Best Practice & Research Clinical Rheumatology 28 (2014) 765e777

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Bone formation in axial spondyloarthritis Rik J. Lories a, b, *, Nigil Haroon c, d a

Laboratory of Tissue Homeostasis and Disease, Skeletal Biology and Engineering Research Center, KU Leuven, Belgium b Division of Rheumatology, University Hospitals Leuven, Belgium c Division of Rheumatology, University Health Network, Toronto, ON, Canada d University of Toronto, Toronto, ON, Canada

a b s t r a c t Keywords: Spondyloarthritis Ankylosing spondylitis Bone Cartilage Inflammation Anti-TNF

The success of targeted therapies directed against tumor necrosis factor for patients with spondyloarthritis has shifted the focus of physicians and scientists towards the prevention of structural damage to the involved structures, in particular the sacroiliac joints and the spine, to avoid loss of function and disability. Structural damage to the skeleton as witnessed by radiography mainly consists of new bone formation potentially progressively leading to spine or joint ankylosis. This important long-term outcome parameter has been difficult to study, not alone because the time window for change may be long but also because human tissues with direct translational relevance are rarely available. Data from rodent models have identified growth factor signaling pathways as relevant targets. Both human and animal studies have tried to understand the link between inflammation and new bone formation. At the current moment, most evidence points towards a strong link between both but with the question still lingering about the sequence of events, disease triggers, and the interdependence of both features of disease. New discoveries such as a masterswitch T cell population that carries the IL23 receptor and the analysis of auto-antibodies directed again noggin and sclerostin are contributing to innovative insights into the pathophysiology of disease. Long-term data with tumor necrosis factor (TNF) inhibitors also suggest that some window of opportunity may exist to inhibit structural disease progression. All these data provide support for a further critical analysis of the available datasets and

* Corresponding author. SBE Research Center, O&N1 Box 813, Herestraat 49, B-3000 Leuven, Belgium. Tel.: þ32 16 342541; fax: þ32 16 342543. E-mail address: [email protected] (R.J. Lories).

http://dx.doi.org/10.1016/j.berh.2014.10.008 1521-6942/© 2014 Elsevier Ltd. All rights reserved.

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boost research in the field. The introduction of novel disease definitions, in particular the characterization of non-radiographic axial spondyloarthritis patients, will likely be instrumental in our further understanding of structural damage. © 2014 Elsevier Ltd. All rights reserved.

Introduction Spondyloarthritis (SpA) is a multifaceted chronic joint disease that includes different diagnostic entities that share clinical, genetic, radiographic, and pathophysiological characteristics [1]. The recent proposal to redefine SpA by distinguishing two important disease subforms (axial and peripheral SpA e axSpA and pSpA) linking the main clinical manifestation is gradually replacing the long list of distinct but oft overlapping disorders that made up the original SpA concept [2]. New insights into the disease processes and signs based on magnetic resonance imaging (MRI) and improved classification criteria [3,4] have boosted this new approach to disease with axSpA encompassing ankylosing spondylitis as well as non-radiographic axSpA that are typically affecting the spine and sacroiliac joints, and pSpA referring to arthritis and enthesitis that are predominant in the peripheral joints and that were most commonly classified before as reactive arthritis, inflammatory bowel disease-associated SpA, many forms of psoriatic arthritis, and undifferentiated SpA. Among chronic inflammatory joint diseases, SpA stands out by the widespread involvement of the axial skeleton and the characteristic radiological evolution of disease [1]. Erosive damage to joints or vertebra is relatively limited but new bone formation with bony outgrowths is dominant, for example, syndesmophytes in the spine. This process of new bone formation, sometimes described as “osteoproliferation,” can lead to progressive joint or spine ankylosis. In axSpA, progressive ankylosis strongly contributes to signs and symptoms, loss of function, and to disability in particular in patients with longstanding disease [5e8]. In pSpA, new bone formation can easily be recognized in many patients but its overall impact on short- and long-term outcome of the disease, including signs and symptoms as well as loss of function and disability, has not been clearly defined. Whereas inflammation appears to be the dominant feature that impacts the quality of life of patients in the early phases of disease, over time, structural damage becomes the dominant factor in determining patient status and outcome [5]. The introduction of targeted therapies such as antibodies or soluble receptors directed against proinflammatory cytokine tumor necrosis factor-alpha (TNFa) has dramatically improved the overall outlook for patients with SpA [9]. Nevertheless, prevention of structural damage is still a challenge as many questions with regard to this particular type of skeletal tissue damage remain. In this overview, we aim to summarize and provide novel insights into the genetic, cellular, and molecular nature of progressive ankylosis and its role in active disease. In general, two issues complicate enormously the study of ankylosis in SpA. First, human tissues from affected sites in the axial skeleton are extremely difficult to obtain due to ethical considerations. Second, ankylosis is a relatively slow process often evolving over decades. These kinetics as well as the high interindividual variation [10] provide additional hurdles for human and translational studies. In addition, as outlined below, animal models are not the perfect answer to this challenge. Taking this perspective into account, we discuss genetic factors as potential players in determining the extent and severity of ankylosis, summarize current insights into the molecular and cellular players involved trying to develop a tissue-level understanding, revisit old and new data on the relationship between inflammation and new bone formation, to finally phrase novel conceptual questions that may help define the research agenda in this field. Genetic factors and their impact on new bone formation and ankylosis The strong association of HLA-B27 with AS was established more than 40 years ago [11]. However, the pathogenic role of B27 is not known. Apart from being a susceptibility factor does HLA-B27 affect the severity of AS? This question has been addressed in several studies with variable results. HLA-B27

