The ease with which the serum can be accessed has rendered it an appealing source of putative proteomic biomarkers of PsA. Presently, serum levels of non-specific inflammatory marker C-reactive protein (CRP) serve as a measure of disease activity in PsA but also in several other inflammatory conditions. In search of better prognostic markers of PsA, Hansson et al. assayed serum S100 calcium-binding protein A8 (S100A8)/S100A9 (S-calprotectin) concentrations in 65 PsA with varying degrees of disease severity [
15]. S-calprotectin levels were significantly higher in PsA patients with polyarthritis as opposed to mono-/oligoarthritis and, overall, were a better predictor for PsA than CRP levels. Their findings highlight the prognostic capabilities of S-calprotectin as a disease activity marker in PsA patients specifically. A detailed list of candidate PsA protein biomarkers described in this review can be found in
Table 1. In-depth investigation of the PsA serum proteome has revealed the upregulation of several pro-inflammatory mediators, including cytokines and chemokines [
16]. Alenius et al. detected significantly higher levels of interleukin-6 (IL-6) in PsA patients relative to PsC patients, regardless of their levels of routine measurable inflammatory markers [
17]. IL-6 also correlated with increased levels of highly sensitive CRP (hs-CRP) and the erythrocyte sedimentation rate (ESR) among PsA patients with joint manifestations, among which there were higher incidences of polyarthritic disease pattern. Levels of IL-6 may, therefore, capture the disease activity of PsA more specifically than current parameters. The C–X–C motif chemokine 10 (CXCL10) has recently been identified as a potential predictor of PsA development among PsC patients [
18]. Luminex assays of baseline serum concentrations of CXCL10 revealed a significantly higher level of the protein in PsC patients who later developed PsA by the annual follow-up visit. These levels however, were shown to decrease post-conversion for reasons that remain to be fully elucidated. More diagnostic biomarkers were discovered by ELISA when Chandran et al. quantified potential candidates in the serum of PsA patients [
19]. Their findings confirmed increased levels of hsCRP, osteoprotegerin (OPG), matrix metalloproteinase 3 (MMP-3), as well as the ratio of C-propeptide Type II collagen to Col2-3/4C
long mono (CPII:C2C) in PsA patients compared to PsC patients. Moreover, they determined CD5-like antigen (CD5L), integrin subunit beta 5 (ITGB5), myeloperoxidase (MPO), Mac-2 binding protein (M2BP), MMP-3 and CRP were strong diagnostic markers of PsA and, when used in combination, they could differentiate PsA from PsC patients better than the use of CRP alone [
20]. The search for circulating autoantibodies in PsA patients led Dalmady et al. to quantify antibodies targeting mutated citrullinated vimentin (anti-MCVs) by ELISA. They observed that PsA patients had significantly increased mean serum anti-MCV concentrations relative to PsC patients and emphasized the possibility of anti-MCVs to serve as a differentiator between mild and severe forms of PsA [
21].
There is a growing interest in detecting early changes in serum biomarker concentrations in response to the initiation of drug therapy. Predictive biomarkers are crucial for distinguishing treatment responders and non-responders to ensure patients are receiving optimal therapy and to avoid unnecessary expenses and risk of adverse events. Several protein candidates have been identified as potential biomarkers of TNF-α inhibitor (TNFi) therapy response. Kuijk et al. investigated early changes in soluble biomarkers in response to initiation of adalimumab treatment [
22]. They observed a significant decrease in serum MMP-3 levels and a significant increase in serum melanoma inhibitory activity (MIA) levels following 4 weeks of treatment. Results of a serum biomarker study by Chandran et al. similarly identified baseline MMP-3 reductions to be associated with response to TNFi therapy [
23]. They also noted an independent association of increased serum cartilage oligomeric matrix protein (COMP) levels to TNFi therapy response. Cauza et al. also quantified the concentration of COMP in the serum of PsA patients following treatment with infliximab, a TNF-α blocker [
24]. However, COMP levels were shown to significantly decrease after 6 weeks of treatment. The conflicting results between these two studies would suggest that COMP may not serve as a reliable marker for response to TNFi treatment. Alternatively, serum MMP-3 and MIA levels are more likely to assist in differentiating between effective and ineffective responses to TNF-α blockers.
High-throughput mass spectrometry (MS) analysis has opened novel avenues for extensive protein identification and quantification. When coupled with heparin affinity chromatography, a total of 384 proteins were identified among RA, PsA, and non-inflammatory arthritis plasma samples, of which 4 proteins were determined to be differentially regulated between RA and PsA. Serpin A11 (SERPINA11), complement factor H-related protein 5 (CFHR5), cartilage acidic protein 1 (CRTAC1) and coagulation factor IX (F9) were specifically upregulated in RA samples but downregulated in PsA samples, suggesting these proteins as a collective may accurately distinguish between PsA or RA patients [
25].