ANA and anti-dsDNA, negative anti-cardiolipin and anti-beta-2-glycoprotein antibodies, and normal C3 and C4. The patient had suspended her medications. Again, the clinical picture abated with prednisone 60 mg/day.
At the end of January 2010, the patient opted for removal of the nickel–titanium implant, assuming it was responsible for her symptoms, since they had began after the implant. Her clinical picture actually improved and 3 months later she was off steroids and mycophenolate. In her most recent follow-up, June 2012, she was clinically asymptomatic; all her laboratory studies were normal [including ferritin (25.6 ng/mL)].
This case highlights the inherent difficulties encountered in daily practice regarding autoimmunity diseases. Before the nickel–titanium chin implant, this patient had a normal life, with an unremarkable history of allergies to common household items during infancy. Her debut with severe malaise, high fever, visceromegaly and multiple adenopathies plus positive ANA, high serum ferritin levels, and all the signs and symptoms described pointed to a severe clinical immune dysfunction. However, the whole clinical and serological picture abated after the implant surgical excision.
In most patients, AOSD is characterized by four cardinal symptoms: spiking fever, an evanescent salmon-pink maculopapular rash, arthritis, and elevated white blood cells, mainly neutrophils . Other features, as sore throat, myalgia, lymph node or spleen enlargement, pleuritis, pericarditis, elevated levels of liver enzymes, and other hematologic disturbances, have been described. None of these features is specific and as a consequence AOSD is an exclusion diagnosis .
Initially, this patient seemed to fall into a polycyclic pattern of AOSD. However, though her high serum ferritin levels suggested AOSD, she did not fulfill major Yamaguchi criteria  (i.e., she had leucopenia instead of leucocytosis and also had rare features like renal involvement). There was no evidence of infection, malignant, or hemophagocytic disease. No signs of vasculitis and no true muscular weakness either. The lack of synovitis, negative RF, and ACPA helped to rule out the rheumatoid arthritis. The combination of pericarditis, arthralgia, renal involvement, anemia, and leucopenia in addition to transient thrombocytopenia suggested systemic lupus erythematosus, but the repeated negative ANA, anti-dsDNA and anti-Sm tests, and normal complement levels did not support the diagnosis. She also had repeated negative antiphospholipid serum profile.
Suggested criteria for ASIA diagnosis
Exposure to an external stimulus (infection, vaccine, silicone, adjuvant) prior to clinical manifestations.
Appearance of autoantibodies or antibodies directed at the suspected adjuvant.
Appearance of one of the clinical manifestations listed below: myalgia, myositis, or muscular weakness. Arthralgia and/or arthritis. Chronic fatigue, non-restful sleeps, or sleep disturbances. Neurological manifestations (especially those associated with demyelination), cognitive impairment, memory loss. Pyrexia. Dry mouth.
Other clinical manifestations (i.e., irritable bowel syndrome).
Removal of inciting agent induces improvement.
Specific HLA (i.e., HLA DRB1, HLA DQB1)
Typical biopsy of involved organs.
Evolvement of an autoimmune disease (i.e., multiple sclerosis, systemic sclerosis).
There must be the presence of at least two major or one major and two minor criteria.
Fulfillment of ASIA criteria
Exposure to an external stimulus prior to clinical manifestations.
Nickel–titanium chin implant 1 year before symptoms began.
Myalgia, arthralgia, pyrexia, and extreme fatigue.
Typical biopsy of involved organs.
‘Reactive hyperplasia’ on two lymphadenopathy biopsies.
Removal of inciting agent induces improvement.
Yes. Since January 2010 until today.
Evolvement of an autoimmune disease.
Multiple clinical systemic features plus serologic evidence of inflammation.
Nickel and immune response
Environmental factors, such as chemicals, infectious agents, or drugs, have been implicated in the expression of autoimmune diseases. Recent findings conclude that crystalline silica, solvent, smoking, and ultraviolet radiation exposure can contribute to the generation of autoimmune disease . Nickel is a ubiquitous trace element, and is the fourth most frequently used metal in the world and the principle cause of allergic contact dermatitis (ACD). Cobalt, chromium, molybdenum, and gold are less often implicated . Nickel is found in many commercial products (zippers, buttons, jewelry, watches, eye glass frames, and mobile phones) and many of these items have been linked to ACD, a delayed-type hypersensitivity reaction, which characteristically does not involve immediate allergic reactions, systemic features, or escalate to anaphylaxis.
