Juvenile Idiopathic Arthritis

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Introduction

Juvenile idiopathic arthritis (JIA) is a term used to describe a group of paediatric inflammatory arthritides which last for longer than six weeks and emerge before the age of 16 years.1,2 JIA is a clinical diagnosis.4

JIA is the most common chronic inflammatory rheumatic disease of childhood. In the United Kingdom, approximately 1 in 10,000 children are diagnosed annually, giving a prevalence of 1 in 1,000 children under 16 years of age.5 JIA is twice as common in females than in males.5,6

There are seven different subtypes of JIA classified according to the International League of Associations for Rheumatology (ILAR):2,3

  1. Oligoarthritis
  2. Rheumatoid factor-positive polyarthritis
  3. Rheumatoid factor-negative polyarthritis
  4. Systemic-onset arthritis (Still’s disease)
  5. Psoriatic arthritis
  6. Enthesis-related arthritis
  7. Undifferentiated arthritis
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Aetiology

The exact aetiology of JIA is unknown however it is thought to occur in genetically susceptible individuals following a trigger by various environmental factors. Several different polymorphisms in the human leukocyte antigen genes (e.g. HLA A2, HLA B27) have been associated with the various JIA subtypes.1.7

Pathophysiology

JIA results from an immune-mediated inflammatory response affecting joints and periarticular structures. Depending on the subtype, there may also be skin and eye involvement.8


Risk factors

Although the exact aetiology remains unknown, the following risk factors are associated with an increased likelihood of developing JIA:9,21

  • Female sex
  • First-degree relative with juvenile idiopathic arthritis
  • Family history of any autoimmune disease
  • Down’s syndrome (trisomy 21)

Clinical features

History

Typical symptoms of JIA include:1

  • Joint pain lasting more than 6 weeks
  • Joint swelling
  • Fever: high grade fever (>5°C), spiking once to twice daily for 2 days/week for2 weeks

Other symptoms may include:1,10

  • Early morning stiffness: typically present on waking or after periods of inactivity, this may improve over a few hours when lower limb joints are involved
  • Mobility: reduced mobility may be due to pain (in active disease) or secondary to joint contractures (in long-standing disease)
  • Uveitis: periocular pain, photophobia, blurry vision, increased lacrimation
  • Nail changes: pitting, onycholysis
  • Connective tissue symptoms: hair loss, mouth ulcers, rash and Raynaud’s phenomenon
  • Pain on chewing: may indicate TMJ disease activity
  • Unintentional weight loss: consider malignancy
  • Interference with sports/schoolwork: ask about handwriting and physical activity (e.g. “does your arthritis ever stop you from doing what you want to do?”)
  • Bowel symptoms: ask about bowel motion frequency and whether any blood/mucus in stool as patients may have co-existing inflammatory bowel disease

The seven recognised subtypes have different clinical features and patterns of joint involvement (Table 1).

Table 1. Clinical features of different JIA subtypes.10,11

Subtype Pattern of joint involvement Other features

Oligoarthritis

1-4 large joints

(knees, ankles, elbows, wrists)

Most common

Rheumatoid factor-negative polyarthritis

5 or more large and small joints

Symmetrical involvement (hands, feet, TMJ, cervical spine)

 

Rheumatoid factor-positive polyarthritis

5 or more large and small joints

Symmetrical involvement

Rapidly destructive

Most severe

Systemic-onset arthritis

1 or more joints

 

Daily fever spikes, plus 1+ of:

  • Erythematous “salmon-colour” rash
  • Generalised lymphadenopathy, hepatosplenomegaly and serositis

Psoriatic arthritis

1 or more joints

Arthritis & psoriasis OR arthritis & 2+ of:

  • Nail changes
  • Psoriasis in 1st-degree relative
  • Knees and small joints of hands and feet affected
  • Erythematous scaly lesions on post-auricular area, scalp, over extensor surfaces of knees and elbows or peri-umbilical area.

