The term “spondyloarthropathy” is derived from the Greek spondylos (spine), artho (joint), and pathos (suffering). A subset of patients with childhood arthritis is at risk of developing spondyloarthropathy, a disease characterized by arthritis and abnormal new bone formation in axial joints. Patients at risk include children with enthesitis-related arthritis, psoriatic arthritis, inflammatory bowel disease-associated arthritis, and reactive arthritis.
Patients who develop spondyloarthropathy (SpA) prior to age 17 years are diagnosed with juvenile spondyloarthropathy (JSpA). Patients typically present with musculoskeletal symptoms such as peripheral arthritis or enthesitis prior to symptoms of axial disease. The axial disease typically starts in the hip joints and progress to the sacroiliac joints and then the spine. Extra-articular manifestations can include uveitis, psoriasis, and colitis. This article reviews diagnostic criteria and means of intervention for patients with these forms of juvenile arthritis.
Differentiation of Axial Diseases
Axial disease typically starts in the hip joints and progresses gradually to the sacroiliac joint, the lumbar spine, and cephalad up the spine. Besides axial disease, the unique distinction in SpA is the process of abnormal new bone formation in the spine, causing ankylosis (immobility due to bone fusion).1 The most widely accepted and validated criteria for diagnosing SpA is the European Spondyloarthopathy Study Group (ESSG) criteria (see Sidebar 1).2
ESSG Criteria for Diagnosis of Spondyloarthropathy
Inflammatory back pain, which is defined as spinal pain with at least 4 of the following:
- At least 3 months duration.
- Onset before age 45 years, insidious onset.
- Improved with exercise.
- Morning spinal stiffness.
Synovitis and at least 1 of the following:
- Family history of a first- or second-degree relative with an HLA-B27–related disease.
- History of psoriasis or inflammatory bowel disease.
- History of alternating buttock pain.
- History of spontaneous pain or tenderness at the insertion of the Achilles tendon or plantar fascia (enthesitis).
- Diarrhea or nongonococcal urethritis/cervicitis within 1 month of onset of arthritis.
- Bilateral grade 2–4 sacroiliitis or unilateral grade 3 or 4 sacroiliitis.
ESSG = European Spondyloarthropathy Study Group.
Adult patients with SpA are categorized into five groups. Three types of spondyloarthropathy present in the context of the underlying disease and those include: psoriatic arthritis, IBD (inflammatory bowel disease) associated arthritis and reactive arthritis (formerly known as Reiter’s disease).
Patients who have SpA without any other associated underlying disease are diagnosed with either ankylosing spondylitis (AS) or undifferentiated SpA. Compared with undifferentiated SpA, X-rays in patients with AS show more destructive changes of the sacroiliac joints. The most widely used criteria of AS is the modified New York criteria (see Sidebar 2).3
Modified New York Criteria for Ankylosing Spondylitis
Clinical component (at least 1 of the following):
- Low back pain and stiffness for ≥ 3 months that improves with exercise but not with rest.
- Limitation of lumbar spine mobility in both sagittal (sideways) and frontal (front and backward) planes.
- Limitation of chest expansion.
- Bilateral grade 2–4 sacroiliitis or unilateral grade 3 or 4 sacroiliitis on plain radiograph.
JSpA and juvenile ankylosing spondylitis (JAS) are diagnosed in patients when the ESSG or modified New York criteria are met prior to 17 years of age. Typically, JSpA patients are male and are rheumatoid factor and antinuclear antigen (ANA) negative. In addition to musculoskeletal complaints, patients with JSpA can have a history of acute anterior uveitis (presenting as pink, painful eye) that sometimes precedes their musculoskeletal complaints.6 However, diagnostic criteria for JSpA and JAS are rarely met prior to adulthood.
