Juvenile arthritis: current concepts in terminology, etiopathogenesis, diagnosis, and management

Abstract

The latest change in terminology from juvenile rheumatoid arthritis (JRA) to juvenile idiopathic arthritis (JIA), established by the International League of Associations for Rheumatology (ILAR), has resulted in some confusion for OMFS and other treating clinicians. JIA comprises a group of systemic inflammatory diseases that result in the destruction of hard and soft tissues in a single or multiple joints. In a significant number of patients, one or both temporomandibular joints (TMJ) are also involved. TMJ disease may be accompanied by pain, swelling, and limitation of motion, as well as mandibular retrognathism, open bite, and asymmetry. The purpose of this article is to provide a review, for the oral and maxillofacial surgeon, of the terminology, etiopathogenesis, diagnosis, and management of children with JIA.

Juvenile arthritis is the most common pediatric rheumatologic condition and a disease well-known to oral and maxillofacial surgeons (OMFS). However, the latest change in nomenclature from juvenile rheumatoid arthritis (JRA) to juvenile idiopathic arthritis (JIA), established by the International League of Associations for Rheumatology (ILAR), has produced some confusion for treating clinicians. The aims of this article are to provide a review of the current terminology, current knowledge about the etiology and pathogenesis, and concepts of diagnosis and management of children with JIA.

Terminology, definitions, and classification

Previously, there were two clinical classifications of arthritis: the European, juvenile chronic arthritis (JCA) and the American, juvenile rheumatoid arthritis (JRA). They had different inclusion and exclusion criteria, which complicated international communication, the diagnosis and treatment of patients, and the interpretation of outcomes research. In order to define homogeneous subgroups of arthritis in children, to ensure uniform collection of information, and to clarify communication between clinicians worldwide, the ILAR introduced new nomenclature in 1995 (with revision in 2004) combining the European and American classifications into one system. The goal of this change in nomenclature was to advance understanding of the pathogenesis of juvenile arthritis and to improve treatment and outcomes in affected children. In this article, the designation JIA as defined and accepted by the ILAR is substituted for the previous designation JRA.

JIA is a broad term, describing a group of heterogeneous arthritides, which includes all forms of arthritis in children. Patients with JIA have a systemic disease that results in inflammation in the synovium and destruction of hard and soft tissues in joints. The temporomandibular joint (TMJ) is involved in more than 40% of patients diagnosed with JIA.

JIA is the most common pediatric rheumatologic condition and affects at least 300,000 children in the USA. The international prevalence ranges from 8 to 400 per 100,000, reflecting variations in different geographic locations. The etiology and pathogenesis of JIA are unknown; a combination of environmental and certain immunogenic factors may contribute to the disease. Without appropriate treatment, it may cause irreversible damage and destruction of hard and soft tissues in joints (including the TMJs) and viscera, leading to devastating physical limitations and disfigurement. There is no single pathognomonic abnormality that defines these disorders. JIA is categorized into subgroups based on history, clinical characteristics, and laboratory findings ( Table 1 ). Most children with JIA have a disease that is phenotypically different from that of adults with rheumatoid arthritis. However, 5–10% of children with JIA demonstrate serum positivity for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies and are thus diagnosed with childhood onset rheumatoid arthritis (CORA), or CCP/RF-positive JIA. JIA is also differentiated from idiopathic condylar resorption (ICR), which affects only the TMJs and is not accompanied by joint inflammation and synovitis.

Table 1
Classification of juvenile idiopathic arthritis.
Type Definition Exclusions a
Systemic onset Fever of ≥2 weeks and arthritis in ≥1 joint, plus one or more of the following:
Erythematous rash
Generalized lymph node enlargement
Hepatomegaly and/or splenomegaly
Serositis
a, b, c, d
Oligoarthritis Arthritis affecting ≤4 joints during the first 6 months a, b, c, d, e
Subtype: Persistent Affecting ≤4 joints throughout the disease
Subtype: Extended Affecting >4 joints after the first 6 months
RF-positive polyarthritis Arthritis affecting ≥5 joints during the first 6 months; RF positive at least two times 3 months apart a, b, c, e
RF-negative polyarthritis Arthritis affecting ≥5 joints during the first 6 months; RF negative a, b, c, d, e
Psoriatic arthritis Arthritis and psoriasis or arthritis and at least two of the following:
Dactylitis
Nail pitting or onycholysis
Psoriasis in a first-degree relative
b, c, d, e
Enthesitis-related arthritis Arthritis and enthesitis, or arthritis, or enthesitis, with at least two of the following:
Presence/history of sacroiliac joint tenderness and/or lumbosacral pain
Presence of HLA-B27 antigen
Onset of arthritis in a male >6 years old
Acute anterior uveitis
History of one of the following in a first-degree relative: ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis
a, d, e
Undifferentiated arthritis Arthritis that fulfills criteria in no category

