AUTREV-01534; No of Pages 4 Autoimmunity Reviews xxx (2014) xxx–xxx

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Review

The diagnosis and clinical significance of polyautoimmunity Juan-Manuel Anaya Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Carrera 24 # 63C-69, Piso 3, Bogota, Colombia

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Article history: Received 7 October 2013 Accepted 13 November 2013 Available online xxxx

Autoimmune diseases (ADs) are chronic and heterogeneous conditions that affect specific target organs or multiple organ systems. The chronic nature of these diseases places a significant burden on the utilization of medical care, direct and indirect economic costs, and quality of life. ADs are observed in genetically susceptible individuals in whom their clinical expression is modified by permissive and protective environments occurring over time. These are complex traits, meaning that their inheritance does not follow a single-gene dominant or singlegene recessive Mendelian law, and thus that they are polygenic. 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. When three or more ADs coexist, this condition is called multiple autoimmune syndrome (MAS), which represents the best example of polyautoimmunity as well as the effect of a single genotype on diverse autoimmune phenotypes. Its study will provide important clues to elucidate the common mechanisms of ADs (i.e., the autoimmune tautology). © 2014 Elsevier B.V. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . 2. Polyautoimmunity . . . . . . . . . . 3. The Multiple autoimmune syndrome(s) 4. Conclusions . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . References . . . . . . . . . . . . . . . .

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1. Introduction The mosaic of autoimmunity describes the multi-factorial origin and diversity of autoimmune disease (AD) expression [1] (Fig. 1). This term implies that different combinations of many factors involved in autoimmunity produce several distinct clinical presentations that represent the wide spectrum of AD. The term “kaleidoscope of autoimmunity” portrays the possible change from one disease to another or the fact that more than one disease may coexist in the same individual or family [2]. The fact that ADs share several clinical signs and symptoms (i.e. subphenotypes), physiopathological mechanisms, and genetic factors has been called the autoimmune tautology and indicates that they have several common mechanisms [3–7]. Autoimmune tautology (from Greek tauto, “the same” and logos, “word/idea”) means that one

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AD is similar to a second one, to a third one, and so on. ADs cannot be equal because the target cell and organ are different in each case, and the trigger factors and age at onset vary among ADs. Several subphenotypes are shared by ADs including signs and symptoms such as arthralgia, arthritis, alopecia, fatigue, photosensitivity, Raynaud's phenomenon as are non-specific autoantibodies (e.g., antinuclear antibodies, rheumatoid factor, anti-Ro antibodies) and high levels of cytokines which raises taxonomic concerns and explain why classification criteria may lack of accuracy. ADs have a heterogeneous spectrum; the disease course differs from patient to patient and through different phases within the same patient. Depending on the duration and activity of the disease, these subphenotypes might change. Mathematical approaches for precisely defining subphenotypes based on accurate clinical and immunological databases combined with strengthening molecular genetic analyses and immunological pathways (e.g., type I interferon activation, reduced B and T cell regulatory function) have significant promise for a better understanding of ADs.

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Please cite this article as: Anaya J-M, The diagnosis and clinical significance of polyautoimmunity, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.049

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J.-M. Anaya / Autoimmunity Reviews xxx (2014) xxx–xxx

Stochastic events

GENETICS

PATHOGENS

B cell

AUTOIMMUNE DISEASE

GENDER

ENVIRONMENT Diet-Toxins-Tobacco

EPIGENETICS

AUTOANTIBODIES CYTOKINE IMBALANCES

PHENOTYPE SUBPHENOTYPE POLYAUTOIMMUNITY

T cell TCR

TIME HERITABLE FACTORS

AUTOIMMUNE ECOLOGY

PRECLINICAL STAGE

OVERT DISEASE

Fig. 1. Etiopathogenesis of autoimmune diseases. Outline showing the plausible stages for a multifactorial etiology to develop over time. Each stage shows the known phenomena that cumulatively will be the causative scenario for the onset of disease(s). First, heritable factors (that is, genetics, including ancestry, and epigenetics) impact over the life of the individuals. They converge and interact to create and increase or decrease the liability an individual would have to develop the phenotype depending on risk and protective effects. Women are more affected than men. Second, the autoimmune ecology is characterized by the interactions between an individual and its environment, which acting stochastically will also influence the risk and course of disease. The additive effects of heritable and environmental risk factors favor the loss of autoimmune tolerance. Then, a preclinical stage characterized by B and T cell dysregulation arises. This third phase may take years before the phenotype becomes clinically evident. TCR: T cell receptor.

