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Towards new measures of inflammation in spondyloarthritis

Turina, M.C.

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Citation for published version (APA):Turina, M. C. (2016). Towards new measures of inflammation in spondyloarthritis.

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Download date: 20 Feb 2020

General discussion and summary 8

114 GENERAL DISCUSSION AND SUMMARY

GENERAL DISCUSSION AND SUMMARY

Spondyloarthritis (SpA) is an inflammatory disease of the axial skeleton and peripheral joints which can be associated with extra-articular manifestations such as uveitis, psoriasis and inflammatory bowel disease (IBD). In this thesis we have addressed four key questions:

1) Can we find tools for early diagnosis? Currently, the delay between first symptoms and diagnosis is still 5-10 years. As non-steroidal anti-inflammatory drugs (NSAIDs) and anti-tumor necrosis factor (TNF) treatment are also effective in early disease, reducing this diagnostic and therapeutic delay could lead to major gains in overall health, function, and quality of life;

2) Can we use serum biomarkers to predict treatment response? Since a number of new treatments are available to treat SpA effectively, it is important to predict which patients will respond optimally to which treatment;

3) Can we identify outcome measures for peripheral SpA? We have well validated outcome measures in axial SpA which allow us to reliably determine the effectiveness of therapeutic interventions; this is currently lacking in peripheral SpA;

4) Can we find markers that predict structural damage? Structural damage in SpA is often characterized by new bone formation rather than by bone destruction (such as in RA). Although we can halt joint destruction with TNF blockade, we are currently not able to significantly modulate new bone formation.

This thesis contributes to addressing these challenges by exploring the value of serum biomarkers, either as single tools or in the context of composite outcome measures.

EARLY DIAGNOSIS

Current strategies

The diagnostic delay of axial SpA is still approximately 5-10 years.1–3 Of note, data on the delay between first symptoms and diagnosis in peripheral SpA are still lacking. Diagnosing SpA in the early phase of the disease has become increasingly important, since 1) disease activity as measured by signs and symptoms of inflammation is similarly high in early and established disease,4,5 2) treatments used to treat signs and symptoms in established disease are equally effective in early disease,6–11 and 3) patients may respond better to treatment in the early phase of the disease.12 In the past decade, a number of strategies have been developed to capture the disease in the early phase.

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The first is the development of early referral procedures from the general practitioner or orthopedic surgeons to the rheumatologists. Several referral criteria have been evaluated, using back pain, inflammatory back pain (IBP), human leukocyte antigen-B27 (HLA-B27) positivity, sacroiliitis on magnetic resonance imaging (MRI), positive family history, and good response to NSAIDs as most important criteria.13–17 Overall, the less complex strategies appeared to be most efficiently leading to the diagnosis of axial SpA by the rheumatologist in 16-45% of the referred patients.13–15,18 Still, the diagnostic delay remained above five years, indicating that there is still need for additional tools for the early detection and diagnosis of SpA.

The second strategy to capture axial SpA in the early phase is the use of MRI. In contrast to classical radiographic imaging, MRI can detect axial inflammation before the appearance of structural changes such as erosions and new bone formation. Although this is a very interesting topic to discuss, it is beyond the scope of this thesis.

To conclude, the combination of early referral strategies and the use of MRIs of the SI joints already decreased significantly the diagnostic delay of axial SpA, but the delay on average still remains more than 5 years. The search for other strategies and tools to detect and identify the disease in (very) early phase thus remains important.

Peripheral blood biomarkers

One potential way to decrease the diagnostic delay is the use of biomarkers. A biomarker is defined as a “characteristic that can be objectively measured and evaluated as an indicator of a normal biologic process, a pathophysiologic process, or a pharmacologic response to a therapeutic intervention”.23 Biomarkers can be derived of any tissue or body fluid. Focusing on one of the target tissues of SpA, the peripheral synovitis, our group has previously reported clear histological, cellular, and molecular differences between SpA and other rheumatic conditions.24–27 Although some of these features may also have a diagnostic value, sampling target tissues is a relatively complex and invasive procedure which cannot easily be used in daily clinical settings. Obviously, peripheral blood would be a much more convenient and reliable source for diagnostic biomarkers. Several peripheral blood-derived biomarkers have already been evaluated for diagnostic properties in SpA:

