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Can we stop progression of ankylosing spondylitis?
Best Practice & Research Clinical Rheumatology 24 (2010) 363–371
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Can we stop progression of ankylosing spondylitis? Georg Schett, MD, Professor of Medicine, Chair of Rheumatology and Immunology a, *, Martin Rudwaleit, MD, Professor of Medicine b a b
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany Department of Internal Medicine I, Charite´ University, Campus Benjamin Franklin, Berlin, Germany
Keywords: ankylosis syndesmophyte bone formation structural progression
Ankylosing spondylitis is characterised by inflammation of the spine and the entheses followed by bone formation. Excessive bone formation in ankylosing spondylitis leads to the formation of bone spurs, such as syndesmophytes and enthesiophytes, which contribute to ankylosis of joints and poor physical function. This process is based on increased differentiation of osteoblasts from their mesenchymal precursors, which allows to rapidly build up new bone. Prostaglandins, bone morphogenic proteins and Wnt proteins play an essential role in this process. By contrast, tumour necrosis factor (TNF) does not appear to be the direct trigger for osteophyte formation in ankylosing spondylitis. The article reviews the current knowledge regarding the mechanisms and clinical role of ankylosis and explains strategies on how to prevent it in patients with ankylosing spondylitis. Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Introduction Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease of unknown origin affecting the axial skeleton including the sacroiliac (SI) joints and the spine and also the peripheral joints and the entheses [1]. Since AS usually starts in the third decade, it affects people for most of their life. AS has a strong genetic component, with HLA-B27 being the most relevant gene. Clinically, pain and stiffness in the back are the leading complaints. In addition, the patient may suffer from peripheral joint pain or enthesitis, typically of the heel, or from bouts of uveitis. With time, bony ankylosis of the SI joints and the spine develops in many patients. Bony ankylosis at the spine may affect the vertebral bodies (syndesmophyte formation) as well as the facet, the zygapophyseal and the costovertebral joints. It is
* Corresponding author. Tel.: þ49 9131 8539131; Fax: þ49 9131 8534770. E-mail address: [email protected] (M. Schett). 1521-6942/$ – see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2010.01.005
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particularly spinal ankylosis, which results in loss of spinal mobility and changes in posture such as the development of thoracic kyphosis and irreversible stiffness. In a large proportion of patients, the disease course in AS that runs is fluctuating with not only periods of flares but also periods of remission or low disease activity. Some patients, however, suffer from persistently high disease activity. Excessive bone apposition in AS Bony overgrowth in AS has traditionally been considered as a structural damage arising from chronic immune activation and inflammation. In contrast to rheumatoid arthritis, where structural changes are of primarily catabolic nature, resulting in a net loss of bone substance in the vicinity of joints, structural changes in AS are dominated by anabolic processes. Bony spur formation, which arises from the cortical bone surface, is a common feature of AS and virtually affects all skeletal compartments that show disease morbidity. In the case of the vertebral column, such lesions are termed ‘syndesmophytes’. These lesions grow usually in a vertical orientation and are bridging vertebral bodies, and are formed by apposition of new bone along the edges of the vertebral bodies and subsequent loss of the intervertebral spaces [2]. When several consecutive vertebrae are affected, it may lead to the appearance of a ‘bamboo spine’. In particular, the insertion sites of the tendons are hot spots of bone apposition in AS and also affect peripheral compartments such as the Achilles tendon or the plantar fascia, resulting in the formation of bony spurs, then termed ‘enthesiophytes’. Moreover, inflammation of the SI joints, the small joints of the spine, such as the facet joints, as well as occasionally the peripheral joints leads to bony appositions followed by ankylosis in patients with AS. Bony spur formation and ankylosis is pathognomonic for AS, progressively limiting the range of motion of patients and leading to functional impairment. This bone anabolic process does not randomly affect intervertebral spaces and joints but is limited to certain predilection sites. Although the prerequisite for bony spur formation is not completely understood, it is likely that both mechanical and inflammatory components of the disease locally trigger increased bone formation. In the case of mechanical components, the fact that these lesions are often found along the insertion sights of the tendons points to a key role of mechanical stress. On the other hand, inflammatory lesions in the neighbouring bone marrow (osteitis) are considered as a risk factor for syndesmophyte formation, although this association is not complete and bony spurs can also be found at sites where no osteitis is seen and vice versa. The notion, however, that mechanical and inflammatory triggers can induce bony overgrowth has suggested that these lesions might represent a ‘response-to-stress mechanism’ and a type of active repair strategy of the joint rather than damage arising from inflammation. Cellular and molecular mechanisms of bone formation in AS A better insight into the molecular regulation of new bone formation is key for defining the optimal intervention strategies to retard or block bony ankylosis in patients with AS. Ankylosis in AS is based on the apposition of new bone along periosteal skeletal sites requiring differentiation of osteoblasts, which are the bone-forming cells. Osteoblasts develop from mesenchymal cell precursor cells, which cover the inactive periosteal bone surface. Growth as well as injury, such as observed during inflammation and also in case of fracture, lead to an activation of the periosteal bone surface and differentiation of osteoblasts, which allow to build up new bone. Osteoblasts synthesise bone matrix, which consists of numerous proteins, the most abundant of which are collagen type I and osteocalcin. Bone formation and ankylosis in AS depends on molecular signals, which regulate differentiation and activity of osteoblasts. Several mediators are of importance for osteoblast differentiation: prostaglandins, such as PGE2, are important local factors; PGE2 has anabolic effects on bone and promotes proliferation and differentiation of osteoblasts, thereby inducing the expression of bone sialoprotein and alkaline phosphatase [3]. Moreover, PGE2 can synergise with bone morphogenic protein (BMP)-2, a member of the TGF/BMP protein family in inducing bone formation [4]. Members of the BMP family, that is, BMP-2, -3 and -7, play a critical role in osteoblast differentiation and induce signalling through Smad proteins upon engaging respective surface receptors on mesenchymal cells [5]. Activation of intracellular Smad signalling indicates an increased activity of BMPs and this process occurs during enthesiophyte formation in AS [6]. Bone anabolic effects of BMPs can be antagonised by noggin,
