Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 16-2

Three-Year-Old Boy

JEANINE RONAN

HISTORY OF PRESENT ILLNESS

A healthy 3-year-old boy presented to the emergency department with significant left ankle swelling and the inability to walk. During the past several months, he has had swelling and tenderness of multiple joints, including his knees, wrists, fingers, and hips. He has also had daily fevers with associated night sweats and an 8-lb weight loss. His mother noted rashes that appeared on his face, back, and chest.

MEDICAL HISTORY

His medical history was unremarkable.

PHYSICAL EXAMINATION

T 38.2°C; RR 24/min; HR 106 bpm; BP 102/64 mmHg; Height 50th percentile; Weight 10th percentile

In general, the boy appeared tired. Musculoskeletal examination revealed multiple painful and swollen joints with limited range of motion, including his right hip, right wrist, and left third digit. His neurologic examination demonstrated intact sensory function and normal deep tendon reflexes. No rash was seen. The remainder of the examination was normal.

DIAGNOSTIC STUDIES

Initial laboratory data revealed a 14 600 WBCs/mm3 with 54% segmented neutrophils, 6% band forms, and 36% lymphocytes. The hemoglobin was 7.9 g/dL and there were 997 000 platelets/mm3. The erythrocyte sedimentation rate was 63 mm/h. Electrolytes, blood urea nitrogen, and creatinine were normal. Liver function tests were normal, except an albumin of 2.9 mg/dL. Blood cultures were subsequently negative. Lyme antibodies and ASO titers were also negative. Radiologic studies were normal including hip and abdominal radiographs.

COURSE OF ILLNESS

Septic arthritis was considered unlikely given the number of joints involved as well as the chronicity of the problem. Throughout the hospital stay the patient continued to have fevers and joint swelling. A salmon colored rash appeared with each temperature elevation and suggested the diagnosis (Figure 16-1).

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FIGURE 16-1. Photograph of the patient’s rash.

DISCUSSION CASE 16-2

DIFFERENTIAL DIAGNOSIS

In a child with fever and refusal to bear weight, infectious causes such as septic arthritis and osteomyelitis must be considered. Children with septic arthritis may have systemic symptoms including irritability and malaise. The affected joint acutely appears erythematous, warm, and tender. Range of motion is typically limited due to pain. In more than 90% of cases, only a single joint is affected. Children with acute hematogenous osteomyelitis manifest symptoms for fewer than 2 weeks. On physical examination there is often erythema, edema, and tenderness over the affected bone. However, the degree of tenderness may be out of proportion to the other findings. The femur, tibia, humerus, and fibula are most commonly involved. Laboratory findings in both septic arthritis and osteomyelitis include leukocytosis and elevation of the erythrocyte sedimentation rate and C-reactive protein. Blood cultures are positive in up to 50% of the children with septic arthritis or osteomyelitis.

Acute rheumatic fever (ARF) may also present with fever. In ARF, the arthritis is classically described as a migratory polyarthritis with pain that is out of proportion to the physical findings and responds quickly to antiinflammatory medication. In addition, there must be evidence of a recent group A Streptococcus infection and fulfillment of the Jones criteria (Table 16-3).

TABLE 16-3. The JONES criteriaa for acute rheumatic fever.

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Arthritis occurs in late-onset Lyme disease. It should also be considered particularly in areas where Lyme disease is endemic. When occurring, the erythema migrans or bullseye rash develops in early disease and will precede joint swelling. Patients may complain of arthralgias during early-onset disease in addition to fever and generalized malaise. In 80% of cases, Lyme arthritis is monoarticular, typically involving the knee joint, but multiple joints are occasionally involved. The affected joint is erythematous and swollen; pain is relatively mild despite the significant joint effusion.

The constellation of fever, rash, and joint pain also suggests systemic-onset juvenile idiopathic arthritis (JIA). However, in many cases the presentation of systemic-onset JIA can be elusive and is sometimes confused with the presentation of leukemia or lymphoma. The systemic-onset JIA patient may have lymphadenopathy and hepatosplenomegaly. The arthritis and joint symptoms may not be apparent initially.

DIAGNOSIS

In this case, the evanescent salmon colored rash strongly suggested the diagnosis of systemic JIA (Figure 16-1). This rash usually appears while the child is febrile.

