Diagnosis

The diagnosis of juvenile idiopathic arthritis (JIA) is made clinically and follows ILAR criteria. The subtype of JIA depends on the pattern of arthritis, which presents and evolves 6 months into the disease course.

Juvenile arthritis is characterized by arthritis that persists for over 6 weeks in a child under the age of 16. This cutoff in age was made more so due to practice patterns and less so due to biological variation in disease [1]. In order to confirm onset type, 6 months of disease duration is required for the full phenotypic features to manifest [1].

Arthritis is defined by loss of range of motion along with any evidence of past or current inflammation, which is evidenced by warmth, swelling, tenderness to palpation, or pain with ranging of the joint. The diagnosis of affected joints is made by clinical exam and is not made by imaging [1]. Classification of JIA is made based on the number of inflamed joints. Joints of the cervical spine, carpus, and tarsus are each counted as one joint.

JIA can be further subdivided into seven subclasses as per the ILAR criteria (as noted above). These include juvenile ankylosing spondylitis (JAS)/enthesitis-related arthritis (ERA), juvenile psoriatic arthritis (psJIA), oligoarticular JIA (persistent or extended), RF-positive polyarticular JIA, RF-negative polyarticular JIA, undifferentiated JIA (fits no category or fits more than one category), and systemic JIA (sJIA).

Although sJIA is listed in the JIA subclasses, there is question as to whether it should be included within these categories as it is thought that it may be an autoinflammatory disease.

Clinical Features

Children with oligoarticular arthritis tend to present in early childhood and are predominantly female. Anti-nuclear antibodies (ANA) positivity in this population is not uncommon. A positive ANA in children with oligoarticular arthritis places children at an increased risk for uveitis. In this population, frequent ophthalmologic screening is paramount to diagnosing this often asymptomatic disease.

Those with oligoarticular extended disease typically present with four or fewer joints involved, but over time evolve to have more than four joints involved. At 6 months after their diagnosis of JIA, these children typically have a higher joint involvement than they did at presentation.

Enthesitis-related arthritis (ERA), in contrast, occurs typically in males in their second decade of life. ERA is considered to be on the spectrum of juvenile ankylosing spondylitis (JAS). Enthesitis with or without axial arthropathy is commonly seen and may evolve into JAS or adult-onset ankylosing spondylitis. This entity is associated with HLA-B27 positivity. Symptomatic anterior uveitis presenting with a painful and red swollen eye is not uncommonly seen as an extra-articular manifestation of this disease.

Psoriatic arthritis (psJIA) has a variable age distribution and can initially present in younger children with dactylitis. This disease involves both small and large joints. Psoriasis can lag over a decade after the onset of arthritis in the pediatric population, which differs from adult-onset psoriatic arthritis.

Rheumatoid factor (RF)-positive polyarthritis parallels that of adult-onset rheumatoid arthritis and portends a poorer prognosis with a more aggressive and erosive disease than RF-negative polyarthritis. Rheumatoid factor-negative polyarthritis has a more variable presentation and outcome.

Systemic JIA typically presents with fevers, rashes, systemic inflammation, and arthritis. It has no autoantibody association and is likely autoinflammatory in nature.

Constitutional signs such as anorexia, fatigue, weight loss, and growth failure are common in children with JIA. Children may present with nighttime pain which can disrupt their sleep and contribute to fatigue (in the setting of these symptoms, consideration should also be given to a marrow-based problem). Any signs of weight loss should take into account the possibility of underlying inflammatory bowel disease or celiac disease [1]. Growth failure may also be a consequence of active JIA and may even delay puberty and secondary sexual characteristics [1].

As in adults, joint stiffness occurs especially after prolonged inactivity. This can be described by the parent as the child moving slowly or with a change in gait in the morning or after napping [1]. Stiffness lasting more than 15 min signifies a considerable level of joint inflammation [1]. Tenosynovitis and bursitis can also be seen in children with arthritis.

