Psoriatic arthritis (PsA) is a chronic inflammatory spondyloarthritis that occurs in combination with psoriasis. The exact prevalence of PsA is unknown, and its pathogenesis has not yet been fully elucidated. Genetic, environmental, and immunologic factors have all been implicated. The appearance of arthritis might precede, succeed or occur concomitant with skin lesions. PsA is sometimes considered a benign form of arthritis, but it affects patient quality of life and also causes functional impairment. Up to 20% of affected patients exhibit extremely destructive and disfiguring forms of the disease, and PsA is associated with increased mortality. The treatment of PsA aims to provide relief from signs and symptoms of the disease, prevent structural damage to joints, improve patient quality of life and decrease mortality. The choice of treatment depends on the severity of clinical presentation. The use of immunobiological agents is restricted to cases that do not respond to conservative treatment.
Introduction
Definition
Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory spondyloarthritis that occurs in combination with psoriasis and is usually seronegative . It was considered independent from rheumatoid arthritis (RA) after rheumatoid factor was discovered in 1948, and it was acknowledged as a distinct entity by the American Academy of Rheumatology in 1964 .
Epidemiology
The prevalence of psoriasis in the general population varies from 2% to 3%, and it affects men and women equally . The exact prevalence of PsA is unknown, varying between 20 and 420 cases per 100 000 individuals in the west and 1 case per 100 000 individuals in Japan. Given the lower prevalence of other forms of spondyloarthropathy in Japan, this difference may be related to ethnicity .
The wide variability in prevalence reported in different populations reflects differences in investigated cohorts, which have ranged from communities to groups of hospitalised patients, and the existence of five different diagnostic criteria with considerable variations of sensitivity and specificity, including Moll and Wright, Bennet, Vasey and Espinoza, Fournié, and CASPAR . The prevalence of PsA amongst psoriasis patients varies between 6% and 42%.
Up to 20% of affected patients exhibit severely destructive and disfiguring forms of PsA . Zhang and colleagues observed a higher frequency of PsA in obese or overweight patients (7.81%) compared to normal weight patients (5.17%, p < 0.01) .
Immunopathogenesis
Psoriasis is the most common T-cell-mediated disease in humans , but its pathogenesis has not yet been fully elucidated. Genetic, environmental and immunological factors have all been implicated. Approximately 20 chromosomal regions have been associated with psoriasis . The antigen required to activate T cells, if any, is still unknown, although some studies suggest that streptococcal antigens may be involved. Structural similarities between streptococcal M protein and type I keratin have led to the hypothesis that they may act as autoantigens, particularly keratin 17 (K17) .
It is believed that some environmental factors may act on genetically predisposed individuals to trigger the immunological alterations that give rise to the disease . Multiple chromosomal loci are associated with susceptibility genes. However, in contrast to psoriasis, the association between PsA and specific HLA antigens is less clear, and most of the antigens coincident with HLA are correlated with the early-onset form of psoriasis . Single nucleotide polymorphisms in the interleukin 13 (IL-13) gene were recently found to be associated with an increased risk of PsA, although these were not correlated with psoriasis . Concordant disease status reaches 70% between monozygotic twins, but is only 20% between dizygotic twins .
Among environmental factors, infection (by Gram-positive bacteria, such as streptococcus, or retroviruses, such as human immunodeficiency virus (HIV)), drugs, and joint trauma (mainly in children) are known to contribute to PsA. Emotional stress plays an important role as a trigger for both skin and joint psoriasis; however, the neuroimmunoendocrine mechanisms involved in this phenomenon have not yet been elucidated . One population-based study suggested that pregnancy and steroid use might trigger PsA in patients with psoriasis .
