Juvenile rheumatoid arthritis (JRA) is an umbrella term for a number of arthritides of unknown etiology that occur in children younger than 16 years of age.
It is the most common rheumatic disease of children in the developed world, occurs in all races and ethnic groups, and is an important cause of morbidity. Use of the term JRA implies that childhood arthritis has a uniform presentation, treatment, and prognosis. To the contrary, it is likely that the subtypes of juvenile arthritis are related but distinct disease processes with varying presentations that require different treatment approaches and have different prognoses.
The difficulty in accurately describing the subtypes of inflammatory arthritis of childhood has been reflected in the number of proposed nomenclature systems for the classification of JRA ( Tables 7-1 through 7-3 ). The most recent classification is the International League of Associations for Rheumatology criteria, which designates juvenile arthritis as juvenile idiopathic arthritis (JIA; Tables 7-4 and 7-5 ). Although widely used, this classification is relatively new and has yet to be validated. The earlier criteria published by the American College of Rheumatology (ACR) use the more familiar term JRA. Lastly, the European League Against Rheumatism has also published criteria for juvenile chronic arthritis (JCA). In addition to being a source of confusion for families and patients, the proliferation of classification schemes leads to great difficulty in comparing studies based on different systems. As with other clinically defined diseases, precise terminology will likely have to await a fuller genetic and pathogenic understanding of juvenile arthritis. For the purposes of this chapter, the general terms juvenile arthritis, oligoarthritis and polyarthritis will be used; in cases in which specific nomenclature is required, the ACR terms will be used because they are widely recognized by most practitioners.
A 6-year-old previously healthy girl presents to her pediatrician with 3 months of left knee swelling. Her parents report that she limps when she gets out of bed, but her gait improves over the course of the day. Additionally, she has difficulty descending the steps from her bedroom in the morning, but does so easily at night. The family notes that the knee has appeared swollen but not warm or erythematous. The girl generally does not report knee pain, but she does not run as quickly in soccer practice as previously, volunteering that her knee hurts when she sprints. Her parents do not recall specific trauma or infections preceding the onset of symptoms. The child has been without fevers, rashes, weight loss, or visual changes. She has continued to go to school, and her energy level and appetite have remained normal. She sleeps through the night.
The child has had no joint complaints in the past, and in general has been healthy with normal growth and development. She has not had prior hospitalizations or surgeries and takes no long-term medications. Her family history is significant because a maternal aunt had hypothyroidism.
On examination, the patient is well appearing and afebrile. Her height is 50th percentile for age and her weight is 25th percentile. The only abnormal findings are limited to the musculoskeletal system: Her left knee is slightly warm and swollen with a ballotable effusion but no erythema. She has pain at the extremes of range of motion, and is unable to flex her knee beyond 75 degrees or extend it beyond 15 degrees. She has a leg length discrepancy of about 1 cm. Her other joints are normal, without evidence of inflammation or restricted motion. She does not have dactylitis or enthesitis.
Laboratory results include normal complete blood counts, an elevated erythrocyte sedimentation rate (ESR) of 23 mm/hour, and a positive antinuclear antibody (ANA) with a titer of 1:320. Rheumatoid factor (RF) and antibodies to cyclic citrullinated peptide are negative. Plain radiographs of the left knee reveal only an effusion.
