Updated clinical practice treat-to-target guidelines for JIA management: the Egyptian College of Pediatric Rheumatology initiative

These updated guidelines aimed to provide appropriate and convenient guidelines for the treatment of various types of juvenile idiopathic arthritis (JIA). Using the Delphi technique, this study was conducted to reach expert consensus on a treat-to-target management strategy for JIA. According to the PICO (patient/population, intervention, comparison, and outcomes) approach, the preliminary scientific committee identified a total of 17 key clinical questions. To assemble evidence on the advantages and dangers associated with JIA treatments, an evidence-based, systematic literature review was conducted. Researchers and clinicians with experience in JIA management were identified by the core leadership team. To establish a consensus on the management suggestions for JIA patients, a Delphi approach (2 rounds) was used. An online survey was applied to the expert panel (n = 27), and 26 of them completed both rounds. At the conclusion of round 2, a total of eighteen (18) recommendation items were gathered, which were divided into four sections to address the four key JIA categories. The percentage of those who agreed with the recommendations (ranks 7–9) ranged from 83.2 to 100% (average 86.8%). The phrasing of all 18 clinical standards identified by the scientific committee was agreed upon (i.e. 75% of respondents strongly agreed or agreed). Algorithms have been proposed for the management of JIA polyarthritis, oligoarthritis, and systemic JIA. A wide and representative panel of experts initiated a consensus about the management of JIA. The created guidelines give a complete approach to the management of JIA for all healthcare professionals involved in its management, as well as a means of monitoring and evaluating these guidelines on a regular basis.

options for JIA, quick commencement of proper medical therapy has become critical in preventing lasting joint and organ damage. Furthermore, these advancements in JIA management have increased the chance of beneficial outcomes for children, such as better illness control. As a result, the treating healthcare practitioner is free to set even higher treatment goals, such as complete remission [5]. As a result, future therapy guidelines may contain an overarching aim of clinical remission or, at the very least, low disease activity [6].
At this time, there is a compelling argument about the impact of early diagnosis and expanded treatment options on standard paediatric rheumatology practice and whether it has made therapeutic medical decision-making more difficult for treating healthcare professionals, caregivers, and patients [7,8]. Treatment recommendations are created to assist healthcare providers in a variety of ways, including encouraging the adoption of a consistent approach to care delivery, supporting the proper and effective use of available resources, and reducing the risk of inappropriate care [9].
Overall, the most significant potential advantage is an improvement in the patient's quality of treatment and improved health outcomes.
While controlling disease activity is certainly the primary goal, attention should also be paid to the patients' overall health, emotional well-being, and their functional, educational, social, and economic status. In 2018, the first recommendations for JIA in Egypt were released [10]. However, recommendations were made to update the methodology approach to ease the adoption of the treat-to-target (T2T) management strategy and make the decision-making process more transparent. Furthermore, considering that Egypt is a low-and middle-income country (LMIC), there is a significant difficulty in terms of limited resources and disparities in the management of this chronic condition. This was the main motive behind developing guidelines specific for Egyptian children living with JIA. By ensuring the optimum standards of care, all children with JIA would have the right to equitable access to the highest quality of clinical care, based on current evidence and delivered by appropriately resourced and experienced multidisciplinary teams. These standards of care are designed to help and support children and young people with JIA and their families, the treating healthcare professional teams, and the health authorities.
This work was carried out aiming at providing updated evidence-based management guidelines for children and adolescents with JIA in its various forms, adopting treatto-target approach and incorporating recently published data. Recommendations for the treatment of chronic and acute JIA-associated uveitis were developed concomitantly and are included in these guidelines.

Design
This was a multistep approach that followed the protocol for the "clinical, evidence-based, guidelines" (CEG) initiative (ethical approval code: 34842/8/21) to create an actionable clinical gold standard for treat-to-target management of inflammatory arthritic diseases. The process of developing the updated guidelines for treat-to-target JIA management had evolved through a pathway starting with the conduction of a scientific literature review and the involvement of experts' opinions using a Delphi technique until the development of consensus regarding treatment options and desired outcome throughout the journey of this chronic disease.
The study design and procedures were developed using a qualitative synthesis of scientific evidence and consensus based on clinical experience and current scientific information. The Egyptian College of Pediatric Rheumatology spearheaded the campaign.

