Biomarkers in Psoriasis and Psoriatic Arthritis: GRAPPA 2008

New data on biomarkers for damage in psoriatic arthritis: Kurt de Vlam

The identification of relevant tools to evaluate the natural course, disease activity, treatment response, and outcome of PsA is of increasing relevance following raised awareness and the development of new therapeutic options. Until now these different aspects have been monitored by artificial patient-centered or physician-centered constructs. Very often the approach is indirect and is open to influences unrelated to disease.

The development of such tools is time-consuming and laborious but has been shown to be very useful in the assessment of patients with various rheumatic diseases. The major drawback with these tools is that they do not reflect directly the biological and pathological processes. Biological biomarkers measure objectively different aspects of the biological and pathological process and may contribute a major advance in the assessments of patients. The appearance of new therapeutic options in PsA raises the need for sensitive biomarkers for both disease activity and outcome. The underlying goal is to develop biomarkers that can provide guidance for individual patients in clinical practice.

For a long time, a “copy-paste” approach from RA was applied for the selection of biomarkers in PsA. Since RA and PsA have fundamentally different disease processes, this approach is now recognized to lead to inappropriate choices of biomarkers and subsequently to incorrect conclusions. The available data about biomarkers in psoriatic disease have recently been reviewed¹³. New potential biomarkers for diagnosis, disease activity, and tissue response were reported during the GRAPPA symposium in Leeds, UK.

The ideal biomarkers for diagnosis must be both specific and sensitive. Analysis of the primary involved tissue, such as synovial tissue and enthesis, is critical to differentiating PsA from other rheumatic inflammatory diseases. In a recent semiquantitative analysis of PsA synovial tissue, increases in vascularity and in the number of neutrophils were demonstrated, compared with RA synovial tissue. RA synovium demonstrated more staining for anti-CCP and the major histocompatibility complex/gp39 complex. Differences were observed only at the group level¹⁴. These differences found among the inflammatory rheumatic diseases appear to be quantitative and not qualitative, with no diagnostic feature emerging to date. Thus, the use of semiquantitative methods such as histopathology may be less appropriate, while flow-cytometric evaluation of the target tissue may be a valuable option. After digestion, the different cell populations of the synovial tissue can be measured by multichannel flow cytometry¹⁵.

Differential gene expression in PsA compared to normal persons and other inflammatory arthritides was recently reported. Gene expression in peripheral blood mononuclear cells for nucleoporin 63-kDa distinguished PsA patients from controls. Overexpression of MAP3K3 followed by CACNA1S can discriminate PsA from RA¹⁶. Specific pathway polymerase chain reaction screening may be an alternative approach. Comparing specific pathways for inflammation and tissue response in fibroblast-like synoviocytes between normals and PsA surprisingly showed downregulation or silencing of specific genes in affected persons compared with normals (K. de Vlam, personal communication).

Biomarkers useful in monitoring disease activity must fulfill 3 conditions: (1) they must increase in active disease, (2) must show correlation with disease activity, and (3) must be sensitive to change. Most of the biomarkers studied for disease activity in PsA have not met these criteria. Synovial biomarkers have been the most extensively studied and include analyses of cellular infiltration such as the number of T cells, B cells, macrophages, blood vessels, adhesion molecule expression, and effector enzymes. Evaluation before and after treatment mostly demonstrates quantitative changes in different cell populations, but normalization of the target tissue is not yet attained. A closer look at activated signaling pathways reveals that some of these pathways are downregulated, but others, such as the p38 MAP kinase pathway, are still active and are even upregulated¹⁷. Although the joint seems clinically quiescent, determining presence or absence of biological disease activity is still a major challenge for the future.

Joint damage in PsA results from cartilage loss, bone destruction, and bone formation. Bone destruction and bone formation are usually assessed by radiographs. Radiographic damage is a rather late phenomenon and quite insensitive for early detection. Most radiological scoring methods for PsA ignore bone formation features, with the exception of the Psoriatic Arthritis Ratingen Score (Wassenberg score)¹⁸. In addition, cartilage loss is generally not assessed. The use of biomarkers could enable early detection of all aspects of joint damage.

