The association of arthritis with psoriasis was described almost 200 years ago, but it was not reported in children until the 1950s. Juvenile psoriatic arthritis (JPsA) is a heterogeneous entity, recognized in patients with frank psoriasis but also in cases in which a psoriatic diathesis is suspected on other grounds. The diagnosis captures certain characteristic phenotypic features of this condition, although clinical overlap with other subtypes of juvenile idiopathic arthritis (JIA) is considerable.
Definition and Classification
Juvenile psoriatic arthritis, as classified by the criteria of the International League of Associations for Rheumatology (ILAR), is arthritis that has its onset before the 16th birthday, lasts for at least 6 weeks, and is associated with either psoriasis or with two of the following: dactylitis; nail pitting or onycholysis; or psoriasis in a first-degree relative. This definition resembles that defined by the older Vancouver criteria ( Table 20-1 ). However, under ILAR criteria the diagnosis of JPsA cannot be made if the patient has a positive test for rheumatoid factor (RF) on two occasions at least 3 months apart, a first-degree family history of an human leukocyte antigen (HLA)-B27–associated disease, or if the arthritis began in a boy over the age of 6 years who is HLA-B27 positive.
| VANCOUVER | ILAR (EDMONTON REVISION) | |
|---|---|---|
| Inclusion | Arthritis plus psoriasis or arthritis plus at least two of the following: | Arthritis plus psoriasis or arthritis plus at least two of the following: |
| Dactylitis | Dactylitis | |
| Nail pits | Nail pits or onycholysis | |
| FHx of psoriasis in a first- or second-degree relative | FHx of psoriasis in a first-degree relative | |
| Psoriasis-like rash | ||
| Exclusion | None |
|
The diagnosis of JPsA is complicated by the presentation of psoriasis in children. Psoriasis in the young child may be subtle, atypical, and transient; initial misdiagnosis as eczema is common. Psoriasis occurs in about 0.5% to 1% of children, with a prevalence rising to 2% to 3% in adulthood. Although skin disease lags behind arthritis in about half of children with JPsA, sometimes by a decade or more ( Table 20-2 ), diagnosis often relies on the presence of dactylitis or family history. Agents such as methotrexate and tumor necrosis factor (TNF) blockers are effective treatments for cutaneous psoriasis and could potentially forestall its appearance in a child treated for joint inflammation. Finally, not every patient with arthritis and psoriasis has psoriatic arthritis. Typical seropositive rheumatoid arthritis (RA) with coincidental psoriasis is well recognized. Confirming that a particular child does, or does not, have JPsA is therefore challenging, and diagnostic uncertainty is common.
| YEAR | FIRST AUTHOR | N | % F | DEFINITION OF JPSA | FOLLOW-UP (Y, MEAN) | PSORIASIS % | % ARTHRITIS BEFORE SKIN | % FHX OF PSORIASIS | DACTYLITIS % | % NAIL CHANGES | UVEITIS % |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1976 | Lambert | 43 | 74 | Lambert | 11 | 100 | 53 | 40 | 71 | 9 | |
| 1977 | Calabro | 12 | 58 | Arthritis + Psoriasis | 100 | 33 | 58 | 92 | 0 | ||
| 1980 | Sills | 24 | 71 | Lambert * | 71 * | 58 | 83 | 8 | |||
| 1982 | Shore | 60 † | 58 | Lambert | 10.8 | 100 | 43 | 42 | 23 | 77 | 8 |
| 1985 | Wesolowska | 21 | 38 | 4.2 | 56 | 86 | 14 | ||||
| 1989 | Southwood | 35 | 69 | Vancouver | 4.4 | 60 | 48 | 88 | 49 | 17 | |
| 1990 | Truckenbrodt | 48 | 44 | Arthritis + Psoriasis | 5 | 100 | 50 | 42 | 17 | 67 | 10 |
| 1990 | Hamilton | 28 | 57 | Arthritis + Psoriasis | 8.8 | 100 | 21 | 73 | 39 | 71 | 0 |
| 1991 | Koo | 11 | 55 | Arthritis + Psoriasis | 65 | 36 | 18 | 45 | 18 | ||
| 1996 | Roberton | 63 | 70 | Vancouver | 7 | 56 | 85 | 35 | 14 | ||
| 2006 | Stoll | 139 | 59 | Vancouver | 2 | 25 | 29 | 53 ‡ | 37 | 47 ‡ | 8 |
| 2009 | Flato | 31 | 77 | ILAR | >15 | 39 | 50 | 75 | 42 | 30 | 19 |
| 2013 | Butbul Aviel | 115 | 67 | Vancouver or ILAR | 6.2 | 83 | 33 | 59 | 31 | 57 | 5 |
* Nail disease counted as cutaneous psoriasis.
