Definition

J Rheumatol. 2004 Feb;31(2):390-2.
Lancet. 2011 Jun 18;377(9783):2138-49.

Juvenile Idiopathic Arthritis (JIA) refers to a heterogeneous group of diseases that share the common feature of arthritis of unknown origin occurring before the age of sixteen. JIA is an inflammatory disorder that primarily affects synovial joints. Each subtype has distinct clinical, immunologic and genetic features. Together, the subtypes of JIA comprise the most common chronic rheumatic disease of childhood.

To be considered JIA, onset of the disease must take place before the age of sixteen, be characterized by inflammation in at least one joint, and last for at least six weeks.

Classification

J Rheumatol. 2004 Feb;31(2):390-2.
Lancet. 2011 Jun 18;377(9783):2138-49.
Orthop Clin North Am. 2012 Apr;43(2):213-25, vi.

The International League of Associations for Rheumatology (ILAR) classification is the most commonly used schema, and includes 8 subtypes. ILAR sought to create mutually exclusive homogeneous subgroups under JIA for research and prognostic purposes, but challenges to classification persist.

Table 1: ILAR classification of JIA (2001)

Type

Features

Systemic JIA 

Arthritis in 1 or more joints with or preceded by fever of at least 2 weeks’ duration that is documented to be daily for at least 3 days, and accompanied by one or more of the following features of systemic inflammation:

  • Evanescent, erythematous rash
  • Lymphadenopathy
  • Hepatomegaly and/or splenomegaly
  • Serositis

Number of joints affected varies, and arthritis may develop after systemic symptoms improve. Early destructive joint change is characteristic.

Oligoarthritis

Arthritis affecting up to 4 joints during the first 6 months of disease.

  • Persistent type: Affecting not more than 4 joints throughout the disease course
  • Extended type: Extending to affect more than 4 joints after six months

Polyarthritis

Arthritis affecting 5 or more joints in the first 6 months of disease.

  • RF positive: at least 2 positive tests for RF at least 3 months apart during the first 6 months of disease.
  • RF negative

Psoriatic arthritis

Arthritis and psoriasis, or arthritis and at least 2 of:

  • Dactylitis
  • Nail pitting or onycholysis
  • Psoriasis in a first-degree relative

Enthesitis-related arthritis 

Arthritis and enthesitis, or arthritis or enthesitis with at least 2 of:

  • The presence of or a history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain
  • The presence of HLA-B27 antigen
  • Onset of arthritis in a male after age 6
  • Acute (symptomatic) anterior uveitis
  • History of any of the following in a first-degree relative: ankylosing spondylitis, enthesitis relatedarthritis, sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis

Undifferentiated arthritis

Arthritis that fulfills criteria in no category or in 2 or more of the above categories.

Classification table notes

RF: Rheumatoid factor
HLA: Human leukocyte antigen
Dactylitis: inflammation of an entire digit (finger or toe)
Serositis: inflammation of a serous membrane (pleura, pericardium, or peritoneum)
Enthesitis: inflammation of an enthesis, the site where a ligament or tendon inserts into bone

Pathogenesis

Orthop Clin North Am. 2012 Apr;43(2):213-25, vi.
Clin Rev Allergy Immunol. 2013 Oct;45(2):227-35.
Autoimmun Rev. 2011 Jun;10(8):482-9.
Immunol Rev. 2006 Aug;212:8-27.
Int J Inflam. 2012;2012:271569.
Nelson Textbook of Pediatrics, 19e, Ch 150
Hochberg Rheumatology 5e, Ch 99
Curr Opin Rheumatol. 2011 Sep;23(5):437-43.

The triggers that initiate and progress the pathology of JIA have not been identified

As with other autoimmune conditions, both genetic susceptibility and environmental factors are implicated in producing disease. 

The overarching mechanism in all JIA subsets is aberrant activation of the immune system. Different components of the immune system are involved in each subtype, and additional variation may exist within subtypes.

