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Towards new measures of inflammation in spondyloarthritis

Turina, Maureen

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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: 16 Jun 2019

https://dare.uva.nl/personal/pure/en/publications/towards-new-measures-of-inflammation-in-spondyloarthritis(0e60ea86-b5ef-4d67-bdaa-7f54a9ddd23b).html

Serum biomarkers in spondyloarthritis-

related diseases: lessons from psoriasis and

inflammatory bowel diseases

Maureen C. Turina, Robert Landewé, Dominique L. Baeten

Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and

immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam,

The Netherlands

Submitted for publication

2

20 SERUM BIOMARKERS IN PSORIASIS AND IBD

SUMMARY

Early diagnosis, monitoring of disease activity, prediction of treatment response, and structural outcome remain major challenges in spondyloarthritis (SpA). Biomarkers could play a role in addressing these challenges, but in SpA there is a lack of suitable biomarkers. As SpA is clinically and pathophysiologically closely related to psoriasis and inflammatory bowel disease (IBD), we reviewed the value of serum biomarkers in these conditions with the aim to find potential candidates for assessing SpA. Candidates of interest were antimicrobial peptides, including human beta defensin-2 (hBD-2) and lipocalin-2 (LCN-2), and class-1 MHC molecule beta2-microglobulin. Since these biomarkers are relevant in psoriasis and/or IBD from a pathophysiological point of view, and may play a role in the pathogenesis of SpA, we recommend further exploration of their value as biomarker in the diagnosis and prognosis of SpA.

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UNMET NEEDS IN SPONDYLOARTHRITIS

Spondyloarthritis (SpA) is an immune-mediated inflammatory disease affecting the spine, the peripheral joints and extra-articular tissues such as the skin, the gut, and the eye.1 The pathology of SpA is characterized by a combination of chronic tissue inflammation, destruction of cartilage and bone, and pathological new bone formation, that may lead to ankylosis. Despite major advances in the field, such as the use of magnetic resonance imaging (MRI) to detect spinal inflammation and to find appropriate patients for treatment with TNF blockers,2–8 several important challenges remain to be addressed.

First, there is a huge diagnostic delay of approximately 5-10 years between the onset of SpA symptoms and the diagnosis.9–11 This delay is due to the fact that the early clinical signs and symptoms are often non-specific, that pathognomonic features of SpA, such as radiologic sacroiliitis, only appear late in the disease course, and that well-known biological markers such as HLA-B27 lack specificity (many healthy individuals carry HLA-B27) and therefore predictive value in the diagnostic context. Second, good biological predictors for treatment response are lacking. Currently, the only informative marker is C-reactive protein (CRP). Nevertheless, CRP as a marker for treatment response falls short because only one third of the patients have elevated CRP levels prior to treatment. Third, the progression rate of new bone formation as observed on consecutive X-rays of the lumbar and cervical spine is very slow and besides only occurs in a relatively small group of patients. Currently, markers predicting which patients will develop significant new bone formation are lacking.

Overall, an early diagnosis, a proper prediction of structural damage, as well as prediction of treatment response, all in individual patients, remain major challenges in SpA. Biomarkers could be of value in addressing these challenges.

BIOMARKERS IN SPONDYLOARTHRITIS

A biomarker is 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”.12 A biomarker should be sensitive, specific, reproducible, and deriving the biomarker from a patient should preferably be a non-invasive procedure. Taking these criteria into account, biomarkers can have an important role to fulfill the previously defined unmet needs in the process of diagnosis, treatment response and prognosis. Several biomarkers have already been studied in SpA. Common markers of systemic inflammation such as CRP and erythrocyte sedimentation rate (ESR) have been used for a long time in the clinical care of SpA patients. Accordingly, elevated CRP is included as a criterion in the ASAS classification criteria for axial SpA criteria but not for ASAS peripheral SpA criteria.2,13


When elevated, CRP levels may correlate with disease activity measures and decrease upon effective treatment.14–17 Moreover, CRP appears to be a predictor for radiographic axial progression.18 However, CRP and ESR are only elevated in 30 to 50% of the SpA patients with clinical signs and symptoms of active disease and inflammation14–17 and, obviously, are not specific for SpA. The limited sensitivity and specificity explains why CRP and ESR can be useful biomarkers at the group level (such as in clinical trials) but lack sufficient predictive value to be used in individual patients.