Data supporting association of nickel with autoimmune disease are scarce. Experimental rat models have demonstrated positivity of serum ANA after both oral and subcutaneous nickel administration, with development of sclerodermic features on the skin being more prominent when the subcutaneous route was used [12, 13]. Others had demonstrated that the parenteral administration of nickel produces greater metal accumulation in the lung, denoted by hydropic and degenerative changes of the endothelium of pulmonary arteries and veins, marked proliferation of alveolar lining cells and thickening of alveolar walls, and hyperplasia of bronchial epithelium . In Norway rats, parenteral administration of nickel chloride can induce morphological and biochemical signs of alveolar macrophage activation, with nickel deposition both in tissue and macrophage cytoplasm even after a single dose . It seems that depending on the nature of contact with nickel ions, as well as length and intensity of exposition and the administration route, this could produce allergy in susceptible individuals.
Nickel and human experience
Two lymph node biopsies only reported reactive hyperplasia, but no immunohistochemical studies were done. Though further studies are needed, it seems that nickel is capable of macrophage activation beyond the alveolar space in genetically susceptible individuals, in a way that resembles macrophage activation in response to aluminum adjuvant in the macrophagic-myofasciitis syndrome . Other monocyte-derived cells could carry nickel particles to secondary lymphoid tissues, including the spleen, and provoke further T cell recruitment.
The remarkable clinical course that finally resolved with removal of the device led us to consider ASIA syndrome, probably the first description of systemic features of autoinflammation in connection with a metal implant. Systemic reactions might not be common, but the potential risk of nickel or the nickel–titanium combination toxicity should not be ignored , especially in the context of a personal clinical history suggestive of allergies in susceptible individuals. It may be relevant to assess immunological functions of patients with an implant or in close contact with a nickel-releasing material prior and post-nickel exposure , since a large part of the general population tests positive to skin patch testing with nickel sulfate yet remains asymptomatic, and conversely, many who complain of metal intolerance test negative .
We suggest better regulatory control of metal exposure  and be alert to the possibility of adverse autoimmune/autoinflammatory signs and symptoms compatible with ASIA syndrome and the need of a high index of suspicion.
Conflict of interest
- Shoenfeld Y, Agmon-Levin N (2011) “ASIA”—Autoimmune/inflammatory syndrome induced by adjuvants. J Autoimmun 36:4–8PubMedView ArticleGoogle Scholar
- Agmon-Levin N, Hughes G, Shoenfeld Y (2012) The spectrum of ASIA: ‘autoimmune (autoinflammatory) syndrome induced by adjuvants’. Lupus 21:118–120PubMedView ArticleGoogle Scholar
- Hughes GRV (2012) Foreword. Lupus 21:117View ArticleGoogle Scholar
- Agmon-Levin N, Paz Z, Israeli E, Shoenfeld Y (2009) Vaccines and autoimmunity. Nat Clin Pract Rheum 5(11):648–652Google Scholar
- Thyssen JP, Menné T (2010) Metal allergy—a review on exposures, penetration, genetics, prevalence, and clinical implications. Chem Res Toxicol 23:309PubMedView ArticleGoogle Scholar
- Thyssen JP, Uter W, McFadden J, Menné T, Spiewak R, Vigan M et al (2011) The EU Nickel Directive revisited –future steps towards better protection against nickel allergy. Contact Dermatitis 64:121–125PubMedView ArticleGoogle Scholar
- Fautrei B (2008) Adult-onset Still’s disease. Best Pract Res Clin Rheum 22:773–792View ArticleGoogle Scholar
