The Treatment of Enthesitis-Related Arthritis: Comparison
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Enthesitis-related arthritis (ERA) represents 5–30% of all cases of juvenile idiopathic arthritis (JIA) and belongs to the spectrum of the disorders included in the group of juvenile spondyloarthritis. In the last decade, there have been considerable advances in the classification, diagnosis, monitoring, and treatment of ERA. New provisional criteria for ERA have been recently proposed by the Paediatric Rheumatology INternational Trials Organisation, as part of a wider revision of the International League of Associations for Rheumatology criteria for JIA. The therapeutic recommendations for ERA are comparable to those applied to other non-systemic JIA categories, unless axial disease and/or enthesitis are present. In such cases, the early use of a TNF-alpha inhibitor is recommended. Novel treatment agents are promising, including IL-17/IL-23 or JAK/STAT pathways blockers.

  • enthesitis-related arthritis
  • juvenile idiopathic arthritis

1. Introduction

Juvenile idiopathic arthritis (JIA) is an umbrella term encompassing arthritis of unknown etiology, lasting for >6 weeks and with onset at <16 years of age [1,2][1][2]. JIA is the most common chronic rheumatic disorder of childhood, with an incidence rate ranging from 1.6 to 23/100,000 [3]. Enthesitis-related arthritis (ERA) is one of the seven JIA subtypes outlined by the International League of Associations for Rheumatology (ILAR) classification for JIA [4].
Together with the ILAR categories of juvenile psoriatic arthritis (JPsA) and some forms of undifferentiated arthritis, ERA also belongs to the broader group of childhood spondyloarthritis (SpA), a family of inflammatory rheumatic disorders that have some key features in common, including peripheral arthritis, axial involvement, and enthesitis.
In recent years, there have been considerable advances in terms of proposed ERA classification, early recognition of axial involvement, disease activity assessment, and treatment options for ERA.

