Spondyloarthritis (SpA) is a heterogeneous group of inflammatory chronic diseases characterized by common clinical features, as inflammatory back pain, peripheral joint involvement, dactylitis and enthesitis (Chimenti et al., 2020b). SpA can be divided into predominantly axial or predominantly peripheral form, with or without psoriasis (PsO), inflammatory bowel disease (IBD) or previous associated infection. Axial SpA (axSpA) encompasses ankylosing spondylitis (AS) with radiological signs of sacroiliitis, and a type without radiographic sacroiliitis, called “non-radiographic axial SpA” (nr-axSpA) (Chimenti et al., 2019a; Ward et al., 2019). All the clinical subtypes share common pathogenic, clinical, and radiologic features such as the genetic predisposition and the association with HLA-B27, the presence of extra-articular involvement and bone remodeling associated with bone resorption and osteoproductive lesions called syndesmophytes (Chimenti et al., 2020b). In axial-SpA the sex prevalence has dramatically changed during the last two decades: SpA were linked to male gender with a ratio of 10:1 with respect to female gender, nowadays the ratio has reduced to 3:1 for AS/axSpA (West, 1949). However, in contrast to AS, nr-axSpA male and female patients present the same prevalence (van der Horst-Bruinsma et al., 2013). Recent evidence supports the hypothesis of different clinical subtypes among males and females, suggesting a genetic and hormonal based pathogenesis. In this direction, the pathogenesis of SpA is not clearly understood to date and the role of immunological and genetic data showed clear sex dimorphisms in SpA patients (Rusman et al., 2018). Certainly, pathogenic mechanisms of SpA comprise a complex interplay among genetic background, environmental triggers, and mechanical stress that leads to the overall activation of inflammation and autoimmunity (Pedersen and Maksymowych, 2018). The role of genetic susceptibility in SpA was strongly associated with the presence of human leukocyte antigen (HLA) and non-HLA alleles that surely takes part in the predisposition to the disease (Brown et al., 2000). The class I HLA allele HLA–B27 is strongly linked with the development of SpA due to its role in the pathogenesis of the disease (Hacquard-Bouder et al., 2007). The revolution of the genome-wide association study (GWAS) era has identified hundreds of genes associated with SpA, mainly IL23R, ERAP1 (Endoplasmic Reticulum Aminopeptidase-1), ERAP2, and MEFV (Mediterranean fever) linked to innate and acquired immune response and cytokines production (Brown et al., 2000). The current interest in Precision Medicine, in order to identify preventive and therapeutic interventions, is increasing in the management of SpA patients. Clinical effect of biological DMARDs (bDMARDs) is now known to be affected by gender, as well as the clinical, genetic, and psychosocial life-style context (Garrido-Cumbrera et al., 2021). This different efficacy in women and men is due to biological differences which may be caused by sex-specific gene expression likely triggered by gene-specific epigenetic modifications. However, in SpA patients, a series of factors may interfere in epigenetic modifications: age, smoke, diet, and environmental factors (Chimenti et al., 2020b). In this context, the clinical phenotype and the response to drugs can be influenced by gender and considered as complex traits in SpA. The study of genetic and epigenetic mechanisms involved in the pathogenesis of SpA may be of help to define novel targets for more effective therapy. The aim of this review was to highlight the role of genetics and epigenetics in the susceptibility and clinical pattern of SpA as well as in bDMARDs treatment response variability with a focus on gender differences and predisposition.

Over the past decades a growing interest in the pathogenesis of SpA has provided rapid advances in understanding the genetic basis of the disease. A family aggregation to SpA has long been recognized and studies of concordance in twins and families of patients affected by AS indicate that susceptibility of the disease is widely due to genetic factors (Brown et al., 1997). More recent studies reported that the major histocompatibility complex (MHC) region gives a contribution of about 20% to the heritability (Ellinghaus et al., 2016).

