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Juvenile idiopathic arthritis; Treatment algorithm



ACUTE
early therapy

1st line – multidisciplinary care and lifestyle modification
Patients with incident or suspected JIA should be managed by a specialist paediatric rheumatology multidisciplinary team.
Physiotherapy and occupational therapy are encouraged in conjunction with medicines. Patients are encouraged to participate in activities such as swimming and cycling, and weight-bearing activities are indicated for those with a greater risk of low bone mineral density.  Moist heat can be a helpful adjunct modality to address pain and stiffness.
Foot orthoses may reduce pain and improve quality of life in children with JIA.
Adjunct – non-steroidal anti-inflammatory drugs (NSAIDs)
Treatment recommended for SOME patients in selected patient group
Primary options
naproxen  : children >2 years of age: 10-20 mg/kg/day orally given in divided doses every 12 hours
OR
nabumetone  : consult specialist for guidance on dose
OR
diclofenac sodium  : 3 mg/kg/day orally given in 2-4 divided doses
OR
meloxicam  : children ≥2 years of age: 0.125 mg/kg orally once daily, maximum 7.5 mg/day
OR
celecoxib  : consult specialist for guidance on dose
OR
ibuprofen  : 10 mg/kg orally three to four times daily
OR
indometacin  : 0.5 to 1 mg/kg orally two to three times daily
OR
piroxicam  : 0.2 to 0.4 mg/kg orally once daily
Occasionally used for control of pain and stiffness but not disease modifying. 



ONGOING
long-term therapy

1st line – methotrexate or sulfasalazine

Primary options
methotrexate  : 10 mg/square metre of body surface area orally/subcutaneously once weekly on the same day of each week initially, adjust dose according to response, maximum 20-30 mg/square metre of body surface area/week

Secondary options
sulfasalazine  : children >6 years of age: 30-50 mg/kg/day orally given in 2 divided doses, maximum 2000 mg/day
Used when disease has failed to respond to conventional medicines. Methotrexate is frequently the first disease-modifying agent to be tried and is generally started within the first few months in polyarticular disease. Methotrexate doses are increased slowly and are held or lowered if liver function tests are elevated or if absolute neutrophil counts are below 2.5 x 10⁹ L (2500/microlitre). Methotrexate can be withdrawn once the clinician considers disease to be in clinical remission.
Sulfasalazine may be used for enthesitis-related disease. Sulfasalazine doses are increased slowly weekly with careful FBC and comprehensive metabolic panel monitoring. Sulfasalazine is to be avoided in individuals with a history of Stevens-Johnson syndrome or hypersensitivities to sulfa drugs.
Plus – folic acid
Treatment recommended for ALL patients in selected patient group
Primary options
folic acid  : children 1-4 years of age: 0.15 mg orally once daily; children 4-9 years of age: 0.2 mg orally once daily; children 9-14 years of age: 0.3 mg orally once daily; children >14 years of age: 0.4mg orally once daily
Folic acid is useful to decrease side effects such as nausea, oral ulcers, and abnormal liver enzymes.
Adjunct – symptom control + lifestyle modification
Treatment recommended for SOME patients in selected patient group
Primary options
naproxen  : children >2 years of age: 10-20 mg/kg/day orally given in divided doses every 12 hours
OR
nabumetone  : consult specialist for guidance on dose
OR
diclofenac sodium  : 3 mg/kg/day orally given in 2-4 divided doses
OR
meloxicam  : children ≥2 years of age: 0.125 mg/kg orally once daily, maximum 7.5 mg/day
OR
celecoxib  : consult specialist for guidance on dose
OR
ibuprofen  : 10 mg/kg orally three to four times daily
OR
indometacin  : 0.5 to 1 mg/kg orally two to three times daily
OR
piroxicam  : 0.2 to 0.4 mg/kg orally once daily
NSAIDs may be used for control of pain and stiffness but are not disease modifying.  Specific NSAIDs are approved for children (e.g., tolmetin, naproxen, meloxicam, and ibuprofen). However, many others are commonly used (e.g., nabumetone, diclofenac). No specific NSAID is superior, and trial and error methods are used to identify the most effective medicine for individual patients.  Specialist dosing guidance is required for nabumetone.
Physiotherapy and occupational therapy are encouraged in conjunction with medicines. Patients are encouraged to participate in activities such as swimming and cycling, and weight-bearing activities are indicated for those with a greater risk of low bone mineral density. 
Adjunct –   anti-emetics
Treatment recommended for SOME patients in selected patient group
Primary options
ondansetron  : children <4 years of age: 1-4 mg orally three times daily depending on body surface area; children 4-11 years of age: 4 mg orally three times daily; children ≥12 years of age: 8 mg orally three times daily
Can be given to relieve the side effects of nausea.
Adjunct –   oral corticosteroids
Treatment recommended for SOME patients in selected patient group
Primary options
prednisolone  : 0.5 to 1 mg/kg orally once daily
Low-dose corticosteroid therapy allows time for other agents to take effect during active disease. It is important that corticosteroids are used judiciously in children and are tapered as soon as possible.
Adjunct –   intra-articular corticosteroids
Treatment recommended for SOME patients in selected patient group
Primary options
triamcinolone acetonide  : consult specialist for guidance on dose
Intra-articular corticosteroid injections can be used alone or as part of a treatment plan involving other systemic treatments. Radiographic assistance may be necessary for injecting some joints. Younger children may need sedation, especially if multiple joints are involved. It is important that corticosteroids are used judiciously in children and are tapered as soon as possible. Doses usually depend on joint size and other individual factors.
Adjunct –   intravenous corticosteroids
Treatment recommended for SOME patients in selected patient group
Primary options
methylprednisolone sodium succinate  : 30 mg/kg/day intravenously given on three consecutive days, repeated one week later, maximum 1 g/day
Patients with systemic-onset juvenile idiopathic arthritis (SoJIA) may occasionally require intravenous corticosteroids for overwhelming systemic inflammation or more serious complications such as macrophage activation syndrome or pericarditis.

