Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory

Accepted Manuscript Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory

Elena Generali, Tanima Bose, Carlo Selmi, J. Willem Voncken, Jan G.M.C. Damoiseaux PII: DOI: Reference:

S1568-9972(18)30163-0 doi:10.1016/j.autrev.2018.04.002 AUTREV 2194

To appear in:

Autoimmunity Reviews

Received date: Accepted date:

5 April 2018 10 April 2018

Please cite this article as: Elena Generali, Tanima Bose, Carlo Selmi, J. Willem Voncken, Jan G.M.C. Damoiseaux , Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory. Autrev (2018), doi:10.1016/j.autrev.2018.04.002

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ACCEPTED MANUSCRIPT Nature versus nurture in the spectrum of rheumatic diseases: Classification of spondyloarthritis as autoimmune or autoinflammatory

Running title: Is spondyloarthritis an autoimmune or autoinflammatory disease?

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and Jan G.M.C. Damoiseaux6*

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Elena Generali1, Tanima Bose2,3*, Carlo Selmi1,4, J. Willem Voncken5,

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Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy, 2

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Leibniz Institute for Neurobiology, Magdeburg, Germany; Institute for Clinical

Neuroimmunology, Ludwigs-Maximilian-University, Munich; 4 BIOMETRA Department,

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University of Milan, Italy; 5 Molecular Genetics, Maastricht University Medical Center, Maastricht, The Netherlands; 6 Cellular Diagnostics & Cell Therapy, Central Diagnostic

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Laboratory, Maastricht University Medical Centre, Maastricht, The Netherlands

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*Corresponding authors: E-mail: [email protected]; Tel: +31 43-3876655.

Abbreviations: AAV, ANCA-associated vasculitis; ACPA, anti-citrullinated protein

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antibodies; AID, autoimmune disease; AIM, autoimmune myopathies; AInfD, autoinflammatory disease; AS, ankylosing spondylitis; DZ, dizygotic; ER, endoplasmic reticulum; FMF, familial Mediterranean fever; GWAS, genome wide association study; HLA, human leukocyte antigen; HR, hazard ratio; IBD, inflammatory bowel disease; MZ, monozygotic; PsA, psoriatic arthritis; RA, rheumatoid arthritis; ReA, reactive arthritis; SLE, systemic lupus erythematosus; SpA, spondyloarthritides; TRAPS: tumor necrosis factor receptor associated autoinflammatory periodic syndrome

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ACCEPTED MANUSCRIPT Abstract Spondyloarthritides (SpA) include inflammatory joint diseases with various clinical phenotypes that may also include the axial skeleton and/or entheses. SpA include psoriatic arthritis, reactive arthritis, enteropathic arthritis and ankylosing spondylitis; the latter is frequently associated with extra-articular manifestations, such as uveitis, psoriasis, and

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inflammatory bowel disease. SpA are associated with the HLA-B27 allele and recognize T cells as key pathogenetic players. In contrast to other rheumatic diseases, SpA affect women

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and men equally and are not associated with detectable serum autoantibodies. In addition,

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but opposite to rheumatoid arthritis, SpA are responsive to treatment regimens including IL23 or IL-17-targeting biologics, yet are virtually unresponsive to steroid treatment. Based on

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these differences with prototypical autoimmune diseases, such as rheumatoid arthritis or connective tissue diseases, SpA may be better classified among autoinflammatory diseases,

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with a predominant innate immunity involvement. This would rank SpA closer to gouty arthritis and periodic fevers in the spectrum of rheumatic diseases, as opposed to

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autoimmune-predominant diseases. We herein provide available literature on risk factors

environmental factors.

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associated with SpA in support of this hypothesis with a specific focus on genetic and

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Keywords: genetics; rheumatoid arthritis; ankylosing spondylitis; inflammasome;

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autoantibody; psoriatic arthritis.

Take home messages: 

Spondyloarthritis are “mixed-pattern diseases”, ranked in between autoimmune and autoinflammatory diseases.

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Genetics, in particular HLA-B27, play a major role in spondyloarthritis pathogenesis, however, contrarily to autoinflammatory diseases, no IL-1 gene cluster has been associated with spondyloarthritis.

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ACCEPTED MANUSCRIPT Environmental factors and microbiota play a crucial role in spondyloarthritis

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development, however no single pathogenic factor has been identified.