Not only genetic variants but also epigenetic mechanisms, such as DNA methylation, histone modification and non-coding RNAs, have shown in the last years to be particularly relevant to explain the SpA pathogenesis. The term epigenetics refers to all mechanisms that produce a change in the gene expression, without modifying the DNA sequence. In recent decades, the interest in epigenetic mechanisms increased due to the evidence that their alterations are present in many diseases, including autoimmune diseases. In SpA, alterations of histone H3 (H3K27ac and H3K4me1) seem to be correlated with RUNX3 expression and the decrease of CD8⁺ T cell in the presence of rs4648889 SNP variant (Cherqaoui et al., 2020). In addition, H3K4me1 methylation regulates the activity of IL23R gene. Among epigenetic mechanisms, miRNAs represent one of the most interesting examples. These small molecules of non-coding RNAs can regulate the expression of multiple genes at a post-transcriptional level by inhibiting translation or inducing messenger RNA degradation. Significant alterations in miRNA expression have been observed in axSpA patients, showing a lower expression of 14 miRNAs in comparison with healthy controls (Prajzlerová et al., 2017; Cherqaoui et al., 2020). Interestingly, most of these miRNAs are involved in osteoblast differentiation or the Wnt signaling pathway while only miR-625-3p was significantly different in nr-AxSpA patients compared to controls. Moreover, also the genetic variability of miRNAs seems to be involved with autoimmune disorders susceptibility, and several associations were already reported (Latini et al., 2017). Until now, however, there is only little evidence of associations with PsA. For example, a Chinese study reported an association between common polymorphisms in mir-146a and mir-499 genes and ankylosing spondylitis (Xu et al., 2015). As already mentioned, epigenetics could play a role in the interactions between genetic and environmental susceptibility factors and might favor SpA development. DNA methyltransferase (DNMT) 3A and 3B are involved in genomic imprinting and X-chromosome inactivation, which may in part explain the different distribution of SpA according to gender (Hanson and Brown, 2017; Hao et al., 2017). Variants in DNMT3A, DNMT3B, and DNMT3L genes have been recently associated with AS, and different methylated positions (DMPs), that can influence HLA-B27, are identified (Ellinghaus et al., 2016; Cherqaoui et al., 2020). In addition, an increased level of Histone Deacetylase 3 (HDAC3), which regulates NF-kB activity, was detected in AS patients (Jiang and Wang, 2016). Additional genetic and epigenetic mechanisms, such as genomic imprinting, could explain the gender difference in inheritance of SpA (Rahman et al., 1999). Genomic imprinting is a normal process that differentially regulates the expression of specific genes depending on the sex of the transmitting parent. Already more than twenty years ago, a higher penetrance of PsO was reported if the father was affected and a similar phenomenon was observed among PsA patients (Burden et al., 1998; Rahman et al., 1999; Karason et al., 2003). Later a significant linkage on chromosome 16q was noted only after conditioning for paternal transmission, suggesting that genetic imprinting may play a role in the inheritance pattern of psoriasis and PsA (Karason et al., 2003; Eder et al., 2012). However, despite some encouraging advances in SpA epigenetic studies, data are still lacking and further studies are needed. Table 1 summary of genes whose variability is involved in SpA. Figure 1 summarizes the interaction among genetic and epigenetic factors and sex in SpA.

