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Pathogenesis of Psoriatic Arthritis

The pathogenesis of psoriatic arthritis is believed to involve a combination of genetic, immunologic, and environmental factors. More than 40% of patients with psoriatic arthritis have a family history (usually a first- or second-degree relative) that includes 1 or more cases of psoriatic arthritis, psoriasis, or spondyloarthritis in their blood relatives. Most pedigrees are presumed to be inherited in a multifactorial fashion, though there have been instances of Mendelian inheritance.11421  Psoriatic arthritis is often described in 3 stages; genetic predisposition (Stage 1), triggering of T cells (Stage 2), and joint inflammation and injury (Stage 3). However, not all cases are associated with a family history of the disease and may occur by chance alone. These cases therefore begin at Stage 2.

Genetic Predisposition: Stage 1

Genetic predisposition, in particular family history, is the first stage in the development of psoriatic arthritis.11421  In a study of greater than 100 probands (i.e., the first affected family member who seeks medical attention for a genetic disorder) of both established psoriatic arthritis patients (n=88) and patients with psoriasis associated with other forms of arthritis (n=20), Moll and Wright found that first-degree relatives of both sets of probands were significantly more likely to be affected by psoriasis than either spouse or population controls. The frequency of peripheral psoriatic arthritis in relatives of probands, measured by K values, was 48.8 times that found in population controls, while the K value determined for spousal controls was only 4.4 times that of population controls, which may be dependent upon the influence of environmental and genetic factors. The K factor is a commonly used index for expressing the degree of familial aggregation. K values greater than 10 should be regarded as a significant index of genetic determination.11508 

Susceptibility to psoriasis or psoriatic arthritis may occur secondary to tumor necrosis factor-α (TNF-α) promoter polymorphisms or a gene in linkage disequilibrium with TNF-α.11653  A study by Balding, et al. (2003), examined the role of functional cytokine gene polymorphisms and their ability to influence disease susceptibility and phenotype in patients with psoriatic arthritis. Seven functional proinflammatory polymorphisms were studied, including interleukin-1 (IL-1), TNF-α-308, and IL-10. Genotype frequency between the control and psoriatic arthritis groups did not differ significantly. However, both TNF-α -308 and TNF-β+252 were significantly associated with the presence of joint erosions. There was also a significant difference in frequency of these genotypes in patients with psoriatic arthritis in whom the number of joint erosions in the hands and feet increased over a median 2-year follow-up compared with a group of nonprogressors.11657 

The HLA-B27 molecule has a considerable influence on the pattern of joint involvement in psoriatic arthritis, and its frequency of presentation is as high as 70% when there is spine involvement. The genetic effect of HLA susceptibility alleles is present in both sporadic cases of psoriatic arthritis as well as those occurring in the presence of a strong family history of the disease. However, despite this evidence, it has been shown that even in families with a strong family history of psoriatic arthritis, the inheritance of HLA alleles does not account for all affected individuals, suggesting that other non-MHC genes may play a role in the susceptibility of psoriatic arthritis.11421 

Previous studies have focused on the association between psoriatic arthritis and HLA-Cw6, in addition to HLA-B13, HLA-B17, and the class II antigen HLA-DR7. However, in psoriatic arthritis the main HLA associations have been found to be with HLA-B27 (particularly in patients with predominant spinal disease), HLA-B38, HLA-B39, and the class II antigen HLA-DR4.11653  Manifestations of spondyloarthropathy have been described in every ethnic group, generally with frequencies paralleling those of the presence of HLA-B27. The highest prevalence of ankylosing spondylitis has been described in certain Native American groups such as the Haidas and the Bella Coolas in British Columbia, where the frequency of HLA-B27 can be as high as 50%.11651  Among African Americans, in whom the frequency of HLA-B27 is much lower (1%-2%), the prevalence of spondyloarthropathies is much less common. Despite this familial aggregation, however, slightly more than 50% of psoriatic arthritis patients have a negative family history and therefore represent sporadic cases of the disease.

Triggering of T Cells: Stage 2

The HLA-B27 molecule and other HLA class I molecules present protein antigens that have been synthesized within the cell (viral, tumor, or self-derived) to αβ T-cell receptors on cytotoxic (CD8+) T lymphocytes. One of the hallmarks of psoriasis is the production of scaly plaques secondary to inflammation.11396  The accumulation of neutrophils and activated CD8+ T cells in the epidermis coupled with an infiltration of CD4+ T cells in the dermis contributes to this inflammation.11401  Presumably, an unknown antigen(s) causes the CD8+ T cells to secrete various cytokines, leading to keratinocyte proliferation and stimulation of inflammatory infiltrate.11402  In a patient with psoriatic arthritis, the joints show a combination of synovitis and enthesitis, with excess CD8+ T cells in the synovial fluid. Compared to rheumatoid arthritis, there is also a reversal of the CD4/CD8 ratio.11403  Activation of CD8+ T-cell clones in the synovial tissue and fluid creates the ensuing enthesitis and arthritis via cytokine and chemokine release as illustrated by the hypothetical scenario depicted in Fig.3100. These CD8+ cells, essentially memory effector cells that are missing the costimulatory molecule CD28, instead have an assortment of receptors that are generally expressed on natural killer (NK) cells, thereby regulating their activation.11421 

