Juvenile idiopathic arthritis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nehal Eid, M.D.[2]

Juvenile idiopathic arthritis (JIA), formerly known as juvenile rheumatoid arthritis (JRA),^[1] is the most common form of persistent arthritis in children.

JIA is sometimes referred to as juvenile chronic arthritis (JCA),^[2] a term that is not precise as JIA does not encompass all forms of chronic childhood arthritis.

Arthritis is the inflammation of the synovium (the lining tissues) of a joint.

JIA is a subset of arthritis seen in childhood, which may be transient and self-limited or chronic. It differs significantly from arthritis commonly seen in adults (osteoarthritis, rheumatoid arthritis), and other types of arthritis that can present in childhood which are chronic conditions (e.g. psoriatic arthritis and ankylosing spondylitis). Inflammatory arthritis affects children and adolescents differently due to special disease affection of the growing musculoskeletal and immune systems in young patients.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]

• Juvenile idiopathic arthritis (JIA) is a heterogeneous group of chronic inflammatory arthritides beginning before 16 years of age.
• A classification system was developed 20 years ago by the International League of Associations for Rheumatology (ILAR)^[1], which categorized patients into groups to facilitate trial enrollment.
• Novel molecular/pathobiologic views have helped in developing a revised classification system, which is still to be finalized.^[2][3]
• Major subtypes include oligoarticular JIA, polyarticular JIA, and systemic JIA (Still’s disease), with additional categories such as enthesitis-related arthritis and psoriatic JIA. These subtypes differ in clinical presentation, immunopathogenesis, complications, and long-term outcomes.
• Most JIA categories lie on a disease continuum that includes corresponding adult inflammatory arthritides.
• Hallmarks of JIA are asymptomatic chronic anterior uveitis and skeletal deformities (including temporomandibular joint deformity).
• Systemic JIA differs from other categories biologically and phenotypically and is associated with a risk of life-threatening complications.
• Outcomes have been profoundly improved with newer targeted treatments however treatment-free remission is still uncommon, and many need continued care in adulthood.
• Classification

JIA consists of at least five clinically and biologically distinct categories:^[2][3]

Most categories lie on a continuum with adult inflammatory arthritides.

• Oligoarticular JIA

• Polyarticular JIA (RF-negative and RF-positive)

• Systemic JIA

• Enthesitis-related arthritis

• Psoriatic JIA

JIA

Oligoarticular JIA

Polyarticular JIA

Systemic JIA

Enthesitis-related arthritis

Psoriatic JIA

Oligoarticular (or pauciarticular) JIA affects 4 or fewer joints. Oligo means few. It was previously known as pauciarticular JIA. Patients with oligoarticular JIA are more often ANA positive, when compared to other types of JIA.^[4]

• Epidemiology: Most common subtype (≈40–50%), predominantly affects girls aged 1–5 years who often have positive antinuclear antibodies (ANA).

• Joint pattern: Knee most commonly involved; ~50% present with monoarthritis, most often of the knee^[5]

• ~50% remain persistent oligoarticular with involvement of 4 or fewer joints and a high likelihood of medication-free remission.

• ~50% progress to extended oligoarticular disease (>4 joints after 6 months) with less likelihood of remission.
• Early wrist or ankle involvement and an elevated ESR predict extension.

• No adult-onset counterpart for early-onset ANA-positive subtype.
• Major complication:

• • Chronic anterior uveitis occurs in up to 30%, often asymptomatic
  • Treatment:
  • Intraarticular glucocorticoid injections may prevent inflammation and prevent further damage
  • In case of inadequate management, complications or extended oligoarticular JIA conventional DMARDs such as methotrexate with or without biologic DMARDs such as TNF inhibitors are administered

Polyarticular JIA is defined by arthritis affecting five or more joints during the first 6 months of disease. It may involve both large and small joints, including the cervical spine and temporomandibular joints.

• RF-Negative Polyarticular JIA
  • More common than RF-positive disease with prevalence of 15-20% of JIA cases with peak incidence between 1-3 years, and >8 years.
  • It lies on a continuum with extended oligoarticular JIA and adult seronegative RA.
  • Predominantly affects girls
  • ANA positivity may be present in up to 50% of patient population
  • Clinical course overlaps with extended oligoarticular JIA with relapsing or chronic course in many patients
  • Complications:
  • Children < 6 years are at high risk of developing anterior uveitis.
  • Treatment:
  • Initiate treatment with synthetic DMARDs such as methotrexate soon after diagnosis. In case of insufficient response within 2-3 months, biologic DMARD usually TNF inhibitor should be administered. After 3 to 6 months of inadequate disease control, the biologic DMARD should be substituted with a different biologic DMARD or a targeted synthetic DMARD along with the original synthetic DMARD.

Pathophysiology of oligoarticular and RF-negative polyarticular arthritis

Activated Th1 and Th17 lymphocytes lead to macrophage activation and fibroblast-like synoviocytes resulting in production of TNF and IL-6.

• RF-Positive Polyarticular JIA
  • Less common, with only 5% prevalence among JIA cases
  • Occurs more often in older children and adolescents, uncommon under 9 years of age.^[5]
  • Rheumatoid factor positive test is required for diagnosis. Anti-citrullinated protein antibodies may be present; ANA may also be positive.
  • It may represent the same disease as adult seropositive RA genetically and clinically.
  • Shares clinical and genetic features with adult seropositive rheumatoid arthritis with prominent B-cell and plasma cell activation along with autoantibody generation.
  • It has a more aggressive and erosive especially without treatment.
  • Treatment:
  • Similar therapeutic approach to RF-negative polyarticular arthritis, however earlier treatment is often initiated due to poor prognosis.

