Using ESSG criteria, the diagnosis of undifferentiated spondyloarthritis may be entertained if the patient has one of the following two major criteria (in the absence of psoriasis, i n \202 ammatory bowel disease, or other evidence of one of the other forms of spondyloarth ritis): \200 In \202 ammatory back pain (onset <40 years old, insidious onset, symptoms (cid:4) 3 months, morning stiffness, improvement with exercise) Asymmetric synovitis (predominantly of the lower extremities) \200 Most of these patients are young men with in \202 ammatory lower back pain and/or an asymmetric oligoarthritis, and are HLA-B-27 positive. Dactylitis and extra-articular manifestations are less common am ong patients with this diagnosis. In general, radiographic evidence of sacroiliitis is mild. Clear evidence of sacroiliitis o n plain radiographs may indicate that the patient is evolving towards a diagnosis of ankylo sing spondylitis. A small number of patients may eventually develop clear evidence of psori atic arthritis. Diagnosis and treatment \200 Diagnosis is based on clinical features. Although most patie nts are HLA-B27 positive, in \202 ammatory markers may not be elevated, and cannot be used to exclude this diagnosis. Early identi \201 cation and treatment of patients who are destined to evolve into ankylosing spondylitis may be key to preventing morbidity associated with this disease. How to identify patients at highest risk for progression, however, is not clear. MRI typically demonstrates evidence of sacroiliitis before changes on visible on plain radi ographs, and may be useful for identifying which patients merit treatment with TNF- A inhib itors. For other patients, non-steroidal anti-in \202 ammatory agents remain the mainstay of ther apy. Methotrexate, sulfasalazine, and le \202 unomide may also play a role in the treatmen t of undifferentiated spondyloarthritis, although this has not been well established. CHAPTER 8 The spondyloarthridities 304 SAPHO Epidemiology and clinical presentation \200 SAPHO is a relapsing and remitting illn ess that primarily affects young adults. The prevalence of SAPHO is unknown, but may be aro und 1/10,000. The acronym describes the components of this disease: Synovitis, Acne, Pustulosis, Hyperost osis, and Osteitis. Older names for this syndrome include: \200 Acne arthritis \200 Pus tulotic arthro-osteitis \200 Sternoclavicular hyperostosis \200 Acne-associated spondyl oarthropathy Palmoplantar pustulosis is the most common skin \201 nding in SAPHO, and is found in over half of patients with this diagnosis. Other skin lesions associated with SAPHO include pso riasis vulagris, severe acne, psoriasis, hidradenitis suppurativa, acne conglobata, pyoderm a gangrenosum, and Sweet \200\231s syndrome. It is important to note, however, that skin le sions may be subtle: 16% of patients may have no skin \201 ndings at all. Hyperostosis, particularly of the sternoclavicular joints, is likely the result of recurren t osteitis. This osteitis is aseptic, and does not respond to antibiotics. That said, 15% f o patients with chronic recurrent multifocal osteomyelitis have infection with Proprionibac terium acnes, although the signi \201 cance of this \201 nding is not completely clear. The synovitis most commonly affects the anterior chest wall; 63% of patients will have invo lvement of the steronoclavicular joints. Peripheral joint involvement may be either symmetr ic or asymmetric. \200 Because of its association with psoriasis, SAPHO is often classi \201 ed as a form of spondyloarthropathy. It is also interesting to note that 10% of patien ts with SAPHO are HLA-B27 positive. Diagnosis and treatment \200 This syndrome has four major subtypes: Osteoarticular manifestations of severe acne \200 Osteoarticular manifestations of palmop lantar pustulosis \200 Hyperostosis with or without dermatosis \200 Chronic recurrent m ultifocal osteomyelitis involving the axial or peripheral skeleton, with or without dermatosis To diagnose SAPHO, infectious causes of osteomyelitis must be excluded. Plain radiographs of the anterior chest wall may demonstrate lytic lesions and sclerosis in the sternoclavicular heads. Involvement of the sternoclavicular heads may be more clearly demonstrated with a Technitium-99 bone scan. Treatment includes non-steroidal anti-in \202 ammatory agents as a \201 rst line therapy. Methotrexate is the most commonly used steroid sparing SAPHO 305 agent, although low-dose glucocorticoids, methotrexate, sulfasalazine, colchicine, and cycl osporine have all been used. Intravenous pamidronate may be particularly effective for the treatment of osteitis. TNF- A blockade with etanercept and in \202 iximab has also been us ed with some success. The overall prognosis is felt to be better than that associated with the other spondyloarthridities, although this is dif \201 cult