Chapter 202. Spondyloarthropathies

The word spondyloarthropathy (referring to arthritis of the spine and sacroiliac joints) evolved in the adult population to distinguish a group of chronic arthritides that differed from rheumatoid arthritis. These conditions were distinct in that they involved axial joints, were associated with the HLA-B27 haplotype, had a frequent family history of these diseases, and were rheumatoid factor negative. Traditionally the specifically named spondyloarthropathies included ankylosing spondylitis, psoriatic arthritis, the arthropathy of inflammatory bowel disease, and Reiter disease.

This characterization has not been entirely satisfactory, because many patients do not comfortably fit into one of these explicitly defined categories.1-3 The efficacy of current pharmacotherapy for AS has driven the development of clinical algorithms (judiciously using magnetic resonance imaging [MRI]) to identify early disease and thereby allowing initiation of appropriate therapy before the development of irreversible damage.4,5

A major deficiency of the earlier classification systems for pediatric chronic arthritis was the failure to adequately distinguish children with arthritis who have, or who might ultimately develop, a spondyloarthropathy, from those with juvenile rheumatoid arthritis.6-8 Although the EULAR classification includes juvenile ankylosing spondylitis and juvenile psoriatic arthritis, these conditions are defined according to adult criteria that require the presence of radiologically identified sacroiliitis or psoriasis, respectively. Children who ultimately develop ankylosing spondylitis (AS), however, will generally not present with back pain or sacroiliitis (the primary requisites for diagnosing AS in adults). Rather, they typically have peripheral arthritis and a constellation of other features including enthesitis, onset later in childhood, a family history of AS or related diseases, and presence of HLA-B27 antigen.9,10 To address these deficiencies, such patients have been variously described as having the syndrome of seronegative enthesopathy and arthropathy (SEA syndrome), pauciarticular onset juvenile rheumatoid arthritis (JRA) type II, late-onset pauciarticular juvenile chronic arthritis (LOPA), and HLA-B27-associated arthropathy and enthesopathy syndrome.11-14 Patients with these various syndromes could also be characterized as having “early” or “undifferentiated” spondyloarthropathy.

The evolution of nomenclature within the International League of Associations for Rheumatology (ILAR) system for classifying pediatric chronic arthritis has encapsulated all of these syndromes in the category of enthesitis-related arthritis (ERA) (see Chapter 201).15Enthesitis, the most common defining clinical feature of these syndromes, refers to inflammation (pain, tenderness, and swelling) of the enthesis, the site of attachment of tendon, ligament, or fascia to bone. Thus, children with juvenile ankylosing spondylitis (JAS) also fulfill criteria for ERA. As will be discussed under the section of this chapter, “Juvenile Psoriatic Arthritis,” children with arthritis and either psoriasis or psoriatic features probably do not represent a homogeneous subset of childhood arthritis despite their current classification within spondyloarthropathies (see Table 202-1). Children with inflammatory bowel disease associated arthritis or Reiter disease may or may not develop axial arthritis and these conditions will also be discussed below.

Because enthesis-related arthritis (ERA) is a recently defined entity, epidemiological information must be extrapolated from data on similar syndromes in the older nomenclature systems. The prevalence of ERA is likely to be approximately 20 per 100,000 children, which is about half as common as oligoarthritis and three to four times as common as psoriatic arthritis. These numbers may vary considerably in different communities depending on factors such as the prevalence of HLA-B27. Children with ERA should be distinguished from other forms of chronic childhood arthritis for etiologic, genetic, prognostic, and therapeutic reasons. In addition to enthesitis, characteristic features distinguishing ERA from the other forms of juvenile idiopathic arthritis include a high frequency of HLA-B27, late childhood onset, male preponderance, familial occurrence of other HLA-B27–associated diseases, and peripheral arthritis that tends to asymmetrically involve the lower limbs (Table 202-1).

Etiology

As with other forms of JIA, the cause of ERA is unknown; however, the strong familial tendency and the high frequency of HLA-B27 reflect a genetic predisposition. The similarity of ERA to reactive arthritis in epidemiology and gut histology additionally implicates bacterial antigens in the process.16,17 There may also be hormonal influences on the expression of the disease.

Clinical Presentations

ERA is distinguished from other forms of chronic idiopathic arthritis by the presence of enthesitis, sacroiliac pain or inflammation, and acute anterior uveitis (usually associated with pain, redness, or photophobia), and by the occurrence of spondylitis, enthesitis-related arthritis, inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis in a first-degree relative.

