A 2-year-old Girl with Knee Swelling and Limp

Pediatric Pathways

A 2-year-old Girl with Knee Swelling and Limp

Our Author

Pediatric Pathways from American Family Children's Hospital: Dr. Grant Syverson

Grant Syverson, MD

After reading this article and answering the review questions, the reader will be able to:

  1. Identify common presenting signs and symptoms of juvenile idiopathic arthritis (JIA)
  2. Differentiate between the most common subtypes of JIA
  3. Explain treatment options for JIA.

Case

A 2-year-old girl is brought to your outpatient clinic for concerns about knee swelling and abnormal gait. Her parents believe her symptoms may have started 5 to 6 weeks ago when they noticed their daughter walking “stiffly” in the morning and after naps. This lasts 30 to 60 minutes. She has remained active and playful. Left knee swelling was noted a week ago after she fell while playing with her older brother. The parents did not witness the fall, but have noticed since this incident that her knee has appeared swollen. There was no associated bruising and there is minimal pain when touching the knee. Initially the family felt this was all due to injury, however, due to persistent knee swelling and the stiffness, she was brought in today.

She has no significant past medical history and takes no current medications. There is also no significant family history and the family lives in Northern Wisconsin. Outside of the lower extremity complaints, the parents have also noted that she seems to be favoring her left hand more than the right. She has otherwise been doing well with no recent infectious symptoms, fevers, rash, poor appetite, weight loss, or decreased energy. She remains interested in activity and continues to try and keep up with her older brother, although episodes of falling have increased.

On exam you note normal vital signs and growth parameters. She is not ill appearing and is interested in playing with her parents. Her physical exam is significant for a large left knee effusion, pain with range of motion (ROM), and a flexion contracture (See Figure 1 on next page). The left knee is slightly warmer than the right and is without erythema. You note decreased left calf muscle bulk. Her right knee is normal. On upper extremity exam her right wrist is swollen with decreased flexion and extension and associated pain with ROM. She has no other joint involvement and the remainder of her physical exam is normal.

Laboratory evaluation: CBC and inflammatory markers (ESR, CRP) are all normal. Liver and kidney function are also normal. Lyme enzyme immunoassay was negative. ANA was positive at 1:320. X-ray of her left knee shows soft tissue swelling but no fracture. Final diagnosis: Based upon chronicity, typical symptoms for inflammatory arthritis, and physical exam she was diagnosed with oligoarticular juvenile idiopathic arthritis.

Final diagnosis: Based upon chronicity, typical symptoms for inflammatory arthritis, and physical exam she was diagnosed with oligoarticular juvenile idiopathic arthritis.

Figure 1a. Large left knee effusion

Figure 1a

Figure 1b. Decreased left knee extension with flexion contracture

Figure 1b

Figure 1c. Normal right knee with normal extension

Figure 1c

Overview of JIA

Juvenile idiopathic arthritis is a general term used to describe a group of conditions characterized by chronic arthritis of unknown cause in childhood. JIA has replaced the older juvenile rheumatoid arthritis (JRA) nomenclature to differentiate childhood from adult rheumatoid arthritis (RA).

JIA is the most common chronic rheumatic disease in children and is a significant source of morbidity including joint destruction, contractures, chronic pain, or even blindness from disease-associated eye inflammation (uveitis). It is estimated to affect 300,000 children in the United States with variable incidence (4 to 14 per 100,000 per year) and prevalence (2 to 86 cases per 100,000 children) worldwide. The pathogenesis of JIA remains poorly understood and is believed to be multifactorial with involvement of both genetic and environmental factors. Both twin and sibling studies have reinforced the genetic component with high concordance rates and increased prevalence compared to the general population.

JIA is a clinical diagnosis made in a child less than 16 years of age with arthritis for at least 6 weeks’ duration without other identifiable causes for the arthritis. Arthritis itself is defined as a joint effusion alone or the presence of two or more of the following: limitations of range of motion, tenderness or pain on motion, and increased warmth. JIA is a diagnosis of exclusion and other illnesses must be ruled out before making a diagnosis. There are no diagnostic tests for JIA, although laboratory studies can be useful to evaluate for other diseases and to determine prognosis and extraarticular risk factors.