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has not stood out as a strong genetic factor affecting radiographic progression in AS. It should however be pointed out that the vast majority of AS patients carry the HLA-B27 gene, while this is not the case in non-radiographic axSpA. This could be because HLA-B27 is a risk factor for sacroiliitis progression. However, only C-reactive protein (CRP) was a significant predictor of progression in a study on 95 patients who progressed to AS at a rate of 10% every 2 years [12]. In other large studies looking at spinal progression of AS HLA-B27, positivity did not predict progression [13]. Interestingly, association with other major histocompatibility complex (MHC) loci has been identified in some studies on radiographic severity in AS [14,15]. Genome-wide association studies (GWAS) have identified a number of novel genetic associations with AS, but none of the early Caucasian studies identified bone-specific markers that would be obviously pathogenic in syndesmophyte formation. Two genes, ANTXR2 and PTGER4, which were strongly associated with AS in the initial GWAS studies, could be linked to osteoproliferation. ANTXR2 codes for anthrax toxin receptor 2, which is the receptor for the anthrax toxin, and aids in the toxin's entry into cells. ANTXR2 is also called capillary morphogenesis 2 protein (CMG2) and is also responsible for maintaining the integrity of the basement membranes and aiding developing capillaries. ANTXR2-mediated internalization of the toxin requires the low-density lipoprotein receptor 6 (LRP6) [16]. LRP5 and 6 are co-receptors in the Wntebeta-catenin signaling pathway, a growth factor cascade with a role in skeletal development, homeostasis, and disease [17]. Excess Wnt signaling can stimulate bone formation and LRP5 point mutations lead to the osteoporosis and pseudoglioma (OPPG) syndrome in humans [18]. A direct link between ANTXR2 and osteoproliferation is yet to be established. PTGER4 (prostaglandin E receptor 4, EP4) is one of four receptors for prostaglandin E2 (PGE2). PGE2 can induce mineralized bone nodule formation through the EP2 and EP4 receptors, which appears to be independent of bone morphogenic protein (BMP) pathways [19]. In addition, EP4 activation can augment BMP-mediated bone formation [20,21]. The association of PTGER4 with AS becomes even more interesting considering the recent reports of a possible disease-modifying potential of nonsteroidal anti-inflammatory drugs (NSAIDs) (see below). Thus, PGE2 activation of EP4 could be an important mediator of osteoproliferation in AS. A GWAS study on Han Chinese AS patients suggested novel associations with HAPLN1, EDIL3, and ANO6. [22] HAPLN1 codes for hyaluronan and proteoglycan link protein 1 (HAPLN1). HAPLN1 stabilizes aggrecan and hyaluronan aggregates in the cartilage extracellular matrix [23]. Mice deficient in Hapln1 develop musculoskeletal abnormalities with suggested abnormalities in endochondral bone formation [24]. Interestingly, HAPLN1 was found to be associated with spinal disc degeneration as well as osteophyte formation [25]. However, this association is deemed to have its effect through cartilage abnormalities rather than through a direct effect on osteophyte formation. EDIL3 codes for EGF-like repeats and discoidin I-like domains 3, an integrin receptor involved in angiogenesis and prevention of the neutrophil adhesion cascade [26]. EDIL3 deficiency in a mouse model of periodontitis and associated bone loss led to increased IL-17 production, which is of interest in AS pathogenesis [27]. EDIL3 is also considered important for cartilage development and organogenesis by modulating the Wnt and BMP pathways [28]. The links with both bone loss and bone formation identify EDIL3 as a receptor of specific interest in SpA. ANO6 codes for Anoctamin 6, a multi-pass transmembrane protein mediating the calciumdependent exposure of phosphatidylserine on cell surface. ANO6 is expressed in differentiating and mature osteoblasts [29]. ANO6 deletion leads to skeletal abnormalities in mice, in particular decreased mineral deposition [29]. Again, a direct link between these novel genes and osteoproliferation in AS has yet to be established but the pathways outlined above could be potential areas to explore. Genes associated with AS and antigen-processing pathway were specifically investigated in the context of AS disease progression [30]. An association between the proteasome gene LMP2 and ERAP1 and progression of spinal disease was documented. LMP2 has been linked previously to uveitis and extra-spinal disease and ERAP1 has been shown to affect HLA-B27 expression in AS patients [31,32]. These findings have to be replicated in larger studies to further establish them as risk factors for severe ankylosis in SpA patients. In a recent study on radiographic severity of AS, more than 2000 patients were pooled from multiple centers [33]. After analyzing association with 498 single-nucleotide polymorphisms (SNPs) in selected genes associated with bone homeostasis, 15 top hits were assessed in the replication cohort.

