Table 2 Breakdown of statements of recommendations, its individual rank by experts opinion, and level of agreement

1

Ι — General principles

A- Paediatric rheumatologists and rheumatologists with experience in paediatric rheumatology are the specialists who should primarily care for patients with JIA

I

8.32 ± 1.78

96

H

B- There should be a good cooperation between rheumatologists and paediatric rheumatologists during transition of JIA cases. Adolescence transition clinic, implementing the appropriate transition care programme based on the available facilities, should be established with at least one adult rheumatologist and one paediatric rheumatologist at each centre

I

8.32 ± 1.78

96

H

C- Baseline assessment of disease activity using JADAS 27 is recommended

I

8.32 ± 1.78

96

H

D- When feasible, ultrasound can be used by healthcare professionals for more accurate evaluation of inflamed joints, monitoring disease activity, and guiding treatment decisions in JIA patients

II

8.32 ± 1.78

96

H

E- Assessment of limited joint mobility and functional ability/health-related quality of life (HRQoL) is recommended

I

8.32 ± 1.78

96

H

F- All patients should be screened for pre-DMARDs and pre-biologics laboratory, vaccination status, and radiological screening

I

8.32 ± 1.78

96

H

G- In children and adolescents with JIA, particularly those with active polyarthritis, poor prognostic factors are defined as the presence of one or more of the following: positive rheumatoid factor, positive anticyclic citrullinated peptide antibodies, anti-nuclear antibody (ANA), involvement of high-risk joints (e.g. cervical spine, hip, and wrist), high disease activity, and/or for those judged by their physician to be at high risk of disabling joint damage (limited mobility, loss of cartilage thickness, erosion, loss of joint space)

I

8.32 ± 1.78

96

H

H- The major therapeutic target, which should be determined on a shared decision with parents/patients, with the overriding goal to achieve clinical and/or imaging (MRI) and/or ultrasound remission, was defined as remission, with the alternative target of low disease activity should be incorporated in all JIA patients’ treatment protocols

I

8.32 ± 1.78

96

H

I- Consider early aggressive therapy particularly in polyarticular JIA with one or more poor prognostic factors or in moderate to severe disease activity status or in the presence of associated uveitis

I

8.32 ± 1.78

96

H

J- Consider JDAS27 in measuring JIA disease activity; the cutoffs of disease activity states are as follows:

 - A joint with inactive disease: JDAS-27, ≤ 1

 - Low disease activity: JDAS-27, ≤ 3.8 (polyarthritis) and ≤ 2 (oligoarthritis)

 - Moderate disease activity: JDAS-27, 3.9–8.5 (polyarthritis) and 2.1-4.2 (oligoarthritis)

 - High disease activity: > 8.5 (polyarthritis) and > 4.2 (oligoarthritis)

 - Changes in the JADAS-27 corresponding to clinically important difference were −5.5 for improvement and +1.7 for worsening

I

8.32 ± 1.78

96

H

K- For patients with systemic JIA, JDAS can be used to assess disease activity, whereas juvenile spondyloarthritis disease activity (JSpADA) index can be used for patients with juvenile spondylarthritis

I

8.32 ± 1.78

96

H

L- Personalize non-pharmacologic interventions to optimize supportive care in JIA patients who at risk of functional limitations, (by using physical therapy and/or occupational therapy and/or surgical intervention)

I

8.32 ± 1.78

96

H

1- Nonsteroidal anti-inflammatory drugs (NSAIDs)

• NSAIDs are the adjunctive therapy in all JIA categories. Naproxen and ibuprofen are effective and can be used safely in JIA patients. Considering safe choices in children and age of approval, diclofenac can be used as an alternative rational NSAIDs (evidence I). Meloxicam (evidence level II). Selective COX inhibitors, such as celecoxib (evidence I) for children and adolescents with JIA, and etoricoxib (evidence I) for children over 12 years old, might be used as alternatives if the former drugs are contraindicated or intolerable

• When using a nonselective COX form, a gastroprotective is better to be used

• NSAIDS can be used in the early state of the disease, particularly in cases with severe pain, until results of the investigations are available and cDMARDs therapy is commenced

I/II

8.08 ± 2.24

92

H

2- Corticosteroids

a. Intra-articular corticosteroids

 • Intra-articular glucocorticoids are used as the first line of therapy for oligoarticular JIA and as adjuvant therapy in other JIA categories (evidence II)

