Lupus (2014) 23, 1273–1275 http://lup.sagepub.com
SPECIAL ARTICLE
The autoimmune tautology with a focus on antiphospholipid syndrome J-S Franco1,2 and J-M Anaya1,2 1
Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogota´, Colombia; and 2Mederi, Hospital Universitario Mayor, Bogota´, Colombia
Autoimmune diseases (ADs) are often diagnosed according to classification criteria; however, they share similar subphenotypes including signs and symptoms, non-specific autoantibodies and other immune changes, which are prone to taxonomic problems. Polyautoimmunity is defined as the presence of more than one AD in a single patient. The close relationship between antiphospholipid syndrome (APS) and systemic lupus erythematosus has been studied throughout the years. However, APS may coexist with several other ADs confirming polyautoimmunity in this systemic disease. Herein, we summarized the common characteristics shared between APS and others ADs in light of the autoimmune tautology (that is, common mechanisms of autoimmune diseases). Lupus (2014) 23, 1273–1275. Key words: Autoimmune tautology; polyautoimmunity; antiphospholipid syndrome; autoimmune diseases; cardiovascular disease
Introduction Autoimmune diseases (ADs) are chronic and heterogeneous conditions initiated by loss of immunological tolerance to self-antigens, and affect specific target organs or multiple systems.1 The chronic nature of these conditions places a significant burden on health care systems, with direct and indirect costs and quality of life impairment.1 The fact that ADs share several subphenotypes, environmental factors and genetic factors has been called the ‘‘autoimmune tautology’’ and indicates that ADs have common physiopathological mechanisms.1 A tautology (from Greek tauto, ‘‘the same’’ and logos, ‘‘word/idea’’) is an obvious statement.1 In logic, tautology is a formula that is true in every possible interpretation.1 Therefore, autoimmune tautology indicates that one AD is similar to other ADs.1 However, ADs are not equal because the target cell and organ are different in each case, and the triggering factors and age at onset may vary among them.1
Correspondence to: Juan-Manuel Anaya, Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 No. 63C-69, 11001000 Bogota´, Colombia. Email:
[email protected]
Polyautoimmunity, defined as the presence of more than one AD in a single patient, represents the main clinical evidence of the autoimmune tautology and highlights the coexistence of distinct autoimmune phenotypes within an individual (that is, carrying a unique genotype).1 When three or more ADs coexist, this condition is called multiple autoimmune syndrome (MAS).1 Factors significantly associated with polyautoimmunity include female gender and familial autoimmunity (that is, the presence of diverse ADs in multiple members of a nuclear family).1
Antiphospholipid syndrome (APS) in light of the autoimmune tautology APS is an AD characterized by the occurrence of venous and arterial thrombosis, accompanied by recurrent fetal loss, in the presence of antiphospholipid antibodies (aPL), such as lupus anticoagulant (LA), anticardiolipin antibodies (aCL) and anti-b2 glycoprotein-I antibodies (b2GPI).2 APS was first described in 1983 by Graham R.V. Hughes in patients with systemic lupus erythematosus (SLE) (revised in Go´mez-Puerta and Cervera2).