to prove. CHAPTER 8 The spondyloarthridities 306 Spondyloarthridities in childhood Epidemiology and clinical presentation \200 This umbrel la term covers a heterogeneous group of diseases associated with HLA B27 that affect children under the age of 16 and produce a spectrum of symptoms in adulthood. The disease group includes: enthesitis and arthritis syndrome \200 juvenile ankylosing spondylitis \200 juvenile re active arthritis \200 juvenile psoriatic arthritis(JPsA) \200 arthritis associated with in \202 ammatory bowel disease Using the ILAR classi \201 cation, this spectrum of diseases is called enthesitis-related arthritis (ERA). Incidence is estimated at 1.44 per 100,000 children. Prevalence has increased over the last 30 years. IgM RF and antinuclear antibodies are not found. 90% patients will be HLA B27 positive. The diagnosis is often more dif \201 cult in childhood as symptoms of back pain and radiol ogical changes are uncommon. The diagnosis rests more often on the presence of lower limb l arge joint arthritis associated with enthesopathy, acute uveitis, psoriasis, or bowel patho logy, and may be dif \201 cult to separate from JIA. The reader is referred to Chapter 9 f or a description of the classi \201 cation criteria for childhood arthropathies. Apart from an increased incidence of peripheral disease and rare axial symptoms, juvenile o nset spondyloarthridities resemble the adult forms. This lack of early axial disease may le ad to initial misdiagnosis as oligoarticular JIA. The Rome and New York criteria for the diagnosis of adult AS have not been validated in chi ldren; nevertheless, a small proportion of children \201 t these criteria and is consider ed to have juvenile AS. Approximately 5 \200\2238% of children attending rheumatology clini cs have AS. This compares with 75% having JIA. Juvenile AS commonly presents with lower lim b large joint arthritis (often knees and ankles) with the early course often episodic. It a lso appears to differ from adult AS in the precocious destruction of the hip joint. The con dition is reported more often in men than women, and 50% of cases go on to develop AS in ad ult life. Enthesitis and arthritis syndrome usually affects the feet and can be disabling. The disease is usually episodic, but some cases are chronic, resulting in bony e rosions and joint ankylosis. Over 70% patients with enthesitis syndrome will ful \201 ll d iagnostic criteria for AS after 5 \200\22310 years from onset. Childhood reactive arthritis and enteropathic arthropathy are essentially similar to adult disease. SPONDYLOARTHRIDITIES IN CHILDHOOD 307 JPsA \200 JPsA is de \201 ned in the ILAR criteria as either arthritis in the presence o f psoriasis, or arthritis and at least 2 of: \200 dactylitis \200 nail abnormalities (pit ting or onycholysis) \200 family history of psoriasis con \201 rmed by a dermatologist i n at least one \201 rst-degree relative. The incidence of JPsA is estimated at 3 per 100,000, with a prevalence of 15 per 100,000. Oligo- or polyarthritis may occur and can affect large or small joints, the spine, and sacr oiliac joints. Anterior uveitis is seen in 10 \200\22320%. \200 JPsA, traditionally group ed with the spondylarthropathies, has greater clinical and laboratory similarity to JIA; im portant dissimilarities with the spondylarthropathies include a lack of association with HL A B27, and AS as an outcome. JPsA is also more common in girls than in boys. Treatment of JPsA \200 The principles of treatment include education, physical therapy, s plints, orthotics, NSAIDs, and intra-articular corticosteroids for peripheral arthritis. Or al corticosteroids may be used for severe arthritis or enthesitis. In the presence of signi \201 cant axial disease, polyarthritis, or persistent oligoarthro pathy, sulfasalazine may be started (initially at 12.5 mg/kg/ day, increasing weekly over 1 month to 50 mg/kg/day in 2 \200\2233 divided doses). However sulfasalazine may be no bette r than placebo, as seen in recent trials. MTX has shown little effect in spondyloarthropathy patients without JPsA. MTX and cyclosporine have been used successfully in the treatment of JPsA alone or in combination. In \202 iximab, etanercept, and adalimumab have been used and appear to be as effective as in adult spondyloarthropathy treatment. They have also been used to treat uveitis. Prognosis in juvenile spondyloarthropathy Remission rates vary widely in studies, with esti mates of 10 \200\22320% in remis- sion at 10 years. A large proportion of children will the refore have persist- ing disease in adult life, with associated disability. This page intentionally left blank 309 Chapter 9 Juvenile idiopathic arthritis (JIA) Introduction 310 Oligoarthritis 312 Systemic arthritis 316 Rheumatoid factor negative polya rticular JIA 322 Rheumatoid factor positive polyarticular JIA 324 Juvenile