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

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ACCEPTED MANUSCRIPT Introduction Systemic rheumatic diseases comprise a group of heterogeneous conditions affecting a wide range of tissues and organs, i.e. joints, eyes, skin, vascular system of lung and/or kidney, and present with significant healthcare costs and increased mortality and disability. Among such diverse clinical manifestations, symptoms and serological profiles of the rheumatic

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diseases, not all conditions can be classified as autoimmune [1]. Autoimmune diseases (AID) are characterized by a striking female preponderance, by the presence of serum

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autoantibodies detected sometimes years before the development of clinical manifestations

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[2], and by B or T cell selection defects characterized by aberrant responses to autoantigens [3]. Also, AID fulfill Koch’s postulates adapted for autoimmunity [4], borrowed from the field of

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microbiology, suggesting that autoantibodies and/or autoreactive T cells are the drivers of autoimmunity: passive transfer of these autoimmune factors to susceptible animals can result

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in the induction of the AID [5]. Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) represent the paradigms of rheumatic AID. Conversely, autoinflammatory diseases

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(AInfD) have no detectable autoantibodies, are characterized by a strong activation of the

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innate immune system, and fever is the most common symptom [6]. Gout and Behçet disease are paradigmatic AInfD, along with periodic fevers [7]. However, a substantial number of systemic rheumatic diseases neither show full-overlap with

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common features of AID nor of AInfD, as in the case for spondyloarthritis (SpA) (Figure 1).

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SpA comprise a heterogeneous group of inflammatory joint diseases, including psoriatic arthritis (PsA), ankylosing spondylitis (AS), reactive arthritis (ReA), arthritis associated with inflammatory bowel disease (IBD) and undifferentiated SpA. While PsA can be considered an extended variant of psoriasis [8], also undifferentiated SpA is debated with respect to being a discrete entity [9].SpA affects both sexes with equal frequency, albeit with different clinical manifestations: e.g. axial involvement being more frequent in men [10]. The incidence rates of SpA vary between 0.48 to 63 per 100,000 individuals, whereas the prevalence ranges from 0.01 to 2.5%. SpA is not considered to be typically associated with specific autoantibodies, although several studies report on the presence of autoantibodies [11]. In

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ACCEPTED MANUSCRIPT PsA, for instance, autoantibodies to carbamylated proteins (anti-CarP) and to anti-PsA peptides have been reported [12-14]. Pathogenecity of these autoantibodies has not been established, but they may add up to the few non-imaging biomarkers that are available [15] [16, 17]. Importantly, SpA was recently suggested to be a “mixed-pattern diseases”, ranked in between AID and AInfD along a continuum of immunological diseases, classified on the

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basis of clinical prominence and characteristics of the pathology [18]. In contrast, SpA has been considered as an AInfD by others, based on the underlying mechanisms and response

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to therapy [19]. Indeed, although both RA as well as SpA have a good response to anti-TNF

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drugs, there seem to be some apparent differences in terms of adverse events and drug survival [20] In this review, we aim to discuss the most recent insights regarding the

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pathogenesis of SpA in light of the ongoing discussion whether SpA should be considered as

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AID or AInfD.

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The genetic perspective

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Genetics plays an important role in SpA pathogenesis, as exemplified by the strong association of SpA with the human leukocyte antigen (HLA)-B27 allele, which is present in 85-90% of AS cases [21, 22]. Moreover, other HLA alleles, especially HLA-C*06, B*39 and

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B*07 have been associated with PsA. HLA-B27 is thought to have a direct pathogenic role in SpA development and various molecular mechanisms have been proposed, mostly related to

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intracellular protein misfolding of this class I surface antigen [23]. Accumulation of nonconventional forms of HLA-B27, such as free heavy chains, was recently reported in the gut and synovial tissue of SpA patients, as well as in HLA-B27 transgenic rats [24]. In vitro and in vivo animal studies show that slow folding of HLA-B27 and its association with ß2microglobulin causes accumulation of misfolded protein in the endoplasmic reticulum (ER) which triggers the unfolded protein response, a pro-inflammatory ER stress response [2527], which induces the expression of IL-23 [28]. In human dendritic cells, ER stress was also shown to increase IL-23 production after toll-like receptor stimulation [29].

