Arthritis and enthesitis
Or
Arthritis and enthesitis, or arthritis or enthesitis with at least two of the following
Presence of or a history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain
Presence of HLA-B27
History of ankylosing spondylitis, enthesitis related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis in a first-degree relative
Acute (symptomatic) anterior uveitis
Onset of arthritis in a male over 6 years of age
Exclusions: psoriasis in patient or first-degree relative, the presence of IgM RF, systemic JIA, arthritis fulfilling two JIA categories
Clinical criteria |
1. Limitation of lumbar spine motion in all three planes (anterior flexion, lateral flexion, and extension) |
2. Pain or history of pain at the dorsolumbar junction or lumbar spine |
3. Limitation of chest expansion to 2.5 cm or less at the level of the fourth intercostal space |
Definite AS |
Grade 3–4 bilateral sacroiliitis on radiography with at least one clinical criterion |
Or |
Grade 3–4 unilateral or grade 2 bilateral sacroiliitis on radiography with clinical criterion 1 or clinical criteria 2 and 3 |
Probable AS |
Grade 3–4 bilateral sacroiliitis on radiography without any signs or symptoms satisfying the clinical criteria |
Adult ankylosing spondylitis criteria have been used in pediatric population and they perform well. The ESSG [25] and Amor criteria [26] can also be applied to children with differentiated and undifferentiated forms of the disease, respectively. The ESSG criteria are useful in pediatrics as axial signs and symptoms are not a mandatory requirement. Evaluation of the ESSG and Amor criteria in children has shown equivalent specificity but less sensitivity when compared with adult SpA [27]. Recently, Assessment in Spondyloarthritis international Society (ASAS) criteria for adult axial and peripheral involvement have been published and may be useful in children (Table 19.3) [28, 29].
Axial SpA | Peripheral SpA | ||
In patients with ≥ 3 months of 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 Plus |
SpA features Inflammatory back pain (IBP) Arthritis Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohn’s /colitis Good response to NSAIDs Family history for SpA HLA-B27 Elevated CRP Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA Definite radiographic sacroiliitis according to modified New York criteria | ≥1 SpA feature Uveitis Psoriasis Crohn’s colitis Preceding infection HLA-B27 Sacroiliitis on imaging Or ≥ 2 other SpA features Arthritis Enthesitis Dactylitis IBP ever Family history for SpA | ||
The proposed model (Fig. 19.1) represents that the disease starts as peripheral arthritis in young age and progresses to develop axial disease. In adults inflammatory back pain (IBP) remains the most important characteristic feature of SpA. However, in children peripheral arthritis and enthesitis are the major features. Beyond the fifth year of disease, the proportion of patients with both juvenile- and adult-onset SpA fulfilling the modified New York criteria for AS increases to reach a maximum around 10 years after onset [30].
Fig 19.1
The modified schematic representation of Rudwaleit’s scheme on the transition of undifferentiated juvenile-onset spondyloarthritis (u-JSpA) to ankylosing spondylitis (AS) in the context of axial and peripheral SpA [30]
Pathogenesis
The exact cause of JSpA or ERA is unknown. The pathogenesis appears to be similar for all diseases classified under the spectrum of JSpA. It seems to be an interplay of genetic and environmental factors
Genetic Background
HLA-B27 is the major genetic factor associated with ERA/JSpA. Disease susceptibility modeling published by Rubin et al. suggested an autosomal dominant pattern of inheritance for ERA, with penetrance of approximately 20 % [31]. The risk of development of ERA or AS in HLA-B27-positive population is approximately 1–2 %, and the risk increases to approximately 20 % in HLA-B27-positive relatives of HLA-B27-positive AS patients. In general, the risk for AS is 16 times greater in the HLA-B27-positive relatives compared with HLA-B27-positive individuals in the population [31]. The general risk that a HLA-B27 heterozygous parent with AS will have a male child with the disease is approximately 5–10 % (20 % if the child is also HLA-B27 positive, close to zero if the child is HLA-B27 negative) [32].
The dominant genetic component is the class I MHC encoded human leukocyte antigen HLA-B27. However, the mere presence of this antigen is insufficient for disease development [12].