† Includes 32 from Lambert 1976.
These challenges have been reflected in the evolution of diagnostic criteria for JPsA. Initially, JPsA was limited to children with chronic arthritis who developed classic psoriasis. Recognizing that the psoriatic diathesis may be suggested by features beyond the typical eruption, including dactylitis, nail pits, and a family history of psoriasis, Southwood et al. extended the diagnosis of JPsA to patients with such features even in the absence of the typical rash, yielding the Vancouver criteria for JPsA ( Table 20-1 ). These criteria have been validated. With the development of the ILAR nomenclature, the definition of JPsA was restricted to make it mutually exclusive with other subtypes of JIA. These definitions remain a work in progress. Both Vancouver and ILAR criteria were designed for research, and in practice the diagnosis of JPsA is often used more fluidly, acknowledging that the diagnosis may change as the clinical phenotype evolves.
Epidemiology
Incidence and Prevalence
The incidence and prevalence of JPsA are unknown. Population data, enumerating largely patients with adult-onset psoriatic arthritis (PsA), suggest a prevalence of 0.10% to 0.25% in the United States. It can occur in all ethnic groups. The proportion of JIA patients with JPsA varies widely depending on the population studied and the diagnostic criteria employed. Series that recognize patients on the basis of frank psoriasis, or using ILAR criteria, find that JPsA represents approximately 7% (range: 0% to 11.3%) of patients with JIA. Series employing the more inclusive Vancouver criteria find that JPsA represents 8% to 20% of JIA.
Age at Onset and Sex Ratio
In the pediatric population, the age at onset of JPsA is bimodally distributed ( Fig. 20-1 ). A first peak (mainly in girls) occurs during the preschool years, and a second is seen during middle to late childhood. JPsA is very uncommon before the age of 1 year. Due to the female preponderance of early-onset JPsA, girls account for 60% of patients in larger series ( Table 20-2 ).
Pathology
Synovial Pathology
Pathological data concerning the psoriatic synovium are available largely from adult-onset disease, with rare exception. Gross examination, as performed by arthroscopy, reveals a synovial lining that is less villous than in adult RA but with distinctive tortuous, bushy superficial blood vessels. This microvascular pattern resembles that of the psoriatic plaque and is also observed in synovial tissue from the spondyloarthropathies. There are histological changes throughout the psoriatic synovium ( Fig. 20-2 ). The lining becomes hypertrophic with expansion of both type A (macrophage-like) and type B (fibroblast-like) synoviocytes. The infiltrate in the loose connective tissue beneath the synovial lining is composed principally of lymphocytes and monocyte/macrophage lineage cells, with occasional neutrophils, plasma cells, and mast cells. Lymphoid follicles may be observed. Recently, a population of myofibroblast-like cells has been identified in synovium from both psoriatic and non-psoriatic spondyloarthritis, but the identity and significance of these cells remains unknown. Compared with RA, lining hypertrophy and sublining infiltrates are typically less extensive. Infiltrating neutrophils are more prevalent in PsA, but they are not invariably present. In general, given the variability between patients and within different parts of the same synovium, pathological findings are inadequate to define the diagnosis in an individual patient.
