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

- Executive Summary

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

- Recommendations

Recommendations for Diagnosis of sJIA (Quick references guide)

* Martini A, Ravelli A, Avcin T, Beresford MW, Burgos-Vargas R, Cuttica R, et al. Toward New Classification Criteria for Juvenile Idiopathic Arthritis: First Steps, Pediatric Rheumatology International Trials Organization International Consensus. J Rheumatol 2019; 46(2):190-7. ⁹

**Ravelli A,  Minoia F,  Dav S,   Horne A,Bovis F, Pistorio A, et al. 2016 Classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. A European League Against Rheumatism/American College of Rheumatology/Paediatric heumatology International Trials Organisation Collaborative Initiative.Arthritis Rheumatol 2016 Mar;68(3):566-76.²⁹

       GPP: Good Practice Point (Consensus by the sJIA Guidelines Adaptation Group)

 Recommendations For Treatment of  sJIA (Quick references guide)

Tibaldi J, Pistorio A, Aldera E, Puzone L, El Miedany Y, Pal P, et al. Development and initial validation of a composite disease activity score for systemic juvenile idiopathic arthritis. Rheumatology (Oxford). 2020;59(11):3505-14.²⁷

*** Boom V, Anton J, Lahdenne P, Quartier P, Ravelli A, Wulffraat NM, et al. Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis. Pediatr Rheumatol 13, 55 (2015). ⁴⁶

 ****  Ambler WG, Nanda K, Onel KB, Shenoi S. Refractory systemic onset juvenile idiopathic arthritis: current challenges and future perspectives. Ann Med. 2022 Dec;54(1):1839-1850.⁴⁷

- Acknowledgements

▪️ The Egyptian Pediatric Clinical Practice Guideline Committee (EPG) would like to present its highest gratitude and acknowledgment to the members of the clinical practice guideline (CPG) adaptation group (GAG) and the external review group. We acknowledge the collaborative support of the Supreme Council for Egyptian University Hospitals during the adaptation of this evidence-based CPG. We would also like to acknowledge the copyright holder of the source guidelines that were adapted in this work for their generous approval and encouragement. Finally, we wish the best for all our patients and their families who inspired us. It is for them this work is being finalized.

Funding

▪️ This work is not related to any pharmaceutical or industrial company. The members of the GDG/ GAG and their institutes and universities volunteered their participation and contributions.

- Abbreviations

- Introduction

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children (Ravelli and Martini, 2007). Systemic juvenile idiopathic arthritis (sJIA) is a very distinctive subtype of JIA with unique clinical manifestations, associated complications, therapeutic options, and prognosis (Lee and Schneider 2018). It differs from the other subtypes of JIA in being an autoinflammatory phenotype, presents usually with fever, rash, lymphadenopathy and marked systemic inflammation (Martini et al., 2019).

➡️ Epidemiology:

Mean annual incidence and prevalence rates of JIA in general, and sJIA in particular differ among countries due to combined immunogenic and environmental factors. In a systematic review conducted by Thierry and colleagues to evaluate the incidence and prevalence of JIA in Europe, the incidence estimates varied from 1.6-23/10⁵ and the prevalence estimates from 3.8-400/10⁵ (Thierry et al., 2014). In Spain, the incidence rate of JIA was 6.9/10⁵ and the prevalence was 39.7 (36.1-43.7)/10⁵ in children aged less than 16 years (Modesto et al., 2010). In Egypt, the prevalence rate of JIA in Sharkia Governate was 3.43/10⁵ in children younger than 16 years and sJIA constituted 13.6% of the patients (Abou El-Soud et al., 2013).
Systemic JIA can present at any time throughout childhood and adolescence prior to the age of 16 years, with peak incidence at 2 years There is no gender nor ethnic predilection, with a higher prevalence rate reported in southeast Asia and Japan (Consolaro et al., 2016). Although it represents 10 to 20% of all JIA subtypes, sJIA accounts for up to two-thirds of the mortalities related to JIA (Salah et al., 2009; Martini et al., 2019). sJIA accounts for 23%-24% of all forms of JIA in Egypt (Hussien et al., 2018), and in Saudi Arabia, sJIA was the most commonly reported subtype of JIA (Bahabri et al., 1997). sJIA forms 10% of JIA subtypes in North America and up to 50% in Asian countries (Fujikawa et al., 1997).

