Arthritis is manifested as a swollen joint having at least 2 of the following conditions: limited range of motion, pain on movement, or warmth overlying the joint. This article discusses an approach to the evaluation of a child with arthritis of one (mono) or several (poly) joints.
In pediatric practice, physicians are often faced with a child presenting with musculoskeletal complaints. The differential diagnosis of musculoskeletal pain is broad and includes a variety of causes, including arthritis. Arthritis is manifested as a swollen joint or a joint having at least 2 of the following conditions: limited range of motion, pain on movement (stress pain), or warmth overlying the joint. The assessment of a child with arthritis must enable differentiation between acute and chronic causes of arthritis and, particularly, recognition of those who may require urgent medical or surgical intervention. Juvenile idiopathic arthritis (JIA) is only one of the many causes of arthritis. This review covers the evaluation of a child with arthritis of one (mono) or several (poly) joints.
Monoarthritis
The differential diagnosis of monoarthritis includes entities in the broad categories of infection, postinfection, inflammation, malignancy, and trauma related to a systemic illness ( Table 1 ). A carefully conducted history taking and physical examination are the initial and most important steps in narrowing the differential diagnosis and guiding the diagnostic evaluation.
| Infection-related | Septic arthritis Osteomyelitis Transient synovitis Reactive arthritis Lyme disease Tuberculosis |
| Trauma | Fracture: accidental and nonaccidental Internal derangement: ligament rupture Foreign body: synovitis |
| Malignancy | Leukemia Neuroblastoma |
| Inflammation | JIA Inflammatory bowel disease Familial Mediterranean fever |
| Hemarthrosis | Hemophilia Pigmented villonodular synovitis Synovial hemangioma |
History Taking
Important aspects to be considered in the history taking are as follows:
- 1.
Characteristics of the pain and/or stiffness (site, number of joints, severity, frequency, duration, pattern, and association of warmth or discoloration). Morning stiffness is a characteristic feature of inflammatory arthritis. Night pain should alert the clinician to a malignancy or an osteoid osteoma
- 2.
Review of systems focused on the presence of fever or other constitutional symptoms (eg, weight loss, anorexia, night sweats, or nocturnal pain)
- 3.
Precipitating factors: traumas, infections (streptococcal, enteric, viral), immunizations, medication exposures, and history of sexual activity
- 4.
Travel to Lyme disease–endemic or tuberculosis (TB)-endemic areas or other risk factors for TB (born in Africa, Asia, Latin America, or Eastern Europe; exposure to a person with TB; close contact with a person with a positive TB skin test result)
- 5.
Presence of extra-articular features (diarrhea, urethral discharge, ocular symptoms, rash)
- 6.
Personal or family history of a bleeding diathesis or HLA-B27–associated diseases (inflammatory bowel disease [IBD], acute anterior uveitis, psoriasis, ankylosing spondylitis).
Physical Examination
Abnormalities detected on physical examination are important clues to the diagnosis of monoarthritis. A detailed general physical examination should include growth parameters and vital signs. The presence of fever should alert the clinician to the potential for more severe conditions requiring urgent treatment (eg, septic arthritis). On general examination, clues to underlying diagnosis include rash (psoriasis, viral exanthema), iritis (IBD or enthesitis-related arthritis), and hepatosplenomegaly/lymphadenopathy suggestive of malignancy. The musculoskeletal examination should include a review of all joints and examination of the gait but with a focus on the affected joints. A recently developed and validated tool is the pGALS (pediatric Gait, Arms, Legs, Spine), which is a simple screening examination that can be performed in a few minutes ( Fig. 1 ).
The focused examination of the affected joint should include inspection of the skin for warmth, redness, swelling, and soft tissue involvement, using the contralateral side for comparison. Importantly, the distinction whether the swelling is of articular or extra-articular (eg, bursitis) origin must be made. Palpation of the surrounding bone is important because the presence of pinpoint bony tenderness is suggestive of fracture, osteomyelitis, or malignancy. Passive and active range of motion should be observed. An exquisite pain in the joint on range of motion or a joint that is severely restricted in its range of motion suggests an etiology other than inflammatory arthritis (eg, septic joint). In the presence of a significant trauma history, stress maneuvers for ligamentous instability should also be performed.