2nd line –   TNF-alpha inhibitor, or interleukin receptor antagonist, or fusion protein
Primary options
etanercept  : (polyarticular JIA) children ≥2 years of age: 0.8 mg/kg subcutaneously once weekly, maximum 50 mg/week
OR
adalimumab  : (polyarticular JIA) children ≥2 years of age and 10 to <15 kg body weight: 10 mg subcutaneously every 2 weeks; children ≥2 years of age and 15 to <30 kg body weight: 20 mg subcutaneously every 2 weeks; children ≥2 years of age and ≥30 kg body weight: 40 mg subcutaneously every 2 weeks
OR
tocilizumab  : (polyarticular JIA) children ≥2 years of age and <30 kg body weight: 10 mg/kg intravenously every 4 weeks, or 162 mg subcutaneously every 3 weeks; children ≥2 years of age and ≥30 kg body weight: 8 mg/kg intravenously every 4 weeks, or 162 mg subcutaneously every 2 weeks; (systemic JIA) children ≥2 years of age and <30 kg body weight: 12 mg/kg intravenously every 2 weeks, or 162 mg subcutaneously every 2 weeks; children ≥2 years of age and ≥30 kg body weight: 8 mg/kg intravenously every 2 weeks, or 162 mg subcutaneously once weekly
OR
abatacept  : (polyarticular JIA) dose depends on age, body weight, and whether the intravenous or subcutaneous formulation is used; consult specialist for guidance on dose
Secondary options
canakinumab  : (systemic JIA) children ≥2 years of age and ≥7.5 kg body weight: 4 mg/kg subcutaneously every 4 weeks, maximum 300 mg/dose
OR
infliximab  : consult specialist for guidance on dose
OR
anakinra  : consult specialist for guidance on dose
Tumour necrosis factor (TNF)-alpha inhibitors include etanercept, adalimumab, and infliximab.
Etanercept is the most widely used TNF-alpha inhibitor in younger children.  Evidence regarding safety and efficacy is limited;  but studies have demonstrated the longer-term safety and efficacy of etanercept in patients with JIA.  It should be avoided if uveitis is present.
Infliximab and adalimumab  are monoclonal antibodies. Pre-medication with diphenhydramine, paracetamol, and a corticosteroid is advised before administration of infliximab to minimise infusion-associated reactions.  Over 70% of children receiving adalimumab in combination with methotrexate had a 70% improvement in at least 3 of the American College of Rheumatology core-set variables after 16 weeks of therapy.  It is also effective in patients with enthesitis-related arthritis in JIA.   The long-term tolerability of adalimumab in JIA has been demonstrated. Use of infliximab is off-label for this indication.
Patients with systemic disease may benefit from therapies including an interleukin-6 (IL-6) receptor antagonist (e.g., tocilizumab), or an interleukin-1 (IL-1) receptor antagonist such as anakinra or canakinumab.
Tocilizumab blocks the activity of IL-6 (a pro-inflammatory cytokine), which exerts a central role in systemic-onset juvenile idiopathic arthritis (SoJIA), and may be useful in children with SoJIA who have not responded to NSAIDs and systemic corticosteroids, and children with polyarticular JIA who have not responded to conventional therapies. Tocilizumab is relatively well tolerated and has shown efficacy for up to 52 weeks. Further studies are warranted to determine its utility as a first-line option for SoJIA.
Canakinumab is considered effective for the treatment of SoJIA with active systemic features; however, long-term safety data are required. 
Evidence suggests that anakinra is safe and effective in some JIA patients, especially those with systemic disease. It is currently being used successfully in a proportion of patients with SoJIA.   Use of anakinra is off-label for this indication.
Abatacept is a recombinant, fully humanised fusion protein used in those who do not respond to, or are intolerant to, treatment with DMARDs (including TNF-alpha inhibitors), and has shown efficacy and long-term safety.  Improvements in health-related quality of life were observed during a phase III, double-blind, placebo controlled trial, providing real-life, tangible benefits to children with JIA and their parents or carers. 
Adjunct –   pre-medication
Treatment recommended for SOME patients in selected patient group
Primary options
diphenhydramine  : children 2-5 years of age: 6.25 mg orally every 4-6 hours when required, maximum 37.5 mg/day; children 6-11 years of age: 12.5 to 25 mg orally every 4-6 hours when required, maximum 150 mg/day; children >12 years of age: 25-50 mg orally every 4-6 hours when required, maximum 300 mg/day
and
paracetamol  : 10-15 mg/kg orally every 4-6 hours when required, maximum 75 mg/kg/day
and
prednisolone  : 0.5 to 1 mg/kg/day orally for 4-6 weeks