• It is defined by inflammation at the entheses, where tendons and ligaments attach to bone.^[5][6] Enthesitis often coexists with synovitis of periphral joints ( upper and lower extremities)^[7] with frequent affection of peripatellar and calcaneal entheses.
• Its prevalence ranges between 9–19%; 33% in parts of Eastern and Southeastern Asia.^[5][8] It is more common in boys and uncommon before 6 years of age.^[6]
• Acute anterior uveitis 11–13%.
• It is on diseases spectrum that includes juvenile spondyloarthritis and juvenile ankylosing spondylitis.
• Clinical manifestations depend on patient’s age at disease onset.
• Symptomatic axial involvement such as sacroillitis or inflammatory spine disease develops in 40 to 60% of patients with enthesitis-related arthritis, usually during adolescence, although one study identified asymptomatic sacroillitis in 30% of patients at time of disease onset on magnetic resonance imaging (MRI).^[9]
• Positive HLA-B27 is associated with more severe presentation, sacroillitis, juvenile ankylosing spondylitis and acute anterior uveitis.^[6][10][11]

• HLA-B27 molecule probably presents arthritogenic antigens to CD8+ T cells, 32^[12] resulting in production of interleukin-17 and TNF-α, leading to tendonal, fibrocartligenous, subchondral bone marrow and synovial inflammation.^[7] These inflammatory processes lead to pathologic bone alterations combined with mechanical stress.^[13]

Treatment: NSAIDs are used for symptomatic relief. They are often combined with sulfasalazine or a TNF inhibitor in case of uncontrolled enthesitis. If sacroillitis is present, biologic DMARDs (commonly TNF inhibitor) should be administered. In case of unresponsiveness to TNF inhibitor, IL-17 inhibitors may be useful.^[14]

• Bimodal peak incidence at 2-4 years of age and >10 years of age.
• Younger patients have a similar presentation to early-onset oligoarticular and RF-negative polyarticular JIA in terms of female predominance, ANA positivity and risk of chronic anterior uveitis.^[5]
• Psoriasis affects 50% of the patients but may appear later in disease course
• Psoriasis familial history, dactylitis or nail pits may support earlier diagnosis.
• Older children may have similar manifestations to adults’ psoriatic arthritis such as enthesitis, peripheral polyarthritis and sacroiliitis.^[6] HLA-B27 is positive in 10 to 12% of patients.

Treatment: Early onset disease is treated similarly to oligoarticular or polyarticular arthritis depending on number of joints affected. Older children with enthesitis and sacroiliitis receive similar treatment to patients with enthesitis-related psoriasis. Biologic medications targeting psoriatic arthritis such as IL-17, IL-12 and IL-23 inhibitors are approved for use in psoriatic JIA.

Is characterized by arthritis, fever and a salmon pink rash. Systemic JIA can be challenging to diagnose because the fever and rash come and go. It affects males and females equally, unlike the other two subtypes of JIA.

Systemic JIA may have internal organ involvement and lead to serositis (e.g. pericarditis).

Systemic juvenile idiopathic arthritis (systemic JIA), also known as Still’s disease, is a distinct subtype of juvenile idiopathic arthritis characterized by arthritis in combination with prominent systemic inflammatory features. Unlike other subtypes of JIA, systemic JIA is considered an autoinflammatory disorder rather than a primarily autoimmune disease.

• Affects males and females equally
• Can occur at any pediatric age
• Accounts for approximately 10–15% of all cases of juvenile idiopathic arthritis
• Systemic JIA and adult-onset Still’s disease probably represent the same disease entity.
• Recent guidelines from an expert joint task force of the European Alliance of As sociations for Rheumatology and the Pediatric Rheumatology European Society propose using the term “Still’s disease” to denote this apparent continuum. ^[15][16]

^[17]

Systemic JIA is characterized by quotidian systemic symptoms that may precede the onset of arthritis.^[16]

• Daily spiking (quotidian) fevers, often occurring in the evening
• Evanescent, salmon-pink macular rash, typically coinciding with fever spikes
• Arthritis, which may be absent at disease onset and develop later
• Generalized lymphadenopathy
• Hepatosplenomegaly
• Serositis, including pericarditis and pleuritis^[18]

• Markedly elevated inflammatory markers (erythrocyte sedimentation rate and C-reactive protein)
• Leukocytosis with neutrophil predominance
• Thrombocytosis
• Elevated ferritin levels
• Absence of antinuclear antibodies and rheumatoid factor in most patients^[19]

• Macrophage activation syndrome, a potentially life-threatening hyperinflammatory condition^[20]
• Chronic destructive arthritis in a subset of patients
• Interstitial lung disease and pulmonary hypertension (emerging recognized complications)

Earlier in the disease course, activation of the innate immune system occurs, with high levels of proinflammatory cytokines; treatment with interleukin-1 and interleukin-6 inhibitors at this time may produce a remarkable clinical response and even remission.^{[21][15] [22]} However, chronic arthritis later in the disease course suggests the involvement of adaptive immunity, with specific lymphocyte activation, along with a strong association with HLA-DRB1*11, a major histocompatibility complex (MHC) class II allele.^[23][24][25]

• It shares pathogenic and clinical features with adult-onset Still’s disease, representing a disease continuum^[26]

• Disease course is variable, ranging from monophasic self-limited illness to persistent chronic arthritis
• Early control of systemic inflammation is associated with improved long-term outcomes

Diagnosis:

Infections and neoplasms must be considered and ruled out before treatment initiation especially if arthritis is absent at presentation.