From an immunological standpoint, PsA is accompanied by changes in both the humoral immune system (production of autoantibodies against dermal and synovial membrane antigens; the presence of circulating immunocomplexes) and the cellular immune system (subpopulations of T-lymphocytes activated in the skin, synovial membrane, and entheses) . Circulating IgA immunocomplexes were identified in 80% of 35 patients with PsA, and disease severity was correlated with serum levels. The presence of autoantibodies against keratins and higher IgA and IgM levels confirms the role of humoral immunity . In PsA patients, most lymphocytes are CD4+, and the CD4+/CD8+ ratio in the synovial fluid compartment can be as high as 2:1. CD8+ cells are more commonly found in entheses . The treatments used for PsA (cyclosporine, methotrexate, IL-10 or tumour necrosis factor (TNF)-α inhibitors) also provide an important source of experimental evidence for the role of cellular immunity in the pathogenesis of PsA.
Unlike in RA, in PsA, synovial tissue is richly vascularised and contains few macrophages. Higher levels of p40 protein, which is a subunit of the IL-12 and IL-23 cytokines, are present in PsA patients compared to healthy controls. This finding might be explained by the psoriasis itself, or it might hint at the potential role of such cytokines in the pathogenesis of PsA. The finding that p40 levels increase proportionally to PsA severity (<4 vs. >4 joints) seems to support the latter hypothesis. In addition to these cytokines, TNF-α, IL-1, IL-6, IL-8 and IL-10 are found at high levels in the synovial fluid of early-onset PsA patients .
Precursor osteoclastic cells seem to play an important role in PsA pathogenesis. Their prevalence is increased in the peripheral blood of patients, and they decrease significantly after only 2 weeks of treatment with TNF-α inhibitors. High TNF-α levels might promote the migration of osteoclastic cells to joints, where the expression of nuclear factor kappa B (NFκB) favours their differentiation and activation, followed by osteolysis .
Higher body mass index (BMI) averages in patients with arthritis compared to patients without arthritis (25.4 vs. 23.7 kg m −2 ; p = 0.002) might be associated with weight gain promoted by chronic pro-inflammatory states. The higher frequency of arthritis in obese psoriasis patients may also be partially attributed to the pro-inflammatory effects of leptin on TNF-α production and T lymphocyte proliferation .
TNF-α inhibition in patients with PsA also promotes a decrease in apolipoprotein-α and homocysteine and an increase of apolipoprotein A-1 and sex hormone binding globulin (SHBG), which are beneficial from a metabolic perspective .
Histologically, both oligo- and polyarticular PsA synovitis exhibit histopathologies that are more similar to those of spondyloarthropathies than that of RA. These biological data do not support the clinical classification of polyarticular PsA as RA-like and oligoarticular PsA as spondylitis-like .
Immunopathogenesis
Psoriasis is the most common T-cell-mediated disease in humans , but its pathogenesis has not yet been fully elucidated. Genetic, environmental and immunological factors have all been implicated. Approximately 20 chromosomal regions have been associated with psoriasis . The antigen required to activate T cells, if any, is still unknown, although some studies suggest that streptococcal antigens may be involved. Structural similarities between streptococcal M protein and type I keratin have led to the hypothesis that they may act as autoantigens, particularly keratin 17 (K17) .
It is believed that some environmental factors may act on genetically predisposed individuals to trigger the immunological alterations that give rise to the disease . Multiple chromosomal loci are associated with susceptibility genes. However, in contrast to psoriasis, the association between PsA and specific HLA antigens is less clear, and most of the antigens coincident with HLA are correlated with the early-onset form of psoriasis . Single nucleotide polymorphisms in the interleukin 13 (IL-13) gene were recently found to be associated with an increased risk of PsA, although these were not correlated with psoriasis . Concordant disease status reaches 70% between monozygotic twins, but is only 20% between dizygotic twins .
Among environmental factors, infection (by Gram-positive bacteria, such as streptococcus, or retroviruses, such as human immunodeficiency virus (HIV)), drugs, and joint trauma (mainly in children) are known to contribute to PsA. Emotional stress plays an important role as a trigger for both skin and joint psoriasis; however, the neuroimmunoendocrine mechanisms involved in this phenomenon have not yet been elucidated . One population-based study suggested that pregnancy and steroid use might trigger PsA in patients with psoriasis .