Data have shown that patients who eventually developed either JSpA or adult onset SpA often had musculoskeletal symptoms during the pre-adolescent to adolescent years, prior to the development of axial disease;4,5 they tended to have a history of peripheral arthritis and enthesitis (an inflammation of entheses, which are areas of attachment of ligaments, tendons, and fascia to bone).
To facilitate early recognition of this “pre-axial” phase of spondyloarthropathy in childhood, the International League of Associations for Rheumatology (ILAR) classification of JIA8 introduced a new subtype of juvenile idiopathic arthritis called enthesitis-related arthritis (ERA). ILAR classification also recognizes psoriatic arthritis of childhood as one of the JIA sub-types. However, two additional types of childhood arthritis are associated with the risk for development of SpA: IBD-associated arthritis and reactive arthritis. These types are not considered “idiopathic” and are not part of JIA classification.
The delayed onset of axial skeleton disease in children, the differences in clinical presentations of arthritis in children and adults and the differences in adult and pediatric classifications make the topic of “spondyloarthropathy” in childhood confusing and complicated.
In the following paragraphs we discuss specifics of “pre-axial” forms of disease in childhood, including ERA, psoriatic arthritis, IBD-associated arthritis and reactive arthritis followed by the description of the shared features of juvenile spondyloarthropathies.
Prior to the current ILAR classification, patients with lower extremity arthritis and enthesitis were classified as having oligoarticular juvenile rheumatoid arthritis type II7 or seronegative enthesopathy and arthropathy (SEA) syndrome.4 According to the current criteria, ERA is diagnosed when the patient has both arthritis and enthesitis. If only enthesitis or arthritis is present, ERA can be diagnosed, provided additional criteria are met (see Sidebar 3).8
2001 Revised ILAR Criteria for Enthesitis-Related Arthritis
Arthritis and enthesitis.
Arthritis or enthesitis with at least 2 of the following:
- Sacroiliac (SI) tenderness and/or inflammatory spinal pain.
- Presence of HLA-B27.
- Family history at least one first- or second-degree relative with a HLA-B27–associated disease.
- Anterior uveitis that is usually associated with pain, redness, or photophobia.
- Onset of arthritis in a boy after 8 year of age.
- History of psoriasis, presence of systemic arthritis.
ILAR = International League of Associations for Rheumatology
Arthritis in ERA usually starts in late childhood, involves predominantly lower extremities and is asymmetrical in distribution. It is typically oligoarticular at presentation (less than five joints involved); but 25% of patients have a polyarticular onset.9 Inflammation of the small joints of the foot (tarsitis) is characteristic of ERA.9 It presents as pain, tenderness, and decreased range of motion in the midfoot. There is a male predominance in ERA with a ratio of 3.4 males to 1 female.10 In a study of 115 children with ERA, the mean age at diagnosis was 11.7 years (range 2.8–17.6 years).10
Enthesitis may affect many entheses, most commonly those around the knee (quadriceps tendon and patellar tendon insertions to patella and tibial tuberosity, respectively), around the pelvis, and in the feet, including the insertion of the Achilles tendon onto the calcaneus at the posterior heel and the insertion of the plantar fascia to the calcaneus at the bottom of the heel (see Figure 1).
Figure 1. Common sites of entheses.Image courtesy of Clara Lin, MD. Reprinted with permission.
Enthesitis of the upper extremities is less common and found mostly around the shoulders. Enthesitis presents with a history of pain with or without swelling and with tenderness on palpation. Sometimes, the entheses can be exquisitely tender, causing a significant disability.
Often, patients with JSpA, especially those without peripheral arthritis, are erroneously diagnosed with osteochondritis, a condition not associated with rheumatic conditions, when they truly have enthesitis. Osteochondritis is caused by microavulsion fractures at articular sites or non-articular sites, and can lead to avascular necrosis caused by repetitive stress and overuse in a developing skeleton. Common sites of osteochondritis are at the tibial tuberosity (Osgood-Schlatter’s disease), or calcaneous (Sever’s disease), and the inferior pole of the patella (Sinding-Larsen-Johansson disease).
