Autoimmune/inflammatory syndrome induced by adjuvants (ASIA) was first introduced in 2011 by Shoenfeld et al. and encompasses a cluster of related immune mediated diseases, which develop among genetically prone individuals as a result of adjuvant agent exposure.
Autoimmune/Inflammatory syndrome induced by adjuvants (ASIA) was first introduced in 2011 by Shoenfeld et al.  and encompasses a cluster of immune mediated diseases, which are likely to develop among genetically predisposed individuals after the exposure to an adjuvant. These conditions share several clinical aspects with the possible appearance of autoantibodies, and trend to improve once the inciting agent is removed . Clustering of autoimmune diseases (AID) in families is well recognized, supporting a common genetic background . It is necessary that external environmental factors (infectious agents, dust, vaccines, etc.) or other adjuvant agents triggering immune activity (dust, silicone, aluminum salts, etc.) cooperate on this favorable genetically determined background, in order to promote the disease onset . Notably, loci in the human leukocyte antigen (HLA), which have been shown to be associated with the development of AID have been suggested to be associated with the classical ASIA syndrome conditions . Further, adjuvants influence both the innate and adaptive arms of the immune system via assorted mechanisms, encouraging the initiation and perpetuation of immune response by the activation of pattern recognition receptors. Nevertheless, enhanced immunogenicity might lead to reactogenicity in a process that does not always begin involving pathological stimulation .
2. Classical Examples of the ASIA Syndrome
The establishment of the ASIA concept in 2011, has allowed to clarify the different pathways leading to the development of assorted autoimmune conditions considered so far to be “enigmatic”. Under the light of the recent discoveries, also supported by our own research results, disorders such as sarcoidosis, Sjögren syndrome (SS), undifferentiated connective tissue disease (UCTD), silicone implants incompatibility syndrome (mainly associated with silicone breast implants), and irAEs were able to be segregated as classical examples of the ASIA syndrome concept.
Sarcoidosis is a systemic granulomatosis disorder of unknown etiology characterized by the formation of immune granulomas in various organs, mainly the lungs and the lymphatic system . Studies have hypothesized that sarcoidosis might be the result of an exaggerated granulomatous reaction occurring after the exposure of a genetically prone individual to an unidentified antigen, that triggers a Th1-type cellular immune response leading to the formation of granulomas . The hyperstimulation of the immune system is most probably prompted by an inorganic material, infection, environmental stimuli and/or autoantigens .
Several genome wide association studies have demonstrated that both HLA and non-HLA alleles are associated with the development of sarcoidosis and with disease phenotype  .
2.2. Silicone Implant Incompatibility Syndrome
Women with silicone-related complaints due to SBIs have been included in the classical models of ASIA syndrome. The silicone present in the breast implants represent an external non-self, chronic stimulus that may lead to hyperstimulation of the immune system in genetically predisposed individuals, appearance of non-specific subjective clinical manifestations, and autoantibody production, which might precede the development of autoimmune diseases, and most rarely lymphoma.
Silicone injections and the subsequent use of SBIs for breast reconstruction and breast augmentation have been reported since 1960's . The safety of silicone breast implants has stirred an intense debate, concerning their potential for induction of autoimmunity and lymphoma . The expression of HLA-DRB1 and HLA-DQ alleles in patients with SBIs can be related with the development of autoimmune symptoms . Several plausible mechanisms have been proposed to explain the link between SBIs and autoimmune phenomena, as it has been shown in animal model studies. For example, injection of silicone-gel in NZB mice has led to the induction of proteinuria and autoimmune hemolytic anemia, whereas implantation of silicone-gel or silicone oil in MRL lpr/lpr mice has led to the increase of anti-ds-DNA antibodies . We have previously shown that silicone can trigger UCTD, SSc and fibromyalgia . Moreover, in a large population-based study, we have recently demonstrated an association between SBIs and the presence of autoimmune/rheumatic disorders such as SS, SSc, and sarcoidosis . Furthermore, we have reported an increased production of a broad range of autoantibodies in asymptomatic and symptomatic women with SBIs . These autoantibodies may predict and precede the development of autoimmune disease in these women. The complex link between SBIs and autoimmunity can be illustrated by the concept of ASIA syndrome .
