Juvenile%20idiopathic%20arthritis Treatment

• Objectives in treating children with juvenile idiopathic arthritis (JIA)
  
  • To achieve disease remission
  • To control pain
  • To preserve range of motion, muscle strength and function
  • To control systemic complications
  • To foster normal nutrition, growth, and physical and psychological development
• Management approach is customized based on the disease subtype and severity, occurrence of poor prognostic factors and response to treatment
• Tuberculosis (TB) infection should be ruled out prior to starting anti-tumor necrosis factor (TNF)-α; testing for hepatitis B and C should be done prior to giving Methotrexate or anti-TNF-α in children with risk factors for infection
• Immunization status must be updated prior to receiving treatment
  
  • Live vaccines should not be given in patients given glucocorticoids or disease-modifying antirheumatic drugs (DMARDs)
  • Inactive vaccines are not contraindicated
  • Yearly immunization with influenza is recommended 

Analgesic

• Paracetamol may be considered for short-term use in treating persistent juvenile idiopathic arthritis (JIA) pain in children and adolescents
• In addition to Paracetamol, Codeine may be given to manage moderate articular pain

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

• Considered the 1st-line drug for the treatment of inflammation and associated pain in children with juvenile idiopathic arthritis
  • Used for the initial management of pain, stiffness and inflammation
• Exert anti-inflammatory, analgesic and antipyretic effects with long-term safety when used appropriately
  • Anti-inflammatory effects in juvenile idiopathic arthritis patients is noted after 4-6 weeks of constant administration
• Nonsteroidal anti-inflammatory drug (NSAID) monotherapy is recommended for patients with low disease activity, with no joint contractures and features of poor prognosis, and during the clinical evaluation of possible systemic arthritis
  • Continued use without additional therapy for >2 months is discouraged in patients with active arthritis regardless of presence of poor prognostic features; continued use for >1 months in patients with active fever is not advised
• Patients with systemic arthritis with active arthritis and without active systemic features may be started on NSAID monotherapy with or without intraarticular corticosteroids if with low disease activity and without poor prognostic features
• Studies have shown that effectivity and tolerability of selective COX-2 inhibitors (eg Celecoxib, Meloxicam) are similar to the non-selective NSAIDs (eg Naproxen)
• Use of NSAIDs alone seldom induce remission of polyarticular or systemic-onset juvenile idiopathic arthritis

Corticosteroids

Intra-articular

• Use for joint injections in active arthritis is recommended regardless of disease activity level, prognostic features, joint contractures, concomitant therapy or juvenile idiopathic arthritis treatment group
• Triamcinolone hexacetonide is commonly used for joint injections due to its superior efficacy
  
  • Improvement of arthritis may be noted after at least 4 months of use and may be repeated as needed
  • Intensification with systemic therapy may be needed when patient improved clinically for only a short duration of time

Systemic

• Recommended as initial therapy for patients with systemic arthritis that have active fever and physician global assessment ≥7 but has no active arthritis
  
  • Started in patients with systemic arthritis that have active fever after 2 weeks of NSAID use
• Recommended for bridge therapy while waiting for the therapeutic response to a disease-modifying anti-rheumatic drug (DMARD), for control of uveitis and for the management of severe systemic illness

Biologic Disease-Modifying Anti-rheumatic Drugs (DMARDs)

• Target specific cytokines (eg interleukin-1, interleukin-6) or interfere with specific cell function through depletion of B cells or suppression of T cell activation

Anti-tumor Necrosis Factor-α (Anti-TNF-α)

• Recommended in patients with ≤4 arthritic joints who have received glucocorticoid joint injections and 3 months of maximum tolerated dose of Methotrexate that have moderate or high disease activity and features of poor prognosis
  
  • Also given to patients who have received glucocorticoid joint injections and 6 months of Methotrexate that have high disease activity with no features of poor prognosis
  • Also recommended in patients with enthesitis-related arthritis who were given glucocorticoid joint injections and a trial of Sulfasalazine (without prior Methotrexate) and have moderate or high disease activity without considering the prognostic features
• In patients with ≥5 arthritic joints, anti-TNF-α is recommended in patients who have received the maximum tolerated dose of Methotrexate or Leflunomide for 3 months and have moderate or high disease activity regardless of prognostic features
  • Also used in patients with low disease activity who have received Methotrexate or Leflunomide for 6 months, irrespective of prognostic features
  • Changing from 1 anti-TNF-α to another may be advised in patients with moderate or high disease activity who have used the current anti-TNF-α for 4 months, regardless of poor prognostic factors
  • In patients who have received Abatacept for 3 months and have high disease activity with features of poor prognosis and in patients who have received Abatacept for 6 months and have moderate or high disease activity with or without features of poor prognosis, switching to anti-TNF-α is recommended
• Recommended more readily in patients with active sacroiliac arthritis
  