2. Polyautoimmunity Polyautoimmunity is defined as the presence of more than one AD in a single patient [8]. When three or more ADs coexist, this condition is called multiple autoimmune syndrome (MAS) [6,9]. Polyautoimmunity was observed in 34.4% of 1083 patients belonging to four AD cohorts [8] with autoimmune thyroid disease (AITD) and Sjögren's syndrome (SS) [8] being the most frequent diseases encountered [8]. Factors significantly associated with polyautoimmunity are female gender and familial autoimmunity [8]. Polyautoimmunity has been reported in most of the ADs including systemic lupus erythematosus (SLE) (41%) [10], systemic sclerosis (SSc) (26%) [11], primary biliary cirrhosis (PBC) (32%) [12], vitiligo (VIT) (27%) [13], myasthenia gravis (MG) (13%) [14], AITD (14%) [15], etc. Sardu et al. [16] reported a 5% prevalence of ADs in Sardinia. Among people with ADs, 95.6% were affected by one AD while the remaining 4.4% were affected by two ADs [16]. The main difference between polyautoimmunity and the overlapping syndromes lies in the fact that the former is the presence of two or more overt clinical conditions (i.e., well-defined autoimmune conditions fulfilling validated classification criteria) while the later is the partial presence of signs and symptoms of diverse ADs. Most of the cases of overlapping syndromes have been described in cross-sectional studies. Long-term follow-up is warranted for patients with overlapping syndromes to define the final phenotype. Just as in the mixed connective tissue disease (MCTD), the classical overlap syndrome, in which some patients will develop SLE, SSc, or RA during the course of the disease, and some will present with a longstanding MCTD [17]. In fact, longterm studies have shown that MCTD remains an overlap syndrome in about 60% of the patients. The remaining 40% progress towards SSc (~20%), SLE (~10%), or rheumatoid arthritis (RA) (~5%) [18]. Protective factors avoiding the progression of MCTD towards a complete phenotype deserve further research. Some authors have considered polyautoimmunity as an “overlap syndrome” confined to “connective tissue diseases” [19] [e.g., SLE, RA, SSc, polymyositis/dermatomyositis (PDM), and SS]. They reduce the spectrum of polyautoimmunity to just the rheumatic diseases and omitted several other systemic and organ specific ADs that are also associated with each other and observed in clusters (Fig. 2) [8]. However, they highlight that, in some cases, polyautoimmunity may be related to a specific autoantibody which supports the hypothesis that these syndromes are not a mere association of two or more ADs in the same patient, but a well-defined clinical entity with specific clinical characteristics [19]. Two of such cases are: 1) Anti-t-RNA synthetase syndrome, characterized by the clinical features of SSc, RA, and myositis