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Fig. 1. Ankylosing spondylitis susceptibility genes with links to new bone formation.

Two SNPs were considered significantly associated with radiographic severity in the study. The first SNP was in the gene RANK (Receptor Activator of Nuclear Factor kB). RANK is an essential receptor in osteoclast development. This raises the intriguing hypothesis that new bone formation and radiographic progression could be linked to local or systemic bone loss (see also below). The second association was with the gene PTGS1 (Prostaglandin Endoperoxide Synthase 1) or Cyclogenase 1. This again brings in the possibility of prostaglandins playing a key role in osteoproliferation in AS. However, considering the borderline significance of the associated genes and the issues around multiple testing, the findings of this study have to be validated independently Fig. 1. Nature of new bone formation in SpA e still enigmatic Our understanding of disease-associated new bone formation or pathological joint remodeling remains surprisingly limited. This is in sharp contrast with our views on bone erosion. Basic, translational, and clinical research have mapped this process at the molecular, cellular, and tissue level with RANKL, with the osteoclasts and the synovitis as respective culprits. However, achieving a similar level of insight into new bone formation has been an enormous challenge. Different factors contribute to this problem. Human tissues directly involved in the disease process are not readily available as biopsies from the spine or sacroiliac joint are difficult to obtain. Most pathology studies have been performed in the previous century and were based on autopsy cases, including a limited number of patients and not being able to capture the kinetics of the disease process. Modern imaging methods such as MRI have been used with great success to document inflammation but specific imaging of processes going beyond anatomical changes in new bone formation have been difficult to document. With biomechanical factors increasingly proposed as players in the onset and progression of the disease process, commonly used mouse and rat models are far from having optimal translational value. Spondylitis and ankylosis are rarely seen in mouse models and many molecular mechanisms involved in the pathological bone formation process have been suggested mainly based on peripheral arthritis models. The enthesis, the anatomical zone in which tendons and ligaments insert into the underlying bone, has been proposed as the primary disease localization in SpA [34e37]. The enthesis concept has been extensively elaborated and fits well with many other concepts that are applied to SpA. Nevertheless, imaging and pathology studies also clearly demonstrated that not only enthesitis but also synovitis and osteitis can be documented and contribute to signs and symptoms [38,39]. Based on the enthesitis concept, it is tempting to speculate that new bone formation specifically originates from this site and is closely linked to the biomechanical forces that are transduced through this multilayered stressdissipating structure. The shape and localization of bony protrusions in the spine but also in peripheral joints and extra-articular sites suggest a close link to the enthesis. However, there is no solid evidence that entheseal cells are the cells that proliferate and differentiate into bone and cartilage.