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a natural inhibitor of BMP. Haploinsufficiency of noggin enhances BMP activity and has been shown to lead to ankylosis of joints. Wnt proteins have also been identified as potent inducers of new bone formation. Wnt proteins bind to a receptor/co-receptor complex on the plasma membrane, which consists of LRP5/6 and Frizzled proteins. Engagement of this receptor complex by Wnt proteins leads to phosphorylation of beta-catenin, which translocates to the nucleus and induces transcription of genes involved in osteoblast differentiation and bone formation [7]. Increased activity of beta-catenin as a surrogate marker for Wnt activation has been observed in bony spur formation, suggesting that Wnt proteins may indeed contribute to new bone formation and ankylosis of joints. Natural inhibitors of Wnt such as Dkk-1 and sclerostin neutralise Wnt activity and actively prevent new bone formation [7,8]. These proteins have shown to be differentially expressed in diseases such as rheumatoid arthritis and AS, with high expression in the former but low expression in the latter disease [9–11]. It is highly likely that inflammation initiates the process of ankylosis in AS. Thus, AS does not represent a disease manifesting with ankylosis per se or where ankylosis is purely driven by a mechanical trigger, but rather reflects diseases, where a chronic inflammatory process in the spine results in ankylosis. This observation implies that inflammation is molecularly linked to ankylosis and that inflammation triggers the process of new bone formation. One of the key inflammatory cytokines involved in AS, tumour necrosis factor (TNF), however, does not induce but rather inhibits bone formation. TNF is a potent inducer of proteins such as Dkk-1 and sclerostin and thus down-regulates bone formation [9,12,13]. It is yet unclear why periosteal bone apposition can still occur in AS patients despite TNF playing a central role in the inflammatory processes of this disease. Importantly, there is a striking difference between cortical bone and trabecular bone in AS: whereas trabecular bone mass decreases and leads to vertebral osteoporosis and increased fracture risk in AS patients, specific sites of the cortical bone start to proliferate and expand [14]. It can be hypothesised that the skeletal effects of TNF, which are down-regulation of bone formation plus enhancement of bone resorption, are reflected by systemic bone loss in the trabecular bone compartment, whereas cortical bone apposition is not linked to the expression of TNF itself. As TNF is not the key trigger for new bone formation in AS, one can hypothesise that other inflammatory mediators drive new bone formation and ankylosis in AS. Classical pro-inflammatory pathways such as interleukin (IL)-1 and IL-17 as well as signalling through the IL-6R/gp130 complex, however, exert negative rather than positive net effects on bone mass, supporting the notion that inflammation and immune activation exert a negative effect on bone formation and promote bone loss rather than bone apposition Fig. 1. These three groups of molecules, PGE2, BMP proteins and Wnt proteins manage differentiation of mesenchymal precursor cells into bone-forming osteoblasts. This differentiation process is accompanied by the expression of key transcription factors, such as Cbfa1 and Osterix, which are important for inducing osteoblast-specific genes. It is yet unclear whether bony-spur formation (osteophytes sensu lato) along peripheral joints (osteophytes sensu strictu), insertion sites of the tendons (enthesiophytes) and along the vertebral bodies (spondylophytes, syndesmophytes) follows similar molecular pathways. There are principally two pathways known to be relevant for bone formation: one is endochondral ossification and the other is membranous bone formation, including chondroidal metaplasia. Studies in humans and mice have shown morphological features of hypertrophic chondrocytes as a sign of endochondral bone formation in axial and peripheral joints [10,15]; also, direct evidence for membranous bone formation and chondroidal metaplasia has been obtained, especially at enthesial sites [16]. Instruments used for assessing treatment responses in AS In the past, the cornerstones of treatment in AS have been physiotherapy and non-steroidal antiinflammatory drugs (NSAIDs). The introduction of anti-TNF agents has resulted in therapeutic effects, which were hitherto unknown to patients with active AS, especially those who had suffered from symptoms despite high doses of NSAIDs. With anti-TNF therapy, at least every second patient achieves a good-to-very-good clinical response and 20–25% of patients achieve clinical remission. On the other hand, traditional disease-modifying anti-rheumatic drugs (DMARDs) and low-to-moderate doses of steroids do not have major therapeutic effects on axial disease in AS [17]. For the assessment of disease activity in AS, patient-reported outcomes, such as the Bath ankylosing Spondylitis Disease Activity Index (BASDAI), play a major role. BASDAI captures five disease domains
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Fig. 1. Interaction between Insult, Inflammation and Pathological Repair Processes in Ankylosing Spondylitis. Initial insults triggering the disease process in ankylosing spondylitis are mechanical stimuli eliciting enthesitis and inflammatory triggers associated with osteitis. Inflammation fuelled by inflammatory cytokines such as TNF, IL-6 and IL-17 gradually decreases in ankylosing spondylitis. At a certain point of time repair processes are initiated (Inflammation/Repair switch) which start to a perpetuating bone anabolic response driven by prostaglandins, Wnt and BMP proteins. In case of chronically persisting inflammation and the establishment of synovitis destructive bone-erosive processes dominate and prevent repair responses.
(fatigue, back pain, pain in other joints, enthesitis and morning stiffness). Each domain is assessed on a scale from 0 to 10 (or 0–100) and the average of the five domains gives the overall BASDAI score [18]. In general, a BASDAI score higher than 4 is considered to indicate active disease. BASDAI has been used in many clinical trials over the past years and has been proven to be reproducible and sensitive to change. A new composite measure of disease activity in AS is the ankylosing spondylitis disease activity score (ASDAS), which is currently being evaluated [19,20]. For measuring response to treatment in AS, absolute changes in BASDAI or, alternatively, certain cut-offs of relative improvement such as BASDAI 50 (50% improvement in BASDAI) have been used in clinical trials. Other well-established response measures are the Assessment of SpondyloArthritis international Society (ASAS) response criteria such as ASAS20, ASAS40 or ASAS partial remission [21,22]. These response criteria are composite indices comprising the four domains – morning stiffness, patient global, total pain and function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). To achieve ASAS20, an improvement of at least 20% in at least three out of the four domains, without worsening in the potentially remaining fourth domain, is required. Accordingly, ASAS40 requires an improvement by at least 40%, while ASAS partial remission defines a state of very low disease activity with all domains having absolute values of 2. The ASAS20 response measure has been developed specifically for typical NSAID trials in AS with up to 50% of NSAID-treated AS patients reaching ASAS20 [23]. For comparison, in AS patients, who have active disease despite NSAIDs (typical anti-TNF trials), an ASAS20 response is reached by 60–70% of patients, an ASAS40 by as many as 40–50% and ASAS partial remission by 20–30% [24]. In general, patients who achieve BASDAI50 are also likely to achieve ASAS40 response because of overlap of domains, which are assessed by these two measures. Over the years, several instruments, such as the Stoke Ankylosing Spondylitis Spine Score (SASSS), the Bath Ankylosing Spondylitis Radiology Index (BASRI) and the modified SASSS (mSASSS), have been evaluated to measure structural damage in AS on plain radiographs. A detailed analysis of these instruments showed the mSASSS to be the most appropriate instrument to assess change [25]. Therefore, in recent clinical trials, the mSASSS was usually applied. In all three instruments, the