Preliminary investigations that are to be considered for the evaluation of monoarthritis are presented in Box 1 . Laboratory investigations of acute or chronic monoarthritis are performed to confirm the clinician’s impression regarding the suspected diagnosis or to exclude conditions. A diagnosis of JIA is made based on history taking and physical examination and after exclusion of other causes.
Basic screening
- •
Complete blood cell count and differential white blood cell count
- •
Erythrocyte sedimentation rate
- •
C-reactive protein
- •
Renal function and liver enzyme
- •
Serum lactate dehydrogenase
- •
Radiographs
Further investigations
- •
Cultures of throat, blood, joint fluid, stool, and/or urine
- •
Partial thromboplastin time
- •
Antinuclear antibody titer
- •
Serologic testing for Lyme disease
- •
Antistreptolysin-O titer
- •
Urinalysis
- •
Tuberculin skin test
- •
Further imaging (ultrasonography, magnetic resonance imaging)
- •
Bone marrow aspiration
- •
Slit lamp examination of the eyes
Laboratory Investigations
Complete blood cell count (CBC) and differential white blood cell (WBC) count, inflammatory markers, and liver and renal functions should be considered in any child with monoarthritis. If the presentation is acute (<72 hours), a joint aspiration must be performed if the clinician is concerned about a septic joint, with the fluid sent for blood cell count, Gram stain, and culture. In addition, culture of the throat, blood, stool, and/or urine should be considered to identify a potential organism in the case of reactive arthritis. An acute presentation is also observed with hematologic and malignant diseases (eg, hemophilia and leukemia), highlighting the importance of CBC and coagulation studies. Antistreptolysin-O (ASO) and anti–deoxyribonuclease B (anti–DNase B) titers are useful to identify a recent streptococcal infection.
In chronic monoarthritis, Lyme serology (when history is suggestive of an exposure) and antinuclear antibody (ANA) and rheumatoid factor (RF) titers should be considered. HLA-B27 testing is most relevant in chronic arthritis when the child is suspected of having a specific category of JIA (enthesitis-related arthritis), which is generally seen in boys older than 8 years and often associated with enthesitis, lumbosacral back pain, and a family history of HLA-B27–associated diseases (eg, IBD, ankylosing spondylitis). The presence of ANA or RF is neither necessary nor sufficient to make a diagnosis of JIA. ANA should not be used as a screening test for rheumatic illness in a primary care setting, because it may be positive in up to 15% of healthy children. ANA is used as a diagnostic test for children with probable systemic lupus erythematosus (SLE) or mixed connective tissue disease (MCTD) and other overlap-like illnesses. In the context of JIA, a positive ANA titer is associated with a significantly increased risk of developing chronic anterior uveitis.
RF has been associated with aging (>60 years), infections (bacterial endocarditis, hepatitis B or C, parasitic disease, viral infection), pulmonary disease (sarcoidosis, interstitial pulmonary fibrosis), malignancy, and primary biliary cirrhosis and thus is not a specific test for the diagnosis of rheumatic disease. Only 5% to 10% of patients with JIA have a positive RF, highlighting the lack of sensitivity for the diagnosis of JIA.
A joint aspiration must be performed when a septic joint (bacterial) is suspected but is also recommended for the diagnosis of TB arthritis. The presence of hemarthrosis suggests coagulation disorder, trauma, or rare causes, including synovial hemangioma or pigmented villonodular synovitis.
The more common and/or serious causes of monoarthritis are addressed in the following sections.