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Adjacent and intimately connected tissues, in particular the periosteum and to a lesser extent the synovium, may be the source of the progenitor cells that undergo pathological differentiation. In this perspective, it should be noted that mesenchymal stem or progenitor cells with multilineage potential have been identified from virtually any joint tissue but that periosteal cells in particular have a strong chondrogenic and osteogenic differentiation potential [40e42]. In addition, the existence of small channels between the enthesis, synovium, and the underlying bone marrow indicates that migration of bone marrow progenitor cells may be an unexpected contributor to onset and progression of ankylosis [43,44]. At the tissue level, three different differentiation and bone-forming processes have been proposed [45e49]. Animal models strongly suggest that endochondral bone formation plays a key role [50]. In this tissue formation cascade, essential during development and growth, new bone is formed through the intermediate formation of a cartilage template, in which the chondrocytes terminally differentiate, attract osteoblast precursors cells, and are progressively replaced by bone [51e53]. In addition to its physiological roles in skeletal development and in the growth plate, endochondral bone formation is typically found when a large piece of bone needs to be formed. A good example is fracture healing where endochondral bone formation is dominant. Direct or membranous bone formation is largely based on juxtaposition of bone by osteoblasts [51]. Human pathology studies provide some support for an important role in ankylosis but the specific contribution is unclear. During fracture healing its contribution is limited and growth through juxtaposition appears to be a relatively slow process. Nevertheless, some detailed imaging and pathology studies suggest that direct bone formation may be more important in human patients than originally proposed in animal models [46,49]. Third, cartilage metaplasia with calcification of the extracellular matrix surrounding chondrocytes has been documented [46]. The molecular mechanism and its relative contribution to ankylosis remain unknown. Molecular aspects of new bone formation in SpA Pathology analysis in human samples and mouse models provided the basis and rationale for studying a number of developmental molecular signaling cascades as factors that could play a role in new bone formation. Typical examples include BMP, Wnt, and Hedgehog signaling. BMPs were demonstrated in an endochondral bone formation process that originates from the enthesis and periosteum in a spontaneous mouse model of ankylosis [54]. Overexpression of BMP antagonist noggin was effective in both preventive and therapeutic strategies in this model, thereby providing the first evidence that ankylosis can be selectively targeted [54]. Wnt signaling has very complex effects on bone formation. Studies initiated to test the effect of antibodies against Wnt receptor antagonist Dickkopf-1 (DKK1) on inflammation-associated osteoporosis in the human TNF transgenic mouse model led to the serendipitous finding that such an approach radically changed the type of joint remodeling occurring in arthritic joints [55,56]. In the absence of the blocking antibody, hTNF transgenic mice develop extensive joint destruction with typical bone erosions. Blocking of DKK1 resulted in increased active Wnt signaling and the formation of osteophytes or enthesophytes. This radical change in a genetic mouse model with transition from a rheumatoid arthritis (RA)-like joint damage pattern towards an SpA-like pattern identified DKK1 and Wnt signaling as critical masterswitches, at least in mouse models. Of interest, DKK1 expression is induced by TNF [55]. Hedghog signaling is associated with a critical step in the endochondral bone formation process [51]. A specific inhibitor of this cascade was demonstrated to be effective in inhibiting new bone formation in the post-inflammatory phase of a serum-transfer model [57]. By specific targeting of this cascade and the hypertrophic chondrocytes, the authors argued that such a targeted approach would have benefits in terms of safety over targeting pivotal pathways such as BMP and Wnt signaling that clearly play homeostatic roles in other organ systems [57]. Different efforts have been undertaken to provide additional translational and clinical evidence in SpA patients to corroborate these in vivo mouse model observations. Unfortunately, patient studies, in particular when searching for biomarkers, have yielded conflicting results. Active BMP signaling was identified in a small number of entheseal biopsies and appeared to corroborate human data [54]. Different BMPs have been measured in the serum of distinct patient groups with conflicting results. Increased levels of both BMP2 and BMP7 were found not only in patients with AS but also in patients