INCIDENCE AND EPIDEMIOLOGY

Juvenile idiopathic arthritis is the most common rheumatic disease of childhood. The incidence is 1:10 000, with a prevalence of 1:1000. JIA encompasses a heterogeneous group of disorders. By definition, JIA includes all forms of arthritis that occur before 16 years of age, persists for greater than 6 weeks, and does not have another known etiology. Arthritis is defined as the presence of a joint effusion plus two of the following: decrease range of motion of the joint, increase in warmth, and pain. Based on the symptom characteristics within the first 6 months of illness, the type of JIA is classified into systemic-onset, oligoarticular (persistent and extended), polyarticular (rheumatoid factor positive and negative), psoriatic arthritis, enthesitis related arthritis, and undifferentiated (Table 16-4). Systemic JIA represents about 10% of all cases and is seen equally among boys and girls. There is no peak age of onset and can present any time throughout childhood. In contrast, oligoarticular JIA is the most common, including about 40% of all JIA cases. Oligoarticular JIA occurs more commonly in girls than boys with a 5:1 ratio. Most children with oligoarticular JIA present between 1 and 6 years of age with a peak at 2-4 years. Polyarticular JIA, which comprises about 25% of JIA cases, is also seen more commonly in girls than boys with a 3:1 ratio. Peak onset of polyarticular JIA occurs between 1-4 years of age and 7-10 years of age until adolescence. The remainder of the cases consists of psoriatic arthritis, enthesitis-related (where tendons and ligaments attach to bone) and undifferentiated.

TABLE 16-4. Subtypes of juvenile idiopathic arthritis.

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CLINICAL PRESENTATION

The term juvenile idiopathic arthritis encompasses a group of diseases that involve the infiltration and proliferation of the synovial membrane resulting in joint swelling. JIA is a multifactorial autoimmune disease that develops due to host and environmental susceptibility factors. Immune dysregulation produces cytokines with an increase in inflammatory mediators within the synovium. Tissue inflammation causes remodeling, cartilage degradation, and bony erosions. The pain classically includes morning stiffness and gait disturbance, in contrast to patients with musculoskeletal pain due to mechanical or overuse injuries, which worsen with use and improve with rest. Patients with musculoskeletal pain will have worsening of symptoms during the day or with exercise and have no associated joint effusion.

Systemic-onset JIA. Systemic-onset JIA presents with high spiking fevers, salmon-colored rash that begins in the groin or axilla and extends to the trunk and extremities, hepatosplenomegaly, lymphadenopathy, with or without the arthritis. Supporting laboratory data include an elevated white blood cell count, anemia, thrombocytosis, and elevated ferritin level. Signs of disseminated intravascular coagulation are due to the macrophage activation syndrome. The sedimentation rate is typically greater than 80 mm/h. Chronic uveitis or iriditis does not typically occur.

Oligoarticular JIA. In oligoarticular JIA, the patient presents with less than four joints involved. This category is further divided into patients with persistent disease in which less than four joints are involved throughout the disease course and extended diseases in which more joint involvement develops after the first 6 months. The typical patient is a preschool girl with isolated knee swelling and difficulty walking. The arthritis usually involves the knees, ankles, wrists, or elbows, while sparing the hips. These patients are at high risk for uveitis. In patients with a positive antinuclear antibody (ANA), the risk is about 80%. Chronic anterior uveitis can be asymptomatic initially, but the complications include corneal clouding, cataracts, glaucoma, and vision loss. Serial ophthalmologic examinations are crucial in this population. Treatment may include NSAIDs or intraarticular steroid injections. This is the mildest form of JIA and these patients may go into permanent remission.

Polyarticular JIA. Polyarticular JIA affects five or more joints at the time of presentation. The joint distribution is symmetrical involving small and large joints including joints of the hands, the temporomandibular joint, or cervical spine. Polyarticular JIA is further categorized by the presence of rheumatoid factor. Rheumatoid factor positive polyarticular JIA is seen most commonly in adolescent girls and the disease course is similar to adult rheumatoid arthritis. The risk for uveitis is not as great in this category, but if the ANA is positive, these patients are also at risk for the complications with anterior uveitis.

Psoriatic arthritis. Psoriatic arthritis involves the knees, hands, and feet. It is seen in patients with psoriasis or with first degree relatives with psoriasis. Nail changes including pitting and onycholysis are typically seen along with dactylitis.

Enthesitis-related arthritis. Enthesitis-related arthritis encompasses inflammatory bowel disease associated arthritis, in which arthritis may precede other symptoms, reactive arthritis and juvenile ankylosing spondylitis. Enthesitis describes inflammation at the site of tendon and ligament attachment within the joint capsule. Many of these patients are HLA-B27 positive and develop progressive involvement of the sacroiliac joint.