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thoracic part of the spine is not included because of technical concerns related to superimposition of the lungs. Excluding the thoracic spine may be considered as a true disadvantage because MRI studies have shown that most of the inflammation takes place in the thoracic spine, and, therefore, most of the damage could be expected in that region [26]. This is even more important given the relatively low rate of progression of structural damage in AS (only w30% of patients have a detectable change after 2 years). To overcome this shortcoming, a recently proposed instrument captures the lower spine from T10 to T12, thereby aiming to increase sensitivity to change [27]. Progression of structural damage in the anti-TNF era Magnetic resonance imaging (MRI) is currently used not only to facilitate early diagnosis [28,29], but also to monitor the course of inflammation in AS. In several controlled clinical trials using the antiTNF agents infliximab, etanercept or adalimumab, serial MRI scans have been performed over time, most of the time imaging the spine. A dramatic improvement of active inflammatory lesions in the spine by up to 80% after 6–24 months of anti-TNF therapy could be observed [30–33]. These findings have raised expectations that once spinal inflammation disappears during anti-TNF therapy, bony ankylosis may also be prevented. In 2-year follow-up studies using all three anti-TNF agents, however, no clear indication of such inhibitory effect of anti-TNF therapy on bony ankylosis could be detected [31–33]. In fact, there seemed to be no difference in the rate of progression between anti-TNF-treated patients and patients from an observational cohort receiving conventional NSAIDs treatment (mean rate of progression of 0.8–1.0 mSASSS points in all groups). Even after adjustment for disease activity at baseline, no significant effect was detectable. Thus, the question was posed as to how inflammation and bone formation are related to each other, particularly in the light of data from animal models suggesting a disconnect between inflammation and bone formation [34]. Subsequent studies have compared MRI findings at baseline with radiographic progression after 2 years. Interestingly, these studies revealed that new syndesmophytes did arise about three times more often at sites where active inflammation was present at baseline. However, the majority of syndesmophytes arose from sites without detectable inflammation on MRI at baseline[35–37] (Table 1). Interestingly, in one[36] but not in another[35] of these studies, it was found that new syndesmophytes occurred mainly at sites where previous active inflammation has completely resolved, but rarely at sites with persistent inflammation. However, the absolute numbers for the latter analysis were small and more data are needed. Nonetheless, these data suggest that inflammation and bone formation are linked to at least some extent. Apart from issues such as appropriateness of the instruments to measure damage (see above) and the low progression rate in AS in general, it may well be that periods longer than 2 years are needed to detect an inhibitory effect of anti-TNF therapy on radiographic progression. An alternative explanation for the findings is that, although the inhibitory effect of anti-TNF agents on inflammation on MRI is substantial (reduction by around 80%), the Table 1 Summary of available data (ref. [35–37]) showing the relation of new syndesmophyte formation after 2 years and inflammation on MRI at baseline. Study population size
MRI status at baseline
New syndesmophytes after 2 years
Odds Ratio
Reference
N ¼ 39
Inflammation (MRI) at baseline No Inflammation (MRI) at baseline
6.5% (10/153) 2.1% (16/769)
3.3
Baraliakos et al. (ref. [35])
N ¼ 29a
Inflammation (MRI) at baseline No Inflammation (MRI) at baseline Inflammation (MRI) at baseline No Inflammation (MRI) at baseline
20% (6/30)b 5.1% (19/370) 14.3% (4/28)b 2.9% (19/617)
4.6
Maksymowych et al. (ref. [36])
Inflammation (MRI) at baseline No Inflammation (MRI) at baseline
10.8% (35/320)d 6.8% (113/1650)
1.6
N ¼ 41c N ¼ 182 a b c d
5.3 van der Heijde et al. (ref. [37])
Cohort 1 in reference [36]; patients treated as part of a randomized controlled trial. Among several reader pairs described in reference [36], only data from reader pair WPM and RGWL is shown in this table. Cohort 2 in reference [36]: patients from an observational cohort. Among two readers described in reference [37] only data from reader 1 is shown in this table.
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inflammation is not yet completely suppressed, allowing low-grade or intermittently occurring inflammation to provide sufficient stimulus for forming new syndesmophytes. Moreover, it may well be that the repair mechanisms, which take place once inflammation abates, are simply exaggerated in AS in comparison to healthy individuals. If this is the case, the question arises whether such repair processes are self-limiting after a certain time or perpetuate themselves [23,38,39]. In the light of data showing no effect on bony proliferation after 2 years of anti-TNF therapy, it is interesting to note that continuous (daily) therapy with NSAIDs seems to retard new bone formation. Such an inhibitory effect of continuous NSAID therapy as compared to on-demand use of NSAIDs has already been suggested from an early observation using phenylbutazone [40], and has recently been reported from a randomised control trial with celecoxib [41]. Further clinical support for an inhibitory effect also comes from surgery: NSAIDs are often given to patients after total hip replacement not only for analgesia but also for the prevention of unwanted ossification. The inhibitory effect of NSAIDs on bone metabolism seems to be related to prostaglandins, which are involved in bone homeostasis as outlined above [42]. If the effect of NSAID on bony proliferation can be confirmed in further trials, it may well be that, in the future, potent anti-inflammatory agents such as TNF blockers will be combined with NSAIDs to suppress inflammation, which is causing pain and other symptoms, and to prevent exaggerated bone repair. Stopping disease progression versus preventing progression of disability Improvement in signs and symptoms is a central goal in the treatment of AS patients. Due to an improvement in conventional and modern anti-rheumatic drug therapy, which includes both NSAIDs and TNF blockers, this goal can often be reached in patients with AS. Reduction of inflammation is pivotal in the management as it triggers pain and stiffness, which reduces physical function in AS patients and impairs quality of life. Disability in rheumatic diseases generally refers to impaired physical function and low quality of life. Importantly, current anti-rheumatic drug therapy, in particular TNF blockade, leads to an improvement in key clinical activity measures of AS, such as back pain, peripheral arthritis and enthesitis, acute phase responses, flares of uveitis, disturbed sleep and overall quality of life, in the majority of patients, despite the fact that new bone formation is not affected and syndesmophyte growth is not arrested or even reversed. This observation suggests that in a substantial proportion of AS patients bony overgrowth is not the key component driving impaired physical function of poor quality of life, but that the health outcome in AS is rather strongly influenced by inflammation itself. The dramatic improvement of back pain and stiffness also improves spinal mobility to some extent and allows the patient to better perform exercises. Thus, by targeting disease activity (inflammation), anti-TNF therapy greatly improves physical function as well, even in patients with advanced ankylosis of the spine, as a recent large open study has demonstrated [43]. Given these treatment benefits, a critical yet unanswered question is how clinically important is the prevention of structural damage to the individual patient in the long run? At times of active disease, the improvement of signs and symptoms, and increments in quality of life, which allow the patient to work and to have a normal life again, is certainly of utmost importance to many patients and may outweigh the lack of an effect of anti-TNF agents on syndesmophyte formation [44]. Still, bony overgrowth cannot be regarded as a physiological process even if we consider it as a repair process. Do molecular mechanisms involved in bony overgrowth provide a clue to stop structural progression in AS patients? Repair of micro- or macro-damage normally leads to reconstitution of the original architecture of bone but not in bony overgrowth. Thus, selective inhibition of bony overgrowth and ankylosis without interfering with physiological repair processes can be considered as an interesting strategy to improve current treatment of AS. The key hurdle to overcome is to dissect the signals, which lead to syndesmophyte growth from those relevant to bone formation and physiological bone repair in general. Such molecular targets would need to be specifically expressed in a bony spur but not in other parts of the skeleton, including the growth plate and fracture callus. In the absence of such specificity, therapeutic interventions retarding bone formation may be associated with considerable side effects such as