Monoarthritis Related to Infection
Septic arthritis
Septic arthritis is a medical emergency that requires prompt antibiotic therapy and orthopedic intervention (drainage and irrigation). This condition is estimated to account for 6.5% of all childhood arthritides. Septic arthritis results from direct puncture injury to a joint, hematogenous spread, or spread from a contiguous infection (eg, osteomyelitis or cellulitis). In children and adolescents, the most common causative agents are Staphylococcus aureus , group A streptococci (GAS), and Streptococcus pneumoniae . In children younger than 2 years, Haemophilus influenzae type B had been the most common pathogen identified, but vaccination of infants for H influenzae has significantly decreased the frequency of infection with this organism. Other important agents are Salmonella in patients with sickle cell disease and Neisseria gonorrhoeae in sexually active adolescents. Kingella kingae has emerged as an important pathogen, particularly in children younger than 4 years. This organism grows better in aerobic conditions; hence synovial fluid and bone aspirates from patients should be inoculated in an aerobic blood culture system in addition to the traditional solid culture media. K kingae is difficult to isolate on routinely used solid culture media, which is why it is proposed that this organism may account for a significant portion of culture-negative cases of septic arthritis. Mycobacterium tuberculosis is an unusual causative agent of septic monoarthritis but must be considered in an at-risk individual.
As outlined earlier, the presence of fever, localized erythema, warmth, and significant pain on passive range of motion are highly suggestive of a septic joint. Children (particularly neonates) can present with pseudoparalysis of the affected limb. Investigations usually demonstrate an elevated WBC count (predominance of neutrophils) and inflammatory marker levels (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]). However, an urgent joint aspiration and a synovial fluid analysis with blood cell count and Gram stain is essential for the diagnosis. The causative agent is recovered in 50% to 70% of cases (blood or synovial fluid).
Initial radiologic examination is not diagnostic and may demonstrate only soft tissue and capsular swelling. The characteristic findings of osteopenia and joint space loss may not be present until 10 days into the illness. Despite prompt recognition with appropriate surgical and antibiotic management, permanent damage is common. A septic hip joint is particularly vulnerable to early damage, with chronic debilitating changes seen within 24 to 48 hours if aspiration and treatment are delayed. Such a delay may result in avascular necrosis related to increased intra-articular pressure that compromises the blood vessels that supply the cartilage and femoral head.
Reactive arthritis
The term reactive arthritis refers to arthritis that develops during or after an infection elsewhere in the body but in which the microorganisms cannot be recovered from the joint. The classic organisms causing reactive arthritis are enteric ( Campylobacter , Yersinia , Salmonella , Shigella ) and genitourinary organisms ( Chlamydia trachomatis ). The triad of conjunctivitis, urethritis, and arthritis, formerly known as Reiter syndrome, may be seen after one of these infections. More recently, reactive arthritis has also been reported after infection with Mycoplasma pneumoniae and Chlamydia pneumoniae . Although the precise role of HLA-B27 in the development of arthritis is not fully elucidated, there is a higher frequency of HLA-B27 positivity in patients who develop reactive arthritis after infection with one of these organisms. The generally short-lived arthritis may be monoarticular or polyarticular, involving the larger joints of the lower extremities; can be quite painful; and usually responds well to nonsteroidal antiinflammatory drugs (NSAIDs). In addition, acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PSRA) are postinfectious arthritides and are discussed in the differential diagnosis of polyarthritis.
Hip monoarthritis
Transient synovitis of the hip
Transient (toxic) synovitis (TS) of the hip presents as a painless limp or a painful hip or knee (referred pain) typically affecting boys younger than 4 years (occasionally up to 8 years). The cause of TS is unknown but it has been postulated to be related to previous infection, most commonly involving the upper respiratory tract. In a large incidence study of family practice visits for nontraumatic hip pain in children, which determined an incidence rate of 148.1 per 100,000 person-years, TS had the highest incidence rate of all diagnoses considered (76.2 per 100,000 person-years). On inspection, the child is generally well appearing (afebrile or only mildly elevated temperature) and can ambulate but may do so with a limp. The affected leg is often held in a position of external rotation and flexion. A few attempts have been made to develop predictors to differentiate septic arthritis from TS. A non–weight bearing status, a history of fever, an ESR greater than 40 mm/h, and a WBC count greater than 12,000 cells/mm is highly predictive of septic arthritis. A radiograph of the affected area should be sought to rule out other pathologic conditions (eg, osteoid osteoma, fracture). Because the diagnosis of TS is one of exclusion, in the case of a child who looks well, with no fever and normal WBC count and ESR, conservative management with close follow-up (1–2 days) is sensible. If there is any concern for an infection being the cause of hip pain and limp (fever, abnormal ESR or WBC count, localized tenderness), an ultrasonography is recommended to document evidence of an effusion followed by a diagnostic aspiration (if an effusion is present).