Undifferentiated arthritis. This includes any arthritis that is not further defined by the above definitions.

DIAGNOSTIC APPROACH

When making the diagnosis of juvenile idiopathic arthritis, by definition the patient must have symptoms for a duration of at least 6 weeks. The history and physical examination should be directed at eliciting clues to changes in gait, the presence of joint effusions, and pain in the joints. It is important to examine all joints including the temporo-mandibular joint and cervical spine for subtle changes. Also, associated symptoms including fever, rash, and adenopathy must be assessed. Looking for signs of psoriasis, nail changes, can also have clues to the diagnosis. Growth parameters should be reviewed. An ophthalmologic examination is also very important. Laboratory data may be a helpful adjunct.

Complete blood count. Patients with systemic JIA often have leukocytosis with neutrophil predominance, thrombocytosis, and anemia.

Antinuclear antibody (ANA). Antinuclear antibody studies are not required for the diagnosis of JIA but are helpful in classifying patients. If JIA patients are ANA-positive, their risk for chronic anterior uveitis is higher. Since chronic anterior uveitis is an asymptomatic condition with devastating complications, including cataracts, glaucoma, and loss of visual acuity, these patients require close ophthalmologic follow-up.

Rheumatoid factor (RF). In general, a positive rheumatoid factor is not helpful in making the diagnosis. In most cases of JIA, the test will be negative with the exception of polyarticular JIA in which approximately 15% of children have a positive result. In this instance, a positive rheumatoid factor is important for prognosis, but not required for the diagnosis, as polyarthritis JIA, RF-positive is most closely related to adult rheumatoid arthritis.

Radiographs. Radiographs are normal early in the course of illness. Radiographs will show joint space narrowing, growth abnormalities of the joint, and bony erosions as persistent arthritis will also lead to bone demineralization and loss of articular cartilage.

Other studies. Erythrocyte sedimentation rate and C-reactive protein will be in most cases of JIA.

TREATMENT

The goals of treatment for JIA are to maintain functional mobility, by controlling inflammation and increasing joint range of motion, as well as limiting the side effects of medications and thereby leading to the normal physical, social, and developmental growth of the patient. Nonsteroidal antiinflammatory drugs (NSAIDs) are the first line of therapy for JIA. NSAIDs are directed at treating the pain and symptoms of JIA but these medications are not disease modulating. NSAIDs can be started at the onset of symptoms prior to classifying the arthritis without resulting clouding the diagnosis. Naproxen is commonly used because it is a twice-a-day medication. The chronic use of NSAIDs requires monitoring of certain data including urinalysis, complete blood count, renal, and liver function tests. A particular skin rash called pseudoporphyria is associated with naproxen. This photosensitive eruption results in small facial vesicles that may lead to permanent scar formation.

Other medications are directed at treating the inflammation and thus are disease modulation. Corticosteroids are used particularly in children with systemic JIA who present with high fevers and severe systemic symptoms. The side effects of systemic corticosteroids make them less appealing for chronic control of inflammation, especially in less severe forms of the disease. In patients with oligoarticular JIA, intraarticular injections with triamcinolone hexacetonide may be very effective treatments.

New data suggest that aggressive therapy at the onset of treatment is more effective in minimizing long-term sequelae. Disease-modifying antirheumatic drugs (DMARDs) including methotrexate are particularly useful in patients with oligoarticular JIA, extended disease, and polyarticular JIA. Methotrexate is usually very safe, but it can be associated with liver toxicity requiring monitoring of hepatic function tests every 4-8 weeks, kidney dysfunction, increase risk of infections, and bone marrow suppression. Folic acid supplementation once a week will decrease the incidence of side effects.

A new area of drug research is focused on targeting inflammatory cytokines to turn off the inflammatory cascade. Biological DMARDs are showing increasing promise in reducing symptoms and altering the disease course. These types of medications include TNF-alpha blocking agents, T-cell co-stimulation modulators, Inter-leukin 1 blocking agents, Interleukin 6 blocking agents, and B cell depletion agents.

Physical therapy is also crucial for these patients to maintain the most active possible lifestyle. Vitamin D and calcium supplements should be encouraged.

SUGGESTED READINGS

1. Goldmuntz E, White P. Juvenile idiopathic arthritis. Pediatr Rev. 2006;27(4):24-32.

2. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet. 2011;322(9783):2138-2149.

3. Prince F, Otten M, van Suijlekom-Smit L. Diagnosis and management of juvenile idiopathic arthritis. BMJ. 2011;342(c6434):95-102.