Characterization of the psoriatic synovial infiltrate by immunohistochemistry shows that the majority of infiltrating lymphocytes are T cells that express the memory CD45RO phenotype, with CD4 helper cells predominating over CD8 cytotoxic cells. These cells are present at frequencies similar to that in RA, as are CD20 + B cells, plasma cells and CD68 + macrophages. T-cell oligoclonality suggests local antigen-driven expansion. CD83 + dendritic cells are less common than in RA, whereas interleukin (IL)-17–expressing mast cells are more common. Increased numbers of macrophages expressing CD163 are identified in adult PsA and the adult spondyloarthropathies, though not as clearly in juvenile-onset disease. CD163 is a scavenger receptor, typically expressed on mature resident tissue macrophages that may help to limit rather than promote inflammation. However, the activity of these cells in the psoriatic synovium is unknown.
Complement-fixing immune complexes are not typically found in the psoriatic synovium, and synovial fluid complement levels are usually normal. Similarly, citrullinated peptides are observed commonly in the rheumatoid synovium but rarely in PsA.
Entheseal Pathology
Entheseal sites are not readily accessible to biopsy, but small series in adult spondyloarthropathies provide a degree of histological insight. A low-grade inflammatory infiltrate is observed, often in association with underlying erosion of bone. This infiltrate is not limited to the surface of the bone and is often more extensive in the bone marrow underlying the enthesis. Such osteitis can be visualized as bone marrow edema by magnetic resonance imaging (MRI). Cells observed at the interface include macrophages, lymphocytes (particularly CD8 + T cells) and occasional neutrophils. A recent studied identified IL-23–responsive T cells in the enthesis, suggesting a key pathway mediating inflammation at these sites. Bone healing is commonly evident, with woven bone filling in the defect left by erosions. This new bone often extends beyond the previous bony surface to interface with the ligament. These observations have given rise to the hypothesis that the new bone formation characteristic of the spondyloarthropathies results from recurrent cycles of injury and healing, perhaps enabled by fluctuations in the degree of inflammation. Whether such a mechanism underlies the hypertrophic periostitis observed in some patients with JPsA (see Fig. 20-4, C ) is unknown.
Pathogenesis
Environmental Contribution
Both psoriasis and psoriatic arthritis exhibit only limited concordance in monozygotic twins, suggesting that environmental contributions play a pivotal role in the development of disease. The Koebner phenomenon, in which physical trauma precipitates skin disease, is evident in at least one third of patients with psoriasis ; there have been reports of psoriatic arthritis being precipitated by physical trauma. Because the entheses are points of mechanical stress, an exaggerated reaction to injury (“deep Koebner phenomenon”) could contribute to clinical enthesitis in JPsA, with potential spread to adjacent structures. In adults, the relationship between cigarette smoking and the risk of PsA is controversial. Interestingly, in ankylosing spondylitis, smoking correlates with accelerated radiographic progression. Obesity increases the risk of PsA among patients with psoriasis, though the basis of this connection is unknown. Streptococcal infection is a known precipitant for guttate psoriasis, raising the possibility that infection with streptococci or other agents could trigger joint inflammation. Indeed, elevated antistreptococcal antibody titers have been observed in adults with psoriatic arthritis compared with other arthritides. In support of a role for bacteria, many rodent arthritis models fail to develop joint disease if deprived of normal bacterial flora. Among these is the rat transgenic for human HLA-B27, which develops features reminiscent of PsA, including synovitis, spondylitis, and nail dystrophy. Varicella infection has been reported to precipitate JPsA, but a survey of childhood arthritis found no correlation between the onset of JPsA and coincident infections with mycoplasma, adenovirus, influenza A or B, parainfluenza, rubella, herpes simplex, or respiratory syncytial virus. Exacerbation of psoriatic arthritis by emotional stress has also been observed in adults and may potentially be modeled by the male DBA/1 mouse, which develops arthritis, dactylitis, and nail dystrophy with aging but only if caged with other mice not originally from the same litter.