2.3. Sjögren’s Syndrome
SS is a chronic systemic autoimmune inflammatory condition primarily involving the exocrine glands in which both genetic and environmental factors play a pathogenic role. Infections represent the most prominent trigger of disease  leading to a dysregulated immune response largely driven by an overexpression of type I interferons, B cell proliferation, aberrant cytokine production, and tissue infiltration. Recent evidence suggests that several agents may act as adjuvants in determining such abnormal immune response possibly contributing to the development of SS . Vaccinations, which should follow a recommended schedule in patients with autoimmune diseases including patients with SS, should preferably be administered during quiescent phases of the diseases due to the possibility to trigger a disease flare  and for same reason live attenuated vaccines should be avoided. Some studies suggested that SS onset can be associated with specific vaccines, still a temporal rather than a causal association should always be considered . Nonetheless, it was shown that, in patients with primary SS, the A/California/7/2009/H1N1-like virus vaccination lead to a significant increase in the mean levels of anti-SSA/Ro and anti-SSB/La antibodies after 1-year of follow-up . Alum, an aluminium-based adjuvant, was able to induce a Sjögren’s syndrome-like disease in an experimental New Zealand Mixed (NZM) 2758 strain of mouse in which ANA positivity, chronic salivary gland dysfunction and lymphocytic infiltrates within the salivary glands was observed.
2.4. Undifferentiated Connective Tissue Disease
Several conditions in the field of autoimmunity are characterized by non-specific signs and symptoms that cannot be classified into a definite nosological entity according to international criteria. An increasing number of patients have been referred to rheumatology consultation for chronic fatigue, myalgia, muscle weakness, arthralgia/arthritis, and interstitial lung disease . The term ‘undifferentiated’ used to describe all these conditions not only reflects an undefined clinical picture but also a poor knowledge of the underlying etiopathogenic mechanisms. UCTD is a term that encompasses a broad spectrum of conditions characterized by signs, symptoms and laboratory features that are suggestive of systemic autoimmune diseases (SADs) . Such a kaleidoscope of clinical presentations poses the question whether the UCTD can be considered as a distinct entity or may be early forms of definite SAD, which is the reason why the classification criteria for UCTD are still a work in progress .
The induction and perpetuation of autoimmunity is a complex process that requires the interaction between the genetic background and the environment. Environmental factors are gaining increasing attention in the pathogenesis of UCTD. Similar to ASIA [95,96], UCTD is an autoimmune condition characterized by non-specific signs and symptoms, alluding to the idea that the exposure to adjuvants can be a trigger of UCTD. To investigate the possible environmental triggers of UCTD, a case–control study on the exposure to different adjuvants in 92 patients with UCTD and in 92 age and sex-matched controls was performed in Italy . Exposure to several adjuvants prior to UCTD onset (during the 10 years before diagnosis) was found to be significantly more frequent than healthy controls, suggesting that nearly half of UCTD patients in our cohort might fall within the spectrum of ASIA. Interestingly, patients exposed to major adjuvants (vaccines containing adjuvants or silicone implants) displayed the typical features of ASIA, particularly fibromyalgia symptoms. The association between vaccinations and autoimmune phenomena has been described as either simple appearance of autoantibodies or as a full-blown autoimmune disease .
