Key points

Arthritis associated with psoriasis was first described in 1956 by Wright. It was not until 1973, however, that Moll and Wright defined the various clinical phenotypes, including asymmetric arthritis, enthesitis, dactylitis, and nail disease. The following year, these authors introduced the concept of spondyloarthritis, a cluster of diseases with shared clinical and immunogenetic features. Despite these advances, the immunopathogenesis of psoriatic arthritis (PsA) remained poorly understood, awaiting a more detailed understanding of immune networks and the inflammatory response. In particular, discovery of the interleukin (IL-23)/T helper 17 (Th17) axis transformed the understanding of mechanisms that underlie not only PsA but also the spondyloarthritis family in general. Data derived from animal models, human tissues, and clinical trials underscore the concept that PsA is fundamentally different from rheumatoid arthritis (RA) ( Table 1 ). Although RA is considered an autoimmune disorder given the strong association with shared epitopes in the DRβ region of the major histocompatibility complex (MHC) and antibodies against citrullinated peptides, a parallel autoimmune response has not been identified in PsA. Indeed, the data point to an immune response that is largely innate in composition, promoting differentiation of both type 1 and 17 T lymphocytes. Moreover, the link between infections and spondyloarthritis raises the possibility that the composition of the microbiome, in the skin, the gut, or both sites, may be important in the cause and persistence of skin and joint inflammation in PsA.

Genetic factors

PsA is a highly heritable, polygenic disease. The recurrence risk (λ) ratio, defined as the ratio of a disease manifestation in family members to the affected individual compared with the prevalence in the general population, is significantly higher in PsA than RA and psoriasis. This high ratio underscores the strong familial component of this disease; the genetic risk factors are discussed in the article in this issue. In contrast to RA, which shows an association with specific MHC class II alleles, psoriasis and PsA are associated with MHC class I alleles. In particular, HLA-C*06 (previously called HLA-Cω06) is the genetic risk factor most strongly linked to psoriasis. Interestingly, this MHC I allele does not track with joint and nail disease. HLA-B*08, B*27, B*38 are found in increased frequency in PsA, and a recent study showed that the presence of glutamine in the HLA-B27 gene at amino acid position 45 significantly increased the risk for PsA, but not psoriasis. Immunochip genotype array case-controlled analysis also identified HLA-C*0602, amino acid position 67 of HLA-B, and HLA-A*0201 as independently associated with PsA in a study that included nearly 2000 PsA patients and 9000 controls. The presence of HLA-B*27 correlates with the severity of axial involvement on MRI studies as well as a shortened interval between the development of skin and joint disease.

Genetic factors

PsA is a highly heritable, polygenic disease. The recurrence risk (λ) ratio, defined as the ratio of a disease manifestation in family members to the affected individual compared with the prevalence in the general population, is significantly higher in PsA than RA and psoriasis. This high ratio underscores the strong familial component of this disease; the genetic risk factors are discussed in the article in this issue. In contrast to RA, which shows an association with specific MHC class II alleles, psoriasis and PsA are associated with MHC class I alleles. In particular, HLA-C*06 (previously called HLA-Cω06) is the genetic risk factor most strongly linked to psoriasis. Interestingly, this MHC I allele does not track with joint and nail disease. HLA-B*08, B*27, B*38 are found in increased frequency in PsA, and a recent study showed that the presence of glutamine in the HLA-B27 gene at amino acid position 45 significantly increased the risk for PsA, but not psoriasis. Immunochip genotype array case-controlled analysis also identified HLA-C*0602, amino acid position 67 of HLA-B, and HLA-A*0201 as independently associated with PsA in a study that included nearly 2000 PsA patients and 9000 controls. The presence of HLA-B*27 correlates with the severity of axial involvement on MRI studies as well as a shortened interval between the development of skin and joint disease.

Environmental factors

The concept that psoriatic plaques develop in response to bacterial antigens originated from clinical observations of a close temporal relationship between streptococcal tonsillitis and guttate psoriasis in young individuals. Streptococci produce a virulence factor (M protein) with sequence homology to keratin 16 and 17. Peripheral blood CD8+ cells from psoriasis patients react to keratin peptides so molecular mimicry was initially proposed to explain plaque development. Subsequent studies found identical T-cell clones in both the skin and the tonsils of patients who developed psoriasis following streptococcal infections. Moreover, psoriatic patients undergoing tonsillectomy for recurrent tonsillitis demonstrated improvement in skin disease not observed in psoriasis patients who did not undergo the procedure. In preclinical studies, immunization of rabbits with Streptococcus pyogenes yielded antibodies reactive against several keratinocyte proteins, and interestingly, sera taken from psoriasis patients also reacted against these keratinocyte proteins. Homology was found between keratinocyte proteins and Streptococcus proteins FcR, RecF, and RopA along with M protein. Individually, these studies support a molecular mimicry hypothesis of autoimmunity driven by CD8+ T cells, yet taken together show different sets of keratinocyte proteins and Streptococcus proteins with molecular homology, suggesting that multiple antigens are important for the development of psoriasis.