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ACCEPTED MANUSCRIPT Nonetheless, HLA accounts only for 40% of the genetic risk for SpA; other polymorphisms in non-HLA genes, involved in innate immune recognition and cytokine signaling pathways, are linked with SpA [30]. Such genes include tumor necrosis factor (TNF) and IL-23 [19], which are shared with IBD and psoriasis [31]. On the other hand, thus far no IL-1 gene cluster mutations have been associated with SpA [32, 33], whereas this locus is clearly implicated in

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AInfD [34]; this observation argues against the definition of SpA as an AInfD. Albeit that genetics plays a major role in SpA development, additional factors are required to

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trigger the disease. In this context, twin studies represent an excellent model to study the

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role of environmental factors. In particular, as monozygotic (MZ) twins share an identical genetic background, diseases with high concordance rates between MZ twins suggest a

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genetic predisposition, while low concordance rates support the role of environmental factors as part of a multifactorial origin of disease [35]. The caveat of this assumption, however, is

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that generation of the T cell repertoire is, to a certain extent, a stochastic process. As such, MZ twins may develop with distinct T cell repertoires. In SpA, relatively few twin-based

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observations are available. Nevertheless, near identical concordance rates for PsA in MZ

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and dizygotic (DZ) twins stress the importance to continue the search for non-genetic effectors in PsA [36]. In AS, conversely, genetic factors seem to exert a more prominent role, as MZ twins have higher concordance rates (±75%), compared to DZ twins (±15%) [37, 38].

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Several candidate gene variants have been identified by genetic mapping in RA. A

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predominant association with the HLA-DRB1 locus was identified decades ago, however recent advances in genome-wide association studies (GWAS) and subsequent metaanalyses have led to the identification of numerous alleles that govern RA susceptibility, with variations according to the population evaluated [39]. In addition to HLA loci, more than 100 common variants in non-HLA loci have been implicated in RA susceptibility [39]. Several polymorphisms identified in RA are involved in immunoregulatory mechanisms, for instance polymorphisms in signaling transducers and activators of transcription-4 (STAT4) and IL-10 genes, and are shared with other prototypic AID [40]. Concordance rates for RA in MZ twins, however, are lower than observed in other AID, approximately around 15% in MZ and 4% in

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ACCEPTED MANUSCRIPT DZ twins [35]. Obviously, RA as well as most other AID cannot be explained by genetic susceptibility alone. With regard to AInfD, we can distinguish rare monogenic diseases, like familial Mediterranean fever (FMF) and tumor necrosis factor receptor associated autoinflammatory periodic syndrome (TRAPS), and polygenic diseases, such as gout and IBD. In gout, serum

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urate levels are influenced by a combination of inherited genetic variants and the environment [41]. The largest GWAS thus far among Europeans involved 110,000 individuals

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and uncovered 28 urate-associated loci [42], of which 10 were previously identified in smaller

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studies [43]. These polymorphisms are mainly located in genes encoding renal and gut uric acid transporters (SLC2A9/GLUT9, ABCG2, SLC22A11/OAT4, SLC22A12/URAT1,

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SLC17A1/NPT1 and the auxiliary molecule PDZK1) [43]. Twin studies have estimated the

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heritability of urate levels to be between 45% and 73% [44].

Is it a matter of sex?

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Sex is genetically determined and is a biologic variable influencing both innate and adaptive

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immune responses. Men and women also differ in their immunological responses to infections and self-antigens [45]. In general terms, women have enhanced antibody production and increased cell-mediated responses following immunization, while men

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produce a more vigorous immune response to infectious organisms [46]. Furthermore,

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women show higher CD4+ T cell counts than men, which contributes to an increased CD4/CD8 ratio, higher levels of plasma IgM and greater T-helper 1 (Th1) cytokine production [47]. Predictably, women and men not only differ in their normal immune response, but there are also differences in the prevalence, clinical presentation and severity of systemic rheumatic diseases [48]. This had fed the notion that an altered immune responses may correlate with increased susceptibility to AID in women [49, 50]. With regard to SpA, men and women are equally affected, but men are 2-3 times more susceptible than women to all forms of axial SpA [51, 52]. With a similar ratio between men and women in gout and Behcet’s disease [53], men are more affected than women at all

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ACCEPTED MANUSCRIPT ages, despite an increase of gout in women following menopause [54]. As mentioned above, the sex bias is quite clear for AID as nearly all conditions are largely more prevalent in women [55, 56], as represented by women being 2-3 times more likely to develop RA compared to men [57]. The lack of a female preponderance in SpA argues against a

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classification as AID and is in favor of SpA being an AInfD (Figure 1).

