Systemic Juvenile Idiopathic Arthritis
Systemic juvenile idiopathic arthritis (sJIA) is an International League of Associations for Rheumatology (ILAR) subclass of JIA, characterized by disease driven more by autoinflammation than by autoimmunity. Diagnostic features include several weeks of fever, classically in a quotidian or double quotidian pattern, evanescent rash, and arthritis, which is not always present at disease onset. Males and females are affected equally with a peak onset between ages 1 to 5 years of age [149]. One of the most life-threatening complications unique to sJIA (vs. other classes of JIA) is macrophage activation syndrome (MAS), which is driven by IFN-\(\gamma\) and can be seen in 10% of patients fulminantly and 30- 40% of patients subclincially [150-152].
In recent years, significant attention has also been directed to the pulmonary complications of sJIA, which include pleuritis, pleural effusions, ILD and pulmonary arterial hypertension [153]. ILD in sJIA is referred to as sJIA-LD. Risk factors for sJIA-LD include younger age of onset (<2 years old), trisomy 21, history of MAS, and prior adverse reaction to biologic drugs (including injection site reactions and delayed type hypersensitivity-like reactions to anti-IL-1 and IL-6 biologics) [154-156]. In a multi-center cohort, median time to LD diagnosis after sJIA onset was 1.6 years. Respiratory symptoms were often absent or subtle. Symptoms in sJIA-LD patients included: hypoxemia (43%), pulmonary hypertension (30%), clubbing (61%), digital erythema (50%), pruritic non-evanescent rashes (56%) and eosinophilia (37%). Mortality was increased in sJIA-LD with a 5-year survival of 42%, significantly lower than patients without sJIA-LD [156]. This mortality rate has likely improved since these 2019 studies, as patients are being diagnosed earlier with less severe LD and opportunity for earlier treatment [157, 158].
Curiously, most cases of sJIA-LD have been reported after biologics became first line therapy for sJIA. It is unclear if this is secondary to increased incidence of sJIA-LD or increased awareness. More recently, it has been shown that sJIA patients treated with IL-1 or IL-6 inhibitors may develop eosinophilia with an atypical rash, in association with HLA-DRB1*15 leading to the hypothesis that a drug reaction was driving the development of MAS and sJIA-LD [154]. This hypothesis potentially affects management, as it raises concern about continued use of biologic agents in treatment of sJIA. However, our group and others have noted that eosinophilia in sJIA can occur prior to any treatment with anti-IL-1 and IL-6 therapy [159, 160], rendering it possible that eosinophilia is a reflection of the type of inflammation characteristic of sJIA, which may be further skewed towards a Th2 phenotype in the setting of IL-1 and IL-6 blockade [161].
Diagnosing sJIA-LD can be challenging – imaging changes may precede development of clinical symptoms, and patients at highest risk are often too young to perform PFTs. There are no consensus guidelines for screening for sJIA-LD. Our center developed a screening algorithm recommending patients with sJIA be referred for pulmonary screening if they have ‘red flag’ features including: diagnosis at age <2 years, presence of the HLA DRB1*15 risk allele, high disease activity (history of MAS, sJIA-related ICU admission, persistently elevated IL-18), anaphylaxis, eosinophilia or atypical rash, respiratory symptoms or an abnormal pulmonary exam [162]. Initial evaluation should include chest x-ray and PFTs, including a 6-minute walk test or exercise saturation testing in ambulatory children. If a patient’s pulmonary screening is abnormal, or if patients have uncontrolled disease, we recommended high-resolution chest CT for more sensitive screening of ILD. Overnight oximetry or polysomnography can be considered to evaluate for low pulmonary reserve or nocturnal hypoxemia, which may also suggest the presence of sJIA-LD. Bronchoalveolar lavage to evaluate for infection is frequently employed when there is concern for sJIA-LD. BAL fluid from patients with sJIA-LD have been found to have high levels IL-18 and CXCL9 compared to patients with congenital alveolar proteinosis [155].
CT scan abnormalities in sJIA-LD can include pleural, interlobular-septal, and bronchial wall/perivascular thickening, peripheral and periobronchovascular consolidations, ground glass and tree-in-bud opacities, crazy paving, and lymph node changes (adenopathy, hyper-enhancing). Fibrosis is uncommon and pleural effusions are rare [155, 156]. Pathologic findings include pulmonary alveolar proteinosis, type II pneumocyte hyperplasia, macrophage accumulation, endogenous lipoid pneumonia, lymphoplasmocytic inflammation, pulmonary vascular abnormalities, and rarely, fibrosis [155, 156].
In a single center study of 18 patients with sJIA-LD, all continued biologic treatment after detection of lung disease with a median of 1 year of follow up and range of 0.5 to 13 years. In that cohort, 50% of patients had stable LD, 22.2% worsened, and 27.8% improved. There was no differentiating characteristics of those who improved and those who did not. Importantly, all patients with improved sJIA-LD had control of their underlying sJIA [155].
There are no management guidelines or randomized controlled trials of therapies in sJIA-LD. As poor sJIA disease control is a risk factor for the development of sJIA-LD, achieving overall disease control is a priority. sJIA is thought to be driven by elevated IL-1, IL-6 and IL-18, and thus first line treatment of sJIA is based on IL-1 and IL-6 blockade with biologics. Regarding additional therapies, there are case reports of successful treatment of sJIA-LD with JAK inhibition [163-165], and in our experience, adding mycophenolate mofetil, calcineurin inhibitors or JAK inhibitors to obtain control of sJIA if this is refractory to or develops while on biologic monotherapy [166]. Case reports exist for successful treatment of sJIA-LD with emapalumab [167], an anti-IFNγ monoclonal antibody used to tackle the related inflammation in MAS, etoposide (also used for MAS) [168], bispecific IL-1/IL-18 blockade [169] and allogeneic hematopoietic stem cell transplant (HSCT) [170].