 • Triamcinolone hexacetonide is the drug of choice in large joints injections, and methylprednisolone acetate is an alternative (evidence I)

b. Systemic corticosteroids

 • Systemic corticosteroids may be used as bridging therapy with short course (< 3 months) of oral glucocorticoids (initial: 0.5–1 mg/kg/day once daily [maximum daily dose: 60 mg/day) with rapid tapering) during initiation or escalation of therapy in patients with high or moderate disease activity to control severe active polyarthritis refractory to other therapies. It also can be used as bridging therapy in the setting of limited mobility and/or significant symptoms (evidence III)

 • Bridging therapy with a very short course (mini pulse steroid, adjusted to the child’s body weight) such as 100-mg daily dose of methylprednisolone for a maximum of 3 days can be used for resistant active polyarticular JIA

 • Bridging therapy with a limited course of oral glucocorticoids (< 3 months) is not advised in patients with low disease activity

 • In all JIA categories, the lowest possible dose of corticosteroids (0.1–0.2 mg prednisone/kg/day or equivalent) should be used and for the shortest possible period to avoid the adverse events particularly on growth and bone

 • Chronic low-dose glucocorticoids are not recommended for JIA patients, irrespective of risk factors or disease activity

 • Intra-articular glucocorticoid injection is considered preferable in patients whose arthritis is hindering their ambulation or interfering with important daily activities and more when prompt disease control is required

 • Supplementation with calcium and vitamin D is advised to avoid long-lasting side effects of systemic glucocorticoids

 • It is advisable to continue physical activity and limit carbohydrate and fat intake in children and adolescents on systemic corticosteroid therapy

I/II

8.32 ± 1.34

92

H

III

III

I

I

8.32 + 1.34

H

I

II

II

3- Conventional disease-modifying antirheumatic drugs (cDMARDs)

a. Initial DMARD therapy is strongly recommended over NSAID monotherapy

b. In patients without risk factors, initial DMARD therapy is recommended over biological therapy

c. In some patients with multiple risk factors and involvement of high-risk joints as cervical spine, hip, and wrist, high disease activity, and/or for those judged by their physician to be at high risk of disabling joint damage, biological therapy may be considered as appropriate initial therapy

d. Triple cDMARDs is not advised

e. Assessment of csDMARDs therapy should be considered at 3 and 6 months from starting csDMARDs therapy

II

8.32 ± 1.22

92

H

Methotrexate (MTX)

 a. MTX is recommended as initial DMARD therapy over leflunomide or sulfasalazine

 b. Initial MTX monotherapy is advised over combined cDMARDs therapy

 c. The usual dose of MTX is 10–15 mg/m2/week or 0.3–0.6 mg/kg/week (max 20 mg/week) parenterally (subcutaneously or intramuscularly) or orally

 d. Intramuscular or subcutaneous MTX injection may be considered is a preferable option than oral MTX

 e. Patient preferences may guide the choice of route of administration

 f. In order to prevent adverse events, folic acid for all children in the dose of 1 mg tablets of folic acid daily, for 6 days except on methotrexate day, or 2.5–5 mg of folic acid once a week on the day after MTX administration

 g. Patients should be reviewed at 1 and 3 months after starting methotrexate therapy. If the patient achieved the treatment target (remission or low disease activity), reassessment should be carried out at 6 months from starting methotrexate therapy

 h. MTX intolerance is one of common causes of stopping MTX treatment and use alternatives, so discussion and shared decision with patient or parents are very important

I

8.32 ± 1.22

92

H

I

Leflunomide (LEF)

Leflunomide could be an alternative option for polyarticular JIA patients unresponsive or intolerant to MTX. The usual dose in children < 40 kg is 10 mg/day, and in those > 40 kg, the dose is 20 mg/day)

LEF might be used in combination with MTX in patients with polyarticular JIA refractory to standard doses of MTX, in the absence of poor prognostic factor or when biological therapy is unavailable

II

8.32 ± 1.22

92

H

Sulfasalazine (SSZ)

 a. Sulfasalazine may be used in some cases of polyarticular JIA where MTX as well as leflunomide are not effective, intolerable, or contraindicated and, also, if biologic therapy is not available

 b. Assessment of G6PD and risks of Stevens-Jonson syndrome should be considered before starting SSZ