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10.1177/0961203314537362
The autoimmune tautology with a focus on antiphospholipid syndrome J-S Franco and J-M Anaya
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Initially, APS was not considered to be a systemic AD, and was thought to occur only in patients with SLE.3 In recent years, distinctive clinical (e.g. non-thrombotic renal disease, migraine, livedo reticularis, pulmonary hypertension, myocardial infarction) and laboratory (e.g. positive antinuclear antibodies (ANAs), hypocomplementemia) features have been described in APS, portraying its multisystemic condition.3,4 Furthermore, some of these manifestations are also present in patients with SLE, complicating the clear differentiation between these entities.4,5 The interplay between APS and SLE has been analyzed over the years, and it is under discussion whether they constitute the same disease.4,5 However, rather than being the spectrum of the same disease, the coexistence of APS and SLE is a reflection of complex disease traits and highlights the common mechanisms shared by ADs. In fact, this polyautoimmunity is one of the best examples of the autoimmune tautology. Ten characteristics supporting this logically valid propositional theory are shown in Table 1.1,6
Table 1
Polyautoimmunity in APS As already mentioned, APS was primarily recognized in patients with SLE and was, therefore, considered to be an overlap syndrome (that is, ‘‘secondary’’ APS).3 The major difference between polyautoimmunity and overlap syndrome is that the former is the presence of two or more welldefined autoimmune conditions (that is, overt clinical manifestations mediated by T or B cell responses) fulfilling validated classification criteria whereas the latter is the partial presence of signs and symptoms of diverse ADs.1 An overlap syndrome may evolve toward a well-defined phenotype or remain as an undifferentiated AD for years (that is, the presence or alternation of some subphenotypes). The international consensus statement on an update of the classification criteria for definite APS advised against using the term ‘‘secondary’’ APS because no difference was found in the clinical consequences of aPL antibodies among the patients in this category (Evidence Level I).7 The consensus is that, rather than distinguishing patients by
APS in light of the autoimmune tautology
Characteristic
Commentary
Female preponderance
Female to male ratio varies from 2:1 to 5:1. There are differences in the clinical presentation between females (e.g. stroke, pulmonary embolism, articular and cutaneous involvement) and males (e.g. gastrointestinal tract thrombosis, myocardial infarction and deep-venous thrombosis). Cutaneous (e.g. livedo reticularis), hematological (e.g. hemolytic anemia, thrombocytopenia), renal (e.g. nonthrombotic nephropathy), and neurological (e.g. stroke) involvement as well as an increased risk for cardiovascular disease are shared characteristics of APS polyautoimmunity. APS may coexist with several autoimmune diseases including SLE, rheumatoid arthritis, systemic sclerosis, primary biliary cirrhosis, autoimmune hepatitis, Sjo¨gren’s syndrome, autoimmune thyroid diseases, dermatopolymyositis, and systemic vasculitis. Familial aggregation has been reported in up to 20% of the relatives of APS patients, with SLE being the most frequent. Even though the presence of aPL antibodies is the hallmark of the thrombotic manifestations in APS, additional proinflammatory pathways have been described including decreased number of CD4þCD25þFoxp3þ T regulatory cells, autoreactive B CD5þ cells associated with aPL antibody production, activation of the classical pathway by the aPL antibodies with generation of C5a, and the dual role of the apoptotic cells (that is, as trigger for aPL antibodies production and as inflammatory targets of these antibodies). Environmental factors including infectious agents (e.g. EBV, CMV, HCV, HIV, varicella zoster), vitamin D deficiency, vaccines (that is, tetanus toxoid), hormones and smoking are associated with APS and other autoimmune diseases. Early age at onset of disease has been associated with central nervous system involvement, venous thrombosis and polyautoimmunity with SLE, whereas late age at onset is related with stroke and angina pectoris. The presence of aPL antibodies have been reported in many countries and ethno-geographical groups, with variability in the prevalence and associated clinical features. In Mestizo patients, APS discloses a distinctive phenotype (that is, central nervous system involvement, pulmonary microthrombosis, arthralgia and early pregnancy loss) as compared with European patients. The genetic risk factors for autoimmune diseases consist of two forms, those common to many conditions and those specific to a given disorder. APS shares genetic factors with other autoimmune diseases both at the MHC (e.g. HLA) and non-MHC loci (e.g. STAT4, BLK). In addition to treatment with long-term anti-coagulation/anti-aggregation, patients with APS may benefit from immunosuppressive treatment, hydroxychloroquine, and B-cell depletion.
