CHAPTER 15 Anne‐Marie McMahon and Evdoxia Sapountzi Sheffield Children’s Hospital, Sheffield, UK The worldwide incidence and prevalence of JIA are unknown. Epidemiological studies have reported a wide variance in different regions of the world, with low rates in Asian populations and relatively higher frequencies in those of European descent. Considering all types of arthritis, the prevalence of JIA ranges from 16 to 150 per 100 000 children. In the UK, the prevalence is approximately 1 in 1000 children. These wide‐ranging numbers are attributable to population differences, particularly environmental exposure and immunogenetic susceptibility. The nomenclature used to define childhood arthritis has changed several times over the last 40 years (Box 15.1). The latest definition, as put forth by the International League of Associations for Rheumatology (ILAR) in 1977 and later revised in 2001, divides JIA into seven subgroups (Table 15.1). The intent of this current classification system was to create consistency amongst international providers in order to identify children with similar characteristics for the purpose of research towards epidemiology, pathogenesis and treatment strategies. However, debate is still ongoing as to whether this scheme should be further redeveloped, with emphasis more on antibody presence, age of symptom onset and symmetry of arthritis. Table 15.1 Classification of chronic arthritis of childhood By definition, JIA is idiopathic with no identifiable cause. It is almost certainly multifactorial and probably differs from one onset type to another. As technology improves, as with the advent of genome‐wide association studies, the underlying genetic susceptibility factors of JIA are beginning to be defined. Familial JIA itself is uncommon and does not follow any mendelian modes of inheritance. One American registry identified 200 sets of siblings with JIA over a 10‐year period, of whom 21 sets were twins. The major histocompatibility complex (MHC) is a diverse and complex genetic loci central to immunity and inflammatory processes. The MHC comprises genes related to antigen presentation, including human leucocyte antigens (HLA) A, B, C, DR, DP and DQ, minor HLA antigens, as well as other genes important in immune function such as tumour necrosis factor (TNF), macrophage inhibitor factor (MIF), interleukin (IL)‐6 and IL‐1a. The HLA class I and II alleles have been identified as a major susceptibility locus for JIA. Possible non‐genetic triggers include bacterial and viral infections (parvovirus B19, rubella, Epstein–Barr, influenza A, Mycoplasma pneumoniae), enhanced immune responses to bacterial or mycobacterial heat shock proteins, abnormal reproductive hormone levels and joint trauma. Some studies have demonstrated persistence of infectious markers within synovial fluid. However, many reports rely on the identification of serological antibodies to viruses, and interpretation of seropositivity can be controversial. Juvenile idiopathic arthritis is an autoimmune disease associated with alterations in both humoral and cell‐mediated immunity. T‐lymphocytes have a central role, releasing proinflammatory cytokines. Complement consumption, immune complex formation and B‐cell activation also promote inflammation. Inheritance of specific cytokine alleles may predispose to upregulation of inflammatory networks, resulting in systemic‐onset disease or more severe articular disease. Systemic‐onset JIA (SoJIA) may be more accurately classified as an autoinflammatory disorder, more like familial Mediterranean fever (FMF) than other subtypes of JIA. This theory is supported by work demonstrating similar expression patterns of phagocytic protein (S100A12) in SoJIA and FMF, as well as the same marked responsiveness to IL‐1 receptor antagonists. All these immunological abnormalities cause inflammatory synovitis, characterized pathologically by villous hypertrophy and hyperplasia with hyperaemia and oedema of the synovial tissue. Vascular endothelial hyperplasia is prominent and is characterized by infiltration of mononuclear and plasma cells with predominance of T‐lymphocytes. Advanced and uncontrolled disease leads to pannus formation (proliferative synovium that grows over the joint surface) and progressive erosion of articular cartilage and contiguous bone. According to the ILAR classification, there are two categories of oligoarthritis. ‘Persistent’ oligoarthritis is defined as a disease which starts in four or fewer joints and never involves more than four joints. The second category, ‘extended’ oligoarthritis, is a form in which the arthritis is oligoarticular for at least the first 6 months, but then extends to involve more than four joints (Table 15.2). Table 15.2 ILAR classification criteria for oligoarthritis Oligoarthritis is the most common form of JIA, characterized by an age of onset less than 6 years, female predominance and a relatively high incidence of complicating uveitis. Progression to extended oligoarthritis has been reported to occur in 20–50% in different series. Extension beyond four joints usually occurs within 2 years of onset but the incidence increases until a plateau is reached by about 5 years after onset. With the onset of oligoarthritis, the child may not always complain of pain and may not be brought to a physician until advanced changes are present. The parents are most likely to have noticed a limp or seen a swollen joint. A very young child may stop walking or standing, or be fussy and unhappy when doing so, especially first thing in the morning (morning stiffness) with