2. Historic Evolution of ERA Definition and Classification

To delve into the definition of ERA, it is important to be familiar with the notion of SpA. In 1974, Moll and coworkers introduced the expression “seronegative spondyloarthritis”, to encompass a group of inflammatory arthritis with overlying clinical features and shared genetic predisposition [6][5]. Common clinical characteristics of SpA include axial involvement (sacroiliitis and/or spondylitis), peripheral arthritis, and enthesitis. SpAs are distinguished by the absence of rheumatoid factor (RF) and by a strong association with the human leukocyte antigen–B27 (HLA-B27) [7][6]. Some extra-articular features may be present, such as acute anterior uveitis, psoriasis, and inflammatory bowel disease (IBD). Certain clinical characteristics of SpA tend to cluster in some disease subgroups, including ankylosing spondylitis (AS) [8][7], psoriatic arthritis, enteropathic arthritis, and reactive arthritis. The term “undifferentiated SpA” has been used to describe patients with SpA who do not fit criteria for one of these subgroups [9,10][8][9]. To date, adult SpAs are classified according to the two sets of the Assessment of SpA International Society (ASAS) criteria, one for patients with axial involvement and one for those with peripheral symptoms [11,12,13][10][11][12]. Axial SpA (axSpA) can be distinguished in radiographic axSpA, which requires the presence of definite radiographic axial disease and corresponds to AS, and non-radiographic axSpA [12][11]. ASAS criteria also include reactive arthritis, arthritis related to IBD, and psoriatic arthritis within SpA, encompassing the broad spectrum of disease, although the ClASsification Criteria for Psoriatic ARthritis (CASPAR) are the most used for the classification of psoriatic arthritis in adulthood [11,12,13,14][10][11][12][13]. Historically, pediatric patients with clinical features resembling adult SpA have been described using different terms: juvenile SpA (JSpA), juvenile ankylosing spondylitis (JAS), seronegative enthesopathy and arthropathy syndrome (SEA), and ERA [15][14]. The term JSpA refers to patients who develop arthritis in late childhood and adolescence having a robust association with HLA-B27 and potential axial disease [16][15], whereas JAS includes children and adolescents having peripheral and axial arthritis that fit the criteria for classification of adult AS [17][16]. Rosenberg and Petty introduced the term “SEA” in 1982 to describe a peculiar form of juvenile SpA in 39 children with arthritis and enthesitis who were RF- and antinuclear antibody (ANA)-negative [18][17]. According to the authors, SEA was distinguishable from both juvenile rheumatoid arthritis as defined at the time by the American College of Rheumatology (ACR) [19][18], and from JAS. Although patients with SEA syndrome had enthesitis together with peripheral arthritis, they did not meet the criteria for AS due to the lack of axial involvement, at least at the onset [8,18][7][17]. As an evolution of the concept of SEA, the term ERA was introduced in the mid 1990s, when the ILAR proposed a set of criteria for the classification of idiopathic arthritis of pediatric age [20][19], revised in 1997 [21][20] and then in 2001 [4], using the umbrella term of JIA and outlining seven disease subtypes. According to the ILAR criteria, ERA is defined as arthritis and enthesitis lasting for at least 6 weeks in a child younger than 16 years, or arthritis or enthesitis plus two of the following: sacroiliac tenderness or inflammatory lumbosacral pain; HLA-B27 presence; onset of arthritis in a male older than 6 years; acute (symptomatic) anterior uveitis; and family history of a HLA-B27-related disorder [4]. To delineate homogenized and mutually exclusive JIA subtypes, the ILAR criteria do not permit the diagnosis of ERA in subjects with psoriasis or with a first-degree relative with psoriasis, or with positive RF test, or with systemic arthritis [4]. ERA is often referred to as the pediatric counterpart of undifferentiated SpA, whereas JSpA is a broader concept including not only ERA but also a subset of juvenile psoriatic and undifferentiated arthritis, JAS, reactive arthritis, and IBD-related arthritis [22][21]. Compared to adult SpA, clinical axial disease is less common at disease onset in ERA and progression to JAS is unpredictable. However, when axial involvement occurs, it is often preceded by peripheral disease. Therefore, it is possible to say that ERA captures the most common presentation of SpA in childhood [15][14]. In the late 2000s, concerns were raised on the validity of the ILAR classification for JIA, particularly its premise of delineating uniform disease subtypes [23,24][22][23]. In light of these concerns, an international expert consensus devised by the Paediatric Rheumatology INternational Trials Organisation (PRINTO) proposed a new set of preliminary criteria for JIA geared to identify more homogeneous disease categories [25][24]. A prospective analysis of clinical and laboratory data is currently ongoing to validate these criteria [25][24]. To highlight the resemblance of ERA and adult undifferentiated SpA, the panelists agreed to rename this condition enthesitis/spondylitis-related JIA, and its definition has been partly harmonized with the adult one. An imaging criterion, based on radiographs [26][25] or magnetic resonance imaging (MRI) [27][26] findings, has been introduced. According to the preliminary PRINTO criteria for JIA, enthesitis/spondylitis-related JIA is defined as peripheral arthritis persisting for at least 6 weeks and enthesitis, or arthritis or enthesitis, plus ≥ 3 months of inflammatory back pain (IBP) [28][27] and sacroiliitis on imaging, or arthritis or enthesitis plus 2 of the following: sacroiliac joint tenderness; inflammatory back pain; presence of HLA-B27 antigen; acute (symptomatic) anterior uveitis; and history of a SpA in a first-degree relative.