1) Genetic risk factors: the major genetic risk factor for ankylosing spondylitis (AS), the prototype of axial SpA, is HLA-B27. Although 80-90% of the AS patients carry the HLA-B27 gene (and 40-60% in other subtypes),28 HLA-B27 is also found in up to 8% of the general Western population. Accordingly, the positive predictive value of HLA-B27 is rather limited in the absence of a clear clinical suspicion.29,30 As discussed for MRI, testing for HLA-B27 positivity is also only meaningful in individuals with sufficient clinical suspicion of SpA.

2) Several serum markers, including C-reactive protein (CRP), erythrocyte sedimentation

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rate (ESR), and calprotectin, were shown to be elevated in full-blown active SpA compared to healthy controls, and to decrease upon effective treatment.31–33 In chapter 3, however, we demonstrated that these serum inflammatory biomarkers were not or, in case of calprotectin, only marginally elevated in the SPACE cohort (n=310) when comparing early axial SpA with ‘control’ early back pain patients, and that therefore these markers are not useful as early diagnostic markers. To screen for other new candidate biomarkers, we first performed a literature search in chapter 2 on informative biomarkers in related immune-mediated inflammatory diseases, namely psoriasis and IBD. We concluded that human beta defensin-2 (hBD-2)34–37 and lipocalin-2,38–44 were the most interesting candidates to test in SpA since these are interleukin (IL)-17 driven markers and since the IL-23/IL-17 is a major pathogenic cytokine pathway in SpA. Second, we identified IL-27, a cytokine belonging to the IL-23/IL-12 family, as an additional candidate maker since one recent report showed elevated serum levels in full-blown AS versus healthy controls.45 In chapter 3 we determined the serum levels of these three markers in AS and healthy controls but did not detect differences between the two groups. Therefore we did not test these markers in the SPACE cohort. We concluded that the aforementioned serum inflammatory biomarkers were not useful for diagnosing axial SpA at the early phase of the disease.

Two important aspects should be considered when interpreting these data. First, as we did not perform a systematic ‘omics’ approach to find diagnostic serum biomarkers but rather used a targeted approach based on literature data, it cannot be excluded that we have missed interesting, yet unknown serum diagnostic biomarkers. Second, our findings are in line with the concept that SpA is a tissue-specific disease rather than a systemic inflammatory disease and that therefore measuring markers in peripheral blood is not informative. This concept is further supported by our unpublished observations that a) disease-specific molecular and cellular signatures found in target tissues (e.g. myogene signature in SpA synovitis),27 cannot be detected in peripheral blood, and b) global transcriptomic analyses by pan-genomic microarray on peripheral blood cells of early SpA patients versus ‘control’ back pain patients from the SPACE cohort failed to reveal disease-specific expression signatures (Yeremenko and Turina, unpublished data).

3) Auto-antibodies: in contrast to many other rheumatic diseases, SpA is not characterized by the presence of disease-specific autoantibodies.46 Several approaches have been used to screen for potential autoantibodies but overall the results have been disappointing. Duftner et al.47 showed that serum concentrations of antibodies binding to the procaryotically expressed 28-kDa protein were higher in AS versus healthy controls. Chou et al.48 found that levels of anti-agalactosyl immunoglobulin-G antibody (anti-Gal(0) IgG) were elevated in AS and psoriatic arthritis when compared with healthy controls. In another study, plasma of AS, rheumatoid arthritis, and healthy controls, were screened for 3498 proteins, using two protein arrays to determine autoantibodies. In total, 44%, 33% and 8% of the individuals in the different groups had a broad autoantibody response, respectively.49 Nevertheless, all the

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aforementioned results had low sensitivities and specificities, and were never reproduced in independent cohorts. Therefore these autoantibodies do not appear to be useful for diagnostic purposes.

