This is a 4 year old female who has been limping with swelling of her right knee for several months. Her parents note that she cannot fully extend her right knee. She sometimes does not want to walk in the morning, but seems fine later in the morning and the rest of the day. Her past medical history is unremarkable. Physical examination demonstrates swelling (effusion) of her right knee, flexion contracture of 10 degrees and flexion to 120 degrees. No increased heat or pain upon range of motion is present. She appears unconcerned about her limp and swelling. Labs: WBC 8,600 with 45 polys, 47 lymphs, 8 monos. Hgb 12. ESR 20. UA normal. Rheumatoid factor negative, ANA 1:640 speckled.
Juvenile rheumatoid arthritis (JRA) is a chronic arthritis of childhood comprised of several different subgroups. It is one of the most common rheumatic diseases of childhood. Because the majority of children are rheumatoid factor negative, it is also known as juvenile idiopathic arthritis or juvenile chronic arthritis. Although the true incidence and prevalence of JRA are unknown, its incidence is estimated at 2 to 20 per 100,000 children per year based on the American College of Rheumatology (ACR) criteria (1,2).
Neither the etiology nor risk factors of JRA have been identified. It is considered to be an autoimmune disease. Chronic synovitis, T-cell abnormalities, abnormal immunoregulation and cytokine production, autoantibodies, immune complexes, and complement activation suggest that cell mediated and/or humoral processes are involved. Infection may have a possible role in developing JRA.
Complex and probably multi-factorial genetic factors are likely to play a role in the genetic predisposition to developing JRA as is evidenced by associations with HLA genetic polymorphisms which have been identified in some patients with JRA (3). There may also be associations with other autoimmune diseases such as insulin-dependent diabetes mellitus and autoimmune thyroiditis.
Currently there is no universal consensus on the classification of JRA. Several distinct subgroups have been suggested. The American College of Rheumatology criteria require that the age at onset of arthritis be less than 16 years, and that arthritis be present in one or more joints for at least 6 weeks. Other causes must be excluded. The onset type of JRA is determined by the first six months of disease and includes pauci- or oligo- articular JRA, polyarticular JRA, and systemic-onset JRA (4). The ACR criteria do not include seronegative spondyloarthropathies and related diseases (juvenile ankylosing spondylitis, juvenile psoriatic arthritis, and arthropathies associated with inflammatory bowel disease). More inclusive classification criteria such as the EULAR (European League Against Rheumatism) and ILAR (International League of Associations for Rheumatology) are also used. This chapter will describe the following subgroups:
A. Pauci-articular JRA
. . . . . 1) Early childhood onset
. . . . . 2) Late childhood onset
B. Polyarticular JRA
. . . . . 1) Rheumatoid Factor Seronegative
. . . . . 2) Rheumatoid Factor Seropositive
C. Systemic-onset JRA
D. Juvenile Psoriatic Arthritis
Arthritis is characterized by synovial tissue inflammation including hypertrophy of the synovium and increased secretion of synovial fluid. Affected joints may be warm, stiff or painful, swollen, limited in range of motion, and occasionally erythematous. Two or more of these signs is necessary for the diagnosis of arthritis (5). Synovial fluid analysis is not specific for JRA and may show an elevated total white count that is predominately polymorphonuclear neutrophils and mononuclear cells, and glucose levels may be decreased. The clinical course of the various subtypes of JRA is diverse. Depending upon the type of JRA, the degree of destruction of synovium and surrounding structures is variable. Rheumatoid factor positive disease tends to be more destructive, whereas the synovitis of seronegative JRA may not cause joint destruction, even after persistent activity.
JRA may involve other organ systems besides the joints depending upon the type of onset. Iridocyclitis/uveitis may be present in all subtypes of JRA, but especially in the pauci-articular disease of early childhood. All children with JRA should have regular ophthalmologic examinations including slit-lamp examinations. Rheumatoid factor positive JRA may demonstrate rheumatoid nodules and vasculitis. Systemic onset disease can develop multiple systemic manifestations. Growth retardation or limb length discrepancies can complicate the course of children with JRA.