RF, rheumatoid factor.

a Exclusions: (a) psoriasis or a history of psoriasis in the patient or first-degree relative; (b) arthritis in an HLA-B27-positive male beginning after the sixth birthday; (c) ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute uveitis – history of one of these or in first-degree relative; (d) presence of IgM RF on at least two occasions at least 3 months apart; (e) presence of systemic JIA in the patient.

Diagnosis of juvenile idiopathic arthritis

The diagnosis of JIA is based on a combination of medical history, clinical presentation, and radiologic and laboratory abnormalities. Patients with juvenile arthritis must have at least two of the following clinical features: joint swelling, pain/tenderness with motion, limitation of joint motion, and calor (warmth or heat) overlying the joint for more than 6 weeks. Appropriate and timely diagnosis and management are essential to relieve symptoms and to prevent, control, or limit the multi-organ sequelae of this disease. There are seven categories of JIA: (1) systemic onset, (2) oligoarthritis, (3) RF-positive polyarthritis, (4) RF-negative polyarthritis, (5) psoriatic arthritis, (6) enthesitis (inflammation at the tendon/ligament insertion into bone)-related arthritis, and (7) undifferentiated arthritis ( Table 1 ).

In systemic JIA, children present with fever, rash, poor weight gain/failure to thrive, decreased growth velocity, anemia, lymphadenopathy, hepatosplenomegaly, and serositis. Skin and nail changes (e.g., dactylitis) are commonly found in children with psoriatic arthritis. Uveitis is a reported complication of oligoarthritis, enthesitis-related arthritis, and less commonly polyarthritis and psoriatic arthritis.

Clinical findings vary and depend on the location, subtype of arthritis, and duration of disease. Children demonstrate a variety of findings, including a limp, morning stiffness, and/or antalgic gait, with difficulty walking or running. They may exhibit extremity overgrowth or undergrowth and asymmetries such as leg length discrepancies in the axial skeleton. Depending on the duration of symptoms, patients will have muscular atrophy around the affected joints and contractures.

If patients seek medical attention soon after the onset of symptoms, plain radiographs often do not show joint or skeletal abnormalities. Subtle radiographic findings that suggest arthritis in the early stages include mild peri-articular osteopenia with soft tissue swelling. In aggressive or rapidly progressive disease, or when there is a significant delay in the diagnosis and initiation of treatment, effusions, erosions, bony overgrowth, and joint space narrowing may be seen. Magnetic resonance imaging (MRI) with intravenous gadolinium is the gold standard imaging method to detect active synovial inflammation (enhancement of the intra-articular soft tissue). The extent of synovitis helps differentiate active inflammation and joint damage from long-standing chronic arthritis.

The detection of synovitis is a key aspect of JIA diagnosis and management and may prevent long-term disability. Although, synovitis can be diagnosed clinically by joint swelling, pain, tenderness, and decreased range of motion, gadolinium-enhanced MRI more accurately reflects synovitis than clinical examination. Active synovitis may be identified in presumed clinically inactive patients with this method.

Laboratory studies frequently provide additional information. For example, patients with significant inflammation may have anemia and/or elevated inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). However, normal laboratory studies do not rule out active arthritis. For example, it is a common misconception that negative antinuclear antibody (ANA) and RF studies exclude the diagnosis of JIA. Of all the children with JIA, only 5–10% have the RF-positive polyarticular JIA subtype. On the other hand, RF-negative polyarticular JIA represents 15–25% of all JIA cases.

Arthritis in children is not simply adult rheumatoid arthritis in a child. There are significant differences in the diseases. Most children with JIA who receive appropriate treatment do not develop the typical ‘rheumatoid’ appearance, i.e., hand/limb/spine deformities. However, the longer the disease is active, the more the child is at risk of developing these deformities. Polyarthritis in combination with an elevated RF is also less common in children. Unlike adults, children may not complain of pain at first, and joint swelling may not be noticeable or can be delayed for a long time after the original fever episodes. The lack of complaints often delays appropriate medical care. However, children may show indirect signs of pain, such as limping, moving slowly, avoiding chewing/eating certain foods, and/or avoiding physical activities like sports. They may have stiffness, most notable upon awakening or with cold weather. This usually improves with movement or time. Families may report that children look worse on rainy or cold days and improve with warm weather or showers. Untreated active arthritis usually results in greater long-term deformity, disability, and morbidity in actively growing or developing children than in mature adult patients.