➡️ sJIA immunopathogenesis:

The term sJIA  was preferred, even though arthritis might be absent in some patients. The Pediatric Rheumatology International Trials Organization (PRINTO) International Consensus has agreed to keep sJIA among the JIA disorders rather than the autoinflammatory disorders (Martini et al., 2019).
Similarities between sJIA and adult onset Still’s disease (AOSD) are both clinical and biological, including the occurrence of the life-threatening condition known as macrophage activation syndrome (MAS) and the associated marked activation of interleukin (IL) 1 and IL-6 as a part of the immunopathogenesis of the diseases. The IL-1 family of cytokines includes 11 cytokines; of these, IL-1β represents the most potent member and a therapeutic target in sJIA (Palomo et al., 2015; Toplak et al., 2018). Therefore, a striking and sustained response to treatment with IL-1β inhibitors was noticed in sJIA and ASOD (Martini, 2012; Castanda et al., 2016).
Systemic JIA progression often follows a biphasic course. In the beginning, there is hyperstimulation of the innate immune response with excessive secretion of IL-1β as a key cytokine. In the second phase, a dominant adaptive immune response is activated with over production of IL-17A, explaining the following chronic arthritis which becomes the leading clinical feature (Kessel et al., 2017). Accordingly, blocking IL-1 is a rational therapeutic choice in the initial phase of sJIA, but it might need to be substituted with other biologics when the condition progresses to persistent polyarthritis (Toplak et al., 2018).

➡️ Diagnosis of sJIA:

Diagnostic criteria of sJIA were defined by the International League of Associations for Rheumatology (ILAR) (Petty et al., 2004).  Validation of ILAR definition of sJIA has faced many challenges because it considered the presence of chronic arthritis a mandatory criterion for the diagnosis, which led to missing up a sizeable proportion of the patients (Martini et al., 2019; Hinze et al., 2018). sJIA was recently defined by PRINTO’s new classification criteria for sJIA as being a fever of unknown origin, after excluding other etiologies such as infections, malignancies or monogenic autoinflammatory disorders. Fever should be documented daily in a quotidian pattern (fever that rises to ≥ 39°C once a day and returns to normal in between) for at least 3 consecutive days and recurring over a duration of at least 2 weeks. To fulfill the definition, fever should be accompanied by 2 major criteria or 1 major and 2 minor criteria. The major ones are (1) presence of arthritis, and (2) evanescent erythematous rash. Minor criteria include: (1) generalized lymphadenopathy, hepatomegaly, and/or splenomegaly, (2) serositis, (3) at least 2 weeks of arthralgia, provided that there is no associated arthritis, and (4) leukocytosis, mainly out of neutrophilia (Martini et al., 2019). The German consensus has proposed the term probable sJIA to refer to the patients lacking chronic arthritis (Hinze et al., 2018).
Disease progression follows one of three courses: a monophasic course with a single episode of fever, or a polycyclic course, which is fluctuating between remissions and flares (Singh-Grewal et al., 2006) and finally the third type of course which is the "chronic persistent". Noticeably, systemic manifestations of the disease tend to respond earlier and easier than the articular manifestations, which can become refractory to multiple therapeutic approaches (Beukelman et al., 2014).
The role of laboratory and radiological investigations for confirming or excluding the diagnosis of sJIA is debatable. Given that ILAR PRINTO diagnostic criteria did not include any investigations except for the leukocytic count, many authors recommend performing other investigational tests to exclude the differential diagnoses and to properly detect any associated complications, mainly MAS (Hinze et al., 2018). Generally, sJIA differs from all other JIA types in the associated elevated inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), platelets, and the reduced levels of hemoglobin and serum albumin (Cimaz et al., 2016). Antinuclear antibodies and rheumatoid factor are typically negative in sJIA

➡️ Assessment of sJIA activity:

Regular assessment of sJIA systemic and articular activities is mandatory to determine the disease progression and response to treatment. The Juvenile Arthritis Disease Activity Score (JADAS) has been accepted as a tool of JIA activity evaluation, but not specifically for sJIA (Consolaro et al., 2016). An updated JADAS specific for sJIA (sJADAS) has been recently released (table 7). The score is composed of 5 main items: 1) Physician global assessment of the overall disease activity (a scale from 0 to 10), 2) Patient global assessment of the well-being (a scale from 0 to 10), 3) number of active joints, 4) CRP or ESR levels, and 5) the modified systemic manifestation score (mSMS), including presence of fever, rash, lymphadenopathy, hepatomegaly, splenomegaly, serositis, anemia or thrombocytopenia (Tibaldi et al., 2020).