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with RA as compared to healthy controls. In AS patients, BMP2 levels correlated with disease activity measured by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) questionnaire, whereas BMP7 levels correlated with the Bath Ankylosing Spondylitis Radiology Index (BASRI) [58]. In another study, such relationships were not found for BMP4 and BMP6 [59]. By contrast, Chen et al. confirmed higher levels of BMP2, 4, and 7 in AS patients with spinal fusions as compared to those without them [60]. In addition, BMP7 levels appear to increase after anti-TNF therapy in SpA patients [61]. DKK1 levels were originally reported as very low in AS patients compared to RA patients and controls [55]. More recently, it appeared that levels of active DKK1 are low, whereas the total amount of DKK1 in AS patients could be increased [62]. Other studies did not show clear differences in DKK1 levels [63,64] but a recent study suggested increased levels of Wnt3a in AS patients [64]. Wnt antagonists such as DKK1 but also sclerostin have been proposed as biomarkers for radiographic progression in SpA [65,66] but the study design has limitations. Taking into account the relative size and dynamics of the formation of single syndesmophytes and the biological role of the markers studied, it is not clear how serum concentrations of Wnt antagonists will relate to the specific anabolic process of interest and not to general skeletal remodeling and the effect of inflammation. Value and limitations of animal models Animal models, in particular in mice and rats, have been instrumental in providing insights into the molecular mechanisms that may underlie new bone formation in SpA. As highlighted above, the difficulties associated with access to human tissues have made the research community largely dependent on these models. However, clinicians and scientists should be aware of the limitations found with these models. Mouse and rats have an intrinsic repair or remodeling potential in the joints that is not commonly found in humans. In most models of transient joint inflammation, the resulting damage will trigger a repair response that usually does not respect the original anatomy of the joint but rather appears to stabilize the affected articulation. This may be a somewhat effective means to reduce pain associated with joint destruction. Therefore, models with non-sustained inflammation will most frequently show joint remodeling. Another clear limitation is that most features of ankylosis, in particular in the spontaneously occurring ankylosing enthesitis, serum, or antibody transfer models, are studied in the peripheral joints and not in the spine or sacroiliac joints. In other models, such as proteoglycan-induced arthritis in mice and in the HLA-B27 transgenic rats, spine remodeling has been documented but molecular and cellular mechanisms involved remain largely unstudied. Link between inflammation and new bone formation The link between inflammation and new bone formation has been in the center of attention in the last couple of years [52,67e70]. After introduction into clinical practice of the highly effective anti-TNF strategies, there was a lot of anticipation that ankylosis, the mean feature of structural damage in SpA, would be delayed or inhibited by successful control of disease activity, much alike earlier observations with regard to bone destruction seen in RA. However, initial cohort studies based on large clinical trial cohorts failed to show a significant effect on structural disease progression in the spine with the different biologics used in clinical practice over a 2-year time period, compared to a historical cohort [71e73]. Such an absence of a direct effect on structural damage had been proposed earlier on the basis of mouse models [74,75]. More recently, a long-term effect could be observed [76]. Different hypotheses quickly developed to explain the apparent complex relationship between inflammation and new bone formation. Appel et al. proposed that inflammation in SpA, in contrast to what is seen in RA, would be more fluctuating rather than sustained, leaving a window of opportunity for tissue repair, a process that apparently is not sufficiently controlled and therefore results in damage [77]. The entheseal stress hypothesis was proposed as an alternative, suggesting that inflammation and new bone formation are linked but largely molecularly uncoupled phenomena that could both be triggered by damage or danger signals at the enthesis [78]. The discovery in mouse models that DKK1 may act as a brake on tissue remodeling led to the TNF-brake hypothesis [67] with the balance between the pro-