|Juvenile Rheumatoid Arthritis (ACR)||Juvenile Chronic Arthritis (EULAR)||Juvenile Idiopathic Arthritis (ILAR)|
|Polyarticular||Polyarticular RF-negative||Polyarticular RF-negative|
|Pauciarticular||Juvenile rheumatoid arthritis RF-positive||Polyarticular RF-positive|
|Pauciarticular||Oligoarticular Persistent Extended|
|Juvenile psoriatic arthritis||Psoriatic arthritis|
|Juvenile ankylosing spondylitis||Enthesitis-related arthritis|
|Age at onset of arthritis||< 16 years||< 16 years||< 16 years|
|Duration of arthritis||≥ 6 weeks||≥ 3 months||≥ 6 weeks|
|Includes inflammatory bowel disease||No||Yes||Yes|
|Other diseases excluded||Yes||Yes||Yes|
|Percent of cases||30||60||10|
|Number of joints involved||≥5||≤4||Variable|
|Age at onset||Bimodal peak:||Peak: 1–2 years||Throughout childhood|
|Systemic involvement||Occasional fevers, uveitis||Uveitis||Fevers and rash|
|Occurrence of chronic uveitis||5%||5–15%||Rare|
|Frequency of seropositivity:|
|Prognosis||Variable in severe joint disease; otherwise good.||Excellent unless vision loss||Moderate to poor|
DIFFERENTIAL DIAGNOSIS OF OLIGOARTHRITIS
The differential diagnosis of a child with oligoarthritis, defined as inflammation of fewer than five joints, includes infectious, traumatic, oncologic and rheumatologic etiologies ( Table 7-6 ). In general, infectious arthritis is less likely to cause a gelling phenomenon, in which the joints are stiff following a period of inactivity, and is more likely to present with pain. Furthermore, in a previously healthy child, the more joints involved, the less likely the process is to be infectious. Septic arthritis caused by virulent organisms such as staphylococcus or streptococcus presents acutely, with fever and a single red, warm, swollen, and painful joint. Septic monoarthritis is more common in children than septic polyarthritis. Lyme arthritis typically has a less fulminant presentation, although at times, it may mimic a bacterial arthritis, including elevated markers of inflammation. A history of a preceding tick bite or rash may be elicited in fewer than 50% of children with Lyme arthritis. Indolent organisms such as kingella, on the other hand, may present with a more gradual onset of discomfort and no joint erythema. Children with an immune deficiency, whether primary or acquired, can develop an oligoarthritis due to opportunistic organisms including mycobacteria, Bartonella henselae and ureaplasma. Lastly, patients with oligoarthritis may have a reactive arthritis secondary to arthritogenic bacteria such as Salmonella, Shigella, Yersinia, Campylobacter, and Chlamydia .
Cases of monoarthritis caused by trauma usually have a clear preceding history. Similarly, a traumatic hemarthropathy can occur in patients with known bleeding diatheses. Less commonly encountered diagnoses to consider include venous or arterial malformations.
Childhood malignancies can present as arthritis, and consideration of cancer is important before initiating treatment, which may obscure the underlying condition. Leukemia is the most common cancer of childhood, and it presents with reports of musculoskeletal symptoms in up to 20% of cases. Primary malignant joint tumors are extremely rare, but pigmented villonodular synovitis, a benign but locally invasive tumor, should be considered when the child has an inflamed joint with significant pain or nighttime symptoms. Neuroblastoma metastasizes to periarticular areas of bone, but the child’s reports of limp and pain may appear to originate in joints. In all such conditions, a history of weight loss and fatigue, or physical examination findings of an ill-appearing child, should suggest the possibility of a nonrheumatologic condition. Plain films may reveal metaphyseal rarefaction or “leukemia lines” in the case of a hematologic malignancy, or periosteal elevation or an abdominal mass in cases of neuroblastoma or bony tumors. Complete blood counts with cytopenias or even normal platelet counts in the face of systemic inflammation should also raise concern for a tumor.
Rheumatologic diseases that can present with oligoarthritis include JRA, other forms of juvenile arthritis such as psoriatic arthritis, and sarcoidosis. Children with psoriatic arthritis often have a remarkably large, swollen knee with a massive effusion. Other characteristic findings that are distinct from those in JRA include asymmetric arthritis involving both large and small joints, dactylitis, and stigmata of psoriasis including nail pits or onycholysis. In the absence of a characteristic psoriasiform rash, a family history of a first-degree relative with psoriasis is necessary for a definitive diagnosis. Sarcoidosis in a child typically presents with the triad of arthritis, uveitis, and rash; pulmonary involvement is less common than in adults, so angiotensin converting enzyme (ACE) levels may be misleading. Joint involvement is characterized by thick, boggy synovitis and often tendinitis, and it typically begins in an oligoarticular pattern, later evolving to involve numerous joints. Drug-induced autoimmune disease as seen with minocycline does not generally cause an oligoarthritis.
TREATMENT OF JUVENILE ARTHRITIS: OLIGOARTHRITIS
As with adult rheumatoid arthritis (RA), the medical management of JRA has changed dramatically during the past two decades. Although nonsteroidal anti-inflammatory drugs (NSAIDs) are helpful in treating the symptoms of arthritis, they no longer form the foundation of the therapeutic pyramid. Rather, early introduction of disease-modifying agents aimed at preventing joint damage has become the norm. Most recently, biologic response modifiers have been added to the armamentarium for treating recalcitrant disease. A particular patient’s regimen is determined by risk-benefit calculations, with more intensive (and potentially more toxic) therapies reserved for children with the most aggressive forms of arthritis. For example, seropositive polyarticular JRA is similar to the adult form of RF-positive rheumatoid arthritis, with a tendency for early and diffuse erosions. Accordingly a more aggressive approach is indicated compared with those patients with pauciarthritis or reactive arthritis.