  • Given to patients with active sacroiliac arthritis who have received an adequate trial of NSAIDs and have high disease activity and poor prognostic features
  • Also recommended in patients who were maintained on Methotrexate for 3 months with high disease activity irrespective of prognostic factors, or with moderate disease activity with poor prognosis, or in patients given 6 months of Methotrexate with moderate disease activity with no poor prognostic features
  • Also given to patients with moderate or high disease activity who have used Sulfasalazine for 3 months, irrespective of prognostic features, or to patients with low disease activity and poor prognostic features who were on 6 months of Sulfasalazine
• In patients with systemic arthritis with active arthritis and without active systemic features, anti-TNF-α is recommended to be initiated or added if patient received Methotrexate for 3 months, with moderate or high disease activity with or without poor prognostic features
• When used up to the maximum recommended dosing regimen, may show response in 2-4 weeks in some patients
  
  • Usually cause significant improvement in symptoms, signs and/or lab parameters within 12-24 weeks
  • Bone mineral density (BMD) was noted to improve after treatment with anti-TNF-α agents even in patients with incomplete disease control
• Adalimumab and Infliximab appear to be more effective in JIA-associated uveitis than Etanercept
  • Recommended for Methotrexate-resistant anterior uveitis
• Some studies indicate that anti-TNF-α dose may be decreased when patients are in remission or in low disease activity, without losing its efficacy
• Adalimumab
  • A fully human, IgG, monoclonal anti-TNF antibody
  • Approved to reduce signs and symptoms of moderate-severe active polyarthritis in patients ≥4 years old
  • Treatment option for children ≥2 years old and with inadequate response to ≥1 disease-modifying anti-rheumatic drug (DMARD)
  • May be used alone or in combination with Methotrexate
• Etanercept
  • Soluble TNF p75 receptor fusion protein that binds to and inactivates TNF-α
  • First anti-TNF-α to be approved for use in juvenile idiopathic arthritis
  • A standard therapy given to patients with arthritis that did not respond to Methotrexate
  • May be used in children as young as 2 years old for treating moderate-severe polyarticular juvenile idiopathic arthritis
  • Shown to be less effective in patients with systemic-onset juvenile idiopathic arthritis than in patients with other forms of juvenile idiopathic arthritis
  • Should not be given to children with infection or history of recurrent infections
  • Can be used continuously for up to 8 years, as indicated by its long-term safety profile
    • Exacerbation and worsening of the disease are the 2 most common serious adverse effects noted beyond 4 years of use
• Infliximab
  
  • A chimeric human/mouse monoclonal antibody that binds to soluble and membrane-bound TNF-α
  • Use in juvenile idiopathic arthritis needs further study because of its potential adverse effects (eg infusion reactions, development of antibodies)
• Golimumab
  • A fully human, IgG, monoclonal anti-TNF antibody that can be administered either intravenously or subcutaneously
  • One study showed subcutaneous Golimumab led to quick and clinically relevant improvement
  • Not approved by the United Stated Food and Drug Administration (US FDA) for treatment of juvenile idiopathic arthritis but intravenous dosing for juvenile idiopathic arthritis is under investigation

Anti-Cytotoxic T Lymphocyte–Associated Antigen-4 Immunoglobulin

• Abatacept
  
  • A fully human, soluble fusion protein that contains the extracellular domain of the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the Fc component of IgG1
  • Selectively inhibits the costimulatory signal needed for T-cell activation
  • Approved for the management of patients with moderate-severe polyarticular juvenile idiopathic arthritis
    • In combination with Methotrexate is indicated for patients ≥6 years old with moderate to severe active polyarticular juvenile idiopathic arthritis and had inadequate response to other disease-modifying anti-rheumatic drugs including ≥1 tumor necrosis factor (TNF) inhibitor
  • Recommended as an alternative management in patients with ≥5 arthritic joints who were maintained for 4 months on anti-TNF-α and have high disease activity, irrespective of poor prognostic features, or moderate disease activity with poor prognostic features
  • Also advised as another treatment approach in patients given ≥1 consecutive anti-TNF-α and have moderate or high disease activity, irrespective of prognostic factors, or low disease activity with poor prognostic features
  • Given to patients with systemic arthritis that has no active systemic features, who have received Methotrexate and anti-TNF-α and with high disease activity, regardless of prognostic features, or patients with moderate disease activity and features of poor prognosis
  • May be as effective as anti-TNF-α agents as shown by different studies; However, maximum efficacy was noted a few weeks later