The role of the environment

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As the development of SpA cannot be fully explained by genetic factors, it has been

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proposed that many environmental components, including smoking, trauma, infections and microbiota are critically involved in the induction of the disease in genetically predisposed

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individuals. Epigenetic regulation of gene activity represents an important operational link between cells and their internal and/or external environment, as it allows them to adapt to

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(physiological) change [58]. Molecular epigenetic regulation occurs at three macromolecular levels, i.e. DNA, RNA and histone proteins, that collectively control gene expression at the

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transcriptional and post-transcriptional levels [59, 60]. The most-studied epigenetic

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mechanisms include DNA cytosine-(hydroxy)methylation and many biochemically distinct combinatorial post-translational modifications to histones (i.a. methyl-, acetyl-, phosphoryl-, ubiquityl-, sumoylation and citrullination), the core components of nucleosomal modules in

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eukaryotic chromatin. In conjunction with various types of non-coding RNAs, DNA and

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histone modifications constitute the nuclear epigenome: nucleosome positioning and chromatin accessibility of effector complexes control e.g. transcription, replication, recombination and repair [61]. Multiple studies have revealed a correlation between gene expression and epigenetic regulation in the context of immune cell development and function, and, of relevance in this review, the involvement of epigenetic deregulation in AInfD and AID [62-64]. Despite these advances, the origin of such epigenetic deregulation often remains obscure. Genetic defects in epigenetic regulatory factors are implicated in various rare syndromes; one of the most prominent examples thereof is the direct connection between intellectual disabilities and

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ACCEPTED MANUSCRIPT genetic mutations in a variety of epigenetic regulators [65, 66]. In the context of immunedysfunction, mutant forms of the DNMT3B (DNA de novo methyltransferase 3B) and AICDA (5-methyl cytidine deaminase) genes have been directly connected to immunodeficiency, centromeric instability and facial anomalies (ICF) and hyper-IgM 2 (HIGM2) syndrome, respectively [67, 68]. Although numerous transcription factors have been implicated in

the involvement of non-coding RNAs is lagging behind [69-71].

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genetic predisposition to immune-disorders, including AInfD and AID, similar knowledge on

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Although immune-(dys)regulation is clearly associated with environmental exposure,

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however, exactly how environmental factors affect epigenetic regulation and may contribute to disease is much less clear [72-75]. The link between nutrition, metabolic status and

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epigenetic transcriptional regulation illustrates a direct functional interaction between genes and their microenvironment, especially in the context of immune function [76-79]. Although

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the underlying etiology is often far from being completely understood, multiple environmental exposures that adversely affect health (i.a. Western type diet, tobacco smoke, particulate

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matter) are known to affect the immune system [80-82].

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It is widely accepted that smoking is one of the factors that contributes to the pathogenesis of AS, while being also associated with disease severity [83]. Smoking may also influence the development of psoriasis and PsA: a recent report showed that childhood exposure to

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environmental tobacco smoke is significantly associated with psoriasis (OR 1.28, 95% CI

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1.10-1.49, p=0.002). Moreover, smokers with a history of >5 pack-years manifest a higher risk for psoriasis (OR 2.18, 95% CI 1.82-2.61, p<0.001). Twin studies have shown that psoriasis risk is 1.23 in the ever-smoking twin among MZ twins (95% CI 0.59-2.56; p=0.578) compared to same-sex DZ twins (OR 2.21, 95% CI 1.36-3.58; p=0.001). The results support that 20% (14-25%; p<0.001) of the correlation between psoriasis and smoking is hereditary, whereas non-shared environmental factors seem to account for an additional 8% (0-22%; p=0.504) [84]. The exact mechanism behind this gene-environment interaction is not known but it may be related to overproduction of pro-inflammatory factors like C-reactive protein, interleukin-6, matrix metalloproteinases [85]. In RA the role of smoking is mechanistically