With conservative use of NSAIDs and bed rest, this self-limited process tends to resolve in 3 to 10 days. It has been suggested that patients with TS should have a repeat radiography within 6 months to exclude Legg-Calvé-Perthes (LCP) disease, which is estimated to be a complication of TS in 1% to 3% of cases. The recurrence rate is 4% to 17%, occurring mostly within 6 months. There has been no identified increased risk of developing JIA after a diagnosis of TS.
When the presentation is one of monoarticular pain involving the hip, additional important considerations are slipped capital femoral epiphysis (SCFE) and LCP disease. Both these conditions are noninflammatory and not typically associated with arthritis.
SCFE
SCFE classically occurs in overweight boys aged 10 to 14 years or in children with endocrine disorders, such as hypothyroidism or pituitary deficiencies (eg, growth hormone deficiency). SCFE is diagnosed radiographically. Both hips should be imaged because SCFE is bilateral in 30% of cases in which the presenting symptoms are unilateral. On diagnosis, an urgent referral should be made to orthopedics; in the meantime, the child should be non–weight bearing and on bed rest and prescribed crutches.
LCP syndrome
LCP syndrome, an idiopathic avascular necrosis of the capital femoral epiphysis, typically affects boys aged between 4 and 10 years. A high index of suspicion is needed to make the diagnosis because initial radiographs are often normal. At this early stage, magnetic resonance imaging (MRI) is most sensitive for the diagnosis, showing changes in the bone marrow related to hypoperfusion. Subsequently, radiographs show fragmentation and then healing of the femoral head, often with residual deformity. Patients with LCP should be made non–weight bearing, with an urgent referral to orthopedics. Treatment focuses on maintaining containment of the femoral head within the acetabulum with the use of abduction splints or, occasionally, surgically with an osteotomy of the proximal femur.
Lyme disease
Lyme arthritis is most commonly recognized in the Northeastern, Mid-Atlantic, and North-Central United States and less commonly in the West Coast and Southern Canada, attributable to the distribution of the white-tailed deer. This tick-borne illness is primarily caused by 3 species of the spirochete Borrelia burgdorferi . The clinical manifestations of Lyme disease vary but early disease manifestations include a flulike illness, rash (erythema migrans), lymphocytic meningitis, cranial nerve VII palsy, arthralgia, and rarely carditis. Arthritis is a late manifestation occurring months to years after the original infection. Often, the child is asymptomatic and may not recall having been bitten by a tick. This underscores the importance of eliciting a history of travel or residence in a Lyme-endemic area. The most frequently involved joint is the knee (in two-thirds of cases), but any large joint may be affected, and more than one joint may be involved at presentation. The arthritis may be painless and episodic; however, chronic arthritis has been described in up to 18% of patients.
The diagnosis is based on suggestive clinical characteristics in addition to confirmatory laboratory tests. Indirect methods to detect infection are preferred over direct detection methods (cultures, stains, or polymerase chain reactions) because the latter have higher rates of false-negative results and it often takes a prolonged period before the results are known. Of the indirect methods, the enzyme immunoassay (enzyme-linked immunosorbent assay) has high sensitivity and low specificity and thus is used as a targeted screening test. In the case of a positive result, Western blot is the confirmatory test with high specificity.
Malignancy
A malignancy must always be considered at the top of the differential diagnosis, even if it can be immediately discounted. Clues that suggest a malignancy as the cause for arthritis include the following: pain out of keeping with the degree of arthritis, the child being irritable and difficult to examine, fever, lymphadenopathy or hepatosplenomegaly, leukocyte or platelet count that are lower than expected, bone pain, and metaphyseal lucencies seen on the radiograph ( Fig. 2 ). Joint involvement in malignancy tends to be oligoarticular (≤4 joints) rather than polyarticular.