It may resemble monogenic autoinflammatory syndromes such as Familial Mediterranean fever.^[27]

• Nonsteroidal anti-inflammatory drugs may be used for mild disease
• Systemic glucocorticoids are effective for severe systemic inflammation or macrophage activation syndrome.^[15]
• Biologic therapies targeting interleukin-1 or interleukin-6 may produce remarkable clinical improvement and remission early in disease course. They are central to therapeutic management.^[28][15][22]
• Early biologic intervention may prevent progression to chronic arthritis^[29]
• Targeted synthetic DMARDs are emerging therapies for refractory systemic JIA.^[15]
• DMARDs such as methotrexate and TNF inhibitors are generally not effective in early systemic JIA, although may be effective if chronic disease develops.

^{[30][31][2][3]}

Subtype	Key Features	Most Common Age at Onset	Female:Male Ratio	Proportion of JIA Cases	Immunopathogenesis	Common Complications	Adult Correlate	Treatment
Oligoarticular JIA	≤4 joints in first 6 months; commonly knees; early childhood onset	1-3 yr	3:1	40–50%; highest among patients of European ancestry[5][8]	Autoimmune; ANA positivity common	Chronic anterior uveitis; limb-length discrepancy	None for early-onset, ANA positive oligoarthritis with uveitis	Treatment: Intraarticular glucocorticoid injections In case of inadequate management, conventional DMARDs such as methotrexate with or without biologic DMARDs such as TNF inhibitors are administered
Polyarticular JIA (RF-negative)	≥5 joints; symmetric small and large joint involvement	Bimodal 1-3 yr and >8 yr	2-4:1	15–20%	Autoimmune; adaptive immune dysregulation	Uveitis; chronic synovitis	Seronegative rheumatoid arthritis	Synthetic DMARDs such as Methotrexate Biologic DMARDs such as TNF inhibitor Targeted biologic DMARDs in case of inadequate control on commonly used biologic ones
Polyarticular JIA (RF-positive)	≥5 joints; resembles adult rheumatoid arthritis	>8 yr	4-13:1	5% among White patients with European ancestry, higher in non-White cohorts[5]	Autoimmune; RF and ACPA positive	Erosive arthritis; functional disability	Seropositive rheumatoid arthritis	Same as RF-negative polyarticular polyarthritis but earlier treatment is recommended
Enthesitis-related arthritis, including juvenile spondyloarthritis and juvenile ankylosing spondylitis	Arthritis with enthesitis	>9 yr	Depends on cohort but approximately 1:1.4–9	9–19%; 33% in parts of eastern and southeastern Asia[5][8]	Mixed autoimmune and autoinflammatory mechanisms	Sacroiliitis; axial disease; chronic pain	Spondyloarthritis, including ankylosing spondylitis	NSAIDS for symptom control Add sulfasalazine or a TNF inhibitor in case of uncontrolled enthesitis. If sacroillitis is present, biologic DMARDs (commonly TNF inhibitor) should be administered. IL-17 inhibitors may be useful in case of unsuccessful treatment with TNF inhibitor
Psoriatic JIA	Arthritis with psoriasis features	Bimodal: 2–4 yr and >9 yr	3:1 for onset at younger age, 1:1 for onset at older age	2–5%[5]	Mixed autoimmune and autoinflammatory mechanisms		Psoriatic arthritis	Early onset disease is treated similarly to oligoarticular or polyarticular arthritis Older children with enthesitis and sacroiliitis receive similar treatment to patients with enthesitis-related arthritis. Biologic medications targeting psoriatic arthritis inhibitors are approved for use in psoriatic JIA
Systemic JIA (Still’s disease)	Arthritis with quotidian fever and evanescent rash	Any age, but somewhat more frequent at 1–5 yr	1:1	10–20% in Europe, United States, and Canada; higher in Asia, Latin America, Africa, and the Middle East[5][8]	Autoinflammatory; innate immune activation (IL-1, IL-6)	Macrophage activation syndrome; serositis; lung disease	Adult-onset Still’s disease	Systemic glucocorticoids are effective for severe systemic [15] IL-1 or IL-6 inhibitors may produce remarkable clinical improvement and remission early in disease course. [28][15][22] TNF inhibitors and methotrexate may be effective in chronic disease. Targeted synthetic DMARDs are emerging therapies for refractory systemic JIA.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]

Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of immune-mediated disorders involving dysregulation of innate and adaptive immunity.^[1]

Juvenile idiopathic arthritis (JIA) comprises a group of disorders with heterogeneous pathophysiologic mechanisms involving dysregulation of the immune system. The relative contributions of innate and adaptive immunity vary by subtype.

In oligoarticular and RF-negative polyarticular JIA, disease is predominantly autoimmune in nature.

• Aberrant activation of adaptive immune responses
• Activation of Th1 and Th17 T lymphocytes and monocytes lead to the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin-6.
• It activates fibro blast-like synoviocytes (FLS) toward an aggressive, proinflammatory phenotype with the production of matrix metalloproteinases, pannus formation, and osteoclast activation, leading to bone erosion.
• CD8 lymphocytes are also recruited and persist in the joint as tissue-resident memory lymphocytes (Trm), which drive joint-specific memory and flares that predominantly involve previously affected joints.
• Although many patients have antinuclear antibodies (ANA), the role of B cells and autoantibodies is unknown.

RF-positive polyarticular JIA shows pathological features similar to that of seropositive rheumatoid arthritis. Activation of Th1 cells and B cells lesults in plasma cells development and autoantibodies production, including anti–citrullinated protein antibodies (ACPA) and RF, with immune complex formation. Neutrophil extracellular traps (NETosis) amplify these autoantibody responses.

Systemic JIA (Still’s disease) is predominantly autoinflammatory in nature. It is characterized by marked activation of neutrophils and monocytes, which is amplified by S100 alarmins leading to inflammasome activation and IL-1 related cytokines production, including interleukin-1β and interleukin-18.

Later in the disease course, systemic JIA can be associated with more autoimmune features, including activation of Th17 and γδ T cells.