2.5. Immune-related Adverse Events
The irAEs are autoimmune complications of check-point inhibitors (CPI) therapy used in cancer treatment. The main difference of IrAEs in comparison with AID is a lack of the chronicity . It is one of the ASIA classical example where the external stimuli are known, and its pathogenesis is well described. In this case “adjuvants” are monoclonal antibodies, that inhibit a receptor associated with cytotoxic T lymphocytes (CTLA-4), a programmed cell death receptor-1 (PD-1), and its main ligand PD-L1. The blockade of control points CTLA-4 and PD-1 reduces the prevention against autorecognition by lymphocytes and contributes to activation of CD-8+ and CD4+ T cells against cancer cells. This overstimulation of immune system breaks the auto-tolerance and leads to autoimmune reactions . According to clinical trials irAES develop up to 90% of patients treated with an anti-CTLA-4 antibody and 70% of patients treated with an PD-1/PD-L1 antibody . The median onset is 3–6 months after the start of treatment. However, late adverse events, which occur after a year or more, are also documented . In mild cases the symptoms might disappear by its own or after termination of CPI exposure, but severe irAEs needs to be managed with immune-modulatory medications, such as steroids, biological therapy, or cytostatic drugs . In addition, the characteristic ASIA symptoms can occur in patients who have developed musculoskeletal toxicities, which are found in 2-12% of cases and can manifest as inflammatory arthritis, myalgia, myositis, and syndromes similar to polymyalgia . Fever is a common complication of immunotherapy. In patients with non-small cell lung cancer, fever was associated with a low level of progression free survival.
ASIA syndrome encompasses various autoimmune conditions that flourish under the influence of triggering factors among predisposed individuals, which provoke immunological reactions characteristic of autoimmune diseases. Conditions for which etiology is so far beyond comprehension, such as sarcoidosis, Sjögren’s syndrome, UCTD, silicone implant incompatibility syndrome, and immune adverse related events, represent classical examples of the ASIA syndrome. The described major (clinical) and minor (immunogenetic) diagnostic criteria enable us to assume the autoimmune nature of inflammation seen in these diseases. The harmful role of adjuvants has already been recognized in the scientific community, and although vaccines contain adjuvants, it is extremely important to highlight that general benefits of vaccination far outweigh the risk of immune-related side effects. In this manner, efforts should be made in order to understand, clarify, and raise the awareness of clinicians regarding the ASIA concept, for a better discernment between the adjuvant-induced pathologies and their prevention among genetically predisposed individuals. They could test for specific genetic markers (largely unknown) for every vaccination. Nevertheless, some open questions remain and should be addressed in future studies, such as “Why is there autonomic dysfunction and neuropathy in women with SBIs as apparent in the production of autoantibodies against specific receptors of the autonomic nervous system and SFN.
The entry is from 10.3390/biom10101436
- Shoenfeld, Y.; Agmon-Levin, N. ‘ASIA’—Autoimmune/inflammatory syndrome induced by adjuvants. J. Autoimmun. 2011, 36, doi:10.1016/j.jaut.2010.07.003.
- Watad, A.; Sharif, K.; Shoenfeld, Y. The ASIA syndrome: Basic concepts. Mediterr. J. Rheumatol. 2017, 28, doi:10.31138/mjr.28.2.64.
- Arango, M. T., Perricone, C., Kivity, S., Cipriano, E., Ceccarelli, F., Valesini, G., & Shoenfeld, Y. HLA-DRB1 the notorious gene in the mosaic of autoimmunity. Immunol. Res. 2017, 65, doi:10.1007/s12026-016-8817-7.
- Molina, V.; Shoenfeld, Y. Infection, vaccines and other environmental triggers of autoimmunity. Auto-immunity 2005, 38, doi:10.1080/08916930500050277.
- Terhune, T.D. & Deth, R.C. Aluminum adjuvant-containing vaccines in the context of the hygiene hy-pothesis: A risk factor for eosinophilia and allergy in a genetically susceptible subpopulation? Int. J. Environ. Res. Public Health 2018, 15, doi:10.3390/ijerph15050901.
- Nancy, A.L.; 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, doi:10.1016/j.autrev.2008.07.026.
- Inbar, R.; Weiss, R.; Tomljenovic, L.; Arango, M.-T.; Deri, Y.; Shaw, C. A.; Chapman, J.; Blank, M.; Shoen-feld, Y. Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil. Immunol. Res. 2017, 65, doi:10.1007/s12026-016-8826-6.
- Sela, O.; Shoenfeld, Y. The association of infecting agents and autoimmune diseases. Harefuah 1987, 112, 285–288.