Recently, one group demonstrated IgG-antibodies against CD74 specific for HLA class II-associated invariant chain peptide (CLIP) with high sensitivity (85.1%) and specificity (92.2%) for SpA.50,51 We are currently in the process of confirming these data in our cohorts. In contrast to the published data, and despite using the same assay in the same laboratory, IgG-antibodies against CD74 levels neither were elevated in full-blown AS versus healthy controls nor in early axial SpA versus early ‘control’ back pain patients. Nevertheless, ongoing analyses suggest that anti-CD74 IgA antibodies may be elevated in active AS versus healthy controls with a sensitivity of 38% and a specificity of 95%. In the near future, we will determine anti-CD74 IgA in the SPACE cohort to see whether these autoantibodies may have an early diagnostic value.

Inception cohorts

A key requisite for the search for novel diagnostic biomarkers is the availability of appropriate inception cohorts. An inception cohort is a longitudinal cohort with a predefined group of persons gathered at a specific time point as early as possible in the development of a specific disorder. These cohorts could facilitate the search for valuable clinical, biological, and imaging biomarkers with the ultimate goal to dramatically decrease the time to diagnosis and start treatment without delay. In contrast to longitudinal studies, cross-sectional studies are found to be obsolete for this purpose.52 Several interesting inception cohort studies have been initiated over the last decade. GESPIC5 is an inception cohort of diagnosed AS and nr-axSpA patients with a maximum symptom duration of 10 and 5 years, respectively, which is very useful for the analysis of progression of structural damage. Esperanza53 is a cohort with patients having SpA features for at least 3 months and at most 2 years. DESIR54 and SPACE55 included patients with inflammatory back pain of 3 years at most, or back pain of 2 years at most, respectively. As described in chapter 4, we have initiated a different inception cohort study of seemingly healthy (i.e. individuals who are not known with musculoskeletal complaints by the general practitioner or rheumatologist) first-degree relatives (FDRs) of HLA-B27 positive patients (the so called ‘Pre-SpA’ cohort). The estimated recurrence risk for SpA in these relatives is 12%, which is much higher than the 0.5-1.5% risk in the general population.29,30,56 In contrast to other cohorts, in which clinical signs and symptoms (most often back pain) are required for inclusion, the Pre-SpA cohort thus focuses on baseline evaluation and prospective follow-up of non-symptomatic individuals at risk. In the first pilot analysis of Pre-SpA, we found that 17 out of 51 (33%) FDRs already fulfilled SpA classification criteria (the Assessment of Spondyloarthritis international Society [ASAS] axial SpA and/or the European Spondylarthropathy Study Group [ESSG] criteria)16,57 at baseline. Although fulfilling classification criteria does not necessarily imply the presence

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of a clinical diagnosis, these preliminary data suggest the presence of unrecognized disease in a significant proportion of FDRs. Interestingly, a similar proportion of HLA-B27+ and HLA-B27- FDRs fulfilled the classification criteria. Moreover, 6 of the 38 (16%) FDRs who did not fulfill the classification criteria had imaging abnormalities suggestive of SpA. Further follow-up of these patients will clarify who will develop established SpA, and will shed light on the question if these early abnormalities should be considered false positive. In the future, we will perform several other analyses in these FDRs (e.g. serum markers, genetics) in the search for new biomarkers with the ultimate goal to decrease the diagnostic delay of SpA. Based on the preliminary data from this pilot study, we are now coordinating a national study in 6 SpA centers of excellence (AMC, VUMC, LUMC, MUMC, UMCG, and Maasstad hospital) aimed to include and prospectively monitor 500 FDRs.

To conclude, diagnosing axial SpA at the early phase of the disease (at an earlier phase than currently possible) is an important but difficult goal. Early referral strategies and MRIs have resulted in a significant decrease of the diagnostic delay, but the delay should be further diminished. Investigations of serum biomarkers have not yet resulted in reliable diagnostic tools. Potential leads are the anti-CD74 IgA antibodies and the use of new ‘omics’ technologies. In all cases, the availability of large and well-documented early and preclinical SpA inception cohorts is essential for the evaluation and validation of diagnostic biomarkers.