Pauci-articular JRA describes the involvement of 4 or fewer joints and affects an estimated 40-60% of children with JRA. At least two distinct subgroups have been identified: Early childhood onset (frequently associated with positive anti-nuclear antibodies and iridocyclitis) and late childhood onset. Some classification criteria further divide early childhood onset into oligoarthritis and extended oligoarthritis.
Early childhood onset pauci-articular JRA affects predominantly girls under the age of 6 years. More common in Caucasian children, it accounts for about 30-40% of patients with JRA. About 50% have monoarticular arthritis. Large joints of the lower extremities are most often involved, including knees and ankles, occasionally elbows. This subtype is associated with positive ANAs (anti-nuclear antibodies) and chronic iridocyclitis. It has been estimated that up to 30% of these children have a risk of chronic iridocyclitis/uveitis in the first several years of disease. Eye involvement is usually insidious with few if any symptoms or signs. These patients require routine slit-lamp examinations to detect early inflammatory changes. Late sequelae of chronic iridocyclitis include posterior synechiae, band keratopathy, cataract formation, glaucoma, visual loss or blindness. Hips are infrequently affected. These children are not systemically ill and usually function well without a great deal of pain. There is a subset of these children who initially present as pauci-articular in the first 6 months of disease, but progress to poly-articular disease thereafter (extended oligoarthritis).
The late childhood onset subgroup of pauci-articular JRA is associated with HLA B27 and development of enthesitis and sacroiliitis. The terms Juvenile Spondyloarthropathy or Juvenile Ankylosing Spondylitis have also been used. It is usually oligoarticular at onset and affects approximately 10-15% of children with JRA. There is a male predominance with the age of onset usually after 8 years of age. The onset of arthritis can be insidious or acute. The clinical course may be episodic and variable resulting in little to significant joint destruction. It often affects the large joints of the lower extremities (hips, knees, ankles). Frequently these patients develop enthesitis (swelling along tendons and at sites of tendonous/ligamentous insertion into the bone). Achilles enthesitis is common. Tarsal involvement may occur. A subset of children who initially present with only enthesitis later develop arthritis. Some patients develop acute iridocyclitis (eye pain, red eyes and photophobia). Although usually absent at onset, some patients develop thoracic and lumbar spine involvement with loss of flexion meeting criteria for ankylosing spondylitis. HLA-B27 is present in about 80% of these children. A family history of spondyloarthropathy such as ankylosing spondylitis, Reiter's disease, inflammatory bowel disease with spondylitis, psoriatic arthritis, and acute iridocyclitis is often obtained.
Polyarticular JRA affects approximately 35% of children with JRA. It can be further sub-divided into Rheumatoid factor positive (seropositive) and Rheumatoid factor negative (seronegative) disease.
The seronegative JRA subtype typically presents at less than 5 years of age, although it may occur at any age during childhood. There is a female predominance. It occurs in 20-30% of patients with JRA and is characterized by a negative test for IgM rheumatoid factor. Symmetric involvement frequently occurs, most commonly in the large joints. The small joints of the hands and feet may also be involved. Cervical spine involvement with limitation of range of motion in the neck and temporomandibular joint involvement are common. Micrognathia may be noted with time. Boutonniere deformities and flexion contractures occur more frequently than swan-neck deformities. Leg length discrepancies, angular deformities and brachydactyly may occur. Morning stiffness and gelling or stiffness after inactivity are frequent. Patients are usually not systemically ill, but low-grade fever, mild anemia, mild lymphadenopathy and hepatosplenomegaly may occur. These children often respond well to therapy and can have little joint destruction despite a number of episodes over several years. Recurrent episodes may tend to cause progressive joint damage and deformity. Uveitis occurs in about 10% of these children and regular ophthalmology examinations are important.
The seropositive JRA usually occurs in children over the age of 8 years with a female predominance. It occurs in 5-10% of patents with JRA and is likely the equivalent of adult rheumatoid arthritis (RA). Like RA in adults, it is frequently an aggressive, destructive and erosive joint disease with joint destruction occurring within 1 year of onset. It can have a poor prognosis with high risk of permanent joint disability and compromised functioning. Early and aggressive therapy is necessary to prevent poor outcomes. It is characterized by extra-articular manifestations such as rheumatoid nodules (sub-cutaneous nodules often found over pressure points such as the elbows, heels, knuckles and extensor surfaces of the finger, and the first metatarsophalangeal joints). Rheumatoid vasculitis resulting in ulcerative lesions may be seen. Felty syndrome (splenomegaly with leukopenia) or Sjogren syndrome (parotitis, dry eyes and mouth) are occasionally noted, but more often in adult disease.