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ACCEPTED MANUSCRIPT better understood. Smoking appears important throughout the preclinical phases of RA development, as it may, in the context of HLA DR-shared epitope proteins, trigger RAspecific immune reactions to citrullinated proteins [86], particularly for seropositive RA [87] and in men [88]. Trauma, injury and heavy lifting have been associated with SpA development, in particular for PsA [89, 90]. Physical trauma is a potential trigger for PsA, as

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evidenced by the long-standing observed Koebner phenomenon in psoriasis [91], where psoriatic plaques develop in areas of physical trauma [92]. A case report of MZ twins

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developing PsA after trauma substantiates this notion [93]. These findings have recently

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been confirmed by a large real-life observational study, in which physical trauma was associated with PsA development in psoriasis patients, with a hazard ratio (HR) of 1.32 (95%

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CI 1.13-1.54). Among traumas displaying a significant association with PsA development were bone and joint traumas, while skin and nerve traumas were not associated [94]. In this

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view, enthesitis, the inflammation of fibrocartilaginous entheses (ligaments), represents the common denominator between SpA, and subclinical enthesitis may be the primary trigger of

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secondary joint synovitis through the release of proinflammatory mediators [95]. Recent MRI

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analyses have enabled important in-depth characterization and showed that enthesitis is a very common feature (30-50%) in distal interphalangeal joints in PsA patients [96, 97]. Enthesitis envelops the nail matrix [98], and high mechanical stress and chronic micro-

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trauma may be the underlying trigger for this inflammatory reaction [95].

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Infections have been recognized as triggers for SpA since a long time, as ReA (previously including Reiter syndrome, with the classic triad of symptoms in a soldier following a digestive infection, and attributed to Treponema pallidum infection [99]. However, ReA is a disease with an ancient history, as Hippocrates around 460 BC may have been the first to postulate the association between arthritis and genitourinary infections, writing that “a youth does not suffer from gout until sexual intercourse” [100]. Even in ancient Egypt, ReA was reported in a medical papyrus [101]. ReA follows an infection of the digestive or genitourinary tract caused by different microorganisms, including: Chlamydia trachomatis, Shigella flexneri, Salmonella

enteritidis,

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typhimurium,

Salmonella

muenchen,

Yersinia

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ACCEPTED MANUSCRIPT enterocolitica, Yersinia pseudotubercolosis, Campylobacter jejuni, Campylobacter fetus, Ureaplasma urealyticum, and Clostridium difficile. Other less common microorganisms involved in ReA include Neisseria gonorrhoeae, Borrelia burgdorferi, Chlamydia pneumoniae and Escherichia coli [102]. The exact mechanism by which these bacteria trigger ReA is currently unknown. Cross-reactivity between the pathogen and self-components has been

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hypothesized as a factor in the onset of ReA, because of the association or ReA with HLAB27 [102]. Interestingly, antibodies directed to microorganism antigens were reported to also

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display affinity for HLA-B27 [102]. However, this argument fails if the association with HLA-

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B27 is attributed to intracellular protein misfolding (vide supra). More studies are needed to test the hypothesis that molecular mimicry plays a role in the development of ReA. This is

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important information for the classification of SpA as AInfD or AID because molecular mimicry implicitly implicates that the adaptive immune system is involved, which is the typical

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hallmark of AID.

Infections have also been related to the pathogenesis of RA. In particular Porphyromonus

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gingivalis, the main cause of periodontitis, is a well-known risk factor. It is the only human

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pathogen known to express peptidylarginine deiminase, the enzyme that generates citrullinated epitopes that are recognized by anti-citrullinated protein antibodies (ACPA) [103]. These enzymes, however, are also abundantly expressed by inflammatory cells, including

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macrophages, that infiltrate the affected synovial tissues.

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Overall, environmental factors seem to play a crucial role in determining SpA, however current research has not identified a single pathogenic trigger. Infections, in particular genitourinary and gastro-intestinal, represent a risk factor for ReA, while mechanical stress for PsA.