PREDICTING TREATMENT RESPONSES

Treatment regimen

Although the number of registered treatment for SpA is still limited when compared with rheumatoid arthritis, the therapeutic choices are rapidly expanding. In axial SpA, treatment options are limited to NSAIDs58 and TNF inhibitors.6,11,59,60 In peripheral SpA, patients can be treated with local steroids, disease-modifying antirheumatic drugs (DMARDs) such as sulfasalazine,61,62 and TNF inhibitors.9,10 In psoriatic arthritis, patients can be treated additionally with DMARDs such as leflunomide,63–65 apremilast66,67 and methotrexate,68,69 although the effectiveness of the latter DMARD is subject to debate despite common use in clinical practice. Ustekinumab (a monoclonal antibody against the p40 subunit of IL-23 and IL-12),70–72 is a non-TNF inhibitor biological recently registered for psoriatic arthritis. An overview of the currently available therapies is given in Table 1.

Besides the currently available drugs, an exciting new therapeutic option in both AS and psoriatic arthritis is blockade of IL-17, either by using monoclonal antibodies directed against IL-17A (such as secukinumab and ixekizumab) or by monoclonal antibodies blocking IL-17 receptors (such as brodalumab). Large phase III studies showed that secukinumab is effective and safe in both AS and psoriatic arthritis, and this drug is currently in the

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Table 1. An overview of currently available treatment options in ankylosing spondylitis and psoriatic arthritis

Registered drug group

Generic name SpA subtype Mode of action Reference

NSAIDs Non-selective inhibitors: aceclofenac, fenylbutazon, ibuprofen, indomethacin, ketoprofen naproxen, piroxicam, etc. Selective COX-2 inhibitors: celecoxib, etoricoxib, meloxicam

ASPsA

Prostaglandin inhibitor 58

DMARDs/small molecules

Sulfasalazine AS (peripheral joint involvement) PsA

Unknown 61,62

Methotrexate PsA Folic acid antagonist 68,69

Leflunomide PsA Dihydro-orotaatdehydrogenase inhibitor

63–65

Apremilast PsA PDE-4 inhibitor 66,67

Biologicals TNF inhibitors:adalimumab, certolizumab-pegol, etanercept, golimumab, infliximab,

AS PsA

TNF inhibition 6,11,59,60 73–75

Ustekinumab PsA IL-23 and IL-12 inhibitor (p40 subunit)

70–72

AS, ankylosing spondylitis; COX-2, cyclooxygenase-2; DMARDs, disease-modifying antirheumatic drugs; IL, interleukin; NSAIDs, non-steroidal anti-inflammatory drugs; PDE-4, Phosphodiesterase-4; PsA, psoriatic arthritis; SpA, spondyloarthritis; TNF, tumor necrosis factor.

registration phase.70,76,77 Many other drugs, including biologics as well as small molecules, are currently in phase II or III clinical trials in AS and/or psoriatic arthritis (Table 2), with many more in preclinical development. An extensive overview of recent and ongoing clinical trials in SpA was recently provided by Paramarta et al.78

The increasing number of treatment options urge an appropriate prediction, preferably prior to the start of therapy, about which patients will respond well to which treatments in the long-term. For example, 20-40% of the patients do not respond well to TNF inhibitors.56 In clinical practice, a significant part of these partial responders are continuing on TNF inhibitors since there are no other treatment options. With the advent of IL-17 blockade and hopefully other compounds in the near future, it becomes increasingly important to select an adequate strategy prior to the start of the treatment.

