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Review 2010
Spondyloarthritis: state of the art and future perspectives
  1. Désirée van der Heijde1,
  2. Walter P Maksymowych2
  1. 1Leiden University Medical Center, Leiden, The Netherlands
  2. 2University of Alberta, Edmonton, Alberta, Canada
  1. Correspondence to Désirée van der Heijde, Department of Rheumatology, C1R, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; d.vanderheijde{at}kpnplanet.nl

Abstract

Advances in the understanding of this group of arthritides over the past decade can be considered transformational from the perspective of basic mechanisms as well as clinical research focusing on the development of imaging technologies and a spectrum of standardised clinical outcomes that aim at a more comprehensive understanding of disease activity, functioning and disability, and prognosis. Prior to this decade, treatment was unsatisfactory and limited to physical modalities and non-steroidal anti-inflammatory agents, while diagnostic ascertainment primarily focused on clinical evaluation and plain radiography. Today, patients with spondyloarthritis (SpA) can look forward to earlier diagnosis and more effective treatment but significant challenges remain. This review will summarise the past decade's major accomplishments in the understanding of the basic mechanisms contributing to the development of SpA, outline those advances in clinical and imaging outcomes that have enabled major therapeutic advances and now permit a broader understanding of the early development of disease and its impact on patient well-being, and will describe new approaches to the development of diagnostic criteria that incorporate advances in imaging.

https://doi.org/10.1136/ard.2009.119529

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    Genetics

    Advances in the genetics of spondyloarthritis (SpA) have demonstrated that disease association is more complex than B27 alone and that there are non-B27 major histocompatibility complex (MHC) and non-MHC genes important in susceptibility to disease.

    B27 subtypes

    While the study of human leucocyte antigen (HLA)-B27 subtypes has accelerated over the past decade to include almost 60 subtypes of B27, this has not been accompanied by a great deal of epidemiological data evaluating associations with disease.1 All subtypes from B*2702 to B*2710 have been reported with SpA as well as B*2714, B*2715, B*2719 and B*2730.2 It was previously thought that B*2709 was a protective subtype although six cases have now been reported in patients with axial disease.3 4 Similarly, recent reports of SpA in Han Chinese carriers of B*2706 indicate that it is not absolutely protective, as originally thought, but has a weaker disease association than another B27 subtype commonly observed in Southeast Asia, B*2704.5 This epidemiological data are of more than academic interest because the sequence differences between disease associated and non-associated subtypes may reveal important clues as to the mechanism of the B27 association with ankylosing spondylitis (AS). B*2706 and B*2709 differ from the disease associated B*2705 subtype at amino acid position 116 (both subtypes) and position 114 (B*2704) in the antigen binding pocket of B27 that binds the C-terminal amino acid of the antigenic peptide so that peptides with arginine or tyrosine at the C-terminus are not bound.6

    Non-B27 MHC genes

    Establishing a role for other MHC-encoded susceptibility genes has been extremely challenging due to the complexity associated with extreme variation at different MHC loci and the extensive linkage disequilibrium observed between loci. No studies have been sufficiently large with sufficient marker densities to identify the specific genes involved although the effect size appears to be substantial with an attributable risk from these haplotypes being estimated at 34%.7

    Non-MHC genes

    The component of the increased risk for disease due to non-MHC loci has been estimated to be greater than for the entire genetic risk for rheumatoid arthritis. Increasingly, investigators have employed high-throughput microarray-based single nucleotide polymorphism (SNP) genotyping techniques to screen increasingly more regions of the human genome to identify genes associated with SpA. While no genome-wide association study has yet been reported, a screen of 14 500 common non-synonymous SNPs has been reported and has identified disease associations with the interleukin 23 receptor (IL23R) and the endoplasmic reticulum aminopeptidase-1 (ERAP1) genes.8 IL23R has been associated with inflammatory bowel disease and psoriasis and its association with SpA has been replicated in Spanish and Canadian case-control cohorts although the primary associated variant remains unclear.9,–,12