improvement later in the day. On examination, there will be a joint effusion, swelling and local warmth, with or without, mild or moderate tenderness. There will be pain on the extremes of motion, limitation of range of motion, and pain on weight bearing or resisted movement. An antalgic gait is likely. The most common joints involved at presentation are the knees. The small joints of the hands and feet are involved in 10% or less. Wrist and elbow involvement may predict extension to polyarticular disease in the long term. Hips are rarely involved. Arthritis isolated to one or both hips should prompt consideration of enthesitis‐related arthritis in the differential. Acute onset, particularly in association with marked tenderness, redness, fever or severe pain and refusal to weight bear requires care to exclude infection or neoplasm, most often leukaemia. A history of tick bite or rash, or intermittent episodes of arthritis, especially in the knee, in patients who have been in endemic areas suggests possible Lyme disease. Growth abnormalities may be generalized or limited to one limb. Arthritis in large joints, especially knees, initially accelerates linear growth, causing the affected limb to be longer and resulting in limb length discrepancy. Continued inflammation stimulates rapid and premature closure of the growth plate, resulting in shortened bones. Generalized growth retardation is becoming much less frequent with the availability of effective treatment. Muscles around inflamed joints may quite quickly become atrophic. Juvenile idiopathic arthritis is a clinical diagnosis of exclusion with many mimics and without diagnostic laboratory tests. The meticulous clinical exclusion of other diseases is therefore essential. Laboratory tests in oligoarthritis are usually normal. Complete blood counts should be normal, but may show moderate increases in white blood cell (WBC) counts or mild anaemia. The ESR may be normal and is not usually greater than 30 mm/h, and higher values may predict progression to polyarthritis. Urinalysis and blood chemistries are normal. Positive rheumatoid factor (RF) is an exclusion for the classification of oligoarthritis. Antinuclear antibodies (ANA) are present in up to 70–80% of young girls with oligoarthritis and are a risk factor for uveitis. Radiographs are usually normal and cannot make a diagnosis of oligoarthritis, but are necessary to rule out other diagnoses (Table 15.3). Magnetic resonance imaging (MRI) may show synovial hypertrophy and is not routinely necessary, but is helpful if there is suspicion of an underlying cause. Table 15.3 Differential diagnosis of monoarthritis Most children presenting with monoarthritis do not need a joint fluid aspiration, but this is necessary if there is concern regarding joint sepsis. The age of onset and sex ratios of the children who develop extended oligoarthritis are the same as those with persistent oligoarthritis. Extension to more than four joints occurs in the first 5 years of disease onset. The frequency of oligoarthritis becoming extended is unknown. Clinical characteristics predictive of disease extension include ankle or wrist disease, symmetrical joint involvement and elevated ESR (Box 15.2). ANA positivity correlates with worse outcome in this group. The incidence of remission is lower and the potential degree of disability is greater than patients with persistent oligoarthritis. The principal differences between children with extended and persistent oligoarthritis are genetic. None of children with extended oligoarthritis have the HLA antigen DR6, although this antigen has a positive genetic association with oligoarthritis generally. Conversely, there is an association with DR1, which is predictive of progression to more joints, and to joint erosion. The disease course and prognosis in children with oligoarthritis have improved considerably in the past 15 years. The frequency of significant joint contractures or leg length inequalities has diminished, probably as the result of prompt institution of pharmacological and physical therapy, in particular the use of intra‐articular steroids. Children with persistent oligoarthritis have a good chance for remission. Those in whom more extensive disease develops have a poorer prognosis. Children with oligo‐arthritis, particularly girls who are ANA positive, with onset earlier than 6 years of age, are at risk for development of chronic uveitis. There is no association between the activity or severity of the arthritis and the chronic uveitis. The most serious complication for all children with oligoarthritis is the potential blindness caused by uveitis. JIA‐associated uveitis has a poor prognosis and a high rate of complications. Early diagnosis and rapid adequate interdisciplinary care are important for the long‐term prognosis. The rates of uveitis in JIA (4–24%) vary because of the characteristics of different medical centres and geographical variations. The risk of uveitis is higher in north Europeans than in Asian populations. Meta‐analysis estimates that the worldwide incidence is 8.3%. The intraocular inflammation is mostly diagnosed between the fourth and sixth years of life. In half of patients, the uveitis manifests shortly before or more than 5 years after the onset of JIA, in some 75% within a year, in 90% within 4 years and later in only 3–5%. In 75% of children the inflammation affects both eyes. Children with unilateral uveitis very rarely develop uveitis in the contralateral eye once more than 12 months have passed. However, there are exceptions, and unilateral