Definition and Classification
Enthesitis-related arthritis (ERA), a term introduced in the International League of Associations for Rheumatology (ILAR) classification of juvenile idiopathic arthritis (JIA), is defined according to the inclusion and exclusion criteria shown in Box 19-1 . It is predominantly a disease affecting joints and entheses of the lower extremities and can eventually affect the spine or sacroiliac (SI) joints. It is characterized by the absence of rheumatoid factor (RF) and by a strong association with the human leukocyte antigen–B27 (HLA-B27). In many instances, the disease evolves to closely resemble ankylosing spondylitis (AS), although the spine and SI joint involvement at disease onset are seldom present in childhood or adolescence. The progression to juvenile ankylosing spondylitis (JAS) is unpredictable but possible and early identification of individuals with axial disease is important so that appropriate therapeutic interventions can be initiated. ERA’s relationship to other subtypes of JIA, such as psoriatic arthritis, is not entirely clear (see Chapters 15 and 20 ).
Arthritis and enthesitis
Arthritis or enthesitis with two or more of the following:
Sacroiliac joint tenderness and/or inflammatory lumbosacral pain
Presence of HLA-B27
Family history of HLA-B27–associated disease (AS, ERA, sacroiliitis with inflammatory bowel disease, reactive arthritis, acute anterior uveitis) in a first-degree relative
Acute symptomatic anterior uveitis
Onset of arthritis in a boy after 6 years of age
Exclusions: Psoriasis in patient or first-degree relative, IgM RF, systemic JIA, arthritis fulfilling two JIA categories
ILAR , International League of Associations for Rheumatology.
JAS is a chronic inflammatory arthritis of the axial and peripheral skeletons, frequently accompanied by enthesitis, characterized by RF seronegativity, paucity of ANA, and having a firm genetic basis. Unlike ERA, radiological evidence of bilateral inflammation of the SI joints is required for a definitive diagnosis. AS in adults is defined by sets of criteria that are based on clinical, laboratory, and radiographic abnormalities. Only a few children or adolescents meet these criteria, principally because of the low frequency of spinal or sacroiliac signs or symptoms in the young patient. In addition, criteria for the diagnosis of AS in adults (see Chapter 15 ) are not applicable to the younger age group for a number of reasons: Normal values for some of the required physical measurements have not been published for children, or, if reported (back range), they have not yet been validated. In addition, limitations of spine and chest motion may reflect disease duration and are therefore of little aid in facilitating early diagnosis. The fact that peripheral joint disease precedes clinical axial involvement by years in many children precludes an early diagnosis by criteria in which abnormalities of spinal mobility or radiological changes are essential diagnostic features. Reasons for these differences between adults and children, whether they have an immunological, genetic, biochemical, or structural basis, are not understood.
The ILAR classification criteria allow most but not all JAS patients to be included into the ERA category because of the requirement to exclude patients with psoriasis, or with a first-degree relative with psoriasis; those with two positive tests for RF at least 3 months apart; or those with signs of systemic JIA in addition to lack of radiological documentation of axial involvement to serve as an inclusion criterion. The term juvenile spondyloarthritis (JSpA) may be used to represent the full spectrum of arthritis that appears in late childhood and adolescents, and which has a strong association with HLA-B27 and potential axial involvement. ERA and JAS are often referred to as the undifferentiated and differentiated forms of JSpA, respectively.
Historical Review of the Spondyloarthritis Concept
Wright and Moll introduced the term spondyloarthritis to include AS, psoriatic arthritis, the arthritis associated with ulcerative colitis and Crohn’s disease, juvenile chronic arthritis, Whipple disease, Behçet syndrome, reactive arthritis, and acute anterior uveitis. They observed that these patients were RF seronegative, lacked subcutaneous nodules, and had inflammatory peripheral arthritis. Many had radiological evidence of sacroiliitis. They also observed a tendency toward familial aggregation. In adults, members of this group are currently included the name seronegative spondyloarthritides: AS, the arthritides of inflammatory bowel disease (IBD), reactive arthritis, and psoriatic arthritis. In addition to a high frequency of HLA-B27, adults with these diseases often share certain clinical features that are associated with AS, the prototypic disease in this category: inflammation of joints of the axial skeleton and entheses, absence of RF and ANA, and the occurrence of uveitis. Juvenile psoriatic arthritis is classified as a separate category of JIA by the ILAR criteria and differs significantly from AS and ERA ( Chapter 20 ). In children with psoriatic arthritis, ANAs are frequent, and the uveitis is usually asymptomatic, similar to that of oligoarticular JIA, rather than acute like that of AS. The fact that RF is absent does not distinguish psoriatic arthritis from most other categories of JIA, which, with the exception of the RF-positive polyarticular JIA, are RF negative. Most children with arthritis associated with IBD have peripheral joint disease, rather than inflammation of the SI joints and spine and do not have the HLA-B27 antigen ( Chapter 21 ). Arthritis with IBD and reactive arthritis are regarded as separate entities outside the JIA rubric of the ILAR classification.