Cross-linked telopeptide of collagen-I, urinary deoxy-pyridinoline, osteoprotegerin, and alkaline phosphatase are increased, reflecting both increased bone resorption and bone formation. Soluble interleukin 2 receptor and circulating osteoclasts are independent biomarkers for erosive disease. TNF-α blockade reduces progression of damage but also decreases the number of circulating osteoclasts. Evaluation of specific pathways in tissue response, such as the bone morphogenetic protein (BMP) pathways, may be an alternative approach. Supervised clustering of genes involved in the BMP pathways have been shown to be upregulated in PsA, with these changes reversed by anti-TNF-α therapy (K. de Vlam, personal communication). Finally, DKK1 (Dickkopf family) was recently suggested as a biomarker for the absence of bone formation in RA compared with AS, but this remains to be confirmed in other cohorts of AS and PsA patients¹⁹.

Biomarkers for joint damage in psoriatic arthritis — design considerations for a longitudinal study: Oliver FitzGerald

GRAPPA has previously identified 2 key areas for biomarker development in psoriasis and PsA: (1) biomarkers of articular disease in patients presenting with psoriasis; and (2) biomarkers of joint damage in PsA. Shortly following this identification, GRAPPA was contacted by the OMERACT biomarker group (Walter Maksymowych, chair) to provide some members who might work with the OMERACT group to develop a longitudinal study design for biomarkers of joint damage in PsA. A similar initiative is also under way in RA and AS. The interaction between GRAPPA and the OMERACT biomarker group has indeed been synergistic. The initial focus has been on testing of the OMERACT 2008 validation criteria, issues related to statistical analysis, and longitudinal study design. Several Web-based surveys were conducted of GRAPPA members seeking agreement on aspects of study design. For consensus, ≥ 70% of respondents voting “Yes” was required for inclusion or ≥ 30% voting “No” for exclusion. As several items still required consideration (having between 30% and 70% respondents), considerable time was spent at the GRAPPA meeting discussing and voting on the outstanding issues. The resulting longitudinal study design for biomarkers of joint damage in PsA is summarized in Tables 2–6.

Note that several issues in the tables were debated in detail and, where consensus has not been achieved, a majority view will likely apply. The first such issue related to study duration (Table 2). The rate of development of new erosions in PsA is slower than in RA, with 47% of patients with recent-onset PsA having erosive disease within 2 years of presentation and the mean number (range) of erosions increasing from 1.2 (0–19) to 3 (0–25)²⁰. Therefore, it was argued that on the one hand a 4-year followup would be appropriate; on the other, 4- or 3-year followup could prove more difficult to fund, and dropout rates could be significant. A compromise decision was that the study would be 2 years initially. Preferably, funding for a 4-year study will be forthcoming; if not, GRAPPA will undertake to complete the study.

The next major discussion items related to the disease process core domains, in particular the instruments to be used in recording enthesitis, dactylitis, and nail involvement (Table 4). Based on the evidence presented by Philip Helliwell, it was agreed that the recently described Leeds Enthesitis Instrument²¹ would be the instrument employed. Nonetheless, there remained considerable support for collecting data on a more extended entheseal set so as to verify the Leeds findings. A demonstration of the appropriate entheseal sites was provided by Philip Mease. Discussion on the appropriate dactylitis instrument to be used proved more controversial. The Leeds Dactylitis Instrument²² was thought by many to be the best instrument available and not too difficult to apply. However, in the setting of a multicenter longitudinal study over 2–4 years, it was argued that a simpler approach, counting the number of swollen and tender digits, might be best. In the recorded decision, the opposing sides were irreconcilable. Finally, in relation to nail involvement, the modified Nail Psoriasis Severity Index score was thought best by a majority, but there was considerable voice for the concern that the instrument would prove too cumbersome and that a better instrument for nail disease was required²³.

Having largely agreed on the longitudinal study design, the next step is to seek appropriate funding support together with OMERACT partners in the other disease areas for these multicenter studies. The appropriate approach to the handling and assessment of biological samples also requires discussion. In the setting of PsA, it has been agreed that the collection of a DNA sample would be appropriate. The assessment of samples might include, for example, assays of candidate biomarkers of cartilage breakdown, but an approach more conducive to discovery using newer technologies such as proteomics might also be considered. It is hoped that these final issues can be resolved and that the study will be under way by 2010.