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osteoporosis, increased fracture risk and impaired fracture healing. Such considerations apply both to strategies to inhibit BMPs, since recombinant BMPs are used to support fracture healing, as well as those enhancing the activity of Wnt antagonists such as Dkk-1 and sclerostin, targeting of which is currently considered as an attractive tool to enhance bone mass in osteoporosis patients [45,46]. Apart from specific interventions to block bony overgrowth in AS, intervention aiming to neutralise the triggers for the exaggerated bone response may represent a strategy, which is more easy to accomplish. If we consider the hypothesis that bony overgrowth in AS is driven by inflammation, rapid and persistent control of inflammation early in disease process may be a strategy, which could prevent bony overgrowth. Such a strategy needs to be started before the molecular switch to an anabolic bone response has occurred. Recent studies suggest that a destructive phase of arthritis is not necessary for triggering bony overgrowth and that even in absence of bone erosions and osteoclasts, bony spurs can emerge [47]. This observation clearly points to inflammation as the main trigger for anabolic bone responses in AS and suggests that rapid control of inflammation in the early phase of disease could prevent structural damage. Ideally, persistent remission of bone marrow lesions in the vertebral bodies as well as in sacral and iliac bone provides the key prerequisites for no further bone apposition at these skeletal sites. Combination of NSAIDs, which not only inhibit inflammation but also suppress bone formation by interfering with osteoblast differentiation, as well as TNF blockers, which are potent inhibitors of axial inflammation in AS, could offer a treatment strategy, which could strongly inhibit bony overgrowth in AS, if used early in the disease process. In summary, bony overgrowth is a hallmark of AS and a major therapeutic challenge. Despite the fact that bony overgrowth can be considered as a kind of active ‘response-to-injury’ process rather than passive bone destruction because of inflammation, this process is inadequate and not physiological [23,39]. Thus, prevention of bony overgrowth can be considered as a therapeutic goal in the treatment of AS. Rapid and effective control of inflammation appears the best preventive strategy to protect from bony overgrowth. In principle, specific drug therapy also, which selectively targets the anabolic pathways involved in bony spur formation, appears possible. However, targets allowing dissecting physiological bone formation from bony spur formation remain to be identified.
Bullet points- Clinical practice Structural changes in AS reflect a pathologically enhanced repair response of bone rather than bone damage. Bone apposition leading to ankylosis is found in diarthrodial joints such as facet and SI joints as well as at the insertion sites of the ligaments (syndesmophytes) and the tendons (enthesiophytes). The modified SASSS is the most appropriate instrument to quantitatively assess structural damage in AS. Functional disability in AS results from spinal inflammation as well as structural damage. TNF blockers improve the signs and symptoms in AS but do not retard new bone formation.
Bullet points- Research agenda Better definition of the temporal relation between inflammation and anabolic bone responses in AS. Definition of biomarkers and risk predictors for bony spur formation in AS. Identification of molecules triggering mesenchymal cell proliferation, osteoblast differentiation and periosteal bone formation in AS. Definition of strategies to selectively inhibit bone apposition in experimental models of ankylosis and their translation to human disease.
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Acknowledgements GS’ work is supported by the Deutsche Forschungsgemeinschaft DFG (SFB643, SPP1468, FOR661), the Bundesministerium fu¨r Forschung und Bildung BMBF (project ANKYLOSS), the European Union projects Masterswitch, Kinacept and Adipoa, the Interdisziplina¨res Zentrum fu¨r Klinische Forschung Erlangen and the Spondyloarthritis Immunology Reserach Alliance (SpIRAL). References [1] Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis: an overview. Annals of the Rheumatic Diseases 2002 Dec; 61(Suppl. 3):iii8–18. [2] Cruickshank B. Lesions of cartilaginous joints in ankylosing spondylitis. The Journal of Pathology and Bacteriology 1956 Jan;71(1):73–84. [3] Samoto H, Shimizu E, Matsuda-Honjyo Y, et al. Prostaglandin E2 stimulates bone sialoprotein (BSP) expression through cAMP and fibroblast growth factor 2 response elements in the proximal promoter of the rat BSP gene. 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[27] Rudwaleit M, van der Heijde D, Khan MA, et al. How to diagnose axial spondyloarthritis early. Annals of the Rheumatic Diseases 2004 May;63(5):535–43. [28] Sieper J, Baraliakos X, Listing J, et al. Persistent reduction of spinal inflammation as assessed by magnetic resonance imaging in patients with ankylosing spondylitis after 2 yrs of treatment with the anti-tumour necrosis factor agent infliximab. Rheumatology (Oxford) 2005 Dec;44(12):1525–30. [29] Braun J, Landewe´ R, Hermann KG, et al. ASSERT Study Group. Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicenter, randomized, double-blind, placebocontrolled magnetic resonance imaging study. Arthritis and Rheumatism 2006 May;54(5):1646–52. [30] Lambert RG, Salonen D, Rahman P, et al. Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis and Rheumatism 2007 Dec;56(12):4005–14. [31] van der Heijde D, Landewe´ R, Einstein S, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis and Rheumatism 2008 May;58(5):1324–31. *[32] van der Heijde D, Landewe´ R, Baraliakos X, et al. Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy Study Group. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis and Rheumatism 2008 Oct;58(10):3063–70. [33] van der Heijde D, Salonen D, Weissman BN, et al. Canadian (M03-606) study group; ATLAS study group. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Research & Therapy 2009;11(4):R127. *[34] Lories RJ, Derese I, de Bari C, et al. Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis. Arthritis and Rheumatism 2007 Feb;56(2):489–97. [35] Baraliakos X, Listing J, Rudwaleit M, et al. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Research & Therapy 2008;10(5):R104. *[36] Maksymowych WP, Chiowchanwisawakit P, Clare T, et al. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis and Rheumatism 2009 Jan;60(1):93–102. [37] van der Heijde D, Landewe R, Baraliakos X, et al. MRI-inflammation of the vertebral unit (VU) only marginally contributes to new syndesmopyhte formation in that unit: a multi-level-analysis. Annals of the Rheumatic Diseases 2008;67(Suppl. II):130. [38] Appel H, Rudwaleit M, Sieper J. Relevance of osteoproliferation as an outcome parameter in ankylosing spondylitis. Nature Clinical Practice. Rheumatology 2008 Nov;4(11):578–9. [39] Schett G, Landewe´ R, Desiree van der Heijde D. TNF blockers and structural remodeling in ankylosing spondylitis- what is reality and what is fiction? Annals of the Rheumatic Diseases 2007;66:709–11. [40] Boersma JW. Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone. Scandinavian Journal of Rheumatology 1976;5(1):60–4. *[41] Wanders A, Heijde D, Landewe´ R, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis and Rheumatism 2005 Jun;52(6):1756–65. [42] Vuolteenaho K, Moilanen T, Moilanen E. Non-steroidal anti-inflammatory drugs, cyclooxygenase-2 and the bone healing process. Basic & Clinical pharmacology & Toxicology 2008 Jan;102(1):10–4. [43] Rudwaleit M, Olivieri I, Boki KA, et al. Adalimumab is effective and well tolerated in treating patients with ankylosing spondylitis who have advanced spinal fusion. Rheumatology (Oxford) 2009 May;48(5):551–7. [44] Braun J, Sieper J. What is the most important outcome parameter in ankylosing spondylitis? Rheumatology (Oxford) 2008 Dec;47(12):1738–40. [45] Govender S, Csimma C, Genant HK, et al. BMP-2 Evaluation in Surgery for Tibial Trauma (BESTT) Study Group. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. The Journal of Bone and Joint Surgery. American Volume 2002 Dec; 84-A(12):2123–34. [46] Li X, Ominsky MS, Warmington KS, et al. Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. Journal of Bone and Mineral Research. 2009 Apr;24(4):578–88. [47] Schett G, Stolina M, Dwyer D, et al. Tumor necrosis factor alpha and RANKL blockade cannot halt bony spur formation in experimental inflammatory arthritis. Arthritis and Rheumatism 2009 Sep;60(9):2644–54.