➡️ Complications of sJIA:

Complications of sJIA include MAS, growth retardation, damage from severe erosive arthritis, osteoporosis, cardiovascular events such as pericarditis, pulmonary hypertension and amyloidosis (Woerner et al, 2015).
Macrophage activation syndrome (MAS): MAS is a potentially life-threatening condition that was described in association with, or as a complication of systemic inflammatory disorders such as sJIA (Ravelli et al., 2016; Çakan et al., 2020). It was reported in 10% of sJIA patients, either initially or along the course of the disease. However, subclinical MAS may occur in up to 30-40% of sJIA cases (Behrens et al., 2007). MAS is characterized by an overwhelming inflammatory reaction due to sustained dysregulated and dysfunctional immune response involving expansion of T lymphocytes and macrophages, leading to exaggerated production of proinflammatory cytokines (Ravelli et al., 2012). MAS is to be suspected when patients develop high, persistent fever, generalized lymphadenopathy, hepatosplenomegaly, central nervous system (CNS) dysfunction, and hemorrhagic diathesis. High levels of ferritin, low fibrinogen and changes in the hematological parameters towards cytopenia, should raise the suspicion of MAS in any sJIA patient (Çakan et al., 2020).
 
Growth retardation: Growth retardation usually complicates long-standing, refractory sJIA patients. Indeed, impaired growth might be the result of combined factors such as altered nutritional status, physical restrictions, emotional impacts, and prolonged use of systemic glucocorticoids, , in addition to the chronic inflammatory status itself (De Benedetti et al., 2015).

➡️Differential Diagnosis of sJIA:

Diagnosis of sJIA is basically depending on excluding the other possible diseases that may mimic the symptoms, most importantly infections, malignancy or hereditary autoinflammatory diseases (Hinze et al., 2018). Abdominal sonography, chest imaging and articular sonography as well as laboratory investigations involving peripheral blood smear, blood cultures, urine analysis, serum S100 proteins, serum procalcitonin and bone marrow aspirate as indicated will help to establish specific diagnosis (Hinze et al., 2018). Furthermore, patients who initially present with MAS need to be differentiated from the other possible etiologies of primary and secondary hemophagocytic lymphohistiocytosis (HLH).

➡️ Broad lines of sJIA Treatment:

The American College of Rheumatology (ACR) has promulgated treatment recommendations for patients with sJIA in 2011 and updated them in 2013 (Beukelman et al., 2011; Ringold et al., 2013) and lastly in 2021 (Onel et al 2022). The German consensus has settled their recommendations based on a treat-to-target approach (Hinze et al., 2018). The course of the disease might follow a pattern of relapses followed by intervals of remission, or an unremitting course with persistent arthritis (Martini et al., 2019). Nevertheless, patients with sJIA do not often respond to treatment with conventional disease-modifying antirheumatic drugs (cDMARDs). Glucocorticoids are mandatory to control the disease relapses, and low-doses of glucocorticoids might be needed to keep the patients in the remission status. However, prolonged glucocorticoid regimens are associated with significant adverse effects such as osteoporosis, short stature, cataract, glaucoma, hypertension and diabetes mellitus type 2. The era of biologics has rescued many patients from the side effects of prolonged courses of glucocorticoids and from the poor response in some refractory cases (Correll et al., 2014). Although biologics targeting IL-1 and IL-6 are the most recommended lines of therapy for sJIA ( Vastert et al., 2014; DeWitt et al., 2012; Onel et al 2022) the long-term commitment to frequent injections or infusions remains a challenge in young children (Yokota et al., 2015).
Refractory, steroid-dependent sJIA patients are treated individually based on the patients’ circumstances and the expert preferences. In patients refractory to IL-1 and IL-6 blocking agents with steroid dependency, other treatments can be considered including adding cDMARD for refractory arthritis and other biological such as abatacept, and the limited trials of JAK inhibtors and anti-IL17 and anti-IL18 agents. The latter may be used in severe sJIA through compassionate investigational new drug use. ( Record et al.,2011; Canny et al., 2017; Canna .,2017)
 
➡️Prognosis:
sJIA accounts for the highest mortality rates among the other subtypes of JIA, given its associated complications (Huang et al., 2019).
Early predictors of articular damage and poor prognosis include young age at the disease onset (<18 months of age), longer disease duration, prolonged use of glucocorticoids, persistent or recurrent thrombocytosis, and high inflammatory parameters (Sandborg et al., 2006; Russo et al., 2013).
Purpose and scope

- Methods

➡️Methods of search:

A comprehensive search for guidelines was undertaken to identify the most relevant guidelines to consider for adaptation. Keywords used for search are: Juvenile Idiopathic Arthritis guidelines, JIA, Systemic Juvenile Idiopathic Arthritis guidelines, sJIA classification, sJIA Guidelines