The immune response in psoriasis may be dominated by an autoinflammatory rather than an autoimmune response. Danger signals, released from dying cells, bind pattern recognition receptors on innate immune cells and activate the NFκB signaling cascade, resulting in sterile inflammation. Pattern recognition receptors include the Toll-like (TLR) and NOD receptors. A specific antigen is not required, and any event that generates a danger signal may ignite psoriasis in the proper genetic context, including infection and trauma. In 1877, Koebner (a German dermatologist) observed the widely recognized phenomena that psoriatic plaques can arise at sites of prior trauma. Similar reports have been published on PsA (reviewed in Ref. ), and these findings increase the possibility that mechanical stress at the enthesis or joint may precipitate PsA.

Microbiome

Humans can be viewed as a superorganism living in harmony with more than 10,000 microbial species of viral, fungal, and bacterial origin. Symbiosis refers to the mutually beneficial relationship between different organisms living in close proximity. Recent studies suggest that colonization with different commensal skin organisms may induce specific T-cell responses that serve as a rheostat for dynamic barrier immunity and a means of educating the adaptive immune system. A fungal microbiota with increased numbers of Firmicutes and Actinobacterium species was identified in psoriasis skin compared with healthy controls. Dysbiosis implies a change within normal microbiome or misrecognition of or aberrant response to normal microbiota within another body environment. Dysbiosis has been proposed as a mechanism for the development of an altered immune response in diseases like psoriasis and inflammatory bowel disease. Thus, multiple organisms might incite disease as opposed to typical infections, where one specific microbe is causal. The innate immune system is capable of recognizing evolutionarily conserved pathogens-associated molecular patterns expressed on a wide variety of microbes through pattern recognition receptors. Examples of pattern recognition receptors include the TLRs, NOD-like receptors, RIG-I-like receptors, and C-type-lectin-like receptors. Links between the gut and psoriasis have been proposed.

Subclinical gut inflammation was found in PsA patients undergoing colonoscopy (without gastrointestinal complaint) compared with control patients undergoing colonoscopy due to a history of benign colon polyps. Patients with psoriasis and particularly those with PsA are at increased risk of developing Crohn disease, as shown in the Nurses’ Health Study. The gut microbiota profile in PsA is reported to be similar to that of inflammatory bowel disease. Psoriasis and PsA patients have a narrower spectrum of gut flora in comparison to healthy controls. Therefore, dysbiosis has been suggested as a mechanism to generate an autoinflammatory response that may precipitate psoriasis and PsA.

Role of obesity

A range of other inflammatory conditions are linked to the development of PsA. Obesity, or overabundance of adipose tissue, is an inflammatory state characterized by a type 1 immune response. Adipocytes produce adipokines, which include classical cytokines such as IL-6 and tumor necrosis factor (TNF)-α, but also soluble molecules such as resistin and leptin (reviewed in Ref. ). Leptin regulates body weight by causing satiety and stimulating expenditure of energy. Leptin has a diverse array of effects on the immune system, and leptin-deficient mice are prone to death by infection. Leptin inhibits T-regulatory cells, promotes naïve T-cell and natural killer (NK) cell proliferation, induces monocyte proliferation, increases macrophage production of TNF-α, IL-6, and IL-12, and increases neutrophil chemotaxis (reviewed in Ref. ). These adipokines are elevated in the sera of PsA and psoriasis patients and fluctuate with disease activity. Epidemiologic studies indicate that obesity is a risk factor for incident psoriasis. Moreover, a meta-analysis of 2.1 million people, which included 200,000 psoriasis patients, found a dose-response relationship between obesity and psoriasis; the odds ratio of obesity was 1.46 for mild psoriasis and 2.23 for severe psoriasis compared with the general population. Obesity was also shown to be a risk factor for PsA, and increasing body mass index was associated with increased psoriasis risk. A causal link between obesity and psoriasis awaits additional research, but one plausible explanation is that unresolved inflammation associated with obesity fosters development of skin and, in some cases, joint inflammation in the genetically predisposed patient. An increased prevalence of type II diabetes mellitus has also been found in patients with psoriasis and PsA. Weight loss intervention through calorie reduction, exercise, or gastric bypass reduces psoriasis severity and improves response to anti-TNF agents in PsA. These studies indicate that obesity may be an essential cofactor in the development of psoriatic disease and may present an opportunity for therapeutic intervention.