Systemic-onset JRA, also sometimes known as Still's disease, is characterized by high, intermittent fevers and other organ system involvement. It affects about 10% of children with JRA, occurring equally in males and females. It often begins before 5 years of age, but can occur throughout childhood into adult life. Fevers of 39.4 degrees (103 F) or higher occur once or twice a day with interim normal or even subnormal temperatures. Fevers tend to occur in the evening, sometimes also in the mornings. Fevers may last from weeks to months. Most patients develop a characteristic, transient rash often described as salmon pink, or red and maculopapular. The rash can occur anywhere on the body and often accompanies the fever. It may occasionally be pruritic. Some patients will also develop lymphadenopathy and hepatosplenomegaly. Pleuritis and pericarditis may occur in up to 50% of patients, for which symptoms may include chest pain and difficulty breathing, although many may be relatively asymptomatic. Rarely, myocarditis may occur. Abdominal pain may occur. Laboratory findings often include an elevated peripheral white blood cell count, sometimes with a left shift, anemia and elevated platelet counts. Mild transaminase elevations or hyperbilirubinemia may be noted. Occasionally severe anemia or disseminated intravascular coagulation and severe hepatic dysfunction may occur. Iridocyclitis is usually absent. Recurrent systemic episodes occur in up to 50% of these children. Children often complain of myalgias and arthralgias. Arthritis may not develop until sometime into the course of the systemic manifestations. These children are often first seen for evaluation of fever of unknown origin and go through the process of eliminating other causes of fever from the differential. Many of these children will develop persistent arthritis within the first few months of onset, although arthritis developing years after the initial febrile episode have been reported. Arthritis is variable and may be polyarticular affecting both small and large joints. Chronic polyarthritis may become the primary problem.
Juvenile psoriatic arthritis affects males and females equally. These children are usually Caucasian. Arthritis often presents asymmetric and oligoarticular with small and large joint involvement. The toes are often involved. Dactylitis is common. Isolated DIP involvement or spondylitis may occur. Other associations include chronic uveitis and nail pitting. Psoriasis or a family history of psoriasis are needed for the diagnosis. ANA may be positive and HLA-B27 is present in about a third of these children. RF is negative.
The diagnosis of JRA depends upon a comprehensive history and physical examination demonstrating the presence of chronic arthritis for at least 6 weeks and exclusion of other conditions. There is no "diagnostic test" for JRA. Laboratory studies may reflect changes consistent with inflammation, but are not diagnostic. Some children have normal labs despite active arthritis. A positive rheumatoid factor in the presence of chronic arthritis and a pattern of disease helps to make a diagnosis in the small percentage of children who have seropositive disease. ANAs are strongly associated with early childhood-onset pauciarticular JRA and chronic iridocyclitis. HLA B27 is strongly associated with spondyloarthropathies, but can also be found in a number of healthy individuals. It is useful if a child presents with history and clinical findings consistent with JRA or spondyloarthropathy, since this may help in classification. X-rays, other imaging tests, joint synovial fluid aspiration and synovial biopsy may be helpful, especially in excluding other conditions. X-rays help detect joint changes, including atlantoaxial subluxation in children with cervical spine involvement. Joint aspiration and biopsy are particularly helpful in monoarticular arthritis where the differential is much broader than for polyarticular arthritis.
