The Conundrum of Juvenile Psoriatic Arthritis A

The conundrum of juvenile psoriatic arthritis A. Ravelli, A. Consolaro, B. Schiappapietra, A. Martini

Istituto Giannina Gaslini and ABSTRACT Evolution of the concept of JPsA University of Genova, Genoa, Italy. Juvenile psoriatic arthritis (JPsA) has Traditionally, JPsA has been grouped Angelo Ravelli, MD provided paediatric rheumatologists with juvenile ankylosing spondylitis, Alessandro Consolaro, MD with a controversial topic for many reactive arthritis, and the arthropathies Benedetta Schiappapietra, MD years. The principal area of contention of inflammatory bowel disease, an as- Alberto Martini, MD centres on the discordance between its sociation based on the concept of the Please address correspondence to: treatment as a single diagnostic catego- seronegative spondyloarthropathies for- Angelo Ravelli, MD, ry in current classification schemes and Pediatria II, mulated by Moll and Wright in the early Istituto G. Gaslini, the demonstration of its heterogeneous 1970s (4). As a result, the category of Via G. Gaslini 5, nature. A further point of debate is the JPsA was not incorporated in the Amer- 16147 Genova, Italy. distinctiveness of JPsA as an entity. Ow- ican College of Rheumatology (ACR) E-mail: ing to these uncertainties, the concept classification for juvenile rheumatoid [email protected] of JPsA has evolved over the years and arthritis (JRA) (5), which excluded the Received and accepted on September 18, there have been several changes in its spondyloarthropathies, but was placed 2015. definition and diagnostic criteria.- Re within the spondyloarthropaties in Clin Exp Rheumatol 2015; 33 (Suppl. 93): cently, strong evidence has been pro- the European League for Rheumatol- S40-S43. vided that the spectrum of JPsA include ogy (EULAR) classification for juve- © Copyright Clinical and at least two distinct subgroups, one that nile chronic arthritis (JCA) (6)(Table I). Experimental Rheumatology 2015. has the same characteristics as early- Although the term JIA was introduced onset ANA-positive JIA, and another in 1997 to replace both JRA and JCA, Key words: psoriatic arthritis, that is part of the spectrum of spondy- for sake of clarity we will use this term juvenile idiopathic arthritis, childhood loarthropathies and resembles the forms throughout the entire manuscript, even arthritis, psoriasis, classification of psoriatic arthritis in adults that be- when earlier studies are discussed. long to the same disease family. These The attribution of JPsA to the spondy- findings call for a revision of the clas- loarthropathy group was challenged sification of childhood arthritis, that re- by Ross Petty in a review published in futes the assumptions that children with 1994 (2). Based on analysis of the exist- JPsA constitute a single homogeneous ing literature, he argued that grouping population and that JPsA should be of JPsA with the spondyloarthropathies considered an individual disease entity. was untenable for several reasons: reported patients with JPsA were most Introduction frequently young girls, whereas juve- Juvenile psoriatic arthritis (JPsA) is nile ankylosing spondylitis (JAS) af- probably the most discussed and con- fects primarily older boys; antinuclear troversial of the various forms of child- antibodies (ANAs) are not present in hood arthritis (1-3). Part of the debate children with JAS, but were quite fre- derives from its characterisation as a quent in those with JPsA; HLA-B27 single diagnostic category in current occurs in up to 90% of children with classifications, despite numerous - dem JAS and Reiter’s syndrome, but in onstrations of its heterogeneous nature. fewer than 30% of those with JPsA; ax- Another disputed issue is whether this ial skeleton arthritis and enthesitis are condition exists as a distinct entity with- typical of JAS, but very uncommon in in juvenile idiopathic arthritis (JIA). JPsA; uveitis is a significant complica- These uncertainties have been reflected tion of both JAS and JPsA, but is char- in the evolution of the concept of JPsA acteristically acute and self-limited in and in repeated changes in definition the former, and chronic in the latter. On and diagnostic criteria. In this article, the other hand, he felt that the pattern we discuss the history of the concept of of distribution of affected joints, par- JPsA, review the proposed definitions ticularly the presence of dactylitis and and classifications, and summarise- re of asymmetric disease in both large and sults of the most recent studies of the small joints, set JPsA also apart from Competing interests: none declared. disease spectrum. oligoarticular-onset JIA.