One major distinction lies in whether the aberrancy involves the innate or adaptive immune system, described as autoinflammatory and autoimmune processes, respectively.

Autoinflammatory vs. autoimmune disorders

In autoinflammatory processes, the innate immune system is responsible for tissue inflammation. The autoinflammatory diseases are a group of hereditary conditions that cause recurrent, unprovoked inflammation in the absence of infection (e.g. systemic JIA). 

Autoimmune processes involve the adaptive immune system and are based on antigen-dependent T-lymphocyte and B-cell autoantibody production. Autoimmune disease results when immune reactions are triggered by environmental factors in a genetically susceptible individual and when these reactions produce clinically significant signs and symptoms. Autoimmune diseases are often characterized by the presence of autoantibodies against autoantigens such as DNA, cell surface molecules, and intracellular proteins. Autoimmune conditions have strong associations with HLA phenotypes.

Cytokine dysregulation is common to the pathogenesis of both autoinflammatory and autoimmune diseases. For example, IL-1β is the proinflammatory cytokine most involved in autoinflammatory diseases. IL-1β binds to its receptor (IL-1R type I) and thus induces the transcription of proinflammatory genes leading to inflammation and tissue damage.

Disorders of innate and adaptive immunity most likely represent a spectrum of immune dysfunction, with many rheumatologic conditions being polygenic in nature.

Pathogenetic mechanisms by JIA subtype

Systemic arthritis (10-20% of JIA cases)

Autoinflammatory disease involving a predominant abnormality of the innate immune system. The trigger is unknown. The multi-system inflammation seen in this subtype is due to complex underlying interactions of immune cells, and the host of cytokines they produce.

Early in the disease process, cells of the innate immune system (monocytes, macrophages and neutrophils) are activated, and secrete pro-inflammatory cytokines and proteins (such as IL-1 β, IL-6, IL-8, IL-18, TNF-a, and macrophage colony-stimulating factor). These cytokines amplify the inflammatory process and generate clinical signs and symptoms. For example, IL-1β has been observed to produce fever, anorexia, pain hypersensitivity, joint destruction, vasculitis, and thrombosis.

Serology: classically negative for RF and ANA

Genetics: No association with HLA genes. Genetic studies have mainly demonstrated mild contributions from cytokine/chemokine gene polymorphisms involving the promoter elements and genes encoding IL-6 and macrophage inhibitory factor (MIF).

Environment: A seasonal pattern of onset suggests a viral etiology. To date, only parvovirus B19 infection has been reported in association with the onset and exacerbation.

Oligoarticular arthritis (50-60%) and polyarticular arthritis (30-35%)

Despite subtle but important molecular differences in the immunopathology of oligo- and polyarticular JIA, the main concepts, presented here, are similar.

Oligo-/polyarticular JIA are understood to be autoimmune diseases involving a predominant abnormality of the adaptive immune system, particularly T cells, but with emerging evidence for a component of innate immune system dysfunction.

It is antigen-driven and lymphocyte-mediated; involves both inappropriate generation of inflammation, and a lack of the normal anti-inflammatory balance.

Auto-antigen(s) (which are not known) in joint tissue activate autoreactive T cells (T helper cells, Th1 and Th17), which produce pro-inflammatory cytokines, namely IFN-γ and IL-17. Large numbers of autoreactive T cells can be found in the arthritic joint, clustered around antigen-presenting cells. 

At the same time, regulatory T cells (CD4+ and CD25+) seem to be inhibited by the milieu of inflammatory factors; TNF and 1L-6, for example, inhibit their activity. Treg cells normally function to maintain immunologic self-tolerance and negative control in both physiological and pathological immune responses.They can actively prevent the activation and effector function of autoreactive T cells that escape other mechanisms of tolerance. In JIA their function appears to be inhibited, and the inflammatory balance is disrupted in favour of inflammation. Self-tolerance to the auto-antigen is lost, and synovial inflammation results. 

The complex balance between pro- and anti-inflammatory mediators in the arthritic joint determines progression and outcome of disease.

