Recent Updates in Juvenile Spondyloarthritis

Synopsis

Spondyloarthritis (SpA) represents a group of disorders characterized by enthesitis and axial skeletal involvement. Juvenile SpA begins before age 16 but exists on a continuum with adult-onset SpA and can progress to ankylosing spondylitis. Joint involvement is usually asymmetric, often affecting weight-bearing joints of the lower extremities and tends to precede axial disease. Bone marrow edema on non-contrast magnetic resonance imaging of sacroiliac joints can facilitate diagnosis. The most significant risk factor for axial disease is HLA-B27, which also increases acute anterior uveitis risk. Non-HLA region genetic variants that account for a small portion of overall heritability support therapies targeting IL-17. Most patients continue to have active disease into adulthood. The presence of enthesitis and sacroiliitis correlates with higher pain intensity and poor quality of life measures. TNFi are the mainstay of biologic therapy for axial disease and enthesitis. While non-TNFi biologics such as IL-17 blockers have shown benefit in adult SpA, none are FDA approved for treatment of JSpA.

INTRODUCTION

Spondyloarthritis (SpA) encompasses a group of disorders characterized by presence of enthesitis, axial skeletal involvement and a common genetic predisposition most notably related to HLA-B27. Ankylosing spondylitis (AS) is the prototypic form of SpA. Children who develop features of SpA before their 16^th birthday have Juvenile spondyloarthritis (JSpA). This chapter highlights recent advances in clinical features and pathogenesis of JSpA.

CLASSIFICATION

JSpA is best understood as an umbrella term that encompasses enthesitis-related arthritis (ERA), juvenile psoriatic arthritis (JPsA) and undifferentiated arthritis categories of the International League of Associations for Rheumatology (ILAR) juvenile idiopathic arthritis (JIA) classification system. Children may also satisfy the European Spondylitis Study Group (ESSG) or Amor criteria for undifferentiated arthritis, the Assessment of SpondyloArthritis International Society (ASAS) criteria for axial or peripheral spondyloarthritis or the modified New York (NY) criteria for ankylosing spondylitis (AS), which are generally applied to adults over 18 years of age. Conditions such as chronic non-infectious osteomyelitis, SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), and hidradenitis suppurativa are sometimes clustered with spondyloarthritis. For the purposes of this chapter, we discuss ERA, JPsA, and undifferentiated sub-categories included in the ILAR classification. We also include studies in which children were classified as JSpA based on ESSG, Amor and ASAS criteria, or modified NY criteria for AS. The limitations of the current classification system have been extensively covered elsewhere ^1–3. Adult classification systems such as Amor, ASAS axial SpA, ESSG, Garmisch-Partenkirchen and ASAS peripheral SpA criteria have been applied to children with good sensitivity (~90%) using expert opinion by pediatric rheumatologists as the gold standard ^4,5. Recently, new JIA classification criteria have been proposed that include JSpA ^4,6. However, lack of harmony with adult arthritis classification and nomenclature continues to be an issue ⁷. Considering JSpA on a continuum with adult spondyloarthritis is crucial for long-term care as most of these children continue to have active disease well into adulthood. It also leverages advances made understanding pathogenesis of adult SpA and developing new treatments.

CLINICAL FEATURES

Epidemiology

The demographics and frequency of HLA-B27 in JSpA vary by geographic region. The mean age at diagnosis is 9.55–10.8 years for ERA ^5,8,9, and there is a male preponderance (56% to 82.5%) ^8,10,11. HLA-B27 positivity in ERA ranges from 38% to 68% ^5,8,11. However, these demographics may be influenced by the fact that male sex, age over 6 years, and HLA-B27 status are included in the ILAR classification criteria for ERA. HLA-B27 positivity in ERA is associated with prolonged disease course, higher incidence of acute anterior uveitis, a family history of spondyloarthritis, and higher erythrocyte sedimentation rate ¹¹.

Children with JPsA classically separate into 2 subgroups ¹², with those less than 4–5 years of age similar to children with early onset oligoarticular and polyarticular JIA with a female preponderance, dactylitis and higher incidence of ANA positivity and uveitis. Children with a later age at onset are more likely to be male and have enthesitis, sacroiliitis and psoriasis ^9,12. Mean age at diagnosis is 3.1 years for early onset JPsA and 8.2–11.2 years for late onset JPsA ^8,9. Early-onset JPsA has a female preponderance of 78%. Late onset JPsA also has a modest female preponderance of 57.7% ⁹. HLA-B27 is positive in only 10.6–12% with JPsA with similar distribution in early onset and late onset JPsA ^8,9 and does not correlate with axial disease.

