Psoriatic arthritis (PsA) is a distinctive inflammatory form of arthritis that may develop in 20% to 25% of individuals with psoriasis . In addition to manifestations of psoriasis in the skin, patients with PsA may present with mild to very severe development of oligoarthritis and/or polyarthritis, enthesitis, dactylitis or axial skeletal manifestations similar to spondyloarthritis. PsA has been considered a seronegative inflammatory arthritis according to the diagnostic criteria first published by Moll et al. in 1973  and then redefined by the Classification Criteria for Psoriatic Arthritis (CASPAR) . All definitions of PsA have in common the seronegative status of the disease because autoantibodies (Abs) such as rheumatoid factor (RF), anticyclic citrullinated autoantibodies and antinuclear autoantibodies are usually absent in PsA. Hence, in contrast to rheumatoid arthritis, autoreactive B lymphocytes are believed to play only a minor role in PsA . Regarding the occurrence of autoantibodies in PsA, increased frequencies of thyreoglobulin Abs (14.29%) and thyroid peroxidase Abs (23%) were reported in PsA, which was explained by a relatively high comorbidity rate, with 26% of patients with PsA having autoimmune thyroiditis . In another study, 20S proteasome autoantibodies were more frequently detected in PsA patients (27.8%) than in in healthy controls (0%), as well as more frequently in systemic lupus erythematosus patients (42%) than in rheumatoid arthritis patients (5%) . However, the numbers of patients were small in these studies (36 PsA patients and 30 healthy controls) , and, in both studies, no patients with psoriasis without arthritic manifestations (PsC) were included. To date, no specific serological markers discriminating patients with PsA from patients with PsC have been identified. Nevertheless, a small but significant occurrence of B lymphocytes was reported in the skin of patients with PsA, but not in patients with PsC .
Recently, we discovered progranulin autoantibodies (PGRN Abs) in a protein array-based screening of plasma from various primary vasculitides and found evidence that these PGRN Abs have a neutralizing effect on PGRN plasma levels . PGRN is a secreted precursor protein that is cleaved at the linker regions between individual granulins by neutrophil elastase , proteinase 3 , matrix metalloproteinase 12 , matrix metalloproteinase 14  and ADAMTS-7 (a disintegrin and metalloprotease with thrombospondin motif 7) . Until recently, most research on PGRN had focused on its role in neurodegenerative diseases such as frontotemporal lobe dementia . However, since Tang et al.  showed that PGRN is a high-affinity ligand of the tumour necrosis factor α (TNF-α) receptors 1 and 2 (TNFR1 and TNFR2) and that its anti-inflammatory effect is caused by direct inhibition of these receptors, PGRN has increasingly become the focus of research on autoimmune diseases.
Recently, Chen et al.  challenged the notion of this interaction of PGRN with TNFR1 and TNFR2 previously reported by Tang et al. , as they could not reproduce the interaction of PGRN with TNFR1 and TNFR2. However, they did not question the anti-inflammatory effect of PGRN . Tang et al. responded in a letter to the editor that Chen et al. utilized PGRN, which might be folded improperly. Furthermore, Tang et al. stated that validation of recombinant PGRN’s functionality based only on its C-terminal binding to sortilin would be insufficient to determine its quality regarding its other biological functions, which are not primarily mediated by PGRN’s C-Terminus. Subsequently, Jian et al. showed in detail that PGRN binds as TNF-α to cysteine-rich domain 2 (CRD2) and CRD3 of TNFR and that proper folding of PGRN is essential for this binding. Furthermore, dithiothreitol treatment of PGRN, which had been performed by Chen et al., abolishes the binding of PGRN to TNFR but enhances its binding to sortilin . Recently, two other groups independently reproduced the binding of PGRN to TNFR1 and TNFR2, and inhibitory effect of this binding on TNF-α-induced effects [17, 18]. Dramatic effects of PGRN deficiency have been shown in vivo in collagen-induced arthritis and collagen Ab-induced arthritis mouse models, resulting in fulminant courses of disease . Furthermore, the administration of recombinant human PGRN or a recombinant PGRN derivative, antagonist of TNF/TNFR signalling via targeting to TNF receptors (ATSTTRIN), that consists of three modified granulin motifs and their accompanying linker regions  had strong anti-inflammatory effects comparable to, or even stronger than, the administration of etanercept . Consequently, PGRN and ATSTTRIN have been regarded as promising next-generation TNF-α blockers . In addition to this strong anti-inflammatory effect mediated by the inhibition of TNFR1 and TNFR2, several other functions of PGRN in humans have been reported .
Interestingly, the previously detected PGRN Abs showed neutralizing effects on PGRN plasma levels detected by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis. This observation, given the anti-inflammatory properties of secreted PGRN, suggested a proinflammatory effect of PGRN Abs, which was supported by our observation that the presence of PGRN Abs is associated with active disease state in granulomatosis with polyangiitis . Apart from primary systemic vasculitis, we also found neutralizing PGRN Abs in systemic lupus erythematosus as well as in rheumatoid arthritis . Some of the rheumatoid arthritis patients with PGRN Abs were actually seronegative for RF or anticitrullinated protein Abs. Furthermore, PGRN Abs were detected in patients with spondyloarthritis. This observation led us to conduct the present study to investigate the presence of PGRN Abs in patients with the seronegative disorder PsA, compare it to patients with PsC and healthy controls and investigate possible functional effects of PGRN Abs in vitro.