Osteochondritis and enthesitis are indistinguishable on physical exam; however, osteochondritis is a self-limiting disease lasting several months to 2 years10 and typically resolves when the growth plate closes. Conversely, enthesitis is a chronic inflammatory disease. Children with osteochondritis should always be screened for arthritis, hip pain, and inflammatory back pain to avoid a delay in the diagnosis of ERA or JSpA.
Typically, psoriatic arthritis is diagnosed in individuals who have psoriasis and develop chronic arthritis; however, arthritis can precede the skin disease.9 A child with chronic arthritis and no psoriatic skin lesions is diagnosed with psoriatic arthritis in the presence of other diagnosic features (dactylitis, nail pitting, family history of psoriasis) (see Sidebar 4).8 The age distribution of psoriatic arthritis is biphasic, with the first peak during preschool years, and the second peak in preteen or teenage years.11
2001 Revised International League of Associations for Rheumatology Criteria for Psoriatic Arthritis
Arthritis and psoriasis.
Arthritis and at least 2 of the following:
- Nail pits or oncholysis.
- Psoriasis in a first-degree relative.
A characteristic finding in the preschool children is dactylitis, which is caused by inflammation of the joints and tendon sheathes in the finger or toe. Due to its appearance, dactylitis is commonly described a “sausage” toe or finger (see Figure 2). Arthritis affecting the wrist, ankle, and small joints such as the distal/proximal interphalangeal joints is more often seen in psoriatic arthritis than other subtypes of oligoarticular arthritis.12
Figure 2. An example of dactylitis.Image courtesy of Clara Lin, MD. Reprinted with permission.
In a study of 104 children with JIA, arthritis of the distal interphalangeal (DIP) joint was rarely detected; when found, it was only present in children with psoriatic arthritis. The preschool children with psoriatic arthritis had a female predominance and were more likely to be ANA positive.11 In this group, the risk of developing chronic uveitis was associated with the presence of ANA similar to other forms of oligoarticular JIA.13 It is not clear what the risk of axial disease and development of SpA is in this patient group.
In contrast, the subgroup of children with older-onset juvenile psoriatic arthritis (pre-teen and teenage years) had a substantial incidence of axial disease, especially sacroiliitis,11 which tends to be asymmetric and is often milder than in those with JAS.14 Compared to the younger-onset subgroup, the course of disease in this patient population resembled adult psoriatic arthritis and was more likely to have presence of human leukocyte antigen B27 (HLA-B27) and exhibit features of enthesitis.11 The male to female ratio was closer to 1:1 compared with the female predominance in the younger-onset subgroup.11
Chronic anterior uveitis can accompany later onset of the disease, similar to children with oligoarticular JIA.11 However, this group can also develop acute anterior uveitis seen in other spondyloarthropathies.15
IBD-associated arthritis is defined as noninfectious arthritis preceding or occurring during the course of IBD,9 and is the most common extra-intestinal manifestation of IBD.17
One study of 102 children with IBD showed arthritis in 9% of children with ulcerative colitis and 15.5% of children with Crohn’s disease.18 A more recent study found a lower incidence of arthritis in 1% to 2% of children with IBD, perhaps due to the use of newer medications for IBD.19
IBD-associated arthritis follows two patterns in children. The more common pattern is arthritis in the peripheral joints, mostly in the lower extremities. The arthritis is episodic, lasting 1 to 2 weeks, and usually occurs when the IBD is active. The joint disease remits when gut inflammation is quiescent.18
The second pattern of IBD-associated arthritis affects the axial skeleton and can lead to SpA. Unlike peripheral joint arthritis, the disease activity of IBD-associated axial joint arthritis does not correlate with the disease activity in the gut.20 This pattern can be associated with enthesitis, and usually lower extremity peripheral arthritis.9 Several studies suggest that the pathogenesis of IBD and axial joint disease may share a common pathway; ileocolonoscopies of patients who had SpA without abdominal complaints or symptoms showed signs of gut inflammation.21