- Zinger, H.; Sherer, Y.; Goddard, G.; Berkun, Y.; Barzilai, O.; Agmon-Levin, N.; Ram, M.; Blank, M.; Tin-cani, A.; Rozman, B., et al. Common infectious agents prevalence in antiphospholipid syndrome. Lupus 2009, 18, doi:10.1177/0961203309345738.
- Caravantes-Cortes, M.I.; Roldan-Valadez, E.; Zwojewski-Martinez, R.D.; Salazar-Ruiz, S.Y.; Carballo-Zarate, A.A. Breast Prosthesis Syndrome: Pathophysiology and Management Algorithm. Aesthetic Plast. Surg. 2020, 1–15, doi:10.1007/s00266-020-01663-9.
- Watad, A.; Quaresma, M.; Brown, S.; Cohen Tervaert, J. W.; Rodríguez-Pint, I.; Cervera, R.; Perricone, C.; Shoenfeld, Y. Autoimmune/inflammatory syndrome induced by adjuvants (Shoenfeld’s syndrome)—An update. Lupus 2017, 26, 675–681.
- Heinle, R.; Chang, C. Diagnostic criteria for sarcoidosis. Autoimmun. Rev. 2014, 13, doi:10.1016/j.autrev.2014.01.035.
- Bindoli, S.; Dagan, A.; Torres-Ruiz, J. J.; Perricone, C.; Bizjak, M; Doria, A.; Shoenfeld, Y. Sarcoidosis and autoimmunity: From genetic background to environmental factors. Isr. Med. Assoc. J. 2016, 18, 197–202.
- Valeyre, D.; Prasse, A.; Nunes, H.; Uzunhan, Y.; Brillet, P.-Y.; Müller-Quernheim, J. Sarcoidosis. Lancet 2014, 383, doi:10.1016/S0140-6736(13)60680-7.
- Jain, R.; Yadav, D.; Puranik, N.; Guleria, R.; Jin, J.-O. Sarcoidosis: Causes, Diagnosis, Clinical Features, and Treatments. J. Clin. Med. 2020, 9, doi:10.3390/jcm9041081.
- Bridges, A.J.; Vasey, F.B. Silicone breast implants: History, safety, and potential complications. Arch. Intern. Med. 1993, 153, doi:10.1001/archinte.153.23.2638.
- Kumagai, Y.; Abe, C.; Shiokawa, Y. Scleroderma after cosmetic surgery: four cases of human adjuvant disease. Arthritis Rheum. 1979, 22, 532–537.
- Kumagai, Y.; Shiokawa, Y.; Medsger, T.A.; Rodnan, G.P. Clinical spectrum of connective tissue disease after cosmetic surgery. Observations on eighteen patients and a review of the Japanese literature. Ar-thritis Rheum. 1984, 27, 1–12.
- Watad, A.; Bragazzi, N.L.; Amital, H.; Shoenfeld, Y. Hyperstimulation of adaptive immunity as the common pathway for silicone breast implants, autoimmunity; and lymphoma of the breast. Isr. Med. Assoc. J. 2019, 21, 517–519.
- Bizjak, M.; Selmi, C.; Praprotnik, S.; Bruck, O.; Perricone, C.; Ehrenfeld, M.; Shoenfeld, Y. Silicone im-plants and lymphoma: The role of inflammation. J. Autoimmun. 2015, 65, doi:10.1016/j.jaut.2015.08.009.
- Levy, Y.; Rotman-Pikielny, P.; Ehrenfeld, M.; Shoenfeld, Y. Silicone breast implantation-induced sclero-derma: Description of four patients and a critical review of the literature. Lupus 2009, 18, doi:10.1177/0961203309347795.
- Soriano, A.; Butnaru, D.; Shoenfeld, Y. Long-term inflammatory conditions following silicone exposure: The expanding spectrum of the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). Clin. Exp. Rheumatol. 2014, 32, 151–154.
- Nesher, G.; Soriano, A.; Shlomai, G.; Iadgarov, Y.; Shulimzon, T. R.; Borella, E.; Dicker, D.; Shoenfeld, Y. Severe Asia syndrome associated with lymph node, thoracic, and pulmonary silicone infiltration fol-lowing breast implant rupture: Experience with four cases. Lupus 2015, 24, doi:10.1177/0961203314562622.