uveitis may persist for many years in a few children before the other eye is involved. According to the classification of the International Standardization of Uveitis Nomenclature (SUN), which seeks to classify intraocular disorders, JIA‐associated uveitis is typically a recurrent, non‐granulomatous, anterior uveitis. Uveitis that occurs in association with JIA presents as chronic anterior uveitis, typically with an asymptomatic ‘white eye’. Uveitis is detected in less than 10% of patients before the onset of arthritis, usually during a routine ophthalmic examination. The early detection of chronic uveitis requires slit‐lamp biomicroscopy, which should be performed at the time of diagnosis in every child with JIA. The recommended frequency of ophthalmological examination is influenced by the level of risk of uveitis. The diagnostic signs of anterior uveitis on slit‐lamp examination are the presence of inflammatory cells and increased protein concentration ‘flare’ in the aqueous humour of the anterior chamber of the eye. Deposition of inflammatory cells on the inner surface of the cornea (keratic precipitate) may be detected at presentation or develop later. Complications of chronic anterior uveitis are frequent and increase with increasing duration of active disease. A recent series reported the frequency of complications as lower than in earlier studies, presumably due to earlier treatment (Box 15.3). Sudden‐onset (acute) uveitis differs in several ways from chronic anterior uveitis and is strongly associated with HLA‐B27 and enthesitis‐related arthritis (ERA). Boys are more commonly affected, it is more often unilateral, and is characterized by a painful, red, photophobic eye. The symptoms are often mistakenly attributed to a foreign body, infection or allergy. Because of the symptomatic nature of this uveitis, the process is usually identified and treated soon after onset. Therefore, long‐term sequelae are less common. The treatment of uveitis should be supervised by an ophthalmologist experienced in the management of children with this disease. The goal of therapy is to achieve normal vision by controlling inflammation in the eye (no cells) and surgical approaches to its complications, particularly cataract. The most exciting development in the medical treatment of JIA‐associated uveitis has been the application of biological drugs in cases resistant to conventional systemic immunosuppressive therapy or cases in which conventional agents cannot be used. In mild disease, treatment may be limited to corticosteroid eye drops. Non‐steroidal anti‐inflammatory drugs (NSAIDs) should not be used as monotherapy in active uveitis. Systemic immunosuppression is required, if using topical steroids does not result in uveitis inactivity within 3 months, if new complications arise, if the dosage of the corticosteroids has to be excessively high or if medication‐related adverse effects develop. In patients with severe inflammation, the treatment can be intensified at an earlier stage. Immunomodulating and disease‐modifying substances (DMARDs) not only make it possible to use lower doses of corticosteroids but also improve the long‐term outcome of uveitis. The most commonly used immunosuppressant is methotrexate. If after 4 months the effect is unsatisfactory, a second conventional or biological DMARD may be considered. Close liaison with paediatric rheumatology centres ensures access to the latest evidence and guidelines in the management of childhood uveitis. Systemic arthritis (SoJIA) represents the childhood‐onset equivalent of adult‐onset Still’s disease. Its onset can be quite non‐specific and may suggest infection, malignancy or another inflammatory disease. The disease is defined as systemic arthritis in the ILAR classification of juvenile idiopathic arthritis, based on the following criteria: presence of arthritis and of documented quotidian fever of at least 2 weeks’ duration, plus one of the following: typical rash, generalized lymphadenopathy, enlargement of liver or spleen or serositis. Criteria and exclusions are shown in Table 15.4. Table 15.4 Systemic juvenile idiopathic arthritis (ILAR) *Evanescent = transient, usually a few hours. Systemic JIA accounts for 10% of children with JIA. The onset of the disease may occur at any time during childhood, with a broad peak of onset between 1 and 5 years of age, but there is a wide variation with a relatively similar frequency of onset at all age groups. Males and females are affected with approximately equal frequency or very minimal female excess 1.1:1. The genetic factors associated with SoJIA are unclear. SoJIA is rarely familial, which is consistent with the hypothesis that the genetic background of the disease is complex. In contrast to classic autoimmune disease, genetic association with HLA class I or II alleles is weak. The most consistently reported associations include polymorphisms in the regulatory sequences of genes coding for cytokines of the innate immune response such as MIF, TNF‐alpha, IL‐6 genes, and the IL‐1 and IL‐1 receptor loci. Autoantibodies and autoreactive T‐cells are not present in SoJIA. However, the number of innate immune cells such as monocytes and neutrophils is increased. Studies of gene expression profiles in blood cells provide evidence of disregulated innate immune response with increased production of inflammatory cytokines. High spiking daily fever is the most important clinical criterion, as it always present at the onset of the disease. Occasionally, it can start later after the development of arthritis. According to the