    The ERAP1 gene has been implicated in two biological functions: (1) the N-terminus trimming of peptides transported into the ER where they bind class I human leucocyte antigen (HLA) molecules before transport to the cell surface and presentation to T cells, and13 (2) trimming of surface expressed cytokine receptors such as tumour necrosis factor receptor 1 (TNFR1), IL6Rα and IL1R2.14,–,16 This association has now been replicated in three Canadian case-control cohorts that also demonstrated a specific ERAP1 haplotype that was strongly associated with disease in all three cohorts.17 It remains to be established which variant is principally associated with disease and its effects on function but this represents an important area of study since the population attributable risk of this gene locus has been estimated at 26%.

    Association of members of the IL1 gene cluster on chromosome 2q13 has been reported in several studies in Caucasian and Asian populations although consistency has been lacking in identifying the principal gene associated with disease.18 19 This region contains nine genes that include the proinflammatory IL1 agonists, IL1A and IL1B, the anti-inflammatory IL1 antagonist, IL1RN, and six genes with unknown function, IL1F5 to F10. A recent meta-analysis demonstrated the strongest association with variants in the IL1A gene although the population attributable risk was estimated at only 4% to 6%.20

    Pathophysiology of B27

    Experimental evidence gathered over the past decade supports a classical and non-classical role for B27 in the pathophysiology of disease. The classical role is to present peptides derived from proteolysis of intracellular proteins in a trimolecular complex with β2 microglobulin (β2m) on the surface of antigen presenting cells to CD8 T cells. Evidence supporting a classical role for B27 has come from further refinement of the B27 transgenic rat model of disease. The introduction of additional human β2m into a disease prone but healthy HLA-B27/human β2m double transgenic rat promotes surface expression of B27 in a trimolecular complex and induces more severe arthritis.21 However, the finding that disease manifestations can occur in the absence of functional CD8 T cells casts doubt on classic T cell recognition of B27.22 Demonstration of disease associated B27-restricted T cell responses has also proven to be difficult and there are few examples of such antigens displaying differential binding to B27 subtypes. To add a further level of complexity, x-ray crystallography has demonstrated that certain self-peptides can bind in a dual confirmation to B*2705 but in only a single confirmation to B*2709 which is associated with a lack of T cell recognition in B*2709 but not B*2705 positive individuals.23

    HLA-B27 biology unrelated to antigen presentation has also been implicated in disease and most attention has focused on the propensity of B27 to misfold.24 This in turn leads to accumulation of B27 heavy chains in the ER where they bind to the protein chaperone immunoglobulin-binding protein (BiP) displacing certain effector molecules which triggers stress responses within the cell that include activation of genes encoding nuclear factor (NF)κB and proinflammatory cytokines. The relevance of this to disease has, however, been questioned by data demonstrating that disease associated and non-associated B27 subtypes fold with the same level of efficiency.25 A second property of B27 implicated in AS has been its ability to form heavy chain homodimers reported in vitro as well as in patients with AS.26 27 Binding of homodimers to various immunomodulatory receptors on B, T, natural killer and monocyte/macrophage cells may stimulate release of TNFα.28

    Immune effectors and target lesion(s)

    More systematic studies of the histopathological and immunopathological lesions in SpA have reinforced the importance of the enthesis concept and the importance of cartilage as a target tissue. Inflammatory lesions at axial and peripheral sites are characterised by soft tissue inflammation and by subchondral bone marrow inflammation with CD8 and CD4 T cells, B cells, macrophages and osteoclasts.29 This is particularly prominent at peripheral entheses subject to biomechanical stress and rich in fibrocartilage containing type II collagen and aggrecan proteoglycan as in the Achilles tendon insertion into the calcaneum. Similarly, studies of the femoral head removed at hip arthroplasty show subchondral inflammation that is no longer observed in femoral heads that are denuded of overlying cartilage.30 Immunisation with aggrecan, found in hyaline cartilage, or versican proteoglycan, found in the annulus fibrosus, spinal ligaments, sacroiliac joint (SIJ), arterial vessel wall and uvea, induces spondylitis resembling human disease.31 32 Recent work has shown that chondrocytes can present antigen to CD8 T cells and B27-restricted CD8 T cell responses to cartilage derived self-peptides have been demonstrated in human disease.33 34