Enthesitis

Tenderness at entheses where tendons and ligaments attach to bones is a characteristic feature of spondyloarthritis. Enthesitis is defined as tenderness on palpation of entheseal sites. However, patients with chronic pain may be tender on palpation in the absence of true enthesitis; use of sonography or MRI may improve sensitivity ^13,14. While enthesitis is classically present in JSpA, it is seen in other subtypes of JIA as well ¹⁵. Enthesitis is reported at diagnosis in 64 to 72% of patients with ERA ^5,15, 18% in undifferentiated JIA and only 2% of patients with JPsA ¹⁵. Over time, 78% of ERA and 19% of JPsA patients develop enthesitis ⁸. Patients with late onset JPsA tend to have enthesitis more frequently (36.8%) compared to early onset JPsA (16.9%) ⁹. Classically, entheses around the patella and Achilles tendon are most commonly involved in JSpA ¹⁰. Table 1 summarizes the entheseal sites involved in various historical JSpA cohorts. There are several enthesitis indices for adult SpA but no validated JSpA-specific enthesitis index for use in clinical practice or research.

Table 1:

Entheseal sites studied in historical JSpA cohorts

Entheseal sites	Percentage
Insertion of infrapatellar tendon on patella	27–44%
Achilles tendon	21–74%
Interosseous ligaments of the SI joint	30.3%
Plantar fascia insertion to calcaneus	12–39%
Tibial tuberosity	23–30%
Quadriceps insertion to upper poles of patella	22–46%
2nd MTP	21%
3rd MTP	16%
1st MTP	14%
Greater trochanter	14%
Iliac crest	14%

MTP – metatarsophalangeal

Data from references: ^5,10,13,15

Peripheral Arthritis

Patients with JSpA have peripheral arthritis more frequently than axial arthritis at disease onset. At presentation, the pattern of peripheral arthritis in ERA and JPsA is predominantly oligoarticular (~75%) ^10,16. However, over the disease course, patients with ERA and JPsA both tend to develop polyarticular arthritis ^8,9. In general, lower extremity joints such as the hips, knees, ankles, and tarsal joints are more commonly involved compared to upper extremity joints. Hip joint involvement is present in 20% of patients at inception in ERA ¹⁰ and increases up to 46% over the disease course ⁵. Hip joint involvement predicts development of sacroiliitis ¹⁷, and is one of the major causes of morbidity including hip arthroplasty in adulthood for patients with juvenile onset AS ¹⁸. Foot joint involvement is common in JSpA with midfoot and subtalar joint involvement accounting for 58% of cases ¹⁹. Classically dactylitis is associated with JPsA (~30%) with higher prevalence in early onset JPsA (~40%) (Figure 1) ⁹.

Figure 1.

Dactylitis of the 2^nd toe on the right foot in a child with juvenile psoriatic arthritis. Courtesy of Dr. Carlos Rose.

Axial Arthritis

Sacroiliitis is the heralding sign of axial disease, and the basis of significant disease burden in JSpA. Sacroiliitis negatively impacts physician global, parent/patient global and clinical juvenile arthritis disease activity (cJADAS-10) scores and predicts a high rate of biologic use (81%) ⁸. Clinically, sacroiliitis is defined as tenderness on palpation of the SI joint(s) and/or inflammatory lumbosacral pain by the ILAR criteria ²⁰, however, concordance between these findings and joint inflammation and/or bone marrow edema on imaging is unclear. In contrast to adult SpA, inflammatory back pain and clinical sacroiliitis are present in only 20–40% of JSpA patients at diagnosis ^5,8,17,21. Factors associated with higher pre-test probability of finding sacroiliitis by MRI at diagnosis include HLA-B27 positivity and elevated CRP ²¹. In addition, patients with a family history of spondyloarthritis have a higher risk of developing both sacroiliitis and persistent active disease ⁵. As noted in the study by Lin et al, although the majority of patients with sacroiliitis by MRI at initial diagnosis had back pain, hip pain, morning stiffness or abnormal physical examination, 50% of patients had a normal exam and one-third were asymptomatic with a normal exam despite continued evidence of active sacroiliitis on imaging during follow-up ¹⁷. Thus, physical examination alone lacks sensitivity and specificity in monitoring axial disease. Children are known to have “silent sacroiliitis” with evidence of inflammation on imaging in the absence of inflammatory back pain and/or clinical signs of sacroiliitis such as SI joint tenderness, pain on SI distraction maneuvers and an abnormal Schober test ²². Sacroiliitis at disease presentation in ERA varies from 29% to 55.6% based on the cohort and the definition of sacroiliitis used in the study ^5,10. Around 40–60% of patients with ERA develop sacroiliitis during their disease course ^5,8. In JPsA, sacroiliitis is more common in the late-onset subgroup with a prevalence of around 12–19% ^8,9. While classically male sex is considered a risk factor for development of sacroiliitis, the CARRA registry reveals an equal sex distribution for sacroiliitis defined clinically and/or by imaging in a cohort that included both ERA and JPsA patients ⁸. Whether this is a result of increased clinical recognition of SpA in females is unknown, but this observation is similar to the equal sex distribution of non-radiographic axial SpA seen in adults ²³.