Genetic susceptibility, environmental triggers, and immune dysregulation interact to initiate and perpetuate inflammation. The pathophysiologic spectrum of JIA overlaps with adult inflammatory arthritides, with systemic JIA forming a continuum with adult-onset Still’s disease.

Macrophage activation syndrome, a life-threatening acquired form of hemophagocytic lymphohistiocytosis (HLH), occurs in at least 10% of patients with systemic JIA.^[2] Primary (e.g., familial) HLH is caused by rare defects in the perforin pathway.^[3] Acquired HLH can be triggered by infection, cancer, or rheumatic disease flares. This disorder can occur at any point in the progression of systemic JIA. Affected patients present with fever, coagulopathy, cytopenias, hyperferritinemia, liver injury, and central nervous system dysfunction.^[4]

Macrophage activation syndrome supposedly results from Interleukin-18 driving production of interferon-γ production.

Enthesitis-related arthritis and juvenile spondyloarthritis are associated with activation of Th1, Th17, and γδ T cells and a cytokine environment dominated by interleukin-12, interleukin-23, and interleukin-17.

Many patients carry the HLA-B27 allele, which encodes a protein that presents arthritogenic antigens to CD8 cells and drives more innate immune inflammatory responses. Inflammation occur at both entheses and the synovium.

Psoriatic JIA has an overlapping pathogenesis that resembles that of juvenile spondyloarthritis or early-onset and ANA-positive disease (oligoarthritis and RF-negative polyarthritis).

Lung disease pathophysiology is unclear. However, an association with the HLA-DRB1*15 allele may be present.^[5][6][7][8] Several hypotheses involving treatment with interleukin-1 and inter leukin-6 inhibitors have been proposed, including cytokine-related lymphocyte plasticity and an unusual pulmonary complication of drug induced hypersensitivity syndrome (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]).^[5][6][7][8]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]

Juvenile idiopathic arthritis (JIA) is a multifactorial inflammatory disease with no single identifiable cause. It arises from the interaction of genetic susceptibility, immune dysregulation, and environmental triggers. The relative contribution of autoimmune and autoinflammatory mechanisms varies by subtype, with adaptive immunity predominating in most forms and innate immune activation central to systemic JIA.

The exact cause of juvenile idiopathic arthritis (JIA) is unknown. JIA is considered a multifactorial disease resulting from the interaction of genetic susceptibility, immune dysregulation, and environmental triggers.

• Genetic factors: Certain genetic variants, including associations with human leukocyte antigen (HLA) alleles, increase susceptibility to JIA. Genetic risk differs among subtypes, with stronger autoimmune associations in oligoarticular and polyarticular JIA and innate immune pathway involvement in systemic JIA.
• HLA-DRB1*11 is present in systemic JIA.
• HLA-DRB1*15 is associated with lung disease. *
• HLA-B27 is present in many ERA patients.
• Variants in HLH-related genes have been found in up to one third of patients with systemic JIA in whom macrophage activation syndrome devel oped.56,57^[1][2]

• Immune dysregulation: Abnormal activation of the immune system leads to persistent synovial inflammation. Adaptive immune mechanisms predominate in most JIA subtypes, whereas systemic JIA is driven primarily by innate immune activation.

• Environmental triggers: Infections or other environmental exposures may act as initiating triggers in genetically predisposed individuals, although no single infectious agent has been consistently identified.

• Loss of immune tolerance: Failure of normal immune regulatory mechanisms results in sustained inflammation, autoantibody production in some subtypes, and chronic joint damage.

Overall, JIA arises from a complex interplay of genetic and environmental factors leading to chronic immune-mediated inflammation rather than a single identifiable cause.

^[3]

The cause of JIA, as the word idiopathic suggests, was supposed to be unknown and currently an area of active research.^[4] Current understanding of JIA also suggests that it arises in a genetically susceptible individual due to environmental factors.^[5]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]

Please help WikiDoc by adding more content here. It’s easy! Click here to learn about editing.

Juvenile idiopathic arthritis is a diagnosis of exclusion. A broad range of infectious, malignant, autoimmune, autoinflammatory, and noninflammatory conditions can mimic its presentation. Careful clinical evaluation, laboratory testing, and imaging are essential to exclude alternative diagnoses, particularly infection and malignancy, before confirming juvenile idiopathic arthritis.

The diagnosis of juvenile idiopathic arthritis (JIA) is a diagnosis of exclusion.

There is no definitive diagnostic test.

Several inflammatory, infectious, malignant, other autoinflammatory and noninflammatory conditions should be excluded before establishing the diagnosis.

Clinical presentation may mimic Familial Mediterranean fever.

Explicit warning in systemic JIA: rule out infection and cancer before treatment if arthritis absent.

• Septic arthritis
• Osteomyelitis
• Lyme disease
• Viral arthritis (e.g., parvovirus B19, Epstein–Barr virus)
• Tuberculosis

• Acute lymphoblastic leukemia
• Lymphoma
• Primary bone tumors

Malignancy should be suspected in children with bone pain disproportionate to examination findings, systemic symptoms, cytopenias, or poor response to anti-inflammatory therapy.

• Systemic lupus erythematosus
• Vasculitides (e.g., Kawasaki disease, polyarteritis nodosa)
• Dermatomyositis
• Inflammatory bowel disease–associated arthritis
• Sarcoidosis

• Periodic fever syndromes
• Cryopyrin-associated periodic syndromes
• Familial Mediterranean fever

These conditions are particularly relevant in the differential diagnosis of systemic JIA due to overlapping fever and inflammatory features.