The list of differential diagnoses causing arthritis or arthropathy is large. Some of these are as follows. Infection related arthritis must be considered in the differential of JRA, including septic arthritis, viral arthritis, toxic synovitis, Lyme disease, reactive arthritis, and osteomyelitis. In Hawaii, acute rheumatic fever (ARF) must be included in the differential particularly in patients of Polynesian descent, who seem to have a predisposition to developing ARF. Malignancy such as leukemia, neuroblastoma, lymphoma, Hodgkin disease, rhabdomyosarcoma and bone tumors may cause frank arthritis or musculoskeletal complaints that mimic arthritis. Trauma must also be considered. Other autoimmune diseases such as systemic lupus erythematosus and dermatomyositis can present with joint pain and/or arthritis, but are often associated with other systemic symptoms. Other vasculitides such as Henoch-Schonlein purpura and Kawasaki disease usually have other extra-articular manifestations in addition to arthropathy.
The differential diagnosis of joint pain may also include growing pains, fibromyalgia, psychogenic pain, avascular necrosis syndromes, osteochondroses (Osgood-Schlatter), enthesitis, patellofemoral or chondromalacia patella syndrome, discitis, and inherited or congenital syndromes. Hypermobility due to either benign hypermobility syndrome, Ehlers-Danlos syndrome or other connective tissue defects such as Marfan syndrome can also cause joint pain and sometimes swelling.
The goals of therapy are to control pain and inflammation; to prevent joint damage; to preserve range of motion and muscle strength; strive for normal function, growth, nutrition, physical and psychosocial development; and to control systemic manifestations. Treatment depends upon many considerations including a child's individual clinical manifestations, overall prognosis, the child and family's social situation, the child's functionality and extent of joint deformity. A multi-disciplinary team approach is essential in optimizing results. Physical therapy and occupational therapy are important for some patients. Orthopedic surgeons may also help in management. Patient and family understanding and participation in management are important. Education of the patient and family is vital and should include the disease, findings, prognosis, outcomes, medications, monitoring, and ancillary therapies. Patients and families need to be supported. Children should be encouraged toward normal play, except for those activities which may damage inflamed joints. Bicycle riding and swimming are usually good activities to avoid too much stress on involved joints.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are important initial agents in the treatment of JRA. In the United States these include naproxen and ibuprofen. Tolmetin is approved for use in children, but is used less frequently. A number of other have been used, but may not be approved for use with JRA in children. Salicylates can also be very effective; however concerns about salicylate toxicity and the association with Reye syndrome have decreased its usage in the United States. Cox-2 specific inhibitors are being evaluated for use in children. It may be necessary to try two or more NSAIDs sequentially as some patients may respond better to one agent versus another. There is no way to predict which patient will respond better to which agent, although it may be useful to try different chemical classes of NSAIDs. In addition to the arthritis, NSAIDs may also help the fever and some of the other manifestations of systemic-onset JRA. They may also have some effect on the iridocyclitis of JRA. NSAIDs can be associated with gastrointestinal side effects, even gastritis or ulcer disease. Renal and hepatic toxicity can occur. A child who is dehydrated or has renal disease is at increased risk for renal toxicity. Headaches or behavior changes have been noted. Pseudoporphyria with photosensitivity has been reported, particularly with naproxen. NSAIDs can also interfere with platelet function and cause prolonged bleeding.
Controlled studies in small numbers of patients have shown that hydroxychloroquine, oral gold salts, and D-penicillamine are not more effective than placebo (6). However, hydroxychloroquine is sometimes used as an adjunct for the treatment of JRA in older children. Ophthalmological exams every 6 months are necessary to monitor patients on hydroxychloroquine since retinopathy can occur. IM gold is used less frequently since the introduction of methotrexate, perhaps in part due to the requirement of weekly injections, the need for close monitoring, and the potential for serious side effects.
Methotrexate is an effective agent in children with severe JRA and is frequently used to treat children who have failed to respond to NSAIDs. Its once a week dosing (parenteral or oral) may help with compliance. Side effects can include bone marrow suppression, gastrointestinal symptoms, alopecia, dermatitis, oral ulcers, headache, acute interstitial pneumonitis, and pulmonary fibrosis. Hepatic fibrosis or cirrhosis is a rare finding in children.
Sulfasalazine may be effective in treatment of JRA, although drug toxicity may be a problem. Side effects include gastrointestinal irritation, dermatitis, oral ulcerations, bone marrow suppression and hepatic toxicity. Sensitivity to salicylates or sulfa, impaired hepatic or renal function, porphyria or glucose-6-phosphate dehydrogenase deficiency are contraindications to its use.