S-40 Juvenile psoriatic arthritis / A. Ravelli et al.

Table I. Comparison of classification criteria for chronic arthritis in childhood. ous disease entity than the distribution of joint involvement or the presence of ACR JRA EULAR JCA ILAR JIA psoriasis. Systemic arthritis Systemic arthritis Systemic arthritis In Martini’s opinion therefore age at Pauciarticular arthritis Pauciarticular arthritis Oligoarthritis: onset and ANA positivity may be more  Persistent  Extended suitable criteria for disease classifica- Polyarticular arthritis Polyarticular arthritis Polyarthritis (RF-negative) tion than the number of joint involved JRA (RF-positive) Polyarthritis (RF-positive) or the presence of psoriasis Spondyloarthropathies Psoriatic arthritis Enthesitis-related arthritis Undifferentiated arthritis Definitions and classifications of JPsA Note: spondyloarthropathies include juvenile ankylosing spondylitis, juvenile psoriatic arthritis, Re- iter’s syndrome, and the arthropathies of inflammatory bowel disease; children with spondyloarthropa- Moll and Wright defined psoriatic - ar thies are excluded from the ACR classification; RF positivity is not a differentiating criterion in the thritis in adults as arthritis occurring ACR classification although it is in the EULAR classification. together with psoriasis. However, this ACR: American College of Rheumatology; EULAR: European League Against Rheumatism; ILAR: International League of Associations for Rheumatology; JCA: juvenile chronic arthritis; JIA: juvenile definition was judged too simplistic to idiopathic arthritis; JRA: juvenile rheumatoid arthritis; RF: rheumatoid factor. capture all forms of psoriatic arthritis in the paediatric age group (2). The first The possible relationship between these findings was that that early-onset definition of psoriatic arthritis in child- psoriasis and arthritis was explained JPsA closely resembles early-onset oli- hood was proposed in 1976 by Lambert by Petty in two ways: a portion of the goarticular JIA, the only difference be- et al. (8), who defined it as “arthritis be- patients diagnosed as having JPsA may ing a higher reported frequency of dac- ginning before the age of 16 years, as- have the coincidental association of tylitis (which was, however, part of the sociated with psoriasis either preceding two diseases, psoriasis and either JIA or diagnostic criteria) and of small joint in- the onset of arthritis or occurring within JAS; another group, however, has a dis- volvement, and a more rapid spread of the subsequent 15 years, and usually tinctive arthropathy which occurs pre- arthritis. Conversely, the older group of with the absence of rheumatoid factor dominantly in children who also have patients with JPsA had a male predomi- in the serum”. This definition accounted psoriasis and is characterised by asym- nance and shared the features of spon- for the possible asynchronous occur- metric and oligoarticular disease with dyloarthropathies. Notably, in studies of rence of the two essential components involvement of large and small joints, children with psoriasis and arthritis in of the disorder, arthritis and psoriasis. with or without dactylitis. He conclud- which patients with enthesitis were not However, its application in two subse- ed that the latter form could represent excluded, some patients presented with quent studies showed that it only seldom “true” JPsA and suggested that it should arthritis and enthesitis or developed allowed the diagnosis of JPsA early in be classified separately from both JIA sacroiliitis during follow-up, similarly the disease course (9, 10). These obser- and the spondyloarthropathies. In his to several adult patients with psoriatic vations raised the concern that JPsA was opinion, a direct effect of psoriasis on arthritis who share features with spon- underdiagnosed due of the frequently arthritis could be deduced from the as- dyloarthropathies (7). long interval between the onset of ar- sociation