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Table 2. An overview of ongoing clinical trials in ankylosing spondylitis and psoriatic arthritis

Drug group Clinical trial phase Mode of action SpA subtype Trial name and reference

Small moleculesTofacitinib Phase 2/Phase 3

JAK inhibitor PsA OPAL

Thalidomide Phase 2 TNF and IL-12 Inhibitor AS NAApremilast Phase 3

PDE-4 inhibitor AS POSTURE

Nilotinib Phase 2 Tyrosine kinase inhibitor

Peripheral and axial SpA

Paramarta et al, unpublished

BiologicalsSecukinumab Phase 3 RCT/

Registration phaseIL-17A inhibitor AS

PsA

79 80

Ustekinumab Phase 2, open label trial

IL-23 and IL-12 inhibitor (p40 subunit)

AS 81

BI-655066 Phase 2 RCT, ongoing IL-23 inhibitor (p19 subunit)

AS NA

Brodalumab Phase 3 RCT IL-17 RA inhibitor PsA NAIxekizumab Phase 3 RCT, ongoing IL-17A inhibitor PsA SPIRIT-P1

SPIRIT-P2

AS, ankylosing spondylitis; IL, interleukin; JAK, janus kinase; NA, not available; PDE-4, phosphodiesterase-4; PsA, psoriatic arthritis; RA, receptor A; RCT, randomized clinical trial.

Current strategies

Several studies have focused on the identification of baseline predictors for treatment response in clinical trials at the group level in axial SpA. Of note, data on baseline predictors in peripheral SpA are lacking. Identifying such baseline predictors is important for designing new clinical studies, in which stratification at baseline is based on these predictors. A post-hoc analysis82 of two clinical trials with active AS patients (n=99) receiving infliximab versus placebo, or etanercept versus placebo and showed that age, Bath ankylosing spondylitis functional index (BASFI), disease duration, and elevated CRP/ESR levels were good predictors for treatment response at week 12, defined by Bath akylosing spondylitis disease activity index (BASDAI). Recently, another large pooled analysis was performed on four randomized controlled trials with etanercept versus sulfasalazine or placebo in 1281 active AS patients to determine the predictors for clinical remission as expressed by ASAS partial remission.83 In this analysis short disease duration of ≤ 2 years and age ≤ 40 years at the time of diagnosis, were good baseline predictors for clinical remission at week 12. Regarding biomarkers in this analysis, patients with elevated CRP levels showed better responses to treatment when compared with patients with normal baseline CRP levels. Similar results were found in other clinical trials with TNF inhibitors83–85 as well as in large observational cohorts with AS patients receiving TNF inhibitors.86,87 To summarize, the baseline predictors short disease

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duration, young age at time of diagnosis, high BASFI scores, and elevated CRP/ESR levels are associated with good response to treatment at week 12. For the scope of this thesis, we have focused exclusively on the biomarkers.

Many recent clinical trials, and mainly those conducted in the early and non-radiographic forms of axSpA (nr-axSpA), have elevated CRP levels or a positive MRI of the sacroiliac (SI)-joints as an important eligibility criterion at screening and/or baseline, which seems justified based on the aforementioned results. Nevertheless, a sub-analysis of ABILITY-1,10 a phase 3 randomized controlled trial with nr-axSpA patients receiving adalimumab or placebo, showed that CRP is indeed a good predictor for clinical response at week 12, but not for response at year 1 and year 3. This finding suggests that CRP does reflect clinical response at the short term but does not reflect a ‘true responder’ who still responds well to adalimumab treatment at the long term. Moreover, CRP is a non-stable biomarker that can easily fluctuate between elevated and normal CRP levels over time, especially around the ‘upper limit of normal’ levels. For example, in the placebo arm of the same ABILITY-1 trial, 14 out of 57 (25%) patients with normal CRP levels at baseline converted into ‘elevated CRP’ between baseline and week 12.88 We recently confirmed the latter result in nr-axSpA patients and AS patients, using the placebo arm of RAPID-axSpA, a phase-3 double-blind randomized controlled trial with certolizumab pegol (MSD) or placebo for 16 weeks.11 Thirteen of the 26 (50%) patients with normal CRP levels at baseline, had elevated levels of CRP in 1-6 consequent visits in the placebo arm (Turina et al., unpublished data). The results of these two analyses suggest that clinical trials should not use single measurements of CRP as a major eligibility criterion. Whether this is also true for MRI, is beyond the scope of this thesis.