The metabolism of medications may be more rapid in pediatric patients when compared to adults. For example, it is common for children to need higher doses of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate than those tolerated by adults.

JIA can be a lifelong disorder. About one third of these pediatric patients will continue to be affected by the disease in their adulthood. Children who have intermittent episodes of disease tend to do better in the long term than those with continuous disease. Even after years of remission, flares of disease can occur in adulthood. In future years, the prevalence of disease in adults may decrease because of continuous improvements in diagnosis and drug therapy.

Diagnosis of juvenile idiopathic arthritis

The diagnosis of JIA is based on a combination of medical history, clinical presentation, and radiologic and laboratory abnormalities. Patients with juvenile arthritis must have at least two of the following clinical features: joint swelling, pain/tenderness with motion, limitation of joint motion, and calor (warmth or heat) overlying the joint for more than 6 weeks. Appropriate and timely diagnosis and management are essential to relieve symptoms and to prevent, control, or limit the multi-organ sequelae of this disease. There are seven categories of JIA: (1) systemic onset, (2) oligoarthritis, (3) RF-positive polyarthritis, (4) RF-negative polyarthritis, (5) psoriatic arthritis, (6) enthesitis (inflammation at the tendon/ligament insertion into bone)-related arthritis, and (7) undifferentiated arthritis ( Table 1 ).

In systemic JIA, children present with fever, rash, poor weight gain/failure to thrive, decreased growth velocity, anemia, lymphadenopathy, hepatosplenomegaly, and serositis. Skin and nail changes (e.g., dactylitis) are commonly found in children with psoriatic arthritis. Uveitis is a reported complication of oligoarthritis, enthesitis-related arthritis, and less commonly polyarthritis and psoriatic arthritis.

Clinical findings vary and depend on the location, subtype of arthritis, and duration of disease. Children demonstrate a variety of findings, including a limp, morning stiffness, and/or antalgic gait, with difficulty walking or running. They may exhibit extremity overgrowth or undergrowth and asymmetries such as leg length discrepancies in the axial skeleton. Depending on the duration of symptoms, patients will have muscular atrophy around the affected joints and contractures.

If patients seek medical attention soon after the onset of symptoms, plain radiographs often do not show joint or skeletal abnormalities. Subtle radiographic findings that suggest arthritis in the early stages include mild peri-articular osteopenia with soft tissue swelling. In aggressive or rapidly progressive disease, or when there is a significant delay in the diagnosis and initiation of treatment, effusions, erosions, bony overgrowth, and joint space narrowing may be seen. Magnetic resonance imaging (MRI) with intravenous gadolinium is the gold standard imaging method to detect active synovial inflammation (enhancement of the intra-articular soft tissue). The extent of synovitis helps differentiate active inflammation and joint damage from long-standing chronic arthritis.

The detection of synovitis is a key aspect of JIA diagnosis and management and may prevent long-term disability. Although, synovitis can be diagnosed clinically by joint swelling, pain, tenderness, and decreased range of motion, gadolinium-enhanced MRI more accurately reflects synovitis than clinical examination. Active synovitis may be identified in presumed clinically inactive patients with this method.

Laboratory studies frequently provide additional information. For example, patients with significant inflammation may have anemia and/or elevated inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). However, normal laboratory studies do not rule out active arthritis. For example, it is a common misconception that negative antinuclear antibody (ANA) and RF studies exclude the diagnosis of JIA. Of all the children with JIA, only 5–10% have the RF-positive polyarticular JIA subtype. On the other hand, RF-negative polyarticular JIA represents 15–25% of all JIA cases.

Arthritis in children is not simply adult rheumatoid arthritis in a child. There are significant differences in the diseases. Most children with JIA who receive appropriate treatment do not develop the typical ‘rheumatoid’ appearance, i.e., hand/limb/spine deformities. However, the longer the disease is active, the more the child is at risk of developing these deformities. Polyarthritis in combination with an elevated RF is also less common in children. Unlike adults, children may not complain of pain at first, and joint swelling may not be noticeable or can be delayed for a long time after the original fever episodes. The lack of complaints often delays appropriate medical care. However, children may show indirect signs of pain, such as limping, moving slowly, avoiding chewing/eating certain foods, and/or avoiding physical activities like sports. They may have stiffness, most notable upon awakening or with cold weather. This usually improves with movement or time. Families may report that children look worse on rainy or cold days and improve with warm weather or showers. Untreated active arthritis usually results in greater long-term deformity, disability, and morbidity in actively growing or developing children than in mature adult patients.