Subphenotypes
Polyautoimmunity
Familial autoimmunity Similar pathophysiology
Autoimmune ecology
Influence of age at onset Influence of ancestry
Genetic factors
Similar treatment
APS: antiphospholipid syndrome; SLE: systemic lupus erythematosus; aPL: antiphospholipid antibodies; EBV: Epstein-Barr virus; CMV: cytomegalovirus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; MHC: major histocompatibility complex. Adapted from Anaya et al.1 and Franco et al.6 Lupus Downloaded from lup.sagepub.com at UNIVERSIDAD DEL ROSARIO on September 16, 2014
The autoimmune tautology with a focus on antiphospholipid syndrome J-S Franco and J-M Anaya
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‘‘primary’’ and ‘‘secondary’’ APS, documenting the coexistence of SLE (or other ADs) is more advantageous for classification.7 In agreement with this argument, we have proposed the term ‘‘polyautoimmunity’’ instead of secondary AD to refer to the coexistence of two or more ADs.8 Polyautoimmunity in APS has been described in most ADs, and may be associated with a modified clinical course (Table 1).6 For instance, APS in SLE is associated with cardiovascular disease (CVD) and increased accrual of damage measured by the SLE Damage Index (SDI).9,10 Furthermore, APS has been reported to be a non-traditional risk factor for CVD in SLE.11 Novel risk factors related to autoimmunity are recognized because the traditional risk factors do not completely explain the high CVD rates.11 APS should be included as a non-traditional risk factor for CVD in SLE and other ADs in further studies.
Conclusions APS is considered a systemic AD and is characterized by multi-organ involvement, heterogeneity of clinical manifestations and production of autoantibodies. The main AD coexisting with APS is SLE; nonetheless, polyautoimmunity with other ADs has also been reported and should be addressed systematically in order to identify high-risk populations and encourage prevention and early therapeutic interventions.
Funding This work was supported by the School of Medicine and Health Sciences, Universidad del Rosario, Bogota´, Colombia.
Conflict of interest statement
Acknowledgments We thank all colleagues at the Center for Autoimmune Diseases Research (CREA) for their fruitful discussions and contributions. We apologize for our inability to reference several additional excellent articles on this subject owing to space constraints.
References 1 Anaya JM, Rojas-Villarraga A, Shoenfeld Y. From the mosaic of autoimmunity to the autoimmune tautology. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, Levy R, Cervera R (eds), Autoimmunity. From bench to bedside. Bogota: Editorial Universidad del Rosario, 2013. pp. 237–245. 2 Go´mez-Puerta JA, Cervera R. Diagnosis and classification of the antiphospholipid syndrome. J Autoimmun 2014; 48–49: 20–25. 3 Taraborelli M, Andreoli L, Tincani A. Much more than thrombosis and pregnancy loss: The antiphospholipid syndrome as a ‘‘systemic disease’’. Best Pract Res Clin Rheumatol 2012; 26: 79–90. 4 Agmon-Levin N, Shoenfeld Y. The spectrum between antiphospholipid syndrome and systemic lupus erythematosus. Clin Rheumatol 2014; 33: 293–295. 5 Shoenfeld Y, Meroni PL, Toubi E. Antiphospholipid syndrome and systemic lupus erythematosus: Are they separate entities or just clinical presentations on the same scale? Curr Opin Rheumatol 2009; 21: 495–500. 6 Franco JS, Molano-Gonza´lez N, Rodriguez-Jimenez M, et al. Polyautoimmunity in antiphospholipid syndrome [submitted for publication]. 7 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306. 8 Rojas-Villarraga A, Amaya-Amaya J, Rodriguez-Rodriguez A, Mantilla RD, Anaya JM. Introducing polyautoimmunity: Secondary autoimmune diseases no longer exist. Autoimmune Dis 2012; 2012: 2543. 9 Mok CC, Chan PT, Ho LY, Yu KL, To CH. Prevalence of the antiphospholipid syndrome and its effect on survival in 679 Chinese patients with systemic lupus erythematosus: A cohort study. Medicine (Baltimore) 2013; 92: 217–222. 10 McClain MT, Arbuckle MR, Heinlen LD, et al. The prevalence, onset, and clinical significance of antiphospholipid antibodies prior to diagnosis of systemic lupus erythematosus. Arthritis Rheum 2004; 50: 1226–1232. 11 Amaya-Amaya J, Sarmiento-Monroy JC, Caro-Moreno J, et al. Cardiovascular disease in Latin American patients with systemic lupus erythematosus: A cross-sectional study and a systematic review. Autoimmune Dis 2013; 2013: 794383.
The authors have no conflicts of interest to declare.
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