Extra-articular Manifestations

Nails

The nail bed is an entheseal organ; extensor tendons of the distal interphalangeal (DIP) joints and joint collateral ligament entheses send interdigitating collagen fibers from the bone that envelop the nail root. Additionally, the nail plate is tethered to the underlying periosteum by collagen fibers ²⁴. Nail abnormalities classically seen in psoriatic arthritis include nail pitting and onycholysis (Figure 2). Nail pitting occurs in 37% of JPsA patients with early and late onset JPsA ⁹.

Figure 2.

Nail pitting in a 9-year old female with juvenile psoriatic arthritis.

Uveitis

Patients with JSpA can present with chronic idiopathic uveitis or acute anterior uveitis. The overall prevalence of uveitis in JSpA is around 7–11% ^25,26, and is similar in ERA (7–13%) and JPsA (7–10%). The prevalence of chronic idiopathic uveitis and ANA positivity in early onset JPsA (18.8%) is similar to that of oligoarticular JIA ⁹. Patients with ERA, late onset JPsA and undifferentiated JIA generally develop acute anterior uveitis (79%) which is typically associated with HLA-B27 positivity. Contrary to idiopathic uveitis, acute anterior uveitis classically presents with pain, photophobia and redness. As per the recent ACR guidelines, ophthalmology screening should occur every 3 months for children with JPsA and undifferentiated arthritis who are ANA positive and less than 7 years of age. Patients with JPsA and undifferentiated arthritis who are older than 7 and are ANA negative and patients with ERA should be screened every 6–12 months ²⁷.

Gastrointestinal Inflammation

Gastrointestinal inflammation is strongly associated with spondyloarthritis, and peripheral and axial arthritis are well known extra-intestinal manifestations of inflammatory bowel disease. Further, up to two-thirds of patients with SpA have subclinical gut inflammation ^28,29. Intestinal inflammation on ileocolonic biopsy has been noted in children with late onset pauciarticular juvenile chronic arthritis ³⁰, which may be due to the inclusion of patients with JSpA. Fecal calprotectin, a surrogate marker for gastrointestinal inflammation can be elevated in ERA ^31,32. The levels of calprotectin vary between children with active and inactive disease and between those with and without sacroiliitis by MRI ³². While in adults with axial SpA, a link between bone marrow edema in SI joints and gut inflammation has been found ³³, it is not known if such an association exists in children. New insights into changes in the gut microbiome are helping shape understanding of the link between gut immunity and systemic inflammatory changes in patients with JSpA ^34,35.

Other Extra-articular Manifestations

Obesity and metabolic syndrome are important comorbidities in adult psoriatic arthritis. Around 36.3% of JPsA patients in the CARRA registry were overweight (calculated BMI ≥ 85^th percentile for age and sex) ³⁸. This group was older at symptom onset and had worse patient/physician global and Childhood Health Assessment Questionnaire (CHAQ) scores when compared to non-overweight children. The prevalence of overweightness in children with JPsA enrolled in the CARRA registry was higher than age-matched RF+ and RF− poly JIA registry patients and the general population non-Hispanic white population in the US. A possible relationship between obesity and medications such as corticosteroids and TNF inhibitors (TNFi) was not explored in this study. Several hypotheses for obesity in JPsA exist, such as the contribution of altered gut microbiota, inflammation triggered by obesity, and greater biomechanical stress on weight bearing joints triggering arthritis; however, these hypotheses require further study.