The metabolism of medications may be more rapid in pediatric patients when compared to adults. For example, it is common for children to need higher doses of non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate than those tolerated by adults.

JIA can be a lifelong disorder. About one third of these pediatric patients will continue to be affected by the disease in their adulthood. Children who have intermittent episodes of disease tend to do better in the long term than those with continuous disease. Even after years of remission, flares of disease can occur in adulthood. In future years, the prevalence of disease in adults may decrease because of continuous improvements in diagnosis and drug therapy.

Diagnosis of TMJ arthritis

Minimal complaints of pain, a lack of swelling or limitation of motion, and the poor sensitivity of conventional radiographs inhibit the diagnosis of TMJ JIA and active synovitis. As a result, the reported prevalence of TMJ disease varies based on inclusion criteria, disease duration, and imaging methods used. The incidence and prevalence of TMJ arthritis, therefore, may be underestimated.

The problem is compounded because the clinician must also differentiate between TMJ arthritis and myofascial pain dysfunction. Both can present with similar signs and symptoms. Too often, any type of jaw pain is assumed to be a result of TMJ arthritis, and myofascial pain dysfunction may not be considered. In addition, TMJ symptoms and signs may be masked by anti-rheumatic therapy.

The reported prevalence of myofascial pain dysfunction in healthy children ranges from 4% to 15%. However, orofacial pain occurs more frequently in children with JIA than in control subjects. Müller and colleagues did not find a statistically significant correlation between jaw pain and active TMJ arthritis. Twilt and colleagues reported that pain with jaw excursion was a predictor of TMJ involvement, while pain at rest was not a statistically significant predictor of disease. Weiss and colleagues determined that the positive predictive value of TMJ pain for synovitis was 100%, but the sensitivity was 26%. They concluded that TMJ pain was a poor screening tool for the detection of TMJ synovitis.

Our group recently reported an overlap in diagnoses of active arthritis and myofascial pain dysfunction in JIA patients with jaw pain. In addition, jaw symptoms were equally as likely to result from myofascial pain dysfunction as arthritis. A subjective finding of pain was not always predictive of TMJ synovitis. Therefore, differentiation between the two is critical, as the management strategies for TMJ arthritis/synovitis and myofascial pain dysfunction are different.

Variability in the nature and severity of physical signs inhibits the diagnosis of TMJ synovitis. Clinicians must be aware of subtle physical findings indicating early TMJ synovitis. We reported that among children with JIA, limited maximal incisal opening (MIO) and deviation of the jaw with opening had high sensitivity and specificity for synovitis (positive predictive value of 1.00). Therefore, it is important for clinicians to obtain MIO and lateral excursive measurements at the earliest time point in the disease process to establish a baseline for follow-up. These measurements should be made with a rigid equilateral triangle measuring device ( Fig. 1 ). Longitudinal open and closed mouth photographs demonstrating jaw opening and facial photographs demonstrating jaw growth over time and the presence of jaw asymmetry should be taken ( Fig. 2 ). The typical presentation of micrognathia (‘bird facies’) ( Fig. 3 ) is less common now, as disease awareness has increased and aggressive treatments are introduced early in the disease process.

Fig. 1
Technique for the measurement of the maximal incisal opening with a rigid equilateral triangle measuring device. (A) The patient opens their mouth maximally and the triangle is inserted in between the incisors. Since the device is an equilateral triangle, it is rotated until the numbers on the upper and lower sides are equal, and that is the MIO. (B) Rigid equilateral triangle measuring device by KLS Martin LP, Jacksonville, FL, USA.

Fig. 2
A 12-year-old girl with JIA and unilateral TMJ involvement. (A) Frontal view at rest demonstrating the typical physical findings: facial asymmetry with deviation of the chin to the right, flattening of the right mandibular contour while the left one looks fuller, and shortening of the right posterior facial height. (B) Frontal view smiling illustrating the occlusal cant and deviation of the chin to the right. (C) Submental view demonstrating an accentuated right antegonial notch, chin deviation to the right, and a contour deficiency of the right mandible and soft tissue. (D) Open-mouth panoramic radiograph showing the right accentuated antegonial notch, right condylar head flattening, short right condylar neck, and shorter right ramus–condyle unit compared to the left side.