Inclusion / exclusion criteria followed in the search and retrieval of guidelines to be adapted:

• Selecting only evidence-based guidelines (guideline must include a report on methodology of development including the systematic literature searches and explicit links between individual recommendations and their supporting evidence)

• Selecting national and/or international guidelines

• Specific range of dates for publication (using Guidelines published or updated 2013 and later or the last 5 years)

• Selecting peer-reviewed publications only

• Selecting guidelines written in English language

• Excluding guidelines written by a single author

The following three categories of databases and websites were searched:

1.      CPG databases and libraries (e.g., GIN, ECRI, SIGN, DynaMed, BIGG-REC PAHO)

2.      Bibliographic databases (e.g., PubMed, Google Scholar)

3.      Specialized professional societies (related to the pediatric Rheumatology)

All retrieved Guidelines were screened and appraised using AGREE II instrument (www.agreetrust.org) ^23-26 by at least two members. The panel decided a cut-off point or rank the guidelines (any guideline scoring above 60% on the rigor dimension was retained)

After reviewing all the previous criteria, the GDG/ GAG recommended using 3 guidelines:

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 did Adolopment for these guidelines: (Adoption, Adaptation, and Development)^27-30

         -    Adoption for most of the guideline recommendations.

         -     Development of Good Practice Statement

Contributors to the guideline development process:

Guideline Development Group (GDG)/ Guideline Adaptation Group (GAG):

The GDG/ GAG included two subgroups; the clinicians/ healthcare providers subgroup and the guideline methodologists’ subgroup.

➡️Clinicians Subgroups

The clinicians’ subgroup or clinical panel for this guideline included experts with a range of knowledge, technical skills and diverse perspectives in the field of pediatric Rheumatology.

The main functions of the clinical panel were adolopment of Jeuvenile idiopathic arthritis in pediatrics Guidelines, determining the scope of the guideline and guideline, reviewing the evidence, and formulating evidence-informed recommendations in case of changing strength of recommendations.

➡️Guideline Methodologists Subgroup

There were 7 guideline methodologists with expertise in guidelines development, adaptation, GRADE and translation of evidence into recommendations. Methodologists provided orientation and overview of evidence-informed guideline development processes using the GRADE approach, guideline adaptation using the Adapted ADAPTE, provided AGREE II assessment of the source guidelines in collaboration with the clinicians subgroup, generation of the EtD frameworks whenever applicable.

➡️External Review Group:

The External Review Group for this guideline comprises 5 clinical experts who have interest and expertise in as well as eminent international reviewers.

They were identified by Egyptian Pediatric Clinical Practice Guidelines Committee (EPG) as people who can provide valuable insights during the guideline development process.

The External Review Group was asked to comment on (peer review) the final guideline to identify any criticism on the content and to comment on clarity and applicability as well as issues relating to implementation, dissemination, ethics, regulations, or monitoring, but not to change the recommendations formulated by the GDG/ GAG. The members of the External Review Group were required to submit declarations of interest before the peer review process.

➡️Guideline Development/ Adaptation Group meetings:

GDG/ GAG meetings were organized virtually (weekly/bimonthly). Due to the extensive scope of the guideline, EPG was responsible for overseeing the adolopment process. the timetable and objectives of each meeting. GDG/ GAG meetings were also attended by members of the methodologists. Working rules for each contributor type were outlined by the chair at the start of each meeting, covering aspects such as vocal rights, voting, and evidence to decision and recommendation formulating processes.

➡️Declarations of interests:

Prospective members of the GDG/ GAG were asked to fill in and sign the standard WHO declaration of interest and confidentiality undertaking forms. All guideline members and methodologists were also asked to fill in and sign the standard WHO declaration-of-interests.

Members of the external review group will be asked to fill in and sign the standard WHO declaration-of-interests form before the peer review process.

➡️Evidence for the guideline:

We used the GRADE system (Grading of Recommendations, Assessment, Development and Evaluation) for assigning the quality of evidence and strength of recommendations that includes the following definitions .

Description of the interpretation of the GRADE four levels of certainty of evidence:

Table 1. Classification of the Quality of Evidence

Table 2. Classification of the Strengths of Recommendations

➡️Developing good practice statements:

The GDG/ GAG also developed good practice statements for this guideline, which are actionable messages relevant to the guideline questions. The justification for each good practice statement was carefully considered by the GDG/ GAG with the emphasis that they are clearly needed. Good practice statements were developed, guided by the following GRADE criteria:

1- Message is necessary about actual healthcare practice

2- Have large net positive consequences (relevant outcomes and downstream consequences) (GRADE EtD domains)

3- Collecting and summarizing the evidence is a poor use of time and resources

4- Include a well-documented, clear rationale connecting indirect evidence

5- Are clear and actionable statements.