Increased cardiovascular burden in adult AS and psoriatic arthritis is well established ^39,40. Adults with a history of juvenile arthritis have a significantly increased risk of metabolic syndrome compared to those without arthritis ⁴¹, which could be a contributing factor to long-term cardiovascular risk. In a small cohort study, children with JSpA had possible early signs of right ventricular diastolic dysfunction compared to healthy controls. A possible association between lower left ventricular systolic function and MRI confirmed enthesitis was noted ⁴². Future prospective studies on cardiovascular function in JSpA are needed.

GENETIC SUSCEPTIBILITY AND PATHOGENESIS

Highlighting the contribution of genetics to disease development, SpA tends to run within families. The most significant genetic risk factor for axial SpA is HLA-B27 ^43,44. Although it is present in about 90% of cases of AS ⁴⁵ compared to less than 10% of unaffected individuals of northern European ancestry, HLA-B27 contributes only about 20% of overall heritability ⁴⁵, underscoring the importance of other genetic and/or environmental modifiers. In fact, risk of disease occurrence is 6–16-fold greater in HLA-B27+ family members of an affected individual compared to unrelated healthy HLA-B27+ individuals ^46,47. Further illustrating the importance of genetic factors outside of the MHC region, the disease concordance rate amongst dizygotic HLA-B27+ twins is significantly lower than for monozygotic HLA-B27+ twins ⁴⁵.

Consistent with AS being a complex genetic disease, multiple risk genes beyond HLA-B27 have been identified. Indeed, genome-wide association studies (GWAS) have uncovered multiple pathways contributing to pathogenesis ⁴⁸, highlighting similarities between phenotypically overlapping diseases (psoriasis, inflammatory bowel disease, and Behcet’s)^49,50, as well as the pathogenic role of the IL-23/IL-17 axis ⁵¹. GWAS of AS patients have identified associations with genes responsible for production of IL-23 (CARD9, IL12B, PTGER4), development of IL-23 responsive cells (IL27, IL7R), and responsiveness to IL-23 (TYK2, STAT3, IL23R)^52–55.

However, well over 100 non-MHC genomic variants identified via GWAS are estimated to contribute only about 7.3% to the heritability of AS ^45,49. This “missing heritability” may be accounted for by yet undiscovered high effect size rare (mean allele frequency < 1%) variants, copy number variation, genetic epistasis, or epigenetic changes. Multiple GWAS have been performed on pediatric chronic arthritis patients ^56–60. These lumped different forms of JIA together, so were likely underpowered to demonstrate associations specific for ERA, and hence offer limited unique insight into ERA pathogenesis. Indeed, fine mapping of the MHC region highlights the genetic heterogeneity between different subtypes of JIA, with ERA correlating poorly with other subtypes ⁶¹. As with systemic JIA ⁶², genetic studies focusing on ERA would likely be more informative. Focusing on pediatric-onset disease, one study examined two well-established single nucleotide polymorphisms (SNPs) in IL23R and ERAP1 that confer risk for AS/psoriatic arthritis (PsA), across different subtypes of JIA. This study revealed an association between ERAP1 in ERA and IL23R in JPsA, yet failed to demonstrate an expected association between ERA and IL23R, possibly due to insufficient power ⁶³.

Common IL23R variants identified through GWAS are also associated with inflammatory bowel disease ⁶⁴ and psoriasis ⁶⁵, highlighting the pathogenic role of the IL-23/IL-17 axis in SpA-related diseases. IL-23 is produced by myeloid cells and promotes differentiation, proliferation, and production of IL-17 from CD4+ Th17 T cells ⁶⁶. It also promotes IL-17 production from cells of the innate immune system, including γδ T cells, certain NK cells, invariant NK T cells, Paneth cells, mast cells, lymphoid tissue inducer cells, and a population of CD4−/CD8−/CD3+ T cells found in the entheses of mice ^67,68. The IL23R SNP (rs11209026) that is most strongly associated with protection from AS and inflammatory bowel disease (IBD) produces a nonsynonymous Arg381Gln substitution in the cytoplasmic region, causing decreased IL-23-induced STAT3 phosphorylation and IL-17 production in Th17 cells ^69–71. In addition to rs11209026, another independent AS associated SNP, rs11209032, exists within the intergenic region of IL23R-IL12RB2 that may influence T cell IFN-γ production in the homozygous state ⁷², suggesting that a Th1 vs. Th17 pathogenic dichotomy may be too simplistic and Th1 immunity may also play a role in SpA pathogenesis ⁷³. It is important to note that combinatorial effects of risk/susceptibility alleles, rather than isolated effects, likely dictate SpA disease development. Indeed, combinatory SNPs within the IL-23/IL-17 axis influence both Th17 and Th1 immune response development ⁷⁴ in SpA.