Fig. 3
A 12-year-old boy with JIA and bilateral TMJ involvement. (A) Frontal view demonstrating the symmetric mandibular contour, centered chin point, no occlusal cant, and short posterior facial height. (B) Submental view illustrating the bilateral accentuated antegonial notch. (C) Profile view demonstrating the typical ‘bird facies’: micrognathia, short chin-to-throat distance, convex profile, and high mandibular plane. (D) Lateral cephalogram demonstrating significant mandibular retrusion with an increased overjet and open bite. (E) Open-mouth panoramic radiograph showing bilateral condylar head flattening, short condylar necks, and short ramus–condyle units.

Multiple radiographic techniques for imaging the TMJs in JIA patients have been evaluated. MRI with gadolinium has been shown to be the best method to detect early inflammation and is the gold standard for the diagnosis of TMJ synovitis ( Figs 4 and 5 ).

Fig. 4
MRI of the patient in Fig. 2 . (A) Post contrast T1 coronal cut of the right condyle demonstrating typical findings of active disease: flattening of the condylar head and synovial enhancement (arrow). (B) Post contrast T1 coronal cut of the left condyle representing a normal condyle. Note the absence of synovial enhancement and the larger condylar head compared to the right side.

Fig. 5
MRI of the patient in Fig. 3 . Post contrast T1 coronal cut of the bilateral condyles demonstrating typical findings of synovitis.

In an attempt to minimize the potential high costs associated with MRI, other radiographic modalities have been studied. Skeletal changes resulting from prior inflammation cannot be distinguished from current active disease by computed tomography (CT) scans, but heterotopic ossification of the TMJs can be identified and can be associated with severe arthritis. However, based on recent evidence of an increase in childhood malignancies associated with high diagnostic radiation dosages, CT scanning is not encouraged. In certain cases where MRI with contrast is not possible (i.e., kidney disease), another alternative to MRI may be TMJ ultrasound. Weiss and colleagues found that ultrasound detected TMJ involvement in only 28% of patients. Jank and colleagues used ultrasound to visualize disk dislocation, condylar erosion, and effusion. However, they were not able to visualize active synovial hypertrophy and bone marrow edema, which are often indicative of early disease activity. In a recent study using ultrasound, Assaf and colleagues were able to detect condylar erosions and abnormal synovial thickness in a majority of their patients. However, they detected bone irregularities and/or joint effusion in less than 25% of patients. Our recently reported that abnormal condyle morphology and accentuated antegonial notching, as demonstrated on panoramic radiographs, are significantly correlated with TMJ synovitis. Therefore, in situations where MRI scanning is not possible or contraindicated (e.g., kidney disease), these panoramic radiographic findings can be used to support the diagnosis of synovitis.

A condition that may mimic JIA and confuse the diagnosis for OMFS is ICR. This condition is uncommon but well known and is defined as a progressive alteration of condylar morphology and loss of condylar mass of unknown etiology. These patients usually present with a chief complaint of progressive loss of chin prominence. They demonstrate progressive clockwise rotation of the mandible, retrognathia, and an open bite. The patients are overwhelmingly female, between ages 15 and 44 years, and the disorder is usually bilateral and symmetrical. Their work-up for systemic rheumatoid disease is negative. They do not demonstrate synovitis on MRI scans. The disease is self-limited and usually burns itself out over time. The entire condyle may be resorbed down to the sigmoid notch, but the disk and synovium are not affected.

Although the exact etiology and pathogenesis of ICR remain unclear, three theories have been proposed. Arnett and colleagues correlated ICR with increased, abnormal joint loading and subsequent pressure resorption. Chuong and Piper postulated that the mechanism of condylar resorption is similar to that of avascular necrosis of the femoral head. Gunson et al., in a recent paper, described an association between 17β-estradiol deficiency and ICR in a series of young females. This subject is discussed in more detail in the Discussion and controversies section below.

Since ICR is not a systemic illness, the malocclusion and jaw deformity can be treated successfully with an appropriate orthognathic surgical procedure when it has burned itself out. During the active phase of the disease, condylectomy is curative, permitting ramus–condyle unit and jaw reconstruction as appropriate.

Management

In this article, only the management of TMJ involvement in JIA is discussed. The management strategies for myofascial pain dysfunction and ICR in children have been described elsewhere in the literature and are not the subject of this review. The treatment of JIA is individualized and depends on the severity of disease, current activity, number of joints involved, and current physical limitations. Attempts to develop guidelines to treat JIA are underway but are currently based on expert opinion and consensus rather than multicenter randomized clinical trials.