Other serum markers of inflammation that have been studied in SpA are Interleukin-6 (IL-6) and calprotectin. IL-6 is the main driver of CRP and, similar to CRP, serum IL-6 levels are significantly increased in active SpA and decrease upon clinical response after tumour necrosis factor (TNF) blockade.19,20 The calcium-binding protein calprotectin, a heterodimer of S100A8 and S100A9, is expressed and secreted during monocyte infiltration into inflamed tissues, including macrophage infiltration in synovial tissue of SpA patients.21,22 Calprotectin serum levels are elevated in SpA, correlate moderately well (r=0.40-0.60) with disease activity, and decrease upon TNF blockade.21–23 Moreover, calprotectin serum levels is an independent predictor for radiological axial progression at the group level.24 Two other biomarkers that were studied in SpA are more related to the pathological processes than to inflammation as such. Vascular endothelial growth factor (VEGF), a growth factor involved in neo-angiogenesis, may be involved in the pronounced hypervascularity in SpA synovitis.25,26 Serum VEGF levels are significantly elevated in SpA versus healthy controls and significantly albeit moderately at best correlate (r=0.22-0.44) with disease activity, but levels do not decrease after short-term treatment with TNF blockers.20,27 Whereas an original report indicated that serum VEGF levels were predictive of new bone formation,28 these results could not be confirmed by others.29

Matrix metalloproteinase-3 (MMP-3) is an enzyme involved in tissue remodelling and cartilage damage. MMP-3 expression was elevated in synovial tissue, synovial fluid and serum in SpA and this expression correlated well with disease activity30–34 and normalized upon effective treatment.30

With regard to predicting new bone formation in ankylosing spondylitis (AS), the prototype of axial SpA, most studies have focused on molecules involved in the regulation of osteoblast activity, including the wnt-pathway, which is involved in the process of new bone formation. Dickkopf-1 (DKK1) and sclerostin are inhibitors of this pathway, and Diarra et al.35 found that serum DKK1 levels were decreased in AS patients versus healthy controls or rheumatoid arthritis patients and low levels were associated to radiographic axial progression as expressed by syndesmophytes formation. These results were confirmed by others.36–38 For sclerostin, discordant results were seen regarding the relationship with radiographic axial spinal progression.36,39–42

Finally, several studies have screened for disease-specific autoantibodies as potential

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diagnostic biomarker in SpA. Unfortunately, most studies did not find disease-specific autoantibodies and the few that were reported could not be independently confirmed.43–45 Recently, one group found elevated levels of IgG autoantibodies CD74 specific for HLA class II-associated invariant chain peptide (CLIP) in SpA.46,47 These data as well as the diagnostic value of this autoantibody should be validated in independent cohorts.

In summary, despite major efforts over the last years only few biomarkers have been described and validated in SpA, and often these biomarkers are useful at the group level but lack specificity to be used in individual patients in clinical care. Interestingly, SpA is genetically, pathophysiologically and clinically associated with psoriasis and inflammatory bowel diseases (IBD), two conditions in which serum biomarkers have been described. Therefore, we reviewed here the value of biomarkers in these conditions and discuss their potential utility for SpA. Reviewing was done for the settings of diagnosis (i.e. difference between disease and healthy or disease and similar inflammatory diseases), with respect to correlation with disease activity and response to effective treatment, as well as for predicting structural damage (in axial SpA). We have evaluated both the pathophysiological and clinical value of these markers.

SERUM BIOMARKERS IN PSORIASIS

Psoriasis is an immune-mediated, chronic inflammatory disease primarily of the skin but can also affect nails and peripheral and axial joints. The disease is characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes and infiltration of immune cells. Roughly 1 in 5 psoriasis patients will develop psoriatic arthritis (PsA), one of the phenotypical forms of SpA.48 At the genetic level, SNPs in IL-23R and Th-17 genes have shown to be associated with both psoriasis and SpA.

In clinical practice, a diagnosis of psoriasis is based on clinical history and examination and, in case of diagnostic uncertainty, skin biopsies. Disease activity is mainly determined by the Psoriasis Area and Severity Index (PASI),49 which includes the percentage of affected skin area, the erythema, the induration, and scaling. Currently, serum biomarkers do not play an important role in clinical practice but are extensively studied in clinical trials (Table 1).