- 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, doi:10.1007/s10067-015-2931-0.
- Shons, A.R.; Schubert, W. Silicone breast implants and immune disease. Ann. Plast. Surg. 1992, 28, doi:10.1097/00000637-199205000-00017.
- Yoshida, S.H.; Swan, S.; Teuber, S.S.; Gershwin, M.E. Silicone breast implants: Immunotoxic and epide-miologic issues. Life Sci. 1995, 56, doi:10.1016/0024-3205(95)00081-X.
- Aharon-Maor, A.; Levy, Y.; Schoenfeld, Y. Fibrosarcoma after silicone breast augmentation: is there a connection? Harefuah 1998, 134.
- Versini, M. & Shoenfeld, Y. The dark side of beauty: About breast implants and lymphoma. Isr. Med. Assoc. J. 2017, 19, 380–381.
- Meier, L.G.; Barthel, H.R.M.; Seidl, C. Development of polyarthritis after insertion of silicone breast implants followed by remission after implant removal in 2 HLA-identical sisters bearing rheumatoid arthritis susceptibility genes. J. Rheumatol. 1997, 24, 1838–1841.
- O’Hanlon, T.; Koneru, B.; Bayat, E.; Love, L.; Targoff, I.; Malley, J.; Malley, K.; Miller, F. Immunogenetic differences between caucasian women with and those without silicone implants in whom myositis de-velops. Arthritis Rheum. 2004, 50, doi:10.1002/art.20587.
- Ueki, A.; Isozaki, Y.; Tomokuni, A.; Ueki, H.; Kusaka, M.; Tanaka, S.; Otsuki, T.; Sakaguchi, H.; Hyodoh, F. Different distribution of HLA class II alleles in anti-topoisomerase I autoantibody responders be-tween silicosis and systemic sclerosis patients, with a common distinct amino acid sequence in the HLA-DQB1 domain. Immunobiology 2001, 204, doi:10.1078/0171-2985-00055.
- Young, V.L.; Nemecek, J.R.; Schwartz, B.D.; Phelan, D.L.; Schorr, M.W. Hla typing in women with breast implants. Plast. Reconstr. Surg. 1995, 96, doi:10.1097/00006534-199512000-00001.
- Schaefer, C.J.; Lawrence, W.D.; Wooley, P.H. Influence of long term silicone implantation on type II collagen induced arthritis in mice. Ann. Rheum. Dis. 1999, 58, doi:10.1136/ard.58.8.503.
- Schaefer, C.J.; Wooley, P.H. The influence of silicone implantation on murine lupus in MRL lpr/lpr mice. J. Rheumatol. 1999, 26.
- Watad, A.; Quaresma, M.; Bragazzi, N. L.; Cervera, R.; Cohen Tervaert, J. W.; Amital, H.; Shoenfeld, Y. The autoimmune/inflammatory syndrome induced by adjuvants (ASIA)/Shoenfeld’s syndrome: descrip-tive analysis of 300 patients from the international ASIA syndrome registry. Clin. Rheumatol. 2018, 37, doi:10.1007/s10067-017-3748-9.
- Scanzi, F.; Andreoli, L.; Martinelli, M.; Taraborelli, M.; Cavazzana, I.; Carabellese, N.; Ottaviani, R.; Allegri, F.; Franceschini, F.; Agmon-Levin, N. 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. 2017, 36, doi:10.1007/s12026-017-8912-4.
- Watad, A.; Rosenberg, V.; Tiosano, S.; Cohen Tervaert, J. W.; Yavne, Y.; Shoenfeld, Y.; Shalev, V.; Cho-dick, G.; Amital, H. Silicone breast implants and the risk of autoimmune/rheumatic disorders: A real-world analysis. Int. J. Epidemiol. 2018, 47, doi:10.1093/ije/dyy217.
- Zandman-Goddard, G.; Blank, M.; Ehrenfeld, M.; Gilburd, B.; Peter, J.; Shoenfeld, Y. A comparison of autoantibody production in asymptomatic and symptomatic women with silicone breast implants. J. Rheumatol. 1999, 26, 73–77.