of isolated dactylitis with pit- Martini’s conclusion was that JPsA is thritis and the onset of a typical psoriat- ting of the nail of the same finger. not a unique condition, but includes two ic rash (10). Notably, in reported series In an editorial published 9 years later, distinct subsets: one is very similar to arthritis was found to precede psoriasis one of the authors of this article, Al- early-onset ANA-positive oligoarthritis, in a substantial proportion of patients berto Martini (3) put forward his view with the possible few aforementioned (23–58%), often by several years (11). that JPsA is a heterogeneous condition. differences; the other shares the features In an attempt to resolve this problem, He noticed that several published case of enthesitis-related arthritis and, there- Southwood et al. (10) devised the so- series had shown a bimodal distribution fore, appears to be part of the spectrum called “Vancouver criteria” (Table II), of age at disease onset, with a first peak of spondyloarthropathies. The consid- which were aimed to allow a diagno- in the preschool years (mainly in girls) eration that the former patient group has sis of JPsA in the absence of psoriasis. and a second during mid to late child- the same key clinical features (asym- Recognising that the psoriatic diathesis hood. In addition, patients with early metric arthritis, early onset, female pre- may be suggested by features beyond onset had an asymmetric oligoarthritis dominance, frequent ANA positivity, the classic eruption, including dactylitis, that could extend over time. Chronic an- high risk for chronic anterior uveitis, nail pits, and a family history of psoria- terior uveitis occurred with a frequency and association with HLA-DR8) that are sis, these authors extended the diagno- similar to that seen in early-onset oli- present in other JIA categories (oligoar- sis of JPsA to patients with such features goarticular JRA (roughly 20%) and was thritis which is persistent or extended, even in the absence of the typical rash. associated with the presence of ANAs. and RF-negative polyarthritis) and sug- Both the study of Southwood et al. (10) An increase in DRw8 was recorded on gest a common background, led Martini and a subsequent validation analysis HLA typing in JPsA patients with ear- to propose that these features may be (12) revealed that including children ly-onset disease. His interpretation of more meaningful to define a homogene- with more subtle psoriatic manifesta-

S-41 Juvenile psoriatic arthritis / A. Ravelli et al. tions allows for the identification of a Table II. Vancouver criteria for diagnosis of juvenile psoriatic arthritis (JPsA) (adapted from population of patients of a younger age ref. 10). at onset than those reported in earlier se- Definite JPsA ries and with clinical characteristics that Arthritis with typical psoriasis differ both from the spondyloarthropa- or Arthritis with at least 3 of the following minor criteria: ties and from classic JIA, as outlined in  Dactylitis the aforementioned review of Petty.  Nail pitting or onycholisis The new classification of childhood ar-  Psoriasis-like rah  Family history of psoriasis thritis was promulgated in 1994 (13), and revised in 1997 (14) and again in Probable JPsA 2001 (15), by the Pediatric Task force Arthritis with 2 of the minor criteria listed above of the International League of Associa- Definitions tions for Rheumatology (ILAR) (Table Arthritis: joint swelling or at least 2 of the following: limited range of motion of the joint, pain on I). The ILAR criteria provided new movement, or tenderness, persisting for at least 6 weeks. Typical psoriasis: unmistakable psoriatic rash observed by the physician or diagnosed as such by a categories for various forms of JIA, dermatologist;rash not necessarily coincident with arthritis. including JPsA (Table III). This condi- Dactylitis: Diffuse digit swelling, extending beyond the margin of the joint capsule. tion was