The prediction of treatment response is not only important for stratification in clinical trials and for clinical research, but also for the decision-making process of the rheumatologist in individual patients in clinical practice. In AS for example, the clinical decision to start TNF inhibitors is based on a strategy that proclaims TNF inhibitor treatment could be started when a patient has consistently active disease, as expressed by BASDAI≥4, despite the optimal use of NSAIDs.89,90 Since the available effective treatments are expensive and come along with numerous side-effects, ideally the rheumatologist should be able to estimate in advance that a certain patient will have beneficial effects from the treatment. All the aforementioned parameters (including elevated CRP) are informative predictors at the group level, but fail to predict at the individual level.91–93 Thus, we need not only more reliable and robust markers of response to treatment but also markers with sufficient sensitivity and specificity to have a high predictive value in individual patients.

Measuring early changes after treatment

Since at the individual patient level biomarkers at baseline cannot predict whether patients will respond to a certain treatment, an interesting alternative concept might be to search for

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early changes of biomarker levels between baseline and shortly after the start of treatment (e.g. baseline and 2 weeks after treatment). One would expect significant decreases in certain biomarker levels over a short period of time when effective treatment is started. This theory is based on the finding that ‘true’ responders will respond early to treatment, as was published in a post-hoc analysis from the phase 3 ATLAS randomized controlled trial.94 Two hundred-two active AS patients of the total 311 (65%) participating patients received at least one dose of adalimumab and completed five years of follow-up. The best predictor for remission (as expressed by ASAS partial remission and Ankylosing Spondylitis Diseases Activity Score [ASDAS]-inactive disease at year 1 and year 5) was the achieved remission (by ASAS partial remission or ASDAS-inactive disease) after 12 weeks of treatment. Similar results were seen in the post-hoc analysis in peripheral SpA in the ABILITY-2 study, a phase 3 randomized controlled trial where patients received adalimumab or placebo at the first 12 weeks (double blind period) prior to the open label phase up to three years.95 ASDAS-inactive disease or Peripheral SpA Response Criteria (PSpARC) remission at week 12 were the best predictors for clinical remission (ASDAS-inactive disease or PSpARC remission) at years 1 and/or 3, when compared to baseline characteristics. The results of the two studies indicate that a ‘true’ responder to TNF inhibitors in the long term can be predicted by reaching an early response (short term outcome, i.e. 12 weeks of treatment) to this treatment rather than by baseline features alone.

An interesting approach to predict treatment responses very shortly after the start of treatment was demonstrated in chapter 5. Here we evaluated early changes in serum biomarker levels after TNF blockade was initiated. Serum was collected from axial and peripheral SpA patients of a randomized controlled trial, and two open label trials with TNF inhibitors. The latter two cohorts were considered as validation cohorts. These were all proof-of-concept trials, indicating that the sample sizes were relatively small. We selected seven serum biomarkers (hs-CRP, interleukin-6, pentraxin-3, alpha-2-macroglobulin, matrix metalloproteinase-3 [MMP-3], calprotectin, and vascular endothelial growth factor [VEGF]) and determined the levels at baseline and after two or four weeks of treatment, depending on the cohort design. We aimed to determine which of the biomarkers had a high sensitivity to rapid change upon effective treatment in SpA in proof-of-concept trials. We found that in all three cohorts, calprotectin and hs-CRP were good markers with high sensitivity to change upon effective treatment in both axial and peripheral SpA, whereas the levels did not decrease in the placebo arm. We did not find similar results for the other five biomarkers. Although this finding was only based on TNF inhibitors, early changes of calprotectin and CRP levels were also detected in our proof-of-concept trial with secukinumab,76 thereby implying that early changes of calprotectin and CRP levels after effective treatment are not restricted to a certain mode of action. Although these results are only applicable at the group level in a proof-of-concept setting, the detection of early changes of biomarker levels is an interesting approach to further study at the individual level. Once this approach is applicable in clinical practice, the rheumatologist could decide on the treatment regimen

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within two weeks, i.e. maintain the treatment or switch between TNF and IL-17 inhibitors in SpA.