    The peripheral synovitis and enthesitis of SpA as well as the gut inflammation is characterised by cellular infiltration with a macrophage subtype that expresses the CD163 scavenger receptor and possesses the capacity to secrete TNFα and IL1 in response to bacterial lipopolysaccharide.35 Recent work in a TNFα overexpressing mouse model points to mesenchymal stromal cells as the principle target cell that is activated by TNFα signalling through the TNFR1 receptor.36 These animals spontaneously develop an inflammatory disease characterised by Crohn-like ileitis, sacroiliitis, enthesitis and peripheral arthritis. Immunohistology has demonstrated dense cellular infiltrates of T lymphocytes and macrophages expressing TNFα in the SIJs of patients with early disease.37 This data together with the major advances in therapeutic intervention with anti-TNFα agents has now clearly established the importance of TNFα as a pivotal cytokine mediating inflammation in SpA.

    The finding of a disease association with variants in IL23R has generated interest in T cells expressing the Th17 phenotype as a potentially important effector in SpA. IL17 induces proinflammatory cytokines in several cell types within the joint and some reports describe elevated levels in synovial fluid and serum of patients with SpA.38 Expression of IL17 is regulated by IL23 which supports the expansion and maintenance of the Th17 subset and therapeutic strategies targeting IL23 have been successful in psoriasis. IL6 also appears to be an important cytokine in SpA by acting together with IL23 in driving differentiation of uncommitted T cells to the Th17 phenotype.39

    Tissue repair responses

    The basic mechanisms driving the sustained activity of tissue repair in SpA, especially new bone and cartilage formation, are now starting to emerge from animal models although translation to humans remains challenging. Interest in these models has increased since data emerged that anti-TNFα agents may not ameliorate new bone formation casting doubt on the hypothesis that inflammation and ankylosis are linked.40,–,42 The principal experimental animal model has been murine ankylosing enthesitis. Ageing male DBA/1 mice spontaneously develop oligoarthritis, particularly in the toes of the hind limbs, after grouped caging of males from different litters. A short period of acute inflammation is followed by entheseal and periosteal cell proliferation, chondrogenic differentiation, bone formation and ultimately, joint ankylosis.43 44 Signalling through bone morphogenetic proteins is critically important in the early stages of disease in these animals and has also been demonstrated in human biopsies from entheseal lesions at the Achilles tendon insertion of patients with AS.43 Etanercept was shown to have no impact on the incidence, severity, or progression of arthritis in these animals.44 In contrast to human AS, entheseal new cartilage and bone formation are only seen in peripheral joints and not in the spine. In other animal models, wingless proteins (Wnt) and their natural inhibitor, Dickkopf (DKK)1, have been shown to regulate new bone formation.45

    However, prospective studies that have non-invasively assessed spinal inflammation using MRI support some link between inflammation and ankylosis. Several reports have described an association between the presence of bone oedema at vertebral corners on MRI and the subsequent development of syndesmophytes at the corresponding vertebral corners on plain radiography after 2 years of follow-up with different levels of association.46,–,49 Nevertheless, the majority of new syndesmophytes develop at vertebral corners where imaging shows no inflammation.