Several sex related differences have been described among the various subtypes of SpA. These can be divided based on joint manifestations. Differences related to gender on joint manifestations are summarized in Table 2. Regarding axial-SpA, relevant differences can be highlighted among gender (Rudwaleit et al., 2009; Conigliaro et al., 2016). First of all, a male predominance (3:1) has been found in the radiographic form while an equal sex distribution is registered in the nr-axSpA (1,03:1) (van der Linden et al., 1984; Rudwaleit et al., 2009). In this condition, disease burden appears to be similar for both sexes (Kennedy et al., 1993; Ward et al., 2009; Baumberger, 2017; Rusman et al., 2020). However, differences emerged concerning clinical and disease activity distribution. Indeed, men seem to display a higher radiological damage and a higher radiological progression (as highlighted with Bath Ankylosing Spondylitis Radiology Index and modified Stoke Ankylosing Spondylitis Spine), showing more marked radiographic spinal changes and worse hip involvement than women (Kennedy et al., 1993; Rusman et al., 2018). Confirming this, Lee et al. (2007) demonstrated a more severe radiographic damage among men who showed higher median BASRI−spine scores both in unadjusted and adjusted analyses for age and disease duration. On the other hand, the signs of peripheral involvements such as dactylitis, enthesitis, or swollen joint count appear to be significantly more prevalent in women (Kennedy et al., 1993; Rusman et al., 2020). Extra-articular manifestations also appear with a higher rate in female patients (Landi et al., 2016). Concerning acute anterior uveitis, a recent review reported a slightly higher predominance in women (M/F = 28/33%) (Zeboulon et al., 2008), as in patients affected by IBD (Stolwijk et al., 2015; Landi et al., 2016) or PsO (M/F = 25/33%) (Stolwijk et al., 2015; Landi et al., 2016) studies report a higher predominance in female patients. Regarding comorbidities such as cardiovascular diseases (CVD) and osteoporosis (Op), non-conclusive data are available on gender differences; evidences on CVD are scarce while a study on young males reported that 51% had a low bone mineral density (BMD) and 15% had Op (Zarco et al., 2015), another study concluded that male patients have a 4 times greater risk for low BMD compared with females (van der Weijden et al., 2012). These latter data are in contrast with those regarding the general population, where Op is typically prevalent in post-menopausal women (van der Weijden et al., 2012). Furthermore, CRP levels appear to be significantly higher, at baseline levels, in male patients compared with females, while no conclusive sex differences have been found for ESR (Jordan and Cooper, 2002; van der Weijden et al., 2011). Finally, women show higher disease activity, mostly in terms of subjective measures, reporting worse baseline BASDAI scores (in particular total and nocturnal back pain, duration of morning stiffness, and fatigue) as widely described in many studies (van der Horst-Bruinsma et al., 2013; Rubio Vargas et al., 2016; Kilic et al., 2017) while just a few studies described differences for baseline scores, being concordantly lower in females, of BASFI (van der Horst-Bruinsma et al., 2013; Rubio Vargas et al., 2016) and ASDAS-CRP (Webers et al., 2016). At the same time, female patients display less improvement in BASDAI, BASFI, and ASDAS-CRP scores after treatment (van der Horst-Bruinsma et al., 2013; Neuenschwander et al., 2020). In addition, women report worse quality of life when the Ankylosing Spondylitis Quality of Life questionnaire (ASQoL) and the Assessment of SpondyloArthritis international Society Health Index (ASA-HI) were used while no gender differences were found using the EuroQoL and the SF-36 Health Survey (Kennedy et al., 1993; Roussou and Sultana, 2011; Tournadre et al., 2013; Lubrano et al., 2017; Ibáñez Vodnizza et al., 2020; Neuenschwander et al., 2020). In summary, men with ax-SpA present higher objective markers of inflammation associated with radiological progression, although severe ankylosis also occurs in females. Nonetheless, women generally have higher subjective indicators of disease activity and, in addition, more peripheral involvement and extra-articular manifestations. As for comorbidities, osteoporosis has an unexpectedly high prevalence in young male patients. Concerning sex related differences in Entheropatic arthritis (EA), few data are available in literature and a small number of studies explored this topic, reporting axial manifestations as more frequently present in male patients than in females and women appear to be more likely to develop both type 1 and type 2 arthropathy (Dougados et al., 1991; Orchard et al., 1998; Turkcapar et al., 2006; Rodríguez-Reyna et al., 2009; Yüksel et al., 2011; Peluso et al., 2013; Picchianti-Diamanti et al., 2020). On the contrary, several findings suggest the presence of sex-related differences in PsA patients. It is reported that male patients have a high prevalence of axial disease and a high frequency of HLA-B27 antigens positivity, while women tend to have a more erosive disease, higher number of swollen joint count and a higher prevalence of disability (Gladman et al., 1992; Queiro et al., 2001; Wallenius et al., 2009; Queiro et al., 2013). Eder et al. (2013) demonstrated, on a large cohort of PsA patients, that axial involvement is more frequent in men as well as radiographic damage in both axial and peripheral joints (assessed with the modified Stokes Ankylosing Spondylitis Spine Score and the modified Steinbrocker score), while women reported with a higher frequency functional limitation and impaired quality of life (reporting higher scores in HAQ and BASFI and lower in the SF-36-PCS). In addition, differences were found in the pattern of arthritis at onset: women presented more frequently with the polyarticular subtype while men presented with olygoarthritis. On the other hand, the authors reported no significant differences in active and swollen joint counts, the presence of dactylitis, inflammatory spinal pain, and PASI score even if psoriatic nail lesions were more frequently found in men (Queiro et al., 2001).