Serum CRP levels were found to be elevated in the moderate and severe forms of psoriasis but not in patients with mild disease, when compared with the healthy individuals.50,51 Several studies have reported CRP elevation in 17-45.7% of the psoriasis patients versus 1% in the control group.51–53 Furthermore, CRP levels decreased significantly after effective treatment was started.51,54–57 It is therefore only a potentially useful marker for disease activity in patients who did not receive systemic treatment for at least one month. In the treated patients, PASI is preferred to monitor disease activity. ESR levels were elevated in


Table 1. Serum biomarkers in psoriasis: elevation in comparison with healthy controls, correlation with disease activity according to PASI, and modulation by effective treatment

Biomarker

Elevation incomparison with healthy controls

Correlation withdisease activitymeasured PASI Treatment response References

CRP + +/- +/- [51–55]ESR + NA NA [58]TNFα + NA + [59, 60]TNFα-R1 + +/- NA [59, 66, 77, 99]IFNγ + NA NA [60]IL-8 + - NA [59, 60, 63]IL-12 +/- + NA [60]IL-17 +/- + + [59, 60, 64, 65]IL-18 + + + [60, 61, 70]IL-22 + + + [59, 62, 65]E-selectin + +/- NA [63, 66–68]ICAM-1 + + +/- [63, 66, 67, 69, 70]VAP-1 + - - [72–74]S100A8/A9 (calprotectin) + + NA [75, 76]LCN-2 + +/- - [77–80]hBD-2 + + +/- [81, 82]Resistin + +/- +/- [83, 90, 91]Leptin + - - [83–87, 90]Adiponectin - +/- +/- [84–86, 88, 90, 92]Ghrelin + + - [89, 90]RBP-4 + + - [80, 85]VEGF + + +/- [59, 62, 93–95]Nitric oxide + +/- + [94, 96–98]

CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; hBD-2, human beta-defensin-2; ICAM-1, intracellular adhesion molecule-1; IFNγ, interferon gamma; IL, interleukin; LCN-2, lipocalin-2; NA, not applicable; PASI, Psoriasis Area and Severity Index; RBP-4, retinol binding protein-4; TNF, tumor necrosis factor; TNFα-R1, tumor necrosis factor alpha-receptor 1; VEGF, vascular endothelial growth factor; VAP-1, vascular adhesion protein-1.

approximately half of the psoriasis patients compared to healthy controls. Elevated ESR was clearly more frequent in the active state of the disease (80%) versus non-active psoriasis.58

Cytokines, including interferon-gamma (IFNγ), TNF-α, TNF-R1, IL-6, IL-8, IL-12, and IL-18, IL-22, and IL-23 have been investigated thoroughly in psoriasis. Coimbra et al. and others59–63 have found that the serum levels of these cytokines were overall significantly higher in psoriasis as compared with healthy controls. But the data on the correlation with PASI were rather conflicting. Psoriasis-specific treatment including methotrexate, UV-A/UV-B treatment, and TNF blockade did have an effect on serum levels of these cytokines.59,60,64,65

Adhesion molecules are expressed by activated tissue cells (e.g. endothelium) as well as leukocytes and allow selective migration of distinct leukocyte subsets to specific tissues and

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sites of inflammation. For example, activated epithelial cells express E-selectin, which can interact with E-selectin on another epithelial cell or with alpha E beta 7 (a member of the integrin family) on CD8 positive T cells. Of the soluble adhesion molecules that can easily be measured in serum, E-selectin, ICAM-1, and VAP-1 are best studied in psoriasis.63,66–74 All of these molecules showed elevated serum levels in psoriasis versus healthy controls. Soluble E-selectin and ICAM-1 levels, however, were consistently (but only weakly to moderately) associated with disease activity as expressed by PASI scores (r=0.44 and r=0.26-0.43, respectively). Accordingly, only E-selectin levels decreased significantly and consistently upon effective treatment.63,67,68,71,72

Among the antimicrobial peptides and proteins (AMP), calprotectin (S100A8/A9 proteins), lipocalin-2 (LCN-2, also called neutrophil gelatinase-associated lipocalin [NGAL]), and human β-defensin-2 (hBD-2) were associated with psoriasis. Highly up-regulated calprotectin levels were found in a proteomic analysis of the epidermis from psoriasis patients.75 In addition, Benoit et al.76 showed that calprotectin levels in serum were significantly elevated when compared to healthy controls and that patients with a high PASI (>15) score also had higher levels of calprotectin. Regarding LCN-2 serum levels, several groups consistently found elevated levels in psoriasis patients when compared with healthy individuals. However, absent or only weak (r=0.27) correlations were found between LCN-2 levels and PASI scores, and serum levels were not normalized by effective treatment.77–80 Serum levels of another AMP, hBD-2, were elevated consistently when compared with healthy donors. Jansen et al.81 reported a high correlation with PASI (r=0.82), whereas another group did not see such a strong correlation (r<0.1, p>0.05).82