The basic categories of disease are multiple joint involvements (polyarticular JIA) with or without systemic involvement, or one affected joint. When multiple joints are affected, systemic therapy is carried out in a hierarchical fashion.

Systemic therapy

The most commonly used initial systemic medications are NSAIDs such as ibuprofen, naproxen, etc. These drugs help to reduce inflammation and to alleviate the sequelae of joint inflammation and pain. The most frequent side effects are abdominal pain and headaches. Children can also develop increased sun sensitivity and hepatic and/or renal dysfunction. NSAIDs should not be used long term as monotherapy for arthritis, since there are many medications that are more effective.

Disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, sulfasalazine, leflunomide, etc., represent the next line of pharmacological management. Methotrexate is the most commonly used DMARD. It has been a mainstay of arthritis therapy for over five decades, with proven efficacy in children. Methotrexate is a folic acid analog that inhibits dihydrofolate reductase and the formation of the 1-carbon carrier needed in purine and thymine synthesis. This reduces T- and B-cell activation and the apoptosis of activated T-cells, and decreases antibody production. Therapy usually starts at a dose of 0.5 mg/kg and is titrated up as tolerated. It is administered orally or parenterally (subcutaneously) once per week. Subcutaneous delivery is generally thought to be superior, especially at higher doses.

Gastrointestinal absorption of methotrexate is best when the drug is given without food. At the standard dose regimen, 60–70% of patients with JIA benefit significantly from methotrexate therapy, with the maximum therapeutic effect usually becoming apparent 4 to 6 months after the beginning of treatment. A multinational, controlled study coordinated by the Pediatric Rheumatology International Trials Organization (PRINTO) is under way to establish whether the methotrexate therapeutic effect can be linked to a specific response curve. Although serious toxicity is uncommon, a prevalence of adverse events as high as 42% has been reported. Side effects include gastrointestinal toxicity (nausea, anorexia, stomatitis), transient elevation of serum aminotransferase levels, and a ‘post-dosing reaction’. This reaction occurs within 24 h after methotrexate and is characterized by malaise, fatigue, gastrointestinal upset, and occasional central nervous system manifestations. There are occasional reports of hematologic toxicity, headache, dizziness, fatigue, and mood changes. Folic acid supplementation has been shown to decrease the side effects of methotrexate. Because it is immunosuppressive, children are predisposed to recurrent infections. Although in vitro studies have shown that methotrexate has mutagenic and carcinogenic potential, in vivo studies in animal models have failed to show any carcinogenicity. There have been some reports of the development of lymphomas in methotrexate-treated patients.

Biological therapies (biologics) are a group of medications that have become increasingly used in the treatment of patients with resistant JIA and/or those who cannot tolerate DMARDs. Biologics such as etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade) block tumor necrosis factor alpha. They also include, abatacept (a fusion protein composed of the Fc region of the immunoglobulin IgG1 fused to the extracellular domain of CTLA-4, which blocks T-cell activation), anakinra (recombinant human injectable interleukin (IL)-1 receptor antagonist), Canakinumab (Ilaris) which also blocks IL-1 and tocilizumab (humanized monoclonal antibody against IL-6 receptor). In general, these have the benefit of being more potent and effective compared to the more traditional therapies, but tend to be more immunosuppressive, with less long-term safety data available.

The response of TMJ arthritis to systemic therapies has not been sufficiently investigated. In one non-randomized series of children with polyarticular or oligoarticular JIA and TMJ involvement, investigators reported that weekly treatment may result in a decrease in TMJ destruction and craniofacial alterations. The effect of the systemic administration of methotrexate on TMJs of rabbits with antigen-induced arthritis was recently reported. The authors found that the systemic administration of methotrexate seemed to have a positive therapeutic effect on the inflammatory process but failed to eliminate arthritis completely. In a pilot study of adults with rheumatoid arthritis, combined methotrexate and infliximab therapy reduced TMJ destruction, but this has not been studied in a pediatric population. Therefore, adjunctive local therapies specifically targeted to the TMJ are currently being investigated.

Intra-articular therapy

Intra-articular steroid injections have been shown to be safe and effective for appendicular/axial joints. However, there have only been a few reports in the OMFS literature describing outcomes after intra-articular steroid injections for the TMJ. Only adults with osteoarthritis have been studied. Although these reports did not discuss treatment in children, they raised concerns that multiple injections of steroids may contribute to cartilage damage and avascular necrosis. For this reason, OMFS have been reluctant to use intra-articular steroid injections in the past.