There is significant evidence from human studies that indicates the IL-23/IL-17 axis is activated in spondyloarthritis ⁷⁵. While serum and synovial fluid levels of IL-17 and/or IL-23 can be elevated across different ages ^76–79, SpA disease activity poorly correlates with serum IL-23 as compared with rheumatoid arthritis ⁸⁰. However, serum or synovial fluid cytokine data should be interpreted with caution, as they may not reflect pathologic processes active in the sacroiliac joints, vertebral bodies, facet joints, or bone marrow adjacent to sites of axial inflammation. For example, tumor necrosis factor (TNF) serum levels are not uniformly increased in spondyloarthritis ^81,82 and can even be lower in AS than healthy controls ⁸³. However, increased expression of TNF has been demonstrated in actively inflamed hip and sacroiliac joints ^84,85, and is an established therapeutic target. Several studies have documented expression of IL-17 and IL-23 at sites of inflammation in spondyloarthritis. In AS, IL-17+ neutrophils (myeloperoxidase [MPO]+/CD15+) and mononuclear cells, as well as IL-23+ myeloid cells, are increased in both subchondral bone marrow and facet joints compared to osteoarthritic controls ^86,87. Taken together, and consistent with animal model data, considerable evidence implicates the IL-23/IL-17 axis in the pathogenesis of human axial spondyloarthritis.

Perhaps the most relevant insights into the pathogenesis of spondyloarthritis come from clinical trials. Neutralization of IL-17A has demonstrated clear efficacy in AS ⁸⁸, psoriasis ⁸⁹, and psoriatic arthritis ⁹⁰, while causing worsening of Crohn disease ⁹¹ possibly due to protective effects of IL-17A in the gut ⁹². While antibodies targeting IL-23 (risankizumab) or IL-12 and IL-23 (ustekinumab) have demonstrated clear efficacy in plaque psoriasis ⁹³, psoriatic arthritis ⁹⁴, and Crohn disease ⁹⁵, they have been surprisingly ineffective in double-blind placebo-controlled trials for ankylosing spondylitis and axial spondyloarthritis, respectively ^88,96, despite results from animal models. Interestingly, NSAIDs, used for decades to treat spondyloarthritis, decrease production of PGE2, the ligand for prostaglandin E receptor 4, which is encoded by the disease-associated gene PTGER4. Interaction between PGE2 and its receptor on T cells and dendritic cells leads to Th1 expansion, as well as IL-23-mediated Th17 differentiation ⁹⁷. In summary, while preclinical data strongly support the role of the IL-23/IL-17 axis in spondyloarthritis, the surprising failure of IL-23 blockade in axial spondyloarthritis underscores the complexity of human inflammatory disease, uncouples an absolute need for IL-23 in sustained IL-17 production, and may hint at temporal roles of both IL-23 and IL-17 in different stages of disease pathogenesis ⁹⁸.

DIAGNOSTIC IMAGING

Radiography and Ultrasound

While plain radiographic changes reflecting SI joint damage are essential for diagnosing adult AS, they have limited utility in early disease and are not required to diagnose non-radiographic axial spondyloarthritis. In children, X-rays of the SI joints have limited utility as a screening tool ⁹⁹ since damage can take considerable time to develop (Figure 3). Ultrasound has emerged as an attractive modality to diagnose peripheral arthritis, enthesitis and tenosynovitis ¹⁰⁰, but it has limited utility in diagnosing sacroiliitis perhaps because of its complex anatomy. Uniform definitions for normal appearance of peripheral joints and entheses on ultrasound in the pediatric population and a standardized scoring system are being developed by the CARRA ultrasound workgroup and may provide an additional tool for monitoring peripheral disease activity longitudinally.

Figure 3.