Adipokines are produced by fat (adipose) tissue and play a role in metabolic processes, but these proteins are also associated with inflammation. Extensively studied adipokines were resistin, leptin, adiponectin, ghrelin, and retinol binding protein-4 (RBP-4). With the exception of adiponectin, all serum and plasma adipokine levels were significantly higher in psoriasis versus healthy individuals.80,83–89 Only resistin levels correlated weakly with PASI (r2=0.027) and none of the adipokines consistently showed a normalization in levels after effective treatment.80,85,88,90–92

Growth factors are involved in angiogenesis and hypervascularity in psoriasis and are well studied as biomarkers. Of these growth factors, VEGF was the most evaluated markers. VEGF was the most promising in psoriasis, since there were differences in serum levels between psoriasis patients and healthy controls and there was a strong correlation (R=0.65) with PASI.59,93,94 However, serum levels did not normalize upon effective treatment.59,62,95

Nitric oxide (NO) is a free radical and is secreted by various cell types, including fibroblasts and endothelial cells. Tekin et al.96 performed a study in 22 psoriasis samples versus 21 healthy controls and found significantly higher serum levels in the former group. These results were reproduced by others.94,97,98 Furthermore, NO plasma and serum levels


decreased after effective treatment.96

In summary, CRP, ESR, IL-18, IL-22, ICAM-1, calprotectin, LCN-2, hBD-2, VEGF, RBP-4, and NO were the most informative biomarkers since these markers are elevated in patients with the disease when compared to healthy controls, show weak to moderate correlations with disease activity, and/or decrease upon effective treatment at the group level, indicating that -at least from a pathophysiological point of view- these are interesting markers. In spite of this, though, the value of these markers as biomarker in clinical practice (at the individual patient level) seems –if investigated- modest at best. In psoriasis, CRP and ESR were the only serum biomarkers used in clinical practice for the evaluation of treatment, despite the disappointing results earlier mentioned. The most interesting serum and plasma biomarkers in psoriasis from a pathophysiological point of view are the antimicrobial peptides hBD-2 and LCN-2: the expression of both peptides is driven by IL-17 and may therefore reflect a key pathophysiological process in psoriasis skin, although the role in clinical practice remains inconclusive.

SERUM BIOMARKERS IN IBD

IBD includes Crohn’s disease (CD) and ulcerative colitis (UC). Peripheral arthritis and sacroiliitis are seen in 7-16%100–102 and 2-32%100,102,103 of the IBD patients, respectively. Similarly, 60-70% of the SpA patients show subclinical signs of gut inflammation on biopsies obtained by ileocolonscopy,104,105 but only 7% of these patients will eventually develop clinically overt IBD over time. The link between SpA and IBD is corroborated by genetic studies, with the best example being polymorphisms in the interleukin 23 receptor (IL23R) gene which are associated both with IBD (OR 0.38 and 0.73 for CD and UC, respectively) and AS (OR=0.53-1.27).106–109

The diagnosis of IBD in clinical practice is based on the combination of clinical history, physical examination, stool findings (i.e. calprotectin and lactoferrin), serological antibodies, inflammatory markers in blood, and colonoscopy.110 The major clinical outcome measure in Crohn’s disease, the Crohn’s Disease Activity Index (CDAI),111 includes clinical and laboratory findings to determine disease activity. In UC, several scores are used to determine disease activity including clinical and endoscopic scores. A frequently used clinical score is Simple Clinical Colitis Activity Index (SCCAI).112 The Mayo activity index is based on clinical as well as endoscopic findings.113

Of the acute phase reactants, CRP was found to be a biomarker for IBD since the serum levels were elevated in CD and to a lesser extent in UC when compared with healthy controls or functional bowel disorders.114,115 Elevated levels were correlated with a higher disease activity.116–118 Louis et al.118 studied a group of 226 CD patients receiving TNF-inhibitors and

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a clinical response was associated with a decrease in CRP with similar results in a larger cohort. There were discrepant data about the ability of CRP to predict disease relapse.119,120 Other well studied inflammatory markers were ESR, procalcitonin, and YKL-40. All three markers correlated with the disease activity but only ESR and procalcitonin differentiated between IBD and healthy individuals or other gastrointestinal diseases.121–128 Moreover, a trend towards elevated levels of YKL-40 was found in more severe CD patients having strictures (i.e. narrowing of the intestinal lumina),124 but since the majority of active patients do not have elevated levels, in clinical practice YKL-40 is of little value.