Three major hypotheses explain the association of HLA-B27 with AS:
- 1.
Arthritogenic peptide theory: It hypothesizes that the disease results from the ability of B27 to bind and present unique arthritogenic peptides to CD8+ cytotoxic T lymphocytes. These peptides are often shared by disease-triggering pathogens which cross recognize a self-peptide [33].
- 2.
HLA-B27 misfolding and unfolded protein response hypothesis: This hypothesis proposes that disease results from the accumulation of aberrantly folded HLA-B27 in the endoplasmic reticulum, resulting in an inflammatory response [34].
- 3.
HLA-B27 free heavy-chain (HC) and surface homodimer hypothesis: This theory proposes that disease results from the immune recognition of aberrantly folded surface B27 molecules or HLA-B27 HC homodimers. These complexes are recognized by receptors on NK cells, T cells, and other APCs triggering an inflammatory response [35].
In a study by Hinks et al., ERAP1-specific single nucleotide polymorphism (SNP) was associated with the ERA subtype, while IL23R SNP was associated with psoriatic arthritis (PsA) although there was a trend toward association in the ERA category. Neither SNPs of ERAP1 nor IL23R were associated with the other JIA subtypes [36].
Infection
The disease onset is sometimes triggered by bacterial infections predominantly of the gut or the genitourinary system. Yersinia, Salmonella, Shigella, and Chlamydia are some of the pathogens implicated in triggering reactive arthritis [37]. In a study by Pacheco-Tena et al., single and several combinations of bacterial DNA were identified in the synovial fluid of patients with long-term undifferentiated and definite juvenile-onset SpA and adult-onset SpA [38]. Toll-like receptors (TLRs) are critical components of the innate immune system that help protect the host from infectious disease through the recognition of pathogen-associated molecular patterns. In ERA there is increased TLR-2 and TLR-4 on synovial cells and leukocytes, which may recognize microbial/endogenous ligands and cause disease exacerbations [39].
Clinical Manifestations
General Consideration
The classical presentation of ERA/JSpA is asymmetrical lower limb oligoarthritis (commonly knee, ankle, or tarsal involvement) with or without enthesitis. The extra-articular manifestations include acute symptomatic anterior uveitis, gastrointestinal involvement characterized by inflammatory bowel disease, genitourinary involvement, and occasional pulmonary or cardiac involvement.
Children with JSpA usually have an insidious onset though sometimes they can have an abrupt presentation. Constitutional features like sleep disturbances, fatigue, and fever are often reported [19]. Arthritis and enthesitis may not parallel each other in terms of onset or severity.
Articular Manifestations
Peripheral Arthritis
Peripheral arthritis is the most frequent sign of JSpA and typically involves large joints of the lower extremities and tends to be asymmetric. Hip involvement is more common when compared to other subsets of JIA. Isolated hip arthritis is reported and is also a significant risk factor for sacroiliitis [40]. Another unique feature of JSpA/ERA is the frequent involvement of the tarsal bones seen in nearly one third of patients (Fig. 19.3) [19]. These patients present with significant mid-foot disease. Small joints of the foot and toes are commonly involved. Upper extremity involvement can be characterized by shoulder involvement and dactylitis. Though oligoarthritis is frequent at presentation, polyarthritis has been reported in up to 60 % of the patients over a period of time [41]. Radiographic findings include osteopenia, joint space narrowing, and, in some cases, ankylosis. Erosive changes are particularly noted in the hip and involve the small joints of hands and feet.
Axial Skeleton
Axial skeleton involvement is characterized by cervical, thoracolumbar, or sacroiliac joint involvement. Axial symptoms may accompany disease activity at peripheral sites or may rarely occur in isolation. Involvement of the sacroiliac joint in adults is often manifested by the presence of inflammatory back pain (IBP) (Table 19.4) [42]. IBP often awakens patients at night, is typically associated with morning stiffness, and shows a good response to NSAIDs. Though this definition is not validated in children, it can be used to define the characteristic IBP associated with JSpA. However IBP is not a common clinical feature of JSpA.