    Imaging

    One of the major advances in the field of SpA is the availability of MRI and particularly the advent of T2-weighted sequences that suppress the signal from bone marrow fat allowing visualisation of the bright signal from free water reflecting inflammation in subchondral bone marrow of the SIJs, vertebrae and posterolateral elements of the spine. This imaging technique makes it possible to visualise inflammation in SIJs and spine, even before structural damage is present. Until recently, the diagnosis and classification of SpA relied typically on structural damage assessed by conventional radiographs or CT scan. As inflammation precedes structural damage, MRI makes it possible to make an earlier diagnosis. This has been incorporated in the newly developed ASAS (for ‘Assessment of SpondyloArthritis international Society’) SpA criteria (see later).50 For making a diagnosis, most focus is on MRI of the SIJs. The reason is that most information is obtained from MRI of the SIJs, the disease frequently starts in the SIJs, and in the validation study of the ASAS SpA criteria most patients with inflammation on the spine MRI showed also inflammation and/or structural damage in the SIJs. In this study the addition of spinal inflammation on the MRI did not add to the information already obtained from the SIJs.50

    However, evaluation of the diagnostic utility of MRI in early disease is still limited to small studies with limited data from age-matched and sex-matched controls, diverse approaches to the evaluation of the SIJs and the recording of lesions, and the use of dynamic MRI with gadolinium contrast enhancement. Summation of this data has provided an estimated likelihood ratio of 9 for the inclusion of MRI in diagnostic algorithms for SpA. The presence of an increased signal on T2-weighted fat-suppressed sequences in subchondral bone of the SIJ on two consecutive semicoronal slices has been proposed as a diagnostic criterion on the basis of expert consensus.51 This will require prospective validation with appropriate controls and plain radiographic follow-up.

    In contrast, spinal inflammation is more frequently used to assess the activity of the disease as an aid to decide if a patient needs to be treated with a TNF blocker and to assess efficacy of treatment. This latter application has successfully been applied to clinical trials with TNF blockers showing major improvement in spinal (and SIJ) inflammation after start of a TNF blocker whereas there was stable activity in patients treated with placebo.52 There are three scoring systems for assessment of spinal inflammation: Ankylosing Spondylitis spine MRI score for activity (ASspiMRI-a), Berlin method and the Spondyloarthritis Research Consortium of Canada (SPARCC).53,–,55 These all demonstrate adequate discrimination between anti-TNF and placebo treatment despite differences in reliability. Scoring of structural lesions in SIJs and spine are less well established. Assessment of structural damage is still mostly performed on conventional radiographs. Methods to assess damage on conventional radiographs are the Bath ankylosing spondylitis radiology index (BASRI), Stoke Ankylosing Spondylitis Spine Score (SASSS) and modified SASSS (mSASSS).56,–,58 The first being a global grading method, also including the SIJs, and the latter two detailed methods scoring features such syndesmophytes at the corners of the vertebrae. The SASSS includes only radiographs of the lumbar spine, the BASRI and mSASSS also cervical spine. The mSASSS is the preferred scoring method because of the inclusion of cervical and lumbar spine, highest reliability and sensitivity to change.

    ASAS SpA classification criteria

    ASAS has developed and validated new criteria for classifying patients with (predominantly) axial SpA, peripheral SpA and the entire group of SpA.59 60 The major disadvantage of the modified New York criteria is that these rely heavily on structural damage in SIJs and consequently cannot make an early diagnosis. Moreover, these criteria focus on axial disease only, while AS is seen nowadays as part of the entire SpA spectrum. The Amor and European Spondyloarthropathy Study Group (ESSG) criteria include indeed the entire SpA spectrum, but the disadvantage is that it is not known what the predominant feature (axial or peripheral) is. The new ASAS criteria has the option to inform on the predominant feature, but still has the possibility to describe the group as a whole.