3. ERA Treatment

3.1. Current Therapeutic Recommendations

As recommended in the current ACR guidelines for the treatment of JIA, ERA management includes pharmacological and nonpharmacological measures depending on several factors, such as the number of active joints, the presence of enthesitis, and the occurrence of axial disease [86,87,88][28][29][30]. According to the international treat-to-target recommendations for JIA published in 2018, therapeutic interventions are aimed to control the disease activity; to prevent joint damage; to avoid comorbidities and medication toxicities; and to optimize functional status, growth and development, quality of life, and social participation [89][31].
Among nonpharmacological interventions, physical exercises emphasizing strength, flexibility, and balance are associated with enhancements in functional activity, body structure, and quality of life in children with JIA, while occupational therapy promotes increased participation in activities of daily living and family routines [86,90][28][32].
The pharmacological options for ERA treatment include nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including sulfasalazine (SSZ) and methotrexate (MTX), and biologic DMARDs (bDMARDs).
In the case of isolated peripheral arthritis without axial disease or enthesitis, the therapeutic strategy depends upon the number of active joints or the presence of poor prognostic features, as for the other non-systemic JIA subtypes. Intra-articular glucocorticoids and NSAIDs are advised as first-line therapy when less than five joints are involved (oligoarthritis population), and as adjunct therapy for peripheral arthritis affecting five or more joints (polyarthritis population). csDMARDs should be initiated in the instance of poor response to NSAIDs or intra-articular glucocorticoids in oligoarthritis and as an initial therapy in polyarthritis. In such cases, MTX is indicated as the preferable csDMARD. bDMARDs are recommended in patients not responsive to (or intolerant of) csDMARDs and, as part of first-line therapy, in polyarthritis with high disease activity or poor prognostic features [87,88][29][30].
The occurrence of sacroiliitis or enthesitis changes the therapeutic approach. The recommended first-line therapy is NSAIDs in both cases, but MTX is not the treatment of choice if NSAIDs are ineffective (or not tolerated). It has been shown that MTX is ineffective in the treatment of axial disease in adults [94,95][33][34]; therefore, even though similar trials have not been performed in children, the ACR guidelines for JIA strongly recommend against MTX monotherapy in children or adolescents with active sacroiliitis despite NSAIDs, based on extrapolation data and clinical experience [88,96][30][35]. In such cases, adding a Tumor Necrosis Factor-α inhibitor (TNFi) is strongly advised. MTX may be used as additional treatment in patients with co-occurrent peripheral polyarthritis or to prevent the development of neutralizing antidrug antibodies against monoclonal TNFi. SSZ may be used in patients with sacroiliitis presenting contraindications to TNFi or having failed more than one TNFi [88][30]. Similarly, the role of MTX is limited in the management of enthesitis: in case of active enthesitis not being responsive to NSAIDs, using a TNFi is conditionally recommended over MTX or SSZ. A trial of csDMARDs can be considered for subjects with enthesitis having contraindications to TNFi or concomitant active peripheral polyarthritis [88][30]. The effectiveness of TNFi in the treatment of ERA has been proven not only by retrospective analysis [55,97][36][37] but also by multiple randomized controlled trials [98,99,100,101,102,103][38][39][40][41][42][43]. Among TNFi, Etanercept is the most widely used in daily practice, while adalimumab is preferred in patients with concomitant uveitis.
In patients with polyarthritis, sacroiliitis, and/or enthesitis, a short course of oral glucocorticoids (<3 months) may be considered as bridge therapy while stepping-up the therapy, and intra-articular glucocorticoid injection may be useful as an adjunct therapy [88][30].

3.2. Emerging Biological Agents and Small Molecules

In recent decades, several studies have shown that the interleukin (IL)-17/IL-23 axis plays a pivotal role in the pathogenesis of JIA [104,105,106][44][45][46]. It has been shown that the synovial fluid of children with ERA present high levels of IL-17, in correlation with the disease activity, and a predominant representation of the T helper 17 lymphocyte population [107,108][47][48]. These findings highlighted the relevance of the IL-23/IL-17 axis as a potential treatment target. Some drugs targeting this pathway have demonstrated a robust therapeutic effect in adult SpA [109,110,111][49][50][51]. The Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently approved a monoclonal antibody against IL-17A, secukinumab, for ERA and JPsA treatment in case of insufficient response to (or intolerance of) conventional therapy, based on data from the Phase III JUNIPERA trial. In this randomized controlled trial, secukinumab was more effective in increasing time to time to disease relapse than placebo and exhibited a good safety profile in a cohort of 86 children and adolescents with active ERA or JPsA [112][52]. Moreover, a recent retrospective monocentric study revealed that secukinumab was able to reduce the JSpADA and the JADAS10 scores in patients with ERA not responsive to TNFi [113][53]. Ixekizumab, another anti-IL-17A agent, has already been approved for the treatment of axial SpA in adulthood, and its effectiveness and safety in children with ERA and JPsA are being currently investigating in a multicenter, open-label trial (ClinicalTrials.gov Identifier: NCT04527380). A case series of another drug blocking the IL-17/IL-23 axis, ustekinumab, in five adolescents with ERA refractory to TNFi, noted an improvement in active enthesitis and arthritis [114][54].
In the last few years, small molecules, such as the inhibitors of Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, have been developed and tested for the treatment of chronic rheumatic diseases, showing promising results. The efficacy of tofacitinib, an oral JAK inhibitor, has been demonstrated in a pivotal trial conducted on a group of patients with a polyarticular course JIA, including 21 subjects with ERA [115][55]. This molecule has been recently approved for the treatment of active polyarticular course JIA by FDA and for the treatment of both polyarticular JIA and JPsA by EMA. In a recent randomized clinical phase 3 trial, another JAK inhibitor, baricitinib, has demonstrated therapeutic effectiveness with an acceptable safety profile in a cohort of 220 JIA patients with inadequate response or intolerance to standard therapy, including 50 subjects with ERA [116][56].

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