Enthesis-related arthritis

1 or more weight-bearing joints (hip and intertarsal joints)

Sacroiliitis 

 

Undifferentiated arthritis

Doesn’t fulfil criteria in any category or fulfils criteria in two or more categories.

Clinical examination

If juvenile idiopathic arthritis is suspected, a thorough clinical examination must be performed. For more information, see the Geeky Medics guide to the paediatric GALS examination.

Typical clinical findings of JIA on examination may include:1,2

  • Swelling of affected joints
  • Erythema or warmth of affected joints
  • Reduced range of motion of affected joints: test all joints including TMJ. It is possible to have co-existing hypermobility and JIA.
  • Tenderness at entheseal insertion points (e.g sacroiliac joint)
  • Schober’s test: tests the flexibility of the spine

Extra-articular manifestations

Extra-articular manifestations of JIA may be present depending on subtype:1,10

  • Psoriatic plaques: erythematous, scaly lesions over extensor surfaces
  • Non-pruritic, erythematous salmon-coloured rash: limited to the trunk and proximal extremities, worse with fever (typical for systemic JIA)
  • Dactylitis
  • Enlarged lymph nodes
  • Enlarged liver or spleen on examination
  • Uveitis: periocular pain, red eye, photophobia, blurry vision, increased lacrimation
  • Nail changes: pitting, onycholysis
  • Mouth ulcers (important to check the roof of the mouth)

Differential diagnoses

Depending on the presenting clinical features, differential diagnoses to consider include:1


Investigations

Laboratory investigations

Relevant laboratory investigations include:1,2

  • Full blood count with blood film: to exclude infection and malignancy. Systemic-onset JIA (SoJIA) usually presents with anaemia, thrombocytosis, and leukocytosis.
  • Inflammatory markers (ESR/CRP, triglyceride and ferritin): non-specific markers, if elevated, they indicate more active disease.
  • Rheumatoid factor (RF): positive in RF-positive polyarticular JIA and associated with aggressive disease.
  • Anti-cyclic citrullinated peptide antibody (anti-CCP): positive in RF-positive polyarticular JIA.
  • Anti-nuclear antibody (ANA): when positive, it indicates an increased susceptibility to uveitis. Positive in oligoarticular JIA and occasionally in polyarticular JIA.
  • HLA-B27: positive in enthesis-related JIA and indicates the development of symptomatic uveitis/iritis.

Imaging

 Relevant imaging investigations include:1,2,13

  • X-ray of affected joints: This is the mainstay of imaging in JIA. Disease-specific changes are usually undetectable in the early stages of JIA. Nonspecific changes such as soft tissue swelling, joint effusion, and osteopenia may be present. It is used to rule out other pathology (e.g. fractures) and provide a baseline.
  • Ultrasound of affected joints: Reliable assessment of synovitis, joint effusion, bone erosions, enthesitis and tenosynovitis. This is abnormal in the early stages of JIA.
  • MRI (contrast-enhanced): the most sensitive imaging modality to detect synovitis, bone erosions and joint oedema.
  • DEXA: important to monitor bone density in patients taking long-term oral steroids

Other investigations

Ophthalmologic investigations are performed to screen for uveitis:14,15 

  • Slip lamp examination
  • Intraocular pressure measurement
  • Age-appropriate visual acuity testing

A fever diary may be useful when considering the diagnosis of systemic JIA.


Diagnosis

The diagnosis of JIA is a clinical diagnosis based on history and examination. Laboratory investigations and imaging are not diagnostic but are important to carry out to help exclude differential diagnoses, classify the subtype of arthritis, and evaluate for extra-articular manifestations.12


Management

The goals of the management of JIA are to:

  • Control joint inflammation
  • Reduce joint damage
  • Promote normal growth, development, and function
  • Minimise toxicity from medications

Multidisciplinary input

Disciplines that are involved in the management of JIA include:16

  • Occupational therapy: provide a pain relief program and optimise activities of daily living
  • Physiotherapy: address range of motion, muscle strengthening and conditioning
  • Paediatric orthopaedics: correction of deformities, limb length discrepancies and management of advanced arthritis
  • Paediatric ophthalmology: screening for and close monitoring for uveitis and associated eye complications with slip lamp (at least annually depending on risk)
  • Paediatric rheumatology: diagnosis and long-term management

Conservative management

It is important to maintain range of motion and muscle strength. Therefore moderate-intensity exercises are recommended:11

  • Aerobic exercises (swimming)
  • Flexibility exercises
  • Strengthening exercises

Medical management

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are used to control inflammation and relieve pain. These are the mainstay of the initial symptomatic treatment of all subtypes of JIA.2 The use of NSAIDs is typically limited to under two weeks at a time.