Anti-CD20

• Rituximab
  
  • A chimeric monoclonal antibody to CD20 that causes selective depletion of CD20-positive B cells which may produce anti-inflammatory effects in arthritis
  • Recommended as an alternative treatment option in patients with ≥5 arthritic joints who have received anti-TNF-α and Abatacept consecutively and have high disease activity, without considering the prognostic features, or in patients with moderate disease activity with poor prognostic features
    
    • More appropriate to use in patients with positive rheumatoid factor (RF)

Interleukin-1 Receptor Antagonist

• Anakinra
  
  • A recombinant human interleukin-1 receptor antagonist
  • Recommended in all patients with systemic arthritis that has active fever and features of poor prognosis, regardless of current therapy
  • Also given to all patients with systemic arthritis that develops or continue to have fever while receiving systemic glucocorticoids
  • May be added or started in patients with systemic arthritis but has inactive systemic features, after receiving Methotrexate and have moderate or high disease activity, irrespective of poor prognostic features
  • Also advised in patients with high or moderate disease activity who have received Methotrexate and anti-TNF-α or Methotrexate and Abatacept, regardless of prognostic factors
  • In patients with systemic arthritis but with inactive systemic features, initiation of Anakinra may be less appropriate later in the disease course than near the disease onset
  • May be switched to anti-TNF-α agents in patients with moderate or high disease activity, irrespective of poor prognostic features; however unmasking of latent systemic disease activity is possible when Anakinra is discontinued
• Canakinumab
  •  A recombinant human monoclonal interleukin-1β antibody
  •  Recommended as an alternative treatment for >2 years old patients with systemic arthritis with active systemic features and with continued disease activity despite therapy with glucocorticoids, Methotrexate and other first-line drugs
  •  Also recommended as an alternative treatment option in patients with systemic arthritis without active systemic features and with >4 arthritic joints after receiving disease-modifying anti-rheumatic drug combined with Anakinra, Tocilizumab, Abatacept, or an anti-TNF-α agent
•  Rilonacept
  • A fusion protein with human cytokine receptor extracellular domains for both IL-1 type 1 receptor and IL-1 accessory protein 
  •  Further studies are needed to prove the efficacy of Rilonacept in juvenile idiopathic arthritis patients
    • Studies have shown uncertain/inappropriate effects of Rilonacept in patients with systemic arthritis with or without systemic features  

Interleukin-6 Receptor Antagonist

• Tocilizumab
  
  • A humanized monoclonal antibody that inhibits the cytokine IL-6
  • Recommended for children and adolescents ≥2 years old with active systemic juvenile idiopathic arthritis who had responded inadequately to NSAIDs, systemic corticosteroids and Methotrexate
  • May also be given to children and adolescents ≥2 years old with refractory systemic onset of juvenile idiopathic arthritis and polyarticular juvenile idiopathic arthritis

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

Methotrexate

• Recommended as the initial therapy for patients with ≤4 arthritic joints that have high disease activity and features of poor prognosis
  
  • Also given to patients with high disease activity without features of poor prognosis and to patients with moderate disease activity with features of poor prognosis after initial glucocorticoid injection
  • After repeated glucocorticoid injections, Methotrexate may be started in patients with moderate disease activity without features of poor prognosis or in patients with low disease activity with features of poor prognosis

• In patients with ≥5 arthritic joints, Methotrexate may be given as initial treatment for patients with high disease activity regardless of poor prognostic factors and for patients with moderate disease activity and features of poor prognosis
  
  • After 1 months of NSAID use, Methotrexate may be started in patients with low disease activity and features of poor prognosis or in patients with moderate disease activity without features of poor prognosis if NSAID was used for 1-2 months

• Recommended for patients with systemic active arthritis but with no active systemic features after ≤1 months of NSAID use irrespective of poor prognostic features
  
  • Not appropriate for initial treatment of patients with active fever and without active arthritis