More recently, there have been multiple reports on the successful use of TMJ intra-articular steroid injections for the management of JIA. Investigators have used triamcinolone acetate (Aristocort) or triamcinolone hexacetonide (Aristospan) with or without radiographic image guidance, depending on institution protocols and patient co-morbidities. Adverse reactions were rare; they included transient facial swelling and/or reversible subcutaneous atrophy at the injection site. The authors reported that a majority of patients had an increase in mouth opening. However, repeated injections only yield minimal benefits, but are thought to be safe. If there is recurrence of TMJ arthritis despite intra-articular injections, additional systemic therapy is indicated.

Intra-articular steroid injections are indicated in patients with oligoarticular disease only affecting the TMJs, or as an adjunct to the systemic treatment of JIA, if the TMJs exhibit persistent active arthritis despite systemic therapy. TMJ injections are also used in patients not responsive to a systemic medication to provide relief during a change in drug therapy. They have the benefit of rapid and effective drug delivery, rapid resolution of local inflammation, potential to avoid using systemic therapies in some patients with associated side effects, and may provide sustained remission of arthritis in up to 70% of children after 1 year.

An MRI scan is repeated approximately 3–4 months post injection. If there is no response or incomplete resolution of the synovitis, the injection can be repeated twice more, with a repeat MRI after 3–4 months. If synovitis is resolved, patients who were receiving systemic therapy continue for another 6 months. If they remain in remission, treatment of any malocclusion or facial deformity can be considered.

Joint lavage and manipulation in addition to intra-articular steroid injection may result in better outcomes when compared to steroid injection alone, as shown in the orthopedic literature. Knee lavage combined with steroid injection improves pain relief and reduces effusion in patients unresponsive to repeated intra-articular steroid injections. Patients with TMJ disease probably have better outcomes after lavage, manipulation, and steroid injections under general anesthesia or sedation compared to patients treated only by steroid injections with or without radiological assistance. Further studies are needed to evaluate the benefits for the TMJ.

Recently, there have been reports of intra-articular infliximab injections for patients with TMJ arthritis refractory to intra-articular corticosteroid injections. These reports included children on systemic immunosuppressive therapy who had failed previous intra-articular corticosteroid injections. Although infliximab injections did not completely resolve TMJ arthritis in all patients, there was improvement in synovitis on MRI. The dosing and frequency of this method is yet to be established. Recent reports of heterotopic bone formation assumed to result from infliximab injections into the TMJ have to be investigated further.

Surgical management of active synovitis, unilateral or bilateral

Occasionally children with JIA will have persistent unilateral or bilateral TMJ synovitis with or without condylar resorption that is unresponsive to systemic therapy and intra-articular steroid injections. These patients are treated with open TMJ exploration, synovectomy, meniscectomy, condylectomy, and reconstruction with temporalis myofascial flaps and costochondral grafts (CCG) as appropriate. This approach allows the excision of all of the pathologic inflammatory tissues and allows reconstruction of the joint(s) at the same time. This is done in almost the same fashion as for an adult with degenerative TMJ arthritis. Synovectomy alone can also be performed endoscopically as a first step before an open joint operation.

Management of facial skeletal deformity

The long-term progression of disease and sequelae of TMJ involvement in JIA are not well known. There is little information in the literature regarding jaw reconstruction in JIA patients who have an end-stage skeletal deformity. The general impression in rheumatology is that the majority of patients with JIA do not proceed to develop chronic adult arthritis. Currently, thanks to an increase in early diagnosis, aggressive early treatment, and new drugs, OMFS in developed countries rarely encounter severe micrognathia, open bite, and clockwise rotation of the mandible (e.g., bird facies). The management of patients with JIA and associated condylar resorption is controversial. Theoretically, because JIA is a systemic disease, it is possible that even if the affected/diseased condyle is removed along with the synovium, a recurrence of TMJ disease will accompany a relapse of systemic disease.