Glucocorticoids may be useful in the short-term treatment of severe systemic disease, severe JRA refractory to other therapies, and iridocyclitis. It is usually used in conjunction with other anti-inflammatory or anti-rheumatic medications. It is desirable to avoid prolonged use because of complications such as growth retardation, osteopenia/osteoporosis, infection, fractures and cataracts. Intravenous pulse dosing of corticosteroids may be helpful in some patients with more severe disease, such as systemic onset arthritis. Intra-articular glucocorticoids may be a therapeutic option in JRA, particularly when activity persists in a few joints despite treatment. Simultaneous injection of multiple joints may also be useful in certain cases.
New biologic agents targeted against TNF-alpha and IL-1 have been approved for use in adult RA and are being studied in children. TNF-alpha antagonists have been studied for use in older children with certain types of JRA.
Immunosuppressive and cytotoxic agents have been used in life-threatening disease or severe progressive arthritis. IV gamma globulin has been used with mixed results and its role in the treatment of JRA is unclear. Autologous stem cell transplantation is also being evaluated in a small number of children with severe disease.
Prognosis varies with the onset type or subtype and clinical course. However, studies indicate that many children with JRA are without serious disability and are able to work and function normally. Amyloidosis is a cause of mortality in some parts of the world, but is very rare in the United States. Even systemic-onset JRA is rarely fatal with our current therapies. The highest risk of morbidity appears to be children with systemic-onset disease and seropositive disease. Iridocyclitis can cause serious disability. Some children who develop spondyloarthropathy may have a more severe course, but their prognosis is fairly good.
1. Which of the following tests has a high positive predictive value for JRA
. . . . . a. erythrocyte sedimentation rate
. . . . . b. C-reactive protein
. . . . . c. HLA-B27
. . . . . d. antinuclear antibody
. . . . . e. white blood count
2. True/False: JRA is largely a clinical diagnosis.
3. True/False: All patients with suspected JRA should be referred to an ophthalmologist for a thorough eye examination.
4. Name three types of JRA and how are they different.
5. List some pharmacologic treatments for JRA that have been used or are being studied.
6. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit inflammation, reduce fever and reduce pain. Theoretically, how does the action of NSAIDs in treating JRA differ from the action of NSAIDs treating an ankle sprain?
1. Cassidy JT, Petty RE (eds). Textbook of Pediatric Rheumatology, 4th ed. 2001. Philadelphia: W.B. Saunders.
2. Gare BA. Juvenile Arthritis - who gets it, where and when? A review of current data on incidence and prevalence. Clin Exp Rheumatol 1999;17:367-374.
3. Blass DN, Giannini EH. Juvenile Rheumatoid Arthritis as a Complex Genetic Trait. Arthritis Rheum 1999;42:2261-2268.
4. Cassidy JT, Levinson JE, Bass JC, et al. A study of classification criteria for a diagnosis of juvenile rheumatoid arthritis. Arthritis Rheum 1986;29:274-281.
5. Schaller JG. Juvenile Rheumatoid Arthritis. Pediatr Rev 1997;18(10):337-349.
6. Ilowite N. Current Treatment of Juvenile Rheumatoid Arthritis. Pediatrics 2002;109(1):109-115.
7. Ruddy S, Harris ED Jr, Sledge CB (eds). Kelley's Textbook of Rheumatology, 6th ed. 2001. Philadelphia: W.B. Saunders.
Answers to questions
1. None of these answers are correct. None of these tests have a high positive predictive value for JRA.
3. True. Iridocyclitis may be difficult to diagnose by a non-ophthalmologist.
4. Polyarticular, pauci-articular, systemic JRA. Refer to the chapter for how they are different.
5. NSAIDs, Cox-2 inhibitors, hydroxychloroquine, oral gold, D-penicillamine, methotrexate, sulfasalazine, glucocorticoids, TNF-alpha antagonists, IV gammaglobulin.
6. In JRA, NSAIDs inhibit an inflammatory reaction which is pathological and destructive. The inflammation which occurs in an ankle sprain is largely a repair process. The benefit of using NSAIDs to inhibit this type of inflammation is less clear.