From an immunological standpoint, PsA is accompanied by changes in both the humoral immune system (production of autoantibodies against dermal and synovial membrane antigens; the presence of circulating immunocomplexes) and the cellular immune system (subpopulations of T-lymphocytes activated in the skin, synovial membrane, and entheses) . Circulating IgA immunocomplexes were identified in 80% of 35 patients with PsA, and disease severity was correlated with serum levels. The presence of autoantibodies against keratins and higher IgA and IgM levels confirms the role of humoral immunity . In PsA patients, most lymphocytes are CD4+, and the CD4+/CD8+ ratio in the synovial fluid compartment can be as high as 2:1. CD8+ cells are more commonly found in entheses . The treatments used for PsA (cyclosporine, methotrexate, IL-10 or tumour necrosis factor (TNF)-α inhibitors) also provide an important source of experimental evidence for the role of cellular immunity in the pathogenesis of PsA.
Unlike in RA, in PsA, synovial tissue is richly vascularised and contains few macrophages. Higher levels of p40 protein, which is a subunit of the IL-12 and IL-23 cytokines, are present in PsA patients compared to healthy controls. This finding might be explained by the psoriasis itself, or it might hint at the potential role of such cytokines in the pathogenesis of PsA. The finding that p40 levels increase proportionally to PsA severity (<4 vs. >4 joints) seems to support the latter hypothesis. In addition to these cytokines, TNF-α, IL-1, IL-6, IL-8 and IL-10 are found at high levels in the synovial fluid of early-onset PsA patients .
Precursor osteoclastic cells seem to play an important role in PsA pathogenesis. Their prevalence is increased in the peripheral blood of patients, and they decrease significantly after only 2 weeks of treatment with TNF-α inhibitors. High TNF-α levels might promote the migration of osteoclastic cells to joints, where the expression of nuclear factor kappa B (NFκB) favours their differentiation and activation, followed by osteolysis .
Higher body mass index (BMI) averages in patients with arthritis compared to patients without arthritis (25.4 vs. 23.7 kg m −2 ; p = 0.002) might be associated with weight gain promoted by chronic pro-inflammatory states. The higher frequency of arthritis in obese psoriasis patients may also be partially attributed to the pro-inflammatory effects of leptin on TNF-α production and T lymphocyte proliferation .
TNF-α inhibition in patients with PsA also promotes a decrease in apolipoprotein-α and homocysteine and an increase of apolipoprotein A-1 and sex hormone binding globulin (SHBG), which are beneficial from a metabolic perspective .
Histologically, both oligo- and polyarticular PsA synovitis exhibit histopathologies that are more similar to those of spondyloarthropathies than that of RA. These biological data do not support the clinical classification of polyarticular PsA as RA-like and oligoarticular PsA as spondylitis-like .
Clinical manifestations
The peak of PsA incidence occurs between 30 and 50 years of age. It is clinically characterised by oedema, pain, tenderness, and stiffness of the joints, ligaments and tendons (dactylitis and enthesitis). Enthesitis occurs most often in the plantar fascia, Achilles tendon, pelvis annexed ligaments, ribs and vertebral spine . The association between synovitis and enthesitis of tendons and ligaments belonging to the same digit is called dactylitis, or ‘sausage-digit’, and it is observed in 30% of PsA patients .
Arthritis is characterised by periods of flare-up and remission; however, inflammation persists when it is not treated. The appearance of arthritis might precede, succeed or be concomitant with skin lesions. Skin involvement precedes arthritis in 75% of cases, whereas simultaneous onset occurs in 10%; in the remaining 15%, arthritis precedes skin lesions. Generally, there is no correlation between the type or severity of skin lesions and the presence, type, or extent of joint affection .
Most PsA patients exhibit vulgar psoriasis . When skin lesions appear after joint involvement – up to 10–15 years later – the condition is known as ‘PsA sine psoriasis’. Due to a lack of pathognomonic clinical, laboratory and radiological elements, only the appearance of psoriasis allows diagnosis confirmation .
Nail alterations appear in up to 90% of patients with PsA but in only 45% of patients with psoriasis . Nail alterations vary amongst patients and may include pitting, thickening, onycholysis and subungual hyperkeratosis .