X-ray of SI joints from a 20-year old male who had disease onset at 14 years of age. X-ray shows bilateral erosion and subchondral sclerosis that is more prominent on the right.

Magnetic resonance imaging

MRI is used for diagnosing, classifying, and monitoring both peripheral and axial disease in JSpA. It has greatest utility in imaging the sacroiliac joint(s), as both clinical exam and plain radiographs lack sufficient sensitivity or specificity for diagnosing sacroiliitis ²¹. The ASAS definition for sacroiliitis developed for adults is generally used in clinical practice to define sacroiliitis in both adults and children. According to the ASAS definition, lesions representative of active sacroiliitis are bone marrow edema, capsulitis, synovitis and enthesitis (Figure 4). Bone marrow edema must be present in 2 consecutive slices or in multiple areas in a single slice ¹⁰¹. However, the ASAS definition has low sensitivity in JSpA using radiologist’s global assessment of sacroiliitis as the gold standard ¹⁰². Active lesions as defined by ASAS are adequately visualized on fluid sensitive sequences and contrast administration does not add incremental value in evaluating for active sacroiliitis in JSpA ¹⁰³. However, in clinical practice contrast MRI of the SI joints is generally used when other causes of back pain mimicking sacroiliitis such as bony tumors, infections, and leukemia are in the differential. It is important to note that developmental changes in the SI joint can be confused with sacroiliitis (Figure 5A & 5B). Furthermore, non-specific bone marrow changes occur in young athletes ¹⁰⁴, and radiologists may overcall active sacroiliitis ¹⁰⁵. Chauvin et al. recently provided a reference description of normative SI joint MRI findings in children that could help reduce the variability in interpretation of SI joint imaging ¹⁰⁶. The Spondyloarthritis Research Consortium of Canada (SPARCC) Scoring System is a reliable tool for objective quantification of sacroiliitis and measuring responsiveness to change in JSpA ¹⁰⁷. Use of calibration modules increases reliability of these composite measures ¹⁰⁸. There is increased interest in using whole body MRI to evaluate overall disease burden in JSpA. Whole body MRI can potentially identify areas of bone marrow edema, synovitis and enthesitis not apparent on clinical evaluation ¹⁰⁹, or validat physical exam findings to aid treatment decisions (Figures 6 & 7).There is an international effort organized through Outcome Measures in Rheumatology (OMERACT) to develop a semi-quantitative scoring system for whole body MRI in JIA ¹¹⁰. Future studies should explore the validity of any proposed scoring systems in initial diagnosis and monitoring longitudinal inflammatory burden in JSpA.

Figure 4.

Coronal oblique STIR image of the SI joints in an 18-year old HLA-B27 positive male demonstrating bilateral sacroiliitis. Bone marrow edema on the iliac and sacral side of the right SI joint is indicative of active sacroiliitis. The left SI joint shows chronic appearing changes, including prominent erosive changes and milder bone marrow edema of the iliac and sacral sides of SI joint (long white arrow).

Figure 5.

5A and 5B. Coronal oblique STIR (5A) and T1 weighted (5B) images of SI joints from an 11-year old normal female child. Notice the areas of homogeneous bilateral symmetric rims of subchondral STIR hyperintensity within subarticular bone of the sacrum (white arrows).

Figure 6.

STIR image from whole body MRI of a 15-year old male with HLA-B27 positive JSpA depicting sacroiliac and hip joints. There is subchondral bone marrow edema and a focal erosion within the right iliac bone adjacent to inferior aspect of the right SI joint (long white arrow). Also note bone marrow edema of the greater trochanters bilaterally (short white arrows), reflecting enthesitis.

Figure 7.

STIR image from whole body MRI of a 15-year old male with HLA-B27 negative JSpA. MRI shows active corner inflammatory lesions of vertebral end plates at multiple levels (straight white arrows), and more chronic appearing disco-vertebral unit changes (curved white arrow).

DISEASE ACTIVITY MEASURES

The Juvenile Spondyloarthritis Disease Activity Index (JSpADA) is the only validated disease activity measure specific for JSpA. It is a composite measure including history, physical exam, laboratory marker and pain visual analog scale (Table 2) where each item is equally weighted and summed. The score can range from 0–8 with higher scores indicating higher disease activity ¹¹¹. A modified version of this scoring system excluding back mobility was validated in ERA ¹¹².