Immunopathology: historical context

Cytokines generated by innate immune cells promote the differentiation of T lymphocytes, key effectors of adaptive immunity. Mosmann and Coffman described 2 types of T-helper lymphocytes in 1986 and proposed a Th1-Th2 paradigm. In this paradigm, interferon (IFN)-γ, released by Th1 cells, inhibit differentiation of IL-4-producing Th2 cells and vice versa. This reciprocal interaction results in a polarized immune response dependent on the type of invading pathogen (virus, bacteria, fungus, or parasite) and, subsequently, the cytokine milieu. In this model, IL-12 triggers a Th1 response and IL-4, a Th2 response. This paradigm proved inadequate though when a new cytokine, IL-23, was described in 2000, which shared a subunit with IL-12. IL-12, comprising p35 and p40 subunits, is released by dendritic cells and leads to differentiation of naïve T CD4+ cells to IFN-γ-producing Th1 cells. The finding that the p40 subunit was shared between IL-12 and IL-23 required the scientific community to reassess years of literature in which anti-p40 antibodies were thought to block or identify IL-12, given that IL-23 also possessed this subunit. Despite the shared p40 subunit, it was apparent that IL-12 remained the key cytokine for Th1 differentiation. In 2005, IL-17-producing CD4+ T-helper cells were described independently by 2 groups, and this finding required a revision of theTh1-Th2 paradigm. Interestingly, IL-17A (then called CTL8) was initially discovered in 1993 as a transcript from a rat CD8+ T-cell hybridoma. Nevertheless, IL-17 research predominately centered on CD4+ helper T cells for years. Subsequent studies revealed several cytokines are required for the differentiation of naïve T lymphocytes to IL-17-producing Th17 cells. In humans, these include IL-1β and transforming growth factor-β along with IL-6, IL-21, or IL-23 to induce the STAT3 transcription factor. The characterization of Th17 as a distinct subset from Th1 became increasingly blurred with the description of IFN-γ and IL-17 double-producer T-helper cells. With these discoveries, it became apparent that helper T-cell subsets showed a great deal of plasticity in the immune response. The discovery of the IL-23-Th-17 axis would have great therapeutic implication for autoimmune diseases, particularly spondyloarthritis and PsA.

Establishing a role for interleukin-17 in psoriatic arthritis

Researchers sought to define the role of Th17 cells in inflammatory arthritis. In RA and PsA, serum levels of IL-17 were not elevated compared with healthy controls. However, an increased percentage of IL-17-producing cells was identified in both RA and PsA compared with controls when peripheral blood T cells are stimulated ex vivo. Moreover, the CD4+ IL-17+ subset was present at higher levels in RA and PsA synovial fluid, whereas CD8+ IL-17− T cells were elevated only in PsA synovial fluid. Furthermore, the number of CD8+ IL-17-producing cells in the PsA patients correlated with disease activity and musculoskeletal ultrasound signals. These findings suggest that CD4+ IL-17+ cells contribute to inflammation in rheumatoid and psoriatic joints, while the IL-17 response in psoriatic synovial tissues involves CD4− cells, specifically, CD8+ cells and innate lymphocytes.

Enthesitis, dactylitis, spondylitis, synovitis, nail disease, and skin plaques are features of PsA. The pathogenetic pathways that underlie this diverse array of phenotypic features remained enigmatic until the discovery of the IL-23/Th17 axis. It is now apparent that cellular events triggered by cytokines in this pathway provide key insights into the disease mechanisms associated with the heterogeneous clinical features associated with both PsA and spondyloarthritis.

