Anti-cyclic citrullinated peptide antibodies and IL-23p19 in psoriatic arthritis

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Summary

Background

Anti-cyclic citrullinated peptide antibodies (anti-CCP) are reported to be found in 5–13% of patients with psoriatic arthritis (PsA). However, whether anti-CCP-positive PsA patients and rheumatoid arthritis (RA) patients have a similar pathophysiological background still remains uncertain.

Objective

To determine the prevalence of anti-CCP antibodies in patients with PsA and characterize these anti-CCP-positive patients of PsA.

Methods

We measured the serum levels of the anti-CCP antibodies in patients with PsA (n = 16), psoriasis (n = 15), RA (n = 9) and healthy controls (n = 11). Serum levels of rheumatoid factor (RF), matrix metalloproteinase-3 (MMP-3), cartilage oligomeric matrix protein (COMP), interleukin (IL)-23p19 and IL-12p40 were also measured in all the samples.

Results

Two of the 16 PsA patients (13%) were positive for anti-CCP antibodies with high titers of RF. However, the serum IL-23p19 levels were two orders of magnitude higher in the anti-CCP-positive PsA patients as compared with those in the RA patients and anti-CCP-negative PsA patients. No significant elevation of the serum levels of MMP-3, COMP and IL-12p40 was found in these patients.

Conclusion

Thirteen percent of the PsA patients were positive for anti-CCP. These patients do not fulfill the American College of Rheumatology (ACR) classification criteria for RA so far. Furthermore, they showed the typical clinical features of PsA rather than those of RA. Although anti-CCP-positive PsA patients may possibly be have a risk of developing RA, we propose that these patients be classified, for the moment, into a independent subtype of PsA, as a different entity from RA.

Introduction

Psoriasis vulgaris is a relatively rare disease in Japan, occurring in 0.05–0.1% of the total population. Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. PsA patients account for 5–30% of patients with all types of psoriasis and this prevalence is the same with the Japanese patients [1], [2], [3]. It is characterized by asymmetric peripheral joint involvement of the upper extremities, especially small joints. In 1973, Moll and Wright identified five different clinical types of PsA: distal arthritis, asymmetric oligoarthritis, symmetric polyarthritis, arthritis mutilans, and spondyloarthropathy [4]. They included seronegativity for rheumatoid factor as an essential criterion for the diagnosis of PsA. However, other groups have reported that about 10% of patients with PsA show seropositivity for rheumatoid factor (RF) [5], [6], [7]. Subsequently, the criteria for the diagnosis of PsA have become broader, and currently, PsA is recognized as “usually seronegative”. When a psoriasis patient presents with a RF-positive polyarthritis, one of the problems that must be resolved is: does the patient have PsA, or is it psoriasis coexistent with rheumatoid arthritis (RA).

Anti-cyclic citrullinated peptide antibodies (anti-CCP) have recently been shown to have a high specificity (89–98%) for RA [8], [9]. They were first described as antiperinuclear factor and subsequently as anti-keratin and anti-filaggrin antibodies [10], [11]. Recently, citrullination of filaggrin has been recognized as an essential step in immunogenicity [12], and cyclic citrullinated peptides are used as antigens in enzyme-linked immunosorbent assays (ELISA) to detect anti-CCP. Van Gaalen et al. reported that 74% of anti-CCP-positive patients with undifferentiated arthritis developed RA during a 3-year of follow-up [13]. Thus, seropositivity for anti-CCP might be a useful marker for predicting the development of RA. On the other hand, according to some previous reports, serum anti-CCP antibodies are also found in 5–13% of PsA patients [5], [6], [7], [14]. Most anti-CCP-positive patients have polyarticular arthritis [5], [7] and the HLA-DRB1 epitope [15], which suggest that they may have coexistent RA. However, whether anti-CCP-positive PsA patients and RA patients have a similar pathophysiological background still remains uncertain.

Interleukin (IL)-23 is a recently discovered cytokine, which has a subunit of p19 and p40 [16], [17]. Th17 cells, activated by IL-23, play a crucial role in the pathogenesis of psoriasis [18], [19]. Furthermore, the IL-23p40 subunit is shared with IL-12, which is a Th1 cytokine and is also a key cytokine of psoriasis. On the other hand, the role of IL-23 in PsA and RA has not been fully studied and remains to be seen [20]. Studies comparing the serum levels of IL-23 might be good approaches to make clear the potential differences in pathogenesis of PsA and RA.

The aim of this study was to determine the seroprevalence of anti-CCP antibodies and the serum levels of IL-23 (IL-23p40 and IL-23p19) in Japanese patients with PsA. Furthermore, we measured the serum levels of RF, MMP-3 and COMP, which are considered to be markers of arthritis degree, and discussed the immunopathophysiology of PsA.

Section snippets

Patients and characteristics

Fifty-one patients from the Department of Dermatology, Faculty of Medicine, University of Tokyo, and the Department of Dermatology, Teikyo University of Medicine and Toshiba Hospital were enrolled. The study subjects included 16 patients with PsA (PsA group), 15 patients of psoriasis without arthritis (Pso group), 9 patients with RA (RA group) and 11 healthy controls (control group). The PsA patients, diagnosed according to the Bennett criteria, consisted of 11 males and 5 females (mean age:

Two out of the 16 patients with PsA were positive for anti-CCP

Of the 16 patients of the PsA group, 2 (2/16; 13%) were positive for anti-CCP; the serum anti-CCP level was high in both patients (195 and 235 U/ml). Eight patients of the RA group (8/9, 89%) were positive for anti-CCP, with the serum levels ranging from 130 to 244 U/ml. Anti-CCP antibodies were not detected in any patients of the Pso group (0/15) or the control group (0/11). The prevalence of the anti-CCP positivity, using the Fisher's exact test, was significantly high in the RA group as

Discussion

In our study, 13% of patients with PsA were seropositive for anti-CCP antibodies. This is the first paper which reported the seroprevalence frequency of anti-CCP antibodies in Japanese patients with PsA.

The diagnosis of PsA is dependent on both clinical and radiological findings. Morning stiffness is thought to be a specific clinical feature of rheumatoid arthritis, although about a half of all PsA patients are also reported to suffer from morning stiffness [2]. As for the types of arthritis,

Acknowledgement

This work was supported by a grant for the Ministry of Education.

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