Clinical Signs and Symptoms

JIA is a chronic disease and presents with an indolent course over weeks to months. There are seven different subtypes defined by the features present during the first 6 months of disease. This overview will focus on oligoarticular, polyarticular, and systemic subtypes. Each subtype of JIA shares some common clinical features including:

  • Morning stiffness (or after periods of inactivity)
  • Improvement of stiffness throughout the day and with activity
  • Chronic joint swelling (arthritis) in one or more joints

These clinical features are important to distinguish JIA from other forms of limp and extremity pain. Patients with noninflammatory joint pain typically experience pain with activity, improvement of pain with rest, transient or no joint swelling, and lack daily morning stiffness. While children with arthritis can limit activities due to pain, often they remain physically active as inactivity causes increased stiffness.

Table 1. International League of Associations for Rheumatology Classification of Juvenile Idiopathic Arthritis

Subtype Definition Frequency (% of JIA) Age of Onset Sex Ratio
Oligoarticular    
  • Persistent
  • Extended
 
Arthritis in 4 or fewer joints in the first 6 months of disease   Affects no more than 4 joints   Affects more than 4 joints after the first 6 months of disease 27-56% Early childhood; peak at 2-4 years F>>>M
Polyarthritis (Rheumatoid Factor negative) Arthritis in 5 or more joints in the first 6 months of disease. RF negative 11-28% Biphasic distribution; early peak 2-4 year and later peak at 6-12 years F>>M
Polyarthritis (RF positive) Arthritis in 5 or more joints in the first 6 months of disease. RF positive on two (or more) occasions 3 months apart 2-7% Late childhood or adolescence F>>M
Systemic onset Arthritis in one or more joints with or preceded by fever of at least 2 weeks’ duration that is documented as daily (“quotidian”) for at least 3 days and accompanied by one or more of the following: (1) rash (evanescent), (2) lymphadenopathy, (3) hepatomegaly or splenomegaly, (4) serositis 4-17% Throughout childhood F=M
Psoriatic Arthritis and psoriasis, or arthritis and at least two of the following: (1) dactylitis, (2) nail pitting, (3) psoriasis in first-degree relative 2-11% Biphasic distribution; early peak at 2-4 years and later peak at 9-11 years F>M
Enthesitis-related Arthritis or enthesitis with two or more of the following: (1) sacroiliac tenderness or lumbosacral pain, (2) presence of HLA-B27, (3) onset of arthritis in male >6 years old, (4) acute anterior uveitis, (5) family history in a first-degree relative of HLA-B27 associated disease 3-11% Late childhood or adolescence M>>F
Undifferentiated Arthritis that fulfills criteria in no category or in two or more of the above categories      

Oligoarticular JIA

Oligoarticular JIA is defined as arthritis that affects 4 or fewer joints during the first 6 months of disease. It is the most common subtype and is associated with the best prognosis. It is further subdivided into persistent (always affects four or less joints) or extended (affects more than 4 joints after first 6 months). There is a female predominance and a peak age between 2-4 years. Patients tend to present with large joint involvement with the knee being most common (89%). Hip involvement at diagnosis is rare. Risk factors for the development of extended disease include ankle or wrist arthritis, hand disease, symmetric arthritis, arthritis of two to four joints, elevated ESR, and elevated ANA titer.

Children with oligoarticular disease are often well appearing and have a monoarticular presentation with associated morning stiffness, joint swelling, mild joint pain. This subtype also is at the highest risk for JIA associated uveitis. While an ANA is not diagnostic of arthritis in children, it does identify those patients that are at the highest risk of uveitis. This is particularly important as uveitis is often asymptomatic and can cause permanent vision loss if left untreated. A high proportion of oligoarticular JIA patients that are ANA positive may develop uveitis (up to 50%). All patients with JIA require ophthalmologic screening for uveitis with the frequency determined by subtype, ANA status and age at onset (Table 2).