Accumulating evidence suggests that gender differences in severity of SpA and treatment response could be due to genetic, immunological and hormonal factors (Brown et al., 1997). Female karyotype includes two X chromosomes, one of which is randomly silenced during embryogenesis. However, about 15% of the genes escape inactivation, leading to overexpression of some X-linked genes in females. The X chromosome encodes several immune-related genes, such as TLR7, TLR8, FOXP3, and IL-2 receptor gamma, whose overexpression may influence the immune response in a sex-dependent manner. For instance, male carriers of TLR9 rs187084 variant allele have an increased production of IFN-γ and TNFα, and women with rs5743836*C allele have a higher risk of developing SpA (Oliveira-Toré et al., 2019). Moreover, in contrast to the Y chromosome, the X chromosome is highly enriched in miRNAs, and some of them are reported to play a role in immunity or autoimmunity (Ortona et al., 2016). Different variants of the ANKH gene, which encode for a protein involved in osteogenesis and structural damage in axSpA, are expressed in men and women with AS. In women, AS seemed to be associated with genetic markers at the 5′ end of the ANKH gene, whereas in men with genetic markers at the 3′ end of this gene (Tsui et al., 2005). In this latter region, haplotype analysis has shown several SNPs associated with AS, supporting the greater predisposition of the male sex to develop AS. Moreover, different haplotypes combinations were significantly associated with AS in men (including rs26307 and rs27356 SNPs) and in women (including rs28006 and rs25957) SNPs) (Ortona et al., 2016). Furthermore, one specific haplotype in TNAP (tissue-non-specific alkaline phosphatase) gene, which interplays with the ANKH gene in ossification, was associated with AS in men but not in women (Tsui et al., 2005). A recent study on AS patients identified an upregulation of IL-17RA gene expression in men compared with women, as well as greater levels of TNFα, IL-18, IL-17A, and peripheral T-helper 17 cells. On the contrary, IL-6 levels were higher in women than in men (Tsui et al., 2007; Gracey et al., 2016). Sex differences in the expression of these genes could explain the higher prevalence and radiographic progression of AS in men compared with women and might be also influenced by sex hormones (Huang et al., 2012; Cutolo and Straub, 2020). Although few studies have investigated sex differences separately, several analyses have assessed sex as a possible predictor in relation to treatment efficacy and drug survival. Recent studies have shown that women tended to discontinue TNFi earlier than men both in axSpA and in PsA (Lubrano et al., 2017; Rusman et al., 2018). This might be partly explained by the lower prevalence of HLA-B27, a longer disease duration, and a greater fat mass in women than men. These factors are associated with a lower TNFi treatment response (Roussou and Sultana, 2011). Moreover, data from registries, such as the DANBIO and BSRBR, suggested that women also suffered from more side effects that have led to the discontinuation of the drugs (Saad et al., 2009; Glintborg et al., 2011). Polymorphisms within the TNF promoter region have been identified to influence clinical efficacy of etanercept in RA, AS, and PsA patients (Pierik et al., 2004; Morales-Lara et al., 2012). TNFR1A variant rs767455/G36A in PsA patients has been associated with a better EULAR response at 3 months to infliximab and similar results were obtained in CD patients (Pierik et al., 2004; Morales-Lara et al., 2012). On the contrary, the TNFAIP3 rs2230926 and rs610604 variant alleles seem to be correlated with better TNFi response in PsO patients, while rs6920220 and rs610604 are associated with an improvement in the quality of life in PsA patients receiving TNFi (Tejasvi et al., 2012; Ovejero-Benito et al., 2019). One study suggested that TNFi failure can occur in AS patient carriers of variants within macrophage migration inhibitory factor (MIF) gene (rs755622), IL-18R gene (rs917997), IL10 (rs1800896), and TNFRSFB1 (rs4355801) (Schiotis et al., 2014). Another study has reported that female gender, elevated basal BASFI index, and being a CHUK gene rs11591741-GC genotype carrier are predictors