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6
Can we stop progression of ankylosing spondylitis? Georg Schett, MD, Professor of Medicine, Chair of Rheumatology and Immunology a, *, Martin Rudwaleit, MD, Professor of Medicine b a b
Department of Internal Medicine 3, University of Erlangen-Nuremberg, Krankenhausstrasse 12, D-91054 Erlangen, Germany Department of Internal Medicine I, Charite´ University, Campus Benjamin Franklin, Berlin, Germany
Keywords: ankylosis syndesmophyte bone formation structural progression
Ankylosing spondylitis is characterised by inflammation of the spine and the entheses followed by bone formation. Excessive bone formation in ankylosing spondylitis leads to the formation of bone spurs, such as syndesmophytes and enthesiophytes, which contribute to ankylosis of joints and poor physical function. This process is based on increased differentiation of osteoblasts from their mesenchymal precursors, which allows to rapidly build up new bone. Prostaglandins, bone morphogenic proteins and Wnt proteins play an essential role in this process. By contrast, tumour necrosis factor (TNF) does not appear to be the direct trigger for osteophyte formation in ankylosing spondylitis. The article reviews the current knowledge regarding the mechanisms and clinical role of ankylosis and explains strategies on how to prevent it in patients with ankylosing spondylitis. Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Introduction Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease of unknown origin affecting the axial skeleton including the sacroiliac (SI) joints and the spine and also the peripheral joints and the entheses [1]. Since AS usually starts in the third decade, it affects people for most of their life. AS has a strong genetic component, with HLA-B27 being the most relevant gene. Clinically, pain and stiffness in the back are the leading complaints. In addition, the patient may suffer from peripheral joint pain or enthesitis, typically of the heel, or from bouts of uveitis. With time, bony ankylosis of the SI joints and the spine develops in many patients. Bony ankylosis at the spine may affect the vertebral bodies (syndesmophyte formation) as well as the facet, the zygapophyseal and the costovertebral joints. It is
* Corresponding author. Tel.: þ49 9131 8539131; Fax: þ49 9131 8534770. E-mail address: [email protected] (M. Schett). 1521-6942/$ – see front matter Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2010.01.005
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particularly spinal ankylosis, which results in loss of spinal mobility and changes in posture such as the development of thoracic kyphosis and irreversible stiffness. In a large proportion of patients, the disease course in AS that runs is fluctuating with not only periods of flares but also periods of remission or low disease activity. Some patients, however, suffer from persistently high disease activity. Excessive bone apposition in AS Bony overgrowth in AS has traditionally been considered as a structural damage arising from chronic immune activation and inflammation. In contrast to rheumatoid arthritis, where structural changes are of primarily catabolic nature, resulting in a net loss of bone substance in the vicinity of joints, structural changes in AS are dominated by anabolic processes. Bony spur formation, which arises from the cortical bone surface, is a common feature of AS and virtually affects all skeletal compartments that show disease morbidity. In the case of the vertebral column, such lesions are termed ‘syndesmophytes’. These lesions grow usually in a vertical orientation and are bridging vertebral bodies, and are formed by apposition of new bone along the edges of the vertebral bodies and subsequent loss of the intervertebral spaces [2]. When several consecutive vertebrae are affected, it may lead to the appearance of a ‘bamboo spine’. In particular, the insertion sites of the tendons are hot spots of bone apposition in AS and also affect peripheral compartments such as the Achilles tendon or the plantar fascia, resulting in the formation of bony spurs, then termed ‘enthesiophytes’. Moreover, inflammation of the SI joints, the small joints of the spine, such as the facet joints, as well as occasionally the peripheral joints leads to bony appositions followed by ankylosis in patients with AS. Bony spur formation and ankylosis is pathognomonic for AS, progressively limiting the range of motion of patients and leading to functional impairment. This bone anabolic process does not randomly affect intervertebral spaces and joints but is limited to certain predilection sites. Although the prerequisite for bony spur formation is not completely understood, it is likely that both mechanical and inflammatory components of the disease locally trigger increased bone formation. In the case of mechanical components, the fact that these lesions are often found along the insertion sights of the tendons points to a key role of mechanical stress. On the other hand, inflammatory lesions in the neighbouring bone marrow (osteitis) are considered as a risk factor for syndesmophyte formation, although this association is not complete and bony spurs can also be found at sites where no osteitis is seen and vice versa. The notion, however, that mechanical and inflammatory triggers can induce bony overgrowth has suggested that these lesions might represent a ‘response-to-stress mechanism’ and a type of active repair strategy of the joint rather than damage arising from inflammation. Cellular and molecular mechanisms of bone formation in AS A better insight into the molecular regulation of new bone formation is key for defining the optimal intervention strategies to retard or block bony ankylosis in patients with AS. Ankylosis in AS is based on the apposition of new bone along periosteal skeletal sites requiring differentiation of osteoblasts, which are the bone-forming cells. Osteoblasts develop from mesenchymal cell precursor cells, which cover the inactive periosteal bone surface. Growth as well as injury, such as observed during inflammation and also in case of fracture, lead to an activation of the periosteal bone surface and differentiation of osteoblasts, which allow to build up new bone. Osteoblasts synthesise bone matrix, which consists of numerous proteins, the most abundant of which are collagen type I and osteocalcin. Bone formation and ankylosis in AS depends on molecular signals, which regulate differentiation and activity of osteoblasts. Several mediators are of importance for osteoblast differentiation: prostaglandins, such as PGE2, are important local factors; PGE2 has anabolic effects on bone and promotes proliferation and differentiation of osteoblasts, thereby inducing the expression of bone sialoprotein and alkaline phosphatase [3]. Moreover, PGE2 can synergise with bone morphogenic protein (BMP)-2, a member of the TGF/BMP protein family in inducing bone formation [4]. Members of the BMP family, that is, BMP-2, -3 and -7, play a critical role in osteoblast differentiation and induce signalling through Smad proteins upon engaging respective surface receptors on mesenchymal cells [5]. Activation of intracellular Smad signalling indicates an increased activity of BMPs and this process occurs during enthesiophyte formation in AS [6]. Bone anabolic effects of BMPs can be antagonised by noggin,