- Dagan, A.; Kogan, M.; Shoenfeld, Y.; Segal, G. When uncommon and common coalesce: Adult onset Still’s disease associated with breast augmentation as part of autoimmune syndrome induced by adju-vants (ASIA). Clin. Rheumatol. 2016, 35, doi:10.1007/s10067-015-2869-2.
- Luciano, N.; Valentini, V.; Calabrò, A.; Elefante, E.; Vitale, A.; Baldini, C.; Bartoloni, E. One year in re-view 2015: Sjögren’s syndrome. Clin. Exp. Rheumatol. 2015, 33.
- 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, doi:10.1016/j.jaut.2014.03.003.
- Colafrancesco, S.; Perricone, C.; Shoenfeld, Y. Autoimmune/inflammatory syndrome induced by adju-vants and sjögren’s syndrome. Isr. Med. Assoc. J. 2016, 18, 150–153.
- Van Assen, S.; Agmon Levin, N.; Elkayam, O.; Cervera, R.; Doran, M. F.; Dougados, M.; Emery, P.; Ge-borek, P.; Ioannidis, J. P. A.; Jayne, D. R. W., et al. EULAR recommendations for vaccination in adult pa-tients with autoimmune inflammatory rheumatic diseases. Ann. Rheum. Dis. 2011, 70, doi:10.1136/ard.2010.137216.
- Furer, V.; Rondaan, C.; Heijstek, M. W.; Agmon-Levin, N.; van Assen, S.; Bijl, M.; Breedveld, F. C.; D’Amelio, R.; Dougados, M.; Kapetanovic, M. C., et al. 2019 update of EULAR recommendations for vac-cination in adult patients with autoimmune inflammatory rheumatic diseases. Ann. Rheum. Dis. 2020, 79, doi:10.1136/annrheumdis-2019-215882.
- Toussirot, E.; Lohse, A.; Wendling, D.; Mougin, C. Sjogren’s syndrome occurring after hepatitis B vac-cination. Arthritis Rheum. 2000, 43, doi:10.1002/1529-0131(200009)43:9<2139:AID-ANR27>3.0.CO;2-3.
- Tabache, F.; El Kartouti, A.; Naitlhou, A.; Hassikou, H.; Tarib, A.; Baaj, M.; Cherrah, Y. Acute polyarthri-tis after influenza A (H1N1) immunization. Jt. Bone Spine 2011, 78, doi:10.1016/j.jbspin.2011.02.007.
- Narváez, J.; Castro-Bohorquez, F.J.; Vilaseca-Momplet, J. Sjögren’s-like syndrome following intravesi-cal bacillus Calmette-Guérin immunotherapy . Am. J. Med. 2003, 115, doi:10.1016/S0002-9343(03)00398-X.
- Pasoto, S.G.; Ribeiro, A. C.; Santos Trindade Viana, V.; Pires Leon, E.; Bueno, C.; Levy Neto, M.; Precio-so, A. R.; Sampaio Tavares Timenetsky, M. do C.; Bonfa, E. Short and long-term effects of pandemic un-adjuvanted influenza A(H1N1)pdm09 vaccine on clinical manifestations and autoantibody profile in primary Sjögren’s syndrome. Vaccine 2013, 31, doi:10.1016/j.vaccine.2013.01.057.
- Antunes, M.; et al. Undifferentiated connective tissue disease: State of the art on clinical practice guide-lines. RMD Open 2019, 4, doi:10.1136/rmdopen-2018-000786.
- Ferri, C.; Manfredi, A.; Sebastiani, M.; Colaci, M.; Giuggioli, D.; Vacchi, C.; Della Casa, G.; Cerri, S.; Torricelli, P.; Luppi, F. Interstitial pneumonia with autoimmune features and undifferentiated connec-tive tissue disease: Our interdisciplinary rheumatology-pneumology experience, and review of the lit-erature. Autoimmun. Rev. 2016, 15, doi:10.1016/j.autrev.2015.09.003.