• Joint hypermobility syndromes
• Trauma or overuse injuries
• Reactive arthralgia
• Growing pains

A thorough history, physical examination, laboratory evaluation, and appropriate imaging are essential to exclude alternative diagnoses before confirming JIA. ^[1]

Category	Conditions	Distinguishing Features
Infectious	Septic arthritis (including kingella in young children) Osteomyelitis Lyme disease Viral arthritis (e.g., parvovirus, Epstein–Barr virus, hepatitis B virus, rubella virus, chikungunya virus) Tuberculosis	Acute onset; fever with marked pain; elevated inflammatory markers; positive cultures or serology; poor response to anti-inflammatory therapy
Postinfectious disorder	Acute rheumatic fever Poststreptococcal reactive arthritis Other reactive arthritis (transient synovitis, postdysenteric reactive arthritis)	ARF presents as migratory polyarthritis affecting large joints (knees, ankles, elbows, wrists) that responds dramatically to salicylates or NSAIDs within days. Carditis is the hallmark feature. PSRA presents as nonmigratory, persistent arthritis that does not respond to aspirin, distinguishing it from ARF. Transient synovitis is a self-limiting inflammatory condition predominantly affecting children, often triggered by viral infection. Postdysenteric reactive arthritis follows gastrointestinal infections and typically presents as asymmetric mono- or oligoarthritis of lower extremities with enthesitis as a hallmark feature.
Malignancy	Acute lymphoblastic leukemia Lymphoma Primary bone tumors	Bone pain out of proportion to exam; night pain; systemic symptoms; cytopenias; poor response to NSAIDs
Autoimmune / Inflammatory	Systemic lupus erythematosus Mixed connective-tissue disease Sjögren’s syndrome Juvenile dermatomyositis Vasculitis (including Kawasaki’s disease and IgA vasculitis) Sarcoidosis Arthritis related to inflammatory bowel disease Celiac disease	Multisystem involvement; characteristic laboratory findings (autoantibodies, complement abnormalities); variable arthritis pattern
Autoinflammatory Syndromes	Periodic fever syndromes Cryopyrin-associated periodic syndromes Familial Mediterranean fever Nonbacterial osteomyelitis (chronic, recurrent multifocal osteomyelitis)	Recurrent fevers; inflammatory episodes without autoantibodies; strong genetic or familial patterns
Noninflammatory / Mechanical	Joint hypermobility syndromes Trauma or overuse injuries Reactive arthralgia Growing pains	Normal inflammatory markers; absence of persistent synovitis; symptoms related to activity or growth
Bone disease	Avascular necrosis Osteochondritis dissecans Skeletal dysplasias Vitamin C and other vitamin deficiencies	The distinguishing features of these bone diseases compared to juvenile idiopathic arthritis (JIA) center on the absence of inflammatory markers and joint inflammation in the bone disorders, along with characteristic imaging and clinical patterns specific to each condition.
Primary immunodeficiency	Inborn errors of immunity	IEI should be suspected when arthritis presents very early in life, particularly with a positive family history.
Pain amplification	Juvenile fibromyalgia Complex regional pain syndrome type 1	Juvenile Fibromyalgia: Widespread musculoskeletal pain , not confined to a single limb Absence of objective physical findings such as swelling, color changes, or temperature asymmetry Complex regional pain syndrome (CRPS) type 1 is distinguished by: Regional distribution Objective autonomic signs, Typical post-traumatic onset

Abbreviations: ABG= Arterial blood gas, ANA= Antinuclear antibody, ANP= Atrial natriuretic peptide, ASO= Antistreptolysin O antibody, BNP= Brain natriuretic peptide, CBC= Complete blood count, COPD= Chronic obstructive pulmonary disease, CRP= C-reactive protein, CT= Computed tomography, CXR= Chest X-ray, DVT= Deep vein thrombosis, ESR= Erythrocyte sedimentation rate, HRCT= High Resolution CT, IgE= Immunoglobulin E, LDH= Lactate dehydrogenase, PCWP= Pulmonary capillary wedge pressure, PCR= Polymerase chain reaction, PFT= Pulmonary function test.