of long-term non-response to TNFi in SpA patients (Polo et al., 2019). Moreover, a lower level of clinical response measured by ASDAS and BASDAI index was observed in females (Rusman et al., 2018). Different miRNAs, such as miR-146a, miR-155, miR-625-3p, and miR-29a were linked to BASDAI, reflecting disease activity in AS with spinal involvement. In addition, miR-146a-5p, miR-125a-5p, and miR-22-3p expression were correlated with the plasma cytokine levels (TNFα, IL-1β, and IL-5), CRP and ESR (Perez-Sanchez et al., 2018). Downregulation of miR-199a-5p has been associated with increased TNFα, IL-17, and IL-23 in AS, suggesting that miRNAs could distinguish SpA phenotypes responsive to inhibitors of TNFα, IL-17, or IL-23 (Berlinberg and Kuhn, 2020). Proinflammatory cytokines, such as IL-17, are decisively involved in all clinical manifestations of SpA, and different concentrations of the cytokines are observed between men and women (Ortona et al., 2016). The use of secukinumab is widely diffused in our clinical practice for SpA management (Chimenti et al., 2019b). Recently the efficacy of secukinumab has been evaluated in patients with SpA, both in PsA and in AS patients. At the multivariate analysis, there was no gender influence concerning treatment efficacy. However, gender difference was observed according to drug-survival, particularly in the AS population: males had a higher persistence rate than females; this was not demonstrated in PsA patients (Chimenti et al., 2020a).

Since last century, the role of sex hormones has been hypothesized for the development of immune mediated diseases. Generally, estrogens have roles in both enhancing and inhibiting immune system activity, whereas androgens and progesterone exert suppressive effects (Cutolo and Straub, 2020). It has been reported that sex steroids can influence epigenetic modulation and expression of microRNAs that interfere with immune responses in autoimmune rheumatic diseases (Gracey et al., 2016). However, their role in SpA has been only partially evaluated. Estrogen has mainly anti-inflammatory effects, by inhibiting TNFα production, but contradicting results were presented (Rusman et al., 2018). This concept was previously supported by an old study demonstrating an improvement of arthritis in AS patients treated with oral estrogen and a worsening of disease in patients with low levels of estrogens (Gracey et al., 2016). Conversely, a more recent report showed neither difference in onset nor severity of AS female patients despite differences in serum estrogen concentration (Huang et al., 2012). For instance, estrogen modulates immune-related processes such as T cell differentiation and cytokine production and animal model studies have suggested that estrogen can inhibit Th17 differentiation from naïve T cells and in human 17β-estradiol (E2) levels are lower in patients with active AS than in those with inactive AS (Tyagi et al., 2012). Experimental models, such as E2-treated mice, showed a relationship among cytokines production and sex hormones: a decreased expression of TNF in the joint tissue was demonstrated supporting the inhibition of TNF production by estrogens (Ito et al., 2001). Estrogen-deficient female rats are also reported to have higher serum TNF than estrogen-supplemented animals and high and medium doses of estrogen increased the production of IL-4, IL-10, and TGF-β, whereas estrogen treatment reduced the production of inflammatory cytokines such as IFN-γ, IL-17, and IL-6. The relevant role of IL-17 in SpA pathogenesis and in particular in axial manifestation is well noted in clinical practice. A link between sex hormones and Th17 activation was demonstrated: estrogen inhibits Th17 cell. In ovariectomized DBA/1 mice with collagen-induced arthritis (CIA), E2 treatment reduces the severity of arthritis and results in fewer Th17 cells in the joints compared with controls (Andersson et al., 2015). Jeong et al. (2017) recently aimed to evaluate the effect of estrogen on the disease activity of SpA in a mouse model of SpA. The E2-treated group had significantly suppressed arthritis compared with both the ovariectomized and the sham groups. Furthermore, the expression of Dkk1 was significantly increased in E2-treated mice compared with