defined as the association of Pitting: 2 or more pits on the fingernails at any examination. Psoriatic-like rash: historical or examination features of a psoriatic rash, but evidence not conclusive. arthritis and psoriasis or, if psoriasis is Family history of psoriasis: diagnosis of psoriasis in first or second-degree relatives. absent, with two of the following: dactylitis, nail pitting or onycholisis, or Table III. ILAR criteria for psoriatic arthritis (adapted from ref. 15). psoriatic arthritis in a first-degree relative. This definition is similar to that of Arthritis and psoriasis or the Vancouver criteria. However, under Arthritis and at least 2 of the following: ILAR criteria, the diagnosis of JPsA  Dactylitis cannot be made if the patient has a first-  Nail pitting or onycholysis  degree family history of an HLA-B27- Psoriasis in a first degree relative associated disease or if the arthritis Exclusion criteria began in a boy over the age of 6 years a. Arthritis in an HLA-B27-positive male with arthritis onset after 6 years of age. b. Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, who is HLA-B27 positive. In addition, Reiter’s syndrome, or acute anterior uveitis in a first-degree relative. the simultaneous presence of JPsA and c. Presence of IgM rheumatoid factor on at least two occasions more than 3 months apart. ERA leads the patient to fall into the d. Presence of systemic arthritis. “undifferentiated arthritis” category. Definitions Thus, the ILAR scheme excludes de Arthritis: swelling within a joint, or limitation in the range of joint movement with joint pain or ten- facto children with spondyloarthropat- derness, which persists for at least 6 weeks, is observed by a physician, and is not due to primarily mechanical disorders or to other identifiable causes. ic features from the JPsA group. This Dactylitis: swelling of one or more digits, usually in an asymmetric distribution, which extends beyond limitation appears undesirable as it pre- the joint margin. cludes identification of those patients Nail pitting: a minimum of 2 pits on one or more nails at any time. who have a form of psoriatic arthritis similar to that seen in adults (16). age at onset appeared to be a less reli- current diagnostic criteria for JPsA pull able predictor of clinical phenotype than together two diverse disease entities, Recent analyses of the clinical dactylitis, which was present in 100% of one that is very similar to early-onset spectrum of JPsA the younger cluster versus 1.3% of the ANA-positive oligoarthritis, the other In a study of 139 children meeting the older cluster. Similar findings in terms that belongs to the spectrum of spondy- Vancouver criteria, Stoll and co-workers of age at onset distribution and clini- loarthropaties (see above) (19). (17) found an age at onset distribution cal differences between early-onset and In a large JIA cohort, we found that similar to that of previous reports, with late-onset children were observed when ANA-positive patients classified by the one peak in early childhood and the oth- the data were reanalysed using the more ILAR criteria into different categories, er near adolescence. Substantial clinical strict ILAR criteria (16). including JPsA, shared similar charac- differences were noted between chil- The authors favoured the hypothesis teristics (e.g. strong predominance of dren with early-onset versus late-onset that there are 2 distinct subsets of JPsA females, early onset of disease, asym- disease, young children were more like- in children, differentiated by the age of metric arthritis, and high risk of chronic ly to be female, to have dactylitis and onset and other clinical features, par- iridocyclitis) (20). This observation polyarticular onset, and to be ANA posi- ticularly the presence of dactylitis (11, confirmed and expanded our previous tive, but less likely to have frank pso- 18), in their interpretation of the results. findings (21) and substantiated -Marti riasis, enthesitis, or axial disease. The In a comment concerning the first arti- ni’s original hypothesis that ANA-posi- existence of two distinct subgroups was cle, Martini argued that the study find- tive patients with JIA constitute a homo- confirmed by cluster analysis, although ings are in keeping with his view that geneous subgroup, irrespective of the