Cytokines measured in serum did not seem to be important markers of disease in IBD, despite their role in the inflammatory process.129,130 The only potential marker is IL-6, the main driver of CRP. Levels of IL-6 in serum were increased in active CD compared with healthy controls but correlation with disease activity was weak.131–133

Of the soluble adhesion molecules, ICAM-1 was the most promising serum and plasma marker as the levels were elevated when compared with healthy controls. Although discrepant data are available on correlation with disease activity, effective treatment down-regulates ICAM-1 levels.134–138 E-selectin levels in serum or plasma were significantly higher in IBD than in healthy controls. However, there was no significant association between disease activity and treatment.134–138 A few studies were published on vascular cell adhesion molecule (VCAM). The serum or plasma levels in IBD were not consistently elevated versus healthy controls and correlations to disease activity were poor.134–136

The adipokines adiponectin, leptin, ghrelin, resistin, and vaspin had been investigated thoroughly in IBD. Only serum levels of resistin and vaspin were consistently elevated in IBD versus healthy individuals. Moreover, strong correlations with PASI were found for ghrelin, resistin and vaspin levels with disease activity.139–147 Ghrelin and resistin levels were decreased upon effective treatment but this was not studied for the other adipokines.148,149

Of the S100 proteins, S100A12 levels in serum were elevated in IBD when compared with healthy controls, but there are conflicting data about the correlation with active disease activity.150,151 Serum levels of S100A8/S100A9, calprotectin, were elevated in IBD versus healthy individuals and correlated with the CDAI.152–154 Similar results were seen in children using pediatric CDAI indices.155 Furthermore, calprotectin serum levels decreased upon treatment with TNF inhibition.154,156 Fecal calprotectin is one of the most extensively studied stool markers in IBD. Calprotectin levels in stool can differentiate between IBD and healthy controls or irritable bowel syndrome (IBS). One meta-analysis of Von Roon et al.157 included 30 studies with 1210 IBD patients, 297 colorectal cancer, 697 IBS, and 3393 healthy controls and reported that fecal calprotectin is a useful biomarker to differentiate between IBD and non-IBD patients. The overall weighted area under curve (AUC) was with 0.95-0.98 (using a cut-off level of 50 ug/g and 100ug/g, respectively) exceptionally high. Moreover, differentiating CD from IBS by fecal calprotectin showed an AUC of 0.97. Van Rheenen et


al.158 determined that fecal calprotectin could be used as screening tool in suspected clinical IBD, thereby decreasing the use of invasive colonoscopy by 67%, but at the cost of false negative results in 6% of the cases. Results of a meta-analysis that included 13 studies (1471 IBD patients), showed that fecal calprotectin is also a good marker for disease activity based on the Mayo activity index.159 Moreover, fecal calprotectin decreased upon treatment160–163 and may predict disease relapse.120,164,165

Several AMPs have been investigated in IBD. Serum LCN-2 (NGAL) levels were elevated in IBD when compared with healthy controls and IBS.166–168 HBD-2 seemed a potential marker since expression levels were increased in inflamed mucosa versus non-inflamed mucosa of the colon.169 However, Yamaguchi et al. found no differences in hBD-2 plasma levels in UC or CD when compared to healthy controls.170

Beta-2-microglobulin (β2-M), which forms a part of the major histocompatibility complex class 1 (MHC 1), had been investigated in two independent studies. In 2001 Zissis et al.171 showed that serum levels were elevated in CD versus healthy controls, and that serum levels were higher when patients had a higher disease activity, but they did not see similar results for UC. Yilmaz et al.172 recently showed similar results but now in the whole IBD population.