The GDG/ GAG collectively drafted and finalized good practice statements with relevant justifications and remarks to help with their interpretation, with close support and input from the consultant and guideline methodologists.

We have used the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension for adapted guidelines (RIGHT-Ad@pt Tool) as a reporting checklist for this guideline adaptation process as recommended by the EQUATOR network.

- Evidence to recommendations: Considerations

The GDG/ GAG was guided by the results of the AGREE II appraisals of the eligible CPGs and thoroughly reviewed the recommendations of the original source WHO CPGs in consideration of local contextual factors related to the national Egyptian health system like burden of the disease, equity, acceptability, feasibility, and other relevant factors. The GDG decided through an informal consensus process to adopt most recommendations. Also, GDG/ GAG develops group of good practice statements to improve acceptability and feasibility.

- Implementation Tools and Considerations

To improve healthcare provision, quality, safety, and patient outcome, evidence-based recommendations must not only be developed, but also disseminated and implemented at national and local levels and integrated into clinical practice.

Dissemination involves educating related healthcare providers to improve their awareness, knowledge and understanding of the guideline’s recommendations. It is one part of implementation, which involved translation of evidence-based guidelines into real life practice with improvement of health outcomes for the patients.

Implementation requires an evidence-based strategy involving professional groups and stakeholders and should consider the local cultural and socioeconomic conditions. Cost-effectiveness of implementation programs should be assessed.

Specific steps need to be followed before clinical practice recommendations can be integrated into local clinical practice, particularly in low resource settings.

Steps of implementing strategies for the transfusion of blood components in pediatric age groups into the Egyptian health system:

1.     Develop a multidisciplinary working group.

2.     Assess the status of nutritional care delivery, care gaps and current needs.

3.     Select the material to be implemented, agree on the main goals, identify the key recommendations for diagnosis, treatment and prevention and adapt them to the local context or environment.

4.     Identify barriers to, and facilitators of implementation.

5.     Select an implementation framework and its component strategies.

6.     Develop a step-by-step implementation plan:

▪️  Select the target populations and evaluate the outcome.

▪️    Identify the local resources to support the implementation.

▪️     Set timelines.

▪️     Distribute the tasks to the members.

▪️     Evaluate the outcomes.

7.     Continuously review the progress and results to determine if the strategy requires modification.

Guideline implementation strategies will focus on the following: -

1.     For Practitioners

▪️      Educational meetings: conferences, lectures, workshops, grand rounds, seminars, and symposia.

▪️   Educational materials: printed or electronic information (software).

▪️    Web-based education: computer-based educational activities.

▪️    A trained person meets with providers in their practice setting to provide information with the intention of changing the provider’s practice. The information may include feedback on the performance of the provider(s).

▪️    Reminders: the provision of information verbally, on paper or on a computer screen to prompt a health professional to recall information or to perform or avoid a particular action related to patient care.

▪️   Optimize professional-patient interactions, through mass media campaigns, reminders, and education materials.

▪️    Practice tools: tools designed to facilitate behavioral/practice changes, e.g., flow charts.

2.     For Patients and care givers

▪️     Patient education materials (Arabic booklet): Printed/electronic information aimed at the patient/consumer, family, caregivers, etc.

▪️    Reminders: the provision of information verbally, on paper or electronically to remind a patient/consumer to perform a particular health-related behavior.

▪️    Mass media campaigns.

3.     For Nurses

▪️  Educational meetings: lectures, workshops or training courses, seminars, and symposia.

▪️    Educational materials: printed.

▪️    A trained person meets with nurses in their practice setting to provide information with the intention of changing the provider’s practice.

▪️   Reminders: the provision of information verbally, on paper or on a computer screen to prompt them to recall information or to perform or avoid a particular action related to patient care.

▪️    Practice tools: tools designed to facilitate behavioral/practice changes.

4.     For Stakeholders

Plans have been made to contact with all the health sectors in Egypt including all sectors of the Ministry of Health and Population, National Nutrition Institute, University Hospitals, Ministry of Interior, Ministry of Defense, Non-Governmental Organizations, Private sector, and all Health Care Facilities.

▪️   Information and communication technology: Electronic decision support, order sets, care maps, electronic health records, office-based personal digital assistants, etc.

▪️   Any summary of clinical provision of health care over a specified period may include recommendations for clinical action. The information is obtained from medical records, databases, or observations by patients. Summary may be targeted at the individual practitioner or the organization.

