Article

The pathogenesis of psoriatic arthritis and associated nail disease: Not autoimmune after all?

Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds and Chapel Allerton Hospital, Leeds, UK.
Current opinion in rheumatology (Impact Factor: 4.89). 06/2009; 21(4):340-7. DOI: 10.1097/BOR.0b013e32832c6ab9
Source: PubMed

ABSTRACT

Both psoriasis and psoriatic arthritis (PsA), and by implication psoriatic nail disease, have been considered as autoimmune disorders. This was based on the assumption that T-cell-directed responses against common skin and synovial antigens led to shared immunopathological mechanisms at these different sites, which was indirectly supported by the human leucocyte antigen-Cw6 disease association. This study draws on recent microanatomical and genetic studies of PsA, psoriasis and psoriatic-associated nail disease to show how the prevailing autoimmunity concepts for psoriatic disease need to be redrawn, especially in the case of joint and nail disease.
Recent microanatomical studies confirm that normal tendon and ligament insertion points to bone (entheses), the key territory for the inflammatory reaction associated with PsA, being subject to microdamage that strongly points to a role for microtrauma in the joints, which is reminiscent of Koebner responses in the skin. Furthermore, the nail is functionally integrated with entheses associated with the distal phalanx that provides anchorage to the skin and joint. Although type 1 psoriasis is strongly linked to the human leucocyte antigen-Cw6, recent genetic studies have suggested that both joint and nail disease do not share this association.
These microanatomical and genetic insights have important implications for a better understanding of PsA and nail disease and for an improved understanding of the psoriatic disease spectrum.

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Available from: Ai Lyn Tan
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    • "Recently, the view on the pathogenesis of psoriatic joint and nail disease has been challenged and a question has been raised of whether psoriatic skin disease shares the same pathogenetic principals as psoriatic joint and nail disease. The alternative pathogenetic model suggests that psoriatic nail and joint disease may be linked to tissue-specific factors that lead to activation of innate immune responses (autoinflammatory basis) rather than adaptive immunity (autoimmune basis)18192021. Additionally, van der Velden et al. cast doubt on whether nail psoriasis is a comorbidity of psoriasis or an isolated disease expression [22]. However, whatever the exact pathogenesis of nail psoriasis is, the disease seems to respond satisfactorily to biological agents [3,78910111213. "
    [Show abstract] [Hide abstract] ABSTRACT: Nail involvement has started playing a major role in the overall assessment and management of psoriatic disease. Biologics indicated for moderate to severe chronic plaque psoriasis are shown to be beneficial in nail disease. This study aimed to assess and compare the serum levels of TNF-α, IL-12/23 p40, and IL-17 in psoriatic patients with and without nail involvement. 52 consecutively selected patients with chronic plaque psoriasis were included in this cross-sectional study. Patients were studied and analyzed after they had been divided into 2 groups regarding the presence (n = 24) or not (n = 28) of nail psoriasis. The mean serum levels of TNF-α were significantly higher in the group of psoriatic patients with nail lesions compared to those without (t-test; 5.40 ± 1.17 versus 3.80 ± 1.63, P = 0.026). However, the median serum levels of both IL-12/23 p40 (Mann-Whitney; 92.52 (34.35-126.87) versus 150.68 (35.18-185.86), P = 0.297) and IL-17 (Mann-Whitney; 28.49 (0.00-28.49) versus 8.59 (0.00-8.59), P = 0.714) did not significantly differ between the 2 groups. These results confirm the important role of TNF-α in the pathogenesis of nail psoriasis and may suggest that anti-TNF agents could be more beneficial in psoriatic nail disease than agents targeting IL-12/23 p40 or IL-17 and its receptors.
    Full-text · Article · Dec 2014
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    • "PsA is likely to be a heterogeneous disease, as the proportion of NK cells among synovial lymphocytes varies between 3 and 35% (data not shown and [18]), and it has been recently proposed that HLA heterogeneity plays a key role [13]. In particular, reports that PsA can develop in absence of autoreactive T cells [16] and is linked to IL-15 in mice [26] suggested that PsA can be driven by the innate rather than the adaptive immune system [17]. However, the mechanisms by which innate immunity and IL-15 could drive PsA have remained elusive. "
    [Show abstract] [Hide abstract] ABSTRACT: NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "Chronic joint inflammation is associated with eventual development of bone erosions; however, new bone formation is also observed in patients with inflammatory arthritis, in particular in PsA patients. The development of bony nodules can be seen at sites different from erosions, suggesting an uncoupling of the osteoblast–osteoclast homeostasis that allows for regulated bone turnover and formation [10]. The potential pathways involved in new bone formation include the Wingless (Wnt), transforming growth factor (TGF)-β/bone morphogenetic protein (BMP), and prostaglandin (PG)E2 pathways [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Psoriatic arthritis (PsA) is characterized by focal bone erosions mediated by osteoclasts at the bone-pannus junction. The bulk of research over the past decade has centered on mechanisms that underlie osteoclastogenesis along with new insights into osteoimmunology; however, recent advances that focus on steps that lead to new bone formation are beginning to emerge. New revelations about bone formation may have direct relevance to PsA given the presence of enthesophytes, syndesmophytes, and bony ankylosis frequently observed in patients with this disorder. In this review, we discuss current developments in the pathogenesis of new bone formation, novel imaging approaches to study bone remodeling and highlight innovative approaches to study the effect of inflammation on bone. Lastly, we discuss promising therapies that target joint inflammation and osteitis with the potential to mediate pathologic bone formation.
    Preview · Article · May 2012 · Current Rheumatology Reports
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