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a natural inhibitor of BMP. Haploinsufficiency of noggin enhances BMP activity and has been shown to lead to ankylosis of joints. Wnt proteins have also been identified as potent inducers of new bone formation. Wnt proteins bind to a receptor/co-receptor complex on the plasma membrane, which consists of LRP5/6 and Frizzled proteins. Engagement of this receptor complex by Wnt proteins leads to phosphorylation of beta-catenin, which translocates to the nucleus and induces transcription of genes involved in osteoblast differentiation and bone formation [7]. Increased activity of beta-catenin as a surrogate marker for Wnt activation has been observed in bony spur formation, suggesting that Wnt proteins may indeed contribute to new bone formation and ankylosis of joints. Natural inhibitors of Wnt such as Dkk-1 and sclerostin neutralise Wnt activity and actively prevent new bone formation [7,8]. These proteins have shown to be differentially expressed in diseases such as rheumatoid arthritis and AS, with high expression in the former but low expression in the latter disease [9–11]. It is highly likely that inflammation initiates the process of ankylosis in AS. Thus, AS does not represent a disease manifesting with ankylosis per se or where ankylosis is purely driven by a mechanical trigger, but rather reflects diseases, where a chronic inflammatory process in the spine results in ankylosis. This observation implies that inflammation is molecularly linked to ankylosis and that inflammation triggers the process of new bone formation. One of the key inflammatory cytokines involved in AS, tumour necrosis factor (TNF), however, does not induce but rather inhibits bone formation. TNF is a potent inducer of proteins such as Dkk-1 and sclerostin and thus down-regulates bone formation [9,12,13]. It is yet unclear why periosteal bone apposition can still occur in AS patients despite TNF playing a central role in the inflammatory processes of this disease. Importantly, there is a striking difference between cortical bone and trabecular bone in AS: whereas trabecular bone mass decreases and leads to vertebral osteoporosis and increased fracture risk in AS patients, specific sites of the cortical bone start to proliferate and expand [14]. It can be hypothesised that the skeletal effects of TNF, which are down-regulation of bone formation plus enhancement of bone resorption, are reflected by systemic bone loss in the trabecular bone compartment, whereas cortical bone apposition is not linked to the expression of TNF itself. As TNF is not the key trigger for new bone formation in AS, one can hypothesise that other inflammatory mediators drive new bone formation and ankylosis in AS. Classical pro-inflammatory pathways such as interleukin (IL)-1 and IL-17 as well as signalling through the IL-6R/gp130 complex, however, exert negative rather than positive net effects on bone mass, supporting the notion that inflammation and immune activation exert a negative effect on bone formation and promote bone loss rather than bone apposition Fig. 1. These three groups of molecules, PGE2, BMP proteins and Wnt proteins manage differentiation of mesenchymal precursor cells into bone-forming osteoblasts. This differentiation process is accompanied by the expression of key transcription factors, such as Cbfa1 and Osterix, which are important for inducing osteoblast-specific genes. It is yet unclear whether bony-spur formation (osteophytes sensu lato) along peripheral joints (osteophytes sensu strictu), insertion sites of the tendons (enthesiophytes) and along the vertebral bodies (spondylophytes, syndesmophytes) follows similar molecular pathways. There are principally two pathways known to be relevant for bone formation: one is endochondral ossification and the other is membranous bone formation, including chondroidal metaplasia. Studies in humans and mice have shown morphological features of hypertrophic chondrocytes as a sign of endochondral bone formation in axial and peripheral joints [10,15]; also, direct evidence for membranous bone formation and chondroidal metaplasia has been obtained, especially at enthesial sites [16]. Instruments used for assessing treatment responses in AS In the past, the cornerstones of treatment in AS have been physiotherapy and non-steroidal antiinflammatory drugs (NSAIDs). The introduction of anti-TNF agents has resulted in therapeutic effects, which were hitherto unknown to patients with active AS, especially those who had suffered from symptoms despite high doses of NSAIDs. With anti-TNF therapy, at least every second patient achieves a good-to-very-good clinical response and 20–25% of patients achieve clinical remission. On the other hand, traditional disease-modifying anti-rheumatic drugs (DMARDs) and low-to-moderate doses of steroids do not have major therapeutic effects on axial disease in AS [17]. For the assessment of disease activity in AS, patient-reported outcomes, such as the Bath ankylosing Spondylitis Disease Activity Index (BASDAI), play a major role. BASDAI captures five disease domains
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Fig. 1. Interaction between Insult, Inflammation and Pathological Repair Processes in Ankylosing Spondylitis. Initial insults triggering the disease process in ankylosing spondylitis are mechanical stimuli eliciting enthesitis and inflammatory triggers associated with osteitis. Inflammation fuelled by inflammatory cytokines such as TNF, IL-6 and IL-17 gradually decreases in ankylosing spondylitis. At a certain point of time repair processes are initiated (Inflammation/Repair switch) which start to a perpetuating bone anabolic response driven by prostaglandins, Wnt and BMP proteins. In case of chronically persisting inflammation and the establishment of synovitis destructive bone-erosive processes dominate and prevent repair responses.