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inflammatory cytokine TNF and Wnt antagonist DKK1 determining the outcome of disease. Since then, additional studies have been performed paying in detail attention towards progression of disease. The recent discovery in the mouse enthesis of a population of IL23 receptor positive T cells may fundamentally change our concepts on inflammation and new bone formation [79]. IL23RþCD3þCD4CD8RorgTþ T cells were identified as rare cells within the enthesis and respond to IL23 stimulation by increasing other pro-inflammatory cytokines, including TNF, interleukin-17, and interleukin-22. Similarly, IL23 effects on entheseal tissue also include upregulation of morphogenetic pathways such as BMPs that could trigger or stimulate new bone formation. In vivo overexpression of IL23 in adult mice triggers enthesitis and arthritis in mice with features that are strongly reminiscent of SpA: inflammation and new bone formation. In addition to the obvious question whether such cells also exist and have similar roles in humans, many questions with regard to events up- and downstream of the activation of the IL23 cascade. Different factors have been proposed as triggers for local or systemic IL23 production. These include a role for HLA-B27, for gut inflammation, and for biomechanical factors [80]. The HLA-B27 molecule has been specifically associated with slow intracellular processing and misfolding, leading to the activation of an unfolded protein response (UPR), which could lead to specific IL23 production [81]. However, most of the evidence supporting this mechanism comes from overexpression studies [82e84] and ex vivo human data would suggest that HLA-B27 affects more autophagy-associated processes than the UPR [85,86]. Other HLA-B27 associated processes include specific antigen presentation as suggested by its primary physiological role, but also direct interactions of immune cells and innate receptors with HLA-B27 leading to immune activation [81]. Gut inflammation both clinically manifest and occult has been strongly associated with SpA [87,88]. Some patients develop Crohn's disease or ulcerative colitis but in many patients lesions are only found at the microscopic level. However, gut inflammation may be a critical source of IL23 production and thereby directly contribute to the development of SpA. Finally, the specific anatomic link between the enthesis and disease strongly suggests that biomechanical stress can play a role. The enthesis has the typical structure of a multilayered transition zone that provides essential strength to translate and dissipate the forces developed by muscle contraction [89]. Local microdamage or direct upregulation of pro-inflammatory molecules that is not sufficiently controlled may thus also provide a trigger for disease. In a series of experiments, tail suspension and thus hindpaw joint unloading was able to reduce severity of arthritis in the TNFdARE mouse model [90]. In this genetic model, a regulatory region of the TNF gene has been deleted resulting in enhanced mRNA stability and endogenous overexpression of the gene. The preventive effect of joint unloading demonstrates that biomechanical factors play a potential role in the development of SpA. Clinical evidence may provide additional insights into the link between inflammation and new bone formation. Inflammatory parameters in the form of CRP or erythrocyte sedimentation rate (ESR) are now well established as strong predictors of progression in AS [12,76,91]. MRI studies have shown that vertebral corners with inflammation are more likely to result in syndesmophytes than those without them [70,92e94]. However, most syndesmophytes develop in vertebral corners without preceding inflammation by MRI. This could be due to the dynamic nature of MRI lesions associated with inflammation. The absence of inflammation at a point in time does not rule out the possibility of inflammation having existed in the vertebral corner before the MRI, or at some point during the followup period. MRI studies also show that resolution of inflammation with fatty replacement is associated with syndesmophyte formation [95,96]. Earlier institution of treatment leads to complete resolution of corner inflammatory lesions while more chronic lesions tend to become fat [97]. This hints at the possible existence of a window of opportunity for disease modification in AS. The recent key role for IL23-mediated cascades that has been suggested based on mouse model and genetic evidence naturally leads to an inflammation-driven concept of the disease with new bone formation downstream and thus secondary effect. However, there is preclinical evidence that the “common trigger” concept may be valid. As highlighted above, inhibition of inflammation has at best modest effects on disease progression. Observations made in a model of another bone-forming disease, fibrodysplasia ossificans progressiva, suggests that inflammation or tissue damage is necessary to trigger new bone formation [98]. Molecules such as BMPs could play an essential role as bridging signals. Local production and signaling of BMPs in the enthesis may attract inflammatory cells to the site [99]. Such a