Only 13% of PsA patients test positive for rheumatoid factor. Other traits that aid differential diagnosis include the participation of distal interphalangeal joints and a lower frequency of symmetric bilateral involvement. A higher degree of joint erythema, enthesitis and spine involvement and a lower degree of tenderness (as measured by dolorimetry) are also suggestive of PsA . PsA is classified as a spondyloarthropathy due to the presence of spondylitis in up to 40% of cases, as well as common extra-articular symptoms such as urethritis, diarrhoea, mucous membrane damage, aortic dilatation and association with HLA-B27. However, less pain, less restricted movement and a tendency towards asymmetry help distinguish PsA from other forms of spondyloarthropathy . Radiological findings also tend to be less severe and asymmetric . Although conjunctivitis and urethritis are not common, PsA exhibits many findings in common with reactive arthritis (asymmetric oligoarthritis, enthesitis, dactylitis and lumbar pain). Erosive osteoarthritis of the hands is a further differential element and should be taken into account, even when inflammatory activity tests are normal or mildly increased and in the absence of skin lesions .
Classification
PsA classification is a controversial subject. Although the Moll and Wright criteria are used frequently, in practice, the five subgroups on this scale exhibit frequent overlap, and the same patient might shift between subgroups over time .
- 1.
Asymmetric oligoarthritis: <5 asymmetrically affected joints.
- 2.
Symmetric polyarthritis: >5 symmetrically affected joints with pattern similar to RA.
- 3.
Distal arthritis: participation of distal interphalangeal joints.
- 4.
Mutilating arthritis: destructive form resulting in deformities.
- 5.
Spondyloarthropathy: affecting the spine (spondylitis), sacroiliac (sacroiliitis) or coxofemoral joint, with or without peripheral arthritis.
Oligoarthritis is the most frequent initial presentation pattern. Distal interphalangeal joint-isolated synovitis and mutilating arthritis patterns are the most PsA-specific findings, although they are less common .
Diagnostic criteria
In 2006, a study by The C l as sification of P soriatic Ar thritis (CASPAR) group established highly sensitive (91–100%) and specific (97–99%) set of criteria that allow diagnosis even in cases of PsA sine psoriasis, as well as in positive rheumatoid factor patients ( Table 1 ).
| □ Inflammatory musculoskeletal involvement (inflammatory arthritis, enthesitis, or lumbar pain) combined with at least 3 points: □ Evidence of current psoriasis (2 points), personal history of psoriasis (1 point), family history of psoriasis (1 point) in unaffected patient □ Affected nails (onycholysis, pitting) – 1 point □ Dactylitis (current or in history, recorded by a rheumatologist) – 1 point □ Negative rheumatoid factor – 1 point □ Radiographic evidence of new juxta-articular bone formation (excluding osteophytes) – 1 point |
Recently, an arthritis symptoms screening technique was developed to improve PsA detection by dermatologists. It consists of a questionnaire that can be self-administered by psoriasis patients (PASE). Scores equal to or greater than 4 have 82% sensitivity and 73% specificity for PsA symptoms .
Radiological findings
The radiological characteristics of peripheral PsA include asymmetric distribution, participation of distal interphalangeal joints, periostitis, bone density preservation, bone ankylosis and pencil-in-cup deformity. The most characteristic radiological finding of PsA is bone proliferation . Findings for axial involvement include paravertebral ossification, syndesmophytes, interspinous or anterior ligament calcification, apophysis sclerosis and asymmetric sacroiliitis. Cervical intervertebral discs may be narrowed and ankylosis may be present, with atlantoaxial fusion or even subluxation . Erosion and condyle osteolysis might be found in the temporomandibular joint ( Table 2 ).
| X-Ray | Ultrasonography | MRI |
|---|---|---|
| Bone proliferation | Tendinitis | Effusions |
| Periostitis | Tendon rupture | Synovitis |
| Calcification | Peritendinitis | Erosions |
| Ankylosis | Bursitis | Tenosynovitis |
| Erosions |
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