Recognition of the seronegative enthesitis and arthritis (SEA) syndrome permitted the identification of children who were different from other children with chronic inflammatory joint disease: Although they had enthesitis in addition to peripheral arthritis, they did not satisfy the criteria for adult AS. Children with the SEA syndrome have some of the characteristics of JAS but, at least at onset, lack the SI joint involvement needed to confirm that diagnosis. These children are seronegative (lack RF and ANA), have enthesitis (usually around the heel or knee), and have arthritis of a few joints, particularly the large and small joints of the lower extremities. The SEA syndrome probably represents, for the most part, children with very early JAS or ERA, rather than a separate disease. The absence or rarity of axial spinal involvement in childhood led to the recognition of ERA rather than AS in the ILAR classification. It will take decades of observation and evaluation to determine whether JAS, ERA, and the SEA syndrome are simply earlier or later, milder or more severe, versions of the same disease; it seems highly likely that they are variants of the same disease.
Many of the challenges of classification of RF-negative arthritides remain. In ERA, clinical or radiographic spine and SI joint involvement is infrequent at disease onset, and most children and teens do not meet the modified New York criteria for AS ( Box 19-2 ). Further revisions of the ILAR criteria may help to represent the ERA and AS spectrum of patients.
Limitation of lumbar spine motion in all three planes
Pain or history of pain at the dorsolumbar junction or lumbar spine
Limitation of chest expansion to 2.5 cm or less at the level of the fourth intercostal space
Grade 3-4 bilateral sacroiliac arthritis on radiography with at least one clinical criterion
Grade 3-4 unilateral or grade 2 bilateral sacroiliac arthritis on radiography with clinical criterion 1 or clinical criteria 2 and 3
Grade 3-4 bilateral sacroiliac arthritis on radiography without clinical criteria
The Assessment in Spondyloarthritis International Society (ASAS) has developed criteria for adults with SpA and categorized patients into predominantly peripheral and axial forms of SpA ( Table 19-1 ). The ASAS classification system, along with its treatment guidelines, has sometimes been applied to the pediatric population and used in conjunction with the ILAR classification system, with ERA and JAS patients best represented by the peripheral and axial forms of SpA, respectively.
|AXIAL SpA||PERIPHERAL SpA|
|In patients with ≥3 months back pain and age at onset <45 years||In patients with peripheral symptoms ONLY|
|Sacroiliitis on imaging * plus ≥1 SpA feature||or||HLA-B27 plus ≥2 other SpA features||Arthritis or enthesitis or dactylitis |
|SpA features ||≥1 SpA feature |
≥2 other SpA features
Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA.
Definite radiographic sacroiliitis according to modified NY criteria.
The data examining the epidemiology of ERA are emerging. For this reason, the discussion that follows relies heavily on the study of patients who fulfilled traditional criteria for AS. Where there is sufficient evidence, ERA-specific information is included.
Incidence and Prevalence
Among children with JIA, the proportion with ERA in published studies ranged from 8.6% to 18.9%. Increasing awareness of the possibility of the occurrence of ERA in childhood and its clinical and laboratory differentiation from other chronic arthritides of childhood will probably result in an increase in the proportion of children with inflammatory arthritis in this category. In contrast, children with JAS accounted for 1% to 7% of children in national pediatric rheumatic disease registries of the United States, Canada, and the United Kingdom, and from studies in Sweden, Finland, and Croatia.
It is estimated that the prevalence of AS in adults is from 0.5% to 1.9% with 8.6% to 11% having onset in childhood. However, the occurrence of AS varies among different racial and ethnic groups as demonstrated by population-based studies, with reported prevalence of AS in adults to be 0.24% in Europe, 0.17% in Asia, 0.10% in Latin America, 0.32% in North America, and 0.07% in Africa. On the basis of the prevalence of HLA-B27 and the frequency of sacroiliitis in the HLA-B27–positive population, the prevalence of AS was estimated to be 0.86% to 1% and was highest in HLA-B27–positive individuals. Although this estimate includes asymptomatic persons, it also excludes the 8% to 10% of the AS population who do not have HLA-B27, and it may be a more accurate reflection of the prevalence of the entire spectrum of AS.
Age at Onset
In cohorts of ERA patients around the world, the mean age at diagnosis has been reported to be around 10 to 13 years (range 2.8 to 17.6 years), similar to that for JAS. The age distribution appears to be homogeneous and presumably is continuous with that described in adult populations, suggesting that, at least on this basis, the disease as seen in adults is the same or very similar to that as seen in children.
