REVIEW URRENT C OPINION
The effect of tumor necrosis factor-blockade on new bone formation in ankylosing spondylitis: what is the evidence? Nigil Haroon a,b
Purpose of review Treatment of ankylosing spondylitis (AS) has seen remarkable advances since the introduction of therapies targeting tumor necrosis factor-alfa (TNFa). In addition to the excellent disease control achieved by these agents, recent evidence points to a possible disease-modifying potential of the drug. This novel finding can potentially change the landscape of AS treatment. Recent findings In this review, existing knowledge on mechanisms of new bone formation and ways to quantify and prevent progression are discussed. Evidence for disease-modifying potential of NSAIDs, short-term and long-term studies on TNFa inhibitors, and AS progression are discussed. A follow-up of more than 4 years is required to study disease modification in AS. Early and long-term therapy with tumor necrosis factor inhibitors appears to slow radiographic progression in AS. Summary New evidence for a disease-modifying potential of tumor necrosis factor inhibitors can change the AS treatment paradigm. Video abstract http://links.lww.com/COR/A16. Keywords bone spur, disease modifying anti-rheumatic drug, modified Stoke’s ankylosing spondylitis spine score, new bone, syndesmophyte
INTRODUCTION Over the past decade, we have seen several developments in the field of ankylosing spondylitis (AS). Ever since the introduction of tumor necrosis factoralfa (TNFa) inhibitors (TNFi), there have been significant changes in our goals and outcome expectations in the treatment of AS patients. With increasing recognition of this condition and earlier diagnosis, in fact the therapeutic response to TNFi appears to be much better than earlier thought. There are still patients who do not respond to these medications, and we are eagerly awaiting results of ongoing studies targeting other pathogenic pathways in AS. Unlike in rheumatoid arthritis (RA), the field of disease modification has not been well addressed in AS. This is probably due to the lack of strong evidence, until recently, that any form of therapy can indeed change the course of relentless progression in AS. Moreover, there is a fundamental difference
in the way we think of disease modification in AS compared with RA. Compared with RA in which our goal is to prevent erosions, in AS disease modification refers to halting osteoproliferation and spinal fusion. We are still not clear what drives new bone formation and whether there is a clear link to inflammation, contributing to our lack of understanding on disease modification in AS. This review aims to dissect the different pathogenic pathways, potential interventions, and the evidence so far on disease-modifying potential of drugs used in AS. a
Department of Medicine and Rheumatology, University of Toronto and University Health Network, Toronto, Ontario, Canada
b
Correspondence to Dr Nigil Haroon, MD, PhD, DM, 1E-425, 399 Bathurst Street, Toronto Western Hospital, Toronto, ON M5T2S8, Canada. Tel: +1 4166035634; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:389–394 DOI:10.1097/BOR.0000000000000077
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BIOLOGY OF NEW BONE FORMATION IN ANKYLOSING SPONDYLITIS The pathogenesis of new bone formation in AS is not known. It is widely recognized that hypertrophic chondrocytes are present at entheseal sites indicating an endochondral bone formation process, but both endochondral and membranous new bone formation have been implicated [1,2]. The genomewide association studies (GWAS) [3,4] in adults of European descent population have not recognized the involvement of any major bone metabolism pathways. The association of AS with prostaglandin E receptor 4 is interesting, as NSAIDs have been shown in some studies [5,6] to have a possible disease-modifying potential. A GWAS in Chinese AS patients reported novel associations with HAPLN1, EDIL3, and ENO6, and all three could be linked to bone homeostasis through osteoblast or osteoclast influences [7]. The single nucleotide polymorphism (SNP) rs4552569 is adjacent to both HAPLN1 and EDIL3, whereas rs17095830 is located in an intron of ANO6. Another study [8] looking at the antigen presentation pathway found significant association of baseline radiographic severity with proteasome component LMP2 and endoplasmic reticulum aminopeptidase 1 (ERAP1) in univariate analysis and LMP2 alone in multivariate analysis. The exact mechanism of how LMP2 or ERAP1 may affect new bone formation is not clear. Sclerostin (SOST) and DKK1 are antagonists of the Wnt signaling pathway. Wnt signaling pathway is important in osteoblastic activity, and low levels of Wnt antagonists DKK1 and SOST can lead to excess osteoblastic activity. SOST expression is significantly reduced in AS [9]. Blocking DKK1 led to fusion of sacroiliac joints in the tumor necrosis factor-transgenic mice [10]. Low levels of functional DKK1 were associated with progression in AS patients [11]. Similarly, noggin, a BMP-antagonist, led to improvement of ankylosis in the DBA-1 mice, a spontaneous model of arthritis and new bone formation [12]. A direct link of DKK1 or BMP in spinal ankylosis of AS patients is still lacking. The difficulty in studying the target tissue has been the major bottleneck in studies on new bone formation in AS.