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mechanistic view, including the concept that common triggers lead to two distinct but interacting processes, is supported by the seminal discovery that patients with spondylitis may have autoantibodies that neutralize the effect of BMP antagonist noggin. These auto-antibodies to both noggin and sclerostin were discovered first in mouse models and then also demonstrated with normal individuals and AS patients, with the latter having much higher levels [100]. This intriguing and unexpected observation could again change our views on the onset of disease. Therapeutic modulation of new bone formation in SpA NSAIDs and disease-modifying potential In a retrospective study on 40 AS patients, continuous users of phenylbutazone had decreased spinal new bone formation compared to intermittent users and nonusers [101]. One randomized controlled trial addressed this question more in depth where AS patients were given celecoxib either daily or on a flexible (“as needed”) basis [102]. Patients who received continuous celecoxib had less progression, but only if they had elevated inflammatory parameters, pointing towards a benefit in the high-risk group [103]. In patients included in the German Spondyloarthritis Inception Cohort (GESPIC) cohort, there was no evidence of a disease-modifying potential in the cohort [104]. In a subset of 18 patients who had baseline syndesmophytes and elevated CRP, a higher dose of NSAIDs led to less progression of mSASSS scores [104]. In a much larger cohort of patients, however, there was no NSAID effect on disease modification [76]. Thus, the data on disease modification with NSAIDs are not very strong. But in patients at risk of progression (elevated inflammatory parameters and baseline damage) there could be a benefit of continuous NSAID use. Tumor necrosis factor inhibitors and disease modification in AS Long-term studies on the effect of TNF inhibition (TNFi) on radiographic progression are now progressively becoming available. A large study including more than 330 patients from five centers in North America reported a 50% reduction in the odds of progression in patients who were on TNFi [76]. Patients who were not on TNFi were from the same centers and followed at the same time, but opted out of biologic therapy or could not access it due to lack of insurance coverage. Multiple statistical tests were done including the use of a propensity-score-based matching to confirm the results. The maximum benefit appeared to be in patients who started TNFi within 5 years of onset of treatment [76]. A significant difference in treatment groups was seen only beyond the first 4 years. Thus, studies designed to assess the disease-modifying potential of therapies in AS should have follow-up of over 4 years. A smaller study compared 22 AS patients who received infliximab to historic controls for the Herne Cohort [105]. As seen in the previous study, there was a significant reduction in progression of spinal damage in patients treated with infliximab, when followed up beyond 4 years. Some earlier studies have looked at this question by comparing patients on TNFi trials to historic controls [71e73]. These trials were of much shorter duration and firm conclusions may therefore not be drawn. Conceptual questions on new bone formation in SpA Despite clear progress, summarized above, important and clinically relevant questions with regard to new bone formation in SpA remain (Fig. 2). The previous work is also helpful to better shape concepts and future research frameworks. The development and increasingly general acceptance of the non-radiographic AxSpA group and its epidemiological characteristics suggest that AxSpA is not by definition a continuum. This provides support for earlier hypothesis that suggested that genetic as well as acquired/environmental factors may be distinct for their contributions to inflammation or structural damage. Such evidence also suggests that the identification of early patients who are at risk for structural damage becomes a further research priority. This observation also forces a critical evaluation of current concepts based on studies only including AS patients. By including AS patients only, there is a risk of selection bias as the criteria applied require structural damage at the sacroiliac

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Fig. 2. Conceptual framework of inflammation and new bone formation in axial spondyloarthritis.

joints that can be visualized on conventional X-rays. This applies, for instance, to studies on radiographic progression and genetics. By only studying AS patients divided into groups, risk factors associated with ankylosis may be overlooked as the inclusion criteria would exclude AxSpA patients not likely to show radiographic signs of disease. In addition, remodeling in the sacroiliac joints as well as in the spine may affect progression of disease in other sites. This fits well with the view that biomechanical factors also play an important role in SpA pathogenesis. Part of the progression of ankylosis over time may therefore be a secondary phenomenon linked to initial damage Fig. 2.

Summary and conclusions We have achieved tremendous success in understanding the pathogenic mechanisms in AS. More work is clearly required to better understand the mechanism of osteoproliferation in AS. There seems to be a window of opportunity in treatment of AS, with a reduction in risk of progression if TNFi are started early in the disease course. The disease-modifying potential of TNFi has to be validated in other large studies with ample follow-up periods. With new therapeutic modalities such as IL-17 and IL23 blockade being introduced in treatment of AS, well-designed studies to look at their disease-modifying potential are necessary.

Practice points  Radiographic evidence of disease progression is difficult to study in AS, as the time window for change may be long.  Rodent models show the importance of growth factor pathways in new bone formation.  Inflammation and new bone formation appear to be linked but questions remain on the sequence of events.  Long-term data with TNF inhibitors suggest a window of opportunity for disease modification in AS.

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Research agenda * The identification of an entheseal T cell population bearing the IL23 receptor and potential role of IL-22 in new bone formation should be explored. * The role of auto-antibodies directed against sclerostin and noggin in the pathogenesis of AS should be explored.