Serology:

ANA: positive in 75-85% of oligoarticular JIA; 50-80% of RF- polyarticular, ~55% in RF+. Children who are ANA positive are at high risk of developing chronic uveitis.

RF: Present in <25% of polyarticular JIA. Children with RF positivity are at risk for more extensive and aggressive disease.

Genetics: Oligoarticular JIA has been consistently associated with HLA genes (HLA-A, HLA-B, and HLA-DR), though these associations are observed in girls and not boys suggesting further disease heterogeneity. Polyarticular JIA has been reported to be associated with HLA-DR4. Genetic association with HLA grants further evidence for oligo/polyarticular JIA as a disease of adaptive immunity. Other genes that may influence the onset or severity of disease include those that regulate cellular activation and cytokine responses (e.g. those encoding TNF-α, MIF, IL-6, and IL-1α). Further, certain cytokine alleles may predispose to upregulation of inflammatory cascades responsible for more severe articular disease.

Environment: In general, infectious agents are the most important environmental factors in the development of autoimmunity. A potential mechanism is the cross-reactive immune response induced through molecular mimicry. The inflammatory response to infection may also support sensitization to auto-antigens through increasing their immunogenicity – for example, antigen-presenting cells may inadvertently prime T cells with broad specificities to the auto-antigen. Infectious agents that have been suggested as triggers include viral infections with influenza A, rubella and parvovirus B19 (though their pathogenicity is still not well proven), and bacterial infections with Mycoplasma pneumoniae and group A streptococcus. Additional risk factors include maternal cigarette smoking, psychological stress and joint trauma.

Enthesitis-related arthritis (ERA)/Spondylo-arthropathies (SpA) (10%)

ERA encompasses Ankylosing Spondylitis, Reactive Arthritis, and Arthritis associated with IBD (though the term “spondyloarthropathies” also includes psoriatic arthritis when sacroiliitis or spondylitis is present).

Traditionally considered to be an autoimmune disease triggered by GI or GU infections in HLA-B27 positive individuals (i.e. infection induces CD8–T-cell clones that react against bacterial antigens and auto-antigens in joint tissue).Recently, an autoinflammatory component has been suggested, with HLA-B27 playing a role in triggering the innate immune system. Specifically, the HLA-B27 molecule may be prone to misfolding within the cell’s endoplasmic reticulum, activating the innate immune system.

Further, it is hypothesized that tissues exposed to either bacterial or mechanical stress (e.g. gut and synovium) are particularly vulnerable to increased immunogenicity. Repeated microtrauma of joints and entheses releases molecules like fibronectin. This activates synovial macrophages via toll-like recep- tors and other pattern-recognition molecules, which leads to the up-regulation of approximately 600 stress-related genes.

A characteristic feature of SpA is subclinical gut inflammation, with up to two-thirds of SpA patients affected and demonstrating histological changes similar to those with Crohn’s disease. Surgical studies have demonstrated a causal link between Inflammatory Bowel Disease (IBD) and SpA, in which patients with ulcerative colitis who underwent colectomy were cured of arthritis. IBD and SpA are linked genetically, both involving polymorphisms of the genes coding for the IL23 receptor and the TNF ligand superfamily. These genes play important roles in mucosal and innate immune responses.

Genetics: Genetics play a major role, with 80-90% of patients with ankylosing spondylitis being HLA-B27 positive. Other genetic factors have been implicated in the perpetuation of inflammation through cytokines (e.g. polymorphism in or near the TNF, IL-1 and IL-23 loci), further supporting the hypothesis that ERA involves innate immune system dysfunction.

Environment: Enteric infection with certain gastrointestinal or genital pathogens can trigger reactive arthritis; environmental triggers for other forms of spondyloarthritis have not been identified.

Psoriatic arthritis (PsA) (5%)

Though grouped under the same subtype, early- and late-onset PsA have strikingly different clinical features; genetic and immunological studies point to equally different pathogenetic mechanisms.