The hidden microbial self Besides the effect of external exposure to microbial organisms on immune reactivity, it is becoming increasingly clear that commensal bacteria (microbiota) have a significant impact on our immunological health. The microbiota, or the ecosystem of microorganisms living on

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ACCEPTED MANUSCRIPT mucosal surfaces and the skin in mutually beneficial coexistence with the host, influences numerous physiological processes, including longevity, metabolism and, relevant to the present discussion, the immune system development and function [104, 105]. Our resident bacterial community should be considered an acquired organ with its own plasticity, organized with stratification and hierarchy and not assembled randomly [106]. It is

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established that disturbances in the microbiota mainly in the gut, or dysbiosis, not only correlates with, but may cause a number of pathological processes, including AID and AInfD

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[107]. The microbiota is in strict relationship with the mucosal immune system, which evolved

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to prevent invasion of resident and pathogenic microbes. As such, the gut microbiota is essential for oral tolerance, the capacity of the enteric immune system to acquire non-

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responsiveness to food and dietary antigens [108].

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Crohn’s disease and ulcerative colitis were, for obvious reasons, the first diseases to be associated with gut dysbiosis, with initial studies showing substantial taxonomic shifts with a reduction in beneficial Clostridia and Bacteroides fragilis subtypes and enrichment in

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Escherichia coli [109]. The interaction at mucosal sites between the microbiota and the

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epithelial cells shapes the adaptive immune system: particular Clostridia clusters allow the fermentation of dietary fibers, leading to the production of short-chain fatty acids, like

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butyrate, which exert anti-inflammatory effects by promoting T regulatory (Treg) cell development [110-112]. Of note, butyrate is a known histone deactetylase inhibitor, and thus

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a potential epigenetic modulator in the context of immune function [113]. Moreover, B. fragilis produces capsular polysaccharide A which induces Tregs, while the exogenous administration of polysaccharide A restores the immunological balance in germ-free mice and has protective effects towards colitis [104, 114]. Additional beneficial effects of the gut microbiota include the induction of IL-22 by bacteria-derived indole metabolites, which promotes the expression of antimicrobial proteins, limits the expansion of commensal segmented filamentous bacteria and inhibits Th17 cell activation [115]. The long-established link between IBD and SpA suggests and involvement of the microbiota in systemic rheumatic disease [116]. Early evidence from animal studies revealed a relevant interaction between

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ACCEPTED MANUSCRIPT HLA surface antigens and microbiota: in HLA-B27 transgenic rats, the presence of the HLAB27 antigen was associated with an altered microbial composition of the gut; the relative abundance of Prevotella spp. and Bacteroides vulgatus was increased, whereas that of Rikenellaceae was decreased [117]. Moreover, it has been demonstrated that prebiotics reduce the severity of colitis and prevent the development of arthritis in these rats [118].

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Human observational studies have assessed whether the composition of the faecal microbiome differs between SpA and controls. Sequence analysis of 16S ribosomal RNA

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genes, whole-microbial genomes and metabolomic analysis, pointed to a decreased

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microbial diversity in PsA patients compared to controls: Akkermansia, Ruminococcus, and Pseudobutyrivibrio populations were significantly reduced [119]. It has also been

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demonstrated that dysbiosis in SpA is disease specific, as there is an abundance of Ruminococcus gnavus compared with both RA and controls [120]. The dysbiosis could be

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influenced by breastfeeding, as AS risk is reduced in subjects that were breastfed, in line with a potentially important involvement of gut microbiota in the onset of the disease [121].

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Complex disturbances in the microbiota have also been associated with RA: whereas germ-

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free mice are protected against experimental arthritis, the reestablishment of intestinal microbiota restores the production of autoantibodies and arthritis [122, 123]. The underlying mechanisms likely involve induction of Th17 cells in the intestinal lamina propria [123],

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possibly via dendritic cell and macrophage activation, production of pro-inflammatory

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cytokines, as IL-1β and IL-6 [124], and induction of IL-10-producing B regulatory cells [125]. Interestingly, in RA the microbiota changes during the disease course, with enrichment in Prevotella copri in the early phases and reduction in long-standing RA [126, 127]. It is currently unclear whether this may reflect a common disease-related evolution in the microbiota composition, or whether this relates to chronic treatment. In addition to changes in gut microbiota RA also correlates with altered oral microbiota, as suggested by its association with P. gingivalis [128]. The gut microbiota was also shown to modulate arthritis in experimental models of gout. In germ-free mice, the production of short-chain fatty acids that are necessary for adequate inflammasome assembly and IL-1β production is decreased,

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ACCEPTED MANUSCRIPT due to the metabolite-sensing receptor free fatty acid receptor 2 (also known as G-protein coupled receptor 43) [129]. Moreover, observations in some experimental models of arthritis show that microbial triggers by commensal bacteria are required to promote disease in genetically predisposed animals [125]. Also in PsA it has been postulated that host genetics may be involved in the balance between microbiome and the inflammatory disease [130].