S-42 Juvenile psoriatic arthritis / A. Ravelli et al. course of joint disease and the presence patients, one that has the same charac- within juvenile psoriatic arthritis: a review of psoriatic features (3). That ANA-pos- teristics as early-onset ANA-positive of the literature. Clin Dev Immunol 2006; 13: 377-80. itive patients with JPsA were similar to JIA, and another that is part of the spec- 12. ROBERTON DM, CABRAL DA, MALLESON their counterpart in other categories and trum of spondyloarthropathies and bears PN, PETTY RE: Juvenile psoriatic arthritis: much different from the ANA-negative a resemblance to the forms of psoriatic followup and evaluation of diagnostic crite- patients in the same category adds to arthritis in adults that belong to the same ria. J Rheumatol 1996; 23: 166-70. 13. FINK CW: Proposal for the development of evidence of the heterogeneity of JPsA. disease family. There is, thus, a strong classification criteria for idiopathic arthritides Owing to the concern that patients with rationale to avoid the assumptions that of childhood. J Rheumatol 1995; 22: 1566-9. a positive family history of psoriasis children with JPsA constitute a single 14. PETTY RE, SOUTHWOOD TR, BAUM J et al.: Revision of the proposed classification crite- could “contaminate” the oligoarthritis homogeneous population and that JPsA ria for juvenile idiopathic arthritis: Durban, category of JIA, thus compromising the should be treated as a single disease 1997. J Rheumatol 1998; 25: 1991-4. search for homogeneity within groups, entity, as done in current classification 15. PETTY RE, SOUTHWOOD TR, MANNERS P et the ILAR Committee decided to include schemes (27). It remains unclear wheth- al.: International League of Associations for Rheumatology classification of juvenile idio- the history of psoriasis in a first-degree er it is worth maintaining a category of pathic arthritis: second revision, Edmonton relative among the exclusions for vari- JPsA in future classifications of child- 2001. J Rheumatol 2004; 31: 390-2. ous categories of JIA (22, 23). However, hood arthritis or whether the presence 16. STOLL ML, LIO P, SUNDEL RP, NIGROVIC PA: this exclusion, which leads to place- of psoriasis or psoriatic features should Comparison of Vancouver and International League of Associations for rheumatology ment of a patient in the undifferentiated be placed only among the descriptors of classification criteria for juvenile psoriatic arthritis category, has been a matter of the extra-articular phenotype. The need arthritis. Arthritis Rheum 2008; 59: 51-8. controversy (23, 24). In our series, as for a revision of JIA classification and 17. STOLL ML, ZURAKOWSKI D, NIGROVIC LE, NICHOLS DP, SUNDEL RP, NIGROVIC many as 82% of patients were classified nomenclature has been recently sug- PA: Patients with juvenile psoriatic arthritis as “undifferentiated arthritis” due to the gested (27). All related issues will be comprise two distinct populations. Arthritis presence of a family history of psoriasis addressed at the consensus conference Rheum 2006; 54: 3564-72. in a first-degree relative (20). We found entitled “Evidence-based revision of the 18. STOLL ML, PUNARO M: Psoriatic juvenile idiopatic arthritis: a tale of two subgroups. that a positive family history of psoria- International League Against Rheuma- Curr Opin Rheumatol 2011; 23: 437-43. sis does not affect the clinical picture tism (ILAR) classification criteria for 19. MARTINI A: What is juvenile psoriatic arthri- and course in JIA patients with oligoar- juvenile idiopathic arthritis”, which will tis? Comment on the article by Stoll et al. thritis, which contradicts the use of such be held in Genoa, Italy on 3–6 Decem- Arthritis Rheum 2007; 56: 1368. 