Early-onset subtype: Peak incidence age 2-3, with female predisposition. It appears to have association with HLA alleles other than B27 (e.g. HLA-DR5). It is characterized by ANA seropositivity in 50%, chronic uveitis, and shares substantial clinical features with early-onset oligo- and polyarticular JIA, therefore raising the possibility that dysfunction of the adaptive immune system plays a dominant role. Enthesitis and axial involvement are not seen.

Later-onset subtype: Peak incidence age 10-12, with male predisposition. It is associated with HLA-B27 positivity, and carries additional features consistent with spondyloarthritis such as enthesitis, axial disease and subclinical gut inflammation. Because of the clinical similarity between older-onset PsJIA and and other spondyloarthritides, innate immunologic mechanisms likely play a critical role in pathogenesis (see ERA Pathophysiology, just above). Classically ANA negative.

Dacytilitis is seen in both subtypes, and thus may be caused by a combination of adaptive immunologic and innate autoinflammatory mechanisms. It follow that, even though early- and late-onset PsA appear to have different arms of the immune system playing a dominant role, both are ultimately involved in each.

Clinical features

Int J Inflam. 2012;2012:271569.
Kelleys Textbook of Rheumatology, 9e, Ch 106
Nelson Textbook of Pediatrics, 19e Ch 149 & 150
Adolesc Health Med Ther. 2012 Jun;2012(3):67-74.
Hochberg Rheumatology 5e, Ch 98

Table 2: Clinical features of JIA subtypes

Subtype

Arthritis

Uveitis

Other

Labs/serology

Systemic JIA

Second most common presenting symptom. Can be preceded by arthralgias and sometimes arthritis develops weeks to months following disease onset. Wrists, knees, and ankles are most commonly involved on initial presentation. Though usually asymptomatic, temporomandibular joint arthritis may be present. Chronic progressive arthritis develops in approximately 30-50% of patients.

Not associated

Fever Spiking, quotidian

Lymphadenopathy 1/3 present with painless generalized lymphadenopthy. Mesenteric adenitis can be painful. Para-aortic adenopathy can be seen on radiography. Reactive changes seen in the nodes on biopsy.

Rash – Salmon-pink, evanescent; morbilliform, macular, often with central clearing. Migratory; typically begins on the limbs and trunk. Appears with febrile episodes. Usually nonpruritic.

Hepatosplenomegaly – 50% have splenomegaly; hepatomegaly less common.

Serositis – Pericarditis most common, then pleuritis; peritonitis rare .

Hb

WBC ↑↑ 

ESR ↑↑

CRP ↑↑

ferritin ↑ 

platelets ↑↑ (normal or in MAS)

Oligoarticular JIA

Large joints of the lower extremities predominantly affected. Often only a single joint is involved

30%, especially if ANA positive

ANA+ in 60%

ESR/CRP mildly

Polyarticular JIA

RF negative: Symmetric or asymmetric; small and large joints; cervical spine; temporomandibular joint

RF positive: Aggressive symmetric polyarthritis

10%

RF positive:

Rheumatoid nodules

Joint deformities (e.g. Boutonnière and Swan neck contractures)

ANA+ in 40%

In both RF+ or –:

ESR ↑↑ 

CRP /normal

mild anemia

Enthesitis-related JIA

Predominantly lower limb joints affected; sometimes axial skeleton

Acute anterior uveitis; associated with reactive arthritis and IBD

Enthesitis – often symmetrical and involving lower extremities; most commonly patellar ligament insertion at the inferior pole of the patella, plantar fascial insertion at the calcaneus, and the Achilles tendon insertion at the calcaneus

Subclinical gut inflammation

45% + for HLA-B27

ANA and RF –

Psoriatic JIA

Asymmetric arthritis of small or medium-sized joints, asymmetric arthritis involving < 5 joints. Both large (knee, ankle) and small (finger, toe) joints can be involved. May have axial involvement, particularly if HLA B27 positive.