Skin

Psoriasis is characterized by hallmark raised, erythematous plaques with silver scale. New psoriatic plaques may form in response to danger signals from infection or injury (Koebner phenomena). In research models, these lesions develop following intradermal injection of IFN-α. Psoriatic skin plaques are thought to develop because DNA released by stressed keratinocytes binds to the antibacterial peptide, cathelicidin LL-37 ( Fig. 1 ). The DNA-LL37 complex binds TLR-9 in plasmacytoid dendritic cells (pDC). In response to TLR-9 activation, the pDC cells release IFN-α activating dermal dendritic cells, which migrate to draining lymph nodes. In the lymph node, the DCs stimulate differentiation of naïve T lymphocytes to Th1 and Th17 cells, which migrate back to the skin through blood vessels. Th1 cells release IFN-γ and TNF-α, while the Th17 cells produce TNF-α, IL-1, IL-17, and IL-22. In the dermis, populations of CD8+ T cells also produce IL-17. When referring to T cells, the α-β T cell receptor is often assumed; however, a greater frequency of γ-δ T cells, also capable of producing IL-17, reside in psoriatic plaques than in peripheral blood. Many T-cell subsets release IL-22, a cytokine responsible for keratinocyte proliferation, including Th17 cells, Th22 cells, and minor populations of CD8+ cells as well as NK cells. Keratinocytes release large amounts of IL-1, IL-6, and TNF-α as well as chemokines. Dermal dendritic cells synthesize IL-23, which leads to further proliferation and survival of Th17 cells. A combination of IL-17A, IL-22, and TNF-α leads to the greatest amount of IL-19 production in skin and in human tissues. IL-19 is strongly upregulated in psoriatic plaques compared with normal skin. Moreover, IL-19 induces production of antibacterial proteins in keratinocytes, including S100A7, S100A8, and S100A9, along with IL-1β, IL-20, CXCL-8, and matrix metalloproteinase-1, and IL-19 levels decrease following phototherapy or anti-TNF therapy. IL-36γ, upregulated by LL-37, is also found in abundance in psoriatic plaques and stimulates release of neutrophil-attracting IL-8 and CXCL1. Neutrophil collections, termed Munro’s abscesses, are formed that develop into psoriatic plaques.

Relationship between skin and psoriatic disease. (1) Keratinocytes may be activated by mechanical trauma or pathogens. (2) DNA and RNA released by damaged keratinocytes are recognized by pattern recognition receptors on pDC, which induce IFN-α release. (3) Interferon-α activates dermal dendritic cells, which traffic to draining lymph nodes where they release cytokines that influence T-cell differentiation. IL-23 triggers the development of IL-17-producing T cells, while IL-12 promotes development of IFN-γ-producing T lymphocytes. (4) T cells migrate from the draining lymph node back to the skin and to distant sites, which include the enthesis and joints, where they release cytokines such as IL-17 and IL-22. (5) IL-22 stimulates keratinocyte proliferation. Proliferating keratinocytes produce IL-19, IL-36γ, and antibacterial proteins S100 proteins. (6) IL-17 triggers release of neutrophil chemotactic factors from keratinocytes. Neutrophils accumulate, leading to the formation of Munro’s abscesses. The abscesses and keratinocyte proliferation lead to the development of a psoriatic plaque.

Recent clinical trials document impressive clinical responses in psoriasis patients treated with agents directed toward molecules in the IL-23/Th17 pathway. Specifically, antibodies blocking the common p40 subunit of IL-23 and IL-12 (ustekinumab) and more recently anti-p19 antibodies markedly reduce psoriasis. Antibodies against IL-17A (secukinumab, ixekizumab) and its receptor (brodalumab) show high efficacy in the treatment of skin and nail disease. The clinical efficacy of blocking the IL-17 pathway underscores its central importance in human psoriatic disease.

Nails

Nail disease is associated with joint disease, particularly distal interphalangeal (DIP) joint involvement, in PsA. The mechanisms responsible for the inflammatory changes in these adjacent structures are not well understood. McGonagle and colleagues, using cadaver specimens, noted the extensor tendon enthesis fuses directly with the nail root, providing a potential link to explain contiguous arthritis and onychodystrophy in the DIP joint and the nail, respectively. They proposed that the nail is part of the enthesis complex.

The nail is composed of 4 epithelial layers (nail matrix, proximal nail fold, nail bed, and hyponychium) and the nail plate ( Fig. 2 ). The nail plate arises from below the proximal nail fold. It comprises dead epithelial cells pushed forward by the dividing cells of the lunula. Psoriasis may affect any part of the nail. If the matrix is involved, pitting, leukonychia, red patches in the lunula, or onchodystrophy may develop. Desquamation of poorly adherent keratinocytes in areas of parakeratosis lead to the nail pits. If the nail bed becomes involved, oncholysis, “oil spots,” splinter hemorrhage, subungual parakeratosis, and hyperkeratosis may be observed.

Nail anatomy. Longitudinal cross-section demonstrating the close proximity of the extensor tendon attachment site, nail, and DIP joint.