INFLAMMATION AND NEW BONE FORMATION Definite proof of inflammation leading to new bone has not been established in AS. One of the strongest predictors of progression of syndesmophytes, as well from nonradiographic axial Spondyloarthritis (nrAxSpA) to AS, was elevated C-Reactive Protein (CRP) at baseline [13]. Vertebral corners with 390
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inflammation at baseline are likely to become syndesmophytes on follow-up [14,15]. However, most syndesmophytes develop from corners with no inflammation documented previously [16]. Does this really mean inflammation is not necessary to kick start the process of new bone formation or is it just reflecting the dynamic nature of MRI inflammation? MRI reflects the state of inflammation at a particular time point and does not tell us if there was inflammation previously. Hence, it is not possible to categorically state that syndesmophytes have developed from corners with no inflammation. To add to the complexity of this scheme, we should consider the effect of entheseal stress, bone damage, and repair. Unfortunately, there is no perfect animal model of spondyloarthritis. In the TNFDARE mouse model, with deregulated tumor necrosis factor production, enthesitis is a dominant feature in addition to intestinal and joint inflammation [17]. Inflammation and erosions appear to be located at anatomically distinct locations and mechanical loading, but no T or B cells appear to driving new bone formation [17]. Steroid treatment or TNFa inhibition does not seem to affect new bone formation in animal models of entheseal new bone formation, although it is questionable how much this is reflective of the process in human disease [18,19]. The role of cytokines in the process of new bone formation is not well understood. Recently, studies conducted on the RA mouse model collagen antibody-induced arthritis revealed significant entheseal inflammation that was driven primarily by interleukin (IL)-23 [20]. Although there was new bone formation associated with enthesitis in this model, IL-22 seemed to be the necessary cytokine for osteoproliferation but not IL-17 or IL-23 [20]. If inflammation is linked to new bone formation, resolution of inflammation should obviate that risk. There is a linear relationship between tumor necrosis factor and DKK1. If tumor necrosis factor drives up DKK1, inhibiting tumor necrosis factor could lead to lower DKK1 that in turn can trigger bone formation. This led to the proposal of a tumor necrosis factor-brake hypothesis, wherein TNFa would act as a brake against new bone formation and TNFi could release this brake [21]. However, an increase in the rate of progression has not been seen in any TNFi studies.
ASSESSING RADIOGRAPHIC PROGRESSION IN ANKYLOSING SPONDYLITIS The most widely used method for assessing radiographic damage and progression in spinal radiographs of AS patients is the modified Stoke’s Volume 26 Number 4 July 2014
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ankylosing spondylitis spine score (mSASSS). On the basis of this system, 24 vertebral corners (anterior corners of cervical and lumbar spine) are graded from the lateral projection for squaring, erosions, sclerosis, syndesmophytes (bone spur), and bridging syndesmophytes (fusion). The scores range from 0 to 3 for each corner and so a patient with bridging syndesmophytes in all corners would have a maximum score of 72. On the basis of this scoring system, the mean rate of progression in AS patients is around 1 mSASSS unit per year [22,23]. There is, however, considerable variability in progression with almost a quarter of patients having no progression at all while some progress at much faster rates [23]. However, those who progress appear to do so in a linear fashion [22]. The other traditional scoring method that has been used in AS is the Bath AS Radiology Index-spine (BASRI-spine) [24]. This method of scoring involves more radiation exposure because of the requirement of AP projection views, and moreover, mSASSS has better inter-reader reliability as well as sensitivity to detect change [25,26]. The addition of lower thoracic spine in the scoring system was proposed to increase the sensitivity to change, but often these vertebral levels are not visible in our standard lumbar spine X-rays that are done in AS patients [27]. The latest proposal is to use a standardized atlas for training based on the SPAR module, developed by consensus among expert rheumatology and radiology readers [28]. In the SPAR module, there are several modifications to the mSASSS scoring system. Erosions and squaring are not scored in the cervical spine, and squaring can be scored in single corners as opposed to the need for both corners to be squared in mSASSS. Perhaps the most significant change is a bold step to identify syndesmophytes as all bone spurs that are not associated with a degenerated disc at that level. There is no requirement for the bone spur to be vertical [28]. It has to be seen whether this new module can be replicated in other cohorts. On the basis of the reported mSASSS progression rates, it is easy to recognize that the rate of progression is quite slow. Although the range of mSASSS scores is quite large from 0 to 72 when looking for change with time, the range of observations is quite narrow for the majority. A rate of 1 mSASSS unit per year will give a mean change of 2 units in a study with 2 years of follow-up and around 4 units for 4 years of follow-up. Because of these small changes, it is difficult to show a significant impact of treatment in short periods of time. For the sake of analysis, patients are categorized as progressors and nonprogressors based on an arbitrary cut off. There is no standard definition for progressors, and the different definitions used so
far include any increase (>0 unit) [6], >2 units per 2 years [5], 1 unit per year [29 ], or 3 units total change [6]. &&
EARLY STUDIES OF DISEASE MODIFICATION IN ANKYLOSING SPONDYLITIS Perhaps the first report of disease modification in AS was a small study [30] from 1976, which showed that continuous use of phenylbutazone decreased spinal new bone formation. More recently, two studies and one re-analysis of an earlier study showed that high dose or continuous NSAIDs could result in lower rates of progression in AS patients [5,6,31]. This effect was limited to those patients at risk of progression with higher baseline CRP and/or the presence of syndesmophytes. The effect of NSAIDs on radiographic progression was not seen in a recent large multicenter observational cohort study [29 ]. &&