Genetic Contribution
There is convincing clinical evidence for a genetic contribution to psoriasis and PsA. More than 50% of patients with childhood-onset psoriasis, with or without JPsA, have a family history of psoriasis ( Table 20-2 ). The risk for both psoriasis and psoriatic arthritis appears to be transmitted more effectively via the paternal line (genetic imprinting). A fiftyfold increased risk for PsA was observed in family members of the adults with PsA, suggesting that a propensity for arthritis is inherited over and above the propensity for psoriasis. Similar results were noted in other studies.
Association studies have begun to shed light on the genes that explain these strong familial associations. In adults, psoriasis with an onset age of younger than 40 years (type I psoriasis) is more strongly familial than older-onset (type II) disease. Type I psoriasis is strongly associated with the major histocompatibility complex (MHC) class I allele HLA-Cw6. This allele is also associated with adult PsA, and possibly with older-onset JPsA in children, but the link appears secondary to risk for psoriasis. Certain alleles, including HLA-B27, are overrepresented in patients with PsA compared to psoriasis controls. The results of studies of HLA associations in JPsA have been inconsistent, likely because of differences in definitions employed and variability within JPsA across the pediatric age spectrum.
Beyond the MHC, JPsA has been linked with single nucleotide polymorphisms (SNPs) near genes involved in the autoinflammatory diseases ( MEFV, NLRP3, NOD2, and PSTPIP1 ). These associations have not emerged in adult genome-wide association scans and have yet to be replicated. In adult studies, psoriasis and psoriatic arthritis have been associated with SNPs in a range of genes, including HCP5 (involved with control of viral replication) and genes related to the cytokines TNF, IL-13, and IL-23. The association with IL-23R has been corroborated in JPsA. The functional consequences of these SNPs remain to be determined, but the cytokine findings are of particular interest. TNF blockade is markedly beneficial in psoriasis and psoriatic arthritis. IL-23 is involved in the differentiation of proinflammatory Th17 cells, which increase in frequency in the circulation and joints of patients with PsA and are present in psoriatic plaques. IL-23–responsive cells are also found in entheses and the aortic root, and IL-23 overexpression in mice can induce a spondyloarthritis phenotype with inflammation at both sites. Genetic studies have linked both psoriasis and PsA to IL12B, encoding the common p40 subunit of both IL-12 and IL-23, as well as to the IL-23 receptor IL23R . IL-13 suppresses the Th17 axis in favor of differentiation along a Th2 pathway, and the risk allele linked to psoriasis is associated with decreased cytokine production. Murine models suggest that Th17 cells may contribute importantly to arthritis. The implication of these findings is that the Th17 axis may be important in both psoriasis and its associated arthritis. Indeed, the anti-IL-12/IL-23 agent ustekinumab is highly effective for cutaneous psoriasis, although its efficacy for PsA is more modest.
Cytokines and Other Mediators
Data on cytokine expression in psoriatic synovium and synovial fluid exhibit considerable variability. The range of mediators expressed is broadly similar to that in other inflammatory arthritides, and includes the classical proinflammatory cytokines TNF, IL-1β, and IL-6, as well as IL-1α; the neutrophil chemoattractant IL-8; the IL-2-like cytokine IL-15; interferon (IFN)-γ; and others. Proangiogenic factors such as vascular endothelial growth factor (VEGF) are also elevated, as are matrix metalloproteinases and their inhibitors. No pattern of mediators has yet emerged as specific for PsA, although compared with RA there are typically higher levels of proangiogenic factors and lower levels of proinflammatory mediators.