20. RAVELLI A, VARNIER GC, OLIVEIRA S et a history as an exclusion criterion (25). ber, 2015. al.: Antinuclear-antibody-positive patients Butbul Aviel (26) and colleagues re- should be grouped as a separate category in viewed the charts of 122 patients who References the classification of juvenile idiopathic- ar met the Vancouver criteria (definite or 1. RAVELLI A, MARTINI A: Juvenile idiopathic thritis. Arthritis Rheum 2011; 63: 267-75. arthritis. Lancet 2007; 369: 767-78. 21. RAVELLI A, FELICI E, MAGNI-MANZONI S et probable) or ILAR criteria for JPsA. 2. PETTY RE: Juvenile psoriatic arthritis, or al.: Patients with antinuclear antibody–posi- Their findings suggested that JPsA may juvenile arthritis with psoriasis? Clin Exp tive juvenile idiopathic arthritis constitute comprise 4 distinct groups (oligoarthri- Rheumatol 1994; 12 (Suppl. 10): S55-8. a homogeneous subgroup irrespective of tis persistent or extended, RF-negative 3. MARTINI A: A e the number of joints in- the course of joint disease. Arthritis Rheum volved or the presence of psoriasis still use- 2005; 52: 826-32. polyarthritis, RF-positive polyarthritis, ful tools to identify homogeneous entities in 22. MERINO R, De INOCENCIO J, GARCIA-CON- and ERA) that are similar to non-JPsA juvenile idiopathic arthritis ? J Rheumatol SUEGRA J: Evaluation of ILAR classifica- JIA regarding presentation, disease 2003; 30: 1900-3. tion criteria for juvenile idiopathic arthritis in Spanish children. J Rheumatol 2002; 29: course, uveitis associations, response to 4. MOLL JMH, WRIGHT V: Psoriatic arthritis. Semin Arthritis Rheum 1973; 3: 55-78. 2731-6. treatment, and outcome. They conclud- 5. BREWER EJ Jr, BASS J, BAUM J et al.: Cur- 23. PETTY RE: Growing pains: the ILAR clas- ed that the presence of psoriasis may rent proposed revision of JRA criteria. Ar- sification of juvenile idiopathic arthritis. have little clinical relevance in the out- thritis Rheum 1977; 20 (Suppl. 2): 195-9. J Rheumatol 2001; 28: 927-8. 6. WOOD P: Special Meeting on: nomenclature 24. BURGOS-VARGAS R, RUDWALEIT M, SIE- come or response to therapy of children and classification of arthritis in children. PER J: The place of juvenile onset spondy- with JIA and that, therefore, psoriasis In: MUNTHE E (Ed.) The Care of Rheu- loarthropathies in the Durban 1997 ILAR may be considered as an extra-articular matic Children. EULAR Publisher, Basle, classification criteria of juvenile idiopathic manifestation seen in JIA, similar to 1987:47-50. arthritis. J Rheumatol 2002; 29: 869-74. 7. HAFNER R, MICHELS H: Psoriatic arthritis in 25. TSITSAMI E, BOZZOLA E, MAGNI-MANZONI uveitis, rather as a feature requiring a children. Curr Opin Rheumatol 1996; 8: 467- S et al.: Positive family history of psoriasis distinct classification grouping. 72. does not affect the clinical expression and 8. LAMBERT JR, ANSELL BM, STEPHENSON E, course of juvenile idiopathic arthritis patients Conclusion WRIGHT V: Psoriatic arthritis in childhood. with oligoarthritis. Arthritis Rheum 2003; 49: Clin Rheum Dis 1976; 2: 339-52. 488-93. There is compelling evidence that sub- 9. SHORE A, ANSELL BM: Juvenile psoriatic 26. BUTBUL AVIEL Y, TYRREL P, SCHNEIDER stantial clinical heterogeneity exists arthritis – an analysis of 60 cases. J Pediatr R et al.: Juvenile psoriatic arthritis (JPsA) : within the group of children with JPsA. 1982; 100: 529-35. juvenile arthritis with psoriasis? Pediatric It appears that the association of psoria- 10. SOUTHWOOD TR, PETTY RE et al.: Psoriatic Rheumatol Online J 2013; 11: 11. arthritis in children. Arthritis Rheum 1989; 27. MARTINI A: It is time to rethink juvenile idi- sis with arthritis leads to the identifica- 32: 1007-13. opathic arthritis classification and nomencla- tion of at least two different groups of 11. STOLL ML, NIGROVIC PA: Subpopulations ture. Ann Rheum Dis 2012; 71: 1437-9.

S-43