psoriatic arthri tis 325 Enthesitis related arthritis 326 Chronic, infantile, neurological, cutaneous, and a rticular syndrome (CINCA) 327 Still \200\231s disease 328 CHAPTER 9 Juvenile idiopathic arthritis (JIA) 310 Introduction \200 The classi \201 cation of childhood onset arthritis has seen several c hanges over recent years. In this chapter, we will discuss juvenile arthritis using heading s and criteria from the International League of Associations for Rheumatology (ILAR). The t erms juvenile rheumatoid arthritis and juvenile chronic arthritis were discarded in the ILA R classi \201 cation. The term juvenile idiopathic arthritis was adopted to indicate arthr itis present for at least 6 weeks and currently of no known cause in a patient <16 years. I t is a diagnosis of exclusion. JIA is one of the most common chronic disorders of childhood, with an estimated US incidenc e of 11.7 per 100,000, and prevalence of 0.5 cases per 1,000 children. \200 The categorie s of JIA are: \200 systemic onset arthritis \200 oligoarthritis (4 or fewer joints) ( \200\234persistent \200\235 or \200\234extended \200\235) \200 polyarthritis (rheumatoid factor positive and negative) \200 juvenile psoriatic arthritis \200 enthesitis relate d arthritis \200 undifferentiated arthritis. Where features of other rheumatic diseases are particular to childhood, these are discussed at the end of the relevant chapter. \200 rheumatoid factor positive polyarthritis (see Chapter 5) \200 psoriatic arthritis and enthesis related art hritis (see Chapter 8) \200 SLE (see Chapter 10) \200 back pain (see Chapter 20). The classi \201 cations were derived for research purposes and are not primarily meant as diagnostic criteria. For a review of classi \201 cation of JIA we recommend Hofer et al. ( 2002). 1 For an overview of the spectrum of pediatric and adolescent rheumatology we recomm end Davies and Copeman (2006). 2 General management principles in juvenile rheumatic diseases \200 Early, aggressive treat ment is generally advocated to prevent disability and improve prognosis. The advent of anti -TNF- A in particular has greatly improved outcomes associated with these diagnoses. A multidisciplinary approach is essential. Allied health professionals provide help with pa tient and family education, exercise, activities of daily living (home and school), mainten ance of psychological well-being in patient and family, and advice on \201 nancial and di sability support. \200 Monitoring of height and weight is needed, and appropriate nutriti onal advice given if needed. Ophthalmic input is required if uveitis is present. 1 Hofer M, Southwood T. Classi \201 cation of childhood arthritis. Best Practice and Resea rch in Clinical Rheumatology 2002; 16: 379 \200\22396. 2 Davies K, Copeman A. The spectrum of pediatric and adolescent Rheumatology. Best Practice and Research in Clinical Rheumatolo gy 2006; 20: 179 \200\223200. INTRODUCTION 311 The dose of corticosteroid should be kept to the lowest possible to reduce the development of growth retardation. That said, higher doses of steroid are oft en required than in adults to gain initial control of disease. Bone density scanning (DEXA) should be considered and calcium and vitamin D should be given. Bisphosphonates should onl y be given under the guidance of a specialist. A close connection with the child \200\231s school is needed. Fatigue is a common symptom a nd may require changes to the child \200\231s school timetable. It is important to continue education as much as possible during hospital admissions. Excellent communication skills are required to explain often complex treatments to patient and family. Coming to terms with a chronic disease is a dif \201 cult process and again wi ll need a close working relationship between members of the multidisciplinary team. The onset of adolescence brings new challenges. It is important to encourage the patient to be more active in decisions about disease management. Adolescence is a time of huge emotio nal and physical changes, and a chronic illness can make these changes more dif \201 cult. Discussion of personal issues such as sexuality, smoking, and alcohol require a good rappo rt with the patient. Parents should be encouraged to help develop the patient \200\231s ind ependence in making treatment decisions, though this can be a long process. Adolescence is also the time to introduce the subject of transition from care by pediatric to adult health professionals. This is a gradual process and should be managed sensitively. CHAPTER 9 Juvenile idiopathic arthritis (JIA) 312 Oligoarthritis (previously termed pauciarticular JRA) \200 This is the most commonly enco untered subset of the childhood chronic arthritides, accounting for 40 \200\22350% of all JIA. The condition is more common in boys than girls (4:1) and peaks between the ages of 1 \200\2233 