• Effective at relatively low oral dose, has relatively fast onset of action and acceptable toxicity (ie absence of risk for oncogenicity and production of sterility)
• Response is usually observed after ≥3 months of use and is advised to be continued for ≥1 year after achieving remission
• May be continued while starting anti-TNF-α (ie Etanercept, Adalimumab) in patients who had partial clinical response to previously given Methotrexate
• Folic acid at 1 mg/day should be given concomitantly to decrease gastrointestinal irritation and mucosal toxicity without decreasing Methotrexate’s effectivity
• Adolescents taking Methotrexate should be advised to avoid alcohol, smoking and pregnancy

Hydroxychloroquine

• Used as additional drug to treat chronic arthritis in older children
  
  • Usually added to NSAID regimen; rarely given as monotherapy

• Therapeutic response is rarely seen before 2-3 months of therapy; should be discontinued if no improvement after 6 months of use
• Eye exam (ie test of color vision and visual fields) should be performed before therapy
• Not recommended for children <4 years old

Leflunomide

• May be used as an alternative to Methotrexate
• One of the treatment options for patients with ≥5 arthritic joints that have high disease activity and features of poor prognosis
  
  • May also be given as initial treatment for patients with high disease activity with no poor prognostic features and for patients with moderate disease activity with poor prognostic features after a brief trial of NSAIDs

• Therapeutic effects may be noted 4 weeks after starting the therapy and continues until 5 months of treatment
• Studies have shown cases of severe liver injury in rheumatoid arthritis patients who used Leflunomide

Sulfasalazine

• Recommended for patients with enthesitis-related arthritis with moderate or high disease activity after glucocorticoid joint injection or NSAID use, regardless of features of poor prognosis
• Effects are noted within 4-8 weeks after starting the therapy
• Generally not advisable to children with active systemic juvenile idiopathic arthritis due to increased hypersensitivity reactions

Nutritional Therapy

• Calcium intake in children with juvenile idiopathic arthritis (JIA) should be monitored and daily intake be increased
  
  • Patients with juvenile idiopathic arthritis have been shown to have low bone mineral density (BMD) regardless of steroid use
  • Pathologic fractures have been noted in 15-26% of children with juvenile idiopathic arthritis
• Calcium plus vitamin D is advised in some patients especially those on corticosteroids
  
  • Corticosteroid causes bone loss which further increases the risk of osteoporosis and osteopenia
  • Steroids reduce calcium absorption and increase urinary calcium loss that leads to bone resorption
• Evaluate and ensure appropriate protein and caloric intake

Orthotics Management

• Splints and foot orthotics may be recommended on an individualized basis
• Benefit of splints depends on the patient’s age, type of orthosis used and the location of the joint affected
• Splints can be used as adjuncts to pharmacological therapy to increase range of movement and prevent contractures
• Help maintain function, maintain good joint position, relieve pain, stretch contracted joints and support inflamed joints

Physical Activity

• Provides important general health benefits and may improve disease outcomes without causing disease exacerbation
• Reduces loss of proteoglycans and cartilage damage, optimizes bone mineral density (BMD), and decreases obesity risk that may worsen joint load
• Reduces the risk of osteopenia and osteoporosis
• A minimum of 6 weeks exercise program may provide:
  
  • Improved aerobic fitness
  • Better muscle strength and function
  • Lesser disease activity
  • Improved self-efficacy, energy level and quality of life
  • Decreased pain and use of medicines
• Aquatic exercises promote range of motion, strength and fitness with lower stress on joints
• Weight bearing exercise should be recommended to develop optimal bone width and density
• Moderate fitness and strengthening exercises are recommended for children with juvenile idiopathic arthritis
  
  • If patient has well controlled disease and have adequate physical activity, competitive or impact sports may be an option
  • Patients with moderate-severe impairment or active joint inflammation should be advised to limit activities within pain thresholds and then gradually return to full activity after disease exacerbation
• Children with neck arthritis should have x-ray screening for C1-C2 instability before joining any contact sports
• Use of appropriately fitted mouth guards and eye protection should be recommended during activities

Thermotherapy

• Heat and/or cold may be advised for relief of juvenile idiopathic arthritis symptoms
  
  • Heat treatments (eg heat packs, deep heat ultrasound, warm baths) may be helpful in lessening joint rigidity, pain and muscle spasms, and increasing joint flexibility
    
    • Morning warm bath or shower may help decrease stiffness and pain
  • Massage, which is often given with heat therapy, may help ease pain, reduce anxiety, promote relaxation, and prevent adhesions in subcutaneous tissues
  • Cold treatment (eg cold packs) causes vasoconstriction in joints with inflammation and may help in pain relief