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Overall, the role of microbiota in inflammatory arthritis has been established, as for instance in the HLA-B27/human beta-2 microglobulin transgenic rat model. However, several studies

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reported gut dysbiosis in different arthritides, with few differences but this could be due to the

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limited number of patients and microbial species examined. Furthermore, the impact of

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epigenetics will need further investigation.

Current status and perspectives

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The available evidence with regards to genetic and environmental involvement show that SpA are chronic inflammatory diseases associated with a strong genetic predisposition, i.e.

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HLA-B27, and with a variable environmental component, which typically induce development

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of the disease. Different from classical AID, such as RA, there is no female predominance in SpA, autoantibodies are undetectable and there are thus far no known shared genetic predispositions. Moreover, whereas in RA environmental agents, among which smoking,

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appear to induce pathogenesis, in SpA the evidence for an etiological involvement of e.g.

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smoking is less robust. In contrast physical trauma and infections appear to trigger SpA development in genetically predisposed individuals. Considering that it is part of human nature to cluster and distinguish disease entities based on discernable criteria, it should be recognized that boundaries between such clusters are often subjective and may even be based on incorrect assumptions. By analogy, several animal species have been clustered in genus and/or families because of morphological characteristics, while genomic analyses eventually pointed towards another direction. Similarly, in the era of omics and big data analyses, a reclassification of immune mediated inflammatory diseases may be revealed in the near future. As for now, AInfD and AID are

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ACCEPTED MANUSCRIPT distinguished primarily based on the involvement of the innate and adaptive immune system, respectively (Figure 1). These immune responses are the consequence of geneenvironment interactions. Obviously, some AInfD, for instance the monogenetic periodic fever syndromes, are exclusively driven by innate immune responses, whereas other AInfD, like psoriasis and IBD, are additionally characterized by T cell involvement next to clear-cut

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innate mechanisms. As such, SpA seems to be more closely related to the typical AID than other polygenic AInfD. Nevertheless SpA display prominent features of autoinflammatory

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conditions and, in our opinion, should, perhaps more justifiably, be classified within the

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autoinflammatory category. This is further underscored by the response to immunemodulating therapies, in particular biologics. As has been shown for neutralization of IL-17

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and IL-23, effective future therapies for AInfD are likely to be also effective for SpA.

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Conclusion

The combined data presented herein suggests that the induced inflammatory reaction is out

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of control in SpA, either due to over-reactivity of the innate immune system, or due to

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insufficient control mechanisms. In addition, the microbiota differentially shape the immune system in SpA compared to RA; conclusive evidence for microbiota involvement for other

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conditions, like gout, is currently not available. The exact etiological involvement and mechanistic underpinnings of epigenetic dysregulation in SpA and other conditions

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discussed throughout this review, is expected to become increasingly clear as technology (acquisition and analysis) required to study chromatin-structure biology and its interaction with the environment further develops.

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ACCEPTED MANUSCRIPT Legend to figure 1:

Figure 1: The spectrum of systemic rheumatic diseases. Based on gene-environment interactions, the immune response will be directed towards predominant innate or adaptive immune system involvement; as such immune-mediated diseases can be separated in

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autoinflammatory (red box) and autoimmune diseases (blue box). Within the category of autoinflammatory diseases the predominance of the innate immunity is strongest on the left

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side and weakest on the right side of the red box. Spondyloarthritis is currently allocated to

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the autoimmune diseases, but classifies as an autoinflammatory disease based on a strong inflammatory component and lack of a female preponderance. The latter is supported by

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effectiveness of therapeutic approaches applied in the autoinflammatory diseases. The distribution of the distinct entities within the category of autoimmune diseases is rather

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arbitrary.

Abbreviations: AAV, ANCA-associated vasculitis; AIM, autoimmune myopathies; IBD,

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inflammatory bowel disease; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

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Figure 1