In ERA, there is a predominance of boys but variations in the male-to-female ratio can be seen among cohorts from Canada (3.4 to 4.1 : 1), United States (1.4 : 1), Taiwan (3.3 : 1), and Spain (8 : 1). JAS has a much higher frequency in boys than in girls: of 247 children with this disorder, 216 were boys, for a male-to-female ratio of 7 : 1. This disproportionate representation of boys may not accurately represent the actual occurrence of the disease in girls. The strong correlation of JAS and ERA with HLA-B27 and the equal distribution of this antigen in males and females suggest that JAS and ERA could be as common in girls as in boys. Furthermore, in radiographic surveys of HLA-B27-positive adult blood donors, SI arthritis was as common in women as in men. In a questionnaire survey of members of the National Ankylosing Spondylitis Society in the United Kingdom, the male-to-female ratio was 2.7 : 1. However, in women, manifestations of the disease may occur later and be less severe, and they may have more peripheral and less axial disease. It is possible that these observations contribute to the relative infrequency of the diagnosis in women.
Geographic and Racial Distribution
Few data are specifically related to geographic and racial differences in the frequency of ERA or JAS. The low incidence of AS in African Americans and the Japanese, and the high frequency in the Haida Indians of Pacific Canada, reflect, in part, the frequency of HLA-B27 in these populations. Other factors may be significant, however, because this antigen occurs in only 50% of African Americans with AS and in 65% to 90% of Japanese with the disease. In a multiethnic Canadian population, ERA was twice as common in children of European ancestry as in those of non-European origin. However, among children of non-European ancestry, children of Asian origin were more likely to develop ERA than any of the other categories of JIA.
Etiology and Pathogenesis
The cause of JAS or ERA is unknown. The clinical, genetic, and epidemiological similarities of these disorders and diseases such as reactive arthritis, in which enteric or genitourinary tract infections play a triggering role, suggest the possibility of an infectious etiology, although none has been proven. Although no organisms have been isolated from the joints of patients with AS, evidence of a local inflammatory response to antigen is supported by some antibody and cellular immune studies, although confirmation of these findings is lacking.
The relationship between gastrointestinal infection and HLA-B27 is complex. The HLA-B27 transgenic rat develops a disease that is remarkably like AS in the presence of intestinal bacteria. In humans with IBD, there is a strong association between HLA-B27 and sacroiliitis. Reports of an association between HLA-B27 and gastrointestinal (GI) isolation of Klebsiella species in adults with AS remain largely unconfirmed. Mielants and associates described the presence of inflammatory gut changes in adolescents with spondyloarthropathies, supporting a pathogenic relationship between spondylitis and inflammation of the GI tract. Clinical or occult GI inflammation may be related in ERA and AS to the association with HLA antigens as well as to cellular immunity to cartilage proteoglycans.
The mechanisms whereby HLA-B27 is involved in disease pathogenesis have been the subject of much debate. As a class I major histocompatibility complex (MHC) molecule, the role of HLA-B27 is to present endogenous peptides to the T-cell receptor on CD8 + lymphocytes. It has been proposed that the HLA-B27 molecule or peptides it presents share amino acid sequences with a microbial antigen (molecular mimicry) and thereby become a target for CD8 + T cells or cross-reacting antibody, resulting in an inflammatory response. However, to date no “arthritogenic peptide” has been identified. Misfolding of the HLA-B27 heavy chain in the endoplasmic reticulum may invoke an inflammatory response. One possible mechanism arises due to a unique Cys67 residue in the HLA-B27 heavy chains that leads to self-association, and homodimerization and misfolding, which results in retention in the endoplasmic reticulum. This, in turn, causes induction of the proinflammatory unfolded protein response. Another mechanism suggests that HLA-B27 homodimers are not retained in the endoplasmic reticulum but are in fact expressed on the cell surface and lead to activation of disease relevant immunoreceptors and downstream pathways (i.e., KIR3DL1, KR3DL2, and immunoglobulin-like transcript 4 receptors on synovial and peripheral monocytes, B and T cells). In support of this mechanism, Myles et al. have demonstrated that membrane-bound toll-like receptors are overexpressed in synovial and peripheral blood monocytes in ERA, which leads to increased levels of interleukin (IL)-6 and IL-8 levels compared with healthy controls. The last hypothesized mechanism has no reference to HLA-B27 homodimerization but relates to the inability of HLA-B27–positive persons to clear intracellular pathogens. In fact, carriers of HLA-B27 are defective in the killing of intracellular bacteria such as Yersinia, Salmonella, Shigella, and Chlamydia , the same pathogens implicated in triggering reactive arthritis. Furthermore, bacterial antigens or DNA have been identified in the synoviocytes of patients with reactive arthritis supporting the role of infection in the pathogenesis of SpA. Finally, genetic microarray studies are providing new insights into the pathogenesis in ERA. Preliminary studies in the peripheral blood and synovial fluid mononuclear cells of ERA patients compared to healthy controls demonstrate a distinct genetic profile with higher expression of genes associated with antigen presentation, scavenger function, chemotaxis, and proteases, along with a lower expression of genes associated with natural killer (NK) cell function, cell adhesion, and inhibition of apoptosis.