Study teams Core team
Four experts with experience in paediatric rheumatology and one expert in uveitis make up the group. The team was in charge of overseeing and coordinating the project, helping to define the project's scope and initial patient/ population, intervention, comparison, and outcomes (PICO) questions and nominating the expert panel and authoring the book.

Literature review team
An experienced literature review consultant is in charge. The team finished the literature search, data abstraction, and evidence quality assessment.

Expert panel
The core leadership team nominated 27 participants. The criteria for their selection included professional knowledge and experience (at least 8 years of experience) in the field of paediatric rheumatology, its management and practice in the Egyptian health system, and active participation in scientific research on paediatric rheumatic diseases.

Scientific literature review
In concordance with the scientific team's previous guidelines [10], it was agreed to set the current guidelines on broad clinical phenotypes rather than ILAR categories. The patient populations addressed in this guideline included (1) polyarticular JIA; these are children with JIA and nonsystemic polyarthritis (≥ 5 joints ever involved), whether rheumatoid factor positive or negative, psoriatic arthritis, and undifferentiated arthritis; (2) oligoarticular

Inclusion criteria
Systematic reviews, randomized controlled trials (RCTs), uncontrolled trials, and observational studies such as cohort, case-control, and cross-sectional studies were among the articles included.

Exclusion criteria
Editorials, commentaries, conference abstracts, and narrative/personal reviews that were not based on evidence were excluded.

Formulation of PICOs
Using the PICO (population, intervention, comparator, outcome) structure [11], a preliminary scientific committee (5 members) has undertaken the task of identifying the key clinical topics, aiming at (1) (Table 1). A systematic search including a series of literature searches in the database MEDLINE/PubMed and the Cochrane Library for human studies published in English focusing on JIA management until the present was conducted on 1st January 2021. For each PICO question, the review was undertaken to accumulate evidence for the benefits and harms associated with treatments. All of the studies found were read in their entirety. Papers that were not related to the main theme (e.g. for a sickness or medicine) were not accepted.

Critical appraisal of identified studies
The degree of evidence in each of the included studies was determined using Oxford standards for evidencebased levels of evidence [12]. The levels of evidence that were employed in the analyses are indicated in the table below (Supplement 4). In terms of confidence and study design, evidence levels are a good indicator of quality. The experts' assessment of the clinical conclusions of the studies was combined with the definition of the evidence levels in defining the recommendations.

Consensus process
Two Delphi rounds were carried out to establish consensus regarding the T2T strategy in JIA. Once the main aspects of this strategy were identified, a discussion group has defined the aspects to be included in the questionnaire with the scientific committee. The structured Delphi approach ensures that the opinions of participants are equally considered, and it is particularly conforming to geographically diverse centres as in Egypt. The Delphi process was conducted through online questionnaires.

Delphi process
The Delphi method is an organized way for gathering vital information about a certain issue that is extensively used. It is based on the main assumption that group projections are often more accurate than individual forecasts. The Delphi method's goal is to build consensus forecasts from a group of experts in a structured iterative manner. Its methodology is based on the completion of a series of questionnaires or "rounds" directed at experts. The Delphi approach is usually divided into the following stages: (1) A panel of specialists is assembled.
(2) Forecasting jobs and problems are distributed among professionals. (3) Preliminary projections and arguments are provided by experts. In order to provide input, the core team compiles and summarises them. (4) Experts receive feedback and utilize it to alter their projections in light of it. This approach can be repeated until an acceptable level of consensus is reached. (5) The expert forecasts are combined to form the final forecasts. This technique has two significant advantages: participant anonymity and regulated feedback [13][14][15].

Chronogram of Delphi rounds
The first round took place between 5th and 8th March 2021 (3 days). Aspects on which there was no agreement in the first round were amended in light of the feedback and incorporated in the second round. The second round took place 1 week after the first and lasted 3 days, from March 11 to March 13, 2021.