years, though it can appear in the teenage years. Overall, the disease affects an estimated 30 per 100 000 children. ILAR classi \201 cation criteria require the presence of arthritis affecting 1 \200\2234 joints during the \201 rst 6 months of disease. The persistent subtype affect s no further joints in the disease course. The extended subtype affects a total of >4 joint s after the \201 rst 6 months of disease. Certain other distinct characteristics include: a single swollen joint in the lower extremity (knee or ankle) in a child who otherwise seems to be in good health \200 chronic anterior uveitis (more common in girls) \200 presence of antinuclear antibodies \200 unique immunogenetics. The ILAR classi \201 cation has the following exclusion criteria: family history of psoriasis in at least one \201 rst- or second-degree relative family history consistent with medically con \201 rmed HLA B27 associated disease in at least one \201 rst- or second-degree relative. \200 a positive rheumatoid factor test on 2 occasions at least 3 months apart HLA B27 positive male with onset of arthritis >6 years of age. \200 Presence of systemic arthritis (see next section). The etiology of the condition is unknown. Several lines of evidence indicate that genetic factors (HLA associations) are involved in disease susceptibility. Clinical features \200 JIA is always a clinical diagnosis of exclusion. There are no spec i \201 c signs, symptoms, or laboratory tests. Nevertheless, the clinical picture is often quite recognizable (as above), and usually milder than conditions such as reactive or infe ctive arthritis. Constitutional symptoms of fever, malaise, weight loss, and anorexia are not part of oligoa rthritis. If present, this virtually excludes the diagnosis. Joints \200 Joint swelling, rather than pain, is the more common complaint. Stiffness may occur but rarely seems to limit function. Two-thirds of cases present with si ngle joint disease, and a further 30% with 2 joints involved. There may be associated juxta -articular muscle atrophy. The child may simply present with a limping gait. The joints most commonly involved are the knee, ankle, and elbow. Disease in 1 or 2 small j oints of the hand is uncommon but can be seen and does not predict progression to polyartic ular disease. Shoulder and hip involvement are very rare; disease here should OLIGOARTHRITIS 313 prompt a search for another condition. Occasionally patients may develop disease of the tem poromandibular joint and cervical spine. A period of 2 \200\2235 years of active arthritis is a typical course for the condition. A patient who remains pauciarticular for 5 years is unlikely to progress to poly articular disease. A minority of cases will progress but the criteria for judging this like lihood remains unclear; that said, some 40% of patients with concomitant uveitis develop po lyarticular disease and, therefore, risk factors for uveitis might be considered partly as criteria for risk of polyarticular disease. Leg length discrepancy can occur due to unequal limb growth, which commonly occurs in children with persistent knee in \202 ammation. When disease begins bef ore 3 years of age there is a risk of the affected limb being longer. Flexing the knee on t he affected side compensates for the discrepancy and this in turn will exacerbate any \202 exion contractures. \200 Disease onset after the age of 9 years may result in a shor ter affected limb; this is a consequence of early epiphyseal closure. Synovial cysts occur and respond to intra-articular steroid injections (which may have to b e given under general anesthetic).They can rupture, presenting as acute intense limb pain a nd swelling. Over 80% of children suffer little or no musculoskeletal disability after 15 years follow-up. Eyes \200 Uveitis (iridocyclitis) is the most serious complication of oligoarticular JIA. Up to 30% of cases develop a chronic, insidious, and potentially sight-threatening uveitis (most often anterior chamber). \200 Slit-lamp examination is crucial in children diagnos ed with oligoarticular JIA. The disease course does not necessarily follow the arthritis, and can be relapsing and remitting. The risk of uveitis is associated with the mode of onset of arthritis and not the later extent of articular disease. Risk factors include: female gender (female to male ratio up to 7.5:1) \200 young onset disease (mean age 4 yea rs) \200 oligoarthritis \200 positive antinuclear antibody. The uveitis is commonly asymptomatic; only 25% of patients complain of redness in the eye, pain, or visual disturbance. Up to two-thirds of patients have bilateral disease though not necessarily at the same time. As such, regular ophthalmic examination is required, even in the absence of symptoms (see Table 9.1). Uveitis and arthritis develop at different times. Uveitis may predate arthritis