10-15%

Psoriasis in 50%

Dactylitis 

Onycholysis, nail pitting 

Subclinical gut inflammation

ANA+ in 50%

ESR ↑ 

CRP / normal

mild anemia

ANA: Anti-nuclear antibody

CRP: C-reactive protein

ESR: Erythrocyte sedimentation rate

IBD: Inflammatory bowel disease

MAS: macrophage activation syndrome, a serious but rare complication that occurs in the setting of systemic-onset JIA; characterized by the rapid development of fever, rash, and encephalopathy; rapid rise of liver transaminase levels; disseminated intravascular coagulopathy; neutropenia; thrombocytopenia; increased triglycerides; low albumin; and a low ESR associated with hypofibrinogenemia. Mortality has been reported as high as 50%, and prompt treatment with corticosteroids is necessary and, if poor response, also with etoposideor anti-thymocyte globulin and cyclosporine.

Pathophysiology 

Hochberg Rheumatology 5e, Ch 99
Nelson Textbook of Pediatrics 19e, Ch 621
Br J Ophthalmol. 2012 Jun;96(6):852-6.
Curr Opin Ophthalmol. 2010 Nov;21(6):468-72. 

Arthritis

  • Defined by intra-articular swelling or the presence of 2 or more of the following:
    • Limitation in range of motion
    • Tenderness or pain on motion
    • Increased heat or erythema
  • The hallmark of arthritis in JIA is inflammation of the synovial lining of the joint, which causes the above signs and symptoms. If uncontrolled, it may lead to joint destruction through progressive erosion of articular cartilage and contiguous bone.
  • Inflammatory synovitis is characterized pathologically by:
    • Villous hypertrophy and hyperplasia
    • Hyperemia and edema of the synovial tissue
    • Hyperplasia of synoviocytes
    • Infiltration of inflammatory cells (lymphocytes, plasma cells, macrophages, and dendritic cells)
    • Pannus formation
      • One of the hallmarks of JIA pathology, especially RF positive polyarticular JIA, pannus is a tumor-like expansion of inflamed synovial tissue which causes much of the joint damage. It spreads over the synovial space, degrades intra-articular cartilage and may lead to anklyosis (fusion of tissues and consequent stiffening). Pannus is caused through synoviocyte proliferation and invasion of the synovial tissue by inflammatory cells recruited from the peripheral circulation.

Uveitis 

  • The uveal tract consists of the inner vascular coat of the eye, and includes the iris, ciliary body, and choroids. It is vulnerable to systemic inflammatory diseases.
  • Inflammation may affect any one aspect of the uveal tract preferentially or all parts together.
  • 70% of patients have bilateral involvement
  • Most common in oligoarthritis and ANA positive patients
  • Approximately 30–70% of patients develop ocular complications.
  • The main causes of poor vision are cataracts, band keratopathy and glaucoma.

Table 3: Uveitis in JIA

Location of Inflammation

Anterior Uveitis (Iritis)

Intermediate Uveitis (Iridocyclitis)

Posterior Uveitis (Choroiditis/Chorioretinitis)

Panuveitis (Panophthalmitis)

% of all JIA types

83%

9%

1%

7%

Signs and symptoms

Pain, photophobia, and lacrimation.

Conjunctival hyperemia.

Rare to have pain, photophobia, or conjunctival hyperemia.

Inflammation may not be noticed until severe and irreversible damage has occurred. Routine screening is therefore necessary.

Blurred vision.

Results in atrophic chorioretinal scarring, often with visual impairment. Secondary complications include retinal detachment, glaucoma, and phthisis.

Severe pain, suppurative, marked congestion of the eye, inflammation of the adjacent orbital tissues and eyelids, and loss of vision.