and the presence of antibodies against aminoacyl-t-RNA synthetase; and 2) Scleromyositis, characterized by features of both SSc and PDM and the presence of anti-PM–Scl antibodies [19]. 3. The Multiple autoimmune syndrome(s) The MAS were described by Humbert and Dupond in 1988 as a syndrome(s) consisting of the presence of three or more well characterized ADs in one patient [20]. While describing the syndrome, their observations led them to a rough classification of clusters based on the cooccurrence of ADs, which they named as type one through three. In MAS-1, the authors grouped together myasthenia gravis (MG), thymoma, PMD, and autoimmune myocarditis. For MAS-2, they grouped SS, RA, PBC, SSc, and AITD. Finally, MAS-3 consisted of AITD, MG and/or thymoma, SS, pernicious anemia (PA), idiopathic thrombocytopenic purpura (ITP), Addison's disease, type 1 diabetes (T1D), VIT, autoimmune hemolytic anemia (HA), and SLE (4). Inspite of the great breakthrough achieved by Humbert and Dupond, providing a new taxonomy for these co-current phenotypes based on clinical evidence, the concept became subject to modifications. Further studies evaluating polyautoimmunity in patients having a primary AD found an association between other ADs not reported in the original report [6,9,21]. Besides MAS, another well known example of polyautoimmunity is the polyglandular autoimmune syndrome, type II (PASII). This syndrome is also universally known as Schmidt's Syndrome owing to a case reported by Schmidt in 1926 of two patients that presented Addison's disease and chronic lymphocytic thyroiditis [22]. Afterward in 1964, Carpenter included in an extensive review of the literature the presence of T1D to the syndrome defining the classic triad for PASII [23]. The diagnosis of PASII is made by the presence of at least two of the previously described conditions in one patient. There are, nevertheless, three more types of PAS [24]. PAS type I is given by the presence of oral candidiasis, hypoparathyroidism, and Addison's disease within an individual associated to mutations in the AIRE gene, a disorder that has an autosomic recessive inheritance. PAS Type III is defined as the presence of AITD, and other AD, including diabetes, but does not typically include adrenal gland malfunction. Other diseases such as PA or celiac disease (CD) may also be observed. Finally, PAS type IV has been described as the association of two or more organ-specific ADs. There is, nevertheless, some controversy around this topic, and some authors argue that PAS type II, type III and type IV are different manifestations of the same syndrome [24]. This disagreement has strong foundations, for there are several reports showing association between organ specific ADs both endocrine and non-endocrine and systemic ADs like SLE, SS or RA [6,9,21]. In fact, the MAS as well as PASII, PASIII

Please cite this article as: Anaya J-M, The diagnosis and clinical significance of polyautoimmunity, Autoimmun Rev (2014), http://dx.doi.org/ 10.1016/j.autrev.2014.01.049

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illustrates the relation between familial autoimmunity and polyautoimmunity in the proband, and the presence of a single genotype responsible for diverse ADs. Sommers et al. [26] by using the United Kingdom General Practice Research Database demonstrated coexistence of RA, AITD, and T1D at higher than expected rates but reduced comorbidity between RA and multiple sclerosis (MS). Current data support a tendency for ADs to co-occur at greater than expected rates within proband patients and their families [27]. Aggregation of autoimmunity was observed in families of MAS patients, mainly AITD and SLE [6]. Familial autoimmunity has been consistently associated with polyautoimmunity [28,29]. Unlike familial AD (that is the same AD in a nuclear family), familial autoimmunity uses the term “autoimmune” as a trait that encircles all accepted pathologies for which evidence suggests an autoimmune origin [29]. There is increased evidence for aggregation of diverse ADs in families of patients with a single AD [9,29]. 4. Conclusions

Fig. 2. Cluster analysis dendogram of autoimmune diseases (ADs). Each node represents a stage in the clustering process. There were four clusters. The most hierarchical was composed of four ADs. AITD: autoimmune thyroid disease (including thyroiditis, Hashimoto disease, Graves disease); SLE: systemic lupus erythematosus; SS: Sjögren's syndrome; APS: antiphospholipid syndrome; T1D: type 1 diabetes mellitus; SSc: scleroderma (including localized, systemic, diffuse, limited); BID: billiary inflammatory disease (including primary biliary cirrhosis, primary sclerosing cholangitis); CD: celiac disease; VIT: vitiligo; AIH: autoimmune hepatitis; RA: rheumatoid arthritis; MG: myasthenia gravis; PMDM: polymyositis/dermatomyositis; PA: pernicious anemia; DAD: demyelinating autoimmune diseases (including multiple sclerosis, transverse myelitis, optic neuromyelitis); AAI: autoimmune adrenal insufficiency (Addison disease); HA: autoimmune anemia; ITP: idiopathic thrombocytopenic purpura; AG: autoimmune gastritis; VAS: vasculitis (including Churg-Strauss syndrome, giant cell arteritis, microscopic polyangiitis, cryoglobulinemia, polyarteritis nodosa, Wegener granulomatosis); PF: pemphigus (including vulgaris, bulloso, foliaceous); IBD: inflammatory bowel disease (including ulcerative colitis, Crohn's disease); AA: alopecia areata; PsA: psoriasis (including psoriatic arthritis); SAR: sarcoidosis; JCA: juvenile chronic arthritis; AS: ankylosing spondylitis; RePo: relapsing polychondritis. From Rojas-Villarraga et al. [8].