in up to 10% of cases. Otherwise, it is usually detected within 7 years (mean 2 y ears) of the onset of arthritis. The main determinants of poor outcome of uveitis are the extent of initial disease at prese ntation, and uveitis documented before the onset of arthritis. Early intervention is probab ly the single most important factor in determining outcome. Chronic asymptomatic uveitis persisting into adulthood is recognized. CHAPTER 9 Juvenile idiopathic arthritis (JIA) 314 Treatment is with topical corticosteroids. Oral corticosteroids may be used for severe dise ase but concerns remain regarding growth retardation. Methotrexate is most frequently used, but azathioprine, cyclosporine, and anti-TNF- A therapies may also be effective. Diagnostic evaluation of oligoarthritis \200 There are no diagnostic procedures. \200 T he acute-phase reactants are usually mildly raised. \200 A persistent high ESR, with no o ther evidence of in \202 ammation on other laboratory tests, might suggest the rare, conge nital disorder hyper \201 brinogenemia. A high ESR should prompt a search for infection, o ccult in \202 ammation, or malignancy, e.g., leukemia. ANA are present in 40 \200\22375% of children. There is no evidence that ANA precede the de velopment of the condition, or that titers correlate with disease activity. Rheumatoid factor is rare; positive in <5% of cases. \200 Plain radiographs are valuable for assessing joint damage; however, the expertise of a pediatric radiologist familiar with normal variants of skeletal developm ent should be sought. Clinical assessment and investigation should seek to exclude the common conditions of childhood rheumatic disease (see Table 9.2). Treatment of oligoarthritis \200 Approximately half of patients with oligoarticular JIA w ill have persistent disease or functional joint problems 10 years after diagnosis. The main principles are the maintenance of normal joint function during active disease, and the early treatment of ocular in \202 ammation. A team approach is required. Initially NSAIDs are given (ibuprofen or naproxyn most often). \200 Intra-articular stero id injections may be useful in several situations: the very young (unable to take oral medication) \200 marked persistent joint swelling \200 synovial cysts causing limitation of movement. Cases with prolonged disease or extension to polyarticular disease require more aggressive treatment. MTX is the drug of choice. Table 9.1 Uveitis surveillance: recommended frequency of slit-lamp examination Condition Frequency Systemic onset Yearly Oligoarthritis and rheumatoid factor negative Onset before age 7: ANA positive: every 2 \200\2233-months for 4 years, then every 6-months for 3 years, then y early ANA negative: every 6-months for 7 years, then yearly Onset after age 7: Every 6-months for 4 years, then yearly OLIGOARTHRITIS 315 Table 9.2 The differential diagnosis of oligoarthritis Condition Examples Monoarticular disease Septic arthritis TB Trauma/hemarthrosis Patellofemoral pain Pigmented villonodular synovitis (requires tissue biopsy) Foreign-body synovitis Thalassaemia/sickle cell/hemophilia Short-lived in \202 ammatory arthropathy Lyme disease Viral arthritis Reactive arthritis Post-streptococcal arthritis The spondy larthropathies Pain conditions Hypermobility/regional pain syndromes Complex regional pain syndromes Avulsion fractures Aseptic (avascular) necrosis Enthesitis Osteoid osteoma/bone pain Anti-TNF therapy is increasingly used, especially in cases unresponsive to MTX. These agent s should only be used under specialist pediatric supervision. Abatacept, a CTLA-4 inhibitor, is approved for patients who fail anti-TNF- A therapy. Motor development and activity is very important. There should always be assessment of growth, development, and social interaction. Physical therapy makes an important contribution to the overall management of the condition. \200 Joint surgery is rarely necessary. \200 Uveitis can be more of a therapeutic challenge than the joint disease. Corticosteroid eye drops and mydriatics to prevent synechiae ( \201 brous bands t hat adhere the iris to the lens) are the typical initial regimen in mild disease. More seve re disease requires oral prednisone. MTX and anti-TNF- A therapies may also help eye diseas e. Surgery may be necessary for cataracts, keratopathy, or glaucoma. CHAPTER 9 Juvenile idiopathic arthritis (JIA) 316 Systemic arthritis (previously systemic onset JRA) \200 Systemic onset disease accounts f or approximately 5 \200\22310% of juvenile arthritis. There is an equal sex incidence in systemic onset disease. \200 The peak age of onset is 5 years. \200 The nonarticular features of the condition make a viral etiology an attractive hypothesis, but there is little evidence for this. HLA studies demonstrate genetic heterogeneity with no clear associations. Clinical