▪️   Administrative policies and procedures.

▪️  Formularies: Drug safety programs, electronic medication administration records.

5.     Other activities to assist the implementation of the adapted guideline’s recommendations include:

▪️   International initiative: Dissemination of the presented adapted CPG internationally via sending the final adapted CPG to the Guidelines International Network (GIN) Adaptation Working Group and contacting the CPG developers.

▪️   Gantt chart has been designed to manage the dissemination and implementation stages for the adapted CPG over an accurate time frame (Appendix). 

➡️Guideline Implementation Tools

Educational materials based on this Adapted CPG for treatment of CAP in children have been made available in several forms including algorithms, pathways, tables, and parents’ educational health guide (in Arabic).

Table (7) : sJADAS10 composite score for assessment of sJIA activity

^a : Up to 10 joints, irrespective of their type, censored at 10. ^b: According to the formula: (value in mm/h – 20)/10, where values 120 mm/h are converted to 120. ^c :According to the formula (value in mg/l – 10)/10, where values 110 mg/l are converted to 110. sJADAS 10: systemic Juvenile Arthritis Disease Activity Score in 10 joints (Adapted from Tibaldi et al., 2020)

^d: Modified systemic manifestations score:

*:Fever is defined as the maximum temperature either in the past 24 h, 3 days or week. In the assessment of fever, the possible pharmacologic suppression of temperature by paracetamol, NSAIDs or glucocorticoids should be taken into

account. 

Table (8) Therapeutic agents commonly used for sJIA treatment

Abbreviations: NSAID, nonsteroidal anti-inflammatory drug; SQ, subcutaneous; IV, intravenous; CNS, central nervous system; MAS, macrophage activation syndrome; q, every; sJIA, systemic juvenile idiopathic arthritis.          Shenoi S, Wallace CA, 2016 (46)

➡️Parent and carer health educational guide (in Arabic)

الالتهاب المفصلي اليفعي الجهازي مجهول السبب

الالتهاب المفصلي اليفعي الجهازي مجهول السببsJIA يعد نوع  مميز من أنواع  الالتهاب المفصلي اليفعي مجهول السبب JIA,يتميزبوجود بعض الأعراض الأكلينيكية التى تميزه عن باقي الأنواع وكذلك المضاعفات وطرق التشخيص والخيارات العلاجية الخاصه به , و يمثل هذا النوع حوالي 10 ٪ إلى 20 ٪ من مجمل  حالات JIA ، مع معدلات إصابة تتراوح من 0.4 إلى 0.8 طفل لكل 100.000 طفل.

يمكن أن تظهرأعراضsJIA في أي وقت خلال الطفولة والمراهقة ، مع ذروة الإصابة عند عمر سنتين,يصاب به الأولاد والبنات على حد سواء, يحدث عند الأطفال من جميع الخلفيات العرقية ، مع معدل انتشار أعلى  في الجنوب الشرقي واليابان.

▪️معايير التصنيف الالتهاب المفاصل البفعي مجهول السبب وفقا لرابطة الجمعيات الدولية للروماتيزم:

يتطلب تشخيص sJIA وجود التهابات في واحد من المفاصل أو أكثر، مع أو قد يسبقها ظهور حمى مستمرة لمدة أسبوعين على الأقل ، تحدث بشكل يومي (على الأقل3 أيام يومية) ، ويرافقها واحد أو أكثر من هذه الاعراض:الطفح الجلدي أحمر غير ثابت في مكانه , تضخم العقد اللمفاوية المنتشرة في الجسم, تضخم الكبد أو الطحال, التهاب في الاغشية المصلية. ولتشخيص الحالة انها sJIA  فيجب استبعاد وجود :

•  مرض الصدفية أواي تاريخ مرضي للاصابه  بها لدى المريض أو أقاربه من الدرجة الأولى.
• ان تكون التهابات المفاصل في طفل ذكر عمره اكتر من ست سنوات ولديه  HLA-B27ايجابي.
•  مرض التيبس الفقاري المناعي ، التهاب المفاصل المرتبط بالتهاب ألأوتار ERA ، الالتهاب المفصلي العجزي الحرقفي المصاحب لالتهابات القولون المناعية ، التهاب القزحي الأمامي الحاد ، أو تاريخ أحد هذه الأمراض لدى المريض او أحد أقاربه من الدرجة الأولى.
• تحليل عامل الروماتويدي RF موجب مرتين يفصل بينهما ثلاثة أشهر علي الاقل.