The dominance of CD8+ T cells in the synovial fluid is thought to be the driving force behind the immune response in the joint.11653  In fact, this accumulation of T cells in sites of synovial fluid inflammation may represent the body’s response to a limited number of distinct immune recognition events. This may signify a highly specific process of T-cell entry into the synovial fluid, regulated by the recognition of certain peptides.11654 

A common neurovascular pathway is suggested by the features of vascular morphology and angiogenic growth factors in the skin and joints, as well as similarities in neuropeptide expression. In fact, Koebner’s phenomenon describes the development of psoriasis on areas of skin irritated by mechanical, physical, or chemical agents and may result from the release of potent proinflammatory neuropeptides from nerve endings.11653,  11655 

There are several cytokines that may also play a role in the development of psoriatic arthritis. These include macrophage-derived TNF-α, interleukin 6 (IL-6), IL-1α, lymphocyte-derived IL-2, and interferon-γ.11421  Tumor necrosis factor-α is a proinflammatory cytokine that plays a role in the development of inflammation in psoriatic arthritis, in addition to other disease states. In addition, TNF-α gene polymorphism analysis suggests a role for TNF-α in disease initiation and possibly disease severity.11656  Further, TNF-α activates T cells, enhances T-cell infiltration, and attracts the release of various chemokines and cytokines that signal the proliferation of keratinocytes in psoriatic plaques.11396,  11401,  11402,  11653 

The infiltrating T cells, abundant in the synovium of active psoriatic arthritis, elaborate chemokines such as RANTES (regulated on activation, normal T cell expressed and secreted). A high level of the chemokine IL-8 is expressed by the synovial lining cells, and to a smaller degree, the cells of the perivascular area. Expression of IL-8 attracts neutrophils to the joint fluid, a feature seen in psoriatic arthritis. Alternatively, the chemokine monocyte chemotactic protein (CCL2), also secreted by the lining cells, attracts and activates monocytes instead of neutrophils. Yet another chemokine with chemotactic activity for neutrophils is GRO-α (growth-regulated protein alpha precursor, CXCL1), produced by macrophages in the lining.11421 

The synovial histology, degree of synovial proliferation, type of mononuclear cell infiltration, and extent of angiogenesis is similar between psoriatic arthritis and rheumatoid arthritis; however, psoriatic arthritis displays a predominantly tortuous synovial vascular pattern, whereas rheumatoid arthritis reveals a more straight, branching pattern of the vessels.11404  In addition, the synovium in rheumatoid arthritis contains more interferon-α and IL-1.11421 

The mechanisms underlying the nature of the immunologic recognition events responsible for the clonal expansion of CD8+ T cells remains unknown. However, there are 2 potential scenarios that may explain the immune response in psoriatic arthritis. Each mechanism highlights different aspects of the immune response that relate to the disease. The first of these, called adaptive immune response (see Fig.3100), represents the more classic view of the immune response. The adaptive immune response is triggered by a specific peptide antigen, resulting in ongoing clonal activation of CD8+ T cells and a sustained response on the target cells producing the autoantigen. This scenario is primarily explained by expression of autoantigen followed by binding of its peptides by major histocompatibility complex (MHC) class I allelic molecules and subsequent clonal activation initiated by dendritic cells. The second mechanism, termed innate immune activation of preexisting memory/effector T cells , is based on expansion of the predominant memory-effector CD8+ T cells in the inflammatory sites. These cells are CD28-negative. They express NK cells, which when activated, provide a signal in response to stressed or injured cells.11421 

Figure 3100 – A Scheme for Pathogenesis of Inflammation and Tissue Destruction Summarizing the Mechanisms of Inflammation in Psoriatic Arthritis

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Winchester R. Psoriatic arthritis. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ., eds. Fitzpatrick’s Dermatology in General Medicine. 7th ed. New York, NY: McGraw-Hill; 2008:194-207 (chap 19). Figure 19-2, Page 196. Copyright McGraw-Hill Companies Inc.