SHORT-TERM STUDIES OF TUMOR NECROSIS FACTOR INHIBITOR ON RADIOGRAPHIC PROGRESSION IN ANKYLOSING SPONDYLITIS There are several short-term studies looking at the effect of TNFi on radiographic progression in AS. Three studies compared patients who were enrolled in clinical trials of etanercept, infliximab, and adalimumab to the Outcome Assessment in Ankylosing Spondylitis International Study (OASIS) cohort. The OASIS cohort is a historic cohort of patients who were enrolled from Belgium, France, and the Netherlands in the prebiologic era and followed over time [22]. Although subsequently 22% of patients went on to receive TNFi, in the initial years all patients received only anti-inflammatories, analgesics, and/or exercise [22]. In all three studies comparing TNFi to OASIS, patients were followed up for 1.5 years on TNFi therapy and there was no significant difference in the rate of progression between the two groups. There were significant baseline differences between the cohorts with TNFi-treated patients having higher Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index while specifically the adalimumab trial patients had higher mSASSS and CRP at baseline. The infliximab trial (ASSERT) patients in addition had higher prevalence of iritis [32]. In all three studies, there was no difference in the rate of progression between the TNFi-treated and control cohorts. Two reports from Germany reported the comparison of infliximab-treated patients with
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(a)
LONG-TERM STUDIES ON TUMOR NECROSIS FACTOR INHIBITOR There are two studies on the effect of TNFi on radiographic progression with more than 4 years of follow-up. The first study [29 ] is a multicenter cohort study of AS patients diagnosed by the modified New York criteria. More than 330 patients were enrolled in longitudinal cohorts followed up at five major centers across North America. All patients were followed up on a regular basis with standardized protocols. Patients received TNFi inhibitors as standard of care if disease activity was not controlled by NSAIDs. The comparison cohort was derived from the same clinics and included AS patients who did not receive TNFi, by personal choice, because of lack of insurance coverage or if deemed not necessary by the treating doctor. Radiographic progression was defined as a rate of increase >1 mSASSS unit per year. All baseline parameters were controlled for in the analysis. In this study [29 ], TNFi inhibitor use was associated with a 50% decreased odds of progression. Extensive statistical techniques were used in this study to confirm the findings. The propensity to receive TNFi inhibitors based on baseline variables was assessed by calculating a propensity score, and the two groups were matched. In this propensitymatched cohort, the odds of progression were 70% lower with TNFi use. Compared with 35% patients showing progression in the control group, only 27% progressed in the TNFi group (Fig. 1a). The difference was more marked in the propensitymatched cohort with only 18% progressing in the TNFi treated group compared with 32% in the control group (Fig. 1b). There could still be unknown factors driving this difference, and to quantitate the magnitude of any unknown factors that could explain this level of difference, a sensitivity analysis was done. Even if this undetected factor was present in 30% of nonprogressors and only 5% of progressors, the odds ratio of this factor would have to be as high as 6.5 to explain this level of difference in radiographic progression. Thus, it seems quite &&
&&
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Whole cohort N = 334 40
Percentage of progressors
the German Spondyloarthritis Inception Cohort (GESPIC) cohort (2-year follow-up) and the OASIS cohort (4-year follow-up) [33,34]. In both studies, there appeared to be a slowing of radiographic progression in infliximab-treated patients although there was no clear-cut statistical significance especially when all patients were considered. However, when patients who are likely to progress (with baseline damage) were compared, the effect of infliximab looked more promising.
(b)
Matched cohort N = 142
40 35
35
35
30
32
30
27
25
25
20
20
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5
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FIGURE 1. Progressors in the TNFi-treated group compared to the control group. Progressors were defined as those patients who had greater than 1 mSASSS unit per year rate of progression. (a) The difference between the groups in the entire cohort. (b) The difference between the groups in the matched cohort. Matching was done based on the propensity to receive TNFi, thus minimizing the differences between the groups. Propensity scores were calculated based on baseline demographics and disease parameters and used for propensity score matching. TNFi, tumor necrosis factor-alfa inhibitor. Data from Haroon et al. [29 ]. &&
possible that the effect seen was because of TNFi use itself. Other important observations of this study include the need for following up these patients for 4 years to show a significant difference in progression with TNFi and the significant difference in disease-modifying potential depending on the duration of disease. The effect on disease progression was best seen in patients with disease duration less than 5 years. As it is unethical to do a long-term placebo-controlled studies on radiographic progression in AS, the best evidence will come from well-established and prospectively followed cohorts like in this study. The results of this study have been corroborated by another smaller study [35 ] comparing patients who received infliximab and followed over 8 years, when compared with the Herne cohort in Germany. The patients who received infliximab did so as part of an investigator-initiated trial while the comparison group did not receive biologic response modifiers and were derived from the Herne cohort established from patients admitted to a hospital in the period 1993–2005. A total of 56 patients were included with 22 patients on infliximab. There was a remarkable similarity to the North American study [35 ] with differences between infliximab &&
&&
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and control groups becoming evident after 4 years only. Thus, it is quite clear that a minimum followup period of 6–8 years is required to show diseasemodifying potential of TNFi. This is the main reason for the negative conclusions drawn from short-term studies.