The pathogenesis of enthesitis, the characteristic abnormality of ERA and JAS, has been extensively studied by Benjamin and McGonagle. An inflammatory infiltrate that includes CD8 + and CD14 + cells develops at sites of enthesitis in subchondral bone with bone absorption and new bone formation. Tumor necrosis factor-α (TNF-α) messenger RNA is increased in affected bone. CD2R, a T-cell activation marker, is expressed at high levels in patients with JAS and JRA. A type 1 helper T-cell (Th1) response has been suggested, with lymphocytic and mononuclear cellular infiltrates. Cells of the synovial membrane express TNF-α, TNF-β, and TNF receptors similar to those of children with other types of JIA.
The major genetic factor in ERA is the association with HLA-B27, as it is with AS. Family studies have indicated that AS is inherited as an autosomal dominant trait with penetrance of about 20%. Although the risk of development of ERA or AS in an HLA-B27–positive person is not precisely known (approximately 1% to 3%), epidemiological studies suggest that AS occurs 10 to 20 times more frequently in relatives of patients with AS (20%) and 50 to 80 times more frequently in their siblings. Thus, HLA-B27–positive persons with a family history of AS have a tenfold greater risk of AS than that of HLA-B27–positive persons with no family history of AS. The general risk that an HLA-B27 heterozygous parent with AS will have a male child with the disease is approximately 5% to 10% (20% if the child is also HLA-B27 positive; close to zero if the child is HLA-B27 negative). The risk of having a female child with JAS is lower. Risk may or may not be increased in first-born children. Familial disease may not be concordant for phenotypes in each member. As less than 5% of HLA-B27–positive individuals develop SpA, there are likely other genetic or environmental influences. Other genes make minor contributions to the genetic risk of AS. Reveille has summarized the genetic factors implicated in SpA ( Table 19-2 ).
|GENE NAME OR CHROMOSOMAL REGION||MOST HIGHLY ASSOCIATED SNP||ODDS RATIO||OVERALL CONTRIBUTION TO AS HERITABILITY (%)|
Family studies, disease concordance in twins, and modeling of genetic risk has implicated genetic factors in AS. The strongest association with AS is with HLA-B27. There are at least 105 different HLA-B27 subtypes. The most common subtypes associated with AS are HLA-B27*05 (Caucasians), HLA-B27*04 (Chinese), and HLA-B27*02 (Mediterraneans). Two subtypes, HLA-B*2706 and HLA-B*2709, seem to have no disease association.
Of 247 children with JAS, HLA-B27 was present in 91%, confirming its strong disease association. The possibility that homozygosity for HLA-B27 was responsible for the juvenile onset of AS was not supported by data in one small study, and the idea that disease severity is genetically determined is unresolved. In 56 Latvian children with JIA (44% ERA patients) who were HLA-B27 positive, 8 HLA-B27 subtypes were identified with HLA-B*2705 being the most commonly associated with ERA. Additionally, the authors suggested that the HLA-B27 subtypes may be useful in predicting the treatment response. Specific single nucleotide polymorphisms (SNPs) of ERAP1 (AS associated gene) and IL23R (AS and PsA associated gene) were studied in JIA patients (N = 1054 including 65 ERA, 76 PsA and 24 undifferentiated patients) and healthy controls (N = 5200). The ERAP1 SNP was most strongly associated with the ERA subtype ( P = 0.005) while the IL23R SNP was best associated with PsA ( P = 0.04), although there was a trend toward association in the ERA category. Neither the SNPs of ERAP1 nor IL23R were associated with the other JIA subtypes. There are few known class II associations with JAS. A higher frequency of HLA-DRB1*08 (44.9%) was reported in a Mexican population with JAS than in a control population (25.4%). Maksymowych and colleagues reported that the LMP2A allele frequency in patients with adult- and juvenile-onset AS with uveitis was twice that in those without this complication (odds ratio [OR], 2.51). Ploski and colleagues reported an increase of B*4001, DRB1*08, and DPB1*0301, and the LMP2 b/b phenotype in patients with JAS compared with HLA-B27–positive controls or adults with AS. It is very likely that JAS and ERA are polygenic disorders.
The onset of ERA may be insidious and characterized by intermittent musculoskeletal pain and stiffness or objective inflammation of peripheral joints, particularly those of the lower extremities, together with enthesitis at one or more sites around the knee or foot. Occasionally, the disease may have an abrupt onset. Systemic signs are often minimal, but fatigue, sleep disturbances, and low-grade fever may be present. Symptoms related to the back are usually absent at onset but become increasingly evident during the disease course in adolescents. Differing modes of presentation and course may characterize specific population groups.
