Evidence Based Strategies: Systemic JIA - Early Recognition to Improve Outcomes

Persistent fever without a clear source is one of the most challenging presentations in pediatrics. For some children, this fever represents systemic juvenile idiopathic arthritis (sJIA), a diagnosis that is frequently delayed because arthritis may be absent at onset. Early recognition by general pediatricians is critical, as prompt treatment can alter disease trajectory and reduce life-threatening complications.

Juvenile idiopathic arthritis (JIA) is defined as chronic arthritis beginning before age 16 and lasting at least six weeks. Systemic JIA accounts for approximately 5% to 20% of JIA cases and differs fundamentally from other subtypes in both immunopathology and clinical course.¹ Rather than a classic autoimmune disease, sJIA is now understood as an autoinflammatory disorder driven by dysregulation of the innate immune system and excessive cytokine production, particularly interleukin (IL)-1 and IL-18.²

Clinical Recognition Beyond Arthritis

Fever is the most consistent feature of sJIA, reported in nearly all patients at presentation. The classic pattern is quotidian with daily spikes above 39°C and rapid return to baseline; this pattern is helpful in diagnosis when present but occurs in less than half of patients.¹ Fever is often accompanied by an evanescent, salmon-colored macular or maculopapular rash that appears during febrile episodes and fades without scarring.

Musculoskeletal symptoms may initially be limited to arthralgia, with arthritis developing weeks to months later. When present, arthritis commonly affects the knees, wrists, ankles, hips, cervical spine, temporomandibular joints, and small joints of hands and feet. Systemic features such as lymphadenopathy, hepatosplenomegaly and serositis further distinguish sJIA from more common causes of prolonged fever.

Laboratory abnormalities are nonspecific but aid in the diagnosis, including elevated inflammatory markers, microcytic anemia, neutrophilia, mild transaminitis and elevated ferritin levels. Importantly, sJIA remains a diagnosis of exclusion, and early rheumatology consultation is necessary when infection and malignancy have been reasonably ruled out.

ILAR Criteria: Useful but Incomplete

The International League of Associations for Rheumatology (ILAR) classification criteria define sJIA as arthritis with fever of at least two weeks in duration (documented quotidian for three days) plus systemic features such as rash, lymphadenopathy, hepatosplenomegaly or serositis.³ While these criteria have standardized research cohorts, they present challenges in clinical practice.

Most notably, ILAR criteria require documented arthritis, excluding children who present early with systemic inflammation alone. Rigid fever requirements and exclusion rules may further delay diagnosis, particularly in primary care settings where children are often seen before arthritis evolves. These limitations have prompted efforts to develop more relevant classification systems.⁴

PRINTO Criteria: A Shift Toward Biology

The Pediatric Rheumatology International Trials Organization (PRINTO) has proposed revised classification criteria that better reflect the autoinflammatory nature of sJIA.⁴ These criteria prioritize fever and systemic inflammation and do not require arthritis at onset, allowing earlier identification of affected children.

Early validation studies suggest that PRINTO criteria improve sensitivity without substantially sacrificing specificity, particularly for patients presenting with fever of unknown origin and evolving systemic features.⁵ For general pediatricians, mindfulness of the existence of these newer criteria reinforces the importance of referral when sJIA is suspected, even if traditional criteria are not yet met (Table 1).

Table 1:

Early Diagnosis Matters

Systemic JIA follows heterogeneous courses, ranging from monophasic disease to persistent, destructive arthritis. Early initiation of IL-1–targeted therapy has been associated with improved outcomes and may prevent progression to chronic arthritis.¹ Serious complications, including macrophage activation syndrome and sJIA-associated lung disease, emphasize the importance of timely diagnosis and close monitoring for these patients.¹

Key Takeaway for Pediatricians

Children with prolonged or recurrent fever, systemic inflammation and evolving musculoskeletal symptoms merit consideration of sJIA, even in the absence of arthritis. Familiarity with updated classification frameworks can support earlier referral, treatment and improved outcomes.

References:

1. Spoorthy RDR, Balan S. Systemic juvenile idiopathic arthritis: the challenges and opportunities. Indian J Rheumatol. 2024;19(4):303-315.
2. Nigrovic PA. Autoinflammation and autoimmunity in systemic juvenile idiopathic arthritis. Proc Natl Acad Sci U S A. 2015;112(52):15785-15786.
3. Petty RE, Southwood TR, Manners P, et al; International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390-392.
4. Martini A, Ravelli A, Avcin T, et al. Toward new classification criteria for juvenile idiopathic arthritis: first steps, Pediatric Rheumatology International Trials Organization international consensus. J Rheumatol. 2019;46(2):190-197.
5. Chen K, Zeng H, Togizbayev G, Martini A, Zeng H. New classification criteria for juvenile idiopathic arthritis. Int J Rheum Dis. 2023;26(10):1889-1892.