- Mosca, M.; Tani, C.; Talarico, R.; Bombardieri, S. Undifferentiated connective tissue diseases (UCTD): Simplified systemic autoimmune diseases. Autoimmun. Rev. 2011, 10, doi:10.1016/j.autrev.2010.09.013.
- Mosca, M.; Tani, C.; Vagnani, S.; Carli, L.; Bombardieri, S. The diagnosis and classification of undifferen-tiated connective tissue diseases. J. Autoimmun. 2014, 48, doi:10.1016/j.jaut.2014.01.019.
- Pellegrino, P.; Clementi, E.; Radice, S. On vaccine’s adjuvants and autoimmunity: Current evidence and future perspectives. Autoimmun. Rev. 2015, 14, doi:10.1016/j.autrev.2015.05.014.
- Guimarães, L.E.; Baker, B.; Perricone, C.; Shoenfeld, Y. Vaccines, adjuvants and autoimmunity. Pharma-col. Res. 2015, 100, doi:10.1016/j.phrs.2015.08.003.
- Yang, H.; Yao, Z.; Zhou, X.; Zhang, W.; Zhang, X.; Zhang, F. Immune-related adverse events of check-point inhibitors: Insights into immunological dysregulation. Clin. Immunol. 2020, 213, doi:10.1016/j.clim.2020.108377.
- Mazzarella, L.; Duso, B. A.; Trapani, D.; Belli, C.; D’Amico, P.; Ferraro, E.; Viale, G.; Curigliano, G. The evolving landscape of ‘next-generation’ immune checkpoint inhibitors: A review. Eur. J. Cancer 2019, 117, doi:10.1016/j.ejca.2019.04.035.
- Jiang, Y.; Zhang, N.; Pang, H.; Gao, X.; Zhang, H. Risk and incidence of fatal adverse events associated with immune checkpoint inhibitors: A systematic review and meta-analysis. Ther. Clin. Risk Manag. 2019, 15, doi:10.2147/TCRM.S191022.
- Michot, J.M.; Bigenwald, C.; Champiat, S.; Collins, M.; Carbonnel, F.; Postel-Vinay, S.; Berdelou, A.; Varga, A.; Bahleda, R.; Hollebecque, A., et al. Immune-related adverse events with immune checkpoint blockade: A comprehensive review. Eur. J. Cancer 2016, 54, doi:10.1016/j.ejca.2015.11.016.
- Nishino, M.; Sholl, L.M.; Hodi, F.S. Anti-PD-1-related pneumonitis during cancer immunotherapy. N. Engl. J. Med. 2015, 373, doi:10.1056/NEJMc1505197.
- Haanen, J.B.A.G.; Carbonnel, F.; Robert, C.; Kerr, K.; Peters, S.; Larkin, J.; Jordan, K. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol. 2017, 28, doi:10.1093/annonc/mdx225.
- Weber, J. S.; Dummer, R.; de Pril, V.; Lebbé, C.; Hodi, F. S. MDX010‐20 Investigators. Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: Detailed safety analysis from a phase 3 trial in patients with advanced melanoma. Cancer 2013, 119, 1675–1682.
- Trinh, S.; Le, A.; Gowani, S.; La-Beck, N. Management of Immune-Related Adverse Events Associated with Immune Checkpoint Inhibitor Therapy: A Minireview of Current Clinical Guidelines. Asia Pac. J. Oncol. Nurs. 2019, 6, doi:10.4103/apjon.apjon_3_19.
- Darnell, E.P.; Mooradian, M.J.; Baruch, E.N.; Yilmaz, M.; Reynolds, K.L. Immune-Related Adverse Events (irAEs): Diagnosis, Management, and Clinical Pearls. Curr. Oncol. Rep. 2020, 22, doi:10.1007/s11912-020-0897-9.
- Kanai, O.; Fujita, K.; Okamura, M.; Horimoto, K.; Takeda, K.; Hashimoto, K.; Nakatani, K.; Sawai, S.; Mio, T. Impact of nivolumab-induced fever on the treatment effect: a retrospective study. Eur. Respir. J. 2019, 54, doi:10.1183/13993003.congress-2019.pa368.