Synthesis: Pathogenesis of Juvenile Psoriatic Arthritis
Despite substantial advances in understanding, much remains to be learned about the pathogenesis of psoriatic arthritis. In the proper genetic context, an environmental trigger such as infection or trauma appears to unleash an inflammatory process involving infiltration of lymphocytes as well as neutrophils and other effectors of innate immunity into entheses and synovium. The target of this immune response remains unknown. Lymphocytes likely play a key role, as suggested by clonal expansion of these cells within the synovium and the role of lymphocytes in relevant murine models. Joint inflammation is accompanied by an exuberant vascular expansion reminiscent of cutaneous psoriasis, with a tendency to promote bone formation as well as injury to cartilage and bone. Whether these principles apply equally to patients with JPsA, including those with early-onset disease, is unknown.
Clinical Manifestations
Subgroups within JPsA
JPsA is clinically heterogeneous. Age-of-onset data reveal a bimodal distribution, particularly in JPsA defined under the Vancouver criteria ( Fig. 20-1 ). This distribution is similar to that of JIA as a whole, with a peak around ages 2 to 3 years and a second, less prominent peak in adolescence. Younger patients with JPsA who develop the disease before they are 5 years of age are more commonly female, antinuclear antibody (ANA) positive, and affected by dactylitis, the sausagelike swelling of individual digits. This subgroup bears marked clinical and demographic similarity to early-onset oligoarticular JIA, although clinical differences include the tendency to develop dactylitis, to involve the wrists and small joints of the hands and feet, and to progress to polyarticular disease in the absence of effective therapy. The merit of distinguishing these younger patients from oligoarticular JIA is controversial ( Box 20-1 ). By contrast, older children exhibit a gender ratio closer to 1 : 1, with a tendency to enthesitis and axial disease, more closely resembling adult psoriatic arthritis. The presence of these clinical subgroups helps to explain the long-standing observation that girls with JPsA develop the disease at an earlier age than do boys and corroborate data that HLA associations within JPsA depend on the age of onset of disease, as is also true in other subtypes of juvenile arthritis.
The recognition of psoriatic arthritis in adults as an entity in its own right emerged gradually out of a number of observations. Inflammatory joint disease is encountered at a rate far higher than expected (10% to 20%) among patients with psoriasis. This arthritis is often clinically distinctive. Rheumatoid factor is usually absent or present in low titer, distal interphalangeal (DIP) and sacroiliac joints are commonly involved, and radiographs demonstrate new bone formation as well as erosions. Even where psoriatic arthritis is clinically indistinguishable from RA, it appears at a younger age and in males and females equally, often clustered within certain psoriatic families. Finally, PsA and RA synovial tissue can be differentiated, to some degree, on the basis of distinctive gross and microscopic features (see the section titled “ Pathology ”). Taken together, these data provide strong support for the existence of psoriatic arthritis in adults as a distinctive syndrome rather than simply the coincident occurrence of two common diseases.
In contrast, the case for JPsA in children remains controversial. In most respects, patients with JPsA fit somewhere in the spectrum of JIA. The hallmark psoriatic rash may take years to emerge. Absence of rheumatoid factor does not separate JPsA from most other JIA subtypes. Histopathological data are limited, and interpretation of genetic studies is complicated by issues of definition. Finally, patients with JPsA respond to the therapies used in other JIA patients and generally appear to do equally well.
Nevertheless, there are reasons to suspect that the association between psoriasis and arthritis spans both adults and children. The prevalence of psoriasis in children is 0.5% to 1%, with most showing symptoms in adolescence. Thus, the identification of a psoriatic diathesis in 7% or more of patients with JIA (of whom 40% or more have the classic rash) is not likely to reflect a chance association. Further, the pattern of arthritis in these children is distinctive in aggregate, if not always in an individual patient. Among younger patients, this includes dactylitis and involvement of small joints in the setting of oligoarthritis; in older patients, it includes an even gender ratio and an appreciable incidence of enthesitis and sacroiliitis. Disease outcome may also differ. Finally, JPsA (but not other subtypes of JIA) is linked genetically with a single nucleotide polymorphism in the IL-23 receptor that is also associated with PsA in adults.