Table 19.4
IBP according to ASAS experts’ to be applied in patients with chronic back pain (>3 months)
1. Age at onset < 40 years |
2. Insidious onset |
3. Improvement with exercise |
4. No improvement with rest |
5. Pain at night (with improvement upon getting up) |
The criteria are fulfilled if at least four out of five parameters are present |
Sacroiliitis is often detected clinically by either distraction (FABER test), constriction of the pelvis, or application of direct pressure over the sacroiliac joints. The modified Schober’s test helps demonstrates the spinal mobility. Values less than 6 cm are often considered abnormal in an appropriate clinical setting. There are many other objective assessment tools to measure the cervical and lumbar spinal range of movements and its associated restriction due to the disease. Thoracic disease or chest wall enthesitis may be reflected as limitation of chest expansion.
Though sacroiliitis appears uncommon in JSpA, “silent” sacroiliitis detected only by imaging was described by Stoll et al. in 21 % of patients who lacked clinical and physical findings suggestive of sacroiliitis [40]. The common predictors of sacroiliitis include the presence of HLA-B27, male gender, family history of AS, hip involvement, and late onset of disease [40, 43].
Enthesitis
The enthesis is the site of attachment of the ligament, tendon, fascia, or capsule to bone and is a key feature of JSpA. It is usually associated with severe pain and disability and can be a more troublesome complaint than arthritis. SpA should be suspected in children complaining of knee, foot, or heel pain. Enthesitis usually occurs either within the joints (like in sacroiliac joints) or in the extra-articular sites (tibial tuberosity enthesitis or Achilles enthesitis). Enthesitis is seen in up to 60–80 % of patients with ERA and is most frequent in the lower extremity. It can be evaluated clinically, and the commonest sites are Achilles tendon insertion and plantar fascial insertion into the metatarsal heads or calcaneus, around the knee at the patellar ligament insertion sites (10, 2, and 6 o’clock positions of the patella), and at the tibial tuberosity (Fig. 19.2). Chest wall enthesitis often manifests as chest pain during deep inspiration, and pain and tenderness at the costo-sternal junction can be elicited on palpation. Clinical evaluation alone tends to overestimate enthesitis, and thus ultrasound and whole-body (WB) MRI are being explored as research tools [44].
Fig 19.2
Composite images of ankylosing tarsitis in a 16-year-old boy with JoAS of 9 years disease duration and complete ankylosis of the tarsal bones. (a, b) Flatfoot and swelling around the ankle. (c–f) T2-weighted fat-suppressed MR imaging showing edema in various tarsal bones, joint spaces (c, d), and soft tissues (e, f) surrounding the tendons of the posterior aspect of the foot on the coronal view (arrows) fat. (g) Complete ankylosis of the tarsal bones and an enthesophyte at the plantar fascia attachment (Adapted with permission from Macmillan Publishers Ltd.: Nat Clin Pract Rheumatol [100], copyright (2009))
Fig 19.3
Sites for assessment of enthesitis for juvenile spondyloarthritis
Extra-articular Manifestations
Uveitis
Acute symptomatic anterior uveitis (AAU) is a common extra-articular manifestation of JSpA. It is commonly seen in HLA-B27-positive individuals and can occur even in isolation without the presence of arthritis or enthesitis. In India it is reported in up to 22 % of children with ERA [19]. It is usually unilateral and recurrent and presents with a severe red eye with photophobia. Occasionally, hypopyon can be noted during active inflammation. Chang et al. reported that 50 % of adult patients with HLA-B27-positive AAU would eventually be diagnosed with some form of SpA [45].
The risk of chronic uveitis is rare; however, young individuals diagnosed with PsA with ANA positivity should be screened at regular interval for detecting chronic inflammation in the anterior chamber of the eye.
Intestinal Inflammation
There is a strong association between Crohn’s disease, ulcerative colitis and nonspecific inflammatory changes of the terminal ileum, and arthritis. The presence of active gut inflammation is often seen in association with active arthritis. SpA may also be the initial manifestation of systemic disorders such as inflammatory bowel disease. Peripheral and axial arthritis occurs in up to 30 % of patients with IBD. Arthritis is about twice as common in Crohn’s disease as compared with ulcerative colitis [46]. Slow growth, poor weight gain, severe anemia, and recurrent abdominal pain with frequent diarrhea can be the first clues to intestinal involvement.