( From Carney CK, Cantrell W, Elewski BE. Nail psoriasis: a review of current topical and systemic therapies. Adv Psor Inflamm Skin Dis 2010;1(3):90; with permission.)

Enthesis

Enthesitis is considered a key feature of PsA and spondyloarthritis. The enthesis is the attachment site of the joint capsule, tendon, or ligament to bone. MRI studies revealed that inflammation at the enthesis is more widespread than originally thought, involving the bone, synovium, and several contiguous structures. An organ is a collection of interactive tissues that carry out the same function. Therefore, the “enthesis organ” comprises tissues that may include sesamoid, periosteal cartilage, or fibrocartilage adjacent to a synovial cavity. The tissues of the enthesis organ cooperate to dissipate mechanical stress at the attachment site to the skeleton. Under normal conditions, the enthesis lacks vasculature or cells. The adjacent enthesis and synovial tissues form a functionally integrated anatomic unit labeled the synovial-enthesial complex. During times of mechanical stress or enthesial damage, danger signals released by stressed tendons or ligaments lead to cytokine and growth factor production by cells of the synovium, including lymphocytes and monocytes. Thus, in PsA, it is hypothesized that the enthesis is the site of origin for the inflammatory response, which is in contrast to RA, where inflammation originates in the synovium (reviewed in Ref. ). This view is controversial, however, and several studies have questioned the primacy of the enthesis in PsA pathogenesis. Mechanical trauma may be an inciting factor for the development of enthesitis as demonstrated in preclinical models. In the TNF (Δ ARE) mouse model, unloading of the hind limbs results in decreased inflammation of the Achilles tendon, supporting a role for biomechanical stress as an early event. Although these findings are of great interest, the relevance to PsA or spondyloarthritis remains to be established.

The enthesial interface of tendon and bones in both murine axial and peripheral joints contains cells that express IL-23 receptor. These IL-23R-expressing cells were further characterized in mice as double-negative T lymphocytes (CD3+ CD4− CD8-Rorγt+). This population was found only at the interface of the tendon and bone and not in the belly of the tendon. In response to IL-23, the enthesis produces IL-17A, IL-22, and Bmp7. Using IL-23 minicircle technology in B10.R111 mice, overexpression of IL-23 resulted in paw swelling, sacroiliitis, axial enthesitis, and arthritis with evidence of erosion and new bone formation and psoriasiform lesions, findings reminiscent of PsA. This model also had aortic wall, aortic valve inflammation, and uveitis, also clinical features of PsA and spondyloarthritis. Furthermore, enthesitis persisted after CD4+ cell depletion, demonstrating that inflammation was not dependent on T-helper cells. Cartilage, osteoid, and new bone were evident at the periosteum. CXCL1 recruited neutrophils to the bone. CCL20 recruited additional IL-23 receptor + cells to the site. Furthermore, transcriptome analyses on murine tissues exposed to IL-22 and IL-23 minicircles demonstrated that IL-17 triggered inflammatory and osteoclast pathways, whereas IL-22 was associated with inflammation and osteogenic signatures. Subsequent studies in several different murine models also provided strong support for the importance of IL-22 and IL-23 in the development of enthesitis ( Table 2 ).

Table 2

Animal models

Species	Manipulation	Skin or Nail	Joint	Enthesitis	Dactylitis	Author
Baboon	Spontaneous	—	+	—	—	Rothschild, 2005
Mouse	Act1-D10N transgenic	+	—	—	—	Wang et al, 2013
Mouse	Amphiregulin expression under control of INF-AR	+	+	—	—	Cook et al, 2004
Mouse	Collagen-induced arthritis	—	+	—	—	Courtenay et al, 1980
Mouse	IL-23 minicircle	—	+	+	—	Adamopoulos et al, 2011; Sherlock et al, 2012
Mouse	Inducible epidermal deletion of JunB and c-Jun	+	+	—	+	Zenz et al, 2005
Mouse	Lacks endogenous MHC class II molecules	+	—	—	—	Bardos et al, 2002
Mouse	Spontaneous in DBA/1 (male)	—	—	+	+	Lories et al, 2004
Mouse	TNF transgenic	—	+	—	—	Keffer et al, 1991
Mouse	β2-microglobulin knockout	+	—	—	+	Khare et al, 1995
Mouse	β-Glucan-Zap70	—	+	+	+	Ruutu et al, 2012
Rat	HLA-B27/B2 transgene	+	+	—	—	Hammer et al, 1995; Yanagisawa et al, 1995

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