Although older-onset JPsA patients resemble their adult counterparts, questions remain about arthritis that begins before 5 or 6 years of age. Like patients with early-onset oligoarticular JIA, patients showing symptoms of early-onset JPsA are most commonly female, frequently ANA positive, and prone to chronic asymptomatic uveitis. Some share expression of the MHC II antigen HLA-DRB1*0801 (DRw8) associated with early-onset oligoarticular and polyarticular arthritis. It seems very likely that shared pathophysiological mechanisms underlie these similarities, and it has been proposed that JPsA in this age group is simply early-onset oligoarticular or polyarticular JIA. However, at least under the Vancouver criteria, the proportion of these patients with a recognizable psoriatic diathesis greatly exceeds the less than 0.5% prevalence of psoriasis in this age group. Further, young patients with JPsA manifest changes such as nail pits and dactylitis that are highly specific for psoriatic arthritis in adults, an association noted even before these features were incorporated into the diagnostic criteria. Therefore, even among younger children, the psoriatic diathesis seems to carry an elevated risk of an arthritis that is phenotypically distinct from other types of JIA. Clarification of the relationship between JPsA and other types of JIA awaits an improved understanding of the biology of these diseases.
Peripheral Arthritis
Arthritis in JPsA begins as an oligoarthritis in approximately 60% to 80% of children ( Table 20-3 ). Initial presentation as monoarthritis is relatively common, and in some patients the disease begins with dactylitis in the absence of other joint involvement. The knee is affected most frequently, followed by the ankle; hip arthritis occurs in 10% to 30% ( Table 20-3 ). Even in children in whom arthritis remains oligoarticular, wrists, ankles, and small joints of the hands are more frequently affected than in oligoarticular JIA. Without effective therapy, polyarticular progression is common. Polyarticular onset is observed in 20% to 40% of cases, though the number of joints involved is often lower than in polyarticular JIA, especially RF-positive disease. As a result, joints affected by JPsA are often asymmetrically distributed. Distal interphalangeal (DIP) involvement was identified in 30% to 50% of patients in early JPsA series but is less common (10% to 30%) in patients diagnosed according to more inclusive criteria. Fortunately, the highly destructive form of adult PsA known as arthritis mutilans is rare in children.
| SERIES | SILLS | SHORE | SOUTHWOOD | TRUCKENBRODT | ROBERTON | STOLL | FLATO | BUTBUL AVIEL |
|---|---|---|---|---|---|---|---|---|
| YEAR | 1980 | 1982 | 1989 | 1990 | 1996 | 2006 | 2009 | 2013 |
| Oligoarticular onset | 73 | 94 | 85 | 73 | 84 | 68 | 55 | |
| Cervical spine | 32 | 17 | 25 | 2 | ||||
| TMJ | 34 | 40 | 7 | 8 | ||||
| Shoulder | 23 | 9 | 8 | 3 | 5 | |||
| Elbow | 43 | 20 | 15 | 30 | 13 | 33 | 14 | |
| Wrist | 33 | 62 | 43 | 31 | 43 | 25 | 42 | 22 |
| Small hand joints | 88 | 60 | 31 | 62 | 61 | |||
| MCP | 53 | 43 | 17 | |||||
| PIP | 40 | 51 | 25 | |||||
| DIP | 63 | 42 | 27 | 9 | ||||
| Sacroiliac joint | 29 | 11 | 17 | 5 | 1 | 0 | 4 | |
| Hip | 33 | 38 | 23 | 21 | 32 | 11 | 23 | 9 |
| Knee | 67 | 77 | 89 | 67 | 84 | 60 | 87 | 67 |
| Ankle | 63 | 63 | 50 | 60 | 51 | 71 | 33 | |
| Small foot joints | 67 | 46 | 25 | 56 | 42 | |||
| Any peripheral small joint | >88 | >53 | 69 | >31 | >62 | 57 | 65 | 42 |
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