Clinical Types
As mentioned earlier JSpA includes both undifferentiated and differentiated forms of the disease [49]. Undifferentiated SpA is of great importance as it has potential to evolve to other forms of SpA. ILAR classification fails to recognize various types of SpA (with PsA being a different disease subtype).
Undifferentiated SpA
This remains the most common type of SpA in children. In the past, these patients were referred as having seronegative enthesopathy and arthropathy syndrome [22], and in the recent time, it is called ERA subgroup of JIA. The spectrum varies from mild disease manifestation to severe disease associated with involvement with axial spine. Many patients in this subcategory would go on to develop AS approximately 10 years later [50, 51]. The presence of HLA-B27 helps in differentiating JSpA/ERA from other JIA subgroups.
Differentiated SpA
- 1.
Juvenile-onset ankylosing spondylitis: This term refers to AS starting before the age of 16 years and in children who fulfill the modified New York criteria [24]. The predominant symptom is IBP [42]. Up to 27 % have acute uveitis, and around 80 % have nonspecific gastrointestinal manifestations. Cardiovascular manifestations, though reported, remain rare in this subgroup. HLA-B27 is present in 90 % of children with JoAS. MRI may show acute sacroiliitis. In fact many patients classified under this subset usually have an undifferentiated form of SpA in the early stage of the disease.
- 2.
Reactive arthritis (ReA): This term often includes patients who are HLA-B27 positive and develop arthritis in relation to an infection triggered by gut-trophic bacteria Salmonella, Yersinia, Campylobacter, and Shigella. It can also be seen following infection with Chlamydia presenting as a urinary tract infection. This subset was earlier defined as Reiter’s syndrome with a triad of arthritis, conjunctivitis, and urethritis or cervicitis. There is usually an interval of 1–2 weeks from the infection to the onset of musculoskeletal symptoms. ReA predominates in the lower extremities [52]. Typical extra-articular manifestation consists of enthesitis, conjunctivitis, acute anterior uveitis, tendinitis, and bursitis and skin involvement noted with erythema nodosum, keratoderma blennorrhagicum, and circinate balanitis [52]. Definitive diagnosis requires identification of a triggering infection and is often dependent on the detection of specific antibodies in the serum as the patient may have already recovered from the gastroenteritis, and the microbe may no longer be detectable [52].
- 3.
Juvenile-onset psoriatic arthritis (PsA):It is defined as concomitant occurrence of arthritis and psoriasis in individuals younger than 16 years. The ILAR criteria include patients with either arthritis or psoriasis and dactylitis, nail pitting, or onycholysis, or history of psoriasis in a first-degree relative [23]. Boys who are HLA-B27 positive older than 6 years of age and those with disease features of ERA are excluded from the study.
PsA appears to be composed of two distinct clinical subgroups [53]. The first one is characterized by early age of onset (<5 years) with features similar to oligoarticular and polyarticular JIA with female predilection who are ANA positive with a risk of chronic uveitis. The second phenotype involves patients who are usually older and have an association with HLA-B27 but not ANA, equal sex ratio, and more frequent dactylitis, enthesitis, nail pitting, and axial involvement [53]. The second group seems more representative of the SpA continuum. Overall, arthritis is the initial manifestation in 50 % of cases, psoriasis in 40 %, and their combination in 10 %. The most common type of arthritis is oligoarticular but 45 % of patients may have polyarticular course [54]. Polyarticular extension of the oligoarticular disease occurs in 60–80 % of patients if not appropriately treated [55, 56]. Arthritis of the distal interphalangeal joints (DIPs) is highly suggestive of psoriatic arthritis, although most children lack DIP involvement. The extra-articular involvement in PsA includes skin, nail, and eye disease. Psoriatic skin lesion occurs in 40–60 % of children with PsA with psoriasis vulgaris being the commonest. Nail changes such as pitting are found in 50–80 % of children with PsA [56]. Chronic painless uveitis occurs in 10–15 % of children with PsA and is indistinguishable from that seen in oligo-JIA [57].Related posts:
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