Osteopenia can occur in young adults who were diagnosed with JIA at a younger age [2]. This places them at an increased risk for fractures in adulthood and for early-onset osteoporosis [3–6]. A determinant of future fracture risk is the peak bone mass achieved by the end of skeletal maturity (typically completed by adolescence) [1].

Muscle atrophy and weakness occurs surrounding affected joints with arthritis resulting in shortened muscles and tendons, which can lead to flexion contractures. Limb length discrepancy may result leading to a pelvic rotation and scoliosis [1]. The involvement of the temporomandibular joint can result in micrognathia or retrognathia.

Uveitis is not uncommonly seen in children with JIA and is characteristically asymptomatic except for those with JAS/ERA where it presents with a painful erythematous eye. Screening guidelines have been implemented for children with JIA as uveitis is commonly silent and can have deleterious effects if left untreated.

Some laboratory evidence of JIA include leukocytosis, thrombocytosis, elevated erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Many children have normal laboratory evaluations including serologies. IgM RF positivity is unusual in a child under the age of 7 [1]. It can be seen in diseases other than JIA and is thus of little utility (although it is included in the ILAR criteria and may indicate a poorer prognosis) [1]. RF positivity is typically seen in older children with polyarticular disease, subcutaneous rheumatoid nodules, and articular erosions [1]. These children typically have a poorer functional class [1]. ANA frequency is the highest in girls with JIA at a younger age of onset with articular disease. There is a 65–85% prevalence among young girls who have oligoarticular arthritis and uveitis [7, 8].

Pathology and Pathogenesis

The etiology of JIA is unknown and is likely multifactorial. Autoantibodies are common in oligoarticular arthritis (anti-nuclear antibody) and RF-positive polyarthritis (IgM rheumatoid factor). ERA/JAS, RF-negative polyarthritis, and psoriatic arthritis are less commonly associated with autoantibodies. ERA/JAS is associated with the genetic marker HLA-B27.

Chronic inflammation in the joints is pathologically mediated by both the innate and adaptive immune system. In all categories of JIA, synovitis is mediated by activated T cells and macrophages, which are pathologically involved.

Treatment

Treatment for JIA has changed by use of intra-articular glucocorticoid therapy, low-dose methotrexate, and biologic therapies (anti-TNF-α, anti-IL-1, anti-IL-6, costimulation-inhibiting biologics). Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in combination with the aforementioned treatments. Response to treatment is based on the child’s clinical course, their objective improvement on physical exam, laboratory evidence of inflammatory markers normalizing, global responses, and charting of the articular severity index [1].

Physical and occupation therapy help to prevent deformity and disability in these children. Orthopedic surgical procedures are not commonly utilized in younger children. Typically, surgical interventions would include treatment for joint contractures, dislocations, and joint replacements, which are seen in older children.

In a study of 44 adults who had a follow-up of 24.7 years after the diagnosis of JIA, those with JIA had greater disability, bodily pains, overall fatigue, lower levels of exercise, poorer health perception, decreased physical function, and lower rates of employment when compared to a healthy control group [8].

Diagnosis

The diagnosis of sJIA is a clinical one. The International League of Associations for Rheumatology (ILAR) diagnostic criteria for sJIA is based on the presence of arthritis in addition to 2 weeks of a quotidian fever (lasting at least 3 days) and one or more of the following: serositis, hepatomegaly or splenomegaly, generalized lymphadenopathy, and an evanescent rash [9, 10]. It is important to exclude patients who are found to have a positive rheumatoid factor (RF) IgM on at least two occasions (at least 3 months apart) as well as patients with or with a history of psoriasis or psoriasis in a first-degree relative [9, 10]. Males with arthritis who are older than 6 years of age and found to have HLA-B27 positivity, enthesitis and arthritis, uveitis, or inflammatory bowel disease or a history of one of these disorders in a first-degree relative should also be excluded from this diagnosis [9, 10].

