Update on Biomarkers in Psoriatic Arthritis: A Report from the GRAPPA 2010 Annual Meeting

Biomarkers that differentiate PsA from psoriasis without PsA (PsC)

The prevalence of undiagnosed PsA is high in patients with psoriasis seen in dermatology clinics⁴. Identifying biomarkers for PsA may help screen patients with psoriasis for appropriate referral to a rheumatologist. Reanalysis of data from a large clinical trial of etanercept in psoriasis showed that patients with PsA and those with higher body mass index have higher median baseline high-sensitivity C-reactive protein (hsCRP) values than patients with psoriasis without PsA⁵. Thus, hsCRP may be used as a marker for PsA, especially in non-obese patients with psoriasis. Serum cartilage oligomeric matrix protein is elevated in patients with psoriatic disease and correlates with CRP and swollen joint count but does not distinguish PsA patients from those with psoriasis without PsA⁶. In a study comparing PsA patients to those with psoriasis without PsA, it was also shown that IL-6 levels are higher in PsA patients and correlate with joint counts, erythrocyte sedimentation rate (ESR), CRP, and serum interleukin 2 (IL-2) receptor-α⁷. Chandran, et al recently evaluated biomarkers related to inflammation, bone, and cartilage damage to identify biomarkers for PsA⁸. A combination of hsCRP, osteoprotegerin, matrix metalloproteinase 3 (MMP-3), and the ratio of C-propeptide of type II collagen (CPII) to collagen fragment neoepitopes Col2–3/4 (long mono) (C2C) in the serum was able to distinguish patients with PsA from those with psoriasis without PsA in a receiver-operating characteristic curve analysis (area under the curve 0.904). Although a combination of the above biomarkers may help screen psoriasis patients for PsA, these findings need validation in prospective studies.

Biomarkers of disease activity

In PsA, a number of processes can be evaluated by biomarkers, including diagnosis, early identification, disease activity or the inflammatory process, and severity or response to treatment. Van Kuijk and colleagues showed that serum levels of MMP-3 increase and melanoma inhibitory activity (MIA) decreases after 4 weeks in adalimumab-treated patients, with no change in either marker in placebo patients⁹. Synovial fluid cytokines including IL-1, IL-1-receptor antagonist (IL-1RA), IL-6, IL-8, and chemokine (C-C motif) ligand 3 (CCL3) appeared to correlate with systemic markers of inflammation (ESR and CRP) and decreased following intraarticular tumor necrosis factor (TNF) administration¹⁰.

Zaba, et al analyzed gene expression profiles in lesional and nonlesional skin of psoriasis patients at baseline and at 1, 2, 4, and 12 weeks after starting treatment with etanercept¹¹. Comparison of responders to nonresponders revealed rapid downregulation of innate IL-1α and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. Therefore, at least in psoriasis, response to anti-TNF therapy is associated with downregulation of IL-17 pathway genes, suggesting a critical role for IL-17 in driving skin inflammation, a finding consistent with the beneficial effect of IL-17 inhibition shown in a recent study in mice¹².

Two studies have attempted to identify biomarkers associated with active treatment in PsA synovial tissue. Van Kuijk and colleagues conducted a prospective, randomized, placebo-controlled study in patients with active PsA using adalimumab⁹. Placebo patients switched to adalimumab after a second synovial biopsy at 4 weeks. After applying a ranked analysis of covariance model to correct for baseline imbalances, a significant effect of treatment was observed on CD3-positive cells: a median reduction of 248 cells/mm² after adalimumab versus placebo (p = 0.035). These findings were confirmed by Pontifex, et al, who conducted synovial biopsies and magnetic resonance imaging (MRI) scans at baseline and after 12 weeks of treatment¹³, in 2 treatment cohorts, the first using etanercept and the second IL-1RA. Change in CD3-positive T cell infiltration in synovial tissue specimens correlated with the change in DAS28 (28-joint Disease Activity Score; R = 0.49, p = 0.023). No significant correlation was found between any clinical variables and changes in CD68 infiltration or with changes in factor VIII expression. Interestingly, a change in CD3 also correlated with a change in a semiquantitative MRI score of the same affected knee joint (R = 0.58, p = 0.009). Thus, a change in CD3 expression in the synovium of PsA correlated with both change in DAS28 and change in MRI following initiation of biologic treatment. These articles identify change in CD3 as a possible candidate biomarker of treatment response in PsA, which contrasts with rheumatoid arthritis (RA), where a change in CD68 infiltration has been identified as the most likely biomarker of treatment response.

Biomarkers of radiologic outcome

Damage in PsA is certainly slower to occur than in RA and is difficult to predict. In the CORRONA (Consortium of Rheumatology Researchers of North America) registry, a reduced prevalence of erosion was seen in PsA compared with RA (OR 0.609; p < 0.001)¹⁴. In an early PsA cohort, 27% of patients presenting within 2 years of symptom onset had erosions at baseline, which increased to 47% at 2 years. The mean baseline Sharp erosion score was low at 1.2 and increased to 3 after 2 years. Features such as periostitis, reflecting new bone formation, were found in 19% at baseline, increasing to 29% at 2 years.

A number of articles from Christopher Ritchlin’s group have examined the questions of bone remodeling, osteoclastogenesis, and bone erosion in PsA. In an examination of the frequency of osteoclast precursors (OCP) in patients treated with etanercept, a decrease in OCP was observed after 3 and 6 months of therapy, but had no correlation with bone marrow edema volume on MRI scanning¹⁵. In a report by Dalbeth, et al, PsA patients had higher circulating concentrations of Dickkopf-related protein 1 and macrophage-colony stimulating factor (M-CSF), compared with psoriasis patients and controls¹⁶. Levels of M-CSF and receptor activator of nuclear factor kappa-B ligand also correlated with erosion, joint space narrowing, and osteolysis scores. Finally, in a study of patients with PsA and RA by Ng and colleagues, bone biomarkers were measured at baseline, 1 month, and 1 and 3 years after commencing treatment with anti-TNF therapy¹⁷. Of interest, both at baseline and following treatment, an increase in bone alkaline phosphatase was seen in PsA. Other markers of bone formation were also increased, although not significantly. These observations are consistent with the observation that patients with PsA, in contrast to RA, frequently show both erosive destruction changes and new bone formation. In a recent study by Finzel, et al that examined the metacarpophalangeal (MCP) joints in patients with PsA and RA using microcomputerized tomography¹⁸, erosions occurred less frequently in PsA, whereas PsA was distinguished by prominent new bone formation over the MCP joint, with a crown of new bone or corona being observed in some patients. A summary of recently identified biomarkers for psoriatic disease is provided in Table 1.

Following discussion at the GRAPPA 2010 meeting, it was agreed that one critical area for future study is the identification of biomarkers of joint damage, including both erosive change and new bone formation, in patients with PsA. This would be consistent with the overall aims of the OMERACT biomarker subgroup, which plans to conduct studies of biomarkers of joint damage in RA, ankylosing spondylitis, and PsA. The RA biomarker study commenced mid-2011. A protocol for a PsA study was drafted and details of the protocol were to be discussed at the GRAPPA 2011 meeting in Naples, Italy.