Although often insidious and episodic, the onset of ERA also may be acute, and may resemble septic arthritis when presenting as a monoarthritic process (see also Reactive Arthritis below). Children with ERA present with morning pain and stiffness relieved by activity, predominantly in joints of the lower extremities and often in the low back and buttocks. They may also complain of pain at the enthuses, commonly around their heels, feet, and knees. Buttock pain when sitting on hard surfaces may represent enthesitis over the ischial tuberosities. Examination may reveal evidence of oligoarthritis asymmetrically involving the knees or ankles, and sometimes the hips or small joints of the feet. (Hip joint involvement at disease onset is uncommon in other types of JIA.) Early involvement of the midfoot (tarsitis, enthesitis, and tenosynovitis) with pain, tenderness, and swelling is less common, but if present, is very characteristic of ERA.18 Exquisite tenderness may be elicited by palpation of the entheses, particularly at the calcaneal insertions of the Achilles tendon and the plantar fascia, beneath the metatarsal heads and the base of the fifth metatarsal, the tibial tuberosities and the 2, 6, and 10 o’clock positions of the patella, over the greater trochanters of the hips, across the iliac crests, and the ischial tuberosities (see Fig. 202-1). Pelvic compression and distraction or direct palpation may elicit sacroiliac joint pain.

Axial involvement should be determined by history and by examining the back for range of movement and flattening of the lower back on forward flexion. Costovertebral motion can be monitored by serial measurements of maximum chest expansion. Cervical disease is not common at presentation, and usually follows lumbar involvement; however, atlantoaxial instability has been reported in early disease.

High fever with constitutional symptoms of anorexia, fever, and weight loss may occur in 5% to 10% of children with ERA; however, these findings should also alert the physician to the possibility of inflammatory bowel disease, particularly if there is growth delay. Subclinical ileocolonoscopic evidence of gut inflammation is reported to occur in up to 80% of patients, and these changes may be predictive of development of AS; this also may have etiologic significance. Acute symptomatic iritis, commonly unilateral, may occur in 5% to 10% of children with ERA. Aortic valve insufficiency is a rare complication. Restrictive lung disease, which has been reported in adults with spondyloarthropathy, probably does not occur in childhood.

Diagnosis

The diagnosis of chronic arthritis and enthesitis is based on clinical findings and history. Pain and tenderness at the entheses can also be caused by mechanical factors related to physical activities, flat feet, or poor posture. Tenderness also may be elicited at these sites (in addition to other soft tissue sites) in patients with pain amplification. In the absence of arthritis, care should be taken in making a diagnosis of ERA simply on the basis of mild tenderness at fewer than three entheses. Laboratory investigations are not diagnostic. Patients may have nonspecific inflammatory changes with a normocytic normochromic anemia, mild leukocytosis, thrombocytosis, and a high ESR. Immunoglobulins, and specifically immunoglobulin A, may be elevated. HLA-B27 is frequently present and with other criteria may help with classification.

Treatment

As for all forms of juvenile idiopathic arthritis, the child with spondyloarthritis is best served by treatment in a multidisciplinary setting by professionals specifically trained in the treatment of childhood rheumatic diseases, including pediatric rheumatologists, nurses, and pediatric physiotherapists and occupational therapists. The first line of pharmacotherapy is regular doses of nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, ibuprofen, or indomethacin.19 Optimal effect from these medications requires at least a month of continuing treatment. While such continuous use of NSAIDs, as distinct from sporadic “symptomatic” use, is the standard of care for peripheral arthritis, recent evidence in adults with AS suggests that continuous use also reduces the rate of radiological progression of axial disease. Intra-articular injection of triamcinolone hexacetonide (1 mg/kg per joint) is valuable if there are a few peripheral joints that are responding poorly to NSAID therapy.

The pain of enthesitis is often difficult to treat; local injection of corticosteroids is generally unsuccessful, and patients often require use of low-dose oral prednisone. For patients in whom NSAID therapy provides inadequate disease control, sulfasalazine and methotrexate are safe and effective second-line therapies. Patients taking these medications require regular monitoring of blood count and hepatic transaminases. While these two medications have shown not to be effective in the treatment of axial disease in adult ankylosing spondylitis, it is not known whether early aggressive use of these medications in juvenile spondyloarthropathy prevents or delays progression of axial arthritis. Anti-TNF therapy has been shown to be effective in the treatment of peripheral arthritis and axial arthritis, and is a reasonable choice for patients with peripheral arthritis who fail standard therapy with sulfasalazine or methotrexate. It may be that early use of anti-TNF therapy should be initiated once axial involvement becomes apparent.4,20

Treatment of mechanical factors affecting symptoms is also important. Many children with ERA benefit from custom-made hard orthotics to redistribute the weight from sites of painful enthesitis; heel cups in the shoes can alleviate stress in the retrocalcaneal area and the knee. Physiotherapy is an important component of treatment for all children with ERA. Treatment should be aimed at promoting general physical fitness, maintaining a healthy body weight, and restoring muscle strength and range of movement of affected joints and surrounding structures. Special attention should be paid to preserving range of movement of the back and chest.