II

8.32 ± 1.22

92

H

4- Biologic agents

a. In children and adolescents with JIA and active polyarthritis, biological therapy recommended in these guidelines refers to anti-TNFs, tocilizumab, and abatacept

b. TNF inhibitors (etanercept, adalimumab, and golimumab)

c. In view of the limited data available regarding infliximab, it can be used as an alternative to other TNF inhibitors if they are not available or contraindicated “in children aged 4 years or above in dose 3 mg/kg”

d. Tocilizumab can be used as initial biologic therapy for children and adolescents with JIA in patients with poor prognostic factors and severe active disease

e. Assessment of risk of patients and family history, e.g. of demyelinating diseases, is recommended before treatment initiation

I

8.76 ± 0.65

96

H

III

I

• Mono biologic versus combined biologic and cDMARD therapy

 a. In children and adolescents with JIA and polyarthritis (whose disease continues to run moderate/severe activity course) in spite of 6 months cDMARDs with appropriate adherence to therapy, initiating treatment with biologics in combination with cDMARDs is recommended over biologics monotherapy (particularly with adalimumab and infliximab)

 b. It is advisable that biological therapy is combined with MTX

II

8.76 ± 0.65

96

H

• In children and adolescents with JIA and active polyarthritis, initiation of treatment with TNF-α inhibitors (etanercept, adalimumab, golimumab, and infliximab) is indicated in polyarticular JIA patients who failed cDMARDs for 6 months, one of which must be MTX in recommended doses for at least 3 months, unless contraindicated, or toxicity/intolerance occurs

• Before 2 years of age, safety and efficacy of TNFi are not established

• The paediatric dose of etanercept is 0.8 mg/kg s weekly not exceed 50 mg/week

• The paediatric dose of adalimumab is 20 mg s/2 weeks if less than 30 kg weight and 40 mg s/2 weeks if exceed 30 kg body weight

• The paediatric dose of golimumab is 30 mg/m² s every 4 weeks not exceed 50 mg/4 weeks

• Tocilizumab is considered as an alternative initial therapy or switch therapy in patients intolerable or contraindicated to anti-TNFs

• Abatacept may be indicated in polyarticular JIA patients, older than 6 years old refractory to treatment with MTX and anti-TNF agents

I

8.76 ± 0.65

96

H

• Switching between treatments is as follows:

 a. In children and adolescents with JIA and active polyarthritis with moderate/high disease activity after receiving first anti-TNF therapy (with or without cDMARDs) for at least 6 months, switching to a non-TNFi biologic (tocilizumab or abatacept) is recommended over switching to a second anti-TNF

 b. A second TNFi may be appropriate for patients with good initial response to their first TNFi (i.e. secondary failure)

 c. Using TNFi, abatacept, or tocilizumab (depending on prior biologics received) is conditionally recommended over rituximab

II

8.76 ± 0.65

96

H

5- Treatment withdrawal or tapering

The decision regarding which medication to stop first is individualized depending upon response to the medication, tolerance of the administration regimen, and other patient factors

Starting treatment tapering may be considered in patients with the following:

 - Persistent inactive disease (for > 6 months)

 - Inactive disease is defined by the criterion of Wallace

 - No joints with active arthritis

 - No active uveitis (defined as “grade 0 cells”, indicating < 1 cell in field sizes of 1 mm by a 1-mm slit beam)

 - Erythrocyte sedimentation rate (ESR) ≤ 20 mm or C-reactive protein (CRP) level ≤ 10 mg/L (or ≤ 1 mg/dl or ≤ 100 μg/dl) or, if elevated, not attributable to JIA (if both ESR and CRP are available, both of them should be in the normal range)

 - Physician’s global assessment of disease activity score (< 10/100 visual analogue scale)

 - Duration of morning stiffness ≤ 15 min (within 7 days before the visit)

In disease remission, tapering of biologic therapy is by decreasing dosage superior to tapering dosing interval

II

8.81 ± 0.55

96

H

General principles

1- Oligoarticular juvenile idiopathic arthritis (JIA) is classified as JIA that affects fewer than five joints

2- It is the most frequent subgroup, representing for around half of all JIA cases

3- This subgroup of JIA is further differentiated into persistent oligoarthritis, which has no new joint involvement after the first 6 months of illness, and extended oligoarthritis, which has additional joint involvement after the first 6 months and eventually affects more than four joints

4- About half of all children with oligoarticular disease develop extended oligoarticular disease

I

8.68 ± 0.68

100

H

Baseline assessment

- Disease activity assessment

- Joint limited mobility

- Functional ability/quality of life (PROMs)