In patients whose TMJ synovitis is under control, the first line of treatment is orthodontia and orthognathic surgery. Since the majority of JIA patients do not have persistent disease throughout their adult lives, orthognathic surgery is appropriate once skeletal maturity is reached. A retrospective review of 16 patients who underwent a combination of Le Fort I osteotomy, bilateral sagittal split osteotomies (BSSO), and genioplasty was reported by Oye et al. Mean relapse was 2.3 mm (range 2–4 mm) during the period of follow-up (1–10 years). In a report of eight patients who underwent BSSO with or without Le Fort I osteotomy and genioplasty, Leshem and colleagues reported relapse of 2.1 mm (range 1–3.1 mm) after 9.6 mm of mandibular advancement (range 3.9–18.3 mm) at a mean of 36 months of follow-up (range 8–66 months). The treatment protocol reported by Stringer et al. consists of an inverted L mandibular osteotomy with removal of the diseased condyle and CCG joint reconstruction concomitant with a Le Fort I osteotomy and a genioplasty. In their report of five patients, the average relapse was 1.5 mm at 9.6 years of follow-up (range 4–14 years). Theoretically, it would be desirable to manage an open bite and clockwise rotation of the mandible in patients with stable disease, when feasible, with a Le Fort I and autorotation of the mandible. This strategy does not include surgery on the mandible and therefore might eliminate the potential for condylar resorption that can occur after BSSO even in the absence of arthritis.

Distraction osteogenesis (DO) to address skeletal deformity in JIA patients has been reported infrequently in the literature. In a case report, Singer et al. described a JIA patient with mandibular hypoplasia and asymmetry and an increased mandibular plane angle. The patient was treated with DO. After 3 months of consolidation, a Le Fort osteotomy and genioplasty were performed. Mackool et al. reported the case of a 26-year-old patient with condylar resorption secondary to arthritis and sleep apnea who had mandibular distraction of 24 mm. No long-term outcome was reported, but an immediate relief of her sleep apnea and an improvement in her facial appearance were noted. Nørholt and colleagues treated 23 patients with JIA who had skeletal asymmetry resulting from unilateral TMJ involvement. They performed DO to vertically lengthen the affected mandibular ramus. At 1 year, patients had improvement in asymmetry, although specific measurements were not reported. Although DO is theoretically possible, compression of the proximal segment against the skull base could potentially contribute to resorption postoperatively.

Occasionally patients will require a total TMJ reconstruction with condylectomy, synovectomy, discectomy, and temporalis flap and CCG or total alloplastic joint reconstruction (TJR). Svensson and Adell reconstructed condyles with CCGs in 12 patients with JIA (mean age 13.7 years), mandibular retrognathia, and an anterior open bite with/without facial asymmetry. Seven patients developed mandibular prognathism or asymmetry secondary to overgrowth of the graft. At the 5-year follow-up (range 2–7.3 years), they had orthognathic surgery for the correction of malocclusion. Perrot and colleagues described a CCG technique leaving only 2–4 mm of cartilage on the graft. None of their 26 patients at a mean follow-up of 48.6 months had vertical overgrowth of the graft. Three of them developed a lateral contour overgrowth of their new condyle head. The linear stability of the graft is explained by the limited amount of cartilage left on the graft. Svensson et al. in their technique left 1–1.5 cm of cartilage. The CCG allows reconstruction of the condylar head and at the same time it increases the posterior facial height, as is needed in cases of severe end-stage facial deformity. Ware and Taylor were two of the first surgeons to use a CCG in growing children to address micrognathia and jaw ankylosis. Later, Ware and Brown presented a series of 10 growing children treated using this approach. All subjects experienced postoperative graft and mandibular growth. Early reconstruction of a severe facial deformity facilitates harmonious facial growth and minimizes the need for secondary surgery as orthognathic surgery.

Data reported in the literature on the long-term follow-up of children who have had a TJR are scarce. In addition, TJR using alloplastic materials has some other disadvantages including the cost of the device, material wear and failure, and unknown long-term stability. There is only one case report in the literature describing TJR in a pediatric population. Mercuri and Swift described the case of a child who underwent resection of a condylar mass at the age of 2 years. Reconstruction with a CCG was performed at age 7 years, but the patient developed ankylosis and facial asymmetry. He underwent gap arthroplasty/debridement, coronoidectomy, and ramus osteotomy with aggressive postoperative physical therapy. At the age of 13 years, he had a TJR. At the 5-year follow-up, his range of motion and function were good and he had no evidence of ankylosis. The longest reported follow-up of TJR was done by Wolford et al., who described a 21-year follow-up of 56 adult patients with a TJR. Patients reported improvements in jaw function, diet, TMJ pain, and quality of life. In theory, even if the TJR remains functional for an average of 20 years, a child who receives a TJR will likely require two to three additional TJRs during his or her lifetime.

Only gold members can continue reading. Log In or Register to continue

Jan 16, 2018 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Juvenile arthritis: current concepts in terminology, etiopathogenesis, diagnosis, and management
Premium Wordpress Themes by UFO Themes