features \200 While arthritis is required to con \201 rm the diagnosis, true jo int in \202 ammation may not be present at the onset of disease; some patients have developed in \202 ammation as late as 9 years after the onset. The ILAR classi \201 cation criteria require the presence of arthritis with, or preceded by, a daily fever of at least 2 weeks duration in association with one or more of the following: an erythematous evanescent rash, generalized lymphadenopathy, hepatomegal y and/or splenomegaly, and serositis (see Table 9.3). Most patients have arthritis at disease onset, and 50 \200\22360% will develop chronic pers istent symptoms. In >75% of cases, the wrists, knees, and ankles are involved. Hip involvem ent occurs in about 50% of cases and is almost always bilateral, and associated with polyar ticular disease. Hip and wrist joints are the most common sites of progressive destructive arthropathy, and one-third of patients with hip involvement will require hip arthroplasty. Tenosynovitis of the carpus and tarsus is common, and of the small joints, the hands are of ten affected more than the feet. Fever is the one extra-articular feature essential to making the diagnosis. The fever pattern is described as quotidian, often rising to 39 C before fallin g rapidly to normal, and typically in the late afternoon or early evening following a regul ar daily pattern. The patient often appears toxic during the fever, with chills and rigors, severe arthralgias and myalgias, and very often a rash. The fever should be present for at least 2 weeks and quotidian in character for at least 3 days to satisfy the diagnosis. Fev er may persist for months even with treatment. The rash of systemic arthritis is a salmon-pink color, most prominent over the chest, abdom en, back, and intertrigenous areas. The rash is usually macular, though occasional urticari al, with individual lesions 3 \200\2235 mm in diameter that may coalesce into larger ones. It has a tendency to come and go with the fever spike. Hepatomegaly, splenomegaly, and lymphadenopathy are common \201 ndings and usually asymptomatic. Mild elevation in serum transaminases occurs freque ntly and is usually not signi \201 cant clinically. This makes assessment of potentially h epatotoxic medications dif \201 cult. Chronic liver disease does not occur. It is, however , a feature of adult onset Still \200\231s disease. Very rarely, an acute fulminant liver f ailure occurs SYSTEMIC ARTHRITIS 317 Table 9.3 Clinical features of systemic arthritis Frequency Feature Very common Spiking fever (with chills and sweats) Evanescent rash Myalgias Arthralgias \200\224oligo/polyarthritis \200\224usually after \201 rst 6 months from onse t Growth abnormalities Common Generalized lymphadenopathy Hepatosplenomegaly Polyserositis Anorexia Weight loss Rare Myocarditis Coagulopathy Eye disease CNS involvement Hematophagocytic syndrome Primary pulmonary disease Renal disease Amyloidosis with encephalopathy, disseminated intravascular coagulation, and bleeding. This syndrome is associated with considerable morbidity and mortality, treatment being supp ortive with corticosteroids and cyclosporine. Involvement of the serosal surfaces is one hallmark of systemic arthritis. Pericarditis, pleuritis, and sterile peritonitis are recognized manifestations o f the disease; pericarditis is by far the more common of these. Most children will have ech ocardiographic evidence of pericarditis during systemic \202 ares, but <15% will be sympt omatic. Rarely, the patient may have myocarditis, suggested clinically by persistent tachyc ardia, cardiomegaly, and congestive heart failure. There should always be a high index of s uspicion in these cases as the mortality rate is high. Valvular disease is almost never see n. This may help to separate systemic arthritis from acute rheumatic fever with myocarditis . Abnormalities of growth are often as a consequence of hypercatabolism, poor nutrient intake, and concomitant use of corticosteroids. Suppression of disease activity and adequate nutrition are the most effective therapy. Growth hormone s upplementation CHAPTER 9 Juvenile idiopathic arthritis (JIA) 318 is reserved for patients whose growth is persistently below the third percentile on height charts and before epiphyseal fusion has occurred. Among the rarer features, CNS manifestations are dominated by irritability and lethargy during fever spikes; renal involvement may occur as a complica tion of treatment or indicate the onset of amyloidosis; and ocular involvement is distinctl y unusual relative to other forms of JIA, though asymptomatic uveitis does occur. \200 Am yloidosis is a serious complication of all subtypes of JIA and is associated with signi \201 cant morbidity and mortality. The most common cause of death wi th amyloidosis is renal failure (80% of cases in most series), followed