A WINDOW OF OPPORTUNITY IN ANKYLOSING SPONDYLITIS One of the remarkable findings in the North American study on radiographic progression is the effect of disease duration on disease-modifying potential of TNFi. The existence of a window of opportunity for treatment response has been quite evident from previous randomized controlled trials. Clinical trials for TNFi in AS patients with mean disease duration below 5 years have reported much better results compared with those with 10 or more years [36–39,40 ,41,42]. In a previous section, we have discussed the relationship of inflammation to new bone formation. It is quite clear that TNFi are quite effective in clearing the inflammatory lesions over time [41,43–45]. TNFi therapy can lead to either complete clearance or fatty corners depending on the state of the vertebral corner inflammation [46 ]. Early inflammatory lesions tend to resolve completely while more chronic changes are likely to become fatty corners [46 ]. While 17% of chronic vertebral corner inflammatory lesions (CILs) became syndesmophytes, only 3% of acute CILs did so [46 ]. Thus, the earlier we treat patients, the more likely is the chance of complete resolution of CILs and reducing the progression of this disabling arthritis. &
&
&
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CONCLUSION Excellent studies and experience with TNFi over the years have increased our confidence in using these medications for controlling inflammation in AS. More recent data clearly point to the need for longer follow-up in understanding the disease-modifying potential of therapeutic modalities in AS. TNFi used for long periods of time and when started sufficiently early could slow the rate of progression in AS. Acknowledgements N.H. is supported by the CIBC-Arthritis Research Foundation Salary Award and the Arthritis Society. Conflicts of interest N.H. has received honoraria/consulting fees from Abbvie, Janssen, Amgen, Pfizer, Celgene and UCB.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Las Heras F, Pritzker KP, So A, et al. Aberrant chondrocyte hypertrophy and activation of beta-catenin signaling precede joint ankylosis in ank/ank mice. J Rheumatol 2012; 39:583–593. 2. Lories RJ, Schett G. Pathophysiology of new bone formation and ankylosis in spondyloarthritis. Rheum Dis Clin North Am 2012; 38:555–567. 3. Wellcome Trust Case Control Consortium, Australo-Anglo-American Spondylitis Consortium (TASC). Burton PR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 2007; 39:1329–1337. 4. Australo-Anglo-American Spondyloarthritis Consortium (TASC). Reveille JD, Sims AM, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet 2010; 42:123–127. 5. Poddubnyy D, Rudwaleit M, Haibel H, et al. Effect of nonsteroidal antiinflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis 2012; 71:1616–1622. 6. Wanders A, Heijde D, Landewe R, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum 2005; 52:1756–1765. 7. Lin Z, Bei JX, Shen M, et al. A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis. Nat Genet 2011; 44:73–77. 8. Haroon N, Maksymowych W, Rahman P, et al. Radiographic severity in ankylosing spondylitis is associated with polymorphism in large multifunctional peptidase 2 (LMP2) in the SPARCC cohort. Arthritis Rheum 2012; 64:1119–1126. 9. Appel H, Ruiz-Heiland G, Listing J, et al. Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis Rheum 2009; 60:3257–3262. 10. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med 2007; 13:156–163. 11. Heiland GR, Appel H, Poddubnyy D, et al. High level of functional dickkopf-1 predicts protection from syndesmophyte formation in patients with ankylosing spondylitis. Ann Rheum Dis 2012; 71:572–574. 12. Lories RJ, Derese I, Luyten FP. Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J Clin Invest 2005; 115:1571–1579. 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 spondyloarthritis. Arthritis Rheum 2012; 64:1388–1398. 14. Baraliakos X, Listing J, Rudwaleit M, et al. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Res Ther 2008; 10:R104. 15. 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 Rheum 2009; 60:93–102. 16. van der Heijde D, Machado P, Braun J, et al. MRI inflammation at the vertebral unit only marginally predicts new syndesmophyte formation: a multilevel analysis in patients with ankylosing spondylitis. Ann Rheum Dis 2012; 71:369–373. 17. Jacques P, Lambrecht S, Verheugen E, et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis 2014; 73:437–445. 18. Abe Y, Ohtsuji M, Ohtsuji N, et al. Ankylosing enthesitis associated with upregulated IFN-gamma and IL-17 production in (BXSB NZB) F(1) male mice: a new mouse model. Mod Rheumatol 2009; 19:316–322. 19. Lories RJ, Derese I, de Bari C, Luyten FP. Evidence for uncoupling of inflammation and joint remodeling in a mouse model of spondylarthritis. Arthritis Rheum 2007; 56:489–497. 20. Sherlock JP, Joyce-Shaikh B, Turner SP, et al. IL-23 induces spondyloarthropathy by acting on ROR-gammatþ CD3þCD4-CD8- entheseal resident T cells. Nat Med 2012; 18:1069–1076. 21. Pedersen SJ, Chiowchanwisawakit P, Lambert RG, et al. Resolution of inflammation following treatment of ankylosing spondylitis is associated with new bone formation. J Rheumatol 2011; 38:1349–1354. 22. Ramiro S, Stolwijk C, van Tubergen A, et al. Evolution of radiographic damage in ankylosing spondylitis: a 12 year prospective follow-up of the OASIS study. Ann Rheum Dis 2013. [Epub ahead of print] 23. Baraliakos X, Listing J, von der Recke A, Braun J. The natural course of radiographic progression in ankylosing spondylitis: evidence for major individual variations in a large proportion of patients. J Rheumatol 2009; 36:997–1002.
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Spondyloarthropathies 24. MacKay K, Mack C, Brophy S, Calin A. The Bath Ankylosing Spondylitis Radiology Index (BASRI): a new, validated approach to disease assessment. Arthritis Rheum 1998; 41:2263–2270. 25. Salaffi F, Carotti M, Garofalo G, et al. Radiological scoring methods for ankylosing spondylitis: a comparison between the Bath Ankylosing Spondylitis Radiology Index and the modified Stoke Ankylosing Spondylitis Spine Score. Clin Exp Rheumatol 2007; 25:67–74. 26. Baskan BM, Sivas F, Inal EE, et al. Comparison of the Bath Ankylosing Spondylitis Radiology Index and the modified Stoke Ankylosing Spondylitis Spine Score in Turkish patients with ankylosing spondylitis. Clin Rheumatol 2010; 29:65–70. 27. Baraliakos X, Listing J, Rudwaleit M, et al. Development of a radiographic scoring tool for ankylosing spondylitis only based on bone formation: addition of the thoracic spine improves sensitivity to change. Arthritis Rheum 2009; 61:764–771. 28. Maksymowych WP, Learch T, Lambert RG, et al. Development and validation of the spondyloarthritis radiography module for calibration of readers using the modified stoke ankylosing spondylitis spine score. Arthritis Care Res (Hoboken) 2014; 66:55–62. 29. Haroon N, Inman RD, Learch TJ, et al. The impact of tumor necrosis factor && alpha inhibitors on radiographic progression in ankylosing spondylitis. Arthritis Rheum 2013; 65:2645–2654. The first study to clearly show a disease modifying effect of TNFi in AS. 30. Boersma JW. Retardation of ossification of the lumbar vertebral column in ankylosing spondylitis by means of phenylbutazone. Scand J Rheumatol 1976; 5:60–64. 31. Kroon F, Landewe R, Dougados M, van der Heijde D. Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis 2012. 32. van der Heijde D, Landewe R, Baraliakos X, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 2008; 58:3063–3070. 33. Baraliakos X, Listing J, Rudwaleit M, et al. Radiographic progression in patients with ankylosing spondylitis after 2 years of treatment with the tumour necrosis factor alpha antibody infliximab. Ann Rheum Dis 2005; 64:1462– 1466. 34. Baraliakos X, Listing J, Brandt J, et al. Radiographic progression in patients with ankylosing spondylitis after 4 yrs of treatment with the anti-TNF-alpha antibody infliximab. Rheumatology (Oxford) 2007; 46:1450–1453. 35. Baraliakos X, Haibel H, Listing J, et al. Continuous long-term anti-TNF therapy && does not lead to an increase in the rate of new bone formation over 8 years in patients with ankylosing spondylitis. Ann Rheum Dis 2014; 73:710–715. This study shows the need for long-term follow-up to demonstrate the diseasemodifying potential of TNFi.