One study looking at the factors differentiating acute leukemia from chronic arthritis found that the presence of a low WBC count (<4 × 10 9 /L), low-normal platelet count (150–250 × 10 9 /L), and history of nighttime pain was 100% specific and 85% sensitive for the diagnosis of acute lymphoblastic leukemia (ALL). Moreover, when pain is the chief complaint of the patient, this may have a strong negative predictive value for the diagnosis of JIA. Isolated musculoskeletal pain, in the absence of other signs or symptoms, is almost never a presenting complaint in children with JIA, and, instead, children (with JIA) more commonly complain of joint swelling and/or gait disturbance.
JIA
Chronic arthritis is the most common rheumatic disease in children, affecting about 1 in 1000 children worldwide. JIA is an umbrella term describing a group of arthritides of unknown etiology lasting more than 6 weeks in children younger than 16 years. JIA is an important consideration in chronic monoarthritis because it is a significant cause of short-term and long-term disability. In addition, there is mounting evidence that early disease identification and treatment may lead to improved quality of life. The most frequently affected joints are the knee, ankle, wrist, and elbow. Chronic monoarthritis can be the presenting manifestation of oligoarthritis, enthesitis-related arthritis, and psoriatic arthritis. JIA rarely presents as monoarthritis involving the hip or shoulder. Consequently, there is a low threshold for further imaging (MRI) once an infectious cause has been ruled out. Up to 20% of children with JIA (oligoarthritis) may develop chronic anterior uveitis. Therefore, a slit lamp examination should be considered for a child with suspected JIA because detection of uveitis would support this diagnosis. JIA is reviewed in detail in this issue of The Clinics .
Other Important Diagnostic Considerations
Hemophilia may cause recurrent monoarthritis. Chronic joint pain and damage is one of the most important causes of morbidity in this X-linked recessive coagulopathy. Hemorrhage into the soft tissues, particularly intramuscularly, may mimic hemarthrosis. The most commonly affected joints are the knees, elbows, and ankles. The classic presentation of hemarthrosis is one of acute onset of increasing fullness in a joint, with loss of range of motion. On examination, the joint is warm and distended. Recurrent hemarthrosis can lead to bone and joint damage and early osteoarthritis, causing a significant effect on the patients’ quality of life. A rarer cause of hemarthrosis is pigmented villonodular synovitis, which may represent a benign neoplasm of the synovium.
An acute or a chronic monoarthritis may easily be confused with extra-articular joint swelling, particularly around the knee joint. Bursitis is another important consideration in the approach to monoarthritis. A bursa is a synovial-lined sac designed to reduce friction between moving structures (eg, tendons rubbing against bones, ligaments, or other tendons). A bursa may communicate with the joint (eg, suprapatellar and popliteal); however, other bursae around the knee do not necessarily do so (eg, infrapatellar and medial collateral ligament). Bursitis typically presents with maximal tenderness at the site of the bursa and localized swelling. In the case of communication with the knee joint, a small joint effusion may also be observed. Although the prevalence of bursitis in childhood is low, it may be higher in athletes and patients with JIA. When bursitis is suspected, an MRI is the preferred imaging modality to confirm the diagnosis. It is important to distinguish between monoarthritis and bursitis because the treatment differs; bursitis may not respond to an intra-articular corticosteroid injection and may require a direct injection into the affected bursa.
Polyarthritis
The differential diagnosis of polyarthritis essentially includes infectious, inflammatory, and malignant causes ( Table 2 ). Although mechanical causes (eg, hypermobility and skeletal dysplasia) and diffuse idiopathic pain syndromes are considered in the differential diagnosis of polyarthralgia, they do not routinely cause polyarthritis. The review of systems and physical examination is critical to establishing a diagnosis because there are clues in the characteristics of the arthritis, fever, rash, and other system involvements that often provide the correct diagnosis ( Table 3 ). When polyarthritis is the presenting complaint, in addition to the investigations outlined in Box 1 , additional investigations may include serum C3 and C4 complement levels, serum levels of quantitative immunoglobulins, urinalysis, serologic testing for viral pathogens, swabs for gonococcal infection as indicated, ASO and anti–DNase B titers, cardiac evaluation (electrocardiography and echocardiography), chest radiography, ANA titer, other autoantibodies (anti-Ro, anti-La, anti-Sm, anti-RNP, anti–Scl 70), and antineutrophil cytoplasmic antibody.
