SJIA – Systemic Juvenile Idiopathic Arthritis

The genetic investigation for the cause of sJIA disease is ongoing. Current research suggests that genetic biomarkers may include a variety of dysregulated pathways including HLA-DRB1*11 (several related haplotypes), MIF-173, IRF5, and NLRC4. Additional findings have demonstrated that patients with IL1RN expression may have lacking response to Anakinra therapy.

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Systemic-onset JIA has an estimated incidence of 1/166,000 and prevalence at 1/32,000 in the pediatric population and is thought to arise from a combination of genetic and environmental factors.

In sJIA, the symptoms may occur at the same time or be spread out through the day or even last weeks and are characterized by flares, which include periods of severe inflammation or worsening of symptoms, which may last days or months and then go into remission.

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Fevers are recurring and often high as temperature reaches 103 °F/39.5 °C and typically spikes in the evenings, normalizing within a few hours. This is a major criterion for diagnosing sJIA. However, the pattern of fevers may vary from patient to patient and occur twice daily (morning and evening) or may continue throughout the day.

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Rash: A flat, pale or pink rash, depending on the child's skin color, often appears on the trunk, arms or legs, and may move around in the body. The rash may or may not be itchy and presents from a few minutes to a few hours, and is often associated with fever spikes.

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Arthritis: Arthritis is the second and most common sign of sJIA. The symptoms of joint swelling, pain, stiffness, and warmth, tend to worsen in the morning, after a nap or prolonged rest/immobility. It may affect 5 or more joints, or it may only affect one and commonly impacts the knees, wrists, and ankles. Children with sJIA may also develop arthritis in the spine (in the neck area), jaw and hip joint.

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Joint problems may develop over time after the onset of fevers and rashes. Young children often cannot verbalize or complain about any joint pain, making the diagnosis process more difficult. It is recommended to observe the child for limping or favoring use of one leg, inactivity, or stiffness in the mornings.

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Lung and organ problems

The inflammation or swelling of the internal organs such as the heart, liver, lungs, spleen and lymph nodes may occur in sJIA. Anemia is also a common finding.

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Lung diseases seen in children with sJIA include pulmonary artery hypertension and interstitial lung disease. Pulmonary artery hypertension is high blood pressure affecting the arteries in the lungs and the right side of the heart. Interstitial lung disease is when lung tissue becomes scarred, impacting the oxygen levels in the bloodstream. Should any signs of breathing problems such as shortness of breath occur along with blue lips, nails or fingers, parents should notify their treating physician immediately.

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High blood pressure (hypertension)

Atherosclerosis is the build-up of plaques (fats and other substances) occurring on the artery walls, which causes hypertension, as seen in children with sJIA. This issue is most likely due to the ongoing inflammation or caused by the heavy use of corticosteroids.

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Macrophage Activation Syndrome (MAS)

MAS is the most serious and life-threatening complication of sJIA affecting about 10% of the patients. It causes a rapid and massive inflammatory response that overwhelms the body and includes unremitting fever, hepatosplenomegaly, hepatic dysfunction, lymphadenopathy, encephalopathy, purpura, and bleeding. Severely affected MAS patients often develop life-threatening multiorgan failure involving dysregulation of the central nervous system, renal malfunction, respiratory distress, and a variety of cardiovascular issues including hypotension and shock.

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Triggers of MAS may include viral infections, medication changes, or an underlying inflammation process. A majority of MAS patients have elevated ferritin and liver enzymes, anemia, abnormal lactase dehydrogenase, frequent thrombocytopenia and neutropenia. Triglycerides are often elevated due to intravascular coagulation, as demonstrated by elevated d-dimer.

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For more information on MAS, please read the 2016 EULAR Classification Criteria for Macrophage Activation Syndrome in patients with Systemic Juvenile Idiopathic Arthritis.

The sJIA diagnostic criteria developed by the International League of Associations for Rheumatology (ILAR) requires:

• a high fever for at least two weeks

• arthritis (joint pain and inflammation) in one or more joints for at least six weeks

• nonpruritic macular or maculopapular salmon colored rash (usually located on trunk or extremities while febrile).

 

Since there are no specific medical or genetic tests for sJIA, a doctor will typically make a diagnosis based on medical history (recollection of all medical events and family history), physical exam, clinical findings, laboratory tests, imaging scans or ultrasound, and possibly skin biopsy. An eye exam to evaluate any ocular inflammation (uveitis) may be warranted.

The overall aim of treatment is to reduce inflammation, which may require several types of interventions including medications, physiotherapy, and surgery. While there is no cure, a spontaneous remission is possible.

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Early treatment is essential for prompt disease control. The past few years have seen a revolution in treatments for sJIA to include biologic medications. However, the standard approach typically begins with NSAIDs and corticosteroids.

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Once systemic symptoms of SJIA have disappeared, nonbiologic, conventional disease-modifying antirheumatic drugs (DMARDs) may be used alone or in combination with biologics for continued therapy for arthritis. Unlike NSAIDs or corticosteroids, conventional synthetic DMARDs may slow joint damage. The treatment goal is to relieve pain and control symptoms.

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Biologic medications that target proinflammatory cytokines, such as anakinra (IL-1α), canakinumab (IL-1β) and tocilizumab (IL-6), help treat both the systemic inflammation and the arthritis, significantly improving the prognosis for pediatric patients. These medications are given by injection or IV infusion.

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A percentage (20 to 40%) of sJIA patients may fail anti-cytokine biological treatment due to adverse reactions or the drugs losing efficacy over time. Newer biologics such as IL-18 and JAK inhibitors targeting IFNs (interferon pathways) appear to be promising therapies for sJIA and its complications SJIA-MAS and SJIA-LD.

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Most children are given calcium and vitamin D supplements and encouraged to eat a diet high on calcium. Physical therapy is also likely recommended to help build up muscle strength and reduce pain and stiffness.

sJIA cannot be diagnosed with blood tests. However, certain laboratory findings may support or disprove the diagnosis. It is commonly seen in children with sJIA to have the following lab results: 

• extremely elevated white blood cell (WBC) and platelet counts

• severe anemia due to poor iron absorption

• extremely elevated ferritin levels

• elevated inflammatory markers (ESR and CRP)

• negative antinuclear antibodies (ANA) and rheumatoid factor antibodies

Rider, P., Carmi, Y., & Cohen, I. (2016). Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations. International journal of cell biology, 2016, 9259646. https://doi.org/10.1155/2016/9259646

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Gurcay, E., & Akinci, A. (2017). Autoinflammatory Diseases and Physical Therapy. Mediterranean journal of rheumatology, 28(4), 183–191. https://doi.org/10.31138/mjr.28.4.183

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Bracaglia, C., Prencipe, G., & De Benedetti, F. (2017). Macrophage Activation Syndrome: different mechanisms leading to a one clinical syndrome. Pediatric rheumatology online journal, 15(1), 5. https://doi.org/10.1186/s12969-016-0130-4

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Andersson, Ulf. (2021). Hyperinflammation: On the pathogenesis and treatment of macrophage activation syndrome. Acta Paediatrica Nurturing the Child. https://doi.org/10.1111/apa.15900

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