Entheses—the sites of attachment of ligament, tendon, fascia, or capsule to bone—are characteristic sites of inflammation, especially in the lower limbs, that occurs in 60% to 80% of ERA and JAS patients. Consequently, many patients with ERA complain of knee, foot, or heel pain. Weiss et al. noted that in 32 newly diagnosed patients with ERA, 66% had at least one tender entheseal site while 44% have more than two sites involved. The presence of an increasing number of tender entheses at presentation was associated with persistence at 6 months (OR 2.18). Although the presence of exquisite, well-localized tenderness at characteristic entheses strongly suggests ERA, it must be noted that enthesitis occurs occasionally in other disorders, including other types of JIA, other rheumatic diseases, and occasionally in children without disease. Osgood–Schlatter disease should also be excluded before making a diagnosis of enthesitis affecting the tibial tuberosities. The presence of enthesitis is, however, the most helpful clinical feature in differentiating ERA from other types of JIA. Enthesitis is a characteristic early manifestation of JAS and occurs with greater frequency in JAS than in adult-onset AS. It frequently produces severe pain and resultant disability, which may be the child’s most important complaints.
A careful history and a thorough but gentle palpation of entheses may document evidence of past or present inflammation. The entheseal exam can include any of the anatomical sites shown in Figs. 19-1 and 19-2 . Enthesitis is diagnosed clinically from the presence of marked localized tenderness or swelling at the entheseal insertion into the bone. A diagnosis of ERA is strongly supported by enthesitis in the lower extremities especially at insertional sites around the patella (10, 2, and 6 o’clock positions especially), heel, and plantar fascial attachments to the heads of the metatarsals ( Fig. 19-2 ). Less commonly, pain can also be demonstrated at insertional sites around the pelvis (including the origin of adductor longus near the pubic symphysis), over the spinous processes, and at the entheses of the upper extremities. Observation of stance and gait (including walking on the toes and heels), may reveal altered weight bearing as the child avoids pressure on inflamed entheses.
Among 59 Italian ERA patients (66% HLA-B27 positive), the most frequently affected joints at disease onset included knees (65%), midfoot (58%), and ankles (48%). The frequency of specific joint involvement after a mean follow-up of 7.6 years was reported by Shen et al. in a series of 73 Taiwanese children with ERA (82% HLA-B27 positive). During the disease course, the knees (52%), hips (42%), ankles (38%), and lumbosacral spine (48%) were most commonly involved. From the cohort of 74 ERA patients (76% HLA-B27 positive) at The Hospital for Sick Children (SickKids), Toronto, Canada, the most frequently affected joints in descending order at disease onset and during the disease course were hips, knees, ankles, and midfoot. Upper extremity involvement was infrequent and lumbosacral spine involvement at disease onset was noted in only 16%.
The presenting joint symptoms recorded in the largest reported series of patients with JAS are summarized in Table 19-3 . Initial musculoskeletal symptoms are often difficult for the child to localize and include pain in the buttocks, groin, thighs, heels, or around the shoulders. The vague quality and localization of this pain and its frequent spontaneous disappearance early in the disease are recurring sources of delay and confusion in the diagnosis.
|CLINICAL EVIDENCE OF JOINT INVOLVEMENT AT ONSET||PERCENTAGE|
|Arthritis, Painful Limitation of Range of Motion|
|Proximal limb joints||35|
|Distal limb joints||44|
|Upper limb joints||16|
|Lower limb joints||82|
|Axial skeleton joints||24|
|Joint Involvement During Course|
|No peripheral joints affected||3|
|1 to 4 peripheral joints affected||43|
|More than 4 peripheral joints affected||54|
|Sacroiliac involvement †||95|
|Lumbosacral spine affected †||90|
|Cervical spine involvement||—|
|Around the knee †||80|
|Around the ankle and foot †||90|
Peripheral Joint Arthritis
The peripheral arthritis in ERA and JAS is often asymmetrical and mainly involves the lower extremities. In most instances, the number of joints involved is limited (four or fewer), although children may have a polyarticular involvement in up to 25% at disease onset and up to 45% during the disease course. Joints of the lower extremity are affected more frequently than the upper extremity. Unlike other types of JIA, hip involvement at disease onset and during the disease course is common. Isolated hip disease may be the presenting feature. Although involvement of one or both knees is characteristic of both oligoarticular JIA and ERA, the child’s age at onset, especially if a boy, is a useful distinguishing feature. Small joints of the foot and toes are commonly involved. The least commonly affected joints are the small joints of the hands. Consequently, symmetrical disease of the small joints of the hands or polyarticular disease, particularly in a girl, is more likely to be another type of JIA. Shoulders are not uncommonly affected, and even the temporomandibular joint may be involved.
Tarsitis (inflammation of the intertarsal joints, overlying tendons, entheses, and soft tissues) is an unique manifestation occurring in up to one third of children with ERA at disease onset ( Fig. 19-3 ). It is accompanied by pain, tenderness, and restriction of movement in the midfoot that, in the presence of disease of the first metatarsophalangeal joint, results in a characteristic forefoot adduction deformity. Burgos-Vargas and associates concluded that a diagnosis of JAS could be confirmed or strongly suspected shortly after onset of disease in children who displayed enthesopathy, midtarsal foot involvement, sparing of the hands, and progressive onset of lumbosacral disease.