Prognosis

Disease course is highly variable. Some patients have a short duration of illness, with pauciarthritis and/or enthesitis that resolves completely within 3 to 6 months. This pattern resembles reactive arthritis, although an inciting pathogen with preceding gastrointestinal or genitourinary symptoms may not be identifiable. More common, however, is a course of episodic flares that lasts for years. Within about 10 years a majority of patients with a more chronic course have a high likelihood of developing symptomatic and radiologically confirmed sacroiliitis with spondylitis, and to fulfill classic criteria for ankylosing spondylitis. They may have an intermittent or slowly progressive course with loss of lumbosacral flexion and decreasing chest expansion. In the most severe cases, involvement progresses to a symmetric erosive and ankylosing polyarthritis by adulthood, predominantly in the lower limbs, together with ankylosing disease of the back and sacroiliac joints and restrictive lung disease. A recent study of the long-term outcome (median 15-year follow-up) of a group of children with ERA from Norway showed that these children had poorer physical functioning and health, and more pain, than a control group of patients who had oligoarticular or polyarticular JIA.21 Sacroiliitis developed in 35% of the ERA patients, and predictors of poor outcome included a family history of ankylosing spondylitis, early hip or ankle disease, and a high number of affected joints during the first 6 months of disease.

Although juvenile ankylosing spondylitis (JAS) is the archetypal spondyloarthropathy in childhood, it is relatively rare, occurring in less than one third of children who present with spondyloarthropathy. Several criteria have evolved to define ankylosing spondylitis in adults including the Rome Criteria (1963), New York Criteria (1968), and the more recent modified New York Criteria.1 In general, AS is distinguished by the presence of persistent low back pain, limitation of motion of the lumbar spine and decreased chest expansion, and sacroiliitis.1 Although these criteria have been utilized in children to classify juvenile ankylosing spondylitis, they are inherently difficult to apply. Presumably because the disease process affects a developing musculoskeletal system differently, disease manifestations in childhood AS differ from those in adult-onset spondylitis.22,23 Thus, in children back symptoms are uncommon: Approximately 10% of children with AS present with spinal or sacroiliac disease, compared with 80% of adults. Direct comparison of juvenile and adult-onset disease is further hampered by the limited data for normal lumbar spine motion and chest expansion in pediatric patients, and difficulty standardizing and interpreting radiographs of growing SI joints. Conversely, 90% of children with AS have peripheral arthritis compared with about 37% of adults. There is a particularly high frequency of tarsitis (78%) and enthesitis (64%), rates that are two to three times higher than in adults. In follow-up, the cumulative frequencies of peripheral arthritis, tarsitis, and enthesitis in pediatric-onset patients are about double those of patients with adult-onset disease.24

Children with back pain are often referred to the pediatric rheumatology clinic with a presumptive diagnosis of arthritis or AS. Although children with chronic synovitis may present with inflammatory back pain, generally this would be an uncommon finding at disease presentation. The differential diagnosis of back pain in a child must include consideration of orthopaedic, traumatic, infectious and malignant disorders, many of which are more likely causes of back pain than arthritis in children. For example, preschool-age children virtually never develop back arthritis, and malignancy (eg, neuroblastoma), discitis, or bone infections should be the primary considerations. In older children, problems such as Scheuermann disease, spondylolisthesis, scoliosis, or trauma must be considered. If night pain, fever, or other constitutional symptoms are present, infection or malignancy must be considered (see Chapter 216). The presence of HLA-B27 is not diagnostic for ankylosing spondylitis, as it is present in 2% to 10% of the general population (higher in frequency in Native American and Scandinavian communities), of whom 80% to 90% never develop arthritis. As with all forms of juvenile arthritis, the diagnosis of ankylosing spondylitis requires supportive clinical evidence of inflammatory joint disease.

Once a diagnosis of ankylosing spondylitis has been made, treatment strategies should be undertaken as outlined under the section “Enthesitis-Related Arthritis,” above. Because the outcome of children and youth with JAS who receive conventional therapy with NSAIDs and methotrexate is likely to be poor, an aggressive approach to treatment, including early consideration of TNF inhibitors, is warranted.