    For the axial SpA criteria, imaging of the SIJs is still a hallmark (figure 1). However, now inflammation on MRI counts as positive for the imaging feature. But in patients without positive imaging, HLA-B27 is a significant feature. In this circumstance, two additional SpA features are required. Another important difference with the older criteria is that no longer inflammatory back pain (IBP) is an obligatory sign. The entry criterion is back pain of at least 3-month duration starting before the age of 45, while the presence of IBP is counted as an extra SpA feature. Also for IBP new ASAS criteria have been developed and validated, which perform better than the widely used Calin criteria.61 The difference in development is that the Calin criteria were derived from the discrimination between patients with AS versus non-AS, whereas the ASAS IBP criteria discriminated IBP from non-IBP in a real patient exercise by experts, validated afterwards in a large prospective study. If four out of five of the following criteria are present, the patient is considered to fulfil the ASAS IBP criteria: age at onset <40 years, insidious onset, improvement with exercise, no improvement with rest and pain at night (with improvement upon getting up) (sensitivity 79.6% and specificity 72.4%). The sensitivity and specificity of axial SpA criteria are 82.9% and 84.4%, respectively. The peripheral SpA criteria have been published as an abstract only. The entry criterion for the peripheral SpA criterion is arthritis, enthesitis or dactylitis. For some of the other criteria only one needs to be present, as for others two criteria are mandatory. The sensitivity and specificity of the peripheral SpA criteria are 78.0% and 82.2%, respectively The criteria for axial SpA and for peripheral SpA can be combined in the following way to get one criteria set for SpA: patients with back pain (with or without peripheral symptoms) follow the criteria set for axial SpA; patients with peripheral symptoms only follow the criteria for the peripheral SpA. This combined set has a sensitivity and specificity of 78.0% and 83.7%, respectively.

    Figure 1
    Figure 1

    ASAS axial SpA criteria. ASAS, ‘Assessment of SpondyloArthritis international Society’; SpA, spondyloarthritis.

    Outcome assessment

    In SpA, there is a major focus on patient-reported outcome measures. These include the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) as well as the ASAS 20 response criteria. Although these generally function well, there was a need to incorporate also objective signs of disease activity in the assessment, particularly as the assessment of disease activity by patients and doctors are driven by completely different aspects and correlate only moderately. In particular, the evaluation and use of more effective (expensive) TNF blockers required better outcome measures. In addition to the ASAS 20 response criteria, more strict criteria have been developed and validated: ASAS 40 and ASAS 5/6 criteria.61 The ASAS 40 use the same four domains as the ASAS 20 response criteria (pain, function, morning stiffness, patient global) but now with 40% improvement and 2 units on a 0–10 scale in at least three domains without worsening in the remaining domain. The ASAS 5/6 criteria are fundamentally different as these include two objective domains: acute phase reactants and spinal mobility. At least five domains should show an improvement of 20%, consequently there needs to be improvement in at least one objective domain.

    Another new development is the ankylosing spondylitis disease activity score (ASDAS), which is a continuous measure of disease activity, similarly developed as the DAS for RA.63 The ASDAS includes patient-reported outcomes as well as C reactive protein (CRP). There has been an extensive validation programme showing that the ASDAS is a reliable, discriminative and sensitive measure, performing at least equally well to BASDAI but in most circumstances better. Cut-offs for improvement, low/moderate/high disease activity and remission will be defined in the near future. The use of the ASDAS as the primary outcome in a trial with a TNF blocker reduces the number of patients by about 40% in comparison to the use of the BASDAI with maintaining similar power. As an alternative to the ASDAS with CRP there is an ASDAS with erythrocyte sedimentation rate to be used in cases where CRP is not available. However, the two ASDAS scores are not interchangeable (figure 2). ASAS has recently published a handbook with detailed description of many of the outcome measures, criteria and examples of imaging.61

    Figure 2
    Figure 2

    Calculation of the ASDAS with CRP (preferred) or ESR (alternative). ASDASCRP is the preferred ASDAS but the ASDASESR can be used in case CRP is not available. CRP in mg/l; all patient assessments on a 10 cm scale. ASDAS, ankylosing spondylitis disease activity score; CRP, C reactive protein; ESR, erythrocyte sedimentation rate.