Acknowledgments Research of R.L. on SpA is supported by research grants from FWO Vlaanderen (Flanders Research Foundation), from KU Leuven, IWT-Vlaanderen and investigator initiated research support from Abbvie (Chair in Psoriatic Arthritis) and Pfizer (LEGEAS project). N.H. is supported by the Arthritis Society, Canada, CIBC/Arthritis Research Foundation, Arthritis Centre of Excellence and Arthritis Program (UHN). N.H. has received consulting fees from Abbvie, Amgen, Pfizer, Celgene, Janssen and UCB. References [1] Dougados M, Baeten D. Spondyloarthritis. Lancet 2011;377(9783):2127e37. [2] Sieper J, Rudwaleit M, Baraliakos X, et al. The assessment of spondyloarthritis international society (ASAS) handbook: a guide to assess spondyloarthritis. Ann Rheum Dis 2009;68(Suppl. 2). ii1e44. [3] Rudwaleit M, van der Heijde D, Landewe R, et al. The assessment of spondyloarthritis international society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis 2011;70(1):25e31. [4] Rudwaleit M, van der Heijde D, Landewe R, et al. The development of assessment of SpondyloArthritis international society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis 2009; 68(6):777e83. *[5] Machado P, Landewe R, Braun J, et al. Both structural damage and inflammation of the spine contribute to impairment of spinal mobility in patients with ankylosing spondylitis. Ann Rheum Dis 2010;69(8):1465e70. [6] Ariza-Ariza R, Hernandez-Cruz B, Collantes E, et al. Work disability in patients with ankylosing spondylitis. J Rheumatol 2009;36(11):2512e6. [7] Bakland G, Gran JT, Nossent JC. Increased mortality in ankylosing spondylitis is related to disease activity. Ann Rheum Dis 2011;70(11):1921e5. [8] Healey EL, Haywood KL, Jordan KP, et al. Impact of ankylosing spondylitis on work in patients across the UK. Scand J Rheumatol 2011;40(1):34e40. [9] Callhoff J, Sieper J, Weiss A, et al. Efficacy of TNFalpha blockers in patients with ankylosing spondylitis and nonradiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis 2014 [in press]. *[10] Baraliakos X, Listing J, von der Recke A, et al. The natural course of radiographic progression in ankylosing spondylitiseevidence for major individual variations in a large proportion of patients. J Rheumatol 2009;36(5):997e1002. [11] Brewerton DA, Hart FD, Nicholls A, et al. Ankylosing spondylitis and HL-A 27. Lancet 1973;1(7809):904e7. *[12] Poddubnyy D, Rudwaleit M, Haibel H, et al. Rates and predictors of radiographic sacroiliitis progression over 2 years in patients with axial spondyloarthritis. Ann Rheum Dis 2011;70(8):1369e74. *[13] Poddubnyy D, Haibel H, Listing J, et al. Baseline radiographic damage, elevated acute-phase reactant levels, and cigarette smoking status predict spinal radiographic progression in early axial spondylarthritis. Arthritis Rheum 2012; 64(5):1388e98. [14] Ward MM, Hendrey MR, Malley JD, et al. Clinical and immunogenetic prognostic factors for radiographic severity in ankylosing spondylitis. Arthritis Rheum 2009;61(7):859e66. [15] Bartolome N, Szczypiorska M, Sanchez A, et al. Genetic polymorphisms inside and outside the MHC improve prediction of AS radiographic severity in addition to clinical variables. Rheumatol (Oxford) 2012;51(8):1471e8. [16] Wei W, Lu Q, Chaudry GJ, et al. The LDL receptor-related protein LRP6 mediates internalization and lethality of anthrax toxin. Cell 2006;124(6):1141e54. [17] Lories RJ, Corr M, Lane NE. To Wnt or not to Wnt: the bone and joint health dilemma. Nat Rev Rheumatol 2013;9(6): 328e39. [18] Gong Y, Slee RB, Fukai N, et al. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 2001;107(4):513e23. [19] Minamizaki T, Yoshiko Y, Kozai K, et al. EP2 and EP4 receptors differentially mediate MAPK pathways underlying anabolic actions of prostaglandin E2 on bone formation in rat calvaria cell cultures. Bone 2009;44(6):1177e85. [20] Namikawa T, Terai H, Hoshino M, et al. Enhancing effects of a prostaglandin EP4 receptor agonist on recombinant human bone morphogenetic protein-2 mediated spine fusion in a rabbit model. Spine 2007;32(21):2294e9. [21] Toyoda H, Terai H, Sasaoka R, et al. Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist. Bone 2005;37(4):555e62.

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