Pain at the costosternal and sternoclavicular joints and the sternomanubrial joint, often in conjunction with tenderness over the proximal clavicle, may be associated with significant impairment of chest expansion. In the work by Schaller and associates, five of seven patients with JAS had decreased chest expansion. Aside from the number and distribution of the affected joints, there is nothing clinically to distinguish the peripheral joint disease of ERA from that of other types of JIA. Burgos-Vargas and colleagues have identified a subgroup of children with typical adult-type onset of disease. Whether this presentation represents a distinct entity or merely an extreme end of the clinical spectrum is not certain.
Involvement of the joints of the axial skeleton (spine or SI joint), although seldom present at disease onset can occur within 5 to 10 years from disease onset. In a population of Mexican children, spinal involvement developed within 3 to 5 years, with some patients reporting axial symptoms within the first year of disease onset. Distinct from AS in adults, children seldom have symptoms of axial involvement at disease onset; only 24% of children with JAS are reported to have pain, stiffness, or limitation of motion of the lumbosacral spine or SI joints at presentation. Many children may have difficulty reporting axial symptoms, but it is important to inquire about any pain in the lower back or buttock regions that is worsened by periods of inactivity (i.e., sitting for prolonged periods). Predictors of sacroiliitis or AS include HLA-B27, DRB1*04, male sex, age at onset of symptoms, family history of AS, arthritis, polyarthritis, enthesitis, tarsitis, hip involvement, axial involvement, and psoriasis.
In children with SI arthritis, pain may be elicited by direct pressure over one or both SI joints, compression of the pelvis, or distraction of the SI joints by the Patrick test (FABER test), or Gaenslen’s test. Examination of the back may demonstrate abnormalities in contour, such as loss of the normal lumbar lordosis, exaggeration of the thoracic kyphosis, or increased occiput-to-wall distance. The contour of the back on full forward flexion may demonstrate loss of the normal smooth curve in the lower part of the thoracolumbar spine ( Fig. 19-4 ), or there may be restriction of hyperextension, signifying early axial disease. The rigid spine of long-standing AS is rare in children. Cervical spine involvement is also a late development. Although observations of abnormalities of the contour of the back are often more informative than actual numerical measurements, sequential measurement of thoracolumbar mobility is useful in documenting progression of the disease. Muscle wasting and weakness of the muscles around the hip joints may be quite prominent.
The modified Schober test provides one index of abnormality ( Fig. 19-5 ). With the child standing with the feet together, a line joining the dimples of Venus is used as a landmark for the lumbosacral junction. A mark is made 5 cm below (point A) and 10 cm above (point B) the lumbosacral junction. With the patient in maximum forward flexion with the knees straight, the increase in distance between points A and B is used as an indicator of lumbosacral spine mobility. Normal values plus or minus 1 standard deviation are indicated in Fig. 19-6 . In general, a modified Schober measurement of less than 6 cm (e.g., an increase from 15 cm to less than 21 cm) should be regarded as abnormal. However, care should be exercised in interpreting this measurement, because there are large normal variations at each age, and the data have not been adequately validated in children with musculoskeletal disease. Measurement of the distance from the fingertips to the floor on maximum forward flexion is often used to quantitate spinal motion but is poorly reproducible and does not correlate with the Schober measurement. Furthermore, finger-to-floor distance reflects hip as well as back flexion.
Thoracic disease may be reflected in limitation of chest expansion. Normal thoracic excursion varies a great deal, and normal age- and sex-adjusted ranges have not been established. However, in a specific child, sequential measurement of thoracic motion may be useful in documenting progressive loss of range. In the adolescent, any thoracic excursion of less than 5 cm (maximum expiration to maximum inspiration, measured at the fourth intercostal space) should be regarded as probably abnormal. Even in the absence of symptoms, chest expansion in children with JAS may be restricted to 1 or 2 cm. Pain and tenderness at the costosternal and costovertebral joints may be elicited by firm palpation. Sternomanubrial tenderness sometimes occurs, but sternoclavicular pain is more common.
The uveitis seen in JAS or ERA is characterized by an acutely red, painful, photophobic eye, and contrasts with the typical asymptomatic anterior uveitis seen in JIA patients with oligoarthritis or polyarthritis. It is usually unilateral, frequently recurrent, and usually, but not always, leaves no ocular residua. It rarely precedes the onset of musculoskeletal complaints. Uveitis has been reported in 3% to 7% of ERA patients from Germany, Canada, the United States, and Taiwan. Polymorphisms in the HLA-linked LMP2 locus was found to be confer a higher risk of developing acute uveitis in a HLA-B27–positive Mexican population of JAS and AS patients.
The presence of gastrointestinal symptoms (chronic abdominal pain, diarrhea, hematochezia) in a child thought to have ERA should raise the question of the possibility of arthritis related to inflammatory bowel disease (see Chapter 21 ). Poor weight gain and slow growth may often be the first clue for gastrointestinal involvement.