Inflammatory arthritis occurs in up to 15% of patients with inflammatory bowel disease (IBD), either Crohn disease or ulcerative colitis.25 Arthralgia is fairly common, likely occurring in 30% of children and adolescents with IBD (see Chapter 410). Musculoskeletal pain in children with IBD may arise from causes other than inflammatory arthritis, including nonspecific myalgia and mechanical and orthopedic issues such as pes planus, deconditioning secondary to illness, glucocorticoid induced osteopenia, or hypertrophic osteoarthropathy. Joint disease may occur at the onset of IBD, and on occasion it may precede the diagnosis of IBD by months to years. For all children with arthritis, systemic complaints such as prominent fatigue, weight loss, unexplained growth failure (height more delayed than weight), and fevers should suggest the diagnosis of IBD. In addition, gastrointestinal complaints including oral ulcers; abdominal pain or tenderness; diarrhea or hematochezia; and extraintestinal manifestations such as erythema nodosum, pyoderma gangrenosum, or clubbing suggest underlying intestinal inflammation. Suspicion is heightened by a family history of IBD, and by evidence of chronic inflammation on laboratory studies (marked anemia; hypoalbuminemia; markedly elevated ESR). Definitive confirmation of a diagnosis of inflammatory bowel disease requires gastrointestinal endoscopy and biopsy with histological evidence of colitis or enteritis.

In patients with IBD, peripheral arthritis (usually involving the large weight-bearing joints) is twice as common as axial arthritis, is more frequent in girls, is not associated with HLA-B27, and usually occurs in association with flares of gut inflammation. Active arthritis associated with active gut disease may be relatively transient, and generally will resolve as the gut inflammation is treated and resolves. Patients with IBD are also at increased risk of developing axial joint involvement, although initially a peripheral arthritis and/or enthesitis consistent with ERA is most characteristic. These patients are predominantly males with HLA-B27. When such patients ultimately develop axial joint inflammation, its course resembles that of juvenile ankylosing spondylitis, typically persistent and independent of bowel inflammation.

Peripheral arthritis in association with a flare of bowel inflammation often responds to aggressive treatment of the enterocolitis with corticosteroids, sulfasalazine, or other second-line agents. NSAIDs are generally beneficial, but there is some concern that these may exacerbate the bowel disease. Otherwise, treatment of the arthritis does not differ significantly from that of ERA: Intra-articular glucocorticoid injections may be indicated for persistent joint disease, and anti-TNF agents (notably infliximab) are effective for treating both the inflammatory bowel disease and the peripheral and axial arthritis.

In the context of the “spondyloarthropathies,” reactive arthritis describes a disease occurring 1 to 4 weeks following gastrointestinal (commonly Yersinia enterocolitica, Y. tuberculosis, Shigella flexneri, Salmonella typhimurium, Campylobacter jejuni) or genitourinary (Chlamydia trachomatis and Ureaplasma urealyticum) infection. Less commonly respiratory infection with Mycoplasma pneumonia or Chlamydia pneumonia, and enteric infections with Clostridium dificile, or the protozoans Giardia lamblaia or Cryptrosporidium, may precede the arthritis. Reactive arthritis with the extra-articular manifestations of conjunctivitis and urethritis may be referred to as Reiter disease, although this rarely occurs in children. Other forms of reactive arthritis (eg, poststreptococcal, post-gonococcal) differ in pattern of involvement, course, and prognosis; these are traditionally not considered among the spondyloarthropathies but should be considered in the differential diagnosis, as should viral arthritis and Lyme disease.

The frequency of reactive arthritis in any community reflects genetic factors as well as the prevalence of arthritogenic infections in the population. Although arthritis can occur in both HLA-B27–positive and HLA-B27–negative individuals, HLA-B27 individuals may be more susceptible to the infection and also are more likely to develop persistent arthritis following infection.