- Poor prognostic markers: if at least one of the following features is present, the patient is considered to have a poor prognosis:

 ° Hip or cervical spine arthritis

 ° Ankle or wrist arthritis

 ° Marked or prolonged elevation of ESR or CRP

 ° Radiographic evidence of joint damage

 ° ANA (for association with uveitis)

- Blood check for ESR, CRP, ANA, rheumatoid factor, anti-CCP

- Baseline pre-DMARDs blood tests

II

8.32 ± 1.46

96

H

Patients with low disease activity + no risk factors

- NSAID: start to relieve symptoms within 2 weeks

- A different NSAID can be tried if no response is seen within the first 2 weeks of therapy

- Intra-articular steroid injection(s)

- If the patient has responded well to the NSAID therapy, the patient should be reassessed every 3 months and reinject joints if required

- The patient should be monitored until a minimum of 6 months of disease inactivity

- Inactive disease: JADAS-27, 1

- Low disease activity: JADAS-27, 2

If arthritis persisted in spite of the NSAID therapy/local injection, arthritis extended > 4 joints or > 2 injections/one joint in 12 months, or severe/erosive arthritis in any joint, or persistent inflammatory arthritis recorded on joint ultrasonography, the patient should be treated as moderate/high disease activity category

I

8.32 ± 1.46

96

H

Moderate/high disease activity (JADAS-27 > 4.2) and/or present > 1 of the poor prognostic features

Initial therapy: methotrexate + intra-articular steroids

The usual dose of MTX is 10–15 mg/m2/week (max 20 mg/week) orally or parenterally (subcutaneously or intramuscularly) (evidence level I, recommendation grade A)

Adjunct NSAID can be used if required

Reassess after 3 months of therapy

If low disease activity: adjust methotrexate dose

If after 3 months of methotrexate therapy, disease activity remained in the moderate-high status (JADAS-27 > 4.2)

Leflunomide might be used in combination with MTX (or instead of MTX when MTX intolerance occurred) in patients with oligoarticular JIA refractory to standard doses of MTX, in the absence of poor prognostic factor, or when biological therapy is unavailable + intra-articular steroids

Adjunct NSAID can be used if required

Reassess disease activity after 3 months

If after 3 months the disease activity remained in the moderate/high status (JADAS-27 > 4.2) or persisted inflammatory arthritis documented by joint ultrasonography

- Add biologic as follows:

 • TNFi

 • Tocilizumab

 • Abatacept (older than 6 years old)

 • The presence of uveitis is an important aspect while choosing the treatment. including type of biologic

- Assess disease activity at 3 and 6 months

6 months after biologic therapy, assess disease activity, if as follows:

Disease activity: in remission

 1. Continue current medication

 2. Monitoring DMARDs/biologic therapy

Disease activity: low; escalate therapy

 -1. Intra-articular steroid injection(s)

 -2. Increase DMARD or biologic dose or change biologic

Disease activity: moderate/high

 -Primary TNF failure: tocilizumab, or abatacept

 -Secondary TNFi failure: another TNFi, followed by tocilizumab or abatacept

In children and adolescents with oligoarticular JIA who have or are at risk of functional limitations, it is recommended to use physical therapy

I

8.32 + 1.46

100

H

III

I

II

I

III

Treatment withdrawal or tapering

The decision regarding which medication to stop first is individualized depending upon response to the medication, tolerance of the administration regimen, sustained remission, comorbidities, and other patient factors

 ° Starting treatment tapering may be considered in patients with the following:

- Persistence of inactive disease (for a period > 12 months)

- MSUS should confirm remission before tapering treatment

- Inactive disease is defined by the criterion of Wallace

No joints with active arthritis,

No active uveitis (defined as “grade 0 cells”, indicating < 1 cell in field sizes of 1 mm by a 1-mm slit beam)

Erythrocyte sedimentation rate (ESR) ≤ 20 mm or C-reactive protein (CRP) level ≤ 10 mg/L (or ≤ 1 mg/dl or ≤ 100 μg/dl) or, if elevated, not attributable to JIA (if both ESR and CRP are available, both of them should be in the normal range)

Physician’s global assessment of disease activity score (< 10/100 visual analogue scale)

Duration of morning stiffness ≤ 15 min (within 7 days before the visit)

 - Strategy of tapering that starts to tapper corticosteroids then biological DMARDs and finally with sustained remission conventional DMARDs