Clinical Features

Children with new-onset sJIA are typically very ill, febrile, and fatigued. They can present with myalgias, arthralgias, and chest and abdominal pain [9]. The other systemic features may predominate, and so the arthritis associated with this disease may initially be overlooked. Many children do not fulfill the ILAR criteria at the onset of disease. The arthritis in sJIA may appear 10 years after systemic symptoms [9]. This contrasts with the Yamaguchi criteria for adult-onset Still’s disease which does not require the presence of arthritis to satisfy criteria. Adult-onset Still’s disease (AOSD) has similar hallmarks to that of sJIA but occurs after the age of 16, and a sore throat is more commonly a symptom of AOSD [11].

Laboratory findings of systemic inflammation are typically seen in those with sJIA including leukocytosis, thrombocytosis, and anemia. There is typically an accompanied elevated erythroid sedimentation rate (ESR) and C-reactive protein (CRP). It is common to see an elevated ferritin, fibrinogen, and D-dimer along with these high inflammatory indicators.

Macrophage activation syndrome (MAS) has a high degree of morbidity and mortality in sJIA associated with 8% of those with sJIA and occurs in at least 7% of those during their disease course [12, 13].

Pathology and Pathogenesis

sJIA is likely related to the dysregulation of the innate immune response evidenced by the dramatic efficacy of treatments with IL-1 and IL-6 inhibitors [9]. The absence of both autoantibodies and autoreactive T cells in this disease point toward sJIA being an autoinflammatory disease [9].

Treatment

Children with sJIA are typically acutely ill and require hospitalization for both the diagnosis and management of their disease. Treatment is often initiated with nonsteroidal anti-inflammatory drugs (NSAIDs) for both treatment of fever and arthritis (oftentimes stronger agents for arthritis are necessary). Glucocorticoids are used with the route of administration and dose based on the severity of the disease onset. Biologic agents such as IL-1 or IL-6 with or without glucocorticoid treatment are often used. Methotrexate is not as efficacious for the arthritis in children with sJIA as it is with the other JIA subtypes.

Diagnosis

Similar to adult-onset SLE, the diagnosis is made using the Systemic Lupus International Collaborating Clinics (SLICC) criteria including 11 clinical and 6 immunologic categories. Similar to adult-onset SLE, four items must be present for the diagnosis of SLE with a minimum of one clinical and one immunologic fulfilled category (if not meeting biopsy-proven nephritis compatible with SLE in the presence of an anti-nuclear antibody (ANA) or an anti-double-stranded antibody (anti-dsDNA)).

Clinical Features

Those diagnosed with childhood onset of SLE typically have a more severe disease activity, organ involvement, and laboratory abnormalities than their adult counterparts [15, 16]. Most children with SLE present with vague constitutional symptoms along with clinical signs of immune activation such as generalized lymphadenopathy and hepatosplenomegaly [14]. Renal involvement is common and children may present with acute nephrosis and nephritis.

Pathology and Pathogenesis

SLE is a disease of immune dysregulation, which involves both the innate and adaptive immune system. The current hypothesis is that there is a loss of tolerance of the host.

Complement deficiencies are more commonly seen in childhood onset of SLE. Oftentimes, those with homozygous deficiencies of certain complements (specifically C1, C2, or C4) have a high incidence of lupus nephritis due to impaired clearance of apoptotic cells and immune complexes. Anti-C1q antibodies can also result in an anti-C1q deficiency [17]. In those with a C1q deficiency, 90% have been found to have SLE [18]. Thirty-three percent of those with a homozygous C2 deficiency develop SLE, while those with C4 allelic deficiencies have an increased risk of SLE [19, 20].

Treatment

Treatment of pediatric SLE is similar to that of adult-onset SLE and depends on disease activity and specific organ involvement. Hydroxychloroquine is commonly used in this population, as the benefits of its use are abundant. Glucocorticoid therapy is often used to treat both systemic and organ-specific involvement in various doses and forms dependent on a multitude of factors including severity of disease and organ involvement. Cyclophosphamide is reserved for severe manifestations of SLE organ involvement. Azathioprine and mycophenolate mofetil have been used as steroid-sparing agents and have been used particularly in treating lupus nephritis. Belimumab has been recently approved for the treatment of childhood SLE. Many other treatments have been trialed with some efficacy in treatment of specific SLE manifestations but with limited or conflicting data.