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36. van der Heijde D, Dijkmans B, Geusens P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 2005; 52:582–591. 37. van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006; 54:2136– 2146. 38. Davis JC Jr, van der Heijde DM, Braun J, et al. Efficacy and safety of up to 192 weeks of etanercept therapy in patients with ankylosing spondylitis. Ann Rheum Dis 2008; 67:346–352. 39. Inman RD, Davis JC Jr, Heijde D, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008; 58:3402–3412. 40. Sieper J, Lenaerts J, Wollenhaupt J, et al. Efficacy and safety of infliximab plus & naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, part 1. Ann Rheum Dis 2014; 73:101–107. This study included very early patients with spondyloarthritis and demonstrated exceptional response rates with both TNFi and NSAIDs. 41. Barkham N, Keen HI, Coates LC, et al. Clinical and imaging efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imagingdetermined early sacroiliitis. Arthritis Rheum 2009; 60:946–954. 42. Song IH, Weiss A, Hermann KG, et al. Similar response rates in patients with ankylosing spondylitis and nonradiographic axial spondyloarthritis after 1 year of treatment with etanercept: results from the ESTHER trial. Ann Rheum Dis 2013; 72:823–825. 43. Maksymowych WP, Salonen D, Inman RD, et al., CANDLE Study Group. Lowdose infliximab (3 mg/kg) significantly reduces spinal inflammation on magnetic resonance imaging in patients with ankylosing spondylitis: a randomized placebo-controlled study. J Rheumatol 2010; 37:1728–1734. 44. Baraliakos X, Brandt J, Listing J, et al. Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum 2005; 53:856– 863. 45. Baraliakos X, Davis J, Tsuji W, Braun J. Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor alpha receptor fusion protein etanercept. Arthritis Rheum 2005; 52:1216–1223. 46. Maksymowych WP, Morency N, Conner-Spady B, Lambert RG. Suppression & of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann Rheum Dis 2013; 72:23–28. This article describes the window of opportunity with regard to new bone formation in AS.
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The effect of tumor necrosis factor-blockade on new bone formation in ankylosing spondylitis: what is the evidence? Nigil Haroon a,b
Purpose of review Treatment of ankylosing spondylitis (AS) has seen remarkable advances since the introduction of therapies targeting tumor necrosis factor-alfa (TNFa). In addition to the excellent disease control achieved by these agents, recent evidence points to a possible disease-modifying potential of the drug. This novel finding can potentially change the landscape of AS treatment. Recent findings In this review, existing knowledge on mechanisms of new bone formation and ways to quantify and prevent progression are discussed. Evidence for disease-modifying potential of NSAIDs, short-term and long-term studies on TNFa inhibitors, and AS progression are discussed. A follow-up of more than 4 years is required to study disease modification in AS. Early and long-term therapy with tumor necrosis factor inhibitors appears to slow radiographic progression in AS. Summary New evidence for a disease-modifying potential of tumor necrosis factor inhibitors can change the AS treatment paradigm. Video abstract http://links.lww.com/COR/A16. Keywords bone spur, disease modifying anti-rheumatic drug, modified Stoke’s ankylosing spondylitis spine score, new bone, syndesmophyte
INTRODUCTION Over the past decade, we have seen several developments in the field of ankylosing spondylitis (AS). Ever since the introduction of tumor necrosis factoralfa (TNFa) inhibitors (TNFi), there have been significant changes in our goals and outcome expectations in the treatment of AS patients. With increasing recognition of this condition and earlier diagnosis, in fact the therapeutic response to TNFi appears to be much better than earlier thought. There are still patients who do not respond to these medications, and we are eagerly awaiting results of ongoing studies targeting other pathogenic pathways in AS. Unlike in rheumatoid arthritis (RA), the field of disease modification has not been well addressed in AS. This is probably due to the lack of strong evidence, until recently, that any form of therapy can indeed change the course of relentless progression in AS. Moreover, there is a fundamental difference
in the way we think of disease modification in AS compared with RA. Compared with RA in which our goal is to prevent erosions, in AS disease modification refers to halting osteoproliferation and spinal fusion. We are still not clear what drives new bone formation and whether there is a clear link to inflammation, contributing to our lack of understanding on disease modification in AS. This review aims to dissect the different pathogenic pathways, potential interventions, and the evidence so far on disease-modifying potential of drugs used in AS. a
Department of Medicine and Rheumatology, University of Toronto and University Health Network, Toronto, Ontario, Canada
b