Voting process
Live online voting was conducted in two rounds, each with a strict time limit. All members of the expert panel were invited to take part and were given advance notice of the start and end times of each round of voting. Anonymous votes were gathered and evaluated, and unique access links were sent out. At the same time as the voting procedure, comments on rephrasing, potential ambiguity, and unidentified overlaps were received for each statement. The statements could only be voted on by members of the expert panel.

Rating
Each statement was scored on a scale of 1 to 9, with 1 representing "total disagreement" and 9 representing "complete agreement". Disagreement, uncertainty, and agreement are represented by the numbers 1-3, 4-6, and 7-9. If a comment is outside of a member's area of expertise, they should refrain from speaking. As a result, a vote of "uncertainty" shows "dissatisfaction with the recommendation's truthfulness". All statements allow for comments, which are reviewed by the core team after each round of voting. In the second round of voting, members were also urged to submit plausibility comments wherever they voted a disagreement. This will allow the panel to notice a misinterpretation of a statement and invalidate the vote on that remark.

Definition of consensus
Prior to data analysis, a definition of consensus was defined. It was determined that if at least 75% of participants attained agreement (scoring 7-9) or disagreement (score 1-3), consensus would be achieved [16][17][18][19]. If a statement received a mean vote of less than 4 or a "poor" degree of agreement, it was retired. In view of the feedback, statements with an uncertainty score of (4-6) were changed. The levels of agreement on each statement of suggestion were considered as "high" if all votes on a statement fell into the agreement bracket following the second round of voting [15,20,21].

Ethical aspects
This study was performed in accordance with the Helsinki Declaration. According to national regulations, ethics approval was not required. All participants in the study were required to give verbal informed consent in accordance with Egyptian national ethical committee requirements. In accordance with data protection standards, all participants were separated from the results and kept anonymous.

Literature research and evidence selection
The study selection process revealed that 6843 potentially relevant studies were identified by the search strategy. By reviewing the titles and abstracts, 6597 were ruled out (studies did not examine population or intervention of interest, did not match study design of interest, or did not report outcome measures of interest). As a result, the comprehensive article review included 246 relevant articles. One-hundred fifty-seven studies were eliminated because the citations did not fit the PICO. In a re-evaluation of the literature, two more studies were discovered. As a result, this research contained 91 studies.

Delphi round 1
The response rate for round 1 was 100% (27/27). The consensus was reached on the inclusion of clinical standards on 82.6% of the items (i.e. ≥ 75% of respondents strongly agreed or agreed). There were comments raised regarding the wording of some of the recommendations. Comments (excluding minor editing suggestions) were more frequent for general principles, polyarthritis section especially usage of corticosteroids, cDMARDs, and biologics. Diversity of opinion was greatest for the item "using sulfasalazine in some cases of polyarticular JIA". Three statements were retired, one on the use of anti-TNFs as initial therapy in polyarticular JIA and 2 statements for similarities to other statements. Following round 1, the following statements were added: 7, 3, 4, 1, and 7 statements in polyarticular, oligoarticular, enthesitis/spondylitis-related JIA, systemic JIA, and uveitis sections, respectively. Several statements were revised after round 1, most edited statements were in polyarticular JIA section (7 statements), only one statement was edited in uveitis section, and 4 statements were edited in each other sections (oligoarticular, enthesitis/ spondylitis-related JIA and systemic JIA).

Delphi round 2
The response rate for round 2 was 96.3% (26/27). The percentage of high-rank recommendations (ranks 7-9) ranged from 83.2 to 100%. One statement was removed because it was too similar to another. On all of the clinical standards, there was agreement (i.e. 75% of respondents strongly agreed or agreed). Table 2 also shows the level of evidence assigned to each statement, in accordance with the Oxford Centre for Evidence-Based Medicine (CEBM) criteria as well as mean ± standard deviation and level of agreement. Agreement was unanimous (> 80% agreement) for the wording of the statements.

Recommendations for the initial and subsequent treatment of children and adolescents with JIA
At the end of round 2, a total of eighteen (18) recommendation items were gathered, which were divided into four sections to address the four key JIA categories. A breakdown is presented in Table 2. Figure 1 shows a summary of primary recommendations for the initial and follow-up therapy of children with juvenile idiopathic arthritis (JIA) and active polyarthritis (1), whereas Fig. 2 shows the management pathway (algorithm) for oligoarthritis JIA, and Fig. 3 shows a suggested treat-to-target approach for systemic JIA. Figure 4 is the treat-to-target management algorithm for systemic JIA, whereas Fig. 5 is the treatment algorithm for chronic anterior uveitis associated with juvenile idiopathic arthritis.