Intra-articular glucocorticoid injections (IAGCI)

Intra-articular glucocorticoid injections are indicated for active arthritis involving a small number of joints. These reduce arthralgia and are the preferred initial management.

Disease-modifying antirheumatic drugs (DMARDs)

DMARDs are used in patients with inadequate response to NSAID and IAGCIs. They are recommended in the following order:18

Corticosteroids

Corticosteroids are used for the acute management of severe arthritis and systemic symptoms of JIA. They are also used topically as eye drops for the management of uveitis.

Corticosteroids should be used for the shortest possible duration due to the risk of side effects.17

It is important to consider calcium/vitamin D supplementation for patients on long-term oral steroids.

Biologic agents

These are monoclonal antibodies which target specific components of the immune system and help to control inflammation.

Biologic agents are the last-line treatment for those with an inadequate response or intolerance to NSAIDs, IAGCI and DMARDs.

These agents reduce systemic inflammation and prevent joint damage. Options include:18

  • Tumour necrosis factor alpha (TNG-a) inhibitors: etanercept, adalimumab, infliximab
  • Interleukin 6 inhibitors: tocilizumab
  • Selective B-cell blockade: rituximab
  • JAK inhibitors: the newest class of immune modulating therapy, usually prescribed when multiple biologics have failed
Pre-biologic/DMARD screening tests

Before commencing biologic agents, all patients need to be screened for

  • Latent tuberculosis due to the risk of reactivation: via chest X-ray and Quantiferon blood test
  • Varicella status (varicella IgG) prior to commencing methotrexate
  • Baseline blood tests: neutrophil count and liver function tests (ongoing monitoring when using a biologic/DMARD)

Complications

Complications of juvenile idiopathic arthritis include:1,17

  • Joint contractures and leg length discrepancies if ongoing inflammation
  • Uveitis: although usually asymptomatic, if left untreated, it can lead to cataracts, glaucoma, and eventual blindness
  • Growth retardation
  • Osteoporosis
  • Joint erosion: may lead to a need for joint replacement in the future
Macrophage activation syndrome (MAS)

Macrophage activation syndrome (MAS) is a rare but potentially life-threatening complication of systemic-onset JIA. MAS presents with a high fever, purpuric rash, hepatosplenomegaly, lymphadenopathy, easy bruising, and mucosal bleeding.21


Key points

  • Juvenile idiopathic arthritis encompasses seven paediatric inflammatory arthritides that emerge before 16 years of age and persist for longer than six weeks.
  • Predisposing risk factors include female sex, a first-degree relative with JIA, and/or a family history of any autoimmune diseases.
  • Clinical features of JIA include joint pain, joint swelling, fever, limp, morning stiffness, limited range of motion, uveitis, and nail changes.
  • The diagnosis of JIA is clinical and is based on history and physical examination findings but should be supported by laboratory and radiological investigations.
  • Initial management of JIA includes intra-articular glucocorticoid injections and a trial of NSAIDs, followed respectively by DMARDs (e.g. methotrexate) and biologics (e.g. TNF-a inhibitors) if there is an incomplete response or intolerance to preceding management.
  • Early diagnosis of JIA prevents long-term complications such as joint contractures, leg length discrepancies, joint erosion, uveitis, osteoporosis, and growth retardation.
  • Macrophage activation syndrome is a potentially life-threatening complication seen in 10% of systemic-onset JIA, which causes cytopenia, liver dysfunction and coagulopathy.