and PASIV correspond to different forms of polyautoimmunity. The importance of polyautoimmunity lies in the relation of diverse phenotypes with a single genotype, which allow a better understanding of the autoimmune tautology. We have recently evaluated a series of 84 patients with MAS [6]. Our results disclosed (i) three main clusters of polyautoimmunity, (ii) aggregation of ADs in families of patients with MAS (i.e., familial autoimmunity) and (iii) eight loci associated with autoimmunity at chromosomes 1p35.1, 6p22.3, 7p15.3, 13q31.1, 14q32.12, 16p12.1, 18q21.32, and 21q22.2 [6]. Out of the 84 patients there were 20 (23.8%) who presented a fourth AD, and one patient presenting five ADs. Cladistic analysis yielded 42 clusters with three ADs predominating: SLE, SS and AITD [6]. One of the first descriptions of MAS corresponded to a young woman presenting with RA, ITP, PA, Hashimoto's thyroiditis, SSc, and CD [25]. Her family study revealed RA, PA and T1D among her FDRs. She carried the HLA-A1, -A2, -B5, -B8, -DR3, and -DR4 groups [25]. This case well

Autoimmune phenotypes represent heterogeneous outcomes of genes underlying similar immunogenic mechanisms, by either cross-phenotype association or by pleiotropy [30]. In this sense, clinical observations indicate the possible shift from one disease to another or to the fact that more than one AD may coexist in a single patient (i.e., polyautoimmunity), or in the same family (i.e., familial autoimmunity). Disease would be considered as a hierarchical biological system composed of molecular and functional cell, tissue and organ interactive networks. Any aberration in one or more networks will not only have local effects but also systemic effects because no cell, tissue or organ is isolated or independent [30]. The MAS represent the best example of polyautoimmunity as well as the effect of a single genotype on diverse autoimmune phenotypes. Its study will provide important clues to elucidate the common mechanisms of ADs, including genetic and environmental components [31–35]. Conflict of interest The author declares no competing financial interests. Acknowledgments This work was supported by the Universidad del Rosario and Colciencias, Bogota, Colombia (122254531722). References [1] Shoenfeld Y, Isenberg DA. The mosaic of autoimmunity. Immunol Today 1989;10:123–6. [2] Weiss P, Shoenfeld Y. Shifts in autoimmune diseases: the kaleidoscope of autoimmunity. Isr J Med Sci 1991;27:215–7. [3] Anaya JM. The autoimmune tautology. Arthritis Res Ther 2010;12:147. [4] Anaya JM. Common mechanisms of autoimmune diseases (the autoimmune tautology). Autoimmun Rev 2012;11:781–4. [5] Cifuentes RA, Restrepo-Montoya D, Anaya JM. The autoimmune tautology: an in silico approach. Autoimmun Dis 2012;2012:792106. [6] Anaya JM, Castiblanco J, Rojas-Villarraga A, Pineda-Tamayo R, Levy RA, Gómez-Puerta J, et al. The multiple autoimmune syndromes. A clue for the autoimmune tautology. Clin Rev Allergy Immunol 2012;43:256–64. [7] Anaya JM, Rojas-Villarraga A, García-Carrasco M. The autoimmune tautology: from polyautoimmunity and familial autoimmunity to the autoimmune genes. Autoimmun Dis 2012;2012:297193. [8] Rojas-Villarraga A, Amaya-Amaya J, Rodriguez-Rodriguez A, Mantila RD, Anaya JM. Introducing polyautoimmunity. Secondary autoimmune diseases no longer exist. Autoimmun Dis 2012;2012:254319. [9] Anaya JM, Corena R, Castiblanco J, Rojas-Villarraga A, Shoenfeld Y. The kaleidoscope of autoimmunity: multiple autoimmune syndromes and familial autoimmunity. Expert Rev Clin Immunol 2007;3:623–35. [10] Rojas-Villarraga A, Toro CE, Espinosa G, Rodríguez-Velosa Y, Duarte-Rey C, Mantilla RD, et al. Factors influencing polyautoimmunity in systemic lupus erythematosus. Autoimmun Rev 2010;9:229–32. [11] Elhai M, Avouac J, Kahan A, Allanore Y. Systemic sclerosis at the crossroad of polyautoimmunity. Autoimmun Rev 2013;12:1052–7.

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