Discussion
Juvenile idiopathic arthritis (JIA for short) is an umbrella term for arthritis of an unknown cause in children under the age of 16. JIA not only causes joint pain, swelling, and stiffness in one or more joints but also decreased healthrelated quality of life and risk of permanent joint damage. Furthermore, the condition can last well into adulthood, resulting in severe morbidity and poor quality of life [16,17,22]. For most individuals with JIA, recent therapy advancements have made remission a realistic goal. JIA has also been the subject of a lot of recent research, with a greater understanding of the underlying biology and more treatments available [5,18]; hence, it was important to update the treatment guidelines to implement treatto-target approach into standard practice and accommodate new lines of management.
This guideline defined patient populations based on their clinical phenotypes rather than ILAR categories. This decision was taken in view of the data reporting that the current JIA categories may not accurately reflect the underlying biology and anticipated treatment responses in patients with juvenile arthritis. Similar approach was adopted in the 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis [19]. This also aligns with the ongoing effort to standardise as many criteria as feasible for disorders that affect both children and adults, whether for use in clinical trials, research, or in regular clinical practice [23][24][25][26][27].
This guideline was developed based on a structured PICO process. This is in agreement with recent publications that provide recommendations for JIA treatment [4,19]. The PICO framework is intended to assist researchers in formulating relevant and precise questions that can be answered in a systematic review structure, as well as to improve the specificity and conceptual clarity of           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   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  clinical questions by breaking them down into smaller, more manageable components that are easier to identify during the literature search process [28]. The Delphi technique is a reliable tool for establishing new concepts and determining the direction of futureoriented research [29]. The technique enlists the help of a group of experts to assess the degree of agreement and settle disagreement on a topic [30]. There was broad agreement among the experts when asked about the feasibility of accomplishing a well-defined objective in osteoporosis. Almost everyone who contributed agreed that the treat-to-target technique may be used in JIA clinical practice. Consensus is reached in Delphi methodology when the percentage of people who agree or disagree is between 50 and 80% [31]. The agreement in our study varied from 83.4 to 100%, demonstrating a strong trend among Egyptian healthcare providers to use a T2T strategy for JIA management. The results of the American College of Rheumatology Guideline for the Treatment of Juvenile Idiopathic Arthritis support these findings [19], the international task force [5], and the German consensus-based strategies in diagnosing and managing systemic juvenile idiopathic arthritis [32] which revealed similar agreement on the treat to target policy.
Although the literature analysis did not reveal trials that compared a treat-to-target method to another or no strategy, it did provide indirect evidence of a better approach to therapy, which aided in the formation of recommendations. In 2018, an international task force issued recommendations for treating JIA with the goal of achieving [5]. The task force discussed particular treatment goals and the T2T technique for achieving them. Their recommendations were meant to provide professional advice on broad treatment options in order to improve patient care in normal clinical practice. This study went above and beyond by presenting a T2T approach to the various JIA categories. According to the task force, there are several goals for treating patients with JIA to target. These include the following: "to control signs and symptoms; to prevent structural damage; to avoid comorbid conditions and drug toxicities; and to optimise function, growth and development, quality of life, and social participation" [5]. The essential premise of a T2T strategy is that a treatment that is aggressively directed at the target will have "domino effects" on all other objectives [33][34][35].