Reactive arthritis commonly presents as florid inflammation of one or two of the large weight-bearing joints. Asymmetric involvement of small and large joints with dactylitis, as well as enthesitis, tenosynovitis, and bursitis, may also occur. The joints may be very hot, red, tender, and painful, and laboratory investigation may show markedly elevated inflammatory indices. A history in the patient of recent infection, infectious contact, or travel should alert to the possibility of reactive arthritis. In the case of monarthritis, the possibility of septic arthritis may necessitate treatment with intravenous antibiotics while awaiting the results of arthrocentesis and joint fluid culture. In the presence of relatively normal “inflammatory” blood tests, several other acutely presenting conditions may have to be excluded. Acute orthopedic conditions of the hips such as slipped capital femoral epiphysis or Legge-Calve-Perthes should be distinguishable radiographically. Reflex sympathetic dystrophy (RSD) may present with an acutely painful, swollen joint, and this may be difficult to distinguish from reactive arthritis in spite of the presence of the characteristic “la belle indifference.” A nuclear bone scan may be diagnostically helpful, with inflammatory processes demonstrating increased perfusion, but RSD characterized by decreased blood flow in the involved area. Support for the diagnosis of reactive arthritis is also provided by intestinal, urethral, and conjunctival cultures revealing one of the organisms known to incite reactive arthritis. However, although suggestive, this is no more definitive in proving the existence of reactive arthritis than does the absence of organisms exclude the possibility. Fortunately, reactive arthritis is most often transient, lasting only days to weeks, so a diagnosis may be assumed in retrospect, following a severe, self-limited arthritis. In some cases the arthritis may persist for months, sometimes with remissions and exacerbations, and in 1% to 3% of cases, patients (especially those with positive HLA-B27) develop chronic synovitis following an arthritogenic infection.

When the course of reactive arthritis is transient or self limited, treatment with NSAIDs may be effective and sufficient in the short term. Sometimes the degree of discomfort and inflammation requires short-term use of glucocorticoids given orally as prednisone, or by intra-articular injection for resistant synovitis. Uncommonly, a patient may develop a persistent arthritis that is indistinguishable from ERA. This should be treated like ERA, and in the long term, such patients risk development of back pain or sacroiliitis, and evolution into full-blown ankylosing spondylitis.

The association of arthritis and psoriasis has been described in the adult literature for more than a century, both conditions occurring in about 3% of the population. Classifying psoriatic arthritis will remain difficult until the biologic basis of the association between psoriasis and arthritis is understood; it remains unclear whether psoriatic arthritis is a unique entity, or if coincidental psoriasis simply modifies the expression of arthritis. There are well-characterized psoriatic phenotypes described in adults: asymmetric oligoarthritis, symmetric rheumatoid-like arthritis, predominant distal interphalangeal joint disease, arthritis mutilans, and spondylitis. Recently, at least two similar subtypes have been described in children.26-30 Psoriatic arthritis traditionally has been classified as a seronegative spondyloarthropathy, even though sacroiliitis or spondylitis at most occurs in only 40% of these patients. Overall, it seems likely that psoriatic arthritis represents a heterogeneous group of diseases that probably should not be lumped together as a spondyloarthropathy.

The association of psoriasis and arthritis in children has only been recognized in the past two to three decades.26 This may be in part because the majority of children develop psoriasis months to years after they develop arthritis. In 1980 the “Vancouver criteria” were proposed to facilitate the diagnosis of juvenile psoriatic arthritis in a child with arthritis who may not have a typical psoriatic rash.27 These elements have been incorporated within current diagnostic schemes: In the absence of psoriasis, key elements in diagnosing psoriatic arthritis include the presence of dactylitis, psoriatic nail abnormalities (pitting or onycholysis), and a family history of psoriasis in a first-degree relative (see Table 201-1).11

Psoriatic arthritis is more frequent in girls than in boys and has an onset peak in early childhood. All of the adult psoriatic arthritis phenotypes described above except arthritis mutilans may occur in children; however, the most common pattern of joint disease at onset is asymmetric involvement of both large and small joints.27 Over time, many patients develop polyarthritis.28,29 Like young children with JIA, those with psoriatic arthritis are at risk of developing asymptomatic chronic anterior uveitis, particularly in the presence of a positive test for antinuclear antigen (ANA). A small minority of children with psoriatic arthritis, primarily those positive for the HLA-B27 haplotype, develop sacroilitis. Overall, however, children with psoriatic arthritis are unlikely to have sacroiliitis, so it seems even less relevant than in adults to classify the whole group of such patients as having a spondyloarthropathy (see Table 202-1).

Long-term studies confirm the persistence of this condition: At 8 to 10 years of follow-up, about one half of children diagnosed with psoriatic arthritis had persisting synovitis, 8% to 10% had severe functional impairment, and about half of these had had joint replacements.26 Thus, principles of treatment are similar to those for children with other forms of arthritis, with an accent on early, aggressive management aimed at preventing chronic joint changes and disability. Further, it is important to remember that children with psoriatic arthritis require monitoring for asymptomatic uveitis with slit-lamp examinations performed every 3 to 6 months.