Correspondence to Dr Nigil Haroon, MD, PhD, DM, 1E-425, 399 Bathurst Street, Toronto Western Hospital, Toronto, ON M5T2S8, Canada. Tel: +1 4166035634; e-mail: [email protected] Curr Opin Rheumatol 2014, 26:389–394 DOI:10.1097/BOR.0000000000000077
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BIOLOGY OF NEW BONE FORMATION IN ANKYLOSING SPONDYLITIS The pathogenesis of new bone formation in AS is not known. It is widely recognized that hypertrophic chondrocytes are present at entheseal sites indicating an endochondral bone formation process, but both endochondral and membranous new bone formation have been implicated [1,2]. The genomewide association studies (GWAS) [3,4] in adults of European descent population have not recognized the involvement of any major bone metabolism pathways. The association of AS with prostaglandin E receptor 4 is interesting, as NSAIDs have been shown in some studies [5,6] to have a possible disease-modifying potential. A GWAS in Chinese AS patients reported novel associations with HAPLN1, EDIL3, and ENO6, and all three could be linked to bone homeostasis through osteoblast or osteoclast influences [7]. The single nucleotide polymorphism (SNP) rs4552569 is adjacent to both HAPLN1 and EDIL3, whereas rs17095830 is located in an intron of ANO6. Another study [8] looking at the antigen presentation pathway found significant association of baseline radiographic severity with proteasome component LMP2 and endoplasmic reticulum aminopeptidase 1 (ERAP1) in univariate analysis and LMP2 alone in multivariate analysis. The exact mechanism of how LMP2 or ERAP1 may affect new bone formation is not clear. Sclerostin (SOST) and DKK1 are antagonists of the Wnt signaling pathway. Wnt signaling pathway is important in osteoblastic activity, and low levels of Wnt antagonists DKK1 and SOST can lead to excess osteoblastic activity. SOST expression is significantly reduced in AS [9]. Blocking DKK1 led to fusion of sacroiliac joints in the tumor necrosis factor-transgenic mice [10]. Low levels of functional DKK1 were associated with progression in AS patients [11]. Similarly, noggin, a BMP-antagonist, led to improvement of ankylosis in the DBA-1 mice, a spontaneous model of arthritis and new bone formation [12]. A direct link of DKK1 or BMP in spinal ankylosis of AS patients is still lacking. The difficulty in studying the target tissue has been the major bottleneck in studies on new bone formation in AS.
INFLAMMATION AND NEW BONE FORMATION Definite proof of inflammation leading to new bone has not been established in AS. One of the strongest predictors of progression of syndesmophytes, as well from nonradiographic axial Spondyloarthritis (nrAxSpA) to AS, was elevated C-Reactive Protein (CRP) at baseline [13]. Vertebral corners with 390
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inflammation at baseline are likely to become syndesmophytes on follow-up [14,15]. However, most syndesmophytes develop from corners with no inflammation documented previously [16]. Does this really mean inflammation is not necessary to kick start the process of new bone formation or is it just reflecting the dynamic nature of MRI inflammation? MRI reflects the state of inflammation at a particular time point and does not tell us if there was inflammation previously. Hence, it is not possible to categorically state that syndesmophytes have developed from corners with no inflammation. To add to the complexity of this scheme, we should consider the effect of entheseal stress, bone damage, and repair. Unfortunately, there is no perfect animal model of spondyloarthritis. In the TNFDARE mouse model, with deregulated tumor necrosis factor production, enthesitis is a dominant feature in addition to intestinal and joint inflammation [17]. Inflammation and erosions appear to be located at anatomically distinct locations and mechanical loading, but no T or B cells appear to driving new bone formation [17]. Steroid treatment or TNFa inhibition does not seem to affect new bone formation in animal models of entheseal new bone formation, although it is questionable how much this is reflective of the process in human disease [18,19]. The role of cytokines in the process of new bone formation is not well understood. Recently, studies conducted on the RA mouse model collagen antibody-induced arthritis revealed significant entheseal inflammation that was driven primarily by interleukin (IL)-23 [20]. Although there was new bone formation associated with enthesitis in this model, IL-22 seemed to be the necessary cytokine for osteoproliferation but not IL-17 or IL-23 [20]. If inflammation is linked to new bone formation, resolution of inflammation should obviate that risk. There is a linear relationship between tumor necrosis factor and DKK1. If tumor necrosis factor drives up DKK1, inhibiting tumor necrosis factor could lead to lower DKK1 that in turn can trigger bone formation. This led to the proposal of a tumor necrosis factor-brake hypothesis, wherein TNFa would act as a brake against new bone formation and TNFi could release this brake [21]. However, an increase in the rate of progression has not been seen in any TNFi studies.