In the absence of joints with overt active illness, treating to target in JIA necessitates a multimodal treatment plan that may include physiotherapy and early pain/ fatigue coping strategies administered by a multidisciplinary team for children with tiredness or chronic pain [8,36,37]. Furthermore, while these treatment guidelines are meant to improve the quality of clinical decision-making, each individual case is unique, and this should be taken into account in everyday practice. The guidelines given indicated T2T-based algorithms for the management of JIA patients. Clinicians require information that is simple to understand and use. The treatment suggestions should spell out the right lines of management, how to keep track of the patient, and how to deal with refractory instances. Nonsteroidal anti-inflammatory medicines, disease-modifying antirheumatic therapies, biologics, and intra-articular and oral glucocorticoids are among the medications recommended in this guideline. There are additional suggestions for using physical and occupational therapy. Treatment algorithms were created to outline the implementation of treatment methods targeted at establishing and maintaining tight disease control in routine paediatric rheumatology practice. This work is the first to include imaging as one of the critical outcomes assessed. Whilst MRI is an approved tool for assessment of sacroiliitis, the role of musculoskeletal ultrasonography remains debatable. For JIA patients, musculoskeletal ultrasonography (MSUS) offers significant benefits, in comparison with other imaging modalities, including safety, non-invasiveness, repeatability, rapid performance, relatively low cost, and high acceptability even among very young patients. In addition, MSUS can detect subclinical synovitis, improve the classification of subtypes, and capture early articular damage, as well as help clinicians monitor treatment response and guide intra-articular injections [38]. Moreover, across a majority of studies, many researchers have agreed that MSUS is superior to clinical examination in detecting synovial hypertrophy and synovial effusion [39]. In addition, ultrasonography has other useful applications, including educating young patients by showing them the appearance of both healthy and damaged joints. This exposure, as a pilot study [40] revealed, led to a 25% increase in young patients' adherence to prescriptions for both disease-modifying antirheumatic drugs and injectable antitumour necrosis factor drugs. This guideline addressed some of the challenges that face JIA treatment in Egypt. The guidelines endorsed the use of combination therapy for patients with moderate disease activity without poor prognostic factors. In addition, the guidelines highlighted the important role of the biologic therapies: anakinra and canakinumab in the management of systemic JIA. This is in agreement with all the previously published guidelines including the 2013 American College of Rheumatology treatment recommendations for systemic JIA [41], the British recommendations regarding therapies for the treatment of juvenile idiopathic arthritis [42], and the German consensus-based strategies in diagnosing and managing systemic JIA [43]. Unfortunately, both biologic therapy agents are not available in Egypt. Therefore, a copy of this guidelines should be forwarded to the decision-makers in the biologic therapy section in the Ministry of Health to facilitate the presence of these 2 medications. High-dose glucocorticoids are commonly used to treat systemic JIA, but they have serious adverse effects including growth failure and osteoporosis [44]. TNF inhibitors and disease-modifying antirheumatic medications (DMARDs) show poor efficacy in sJIA [45,46]. The discovery of the critical function of the proinflammatory cytokines interleukin 1 (IL-1) and interleukin 6 (IL-6) led to the creation of specific therapy techniques [47][48][49][50] that are very effective in the near term and may lead to a considerable shift in the disease's natural history.
We are in agreement with 2021 ACR Guideline for the Treatment of Juvenile Idiopathic Arthritis [51] in almost all lines of treatment in all categories of JIA, but we consider T2T strategy, and ACR 2021 consider temporomandibular joint in separate section and separate algorithm. And we in these recommendations added a separate section for uveitis management in JIA.
In our study, we depend on PICO manoeuvre and also consensus-based recommendations. We consider the treat-to-target strategy which differs than other previous recommendations; also, we had two steps recommendations: the first step was drug-dependent and then the second step was JIA subgroup-dependent; although these steps had more details, but it gives more clarifications.
The study's key strengths include the participants' variety as well as their experience, the high levels of consensus reached, and agreement with the most recently published JIA treatment recommendations. Though the treatment recommendations included in this guideline are in agreement with all the recently published guidelines [4,5,19,[41][42][43]52], the study's main limitation remains the study's scope, which was conducted in Egypt, and the results may not be applicable to other nations.
In conclusion, Clinicians' treatment techniques can differ, and these advice notes offer a way to establish best practice based on current evidence or expert consensus. They will also help to improve practice consistency and promote the highest levels of care. The necessity of early and successful treatment for children and adolescents with JIA in its various manifestations is highlighted in this guideline and treatment recommendations. They also endorse a strict disease control strategy based on the treat-to-target method, with the goal of inactive illness. Because children with JIA are typically asymptomatic, it is critical that they be checked for poor prognostic markers and have routine ophthalmology screenings to detect uveitis early.