the ovariectomized and sham groups and the expression of Wnt inhibitors was inhibited by estrogen (Jeong et al., 2017). Considering that blockade of Wnt inhibitors induced the fusion of sacroiliac joints and increased bone formation, estrogens might act in controlling Wnt pathway and used as a therapeutic target (Uderhardt et al., 2010). Unfortunately, in SpA, neither androgens and androgen receptors nor estrogen receptors polymorphisms were evaluated. Shorter CAG repeats of the androgen receptor gene presenting high levels of transactivation activity were demonstrated in a Japanese cohort of AS patients, supporting a role in male AS development (Mori et al., 2000). The role of microbiota has been previously described in SpA and its link with HLA B27 has been reported (Chimenti et al., 2018). Interestingly, women and men tend to have different gut microbiota, suggesting that sex hormones might have an effect on microflora, even if the mechanism still remains unclear (Cutolo and Straub, 2020). Sex-dependent differences in gut microbiota may lead to genetic or epigenetic changes in local gastrointestinal inflammation, systemic immunity, and susceptibility to a range of rheumatic diseases (Rizzetto et al., 2018; Cutolo and Straub, 2020). However, no progress has been made in decoding the unequivocal role of sex steroids in gut microbiota-related effects on SpA patients. Moreover, several studies in humans have highlighted that sex- related differences in the microbiota can occur across the lifespan of an individual, making results questionable (Ding and Schloss, 2014; Jaggar et al., 2019). Other relationships between gender and hormones are associated with levels of circulating adipokines. It is well known that obesity, body composition, and adipokines have an influence on differences in disease activity, progression, and response to treatment, between men and women with SpA (Rusman et al., 2018). Body fat content is higher in women than men and obesity is related to worse disease activity scores in SpA. In details, leptin, which is usually found at higher levels in overweight women and higher in women than men, was associated to spinal radiographic progression. Moreover, women also have higher circulating adiponectin levels, which is an insulin-sensitizing hormone. Positive correlations with inflammatory biomarkers, such as CRP and TNF, have been observed for leptin (Graßmann et al., 2017). Being a woman and being obese, mainly because of the body fat content, are related to a worse response to TNF-α blockers (Ibáñez Vodnizza and van der Horst-Bruinsma, 2020).

Based on genetic predisposition related to HLA-B27, SpA was generally considered as a male disease. As a matter of fact, in 1949, the male:female ratio was estimated to be 10:1 for AS patients; yet recent data have established a new 2–3:1 ratio (Kennedy et al., 1993). This epidemiological difference from past to present is due to several considerations: (1) the improvement and the development of new classification criteria aiming at the inclusion of early disease phases as well as the definition of non-radiographic SpA, (2) the better knowledge of clinical manifestations of SpA in the rheumatological field but also in other disciplines, (3) the improvement of radiological techniques for diagnosis and management. However, the highest prevalence of some clinical manifestations in females with respect to male suggested differences in the pathogenesis of SpA. The relevance of genetic and epigenetic phenomena in SpA pathogenesis was highlightened in this review, as well as the role of sex hormones, supporting the need of a redefinition of clinical and therapeutic targets. bDMARDs dramatically improved the management and quality of life of patients affected by SpA. With the availability of TNFi, research interests were oriented in order to identify potential clinical variables and biomarkers able to define the best responder to these drugs (Rubio Vargas et al., 2016). Different drugs with different mechanisms of action such as Il-17 inhibitors or Jak-inhibitors may have the same effect and efficacy in both men and women.

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with the authors RP, PT, PC, and MC.

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