▪️الاعراض الاكلينيكية:

§     حمى يومية ترتفع فيها الحرارة الي39-40 درجة مئوية مرة أو مرتين في اليوم ثم تنخفض سريعا إلى  الطبيعي.

§      طفح جلدي بقعي أو لطاخي متحرك من مكان لمكان (غير ثابت)، غير مسبب للحكة، يظهر في الجذع والرقبة والجزء من الأطراف القريب من الجذع ,ومن المميز له ظهوره مع نوبات الحمى وتلاشيه عند زوال الحمى.

§     التهابات المفاصل تكون في أربع مفاصل أو أقل أو فد تكون متعددة الي أكثر من خمس مفاصل و المفاصل الأكثر التهابا (المعصمين, الركبتين, والكاحلين). ظهور التهاب المفاصل عادة يكون في خلال الأشهر الثلاثة الاولي من ظهور المرض، إلا أنه قد يتأخر في الظهور لأسابيع اوأشهرأو نادرًا الي سنوات.

§     تضخم العقد اللمفاوية المنتشرة في الجسم ويكون التضخم واضح مما يثير الشكوك من انه ورم خبيث.

§      تضخم الكبد والطحال.

§     التهاب في الأغشية  المصلية والذي يكون عادة  بدون أعراض ويمكن اكتشافه فقط بمخطط صدى القلب أو تصوير شعاعي للصدر.

▪️التشخيص

لا توجد تحاليل محددة لـتشخيص مرضsJIA)). التحاليل المعملية تعد داعمة للتشخيص وتعكس الطبيعة الألتهابية للمرض ولاستبعاد الحالات التي تسبب أعراض مماثلة.صورة الدم قد تشير الي وجود زيادة في عدد كريات الدم البيضاء والصفائح الدموية وانيميا فقر الدم,ويلاحظ وجود ارتفاع في معاملات الألتهاب  مثل معدل ترسيب كرات الدم الحمراء (ESR) ، بروتين سي التفاعلي (CRP) ونسبة الفيرتين بالدم. اما الأجسام المضادة الذاتية مثل الأجسام المضادة الذاتية المضادة للنواة (ANA) والعامل الروماتويدي (RF) فتكون دائمًا سلبيًة ولا تفيد في التشخيص(لوحظ وجود ANA إيجابي في حوالي 4٪ إلى 6٪ من مرضى sJIA)).قد نحتاج الي نضح وخزعة نخاع العظام لاستبعاد الأورام الخبيثة في الدم.

الفحص الإشعاعي قد يبين تورم الأنسجة الرخوة وهشاشة في العظام.فقدان الغضاريف وتاكل العظام عادا ما يظهر في غضون عامين من ظهور المرض.

▪️المضاعفات

متلازمة تنشيط البلاعم MAS هي أحد مضاعفات التي تهدد حياةالأطفال المصابين بـ sJIA.حيث يعاني  المريض من حمى شديدة غير مستجيبة وتدهور للحالة العامة للمريض, مع تضخم بالكبد والطحال، وخلل عصبي، ومظاهر نزفية, وفشل متعدد في وظائف أعضاء الجسم.تظهر التحاليل المعملية انخفاض بكريات الدم , وارتفاع في وظائف الكبد ونازعة هيدروجين اللاكتات والدهون الثلاثية والفيرتين بالدم ، مع انخفاض مستويات الفيبرينوجين وانخفاض نسبة سرعة الترسيب ESR بعد أن كانت مرتفعة سابقا ، مع استمرار ارتفاع البروتين التفاعلي CRP. قد نحتاج الي نضح وخزعة نخاع العظام للتأكد من تشخيص MAS.

التهاب المفاصل التآكلي المبكر من المضاعفات المتكررة في حالات المصابين بsJIA وتؤثر عادة علي الركبتين والكاحلين والرسغين. كذلك هشاشة العظام وتأخر النمو من المضاعفات المحتملة الي جانب المضاعفات الناتجة عن تناول الأدوية مثل عقار الكورتيزون لفترات طويلة والادوية المثبطة لجهازللمناعة والتى تزيد نسبة الإصابة بالعدوي والأورام الخبيثة.

المرضي المصابين ب sJIA لديهم احتمال أكبر لحدوث عجز وظيفي متوسط و شديد مقارنة بالأنواع الاخرى من JIA و قد يعزى هذا إلى عدد المفاصل واجهزة الجسم المتأثرة  بالاصابة.