(fatigue, back pain, pain in other joints, enthesitis and morning stiffness). Each domain is assessed on a scale from 0 to 10 (or 0–100) and the average of the five domains gives the overall BASDAI score [18]. In general, a BASDAI score higher than 4 is considered to indicate active disease. BASDAI has been used in many clinical trials over the past years and has been proven to be reproducible and sensitive to change. A new composite measure of disease activity in AS is the ankylosing spondylitis disease activity score (ASDAS), which is currently being evaluated [19,20]. For measuring response to treatment in AS, absolute changes in BASDAI or, alternatively, certain cut-offs of relative improvement such as BASDAI 50 (50% improvement in BASDAI) have been used in clinical trials. Other well-established response measures are the Assessment of SpondyloArthritis international Society (ASAS) response criteria such as ASAS20, ASAS40 or ASAS partial remission [21,22]. These response criteria are composite indices comprising the four domains – morning stiffness, patient global, total pain and function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). To achieve ASAS20, an improvement of at least 20% in at least three out of the four domains, without worsening in the potentially remaining fourth domain, is required. Accordingly, ASAS40 requires an improvement by at least 40%, while ASAS partial remission defines a state of very low disease activity with all domains having absolute values of 2. The ASAS20 response measure has been developed specifically for typical NSAID trials in AS with up to 50% of NSAID-treated AS patients reaching ASAS20 [23]. For comparison, in AS patients, who have active disease despite NSAIDs (typical anti-TNF trials), an ASAS20 response is reached by 60–70% of patients, an ASAS40 by as many as 40–50% and ASAS partial remission by 20–30% [24]. In general, patients who achieve BASDAI50 are also likely to achieve ASAS40 response because of overlap of domains, which are assessed by these two measures. Over the years, several instruments, such as the Stoke Ankylosing Spondylitis Spine Score (SASSS), the Bath Ankylosing Spondylitis Radiology Index (BASRI) and the modified SASSS (mSASSS), have been evaluated to measure structural damage in AS on plain radiographs. A detailed analysis of these instruments showed the mSASSS to be the most appropriate instrument to assess change [25]. Therefore, in recent clinical trials, the mSASSS was usually applied. In all three instruments, the
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thoracic part of the spine is not included because of technical concerns related to superimposition of the lungs. Excluding the thoracic spine may be considered as a true disadvantage because MRI studies have shown that most of the inflammation takes place in the thoracic spine, and, therefore, most of the damage could be expected in that region [26]. This is even more important given the relatively low rate of progression of structural damage in AS (only w30% of patients have a detectable change after 2 years). To overcome this shortcoming, a recently proposed instrument captures the lower spine from T10 to T12, thereby aiming to increase sensitivity to change [27]. Progression of structural damage in the anti-TNF era Magnetic resonance imaging (MRI) is currently used not only to facilitate early diagnosis [28,29], but also to monitor the course of inflammation in AS. In several controlled clinical trials using the antiTNF agents infliximab, etanercept or adalimumab, serial MRI scans have been performed over time, most of the time imaging the spine. A dramatic improvement of active inflammatory lesions in the spine by up to 80% after 6–24 months of anti-TNF therapy could be observed [30–33]. These findings have raised expectations that once spinal inflammation disappears during anti-TNF therapy, bony ankylosis may also be prevented. In 2-year follow-up studies using all three anti-TNF agents, however, no clear indication of such inhibitory effect of anti-TNF therapy on bony ankylosis could be detected [31–33]. In fact, there seemed to be no difference in the rate of progression between anti-TNF-treated patients and patients from an observational cohort receiving conventional NSAIDs treatment (mean rate of progression of 0.8–1.0 mSASSS points in all groups). Even after adjustment for disease activity at baseline, no significant effect was detectable. Thus, the question was posed as to how inflammation and bone formation are related to each other, particularly in the light of data from animal models suggesting a disconnect between inflammation and bone formation [34]. Subsequent studies have compared MRI findings at baseline with radiographic progression after 2 years. Interestingly, these studies revealed that new syndesmophytes did arise about three times more often at sites where active inflammation was present at baseline. However, the majority of syndesmophytes arose from sites without detectable inflammation on MRI at baseline[35–37] (Table 1). Interestingly, in one[36] but not in another[35] of these studies, it was found that new syndesmophytes occurred mainly at sites where previous active inflammation has completely resolved, but rarely at sites with persistent inflammation. However, the absolute numbers for the latter analysis were small and more data are needed. Nonetheless, these data suggest that inflammation and bone formation are linked to at least some extent. Apart from issues such as appropriateness of the instruments to measure damage (see above) and the low progression rate in AS in general, it may well be that periods longer than 2 years are needed to detect an inhibitory effect of anti-TNF therapy on radiographic progression. An alternative explanation for the findings is that, although the inhibitory effect of anti-TNF agents on inflammation on MRI is substantial (reduction by around 80%), the Table 1 Summary of available data (ref. [35–37]) showing the relation of new syndesmophyte formation after 2 years and inflammation on MRI at baseline. Study population size
MRI status at baseline
New syndesmophytes after 2 years
Odds Ratio
Reference
N ¼ 39
Inflammation (MRI) at baseline No Inflammation (MRI) at baseline
6.5% (10/153) 2.1% (16/769)
3.3
Baraliakos et al. (ref. [35])
N ¼ 29a
Inflammation (MRI) at baseline No Inflammation (MRI) at baseline Inflammation (MRI) at baseline No Inflammation (MRI) at baseline
20% (6/30)b 5.1% (19/370) 14.3% (4/28)b 2.9% (19/617)
4.6
Maksymowych et al. (ref. [36])
Inflammation (MRI) at baseline No Inflammation (MRI) at baseline
10.8% (35/320)d 6.8% (113/1650)
1.6
N ¼ 41c N ¼ 182 a b c d
5.3 van der Heijde et al. (ref. [37])
Cohort 1 in reference [36]; patients treated as part of a randomized controlled trial. Among several reader pairs described in reference [36], only data from reader pair WPM and RGWL is shown in this table. Cohort 2 in reference [36]: patients from an observational cohort. Among two readers described in reference [37] only data from reader 1 is shown in this table.