Edmonton criteria for JIA, fever must have been present for at least 2 weeks, and documented to have a quotidian pattern (a single spike of fever per day) for at least 3 days. Typically, fever occurs in the afternoon or early evening, reaching 39 °C or more. The peak is followed by a sharp decrease under 37 °C. Chills are frequent at the time of fever, but rigors are rare. These children are often quite ill while febrile but may be surprisingly well during the rest of the day. The fever usually lasts for several months, may recur with flares of disease, and occasionally persists for years. The rash is the second typical extra‐articular manifestation and is present in more than 90% of cases at onset. The classic rash is evanescent, erythematous macules 2–5 mm in size that may appear in linear streaks, or more discrete occurring in areas of exposure to air or touch (Koebner phenomenon). The rash is usually described as salmon pink. It occurs typically with fever spikes, but may persist when fever is resolved. Sometimes, it can resemble urticaria, and can be quite pruritic. Hepatomegaly is often present but it is mild and not tender. Chronic liver disease generally does not occur but there are reports of hepatic nodular regenerative hyperplasia, which can lead to portal hypertension. Spleen enlargement occurs in 30% of cases and is usually mild. Massive splenomegaly is uncommon and raises suspicion for another diagnosis, particularly malignancy. Lymphadenopathy is found in up to 50% of cases, usually painless, freely mobile in the cervical, axillary and inguinal area. Mesenteric lymphadenopathy may cause abdominal pain, sometimes leading to a debate about possible surgical emergency in an undiagnosed child. Pericarditis with or without pleural effusion is common and usually asymptomatic. However, chest pain with or without dyspnoea, especially in supine position, is a classic symptom of acute pericarditis. Tamponade is rare but some children will require drainage of pericardial fluid. Pericarditis is not a poor prognostic factor and is not related to gender or severity of joint disease, but appears to be more common in children with disease onset who are younger than 18 months of age. Myocarditis is not common, although it may occur in the absence of pericarditis, leading to cardiomegaly and congestive heart failure. Endocarditis is very rare. Pleural effusion is the most common respiratory manifestation, usually asymptomatic and an incidental finding on chest radiographs. Parenchymal pulmonary disease is rare. Acute neurological events are rare. Encephalopathy, seizures and intracranial haemorrhages are serious manifestations of central nervous system involvement in macrophage activation syndrome (MAS) (see below), and associated with significant mortality risk. Arthritis is absent at onset in about one‐third of the cases, rendering the diagnosis difficult. Even if it is not present at onset, it usually develops within the next few months, or one or more years. Arthritis is generally symmetrical, affecting more than four joints in about one‐quarter of the patients. The most commonly affected joints are knees, ankles and wrists but small joints, hips and cervical spine can be affected. The arthritis in SoJIA can involve any site that contains synovial membrane. Myalgia is common, especially during the febrile phase of disease, but there is no elevation in muscle enzymes. The diagnosis of SoJIA is made clinically, supported by typical laboratory findings, but it is a diagnosis of exclusion. The presence of characteristic rash and quotidian fever are very suggestive but the diagnosis may be difficult. Infections and septicaemia may mimic the disease initially, and the possibility of malignancy, other connective tissue diseases or vasculitis should be considered (Box 15.4).
Juvenile Idiopathic Arthritis
Epidemiology
Classification
Organization
European League Against Rheumatism (EULAR)
American College of Rheumatology (ACR)
International League of Associations for Rheumatology (ILAR)
Criterion name
Juvenile chronic arthritis
Juvenile rheumatoid arthritis
Juvenile idiopathic arthritis
Year
1977
1986
1997, revised 2001
Age of onset
<16 years
<16 years
<16 years
Duration
≥3 months
>6 weeks
>6 weeks
Subsets
Etiology
Pathogenesis
Oligoarthritis
Definition
Exclusions
Arthritis affecting 1–4 joints during the first 6 months of disease. Two subcategories are recognized:
Persistent oligoarthritis
Clinical features
Diagnosis
Acute monoarthritis
Chronic monoarthritis
Oligoarthritis
Enthesitis‐related arthritis
Psoriatic arthritis
Septic arthritis
Reactive arthritis
Leukaemia
Neuroblastoma
Oligoarthritis
Enthesitis‐related arthritis
Psoriatic arthritis
Hemangioma
Synovial chondromatosis
Lipoma arborescens
Mevalonate kinase deficiency
Chronic infantile neurocutaneous and articular syndrome
Neonatal‐onset multisystem inflammatory disease
Extended oligoarthritis
Genetics
Prognosis
Uveitis
Epidemiology
Insidious‐onset (chronic) uveitis
Sudden‐onset (acute) uveitis
Management of JIA‐associated uveitis
Systemic juvenile idiopathic arthritis
Criteria
Exclusions
Arthritis with or preceded by daily fever of at least 2 weeks duration, that is documented to be quotidian (24 hours apart) for at least 3 days, and accompanied by one or more of the following:
Pathogenesis
Extra‐articular clinical features
Fever
Rash
Organomegaly and lymphadenopathy
Serositis and other visceral manifestations
Central nervous system disease
Musculoskeletal manifestations
Diagnosis and differential diagnosis
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