Diseases		Clinical manifestations								Para-clinical findings									Gold standard	Additional findings
		Symptoms					Physical examination
										Lab Findings				Imaging				Histopathology
		Headache	Fever	Weight loss	Arthralgia	Claudication	Bruit	HTN	Focal neurological disorder	Biomarker	CBC	ESR	Other	CT scan	Angiography	Ultrasound/ Echocardiography	Other
Kawasaki disease[1]		–	+	+/-	+	+	–	+/-	–	NT-proBNP, Meprin A, Filamin C	Normochromic anemia, ↑WBC with a left shift, Thrombocytosis	↑	Acute-phase reactants, ↓Cholesterol, ↓HDL, ↓ApolipoA	Coronary artery calcifications	Coronary artery aneurysms, stenosis or occlusion	Coronary artery anomaly in echocardiography	Electron beam CT (EBCT)	Acute destruction of the media by neutrophils, with loss of elastic fibers	History and physical examination	Diarrhea, Vomiting
Polyarteritis nodosa[2]		+	+	+	+	+	+	+/-	+/-	LAMP-2 protein autoantibodies	Leukocytosis, Normochromic anemia, Thrombocytosis	↑	↑ Cr or BUN, ↑ ALT or AST, Proteinuria	Focal regions of infarction or hemorrhage	Multiple microaneurysms, Hemorrhage due to focal rupture, Occlusion	Aneurysms and renal arteriovenous fistula in color Doppler sonography	–	Necrotizing inflammatory lesions	Angiography	Sudden weight loss, Abdominal pain
Hepatitis B virus-associated polyarteritis nodosa[3]		+/-	+/-	+	+	+/-	+/-	+	–	HBsAg	Leukocytosis, Normochromic anemia, Thrombocytosis	↑	↑ ALT or AST	Focal regions of infarction or hemorrhage	Microaneurysms in mesenteric artery	Aneurysms and renal arteriovenous fistula in color Doppler sonography	–	Necrotizing inflammatory lesions	Angiography	Peripheral neuropathy, Livedo reticularis
Infectious disease	Parvovirus B19 infection[4]	+	+	+	+	–	–	–	+/-	B19 DNA, ↓Reticulocyte count	Anemia	↑	anti–parvovirus B19 IgM	–	–	Hydrops in fetal ultrasonography	–	–	B19 DNA	Purpuric rash, Erythema multiforme
	Scarlet fever[5]	+	+	+/-	+	–	–	–	–	Antistreptolysin-O (ASO) titers	Leukocytosis	↑	↑CRP	Thickened pulmonary markings if pneumonia	–	–	–	Sparse neutrophilic perivascular infiltrate	History and physical examination	Sand-paper rashes, Sore throat
	Toxic shock syndrome[6]	+	+	+	+	–	–	–	+/-	Procalcitonin	Leukocytosis with left shift	↑	Myoglobinuria, Sterile pyuria	Acute respiratory distress syndrome	–	–	–	Necrolysis of keratinocytes in epidermis, Perivascular lymphocytic infiltrate	Clinical criteria	Peeling or rashes, Organ dysfunction
	Mononucleosis[7]	+	+	+	+	–	–	–	–	EBV DNA	Atypical lymphocyte	↑	Heterophile antibodies	CNS involvement	–	Splenomegaly	Encephalitis in MRI	Lymphoproliferative response in oropharynx, Lymphocytic infiltration in spleen	Heterophile antibody test	Splenomegaly, Palatal petechiae
	Leptospirosis[8]	+	+	+	+	+/-	–	–	–	IL-6, IL-8 and IL-10	Anemia	–	↑Cr or BUN, ↑ALT or AST, Proteinuria	Diffuse alveolar hemorrhage	–	–	–	Toxin-mediated break down of endothelial cell membranes of capillaries	Culture and the microscopic agglutination test	Red eyes, Skin rash
	Lyme Disease[9]	+/-	+	+/-	+	+/-	–	–	–	CXCL9 (MIG), CXCL10 (IP-10) and CCL19 (MIP3B)	Leukopenia, Thrombocytopenia	–	Microscopic hematuria, Proteinuria, ↑ALT or AST	Punctate lesions in periventricular white matter in brain SPECT	–	–	–	Acrodermatitis chronica atrophicans	Serologic tests	Erythema migrans
	Measles[10]	+/-	+	+/-	+	–	–	–	–	Measles IgM	Leukopenia, Lymphocytosis, Thrombocytopenia	–	↑ALT or AST	Pneumonia	–	–	CXR	Spongiosis and vesiculation in the epidermis with scattered dyskeratotic keratinocytes	PCR	Generalized rash, Cough, Coryza, or Conjunctivitis
	Rocky Mountain Spotted Fever[11]	+	+	+	+	–	–	–	–	R rickettsii serology	Thrombocytopenia, Anemia	–	↑ALT or AST, Hyponatremia	Infarction, edema, and meningeal enhancement	–	Myocardial or conduction abnormalities in echocardiography	–	Immunofluorescent or immunoperoxidase staining of R rickettsii	Clinical criteria and tick exposure	Rash on the palms and soles
	Staphylococcal Scalded Skin Syndrome[12]	+	+	+	+	–	–	+/-	+/-	Anti exfoliatin and anti alpha-toxin antibodies	Leukocytosis with left shift	↑	Blood culture	Pneumonia	–	–	–	Intraepidermal blister, dense superficial perivascular lymphohistiocytic infiltrate	Blood culture and clinical findings	Widespread skin erythema, fluid-filled blisters
	Toxic Epidermal Necrolysis[13]	–	+	+	–	–	–	–	+/-	MicroRNA-124	Normochromic normocytic anemia, Eosinophilia	↑	Fluid loss and electrolyte abnormalities	Tracheobronchial inflammation	–	–	–	Necrotic keratinocytes with full-thickness epithelial necrosis	Histopathology and clinical findings	Erythematous macular rash with purpuric centers
Systemic disease	Antiphospholipid Syndrome[14]	+	+	–	–	–	–	–	+/-	Antiphospholipid antibodies	Thrombocytopenia, Hemolytic anemia	–	Lupus anticoagulant (LA)	Stroke, Pulmonary embolism, Budd-Chiari syndrome	Thrombus in major vessels	Valve thickening, vegetations, or insufficiency in echocardiography	–	Noninflammatory bland thrombosis without perivascular inflammation	Hx of thrombosis and antiphospholipid antibodies	Miscarriage, Pulmonary hypertension
	Juvenile Idiopathic Arthritis[15]	–	–	–	+	+/-	–	–	–	Rheumatoid factor (RF), S100A12	Lymphocytosis, Thrombocytopenia	↑	Myeloid-related proteins 8/14 (MRP8/14)	Synovial hypertrophy, Joint effusions	Cerebral vasculitis	Inflamed synovium	Bone scanning	Vascular congestion, RBC extravasation, Venular lumen occlusion	Conventional radiography	Evanescent rash, Dactylitis

Table below provides a differential diagnosis of disorders affecting the joints:^[16]

• Juvenile Rheumatoid Arthritis (JRA)
• Chronic Recurrent Multifocal Osteomyelitis (CRMO)
• Rickets