    Treatment

    Although the basic treatment has remained the same (education, physical therapy and non-steroidal anti-inflammatory drugs (NSAIDs)), the coming of TNF blockers has advanced treatment tremendously. The overall management of the disease is summarised by the ASAS/European League Against Rheumatism (EULAR) recommendations.64 International recommendations to treat patients with TNF blockers have also been published.65 For the treatment of AS it is important to make a difference between patients with axial symptoms and patients with peripheral symptoms (arthritis, enthesitis). Axial symptoms do not respond to disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine, methotrexate or leflunomide. Sulfasalazine is moderately effective in patients with peripheral symptoms. Several placebo-controlled trials evaluating infliximab, etanercept, adalimumab and golimumab have now demonstrated substantial symptomatic benefit in NSAID-refractory patients with reduction in pain, stiffness, function and fatigue which may be seen as soon as 2 weeks after the start of treatment while improvement in spinal mobility is also evident from 12 weeks onwards.62 66,–,68 Maximal benefit is seen by 12 weeks and is sustained over prolonged periods of several years. Other benefits include improved quality of life, reduced sick leave, improvement in work productivity, reduced acute phase reactants, improvement in synovial histopathology and reduction in MRI features of inflammation that are sustained over several years. These agents appear to be of similar clinical efficacy for axial and peripheral joint inflammation with clinically evident responses being observed in about 60% of patients. All categories and subgroups of patients appear to respond though younger patients with shorter disease duration, minimal impairment of function, elevated CRP and MRI features of inflammation appear to respond best. However, even patients with complete spinal ankylosis report significant symptomatic improvement. Small studies in patients with early SpA, not yet fulfilling the modified New York criteria show that the efficacy of TNF blockers is similar as to patients with established disease. Larger studies are underway.

    Prevention of radiographic progression has not yet been demonstrated in these trials and further work is required, particularly in early AS cohorts, to determine if this might reflect the inclusion of patients with long-standing disease and/or TNF independent pathways of new bone formation. Interest in NSAIDs as disease-modifying agents has been rekindled by data indicating reduced progression in patients on continuous as opposed to on-demand treatment with NSAIDs.69 Further work is required to determine the underlying mechanism and whether this observation can be replicated in other studies.

    Research agenda and anticipated progress

    Advances in genetics will undoubtedly identify additional disease-associated genes while fine mapping will identify the principal variants associated with disease as a prelude to functional studies. Several genome wide association scans followed by meta-analytical studies will be necessary to provide adequate power to identify genes with relatively modest effects (OR 1.2) and this will require high-throughput microarray-based SNP genotyping technologies together with genotyping chips that will allow assessment of a large number of markers across the entire genome (≥500 000 SNPs). Pinpointing genetic associations will facilitate understanding of pathophysiology and identify new directions in treatment as exemplified by the discovery of disease associations with ERAP1 and IL23R. Quantitative traits such as radiographic progression will likely be investigated in multicentre cohort studies where patients have been carefully phenotyped. These may identify prognostic biomarkers, which may facilitate studies of disease-modifying therapies by selecting for ‘rapid progressors’. Rapid progress in our understanding of the role of IL23, IL17 and IL6 are anticipated based on continuing work in animal models and the assessment of responses to targeted therapies in human disease. Further clarification of the link between inflammation and ankylosis will facilitate optimal treatment. If inflammation is indeed the principal trigger for reparative responses, a strong case will be made for early and aggressive anti-inflammatory treatment. Conversely, if inflammation and reparation are triggered by common factors but proceed along largely independent pathways, new therapeutic approaches targeting excessive reparation will need to be developed for effective disease modification. This in turn places a high priority on prognostic studies aimed at identifying clinical, imaging and serological biomarkers that have high predictive validity for radiographic progression so that patients at risk can be readily identified in the clinic.

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    Footnotes

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Competing interests DvdH is a consultant for Abbott, Centocor, Lilly, Merck, Novartis, Pfizer, Roche, Schering-Plough, UCB and Wyeth. WM is a consultant for Abbott, Centocor, Pfizer, Schering-Plough and Wyeth.