ASSESSING RADIOGRAPHIC PROGRESSION IN ANKYLOSING SPONDYLITIS The most widely used method for assessing radiographic damage and progression in spinal radiographs of AS patients is the modified Stoke’s Volume 26 Number 4 July 2014
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ankylosing spondylitis spine score (mSASSS). On the basis of this system, 24 vertebral corners (anterior corners of cervical and lumbar spine) are graded from the lateral projection for squaring, erosions, sclerosis, syndesmophytes (bone spur), and bridging syndesmophytes (fusion). The scores range from 0 to 3 for each corner and so a patient with bridging syndesmophytes in all corners would have a maximum score of 72. On the basis of this scoring system, the mean rate of progression in AS patients is around 1 mSASSS unit per year [22,23]. There is, however, considerable variability in progression with almost a quarter of patients having no progression at all while some progress at much faster rates [23]. However, those who progress appear to do so in a linear fashion [22]. The other traditional scoring method that has been used in AS is the Bath AS Radiology Index-spine (BASRI-spine) [24]. This method of scoring involves more radiation exposure because of the requirement of AP projection views, and moreover, mSASSS has better inter-reader reliability as well as sensitivity to detect change [25,26]. The addition of lower thoracic spine in the scoring system was proposed to increase the sensitivity to change, but often these vertebral levels are not visible in our standard lumbar spine X-rays that are done in AS patients [27]. The latest proposal is to use a standardized atlas for training based on the SPAR module, developed by consensus among expert rheumatology and radiology readers [28]. In the SPAR module, there are several modifications to the mSASSS scoring system. Erosions and squaring are not scored in the cervical spine, and squaring can be scored in single corners as opposed to the need for both corners to be squared in mSASSS. Perhaps the most significant change is a bold step to identify syndesmophytes as all bone spurs that are not associated with a degenerated disc at that level. There is no requirement for the bone spur to be vertical [28]. It has to be seen whether this new module can be replicated in other cohorts. On the basis of the reported mSASSS progression rates, it is easy to recognize that the rate of progression is quite slow. Although the range of mSASSS scores is quite large from 0 to 72 when looking for change with time, the range of observations is quite narrow for the majority. A rate of 1 mSASSS unit per year will give a mean change of 2 units in a study with 2 years of follow-up and around 4 units for 4 years of follow-up. Because of these small changes, it is difficult to show a significant impact of treatment in short periods of time. For the sake of analysis, patients are categorized as progressors and nonprogressors based on an arbitrary cut off. There is no standard definition for progressors, and the different definitions used so
far include any increase (>0 unit) [6], >2 units per 2 years [5], 1 unit per year [29 ], or 3 units total change [6]. &&
EARLY STUDIES OF DISEASE MODIFICATION IN ANKYLOSING SPONDYLITIS Perhaps the first report of disease modification in AS was a small study [30] from 1976, which showed that continuous use of phenylbutazone decreased spinal new bone formation. More recently, two studies and one re-analysis of an earlier study showed that high dose or continuous NSAIDs could result in lower rates of progression in AS patients [5,6,31]. This effect was limited to those patients at risk of progression with higher baseline CRP and/or the presence of syndesmophytes. The effect of NSAIDs on radiographic progression was not seen in a recent large multicenter observational cohort study [29 ]. &&
SHORT-TERM STUDIES OF TUMOR NECROSIS FACTOR INHIBITOR ON RADIOGRAPHIC PROGRESSION IN ANKYLOSING SPONDYLITIS There are several short-term studies looking at the effect of TNFi on radiographic progression in AS. Three studies compared patients who were enrolled in clinical trials of etanercept, infliximab, and adalimumab to the Outcome Assessment in Ankylosing Spondylitis International Study (OASIS) cohort. The OASIS cohort is a historic cohort of patients who were enrolled from Belgium, France, and the Netherlands in the prebiologic era and followed over time [22]. Although subsequently 22% of patients went on to receive TNFi, in the initial years all patients received only anti-inflammatories, analgesics, and/or exercise [22]. In all three studies comparing TNFi to OASIS, patients were followed up for 1.5 years on TNFi therapy and there was no significant difference in the rate of progression between the two groups. There were significant baseline differences between the cohorts with TNFi-treated patients having higher Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index while specifically the adalimumab trial patients had higher mSASSS and CRP at baseline. The infliximab trial (ASSERT) patients in addition had higher prevalence of iritis [32]. In all three studies, there was no difference in the rate of progression between the TNFi-treated and control cohorts. Two reports from Germany reported the comparison of infliximab-treated patients with
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(a)
LONG-TERM STUDIES ON TUMOR NECROSIS FACTOR INHIBITOR There are two studies on the effect of TNFi on radiographic progression with more than 4 years of follow-up. The first study [29 ] is a multicenter cohort study of AS patients diagnosed by the modified New York criteria. More than 330 patients were enrolled in longitudinal cohorts followed up at five major centers across North America. All patients were followed up on a regular basis with standardized protocols. Patients received TNFi inhibitors as standard of care if disease activity was not controlled by NSAIDs. The comparison cohort was derived from the same clinics and included AS patients who did not receive TNFi, by personal choice, because of lack of insurance coverage or if deemed not necessary by the treating doctor. Radiographic progression was defined as a rate of increase >1 mSASSS unit per year. All baseline parameters were controlled for in the analysis. In this study [29 ], TNFi inhibitor use was associated with a 50% decreased odds of progression. Extensive statistical techniques were used in this study to confirm the findings. The propensity to receive TNFi inhibitors based on baseline variables was assessed by calculating a propensity score, and the two groups were matched. In this propensitymatched cohort, the odds of progression were 70% lower with TNFi use. Compared with 35% patients showing progression in the control group, only 27% progressed in the TNFi group (Fig. 1a). The difference was more marked in the propensitymatched cohort with only 18% progressing in the TNFi treated group compared with 32% in the control group (Fig. 1b). There could still be unknown factors driving this difference, and to quantitate the magnitude of any unknown factors that could explain this level of difference, a sensitivity analysis was done. Even if this undetected factor was present in 30% of nonprogressors and only 5% of progressors, the odds ratio of this factor would have to be as high as 6.5 to explain this level of difference in radiographic progression. Thus, it seems quite &&
&&
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Whole cohort N = 334 40
Percentage of progressors
the German Spondyloarthritis Inception Cohort (GESPIC) cohort (2-year follow-up) and the OASIS cohort (4-year follow-up) [33,34]. In both studies, there appeared to be a slowing of radiographic progression in infliximab-treated patients although there was no clear-cut statistical significance especially when all patients were considered. However, when patients who are likely to progress (with baseline damage) were compared, the effect of infliximab looked more promising.