First-line treatment for patients with oligoarthritis includes NSAIDs ( Tables 7-7 and 7-8 ) or intra-articular corticosteroid injections. Most practitioners choose naproxen as the initial NSAID, given its extensive experience in JRA and the convenience of twice-daily administration. Numerous other agents are also approved for the treatment of JRA, including most recently celecoxib. Patients should be encouraged to take all NSAIDs with food, and children should wear sunscreen while taking naproxen to avoid pseudoporphyria. With the exception of anti-cycloogenase-2–specific agents, all NSAIDs have similar adverse side effects, including gastritis, peptic ulcer disease, transaminitis, and dermatologic complications. Duffy and colleagues studied central nervous system toxicity in children taking NSAIDs and found that up to 33% reported headache. There were rare reports of seizures in patients taking indomethacin in this case series. Finally, the impact of chronic NSAID use on a child’s cardiovascular risk remains to be determined. However, NSAIDs are generally well tolerated by children, with the major limitation to their use being lack of efficacy.
|Drug||Dose (mg/kg/day)||Doses per day||Maximum dose/day|
|Celecoxib||10–25 kg: 50 mg/dose||2||100|
|> 25 kg: 100 mg/dose||2||200|
|> 40 kg: 200 mg/dose||2||400|
Intra-articular steroid injections are an efficient and effective approach to treating pauciarthritis in children. Response rates are up to 90%, benefits persist for more than 12 months in up to 80%, and onset of action is more rapid than with systemic agents. The risks of intra-articular steroids, including infection and subcutaneous atrophy at the site of the injection, are generally outweighed by the benefits. Most practitioners inject the same joint no more than twice in the same year to avoid possible adverse effects on cartilage and growth plates. Triamcinolone hexacetonide at a dose of approximately 1 mg/kg has the longest duration of action and is generally well tolerated, although some practitioners prefer methylprednisolone acetate or triamcinolone acetonide.
Treatment of arthritis in children is predicated on complete control of articular inflammation. Even low-grade ongoing synovitis may result in life-long consequences, including leg length discrepancies, valgus or varus deformities, and a learned preference to avoid physical activities. Further management of children with oligoarthritis who continue to have active arthritis after use of NSAIDs or intra-articular steroids depends upon a variety of diagnostic, prognostic, and therapeutic considerations. A percentage of such children go on to develop polyarticular disease, so-called extended pauciarthritis. They should be treated in the same way as children with polyarticular involvement from disease onset (see the section on Management of Polyarthritis). Risk factors for developing extended joint involvement include ankle and/or wrist arthritis, systemic inflammation on laboratory studies, and symmetric synovitis at disease onset. Sedimentation rates that are significantly elevated at diagnosis should prompt evaluation for uveitis, inflammatory bowel disease, or concomitant infection, because most patients with isolated pauciarthritis generally do not have evidence of systemic inflammation, as illustrated in Case 1 .
Once a patient has failed to respond completely to NSAIDs and intra-articular corticosteroid injections, consideration of a disease-modifying antirheumatic drug (DMARD) is warranted. Knees, hips, and wrists are particularly prone to debilitating complications with prolonged inflammation, so DMARDs should be started earlier in children with such involvement, even when they are asymptomatic. Involvement of ankles, on the other hand, may persist for months or years without leading to significant chronic changes. Thus, practitioners take into account a child’s age, the severity of the inflammation, and the speed with which control must be achieved, when choosing among disease-modifying agents.
Sulfasalazine is most often used in children with inflammatory bowel disease or a spondyloarthropathy. It has been used to treat arthritis for more than 70 years, so unexpected side effects are rare. Nonetheless, sulfasalazine does not halt erosive disease, so it is most appropriately used in milder cases of JRA, particularly oligoarticular disease. Sulfasalazine is administered at a dose of 40 to 70 mg/kg/day divided bid or tid. Headache and gastrointestinal upset—especially with preparations that are not enteric coated—are the most common side effects. More severe toxicity is common to the family of sulfa drugs, including bone marrow suppression, agranulocytosis, photosensitive eruptions, and hypersensitivity reactions such as Stevens-Johnson syndrome. Sulfasalazine is contraindicated in children with known intolerance of sulfa drugs, as well as in children younger than 2 years of age, in whom neurotoxicity may occur. Finally, children with systemic onset JRA should not be treated with sulfasalazine, because use of this medication can precipitate macrophage activation syndrome and other severe complications.