Reactive arthritis (ReA), formerly called Reiter’s disease, is nonseptic arthritis that develops approximately 4 weeks after an enteric or genital infection. Bacteria typically associated with reactive arthritis include: Yersinia, Salmonella, Shigella, Campylobacter, or Chlamydia.22
The classic triad in reactive arthritis is conjunctivitis, arthritis, and urethritis.9 Children with ReA typically present with arthritis within 4 weeks of enteric infection, cervicitis, or urethritis and are also at risk for developing SpA.1 Unlike JIA, ReA can present with acute pain and erythema over the joint.9 The knee and ankle joints are most commonly involved in the initial episode; however, the axial skeleton can also become involved.9
Enthesitis can occasionally be found. If a child presents with arthritis, one should always ask about a preceding history or dysuria, diarrhea, vomiting, or bloody stools to screen for ReA. In patients with arthritis and a history of urethritis or cervicitis, one will need to differentiate between ReA and gonococcal arthritis. In patients with arthritis and a history of abdominal symptoms, one needs to differentiate between ReA and IBD-associated arthritis. The most widely used diagnostic criteria are the 1995 Berlin criteria (see Sidebar 5).22
1995 Berlin Criteria for Reactive Arthritis
Peripheral arthritis (oligoarticular asymmetrical presentation predominantly in the lower limbs)
Clear history of diarrhea of urethritis within the preceding month (laboratory confirmation desirable, but not required)
If there is no clear history of infection, laboratory confirmation is required
Epidemiology and Genetics
Suspicion of JSpA in children with joint pain is essential to its early detection and treatment. Teenage years, male gender and a family history of spondyloarthopathy indicate higher risk for ERA and JSpA in patients with arthritis. In adults, the incidence of AS was low among black23 and Japanese populations,24 and high in Pacific Canada’s Haida Indian population.25
There is a strong genetic predisposition most often associated with HLA-B27; however, this explains only about 40% of one’s genetic susceptibility.26 While only 5% of HLA-B27 carriers develop AS,26 having a family member with AS or an HLA-B27–related disease greatly increases one’s risk of developing SpA.26
Other genetic markers such as endoplasmic reticulum aminopeptidase 1 (ERAP1) and interleukin 23 receptor (IL23R) were associated with AS in the first genome-wide association study and other genetic studies for the disease.27
As noted, children with JSpA typically do not present initially with hip or back pain. They more often initially present with peripheral arthritis or enthesitis and develop axial joint involvement later in the disease course. Axial disease typically starts in the hip joint then progresses cephalad to the sacroiliac joint and then to the spine; thus, hip arthritis is a major risk factor in developing sacroiliitis and spinal disease.28
Because the hip joint is deep, making it difficult to assess for typical signs of arthritis such as swelling and warmth, range of motion and pain on end range of motion are more important in evaluating inflammation in the hip joint. Decreased range of motion is usually first seen on internal rotation and is most easily assessed by having the patient lie prone, knees together, then swinging their feet laterally.
External rotation of the hip can be assessed with the patient lying supine, putting the ipsilateral foot on the contralateral knee, and swinging the ipsilateral knee laterally. Noting asymmetry in range of motion between the hip joints is key.
The sacroiliac joint is a difficult joint to evaluate on clinical exam. Patients with sacroiliitis may complain of buttock or lower non-midline back pain that is worse in the morning or wakes them up at night. Patients may complain of morning stiffness that improves with activity or nonsteroidal anti-inflammatory medications. On clinical exam, one should palpate over the sacroiliac joints for tenderness. One can also stress the joint by clinical maneuvers such as lateral pelvic compression (by applying pressure with one’s hands on both iliac crests) or the FABERE (Flexion, Abduction, External Rotation, and Extension) test by flexing and externally rotating the hip with the knee flexed while putting pressure on the knee and opposite anterior iliac spine.