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inflammation is not yet completely suppressed, allowing low-grade or intermittently occurring inflammation to provide sufficient stimulus for forming new syndesmophytes. Moreover, it may well be that the repair mechanisms, which take place once inflammation abates, are simply exaggerated in AS in comparison to healthy individuals. If this is the case, the question arises whether such repair processes are self-limiting after a certain time or perpetuate themselves [23,38,39]. In the light of data showing no effect on bony proliferation after 2 years of anti-TNF therapy, it is interesting to note that continuous (daily) therapy with NSAIDs seems to retard new bone formation. Such an inhibitory effect of continuous NSAID therapy as compared to on-demand use of NSAIDs has already been suggested from an early observation using phenylbutazone [40], and has recently been reported from a randomised control trial with celecoxib [41]. Further clinical support for an inhibitory effect also comes from surgery: NSAIDs are often given to patients after total hip replacement not only for analgesia but also for the prevention of unwanted ossification. The inhibitory effect of NSAIDs on bone metabolism seems to be related to prostaglandins, which are involved in bone homeostasis as outlined above [42]. If the effect of NSAID on bony proliferation can be confirmed in further trials, it may well be that, in the future, potent anti-inflammatory agents such as TNF blockers will be combined with NSAIDs to suppress inflammation, which is causing pain and other symptoms, and to prevent exaggerated bone repair. Stopping disease progression versus preventing progression of disability Improvement in signs and symptoms is a central goal in the treatment of AS patients. Due to an improvement in conventional and modern anti-rheumatic drug therapy, which includes both NSAIDs and TNF blockers, this goal can often be reached in patients with AS. Reduction of inflammation is pivotal in the management as it triggers pain and stiffness, which reduces physical function in AS patients and impairs quality of life. Disability in rheumatic diseases generally refers to impaired physical function and low quality of life. Importantly, current anti-rheumatic drug therapy, in particular TNF blockade, leads to an improvement in key clinical activity measures of AS, such as back pain, peripheral arthritis and enthesitis, acute phase responses, flares of uveitis, disturbed sleep and overall quality of life, in the majority of patients, despite the fact that new bone formation is not affected and syndesmophyte growth is not arrested or even reversed. This observation suggests that in a substantial proportion of AS patients bony overgrowth is not the key component driving impaired physical function of poor quality of life, but that the health outcome in AS is rather strongly influenced by inflammation itself. The dramatic improvement of back pain and stiffness also improves spinal mobility to some extent and allows the patient to better perform exercises. Thus, by targeting disease activity (inflammation), anti-TNF therapy greatly improves physical function as well, even in patients with advanced ankylosis of the spine, as a recent large open study has demonstrated [43]. Given these treatment benefits, a critical yet unanswered question is how clinically important is the prevention of structural damage to the individual patient in the long run? At times of active disease, the improvement of signs and symptoms, and increments in quality of life, which allow the patient to work and to have a normal life again, is certainly of utmost importance to many patients and may outweigh the lack of an effect of anti-TNF agents on syndesmophyte formation [44]. Still, bony overgrowth cannot be regarded as a physiological process even if we consider it as a repair process. Do molecular mechanisms involved in bony overgrowth provide a clue to stop structural progression in AS patients? Repair of micro- or macro-damage normally leads to reconstitution of the original architecture of bone but not in bony overgrowth. Thus, selective inhibition of bony overgrowth and ankylosis without interfering with physiological repair processes can be considered as an interesting strategy to improve current treatment of AS. The key hurdle to overcome is to dissect the signals, which lead to syndesmophyte growth from those relevant to bone formation and physiological bone repair in general. Such molecular targets would need to be specifically expressed in a bony spur but not in other parts of the skeleton, including the growth plate and fracture callus. In the absence of such specificity, therapeutic interventions retarding bone formation may be associated with considerable side effects such as
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osteoporosis, increased fracture risk and impaired fracture healing. Such considerations apply both to strategies to inhibit BMPs, since recombinant BMPs are used to support fracture healing, as well as those enhancing the activity of Wnt antagonists such as Dkk-1 and sclerostin, targeting of which is currently considered as an attractive tool to enhance bone mass in osteoporosis patients [45,46]. Apart from specific interventions to block bony overgrowth in AS, intervention aiming to neutralise the triggers for the exaggerated bone response may represent a strategy, which is more easy to accomplish. If we consider the hypothesis that bony overgrowth in AS is driven by inflammation, rapid and persistent control of inflammation early in disease process may be a strategy, which could prevent bony overgrowth. Such a strategy needs to be started before the molecular switch to an anabolic bone response has occurred. Recent studies suggest that a destructive phase of arthritis is not necessary for triggering bony overgrowth and that even in absence of bone erosions and osteoclasts, bony spurs can emerge [47]. This observation clearly points to inflammation as the main trigger for anabolic bone responses in AS and suggests that rapid control of inflammation in the early phase of disease could prevent structural damage. Ideally, persistent remission of bone marrow lesions in the vertebral bodies as well as in sacral and iliac bone provides the key prerequisites for no further bone apposition at these skeletal sites. Combination of NSAIDs, which not only inhibit inflammation but also suppress bone formation by interfering with osteoblast differentiation, as well as TNF blockers, which are potent inhibitors of axial inflammation in AS, could offer a treatment strategy, which could strongly inhibit bony overgrowth in AS, if used early in the disease process. In summary, bony overgrowth is a hallmark of AS and a major therapeutic challenge. Despite the fact that bony overgrowth can be considered as a kind of active ‘response-to-injury’ process rather than passive bone destruction because of inflammation, this process is inadequate and not physiological [23,39]. Thus, prevention of bony overgrowth can be considered as a therapeutic goal in the treatment of AS. Rapid and effective control of inflammation appears the best preventive strategy to protect from bony overgrowth. In principle, specific drug therapy also, which selectively targets the anabolic pathways involved in bony spur formation, appears possible. However, targets allowing dissecting physiological bone formation from bony spur formation remain to be identified.
Bullet points- Clinical practice Structural changes in AS reflect a pathologically enhanced repair response of bone rather than bone damage. Bone apposition leading to ankylosis is found in diarthrodial joints such as facet and SI joints as well as at the insertion sites of the ligaments (syndesmophytes) and the tendons (enthesiophytes). The modified SASSS is the most appropriate instrument to quantitatively assess structural damage in AS. Functional disability in AS results from spinal inflammation as well as structural damage. TNF blockers improve the signs and symptoms in AS but do not retard new bone formation.
Bullet points- Research agenda Better definition of the temporal relation between inflammation and anabolic bone responses in AS. Definition of biomarkers and risk predictors for bony spur formation in AS. Identification of molecules triggering mesenchymal cell proliferation, osteoblast differentiation and periosteal bone formation in AS. Definition of strategies to selectively inhibit bone apposition in experimental models of ankylosis and their translation to human disease.
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Acknowledgements GS’ work is supported by the Deutsche Forschungsgemeinschaft DFG (SFB643, SPP1468, FOR661), the Bundesministerium fu¨r Forschung und Bildung BMBF (project ANKYLOSS), the European Union projects Masterswitch, Kinacept and Adipoa, the Interdisziplina¨res Zentrum fu¨r Klinische Forschung Erlangen and the Spondyloarthritis Immunology Reserach Alliance (SpIRAL). References [1] Sieper J, Braun J, Rudwaleit M, et al. Ankylosing spondylitis: an overview. Annals of the Rheumatic Diseases 2002 Dec; 61(Suppl. 3):iii8–18. [2] Cruickshank B. Lesions of cartilaginous joints in ankylosing spondylitis. The Journal of Pathology and Bacteriology 1956 Jan;71(1):73–84. [3] Samoto H, Shimizu E, Matsuda-Honjyo Y, et al. Prostaglandin E2 stimulates bone sialoprotein (BSP) expression through cAMP and fibroblast growth factor 2 response elements in the proximal promoter of the rat BSP gene. 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