Disease name	Age of onset	Signs/Symptoms	X-ray findings	MRI findings
NOMID/CINCA[16][17]	Early infancy	Parietal and frontal bossing Joint pain Knee valgus or varus Limb length differences Saddleback nose Contractures Urticaria-like rash Fever Chronic aseptic meningitis	Physis is the epicenter Early radiograph: enlargement of the unossified physis, resulting in a mass-like lesion Late radiograph: stippled ossification/calcification causing deformed adjacent epiphysis Possible involvement of multiple joints simultaneously or at different times	Enlarged, heterogenous physis with hypointense calcifications on T1 & T2 weighted images Heterogenous enhancement at the physis in post-gadolinium images Presence of popliteal lymph node Absence of bony erosion
Juvenile Rheumatoid Arthritis (JRA)[18][19]	Younger than 16 years old	Fever Arthritis Rash Lymphadenopathy Hepatosplenomegaly	Involvement of the articular surface of the joints Initially, soft tissue swelling and enlarged epiphyseal enlargement due to hyperemia As the disease progresses, joint space narrowing and bony erosion are the dominant features	First, joint effusion, cartilage thinning and loss Later, joint erosion and evidence of secondary osteoarthritis Potential complications such as avascular necrosis
Chronic Recurrent Multifocal Osteomyelitis (CRMO)[20][21][22]	Childhood and adolescence	Episodes of pain and joint swelling Fever may be present or not may occur as part of a syndrome or alone	Multiple symmetrical metaphyseal lesions Lesions ranges between purely osteolytic, osteolytic with a sclerotic rim, mixed lytic and sclerotic, and purely sclerotic	Early phases: marrow edema with hypointense appearance on T1-weighted images Hyperintense on T2-weighted images Synovial thickening Joint effusion Destruction of joint cartilage Subchondral bone
Rickets[23][24]	Childhood (depends on the severity of deficiency)	Delay in fontanel closure Parietal and frontal bossing Rachitic rosary Harrison sulcus (or groove) Widening of the wrist Bowing of the distal radius and ulna Progressive lateral bowing of long bones	Widening, cupping and fraying of the metaphysis Irregular and widened epiphyseal plate Periosteal reaction	High signal intensity of unossified cartilage in the physis of the primary and secondary ossification centers No mass lesion or ossification in the physis

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]

Juvenile idiopathic arthritis is the most common chronic inflammatory rheumatic disease of childhood. It occurs worldwide with variable incidence and prevalence. Disease onset is before 16 years of age, with a female predominance overall, although sex distribution and age at onset vary by subtype.

Despita Juvenile idiopathic arthritis being a common diagnosis, its incidence and prevalence aree unclear. Estimates vary, depending on research methods, geographic location, and the racial and ethnic compositions of study populations.^[1][2][3][4] It affects an estimated 30 cases per 100,000 children in Europe and North America.^[2][5]

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of childhood. The incidence and prevalence vary by geographic region, ethnicity, and subtype.

• The prevalence is estimated at 30 cases per 100,000 children in Europe and North America
• Disease onset occurs before 16 years of age, with peak incidence in early childhood
• Overall, females are affected more frequently than males
• Age at onset varies by subtype, with early childhood predominance in oligoarticular JIA and later childhood or adolescence in polyarticular and enthesitis-related disease
• Geographic and ethnic variation in subtype distribution and disease severity has been reported, suggesting contributions from genetic and environmental factors.^[6]

Subtype-specific demographic patterns are observed.

• Oligoarticular JIA:
• It is the most common subtype representing approximately 40% of 50% of JIA cases. It predominantly affects girls aged 1–5 years.
• Polyarticular JIA:
• RF-Negative subtype is more common representing 15-20% of JIA cases with bimodal peak incidence between 1-3 years and >8 years. It predominantly affects girls.
• RF-Positive subtype is less common representing only 5% of JIA cases. It usually affects older children and adolescents, uncommon under the age of 9.
• Systemic JIA:
• It accounts for approximately 10-15% of all JIA cases. It affects males and females equally. It can occur at any pediatric age.
• Enthesitis-related arthritis:
• Its prevalence ranges between 9-19%, Prevalence may raise to 33% in parts of Eastern and Southeastern Asia. It is uncommon before 6 years of age. It is more common in males
• Psoriatic JIA:
• Bimodal peak incidence at 2-4 years of age and >10 years of age.
• Younger patients have a similar presentation to early-onset oligoarticular and RF-negative polyarticular JIA in terms of female predominance, ANA positivity and risk of chronic anterior uveitis.
• Psoriasis affects 50% of the patients but may appear later in disease course
• HLA-B27 is positive in 10 to 12% of patients.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dheeraj Makkar, M.D.[2] Nehal Eid, M.D.[3]

Juvenile idiopathic arthritis may lead to significant articular and extra-articular complications, including joint damage, growth disturbances, ocular disease, and systemic inflammatory sequelae. The risk and severity of complications vary by disease subtype and duration of uncontrolled inflammation. Early diagnosis and timely initiation of effective therapy are critical to minimizing long-term morbidity and preserving function. Before the 2000s, 25 to 40% of JIA cases had moderate-to-severe disease, with lifelong complications.^[1][2] Since the development of the new anti-inflammatory, biologic disease-modifying antirheumatic drugs (DMARDs) in 1999, there has been a noticeable decrease in joint destruction, joint deformities, and disease-related disability previously seen in patients with JIA.

The natural history of juvenile idiopathic arthritis (JIA) is heterogeneous and varies according to disease subtype, age at onset, and response to therapy. Disease course may be monophasic, relapsing–remitting, or persist into adulthood. Treatment-free remission is uncommon, with many patients needing treatment in adulthood. Up to 70% achieve meaningful disease control with modern therapies. Disease flares are common after therapy stoppage ranging from 30% up to 100%. 50% of patients don’t fully regain control after disease flare.

