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

- 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