Table 2. AAP Guidelines for Ophthalmologic Screening Eye Examinations

JIA Subtype Risk of Uveitis Examination Frequency

Oligoarticular or polyarticular, onset <7 years of age and ANA+

High risk

Every 3-4 months

Oligoarticular or polyarticular, any age of onset, ANA (-)

Medium risk

Every 6 months

Onset >7 years of age, ANA+ or ANA (-)

Medium risk

Every 6 months

Systemic onset JIA

Low risk

Every 12 months

Laboratory testing for oligoarticular arthritis is often normal and is targeted at ruling out other disease processes. Rheumatoid factor (RF) should be negative and an ANA is positive in 70-80% and is used to determine risk of uveitis rather than screening for systemic lupus erythematosus (SLE). Diagnostic considerations for a patient with oligoarticular arthritis include injury, postinfectious (reactive) arthritis, malignancy, and septic arthritis. Patients with septic joint or malignancy appear ill which distinguishes them from patients with oligoarticular disease. Injuries are often associated with bruising and should not be associated weeks to months of swelling and stiffness. Distinguishing Lyme arthritis can be difficult as the arthritis typically appears weeks to months from the initial infection. In Lyme endemic areas such as Wisconsin, screening patients with appropriate laboratory testing is important.

Polyarticular JIA

Polyarticular JIA is defined as arthritis in 5 or more joints during the first 6 months of disease. This subtype is further divided in to RF positive and RF negative. Patients with RF positive disease (2-7% of JIA) tend to be adolescent females and often present with symmetric small joint disease of the hands (Figure 4) and feet. Every adolescent patient with polyarticular disease should have a RF tested, as it is an important prognostic indicator. These patients tend to have more aggressive and persistent disease and are felt to have early adult rheumatoid arthritis (RA). Similar to adult RA patients they can also develop rheumatoid nodules (rare in other forms of JIA) and characteristic joint deformities such as swan neck deformities.

Figure 4a. Right hand with evidence of arthritis in second, third, fourth and fifth PIP joints along with second and third DIP joints.

Figure 4a

Figure 4b. Left hand with evidence of arthritis in second, third and fourth PIP joints along with third DIP joint.

Figure 4b

RF negative patients (11-28% of JIA) have a biphasic age distributions (2-4 and 6-12 years of age) with disease occurring more often in females. Those with earlier age of onset disease tend to have asymmetric joint involvement, often have positive ANAs, and have a higher risk of uveitis. Patients who develop disease later in childhood tend to have a symmetric large and small joint involvement. They often have a negative ANA and have a decreased risk of uveitis.

Diagnostic considerations for a patient with polyarticular arthritis include infectious or postinfectious arthritis, malignancy, inflammatory bowel disease, drug induced syndromes, or other systemic autoimmune diseases such as SLE, vasculitis, sarcoidosis, or inflammatory myositis. Laboratory studies often show a normal WBC, thrombocytosis, elevated inflammatory markers. An ANA is useful as a test for risk of uveitis and as a screening study for SLE. If a patient is ANA positive, completing the evaluation for SLE with more specific antibodies, serum complements and liver and kidney function are imperative.

Systemic Onset JIA

Systemic onset JIA (SOJIA) presents differently from the other subtypes with distinct clinical features. Compared to the other forms there is an equivalent risk for males and females and there is no clear age distribution. As the name implies patients have systemic features including high fever, rash, and very elevated markers of inflammation. The diagnosis of SOJIA requires the presence of arthritis along with 2 weeks of a typical quotidian fever pattern (once to twice per day) with a return to normal temperatures in between. In addition to fever patients must have at least one of the following: evanescent, erythematous (salmon colored) rash that often appears with fevers and resolves as the fever goes away, hepatomegaly or splenomegaly, generalized lymphadenopathy, or serositis. When not febrile, children with SOJIA can be well appearing.

Diagnosing a patient with SOJIA often requires excluding other illnesses, as the systemic features can occur before the development of arthritis for weeks or months. Infections, malignancy, systemic autoimmune diseases, inflammatory bowel disease, and acute rheumatic fever must be considered. Due the fever and rash is it common for these patients to be evaluated and treated as Kawasaki’s disease (KD). Unlike patients with KD, children with SOJIA will continue to remain febrile after treatment with IVIG. Laboratory studies show leukocytosis (neutrophil predominant), anemia, very elevated ESR and CRP, and thrombocytosis. ANA and RF are negative.

