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

Disease/Condition: Systemic Juvenile Idiopathic Arthritis (sJIA)

Guideline Objective(s)

1)  Establish early diagnosis of sJIA

2)  Clarify the role of investigations in disease assessment and follow up

3)  Identify treatment modalities for controlling the disease activity as well as prevention and treatment of complications.

 ▪️Health / Clinical Question (PIPOH)

P: Patient (Target Population):

      Children and Adolescents (Less than 18 years old)

I: Interventions and Practices Considered / CPG Category:

    Diagnosis, and treatment and prevention of complications

P: Professionals (Intended / Target Users or Stakeholders)  :

    Pediatric Rheumatologists

    General Pediatricians

    Family Physicians

    General Practioners

O: Major Outcomes Considered:

     Primary (Specific) outcome: Early diagnosis of sJIA, proper control of disease activity, and  prevention and treatment of complications

    Secondary (general) outcome: Prevent delay in diagnosis, reduce inappropriate management and undue complications, improve patient outcome and quality of life, decrease hospitalization, and alleviate burden of drug side effects.

H: Healthcare Settings:

    Governmental and private healthcare facilities (hospitals and clinics)

▪️Guideline development process and methods

After reviewing all the inclusion and exclusion criteria and quality appraisal results, the GDG/ GAG recommended using the following source original clinical practice guidelines (CPGs):

1. 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. Onel KB, et al. Arthritis Care Res (Hoboken). 2022 Apr;74(4):521-537. doi:         10.1002/acr.24853.1
2. Treating juvenile idiopathic arthritis to target: recommendations of an international task force 2018. Ravelli A, et al. Ann Rheum Dis 2018;77:819–828. doi:10.1136/annrheumdis-2018-2130302
3. Practice and consensus-based strategies in diagnosing and managing systemic juvenile idiopathic arthritis in Germany 2018 Hinze et al. Pediatric Rheumatology (2018) 16:7.  doi:10.1186/s12969-018-0224-23

We conducted Adolopment for these guidelines: (Adoption, Adaptation, and Development)

         -   Adoption for most of the guideline recommendations.

         -     Development of Good Practice Statements

 ▪️Recommendations and Good Practice Statements (GPS)

This version of the CPG includes recommendations and good practice statements on the following four sub-sections:

A. DIAGNOSIS OF JUVENILE IDIOPATHIC ARTHRITIS

B. INVESTIGATION REQUIRED AND POSSIBLE DIFFERENTIAL DIAGNOSIS

C. TREATEMENT RECOMMENDATIONS FOR JIA.

D. LONG TERM MONITORING OF PATIENTS. 

We can summarize the guidelines’ recommendations in the following:

 ▪️   JIA comprises a group of inflammatory disorders that begin before the 18th birthday and persist for at least 6 weeks with other known conditions excluded (GPP)

 ▪️  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 include Evanescent (nonfixed)erythematous rash and Arthritis.

Minor criteria include Generalized lymph node enlargement and/or hepatomegaly and/or splenomegaly, Serositis, Arthralgia lasting 2 weeks or longer (in the absence of arthritis) and Leukocytosis (≥ 15,000/mm3) with neutrophilia. (GPP)

 ▪️ Once a child is suspected to have sJIA they should be referred to a pediatric rheumatologist ( GPP)

 ▪️ 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 (Strong recommendation, High LOE)

 ▪️  Measurement of specific auto antibodies may be useful to rule out other conditions. (Weak recommendation, very low LOE)

 ▪️  Sonography and MRI are important modalities to assess joint manifestations, to differentiate from other conditions and to monitor disease activity (Weak recommendation, very low LOE)

 ▪️ 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. (Weak recommendation, very low LOE)

 ▪️   Infections are important differential diagnoses for sJIA. An adapted search for infections should be pursued as a case of fever of unknown origin (Weak recommendation, very low LOE)

 ▪️ 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 recommendation, very low LOE)

 ▪️ 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)

 ▪️  High-dose systemic glucocorticoids are an effective and proven treatment for sJIA. (Strong recommendation, High LOE)

 ▪️  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. (Strong recommendation, Intermediate LOE)

 ▪️  Alternatively, IL-1 or IL-6 blockade may be applied, possibly in combination with glucocorticoids and/or methotrexate. (Strong recommendation, High LOE)

 ▪️ In case of insufficient treatment response, 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. (Strong recommendation, High LOE)

 ▪️  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 (Strong recommendation, Intermediate LOE)

 ▪️ Tapering and discontinuing glucocorticoids is strongly recommended after inactive disease has been attained (Weak recommendation, very low LOE)

 ▪️ Tapering and discontinuing biologic DMARDS is conditionally recommended after inactive disease has been attained (Weak recommendation, very low LOE)

 ▪️ Glucocorticoids are conditionally recommended as part of the initial treatment of sJIA with MAS.IL-1 and IL-6 inhibitors are conditionally recommended over calcineurin inhibitors alone to achieve inactive disease and resolution of MAS (Weak recommendation, very low LOE)

 ▪️   Moderate doses of etoposide can be used in refractory cases of MAS. Intravenous immunoglobulins might be considered in refractory cases with variable success (GPP)

 ▪️ Disease activity should be assessed and documented regularly using a validated composite instrument. (JADAS score) (Weak recommendation, Intermediate LOE)

 ▪️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 (Weak recommendation, very low LOE)

 ▪️  The following interim targets are aimed for:

i. Resolution of fever within one week of the start of treatment (Strong recommendation, Intermediate LOE)

ii. Improvement of CRP by at least 50% within one week of the start of treatment (Strong recommendation, Intermediate LOE)

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 (Strong recommendation, Intermediate LOE)

iv.Clinically inactive disease is aimed for within six to twelve months (Weak recommendation, Intermediate LOE)

  ▪️Guideline Registration

PREPARE (Practice guideline REgistration for transPAREncy), WHO Collaborating Center for Guideline Implementation and Knowledge Translation, EBM Center, University of Lanzhou, Lanzhou, China. Registration Number: ( ). Link: http://www.guidelines-registry.org/