Diagnosis and Treatment of Systemic Juvenile Idiopathic Arthritis (sJIA) in Pediatric Age Groups

Health Question

Diagnosis Recommendation

SOR

LOE

Source guidelines

1-      What is the general definition of JIA?

JIA comprises a group of inflammatory disorders that begins before the 18th birthday and persists for at least 6 weeks wit other known conditions excluded.

GPP*(9)

2- What are the classification criteria for definite diagnosis of systemic JIA?

-Systemic JIA is grouped among JIA disorders.

-Fever of unknown origin

(Excluding infectious, neoplastic, autoimmune, or monogenic autoinflammatory diseases) that is documented to be daily: quotidian fever that rises to ≥ 39°C once a day and returns to ≤ 37 °C between fever peaks for at least 3 consecutive days and reoccurring over a duration of at least 2 weeks 

plus

2 major criteria OR

1 major criterion and 2 minor criteria.

Major criteria:

1- Evanescent (nonfixed)erythematous rash

2-Arthritis.

Minor criteria:

1-Generalized lymph node enlargement

and/or hepatomegaly and/or splenomegaly

2-Serositis

3-Arthralgia lasting 2 weeks or longer (in the absence of arthritis)

4-Leukocytosis (≥ 15,000/mm3) with neutrophilia.

GPP*(9)

3-When to refer to pediatric rheumatologist

Once a child is suspected to have sJIA they should be referred to a pediatric rheumatologist.

GPP

4- What is the role of investigations in diagnosis of sJIA?

- The demonstration of systemic inflammation, i.e., usually elevated C-reactive protein, erythrocyte sedimentation rate, leukocytes and/or ferritin) is essential for diagnosing sJIA at disease onset

-Measurement of specific autoantibodies may be useful in order to rule out other conditions.

-Sonography and MRI are important modalities to assess joint manifestations, to differentiate from other conditions and to monitor disease activity.

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Weak

Weak

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Very low

The German 2018 ³

Statement 2

Statement 3

5-What is the differential diagnosis of sJIA?

-Malignancies are important differential diagnoses for sJIA. If suspected, an extended panel of diagnostic tests, including chest radiography, ultrasound of the abdomen and pelvis, bone marrow aspiration, and, if appropriate, biopsy of lymph nodes or other involved organs should be pursued. An elevated LDH, uric acid and cytopenias represent pertinent findings.

-Infections are important differential diagnoses for sJIA. An adapted search for infections should be pursued as a case of fever of unknown origin

-Hereditary autoinflammatory syndromes are other important differential diagnoses for sJIA. Molecular genetic testing should be pursued if clinical suspicion for a known hereditary autoinflammatory syndrome exists.

Weak

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Very low

The German 2018 ³

Statement 3

    6-What are the classification criteria for diagnosis of macrophage activation syndrome (MAS) in patients with sJIA?

A febrile patient with known or suspected sJIA is classified as having MAS if the following criteria are met:

Ferritin > 684 ng/ml and 2 of the following

·        PLT count ≤ 181x10⁹/liter

·        AST> 48 U/liter

·        TGs > 156mg/dl

·        Fibrinogen ≤ 360 mg/dl

Abnormalities not otherwise explained by other patient condition, such as concomitant ITP, infectious hepatitis, visceral leishmaniasis, or familial hyperlipidemia.

GPP**(29)

Health Questions

Treatment Recommendations

GOR

LOE

Adapted Guidelines

1-What are the treatment strategies for sJIA without MAS?

A) Glucocorticoids: High-dose systemic glucocorticoids are an effective and proven treatment for sJIA.

B) In the case of   sJIA with arthritis, high-dose systemic glucocorticoids may be used, either as IV pulse therapy and/or as daily glucocorticoids with subsequent dose reduction.

C) Alternatively, IL-1 or IL-6 blockade may be applied, possibly in combination with glucocorticoids and/or methotrexate.

D) In case of insufficient treatment response (see treatment targets in (3C), IV glucocorticoid pulse therapy may be repeated, or IL-1 or IL-6 blocking agents may be increased in dose (if feasible). In case of initial glucocorticoid therapy, IL-1 or IL- 6 blockade may be initiated. In case of initial biological monotherapy, glucocorticoids may be added (systemically or locally), the biological agent may be changed, or methotrexate may be added.

E) In case of a predominant polyarticular arthritis and in case of lack of treatment response despite the utilization of the approved biological agents, second-line agents, e.g., TNF blockers (etanercept or adalimumab) or abatacept may be applied. In addition, the use of methotrexate is reasonable and intraarticular glucocorticoids may be applied

F) Tapering and discontinuing glucocorticoids is strongly recommended after inactive disease has been attained

G) Tapering and discontinuing biologic DMARDS is conditionally recommended after inactive disease has been attained

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Intermediate

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The German 2018³ Statement  5

Statement  7

ACR 2021 ˡ

2- What are the treatment strategies for sJIA with MAS?

(A)   Glucocorticoids are conditionally recommended as part of initial treatment of sJIA with MAS.

(B) IL-1 and IL-6 inhibitors are conditionally recommended over calcineurin inhibitors alone to achieve inactive disease and resolution of MAS

(C)   Moderate doses of etoposide can be used in refractory cases of MAS

(D)   Intravenous immunoglobulins might be considered in refractory cases with variable success

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Weak

Very Low

Very Low

GPP***(46)

GPP**** (47)

ACR 2021 ˡ

       ACR 2021 ˡ

  3- When and how to monitor the patient with sJIA while on treatment?

(A) Disease activity should be assessed and documented regularly using a validated composite instrument. (JADAS score (27)

(B)  sJIA with active systemic manifestations will require weekly assessment till resolution; monthly to every 3 months evaluations for patients who have high/moderate disease activity; and less frequent assessments, in states of persistent clinical remission.

(C) The following interim targets are aimed for:

i. Resolution of fever within one week of the start of treatment

ii. Improvement of CRP by at least 50% within one week of the start of treatment

iii. Marked improvement of overall disease activity within four weeks of the start of treatment, i.e., Improvement of the physician global disease activity by at least 50%, reduction of actively inflamed joints (if present) by at least 50% and/or a JADAS10-Score of maximally 5.4

iv.Clinically inactive disease is aimed for within six to twelve months

v. Once the treatment target has been achieved, it should be sustained. Ongoing monitoring should occur to ensure maintenance of the target.

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Treat to Target2018 ²

The German 2018³

Statement 4

Treat to target 2018²