Overall cardiovascular disease is uncommon in ERA or JAS. However, it can occasionally be severe, and marked aortic insufficiency has been reported in at least seven patients with JAS. The apparently low frequency of such complications in children may reflect the fact that follow-up is generally of shorter duration than in adults, in whom cardiac disease (aortic insufficiency, heart block) develops in approximately 5% of patients an average of 15 years after disease onset. However, one study of a Mexican JAS cohort followed for an average of 20 years confirmed that aortic abnormalities are less frequent compared with adult-onset AS. Rarely, cardiac involvement precedes development of SI disease.
None of 36 consecutive patients with JAS who were monitored for a mean of 4.3 years had symptoms related to the cardiovascular system, and only 1 developed the murmur of aortic regurgitation. Echocardiographs documented no structural cardiac abnormalities and electrocardiography no conduction defects, but color Doppler assessment confirmed mild mitral regurgitation in two patients and mild aortic regurgitation in three; systolic ventricular function was impaired in one. In contrast, transesophageal echocardiography in adults with AS demonstrated aortic root abnormalities and valvular disease in 82% compared with 27% in controls. Valve thickening was demonstrable as nodularity of the aortic cusps and basal thickening of the anterior mitral valve leaflet, creating the characteristic subaortic bump. Aortic valve regurgitation was present in almost one half of the patients.
Few data relating to pleuropulmonary disease are available. In a study of 18 children aged 8 to 17 years who fulfilled the Amor criteria, abnormalities of pulmonary function were present in 33%. All patients had normal chest radiographs at baseline and on follow-up at 2 years. No patient had symptoms attributable to the respiratory system, and all had normal chest expansion. Nonetheless, six patients (33%) had abnormal pulmonary function tests. The most common abnormality was reduction in the forced vital capacity (22%); occasionally, increased functional residual capacity (11%) and residual volume (5%) were observed. Restrictive patterns were more common than diffusion defects, and diffusing capacity of the lungs for carbon monoxide was reduced in only 11%. Small airways disease was not present.
In adults, although diminished chest expansion and resultant decreased vital capacity are not infrequent, clinical parenchymal pulmonary disease is rare. In the review by Rosenow and associates, 1.3% of 2080 adults with AS had radiographic evidence of pleuropulmonary disease (apical pleural thickening). In a systematic review, the prevalence of lung abnormalities in AS using high-resolution computed tomography (CT) was found to be 61%. These finding included upper lobe fibrosis (6.9%), emphysema (18.1%), bronchiectasis (10.8%), ground glass attenuation (11.2%), and nonspecific interstitial abnormalities (33%) such as pleural thickening and parenchymal bands. Cor pulmonale can develop secondary to kyphoscoliosis and decreased chest wall movement, characteristic of advanced spondylitis, but it has not been reported in children or adolescents.
Nervous System Disease
Intrinsic central nervous system disease does not occur in ERA, but atlantoaxial subluxation has been reported in three JAS patients (one boy with severe cervico-occipital pain, a 12-year-old boy 8 years after disease onset, and in one HLA-B27–negative girl, ), in two boys with SEA syndrome, and in a 12-year-boy with ERA. Additionally, it was also seen in a 10-year-old boy who was diagnosed with polyarthritis affecting only the joints of the lower extremities. Atlantoaxial subluxation has been reported in AS occurring as an initial manifestation or developing during the disease course. The cauda equina syndrome, caused by bony impingement on the cauda equina and characterized by weakness of bowel and bladder sphincters, saddle anesthesia, and leg weakness, occurs in adults but has not been reported in children.
Renal abnormalities are rare. Papillary necrosis, perhaps secondary to nonsteroidal antiinflammatory drugs (NSAIDs), has been reported. Immunoglobulin A (IgA) nephropathy, occasionally with uveitis, was observed in 115 adults with SpA. Most of these patients had elevated serum IgA concentrations; some had impaired renal function and hypertension. Ansell documented amyloidosis in 3.8% of 77 patients with JAS seen before 1980; she noted its association with severe peripheral arthropathy and a persistently elevated erythrocyte sedimentation rate (ESR).
Cardiopulmonary, central nervous system, and renal diseases appear to be very rare in children with ERA. Most of these complications occur after many years of disease in patients with JAS or AS. It is likely that with very long-term follow-up, these rare, but important, complications will be recognized in children with ERA.
The pathology of JAS or ERA has not been studied, but it is probable that abnormalities are similar to those of AS. The synovitis is in general much milder, and the degree of cartilage erosion in peripheral joints much less, in AS compared with adult rheumatoid arthritis (RA). The synovitis itself is otherwise virtually indistinguishable from that of RA, although there may be relatively more polymorphonuclear leukocytes present.
The characteristic pathological changes in the apophyseal and SI joints are enchondral and capsular ossification. The earliest lesion in the SI joints is subchondral inflammation, rather than synovitis, with formation of granulation tissue with few inflammatory cells. The surfaces of the SI joints are minimally affected, and pannus is not present. Enchondral ossification on the iliac side of the joint accounts for the radiographic appearance of erosions. As Ball commented : “As a rule, it seems that in any synovial joint in AS, the outcome represents a balance of erosive synovitis and capsular and/or ligamentous ossification. In joints of low mobility the ossific process tends to be the dominant feature.”