Pre-medication with diphenhydramine, paracetamol, and corticosteroids is advised to minimise infusion-associated reactions with infliximab.  Methotrexate can be withdrawn once the clinician considers that the disease is clinically in remission. 
It is important that corticosteroids are used judiciously in children and are tapered as soon as possible.
Adjunct –   methotrexate plus folic acid
Treatment recommended for SOME patients in selected patient group
Primary options
methotrexate  : 10 mg/square metre of body surface area orally/subcutaneously once weekly on the same day of each week initially, adjust dose according to response, maximum 20-30 mg/square metre of body surface area/week
and
folic acid  : children 1-4 years of age: 0.15 mg orally once daily; children 4-9 years of age: 0.2 mg orally once daily; children 9-14 years of age: 0.3 mg orally once daily; children >14 years of age: 0.4 mg orally once daily
If tolerated, methotrexate should be used as an adjunct to adalimumab or infliximab in severe refractory disease.
If inflammatory bowel disease co-exists, methotrexate will help avoid the development of human anti-chimeric antibodies.  Methotrexate can be withdrawn once the clinician considers that the disease is clinically in remission. 
Folic acid is useful to decrease side effects such as nausea, oral ulcers, and abnormal liver enzymes.
Adjunct –   symptom control + lifestyle modification
Treatment recommended for SOME patients in selected patient group
Primary options
naproxen  : children >2 years of age: 10-20 mg/kg/day orally given in divided doses every 12 hours
OR
nabumetone  : consult specialist for guidance on dose
OR
diclofenac sodium  : 3 mg/kg/day orally given in 2-4 divided doses
OR
meloxicam  : children ≥2 years of age: 0.125 mg/kg orally once daily, maximum 7.5 mg/day
OR
celecoxib  : consult specialist for guidance on dose
OR
ibuprofen  : 10 mg/kg orally three to four times daily
OR
indometacin  : 0.5 to 1 mg/kg orally two to three times daily
OR
piroxicam  : 0.2 to 0.4 mg/kg orally once daily
NSAIDs may be used for control of pain and stiffness but are not disease modifying. Specific NSAIDs are approved for children (e.g., tolmetin, naproxen, meloxicam, and ibuprofen). However, many others are commonly used (e.g., nabumetone, diclofenac). No specific NSAID is superior, and trial and error methods are used to identify the most effective medicine for individual patients. Specialist dosing guidance is required for nabumetone.
Physiotherapy and occupational therapy are encouraged in conjunction with medicines. Patients are encouraged to participate in activities such as swimming and cycling, and weight-bearing activities are indicated for those with a greater risk of low bone mineral density. 
Adjunct –   anti-emetics
Treatment recommended for SOME patients in selected patient group
Primary options
ondansetron  : children <4 years of age: 1-4 mg orally three times daily depending on body surface area; children 4-11 years of age: 4 mg orally three times daily; children ≥12 years of age: 8 mg orally three times daily
Can be given to relieve the side effects of nausea.
Adjunct –   oral corticosteroids
Treatment recommended for SOME patients in selected patient group
Primary options
prednisolone  : 0.5 to 1 mg/kg orally once daily
Low-dose corticosteroid therapy allows time for other agents to take effect during active disease. It is important that corticosteroids are used judiciously in children and are tapered as soon as possible.
Adjunct –   intra-articular corticosteroids
Treatment recommended for SOME patients in selected patient group
Primary options
triamcinolone acetonide  : consult specialist for guidance on dose
Intra-articular corticosteroid injections can be used alone or as part of a treatment plan involving other systemic treatments. Radiographic assistance may be necessary for injecting some joints. Younger children may need sedation, especially if multiple joints are involved. It is important that corticosteroids are used judiciously in children and are tapered as soon as possible. Doses usually depend on joint size and other individual factors.
Adjunct –   intravenous corticosteroids
Treatment recommended for SOME patients in selected patient group
Primary options
methylprednisolone sodium succinate  : 30 mg/kg/day intravenously given on three consecutive days, repeated one week later, maximum 1 g/day
Patients with systemic-onset juvenile idiopathic arthritis (SoJIA) may occasionally require intravenous corticosteroids for overwhelming systemic inflammation or more serious complications such as macrophage activation syndrome or pericarditis.

Jacqui Clinch, Ripal Shah, (January 2019) Juvenile idiopathic arthritis, Available at: https://bestpractice.bmj.com/topics/en-gb/806 (Accessed: April 2019).