• Some patients experience a self-limited course with remission within months to years
• Others develop chronic, progressive arthritis with joint damage and functional impairment
• Oligoarticular JIA may remain limited or progress to extended disease. 50% of patients have persistent oligoarticular course, the other 50% have extended disease. High ESR and wrist/ankle affection predict extensive course.
• Symptomatic axial involvement (sacroillitis, inflammatory spine disease, or both) develops in 40 to 60% of patiets withh enthesitis related arthritis. Asymptomatic sacroillitis is present in 30% of patients at time of disease onset.
• Polyarticular JIA is more likely to follow a chronic course, particularly in RF-positive disease
• Systemic JIA may evolve from predominant systemic inflammation to chronic destructive arthritis

Extra-articular complications, including uveitis, growth disturbances, lung disease and macrophage activation syndrome, may influence long-term outcomes. Advances in early diagnosis and biologic therapy have significantly improved disease control and functional prognosis. ^[3]

Juvenile idiopathic arthritis (JIA) may be associated with a range of articular and extra-articular complications that vary by disease subtype, severity, and duration of inflammation.

A serious complication in patients with systemic JIA is lung disease, which can cause hypoxic respiratory failure and even death.^[4][5] The prevalence of lung disease among patients with systemic JIA is increasing and appears to be temporally associ ated with the increased use of interleukin-1 and interleukin-6 inhibitors. Children with systemic JIA and lung disease are generally younger at diagnosis and have more severe systemic disease (including macrophage activation syndrome).

• Chronic synovitis leading to joint damage and deformity
• Reduced range of motion and functional impairment
• Limb-length discrepancy due to asymmetric growth at epiphyseal growth plates as a result of inflammatory hyperemia.^[6]
• Temporomandibular joint involvement causing facial asymmetry and micrognathia.^[7] Usage of contrast enhanced MRI helps in early detection of temporomandibular joint arthritis and timely treatment may prevent severe micrognathia, facial deformities, heterotopic calcification, and jaw dysfunction.^[8]
• Growth retardation related to chronic inflammation or glucocorticoid exposure before DMARD development

• Prevalence: It presents within 10 to 30% of patients, according to JIA classification, with highest prevalence among girls under 6 years with positive ANA.^[9] It is particularly common in ANA-positive oligoarticular and RF-negative polyarticular JIA or psoriatic arthritis.^[10]It is less common in older ages and rare in systemic JIA, RF-positive polyarticular JIA, or enthesitis-related arthritis. 90% of cases occur within 4 years of disease onset.
• Complications: Increased risk of cataracts, glaucoma, band keratopathy, and vision loss if untreated
• Screening: Ophthalmologic proactive screening is recommended every 3 to 6 months for several years after diagnosis due to asymptomatic initial disease course.^[11][12][13]
• Treatment: Topical glucocorticoid eye drops can be used initially, but more than 40% eventually require systemic therapy, usually with methotrexate, a TNF inhibitor, or both.^[14]

It affects 11 to 13% of JIA patients. It is usually seen in enthesitis-related arthritis. It presents as rapid onset ophthalmoplegia, conjunctival erythema and photophobia. It responds well to topical glucocorticoids but systemic DMARDS should be considered in case of two or three annual episodes of acute anterior uveitis.

• Macrophage activation syndrome, a life-threatening hyperinflammatory state most commonly associated with systemic JIA, it is prevalent in at least 10% of patients with systemic JIA.^[15] It can occur at any point in the disease progression. Affected patients present with fever, coagulopathy, cytopenias, hyperferritinemia, liver injury, and central nervous system dysfunction.^[16] Patients often have marked elevation of IL-18 inducing Interferon-gamma production.^{[17] [18]}Interferon gamma inhibitors are effective in treatment.^[19] Other therapeutic modalities include high dose glucocorticoids and high dose IL-1 inhibitors.^[20]
• Serositis, including pericarditis and pleuritis
• Interstitial lung disease and pulmonary hypertension, particularly in systemic JIA with increasing prevalence that appears to be temporally associated with IL-1 and IL-6 inhibitors. Several pathogenesis hypotheses involving treatment with IL-1 and IL-6 inhibitors have been proposed, including cytokine-related lymphocyte plasticity and an unusual pulmonary complication of drug induced hypersensitivity syndrome.^[21][22] More studies are needed to determine disease pathogenesis, as well as effective approaches to identification, screening, and management.^[23][24] Children with systemic JIA and lung disease are often diagnosed earlier and have more severe systemic disease.

• Chronic pain and fatigue
• Impaired quality of life and psychosocial stress
• Persistence of active disease into adulthood requiring long-term rheumatologic care

Early recognition and appropriate treatment are essential to reduce the risk of long-term complications and improve functional outcomes.

^[25]

• Wearing away or destruction of joints (can occur in patients with more severe JRA)
• Slow rate of growth
• Uneven growth of an arm or leg
• Loss of vision or decreased vision from chronic uveitis (this problem may be severe, even when the arthritis is not very severe)
• Anemia
• Swelling around the heart (pericarditis)
• Chronic pain, poor school attendance

The prognosis of juvenile idiopathic arthritis (JIA) is variable and depends on disease subtype, age at onset, severity of inflammation, and response to treatment. Many patients achieve clinical remission with modern therapy, while others experience persistent or relapsing disease.

• Oligoarticular JIA generally has a favorable prognosis, particularly when disease remains limited
• Polyarticular JIA, especially RF-positive disease, is more likely to follow a chronic and erosive course
• Systemic JIA may be monophasic, relapsing, or evolve into chronic arthritis
• Early diagnosis and use of biologic therapies are associated with improved functional outcomes
• Some patients continue to have active disease or disability into adulthood

Overall, advances in early intervention and targeted biologic treatments have significantly improved long-term outcomes and quality of life for many patients with JIA.

JRA is seldom life threatening. Children who have many joints involved, or who have a positive rheumatoid factor are more likely to have chronic pain and poor school attendance, and to be disabled.

Long periods with no symptoms are more common in those who have only a small number of joints involved. Many patients with JRA eventually go into remission with very little loss of function and deformity.

^[26]

Template:WH Template:WS