Enthesitis is characterized by nonspecific inflammation. Granulation tissue, infiltrated with lymphocytes and plasma cells and causing a localized osteitis, undermines the bony and cartilaginous attachment of the ligament or tendon. Healing of this lesion gives rise to a bony spur, such as a calcaneal spur at the insertion of the plantar fascia into the calcaneus or a syndesmophyte at the attachment of the outer fibers of the annulus fibrosus to the anterolateral aspects of the rim of the vertebral body.
At onset, ERA most closely resembles oligoarticular JIA (OJIA). However, whereas OJIA is characteristically a disease of young girls, ERA typically occurs in older boys and adolescents. The presence of enthesitis is the distinguishing clinical feature in children with ERA. ERA may mimic other inflammatory arthropathies, mechanical causes of back or lower extremity pain, or, very occasionally, infection or malignancy. A history of cramping abdominal pain, diarrhea, weight loss, and fever suggests an accompanying IBD in a child who otherwise has typical ERA. A few children with ERA also have psoriasis and would fulfill criteria for psoriatic arthritis. In most instances, however, children with ERA lack SI and back symptoms at onset, but, unlike children with OJIA, may have hip joint involvement.
In older children with established ERA, signs and symptoms of spine and SI arthritis clearly differentiate the child from one with OJIA. The disease then resembles JAS or AS. Arthritis of the cervical spine is infrequent and, when present, mimics that in children with polyarticular JIA. Thoracolumbar pain may reflect Scheuermann disease. Lumbar and lumbosacral pain has a myriad of causes, including spondylolysis, spondylolisthesis, osteoid osteoma, osteomyelitis, diskitis, and (rarely) lumbar disk herniation. Trauma may cause chronic pain in the sacrum and coccyx. SI tenderness and pain occurs in many patients with JAS, but septic SI disease, osteomyelitis, Ewing sarcoma of the ilium, and familial Mediterranean fever also produce pain in and around these joints.
Pain that mimics enthesitis may result from a number of causes, including excessive running or jogging. Usually, the pain of traumatic enthesopathy is less severe and more diffuse than that caused by inflammation. Osteochondrosis of the tibial tuberosity (Osgood–Schlatter disease), of the inferior pole of the patella (Sinding–Larsen–Johansson syndrome), or of the apophysis of the calcaneus (Sever disease) may mimic inflammatory enthesitis at those sites. The coexistence of enthesitis at multiple sites usually eliminates these disorders from consideration. The absence of HLA-B27 positivity also assists in differentiating these disorders from the inflammatory enthesitis of JAS. Pressure over bony prominences, including entheses, may produce pain in children with leukemia or bone tumors. In most instances, however, the pain resulting from such infiltrative diseases is less discrete and more severe than that of inflammatory enthesitis and frequently awakens the child from sleep.
There are few distinguishing laboratory features. Anemia is usually mild and characteristic of the anemia of chronic disease. White blood cell counts are usually normal or moderately elevated with normal differential counts. Indices of inflammation may not be a reliable measure of disease activity as they can be normal or minimally elevated even with clinically active disease. Very high values for the ESR (above 100 mm) occasionally occur but should also suggest the possibility of occult IBD.
Elevated immunoglobulin levels reflect inflammation, and selective IgA deficiency has been reported. High levels of IgA and C4 and of circulating immune complexes in adults with AS suggest an immunoreactive state. In a cohort of Chinese JAS patients, significantly higher levels of serum IgA were found compared with adult-onset AS patients and reflected the worse functional outcome and global assessment of disease activity in the JAS patients. Characteristically, RFs are absent. ANAs do not occur in children with ERA more commonly than in a healthy population. Antiphospholipid antibodies have been demonstrated in 29% of adults with AS, but children with ERA have not been studied. Although there are no reports of systematic studies of other autoantibodies in ERA or JAS, experience suggests that they are not common. Fecal calprotectin levels are high in children with ERA compared to those with other types of JIA.
HLA-B27 is present in 90% of children with JAS, 60% to 80% of ERA patients, and in approximately 8% of the overall white population; it does not constitute a diagnostic test but rather an indicator of risk. The diagnosis of ERA rests on clinical characteristics, and the use of HLA typing for diagnosis may lead to misdiagnosis, although typing is important as a criterion to classify patients for study.
There are no specific studies of synovial fluid, but the changes are probably similar to those in adults with AS, in which the differential white blood cell count includes more neutrophils and fewer lymphocytes than in RA. It has been reported that the predominant large mononuclear cell in synovial fluid in RA is lymphocyte derived, whereas that in AS is of macrophage origin. Macrophages containing degenerated neutrophils are more common in the synovial fluid of patients with AS and related diseases such as reactive arthritis than in those with RA. Descriptions of the synovial fluid are otherwise similar to those for RA, except that the complement level is usually normal or increased.