IDENTIFYING OUTCOME MEASURES IN SPA

Objective markers for inflammation versus patient-reported outcomes

Biomarkers may not only be useful for early diagnosis and prediction of treatment responses but also for monitoring disease activity in trials, clinical research as well as clinical practice. Historically, the BASDAI and the Visual Analogue Scales (VAS) for pain or patient global assessment of disease activity have been well validated and broadly used. These measures, however, have two major drawbacks.

First, as most outcome measures used in clinical research in the field of SpA, the BASDAI (a composite score of questions on tiredness, back pain, peripheral pain, enthesitis and morning stiffness) and VAS measures rely completely on patient-reported outcomes (PROs) and therefore may be influenced by many other factors (e.g. intercurrent pathologies, psycho-social factors) besides genuine ‘biological disease activity’. The major issue here is that we still lack biomarkers that directly reflect disease activity in SpA, with CRP levels probably being currently the best ‘proxy’. Therefore, combination of PROs and objective measures such as CRP in a composite index might be the most informative manner to determine disease activity in SpA at the moment. One disease activity index that includes both PROs and an objective measure, is the Ankylosing Spondylitis Disease Activity Score (ASDAS).96,97 ASDAS is a composite of CRP levels and of questions on back pain, patient global, peripheral pain/swelling, and morning stiffness. The discriminatory ability of ASDAS is higher than that of BASDAI, a purely PRO driven composite index.96,98

Second, most disease activity measures have only been validated and used in axial disease, and it remains unknown if they also adequately reflect peripheral disease manifestations. Several other tools have been used to measure peripheral arthritis, enthesitis, and dactylitis in psoriatic arthritis, but these outcome measures then do not capture axial disease activity. As a large proportion of SpA patients display both axial and peripheral disease, we assessed in chapter 6 if composite disease activity indices used in axial SpA could also be used to assess peripheral SpA. Comparing several continuous outcome measures in two independent randomized controlled trials with adalimumab versus placebo in peripheral SpA, we showed that ASDAS and BASDAI performed equally well in terms of sensitivity to change and in discriminatory ability in peripheral disease. Since ASDAS does perform better than BASDAI in axial SpA, we recommend the use of ASDAS (which includes CRP) as preferred outcome measure in SpA.

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PREDICTING STRUCTURAL DAMAGE

In SpA, structural damage is characterized by bone and cartilage destruction as well as by new bone formation, which can eventually lead to total fusion (ankylosis) of the axial skeleton (the spine) and peripheral joints. Total fusion of the spine occurs in 28% and 43% of AS patients with a disease duration of 30-40 years and above 40 years, respectively.99 Accordingly, the structural damage due to new bone formation is an important co-determinant (together with active inflammation) of spinal mobility, function, and quality of life over time.100 Whereas TNF blockers can potently inhibit inflammation and joint destruction in SpA, they unfortunately fail to significantly halt new bone formation. Therefore, an ultimate challenge is to halt or even prevent radiographic spinal progression. We will discuss here the different theories on new bone formation in SpA as well as potential strategies to predict which patients will suffer most from this aspect of the disease. Such prediction is very important for a number of reasons. First, it allows to reassure those patients who will not develop pronounced osteoproliferation. Second, it is needed to stratify patients in clinical research on structural damage in SpA. And third, it will be an essential determinant of individualized treatment if future research demonstrates that either very early treatment or drugs targeting different pathogenetic mechanisms (such as potentially the previously discussed IL-17 inhibitors) do halt new bone formation.

Inflammation and new bone formation

There are three main theories about pathophysiological new bone formation. First, Sieper et al.101 hypothesized that remodeling is a repair process triggered by an initial phase of inflammation and tissue destruction. In case this theory is correct, TNF blockade might be able to halt new bone formation only when started in a very early disease stage, again emphasizing the importance of decreasing the diagnostic delay. The key question would then become which patients benefit most from such an early and aggressive treatment approach. Second, Lories et al.102 hypothesized that “entheseal stress” leads to triggering of two largely independent processes: an acute inflammatory reaction, which evolves then to chronic inflammation, and activation of progenitor cells that generate new bone. The uncoupling of inflammation and new bone formation in this model implies that, whereas all patients may require anti-inflammatory therapy, a specific treatment to target the bone remodelling pathway should be developed and given to patients prone to develop spinal new bone formation. Third, based on data in pre-clinical models, our group proposed that new bone formation is directly driven by inflammatory mediators distinct from soluble TNF, including transmembrane TNF (van Duivenvoorde et al., unpublished data) and IL-17A (van Tok et al., unpublished data). If this concept can be translated to human SpA, it would imply that it is crucial to identify which patient will not show extensive new bone formation and may thus be effectively treated with NSAID or TNF inhibitor versus those who may benefit

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from other targeted treatments such as IL-17 blockade.