by infection (10% o f cases). Secondary amyloidosis is rare if in \202 ammation can be controlled. Macrophage activation syndrome may be seen in association with systemic onset JIA. This is characterized by fever, hepatosplenomegaly, bruising, and encep halopathy. Acute phase reactants (particularly the ferritin) are highly elevated. Differential diagnosis \200 The differential diagnosis of systemic arthritis should alway s be kept in mind and looked for as many infectious and post-infectious disorders, other in \202 ammatory diseases, and malignancy have similar clinical manifestations. In particula r, Kawasaki \200\231s disease and other forms of vasculitis should be excluded, as well as the fever syndromes. \200 Features that may raise suspicion of another diagnosis include: leukopenia, thrombocytopenia \200 child looks ill even during afebrile episodes \200 bo ny tenderness \200 \200\234hard \200\235 hepatosplenomegaly/lymphadenopathy \200 recen t antibiotic use \200 monoarthritis \200 persistent diarrhea \200 marked weight loss. Diagnostic evaluation of systemic arthritis \200 There are no speci \201 c diagnostic te sts. \200 Characteristic hematological abnormalities include anemia, thrombocytosis, and leukocytosis; the latter two abnormalities are hallmarks of the conditi on, so much so that normal counts raise suspicion about the diagnosis. Acute phase markers are usually increased; the ESR, CRP, gammaglobulins, and serum complement (this may help to differentiate the disease from SLE). The ESR may be normal or elevated in the hematophagocytic syndrome complicating systemic a rthritis. \200 Hypoalbuminemia may be multifactorial in etiology (poor diet, reduced synthesis, intestinal leak), but should prompt the search for proteinuria, which, i f \200\234heavy, \200\235 could suggest amyloidosis and the need for renal or rectal biops y, or scintigraphy using iodinated serum amyloid-P to detect deposits. Most children are seronegative for ANA and RF. No antinuclear antibody speci \201 cities have been consistently identi \201 ed. SYSTEMIC ARTHRITIS 319 The following tests are suggested for all patients in the initial diagnostic investigation of systemic arthritis: \200 Complete blood count and differential \200 Renal and liver function tests \200 Coagulation screen \200 Serum immunoglobulins \200 Serum albumin \200 Antinuclear antibody titer \200 Blood cultures \200 Chest radiograph \200 Plai n radiographs of selected affected joints \200 Abdominal and pelvic ultrasound \200 Ele ctrocardiograph \200 Ocular slit lamp examination. The following tests should also be con sidered: \200 Muscle enzymes \200 Rheumatoid factor \200 Viral serology \200\224parvo virus, adenovirus etc. \200 Antistreptolysin antibody titers \200 Serum IgD \200 Urin e homovanillic and vanillylmandelic acid \200 Joint aspiration (for monoarthritis) \200 Tissue biopsy (including bone marrow aspirate) \200 Echocardiogram \200 Upper gastroin testinal barium series \200 Isotope bone and/or gallium scan. Table 9.4 Radiological abnormalities seen in systemic jia Feature Percentage Soft tissue swelling 80% Joint space narrowing 50% Growth abnormalities 50% Erosions 40% Subluxation 20% Ankylosis 20% Joint destruction 15% Protrusio acetabulae 10% Periosteal new bone 10% CHAPTER 9 Juvenile idiopathic arthritis (JIA) 320 The treatment of systemic arthritis \200 The general approach to the management of the ar thritis assumes the same principles as oligoarthritis. 1 However, there is increased drug- related toxicity in systemic JIA. This is seen with salicylates, NSAIDs, and DMARDs. Initial control of fever, joint pain, and serositis should be with NSAIDs; ibuprofen (60 mg /kg/day in 6 divided doses) indomethacin (1 \200\2232 mg/kg/ day in 2 divided doses) are co mmonly used. The dose should be decreased in the presence of severe hypoalbuminemia as the drugs are protein-bound. NSAIDs should be tried for at least 1 week before being deemed to have failed. Indomethacin is particularly useful for pericarditis; otherwise, this may resp ond to pulsed methylprednisolone, as does myocarditis. When NSAIDs fail to control symptoms, regular or pulsed corticosteroid treatment is indicated. Steroids will control symptoms but they do not limit the duration or alter the prognosis of the disease and should be used judiciously. The dai ly dose should be at 1 \200\2232 mg/kg/ day in divided doses. If symptoms persist past 4 \200\2238 weeks, MTX should be added, although MTX is not as effective in this situation as in oligoarticular JIA. Patients who have evide nce of severe systemic disease (including anemia, high fevers, severe serositis, malnutriti on, or macrophage activating syndrome) should be treated simultaneously with glucocorticoid s. \200 If the patient does not respond, consideration should be given to the use of IL-1 or TNF- A blockade. Anakinra may be particularly effective for the treatment of systemic arthritis, even among patients who have previously failed other therapies. Anti-TNF- A therapies may be effective in systemic JIA with persistent polyarthritis, but studies imply that in \202 iximab may be more effective than etanercept. Tocilizumab, an IL-6 receptor inhibitor, has also been approved for treatment of systemic onset JIA patients older than 2 years. Signi \201 cant cardiac compromise from effusion may require pericardiocentesis. Most patients with systemic onset JIA will experience one of three disease courses: monocyclic (11%), polycyclic (34%), or unremitting (55%). 