In disease remission, tapering of biologic therapy is by decreasing dosage superior to tapering dosing interval

III

8.56 ± 0.98

100

H

Enthesitis

• Ultrasonography is recommended as a method of choice in diagnosis and activity assessment of enthesitis

• NSAIDs are the first-line drugs in all enthesitis. Diclofenac, naproxen, ibuprofen, and indomethacin are effective and can be used safely in JIA patients (evidence I). Meloxicam (evidence II) and celecoxib (evidence I) and etoricoxib (evidence I) for children over 12 years old might be used as alternatives if the former drugs are contraindicated

• In case of a limited number of the affected entheses along with low-moderate disease activity, local glucocorticoid injection for management of enthesitis can be used as a first-line treatment

• In children and adolescents with JIA and active enthesitis despite treatment with NSAIDs, local glucocorticoid injections and using a TNFi are conditionally recommended over methotrexate or sulfasalazine

• In children and adolescents with JIA and chronic active enthesitis despite treatment with NSAIDs, and local glucocorticoids injections particularly those with high disease activity, limited mobility, and/or significant symptoms, bridging therapy with a limited course of oral glucocorticoids (< 3 months) during initiation or escalation of therapy is advised

• Sulfasalazine is recommended in enthesitis-related arthritis

• In children and adolescents with JIA and enthesitis who have or are at risk for functional limitations, using physiotherapy is recommended

I/II

8.68 ± 0.73

100

H

II

Sacroiliitis

• X-ray/MRI sacroiliac joints can be used to assess sacroiliitis, with MRI sacroiliac joints is recommended as the method of choice in the diagnosis and assessment of early as well as established sacroiliitis

• In children and adolescents with JIA and active sacroiliitis, treatment with an NSAID is strongly recommended over no treatment with an NSAID

• If the decision of using NSAIDs is made, they should be given at a full dose and continuously (not on demand). No combinations should be made. In case of using nonselective COX inhibitor, gastroprotective should be used. If contraindicated or intolerable, switching to selective COX-II inhibitors is recommended. Assessment of the treatment response should be done after 4 weeks of NSAIDs initiation. If no response, another NSAID from another family may be used with application of the previously mentioned roles. If no response after 4 weeks, switching to anti-TNF therapy is recommended

• In children and adolescents with active sacroiliitis despite NSAIDs, adding a TNFi is strongly recommended over continued NSAID monotherapy

• In children and adolescents with active sacroiliitis despite NSAIDs, using sulfasalazine for patients who have contraindications to TNFi or have failed more than one TNFi can be an option

• Non-TNFi biologics (e.g. interleukin-17 [IL-17] inhibitors) have not been included in these guidelines as there are no published paediatric studies

• In children and adolescents with active sacroiliitis despite NSAIDs, it is not recommended to use methotrexate monotherapy

Steroids:

• In children and adolescents with active sacroiliitis despite treatment with NSAIDs, intra-articular glucocorticoid injection of the sacroiliac joints as adjunct therapy may be useful

• In children and adolescents with sacroiliitis who have or are at risk for functional limitations, using physiotherapy is advised

II

8.6 ± 0.98

96

H

General considerations

• The manifestations of systemic inflammation (i.e. elevated C-reactive protein, erythrocyte sedimentation rate, leukocytes, and/or ferritin) are essential for diagnosing SJIA at disease onset

• Many conditions should be ruled out before diagnosis of SJIA as malignancies, infections, and other autoinflammatory disorders

• When malignancy is suspected, bone marrow aspiration should be done before initiating a glucocorticoid therapy

• When there is insufficient response to corticosteroids, interleukin-1, or interleukin-6 blockade, the diagnosis of SJIA should be revised

• Macrophage activation syndrome (MAS) should be considered in patients with clinical or laboratory deterioration especially if associated with dropped ESR

• Assessment of disease activity should be carried out using sJADAS

• Treat to target should be considered achieving a clinically inactive disease (resolution of fever and improvement of sJADAS score and CRP by at least 50%)

• The only approved DMARD for treating SJIA is methotrexate

8.84 ± 0.61

100

H

Statements

Mild-to-moderate acute disease

 • Mild-to-moderate acute disease means non-disabling symptoms (fever, rash, mild-moderate arthritis) without evidence of MAS