Patients with SOJIA are at risk for macrophage activation syndrome (MAS), which is a life threatening complication that occurs in 5-8% of patients. MAS is a state of excessive macrophage activation and characterized by persistent fever, pancytopenia, liver dysfunction, hepatosplenomegaly, coagulopathy, neurologic symptoms and hemophagocytosis in the bone marrow. Patients are very ill appearing. Laboratory studies can show a rapid fall in ESR due to consumption of fibrinogen along with prolonged PT and PTT, elevated D-dimer, elevated triglycerides and elevated ferritin. MAS requires aggressive treatment to avoid organ failure or death.

Treatment of JIA

Treatment of JIA is based upon medications, physical and occupational therapy, and psychosocial support. There is no cure for JIA and therefore the goal of medical therapy is to reach disease remission, which is defined as a normal exam, no symptoms of arthritis, and normal laboratory studies, along with preventing morbidity from the disease. Advances in current therapies have revolutionized the outcomes for children with arthritis.

  • Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs are the foundation of therapy and are often the first line treatment for JIA as they function as both an antiinflammatory and as a pain reliever. These therapies are usually well tolerated and have liquid formulations available. The most commonly used NSAIDs include naproxen, ibuprofen, meloxicam, and indomethacin. A typical trial is for 6-8 weeks of NSAID monotherapy prior to having a steroid joint injection or starting another agent. For patients with mild JIA, NSAIDs alone may be enough to control disease.
  • Intra-articular steroid injections: Injections can be used as first-line treatment for patients with limited disease or can be a useful adjunct after a trial of NSAIDs. Often these injections can provide a prolonged treatment response and avoid the use of systemic immunosuppressive therapies. Triamcinolone hexacetonide is the preferred agent, although it is currently in short supply and may be unavailable in many areas.
  • Prednisone: Use of prednisone has decreased in most patients with oligo- or polyarticular arthritis due to the advances in other medication classes. It is used more often in patients with SOJIA whose disease is not well controlled with NSAIDs. Prednisone may also be useful to control pain and inflammation while patients are waiting for the full therapeutic benefits of a second-line agent. Use of prednisone should be limited due to associated side effects.
  • Methotrexate: Methotrexate is considered the “gold standard” medication for patients with persistent, active arthritis. It is effective in over 75% of patients with JIA and is well tolerated. Methotrexate is considered a disease-modifying antirheumatic drug (DMARD). These drugs slow progression of disease. Methotrexate can be given once per week orally or by subcutaneous injection. Improvement is usually seen after 6-12 weeks of therapy. Adverse effects include nausea and fatigue, which can be improved with use of folic acid. Patients using methotrexate should have medication monitoring labs to look for cytopenias and liver dysfunction. Methotrexate is immunosuppressive and patients should not receive live viral vaccinations. If a child has symptoms of infection they should be evaluated and the medication is often held.
  • Biologics: The newest medication class for children with JIA is the biologic agents. Biologics target specific cytokines and receptors that are involved in the inflammatory response in humans. All of these agents should be considered immunosuppressive and there is risk for serious infection. They should not be given while a child is ill and, similar to methotrexate, live viral vaccines should be avoided.

Patients with JIA have elevated levels of tumor necrosis factor alpha (TNF-α) and, therefore, agents that block TNF activity (etanercept, adalimumab, and infliximab) can be highly effective. Etanercept was the first biologic to receive FDA approval for JIA in 1999. It is a soluble TNF receptor and inhibits TNF-α activity. It is a weekly injection and has been shown to be highly effective for patients with extended oligoarticular or polyarticular JIA that was not responsive to NSAIDs or methotrexate. Adalimumab was FDA approved in 2008. It is a fully humanized monoclonal antibody to TNF and it is given every 2 weeks. Infliximab is a human-mouse chimeric monoclonal anti-TNF antibody and is given intravenously. Compared to the other two anti-TNF agents, infliximab is associated with more frequent and serious adverse effects.

Patients with SOJIA have elevated levels of both IL-1 and IL-6 and therefore biologic agents targeting these cytokines have also been developed.

Summary

JIA is the most common rheumatic disease of childhood. Early diagnosis and treatment is imperative to avoid complications related to the disease. Diagnosis is based upon the presence of arthritis along with features of inflammatory joint pain, as there are no diagnostic laboratory studies for JIA. Patients with JIA are at risk of disease-associated uveitis and must have appropriate ophthalmologic screening. While NSAIDs and methotrexate remain the most common treatments for JIA recent major advances in medical therapy have revolutionized outcomes for patients with JIA.

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References

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