1 Weiss JE, Ilowite NT. Juvenile idiopathic arthritis. Pediatr Clin N Am. 2005; 52: 413 \200\223442. SYSTEMIC ARTHRITIS 321 CHAPTER 9 Juvenile idiopathic arthritis (JIA) 322 Rheumatoid factor negative polyarticular JIA (previously polyarticular onset JRA) General p oints \200 There are two subtypes; rheumatoid factor (RF) negative (80%) and factor positive (20%). The arthritis usually affects 5 or more joints within the \201 rst 6 months of disease. T here must be no psoriasis in the patient or in any \201 rst- degree relative. Polyarticular onset occurs in about 25% of all patients with JIA. Clinical manifestations \200 There are three clinical subsets that have been recognized ( Table 9.5): \200 Early onset oligoarthritis, which is asymmetric, and associated with ANA -positivity and a high risk of uveitis. This form has an average age of onset <6 years old, and tends to affect girls more than boys. Symmetric synovitis with a predilection for the MCPs and tenosynovitis of the wrists and ankles. The average age of onset is 7 \200\2239 years old. Dry synovitis, which is associated with stiffness, and leads to \202 exion contractures a nd joint destruction. Carpal fusion and tendonopathies are common in the hands, leading to classical features such as boutonniere and swan-neck deformities. Flexion contracture is th e \201 rst manifestation of elbow involvement, and the shoulders are commonly affected. T his form often responds poorly to treatment. Cervical spine involvement is common with features akin to RA; apophyseal joint fusion, ins tability, and risk of cord compression. There is often fusion of the apophyseal joints of C 3 \200\223C5 leaving rigid segments that sublux above and below. Atlantoaxial subluxation, seen in RF-positive arthritis and juvenile ankylosing spondylitis, is rare in RF-negative p olyarthropathy. Temporomandibular joint involvement is common, leading to reduced growth and micrognathia. Dental malocclusion may require surgery when growth is completed. Growth disturbance is als o common, and occurs in proportion to the degree and duration of in \202 ammation. Laboratory tests The laboratory features are nonspeci \201 c in RF-negative polyarthritis. The ESR, CRP, leukocyte count, and platelet count can be elevated or normal. A low red cel l count is unusual and should prompt a search for an alterna- tive diagnosis. In patients w ith a prior diagnosis of RF-negative polyarticu- lar JIA, radiographs of the joints should be obtained yearly. Treatment \200 The management of this condition involves a common approach as discussed i n the \201 rst two sections of this chapter, with adaptations according to the different subtypes shown. RHEUMATOID FACTOR NEGATIVE POLYARTICULAR JIA 323 Table 9.5 Proposed subclassi \201 cation of RF-negative polyarthritis Subclassi \201 cation Percentage of cases Characteristics 1. Early onset oligoarthritis About 40% Female preponderance Most cases in very young (<3 years of age) Possible increased risk of eye disease Severe polyarthritis 2. Symmetric synovitis 15% Mild pain Thick pannus Equal in sexes Functional impairmen late Tenosynovitis common 3. Dry synovitis Little joint swelling 15% Progressive stiffness Chronic muscle wasting Often referred late in to onset Treatment should start with a trial of an NSAID for 4 \200\2238 weeks, moving to a second NSAID for the same period of time if the \201 rst fails. Ibuprofen, na proxyn, and diclofenac are commonly used. In nonresponders to NSAIDs, intra-articular steroid injections may be necessary. Topical st eroids should also be used from the onset with eye disease. DMARDs should also be introduced immediately, since NSAIDs alone are unlikely to induce remission. Methotrexate is the \201 rst-line drug of choice . Sulfasalazine may be used if there are features of spondyloarthropathy. Treatments should be continued for at le ast 6 months following remission. The TNF- A inhibitors are used for patients intolerant of or unresponsive to, methotrexate. In all cases, surgery and rehabilitation play an important role in management, and physical therapy and occupational therapy advice should be employed early. CHAPTER 9 Juvenile idiopathic arthritis (JIA) 324