Of the serological antibodies studied in IBD,173–177 anti-saccharomyces cervisiae antibodies (ASCA) and perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) showed the highest diagnostic accuracy. Sensitivity and specificity for ASCA were 60% and 91% and for pANCA 50% and 95% respectively, when distinguishing IBD from healthy controls. Sensitivity and specificity for distinguishing between CD and UC were for ASCA (CD): 60% and 86%, and for pANCA (UC): 50% and 94% respectively.178 Similar results were seen in other studies.179,180 Also, when discriminating CD from UC or when comparing with other gastrointestinal diseases, including celiac disease, the specificity was too low for these antibodies.174–178 Both autoantibodies had a positive predictive value of 80-90% and a negative predictive value of 50-80%. The number of false-positive and false-negative individual was too high to recommend these autoantibodies for routine diagnostic procedures. Ester et al.181 found no association of ASCA or pANCA with response to infliximab treatment, but ASCA positivity was associated with worse disease progression: a more severe disease type (from inflammation to structuring (or stenosis) and penetrating) disease in CD.182 Recently, Bonneau et al.183 published a systematic review in which anti-glycan, anti-GP2, and anti-GM-CSF antibodies were also described as having low sensitivity but high specificity to CD when compared with UC but the contribution of these antibodies to diagnosis is not yet clear.

To summarize, CRP and ESR, the S100 family proteins S100A12 and S100A8/A9 (calprotectin), the antimicrobial peptides LCN-2 and hBD-2, the MHC class 1 molecule β2-M, and ASCA antibodies are of interest as biomarkers in IBD from a pathophysiological point of view. In clinical practice however, only a few of these markers are used, including CRP, ESR, and fecal calprotectin. Since CRP correlates with disease activity and CRP levels normalize upon

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effective treatment, evaluation of therapy by CRP is often applied in general practice. Fecal calprotectin, but not serum calprotectin, is extensively used in clinical practice to identify IBD patients with intestinal inflammation, providing high sensitivity and specificity in detecting IBD. Nevertheless, the ileocolonoscopy remains the gold standard. With regard to antibodies, ASCA antibodies are able to differentiate between CD and UC and are used in clinical practice although not as a screening diagnostic procedure. Other markers in IBD that are of pathophysiological interest are the IL-17 driven LCN-2, hBD-2, and β2-M, that forms part of the MHC class-I molecule (Table 2).

Table 2. Serum biomarkers in IBD levels: elevation in comparison with healthy controls, correlation with disease activity according to CDAI, SCCAI, or endoscopic activity, modulation by effective treatment, and outcome of structural damage

Biomarker

Elevation In comparison with healthy controls

Correlation with disease activity measured by CDAI or SCCAI or endoscopic activity

Treatment response

Outcome structural damage References

CRP + + + + [114–121]ESR + + NA NA [114, 128]Procalcitonin + +/- NA NA [125–127]YKL-40 +/- + NA +/- [122–124]IL-6 + +/- NA NA [131–133, 156]ICAM-1 +/- - + NA [134–138]E-selectin + - - NA [134–138]VCAM +/- - - NA [134–136]Adiponectin + - - NA [145–147, 149, 184]Leptin +/- - +/- NA [145, 146, 148, 149, 184]Ghrelin + + + +/- [140, 141, 146, 184, 185]Resistin + +/- + NA [142, 143, 146, 149, 184]Vaspin +/- - NA NA [144]S100A12 + +/- + NA [150, 151]S100A8/A9 + NA NA + [152–155]LCN-2 + + NA NA [166–168]hBD-2 - - NA NA [169, 170]β2-M + + NA NA [171, 172]

ASCA + + - +[173, 175, 177, 178, 181, 182]

pANCA + - + - [173–178, 181, 182]

ASCA, anti-saccharomyces cerevisiae antibodies; β2-M, β2-microglobulin; CDAI, crohn’s disease activity index; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; hBD-2, human beta-defensin-2; ICAM, intracellular adhesion molecule-1; IL, interleukin; LCN-2, lipocalin-2; NA, not applicable; pANCA, perinuclear anti-neutrophil cytoplasmic antibodies; SCCAI, simple clinical colitis activity index; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.


LESSONS TO BE LEARNED FROM POTENTIAL SERUM

BIOMARKERS IN PSORIASIS AND IBD

Several biomarkers studied in psoriasis and IBD may be informative in SpA as well. CRP, ESR, calprotectin, and VEGF are interesting in psoriasis and IBD. These markers have already been studied in SpA (as mentioned above). While they may be discriminatory at the group level, sensitivity and/or specificity are too low to be used in clinical practice for diagnosis, disease activity measurement, evaluation of treatment response, or prediction of axial spinal progression.