- Bagnari V, Colina M, Ciando G et al (2010) Adult-onset Still’s disease. Rheumatol Int 7:855–862View ArticleGoogle Scholar
- Yamaguchi M, Ohta A, Tsunematsu T et al (1992) Preliminary criteria for classification of adult Still’s disease. J Rheumatol 19:424–430PubMedGoogle Scholar
- Jara LJ, Medina G, Gómez-Bañuelos E, Saavedra M, Vera-Lastra O (2012) Still’s disease, lupus-like syndrome, and silicone breast implants. A case of ‘ASIA’ (Shoenfeld’s syndrome). Lupus 21(2):140–145PubMedView ArticleGoogle Scholar
- Miller FW, Alfredsson L, Costenbander KH et al (2012) Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. J Autoimmun 39(4):259–271PubMedPubMed CentralView ArticleGoogle Scholar
- Al-Mogairen SM, Meo SA, Al-Arfaj AS et al (2010) Nickel-induced allergy and contact dermatitis: does it induce autoimmunity and cutaneous sclerosis? An experimental study in Brown Norway rats. Rheumatol Int 30:1159–1164PubMedView ArticleGoogle Scholar
- Al-Mogairen S (2010) Induction of autoimmunity in Brown Norway rats by oral and parenteral administration of nickel chloride. Lupus 19:262–267PubMedView ArticleGoogle Scholar
- Knight JA, Rezuke WN, Gillies CG et al (1988) Pulmonary histopathology of rats following parenteral injections of nickel chloride. Toxicol Pathol 16:350–359PubMedView ArticleGoogle Scholar
- Sunderman FW Jr, Hopfer SM, Lin S-M et al (1989) Toxicity to alveolar macrophages in rats following parenteral injection of nickel chloride. Toxicol Appl Pharmacol 100:107–118PubMedView ArticleGoogle Scholar
- Kosboth M, Chin-Loy A, Lyons R, Wesson SK, Reeves WH (2007) Malar rash caused by metal allergy in a patient with systemic lupus erythematosus. Nat Clin Pract Rheumatol 3:240–245PubMedView ArticleGoogle Scholar
- Hostynek JJ (2002) Nickel-induced hypersensitivity: etiology, immune reactions, prevention and therapy. Arch Dermatol 294(6):249–267View ArticleGoogle Scholar
- Jensen ChS, Menné T, Lisby S, Kristiansen J, Veien NK (2003) Experimental systemic contact dermatitis from nickel: a dose-response study. Contact Dermatitis 49:124–132PubMedView ArticleGoogle Scholar
- Cazzato IA, Vadrucci E, Cammarota G, Minelli M, Gasbarrini A (2011) Lactose intolerance in systemic nickel allergy syndrome. Int J Immunopathol Pharmacol 24:535–537PubMedGoogle Scholar
- Fukahara K, Minami K, Reiss N, Fassbender D, Koerfer R (2003) Systemic allergic reaction to the percutaneous patent foramen ovale occluder. J Thorac Cardiovasc Surg 125:213–214PubMedView ArticleGoogle Scholar
- Moed H, Boorsma DM, Stoof TJ et al (2004) Nickel-responding T cells are CD4+ CLA+ CD45RO+ and express chemoquine receptors CXCR3, CCR4 and CCR10. Br J Dermatol 151:32–41PubMedView ArticleGoogle Scholar
- McFadden JP, Dearman RJ, White JML et al (2011) The Hapten-Atopy hypothesis II: the ‘cutaneous hapten paradox’. Clin Exp Allergy 41:327–337PubMedView ArticleGoogle Scholar
- Schnuch A, Westphal G, Mossner R, Uter W, Reich K (2011) Genetic factors in contact allergy—review and future goals. Contact Dermatitis 64:2–23PubMedView ArticleGoogle Scholar
- Thyssen JP, Linneberg A, Menné T, Johansen JD (2007) The epidemiology of contact allergy in the general population—prevalence and main findings. Contact Dermatitis 57:287–299PubMedView ArticleGoogle Scholar
- Gherardi R, Authier F (2012) Macrophagic myofasciitis: characterization and pathophysiology. Lupus 21(2):184–189PubMedPubMed CentralView ArticleGoogle Scholar
- Patil SU, Long A (2012) Nickel hypersensitivity and coronary artery stents. In: Basow DS (ed) UpToDate. UpToDate, WalthamGoogle Scholar
- Thyssen JP, Johansen JD et al (2009) Nickel allergy in Danish women before and after nickel regulation. N Engl J Med 360:2259–2260PubMedView ArticleGoogle Scholar