(b)
Matched cohort N = 142
40 35
35
35
30
32
30
27
25
25
20
20
15
15
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10
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5
18
0
0 TNFi
TNFi
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FIGURE 1. Progressors in the TNFi-treated group compared to the control group. Progressors were defined as those patients who had greater than 1 mSASSS unit per year rate of progression. (a) The difference between the groups in the entire cohort. (b) The difference between the groups in the matched cohort. Matching was done based on the propensity to receive TNFi, thus minimizing the differences between the groups. Propensity scores were calculated based on baseline demographics and disease parameters and used for propensity score matching. TNFi, tumor necrosis factor-alfa inhibitor. Data from Haroon et al. [29 ]. &&
possible that the effect seen was because of TNFi use itself. Other important observations of this study include the need for following up these patients for 4 years to show a significant difference in progression with TNFi and the significant difference in disease-modifying potential depending on the duration of disease. The effect on disease progression was best seen in patients with disease duration less than 5 years. As it is unethical to do a long-term placebo-controlled studies on radiographic progression in AS, the best evidence will come from well-established and prospectively followed cohorts like in this study. The results of this study have been corroborated by another smaller study [35 ] comparing patients who received infliximab and followed over 8 years, when compared with the Herne cohort in Germany. The patients who received infliximab did so as part of an investigator-initiated trial while the comparison group did not receive biologic response modifiers and were derived from the Herne cohort established from patients admitted to a hospital in the period 1993–2005. A total of 56 patients were included with 22 patients on infliximab. There was a remarkable similarity to the North American study [35 ] with differences between infliximab &&
&&
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and control groups becoming evident after 4 years only. Thus, it is quite clear that a minimum followup period of 6–8 years is required to show diseasemodifying potential of TNFi. This is the main reason for the negative conclusions drawn from short-term studies.
A WINDOW OF OPPORTUNITY IN ANKYLOSING SPONDYLITIS One of the remarkable findings in the North American study on radiographic progression is the effect of disease duration on disease-modifying potential of TNFi. The existence of a window of opportunity for treatment response has been quite evident from previous randomized controlled trials. Clinical trials for TNFi in AS patients with mean disease duration below 5 years have reported much better results compared with those with 10 or more years [36–39,40 ,41,42]. In a previous section, we have discussed the relationship of inflammation to new bone formation. It is quite clear that TNFi are quite effective in clearing the inflammatory lesions over time [41,43–45]. TNFi therapy can lead to either complete clearance or fatty corners depending on the state of the vertebral corner inflammation [46 ]. Early inflammatory lesions tend to resolve completely while more chronic changes are likely to become fatty corners [46 ]. While 17% of chronic vertebral corner inflammatory lesions (CILs) became syndesmophytes, only 3% of acute CILs did so [46 ]. Thus, the earlier we treat patients, the more likely is the chance of complete resolution of CILs and reducing the progression of this disabling arthritis. &
&
&
&
CONCLUSION Excellent studies and experience with TNFi over the years have increased our confidence in using these medications for controlling inflammation in AS. More recent data clearly point to the need for longer follow-up in understanding the disease-modifying potential of therapeutic modalities in AS. TNFi used for long periods of time and when started sufficiently early could slow the rate of progression in AS. Acknowledgements N.H. is supported by the CIBC-Arthritis Research Foundation Salary Award and the Arthritis Society. Conflicts of interest N.H. has received honoraria/consulting fees from Abbvie, Janssen, Amgen, Pfizer, Celgene and UCB.
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36. van der Heijde D, Dijkmans B, Geusens P, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum 2005; 52:582–591. 37. van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2006; 54:2136– 2146. 38. Davis JC Jr, van der Heijde DM, Braun J, et al. Efficacy and safety of up to 192 weeks of etanercept therapy in patients with ankylosing spondylitis. Ann Rheum Dis 2008; 67:346–352. 39. Inman RD, Davis JC Jr, Heijde D, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 2008; 58:3402–3412. 40. Sieper J, Lenaerts J, Wollenhaupt J, et al. Efficacy and safety of infliximab plus & naproxen versus naproxen alone in patients with early, active axial spondyloarthritis: results from the double-blind, placebo-controlled INFAST study, part 1. Ann Rheum Dis 2014; 73:101–107. This study included very early patients with spondyloarthritis and demonstrated exceptional response rates with both TNFi and NSAIDs. 41. Barkham N, Keen HI, Coates LC, et al. Clinical and imaging efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imagingdetermined early sacroiliitis. Arthritis Rheum 2009; 60:946–954. 42. Song IH, Weiss A, Hermann KG, et al. Similar response rates in patients with ankylosing spondylitis and nonradiographic axial spondyloarthritis after 1 year of treatment with etanercept: results from the ESTHER trial. Ann Rheum Dis 2013; 72:823–825. 43. Maksymowych WP, Salonen D, Inman RD, et al., CANDLE Study Group. Lowdose infliximab (3 mg/kg) significantly reduces spinal inflammation on magnetic resonance imaging in patients with ankylosing spondylitis: a randomized placebo-controlled study. J Rheumatol 2010; 37:1728–1734. 44. Baraliakos X, Brandt J, Listing J, et al. Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum 2005; 53:856– 863. 45. Baraliakos X, Davis J, Tsuji W, Braun J. Magnetic resonance imaging examinations of the spine in patients with ankylosing spondylitis before and after therapy with the tumor necrosis factor alpha receptor fusion protein etanercept. Arthritis Rheum 2005; 52:1216–1223. 46. Maksymowych WP, Morency N, Conner-Spady B, Lambert RG. Suppression & of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann Rheum Dis 2013; 72:23–28. This article describes the window of opportunity with regard to new bone formation in AS.
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