Some of the biomarkers of interest in in psoriasis and IBD have also been studied in SpA. Negative or variable results were found for serum-IL-18,186 ICAM-1,187–189 RBP-4,190,191 and NO.192,193

ASCA antibodies can help to discriminate CD from UC, have already been studied in SpA. The levels of ASCA antibodies were found to be higher in SpA patients than in healthy controls, as reported by different studies.194,195 One study determined these antibodies in non-IBD SpA patients, and 30% of them appeared to be ASCA-positive. Nevertheless, levels did not correlate with disease activity.196

The AMPs are a new family of relevant biomarkers in psoriasis and IBD as was found in several studies. AMPs have not yet been extensively studied in SpA. The most interesting members of this family are LCN-2 and hBD-2, both of which are driven by IL-17 and are reflecting active disease in psoriasis as well as IBD. And because the reliable measurement of IL-17 in serum remains a challenge, these biomarkers may be used as a proxy for IL-17-mediated tissue inflammation in psoriasis and IBD. As SpA is also an IL-17-driven disease,197–201 these markers certainly deserve further study in this condition. It should be noted, however, that these AMPs are mainly produced by epithelial cells and may thus be more useful in skin and gut diseases than in other IL-17-related inflammatory conditions. Along the same line, IL-22 is an IL-10 cytokine family member which is produced by Th17 cells under the control of IL-23. It was shown that plasma IL-22 levels were increased in SpA versus healthy individuals, but no correlation was found with Bath ankylosing spondylitis disease activity index (BASDAI).202 The reliability of serum IL-22 measurement and the validity of these findings require replication in independent studies.

Another biomarker which was identified in IBD and may be directly related to the pathological processes in SpA is β2-M. β2-M is a component of class I MHC molecules, including HLA-B27, which is (still) the major genetic risk factor for SpA. Although the exact role of HLA-B27 in the disease pathogenesis is not yet clear, several hypotheses suggest that the level of expression of β2-M may modulate the pathological role of HLA-B27. One hypothesis proposes that β2-

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M-free HLA-B27 heavy chains form disulphide-linked homodimers which can be recognized by the KIR3DL2 receptors on NK-cells and T-cells.203 The second hypothesis concerns HLA-B27 heavy chain misfolding prior to binding of β2-M and peptide, resulting in unfolded protein responses (UPR), which subsequently may lead to an inflammatory cytokine release.201,204 Interestingly, modulation of β2-M expression levels in the HLA-B27 transgenic rat model of SpA did profoundly affect the phenotype of the disease,205–207 confirming the potential importance of this molecule in SpA. Therefore, serum β2-M expression levels should be further explored as potential biomarker in SpA.

EXPERT COMMENTARY

To conclude, of the serum biomarkers identified in psoriasis and IBD, the IL-17 driven anti-microbial peptides hBD-2 and LCN-2, and the class I MHC molecule β2-microglobulin are the most interesting candidates from a pathophysiological standpoint to be further explored in SpA for clinical purposes.

KEY POINTS

• SpA is an immune-mediated inflammatory disease affecting the spine, the peripheral joints, and extra-articular tissues such as the skin, the gut, and the eye.

• Serum biomarkers could address several challenges in SpA (diagnosis, disease activity monitoring, treatment response, and outcome).

• Serum biomarkers well studied in spondyloarthritis are CRP, ESR, IL-6, calprotectin, VEGF, MMP-3, DKK-1, and sclerostin.

• Although the aforementioned biomarkers are useful at the group level in SpA, these markers lack specificity for the use in individual patients in clinical care.

• SpA is a clinically and pathophysiologically closely related to psoriasis and inflammatory bowel disease.

• In psoriasis, CRP, ESR, IL-18, IL-22, ICAM-1, calprotectin, LCN-2, hBD-2, VEGF, RBP-4, and NO were the most interesting markers from a pathophysiological standpoint.

• In IBD, CRP and ESR, hBD-2, LCN-2, and ASCA antibodies were of interest from a pathophysiological point of view.

• HBD-2, LCN-2, and β2-microglobulin are the most interesting candidates from a pathophysiological standpoint to be further explored in SpA for clinical purposes.


REFERENCES

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