Pediatric patients typically do not present with back pain, and spinal disease usually presents in early adulthood. Therefore, a child with back pain should be evaluated carefully. One should have a broad differential diagnosis including malignancy, trauma, spondylysis, or diskitis.
The pediatric modified Schober’s exam (see Figure 3) should be performed to measure spinal mobility on anterior spine flexion. This is done with the patient standing with the patient’s back facing the examiner. The examiner then identifies the dimples of Venus on the back and draws a horizontal line to connect the dimples of Venus. A tape measure is placed vertically at midspine and a point is drawn 10 cm above the horizontal line (Point A). A second point is drawn 5 cm below the horizontal line (Point B). The patient is then asked to maximally flex the hips by trying to touch the floor with knees straight.
Figure 3. Demonstration of pediatric modified Schober’s exam. Distance between point A and B on anterior flexion should be at least 21 cm.Images courtesy of Clara Lin, MD. Reprinted with permission.
While the patient maintains this position, the examiner measures the distance between points A and B. This value should be compared to normal values. Typically, the measurement with a less than 6-cm increase should be regarded as abnormal. The pediatric modified Schober’s test is only valid for patients older than 10 years.29 A thorough musculoskeletal exam should be done to detect arthritis in other joints. One should remember to evaluate the shoulders and temporal mandibular joints (TMJ), as these are often missed on examination. With TMJ involvement, patients may have a history of jaw pain, clicking, or locking. On exam, patients will have a decreased oral aperture of less than 3 finger breaths or tenderness to palpation over the joint.
Uveitis in other types of JIA is usually asymptomatic, bilateral, and insidious. Uveitis associated with this subset of patients is typically acute, unilateral, and symptomatic. Patients will have red conjunctivae, photophobia, and decreased visual acuity (see Figure 4). One should ask the patient about a history of red, painful eyes, photophobia, or blurry vision. Due to similar symptomatology, acute anterior uveitis can be misdiagnosed as infectious or allergic conjunctivitis. A slit lamp eye exam is used to visualize inflammatory cells in the anterior chamber to diagnose uveitis.
Figure 4. Acute anterior uveitis and posterior synechiae.Image courtesy of University of Michigan Kellog Eye Center. Reprinted with permission.
The patient’s abdominal system should be reviewed for signs of IBD or enteric infection associated with ReA. Patients with IBD or ReA may have nausea, abdominal pain, diarrhea, constipation, or bloody stools. Abdominal symptoms in patients with ReA should precede onset of joint disease. Patients with IBD may have poor weight gain or weight loss, suggesting a chronic disease. They may also have history of recurrent aphthous ulcers, which may be associated with IBD.
The skin should be carefully evaluated for signs of psoriasis or IBD-associated rashes. One should inspect the skin thoroughly, including the scalp and behind the ears, for any erythematous, scaly patches that could be consistent with psoriasis. The nails should be examined for nail pits, which are associated with psoriasis (see Figure 5). In patients with erythema nodosum or pyoderma gangrenosum, one should suspect IBD.
Figure 5. Nail pits in a patient with psoriatic arthritis.Image courtesy of Clara Lin, MD. Reprinted with permission.
Several extra-articular manifestations are seen in adults but are rare or have not been described in children. These manifestations include cardiac disease (usually aortic insufficiency or heart block);30 IgA nephropathy;31 pulmonary disease (interstitial lung disease);32 restrictive lung pattern and decreased forced vital capacity;32 and cauda equina syndrome.33 Renal disease can be seen in children with JSpA secondary to chronic nonsteroidal anti-inflammatory drugs (NSAIDs) such as papillary necrosis.34 Atlantoaxial subluxation is a rare but serious complication in children with spondyloarthopathy.35
HLA-B27 is the major genetic marker for JSpA, although its absence does not exclude ERA or any type of JSpA. Other serologic markers, such as rheumatoid factor, anti-citrullinated peptide, or ANA are absent. Acute phase reactants such as erythrocyte sedimentationrate (ESR), C-reactive protein (CRP), and platelet count may be elevated, but are often normal. In cases with significantly elevated ESR or chronic microcytic anemia, one should consider underlying IBD. Stool guiaic testing should be done if IBD is suspected.