 • Initial therapy with nonsteroidal anti-inflammatory drug (NSAID) as monotherapy should last no more than 1 or 2 weeks. (evidence level I, recommendation grade B)

 • In patients who resist NSAIDs or develop significant symptoms despite use of NSAIDs (such as continued high fevers, rash, arthritis, serositis organomegaly, and lymphadenopathy) should be managed as with moderate-to-severe disease

I

8.88 + 0.32

100

H

Moderate-to-severe disease

 • Moderate-to-severe disease: patients with initial symptoms include serious systemic manifestations as serositis, moderate-to-severe polyarthritis, high fevers with a poor response to NSAIDs, or early MAS

 • High dose of systemic corticosteroids (either i.v pulse and/or as daily corticosteroids with subsequent dose reduction) is an effective and proven treatment for SJIA

 • Using the minimum dose and duration of systemic corticosteroids therapy whenever possible is recommended to minimize their side effects (as possible as you can keep the dose below 0.5 mg/kg per day of prednisone (or its equivalent), with the duration of therapy should not exceed 6 months)

 • Intravenous pulse corticosteroids (30 mg/kg/d for 1–3 days) could be used to reduce the toxicity associated with daily oral glucocorticoids or to treat pericarditis severe anaemia or MAS

 • Intraarticular corticosteroids may be used in treatment of arthritis in patients with SJIA

 • Using biologics may be more effective if used early in the disease course, rather than as “rescue” therapy when other therapies have failed

 • Starting one of the biologic drugs as interleukin (IL)-1 inhibitor or IL-6 inhibitor, such as anakinra, canakinumab, or tocilizumab, is recommended for patients with predominant systemic features. Methotrexate can be added as a first-line option besides steroids in patients with predominant arthritis

 • Anakinra is the first biologic of choice in SJIA due to its rapid action and short duration that allows dose modification or switching to other biologics in nonresponders or when side effects occurred

 • If biologics are unavailable; start with corticosteroids, and methotrexate may be an option

 • Methotrexate can be used as a steroid-sparing agent and adjunct to a treatment regimen containing a biologic therapy if the arthritis is not adequately controlled (with dose 0.5 to 1 mg/kg) per week, with a maximum dose of 25 mg per week. Above 15 to 20 mg/m2 (roughly 0.5 mg/kg), oral absorption is unreliable, and parenteral administration may be advantageous)

 • Starting biologics gives more effect than nonbiologic disease-modifying antirheumatic drugs

 • In case of inadequate response, i.v pulse corticosteroids therapy may be repeated, or biologics dose increases, or a change of the biologic can be considered

 • Biological therapy may be applied in combination with corticosteroids and/or methotrexate

 • IL-1 or IL-6 inhibitors are the most effective biologics in managing both systemic manifestations (e.g. fever, rash, and serositis) and may be effective for chronic arthritis as well

 • TNF inhibitors and T-cell costimulation blockers (abatacept) are not recommended for initial therapy or systemic disease; these agents, particularly in combination with methotrexate, can be helpful for chronic arthritis management

 • Other nonbiologic DMARDs, such as cyclosporine and tacrolimus, and cytotoxic drugs, such as cyclophosphamide, are also options in patients who fail standard therapy, including biologic agents

I

8.8 ± 0.49

100

H

II

I

I

I

II

III

• Patients presenting with severe symptoms or who have suspected early MAS: should be treated with i.v. pulse corticosteroids in addition to an anti-IL-1 or anti IL-6 (if anti-IL-1 is not available). Concomitant use of a biologic agent may allow relatively rapid tapering of corticosteroids

• Refractory acute disease: for patients started on a biologic DMARD as part of the initial therapy, add a corticosteroids within a week if there is continued polyarthritis, fever, and rash. A corticosteroids should be added sooner if there was evidence of MAS or severe serositis. IVIG may be used in refractory cases

I

8.8 ± 0.4

100

H

II

General considerations

• Juvenile idiopathic arthritis-associated uveitis often occurs in oligoarticular JIA and enthesitis-related arthritis

• Risk factors for the development of JIA-associated uveitis (younger age at the onset of JIA, oligoarticular JIA and enthesitis-related arthritis, ANA-positive, females gender, high ESR at the time of JIA diagnosis)

• Early diagnosis is essential in uveitis to prevent serious vision-threatening complications

• If uveitis is severe with sight-threatening complications, adalimumab or infliximab (monoclonal antibody TNF inhibitors) are preferred to etanercept as an added option with methotrexate