▪️العلاج

الهدف من العلاج هو السيطرة على الألتهاب النشط من أجل تخفيف الأعراض والوقاية من المضاعفات المرتبطة بالمرض.نظرًا لطبيعة مرض sJIA وتأثيره علي العديد من أجهزة الجسم، يجب أن تركز بروتوكولات العلاج على  الطفل ككل وليس على جانب واحد فقط من المرض.يشمل العلاج الناجح كلا من التدخل الدوائي وغير الدوائي بما في ذلك التغذية العلاجية والعلاج الطبيعي والدعم النفسي والأجتماعي للمريض.

في البداية ، تستخدم مضادات الألتهاب غير الستيرويدية والكورتيزون للسيطرة على المرض, ولكن بسبب الآثار الجانبية غير المرغوب فيها والمرتبطة باستخدام هذه الأدوية فتهدف البروتوكولات الحديثة في العلاج إلى التقليل التدريجي أو التوقف التام عن استخدام هذه الأدوية بعد ان يتم إجراء التشخيص الدقيق للمرض.

تم استخدام العلاج البيولوجى مثل مثبطات TNF بشكل متكرر، ولكنها أظهرت فعالية منخفضة مقارنة بنتائجها في المرضى المصابين بالأنواع الأخرى من .JIAاما العلاجات المضادة لـ IL-1 و IL-6 اثبتت فعالية كبيرة في مرضي sJIA وكلما كان العلاج بهذه العقاقير مبكرا كلما اعطي فرصة افضل لتحسين النتايج.

الحالات المصابة ب MASتحتاج لجرعات كبيرة من الكورتيزون عن طريق الوريد اولا (ميثيل بريدنيزولون لمدة ثلاثة أيام متتالية) متبوعًا بالكورتيزون عن طريق الفم  و يستخدم عقارالسيكلوسبورين وهو مثبط الكالسينيورين  كعلاج ثانوي وكذلك العلاجات البيولوجية وخاصة مضادIL-1((Anakinraالذي يستخدم بنجاح في علاج كل من MAS و sJIA النشط ويعد مفيدًا في تحقيق التخفيض السريع لجرعة الكورتيزون.

- Limitations and suggestions for further research needs

▪️Resource barriers
Treatment guidelines are hard to implement in daily practice due to a lack of resources of patients particularly the cost of biologic therapy
▪️System barriers
Treatment guidelines are not approved by official bodies e.g. MOH
▪️Attitudinal barriers
              Physicians’ autonomy in practice using their usual approach.
              Disagreement of Senior Pediatrician with the guidelines recommendations.
               Treatment guidelines may limit flexibility and individual approach.

Patient barriers

Patients do not want doctors to conform to treatment guidelines (expensive medication, for fear of side effects)

In addition, Lack of relevant national data or JIA registry disable our estimates for diagnostic and management difficulties. We have no multicenter studies from which reasonable conclusion could be derived and included in the recommendations.

There is no financial funding from any source for our EPG project till now which of course limit our ability for research, developing evidence-based recommendations and doing an effective implementation plan.

Some of the relevant international guidelines did not grant permission for adaptation or did not respond. Others may ask for a paid adaptation permission which is unaffordable.

- Monitoring and evaluating the impact of the guideline.

The following are two performance measures or indicators for implementing this adapted CPG for Jeuvenile idiopathic arthritis  in children:

1.  Adherence to JIA Guidelines

▪️Numerator: Number of children who received treatment as per guideline recommendations.

▪️ Denominator: Total number of children who received treatement.

▪️  Data Source: Hospital or clinic patient records.

2.     Adherence to JIA  guidelines

▪️  Numerator: Number of children readmitted with symptoms of JIA within a certain period (e.g., 30 days) and managed according to the guidelines.

▪️  Denominator: Total number of children admitted with JIA.

▪️   Data Source: Hospital readmission records. 

These key performance indicators are designed to measure effectiveness and adherence to the guidelines.

- Updating of the guideline

The EPG Rheumatology GAG has decided to conduct the next review of this adapted CPG for updates after five years. This should be carried out in 2028 after checking for updates in the source CPGs, consultation of expert opinion on the changes needed for updating according to the newest evidence and recommendations published in this area and the clinical audit and feedback from implementation efforts in the local healthcare settings except if any breakthrough evidence- based recommendations are published before that date. The process will be guided by the Checklist for the Reporting of Updated Guidelines (CheckUp) Tool that is freely provided by the AGREE Enterprise and by the Reporting Items for Practice Guidelines in Healthcare (RIGHT) extension for adapted guidelines RIGHT-Ad@pt Checklist.

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- Annexes

Annex Table 2. Results of the AGREE II assessment of the three source guidelines for transfusion of blood components in pediatric age groups

Practice guideline REgistration for transPAREncy (PREPARE) Guideline Protocol Registration Receipt