Table 2:

Elements in the Juvenile Spondyloarthritis Disease Activity Index (JSpADA)

Item	Score
Active joint count	0 joints=0
	1–2 joints=0.5
	>2 joints=1
Active enthesitis count	0 entheses=0
	1–2 entheses=0.5
	>2 enthesis=1
Pain – VAS (0,10)	0–0
	1–2=0.5
	5–10=1
ESR or CRP related to JSpA activity	Normal=0
	1–2 times normal=0.5
	>2 times normal=1
Morning stiffness (greater than 15 min)	Absent=0
	Present=1
Clinical sacroiliitis	Absent=0
	Present=1
Uveitis	Absent=0
	Present=1
Back mobility	Normal=0
	Abnormal=1

VAS – Visual analog scale

ESR – Erythrocyte sedimentation rate

CRP – C-reactive protein

^*Each item is equally weighted. Range of possible scores: 0 to 8, with higher scores indicating more disease activity.

Adapted from Weiss PF, Colbert RA, Xiao R, et al. Development and retrospective validation of the juvenile spondyloarthritis disease activity index. Arthritis care & research. 2014;66(12):1775–1782.

TREATMENT

The 2019 American College of Rheumatology guidelines for treatment of JIA ¹¹³ includes recommendations for sacroiliitis and enthesitis. Initial treatment with NSAIDs is strongly recommended. In the event of a poor response to NSAIDs, use of TNFi is strongly recommended in those with sacroiliitis and conditionally recommended over conventional disease-modifying anti-rheumatic drugs (DMARDs) in those with enthesitis. Sulfasalazine is conditionally recommended in those who fail TNFi or have contraindications to their use in sacroiliitis. Methotrexate monotherapy is strongly discouraged for the management of sacroiliitis, and glucocorticoids are recommended only as bridging therapy. Intra-articular injection of SI joints is conditionally recommended as an adjunct therapy. Use of physical therapy is conditionally recommended for both sacroiliitis and enthesitis. While non-TNFi biologics such as IL-17 blocking agents and small molecules such as JAK inhibitors have shown promise in treatment of adult SpA, they are not currently FDA approved for JSpA.

SUMMARY

Juvenile spondyloarthritis exists on a continuum with adult spondyloarthritis. Any new nomenclature or classification system should be based on molecular classification. There are genetic factors beyond HLA-B27 that determine heritability and influence the pathogenesis of disease. Enthesitis and sacroiliitis are the most challenging aspects of treatment. Physical examination for evaluation of enthesitis and sacroiliitis lack sensitivity/specificity and additional imaging is required for longitudinal monitoring. Recent ACR guidelines have helped address management of sacroiliitis and enthesitis in JSpA, but additional studies are needed.

CLINICAL CARE POINTS

• Effective treatment of JSpA requires prompt recognition and distinction from other forms of juvenile arthritis

• Enthesitis, a key clinical feature of JSpA, must be distinguished from other causes of soft tissue or musculoskeletal tenderness

• While HLA-B27 is a key predisposing genetic factor, its absence does not rule out JSpA, nor does its presence establish a diagnosis

• Sacroiliitis should be considered even in the absence of prominent symptoms of inflammatory back pain, and may warrant more aggressive treatment

• Considering JSpA on a continuum with adult-onset SpA is strongly supported and facilitates the approach to treatment as well as communication during transition of care.

KEY POINTS.

• Juvenile spondyloarthritis (JSpA), an umbrella term that includes enthesitis-related arthritis (ERA), juvenile psoriatic arthritis (JPsA), and undifferentiated juvenile idiopathic arthritis (JIA), exists on a continuum with adult onset spondyloarthritis.

• The hallmark characteristic of JSpA is enthesitis, with HLA-B27 being a risk factor for axial skeletal involvement, acute anterior uveitis, and prolonged disease course.

• Lower extremity oligoarticular disease usually occurs before the onset of axial inflammation, defined by the presence of characteristic bone marrow edema on magnetic resonance imaging of sacroiliac joints.

• While the presence of HLA-B27 is the most significant risk factor for axial SpA, the vast majority of HLA-B27+ individuals are healthy, highlighting the role of additional genetic factors.

• Genome-wide association studies (GWAS) have only identified about 7% of the non-MHC heritability of ankylosing spondylitis, but genetic variants support the therapeutic benefit of targeting IL-17.