• If active uveitis is refractory to methotrexate and two monoclonal antibody TNF inhibitors, alternative options for nonbiologic DMARDs include leflunomide, mycophenolate, and cyclosporine and for biologic DMARDs include tocilizumab or abatacept

• Other biologics that have demonstrated efficacy for arthritis may also serve as rescue options for treatment-refractory uveitis, including IL-6 inhibitors, T-cell costimulation modulators, JAK inhibitors, and CD20 inhibitors

• Due to the relatively short duration of acute anterior uveitis episodes in patients currently on systemic therapy for JIA spondyloarthritis, it is recommended that they continue their current regimen and add topical glucocorticoids as a first step

• Treatment of uveitis should be carried out in collaboration of the managing paediatric rheumatologist and ophthalmologist, and decision to treat should be a shared rheumatology-ophthalmology decision in management of uveitis associated with JIA

• Infection and parasitic infestation should be excluded first particularly before application of steroid therapy

I

8.8 ± 0.63

100

H

II

II

Control of activity

Bottom line: uveitis associated with JIA is an aggressive vision-threatening disease. It is in the best interest of the affected child that the treating team should have zero tolerance to uveitis activity of any grade

We use the following stepladder approach:

If a certain step is inadequate, we add and not replace

1) Topical steroids

 - Prednisolone achieves a higher intraocular bioavailability than dexamethasone

 - An aggressive hourly application regimen is needed

 - If activity is controlled (no cells in anterior chamber), slow and cautious tapering is started, accompanied by frequent meticulous examinations for any recurrence of activity

2) Oral NSAID

 • A variety can be used, but the one with the longest track record is naproxen

3) Immunomodulatory therapy (IMT)

 • A variety can be used, but the one with the longest efficacy and safety track record is methotrexate

 • Methotrexate therapy is commenced in the dose of 10–15 mg/m2/week. Dose to be adjusted to, as required and as tolerated, to achieve the goal of treatment. In general, uveitis associated with JIA requires higher doses of methotrexate to attain and to maintain a remission than arthritis associated with JIA, so in many cases, the dose is titrated according to the ocular activity rather than the joint inflammation activity

 • Dose increments are made at 6–8 weekly intervals

 • Methotrexate is maintained for a minimum of 2 years after the above-mentioned goal is achieved: “Freedom of ALL recurrences of ALL forms of intraocular inflammation at ALL times of the day (due to the diurnal variation observed in the activity of uveitis) off ALL steroids (by any route including the topical route)”

 • As the bioavailability of methotrexate after oral administration is variable, subcutaneous administration is the preferable route of administration

 • Careful monitoring for the complications of methotrexate, both clinically and by lab tests, is mandatory

 • In particular, in view of the higher doses of methotrexate used to control uveitis, CBC and liver enzymes are requested monthly, and the symptoms of interstitial pneumonitis such as dry cough are periodically reviewed with the child and his parents

 • Folic acid supplement is administered

4) Adalimumab (currently, it is the only FDA-approved medication for use in noninfectious uveitis)

 • Adalimumab every 2 weeks dose in children: (< 30 kg is 20 mg and in children > 30 kg is 40 mg)

 • 40 mg every 2 weeks, in combination with methotrexate

 • When the aforementioned goal of therapy is achieved, we stop the adalimumab and maintain the methotrexate

 • Children, who develop complications during the use of methotrexate, are given mycophenolate mofetil or oral prednisolone.

 • If oral prednisolone is used, it should not be given for longer than 3 months. If the treatment goal is not achieved, we shift to mycophenolate mofetil or to adalimumab

I

8.88 ± 0.43

100

H

II

I

I

Management of complications

1) Glaucoma

 • Tension-lowering drops are administered. Prostaglandin analogues are not the first line due to their potential to promote inflammation

 • Iris bombe is an indication for peripheral iridotomy if it is associated with secondary glaucoma caused by the pupillary block

 • An elevated intraocular pressure that is not controlled by medical treatment is indicated for glaucoma surgery in order to save the optic nerve

2) Band-shaped keratopathy

 • If visually significant, it is indicated for chelation using EDTA (ethylenediaminetetraacetic acid)

3) Cataract

 • If visually significant, it is indicated for cataract extraction

 • Before the surgery, a period of 6 months of clinical quiescence is needed

 • Primary intraocular lens implantation will usually do more harm than good

II

8.8 ± 0.62

100

H