Current strategies in predicting new bone formation

The “Outcome in AS International Study” (OASIS) cohort, a longitudinal study of 217 consecutive AS patients with a follow-up period of 12 years with clinical and imaging data, allowed to identify a series of clinical and imaging risk factors for radiographic progression of disease. The most important predictors in this study were high disease activity, smoking, HLA-B27 positivity, male gender, older age, and already existing syndesmophytes at baseline.103–105 Also serum biomarkers had been explored in the context of radiological progression of spinal disease, including CRP,106,107 ESR,103 matrix metalloproteinase (MMP-3),108,109 dickkopf-1 (Dkk-1),110–112 visfatin, leptin,113–115 and VEGF.116,117 In chapter 7, we additionally determined the value of calprotectin using the GESPIC cohort. Calprotectin was found to be an independent predictor for new bone formation, but was not superior to CRP. It thus appears that several biomarkers are significantly associated with new bone formation at the group level but, unfortunately, none of these markers is sensitive and specific enough to be used for prediction of structural damage in individual patients. Besides clinical features and biomarkers, multiple studies have explored the value of MRI visualization of inflammation and fatty changes as predictor of new bone formation. As the published results are partially discrepant118,119 and as imaging was not the focus of this thesis, we will not discuss this here in detail. However, it is crucial to realize that novel imaging technologies, including but not restricted to MRI, may form a very promising venue to measure objectively inflammatory and structural tissue changes in SpA and thereby may in the future be more appropriate than serum biomarkers for SpA detection, monitoring, and prediction. To illustrate this concept, we will briefly discuss here novel developments in the use of PET-CT in axial SpA.

PET-CT imaging with specific tracers for the detection of new bone formation

Positron emission tomography-computed tomography (PET/CT) or PET/MRI allows to visualize the uptake of specific radiolabelled tracers in tissues and cells. For example, labelled glucose will be taken up by metabolically active tissues. Our colleagues form the VUMC recently explored the value of PET/CT with [18F]-fluoride as the uptake of this specific tracer in bone represents the blood flow and osteoblastic bone synthesis and activity at a specific location. A pilot study compared [18F]-fluoride PET/CT, MRI and X-ray of the spine in six TNF inhibitor naïve AS patients.120 An increased uptake of [18F]-fluoride on PET/CT was associated with corner inflammatory lesions (CIL) on MRI, and with existing syndesmophytes on the X-ray of the spine (OR=55.1; 95% CI, 7.3-422.3; p<0.001). Buchbender et al.121 studied PET/MRI-SI joint and spine in 13 active, TNF inhibitor naive AS patients according to the mNY criteria. They reported that [18F]-fluoride PET/MRI bone marrow edema and to a lesser extent fatty deposition was associated to osteoblastic activity, whereas structural changes (including

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sclerosis, erosions, ankylosis) were not frequently associated with osteoblastic activity. This is an interesting finding since the osteoblast activity was seen at sites where no structural changes were seen on MRI. Moreover, at several sites, elevated [18F]-fluoride uptake was seen whereas simultaneous MRI abnormalities were not depicted.

Although these studies are still preliminary and more data from follow-up studies are awaited, both studies illustrated well the potential of new molecular imaging techniques to visualize, measure, and monitor the disease processes in the target tissues of SpA. As our data presented here in this thesis tend to suggest that SpA disease processes are not easily captured by serum biomarkers and as most target tissues of SpA (such as spine, SI joints, and entheses) are difficult to approach, molecular imaging should probably be an area of major research investment in the future years.

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