Long term consequences

  • Long-term consequences of childhood-onset arthritis include:
    • Local growth disturbances and limb-length discrepancy: Inflammation initially accelerates linear growth; continued inflammation stimulates premature closure of the growth plate, resulting in shortened bones.
    • Generalized growth disturbance: Generalized growth disturbance – delayed growth and low weight – may occur in children with active disease and is related to active disease intensity and duration. Height may return to normal in 2 or 3 years after quiescence of the disease, as long as premature epiphyseal closure has not occurred. The etiology of generalized growth disturbance is unclear, but it is tightly linked to the degree of overall inflammation.
    • Osteopenia: Active disease, poor nutrition (i.e. low calcium and vitamin D intake), medications such as corticosteroids, lack of exercise, and delayed menarche can all affect the peak bone mass attained in adolescence
    • Functional disability: Including unemployment, pain and decreased overall quality of life.

Treatment

Adolesc Health Med Ther. 2012 Jun;2012(3):67-74.
BMC Pediatr. 2012 Mar 15;12:29.
Arthritis Care Res (Hoboken). 2011 Apr;63(4):465-82.

  • The treatment approach to JIA has shifted from a pyramidal approach to early aggressive therapy.
  • Risk stratification guides optimal management, and thus treatment is individualized according to subtype of JIA, and severity of disease as measured by affected joint count, systemic features, and poor prognostic features.
  • General approach to treatment involves anti-inflammatory and immunomodulatory medications in combination with physical and occupational therapy, an occasional need for surgery, nutritional support, and psychosocial and educational partnership with patients and parents.

Table 4: Common medications used in the treatment of JIA 

Medication

Mechanism of action

Non-steroidal anti-inflammatory drugs (NSAIDs)

Inhibit the enzyme cyclooxygenase (nonselective inhibitors inhibit both COX-1 and COX-2 isoenzymes), preventing prostaglandin production.

Intra-articular glucocorticoids

Believed to act by altering transcription; reduce numbers of inflammatory cells, and thus inflammatory mediators

     Non-Biologic Disease-Modifying Anti-Rheumatic Drugs (DMARDs)

Methotrexate

Folate antimetabolite; inhibits DNA synthesis, repair and cellular replication

     Biologic DMARDs

Etanercept

Anti-TNF-a

Adalimumab

Anti-TNF-a

Infliximab

Anti-TNF-a

Abatacept

Selective T-cell co-stimulator inhibitor

Anakinra

Anti IL-1

Tocilizumab

Anti IL-6

Summary of ACR 2011 recommendations

NSAIDs are first-line treatment for oligoarticular arthritis, often with intra-articular glucocorticoids.

Methotrexate is used next, if treatment response is inadequate, or if 5 or more joints are involved (in addition to an NSAID and joint injections).

TNF-a inhibitors are added if disease activity remains moderate or high. If one TNF-a inhibitor is not sufficient to adequately decrease disease activity, a second TNF-a inhibitor or Abatecept is added.

Anakinra is used only in Systemic Arthritis, alongside systemic glucocorticoids for systemic features, and methotrexate and TNF-a inhibitors for active arthritis.

Medical therapy 

NSAIDs have not been shown to alter the disease course or prevent joint damage, and are used instead to treat pain, stiffness, in addition to fever in systemic JIA. No individual NSAID has been shown to have a clear advantage over others in treating arthritis. NSAIDs commonly used are tolmetin, naproxen, ibuprofen, meloxicam, and celecoxib.

Because of the various undesirable side effects of corticosteroids, particularly with respect to bone and growth, the use of systemic corticosteroids to treat arthritis is minimized. They may, however, be used as a bridging medication until other DMARDs take effect. The main indications for the use of systemic corticosteroids are severe fever, serositis, and the macrophage activation syndrome in patients with systemic JIA. Intra-articular corticosteroid injections have demonstrated efficacy in patients with oligoarthritis.

DMARDs have demonstrated superior efficacy, and have been used increasingly in the treatment of JIA. DMARDs interfere directly with immune cells or their function to reduce inflammation. They are classified as either biologic (created by biologic processes) or non-biologic (synthetic).

Treatment of uveitis: Corticosteroids remain the mainstay of initial treatment for uveitis. For patients requiring chronic therapy, the initial agents of choice are typically antimetabolites including methotrexate, mycophenolate mofetil and azathioprine.