Reviewers

Dr Susan Harvey

Post-CCT Fellow and Special Lecturer in Paediatrics 

Dr Sheena Coyne

Specialist Registrar in Paediatrics


Editor

Dr Chris Jefferies


References

  1. BMJ Best Practice. Juvenile Idiopathic Arthritis. Published in 2021. Available from: [LINK]
  2. Thatayatikom A., Modica R., De Leucio A. Juvenile Idiopathic Arthritis. Published in 2022. Available from: [LINK]
  3. Petty E R., Southwood R. T., Manners P., Baum J., Glass N. D., Goldenberg J., He X., Maldonado-Cocco J., Orozco-Alcala J., Prieur A. M., Suarez-Almazor E. M., Woo P., International League of Associations for Rheumatology. The Journal of Rheumatology. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. Published in 2004. Available from: [LINK]
  4. Classification of juvenile idiopathic arthritis. Published in 2020. Available from: [LINK]
  5. Costello R., McDonagh J., Hyrich L. K., Humphreys H. J. Incidence and prevalence of juvenile idiopathic arthritis in the United Kingdom, 2000-2018: results from the Clinical Practice Research Datalink. Published in 2022. Available from: [LINK]
  6. Cattalini M., Soliani M., Caparello C. M., Cimaz R. Sex Differences in Pediatric Rheumatology. Published in 2019. Available from: [LINK]
  7. Rigante D., Bosco A., Esposito S. The Etiology of Juvenile Idiopathic Arthritis. Published in 2015. Available from: [LINK]
  8. Zaripova N. , Midgley A., Christmas E. S., Beresford W. M., Baildam M. E., Oldershaw A. R. Juvenile idiopathic arthritis: from aetiopathogenesis to therapeutic approaches. Published in 2021. Available from: [LINK]
  9. Prahalad S., Glass N. D. A comprehensive review of the genetics of juvenile idiopathic arthritis. Published in 2008. Available from: [LINK]
  10. Kim H. K., Kim S. D. Juvenile idiopathic arthritis: Diagnosis and differential diagnosis. Published in 2010. Available from: [LINK]
  11. Drupals M., Ware Matthaeus. Toronto Notes 2021. Published in 2021.
  12. Sherry D. D. Juvenile Idiopathic Arthritis Workup. Published in 2022. Available from: [LINK]
  13. Sheybani F. E., Khanna G., White J. A., Demertzis L. J. Imaging of Juvenile Idiopathic Arthritis: A Multimodality Approach. Published in 2013. Available from: [LINK]
  14. Feldman H. B., Tripathy K., Muthappan V., Dahrab M., Lind R. T., Lopez A. M. A., Palestine A., Shantha J., Prakalapakorn G., Larochelle M., Marcet M. M., Saboo S. U. Juvenile Idiopathic Arthritis Associated Uveitis. Published in 2022. Available from: [LINK]
  15. The Royal College of Opthalmologists. Guidelines for Screeening for Uveitis in Juvenile Idiopathic Arthritis (JIA). Published in 2006. Available from: [LINK]
  16. Sherry D. D. Juvenile Idiopathic Arthritis Treatment and Management. Published in 2022. Available from: [LINK]
  17. Mayo Clinic Staff. Juvenile Idiopathic Arthritis. Published in 2020. Available from: [LINK]
  18. Ruth M. N., Passo H. M. Juvenile idiopathic arthritis: management and therapeutic options. Published in 2012. Available from: [LINK]
  19. American College of Rheumatology. 2021 American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Oligoarthritis, Temporomandibular Joint Arthritis, and Systemic Juvenile Idiopathic Arthritis. Published in 2022. Available from: [LINK]
  20. Grom A. A., Macrophage Activation Syndrome. Published in 2010. Available from: [LINK]
  21. Basic Science in Paediatric Rheumatology. AB0223 Trisomy 21 and Juvenile Idiopathic Arthritis: Are There Joint Distribution Patterns and Response to Methotrexate? Published in 2015. Available from: [LINK]

 

 
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