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Joint Inflammation and Injury: Stage 3

Skeletal modeling is central to bone growth, maintenance, and repair and is tightly regulated by the interactions of osteoclasts and osteoblasts, which resorb bone and produce bone matrix, respectively.11658,  11659  In the presence of pathology, such as that seen in arthritis, the balance between bone resorption and bone production is altered, leading to excess bone resorption and/or new bone deposition.11660  In many patients with psoriatic arthritis, bone remodelling is highly dysregulated. It is not uncommon to see new bone formation in the form of bulky syndesmophytes, bony ankylosis, and periostitis on radiographs of psoriatic arthritis joints, causing persistent joint pain and stiffness.11653  The receptor activator of nuclear factor κB ligand (RANKL)-RANK signalling pathway has been shown to play a role in osteoclast differentiation (osteoclastogenesis) and subsequent bone resorption. RANKL is expressed on the surface of osteoblasts and stromal cells in the bone marrow and infiltrating T lymphocytes and synoviocytes in the inflamed joint. RANKL binds to RANK, a cell-associated TNF-receptor – related protein expressed on a variety of cell types, including osteoclast precursors and osteoclasts. In the presence of macrophage colony stimulating factor (M-CSF), this interaction causes osteoclastogenesis and subsequent bone resorption, a feature seen in psoriatic arthritis.11661,  11662 

Content on this page was last reviewed on July 31, 2008.

Content on this page was last changed on March 19, 2009.

References:

11396.  Bennett RM. Psoriatic arthritis. In: Koopman WJ, Moreland LW, eds. Arthritis and Allied Conditions . 15th ed. Philadelphia, PA: Lippincott, Williams and Wilkins; 2005:1357-1374.
11401.  Prens E, Debets R, Hegmans J. T lymphocytes in psoriasis. Clin Dermatol . 1995;13(2):115-129.
11402.  Nestle FO, Turka LA, Nickoloff BJ. Characterization of dermal dendritic cells in psoriasis. Autostimulation of T lymphocytes and induction of Th1 type cytokines. J Clin Dermatol . 1994;94(1):202-209.
11403.  Costello P, Bresnihan B, O’Farrelly C, FitzGerald O. Predominance of CD8+ T lymphocytes in psoriatic arthritis. J Rheumatol . 1999;26(5):1117-1124.
11404.  Ceponis A, Konttinen YT, Imai S, et al. Synovial lining, endothelial and inflammatory mononuclear cell proliferation in synovial membranes in psoriatic and reactive arthritis: a comparative quantitative morphometric study. Br J Rheumatol . 1998;37(2):170-178.
11421.  Winchester R. Psoriatic arthritis. In: Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, eds. Fitzpatrick’s Dermatology in General Medicine . 7th ed. New York, NY: McGraw-Hill; 2008:194-207.
11508.  Moll JM, Wright V. Familial occurrence of psoriatic arthritis. Ann Rheum Dis . 1973;32(3):181-201.
11651.  Reveille JD. Seronegative spondyloarthropathies. In: Klippel JH, Crofford LJ, Stone JH, Weyand CM, eds. Primer on the Rheumatic Diseases . 12th ed. Atlanta, GA: Arthritis Foundation; 2001:239-245.
11653.  Veale DJ, Ritchlin C, FitzGerald O. Immunopathology of psoriasis and psoriatic arthritis. Ann Rheum Dis . 2005;64(Suppl 2):ii26-ii29.
11654.  Costello PJ, Winchester RJ, Curran SA, et al. Psoriatic arthritis joint fluids are characterized by CD8 and CD4 T cell clonal expansions that appear antigen driven. J Immunol . 2001;166(4):2878-2886.
11655.  Eedy DJ, Johnston CF, Shaw C, Buchanan KD. Neuropeptides in psoriasis: an immunocytochemical and radioimmunoassay study. J Invest Dermatol . 1991;96(4):434-438.
11656.  Fraser A, Fearon U, Billinghurst RC, et al. Turnover of type II collagen and aggrecan in cartilage matrix at the onset of inflammatory arthritis in humans: relationship to mediators of systemic and local inflammation. Arthritis Rheum . 2003;48(11):3085-3095.
11657.  Balding J, Kane D, Livingstone W, et al. Cytokine gene polymorphisms: association with psoriatic arthritis susceptibility and severity. Arthritis Rheum . 2003;48(5):1408-1413.
11658.  Teitelbaum SL. Bone resorption by osteoclasts. Science . 2000;289(5484):1504-1508.
11659.  Massey HM, Flanagan AM. Human osteoclasts derive from CD14-positive monocytes. Br J Haematol . 1999;106(1):167-170.
11660.  Gravallese EM. Bone destruction in arthritis. Ann Rheum Dis . 2002;61(Suppl 2):ii84-ii86.
11661.  Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature . 2003;423(6937):337-342.
11662.  Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum . 2000;43(2):250-258.

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