Anterior posterior view of the pelvis by plain radiograph is often used to screen patients with potential SpA; however, plain radiographs can only detect structural damage, which appears late in disease, and are not frequently seen in children with SpA. MRI, particularly STIR sequence, and gadolinium-enchanced images have the ability to detect early inflammation and lesions in the sacroiliac joints.39–41 With the advancement of technology, whole-body MRI may become useful to provide additional information for detecting changes in the shoulder, chest, and enthuses.42 Ultrasound technology using high-frequency probes and micro-bubble contrast media has shown promise for detecting sacroiliitis in adults,43 but no data exist yet for children.
The first-line therapy in treating spondyloarthopathy is NSAIDs. Some patients will experience significant pain relief with NSAID monotherapy. Indomethacin is effective for treating SpA, but is not very well-tolerated due to GI side effects. It is believed that tolmentin and sulindac are also particularly effective for SpA. Due to its simple dosing regimen and tolerability, naproxen is often used as well as ibuprofen. Several studies suggest that NSAIDs may slow new bone formation and the radiographic progression of disease.44
The most effective long-term anti-inflammatory treatments for sacroiliitis are anti-tumor necrosis factor (anti-TNF) agents, which have been shown effective in decreasing inflammation and symptoms.45 Commonly used anti-TNF agents in children with JSpA include etanercept, adalimumab, and infliximab. The latter two should be used in IBD-associated arthritis because they treat both gut and joint inflammation.46 Golimumab and certolizomab have been used in adults with SpA. Unfortunately, in adult studies, anti-TNF therapy has not been shown to slow radiographic progression of the disease.47 It is unknown whether anti-TNF therapy would alter the disease course in children. It has been shown in other types of JIA that there is a “window of opportunity” for early aggressive treatment to alter the course of the disease.48 It is not known if the same “window of opportunity” applies to children who eventually develop SpA.
Nonpharmacologic treatments for SpA include patient education, physical therapy, and exercise. Physical therapy should be focused on preventing loss of range of motion of joints, including spinal mobility. Daily stretching exercises are recommended.
Patients with entheses in their feet may benefit from orthotics that support and cushion the heel and metatarsal joints. Orthopedic surgery has a limited role in the management JSpA, and joint replacement is usually done in adults with long-standing disease.
Disease Course and Prognosis
Early in the disease course, patients with JSpA usually present with enthesitis or peripheral joint arthritis and then later develop symptoms of axial disease. Range of motion in both peripheral and axial joints should be closely monitored for subtle loss of function and pain. Children with ERA have lower levels of physical functioning, poorer physical health, and more pain compared with patients with oligoarthritis or polyarthritis, or with normal healthy controls.51
The life expectancy of adults with AS is reduced compared with the normal population.49
One study has shown that patients with juvenile AS have worse outcomes than those with adult-onset AS.50
Spondyloarthopathy is a chronic arthritis affecting the axial skeleton. It can present with enthesitis and peripheral arthritis prior to onset of axial disease that typically starts in the hips, then progresses to the sacroiliac joints, and cephalad up the spine. Early identification of spondyloarthopathy requires a high index of suspicion. Spondyloarthopathy can lead to significant functional disability, but with early NSAID use, anti-TNF factor therapy, and nonpharmacologic interventions such as physical therapy, the outcomes of SpA can be significantly improved. However, it is unclear whether early aggressive treatment can alter the disease course.
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