Pleural Involvement

Pleurisy is the most common pulmonary manifestation of JIA. It is more common in sJIA, which is included as one of the diagnostic criterium for sJIA in both the ILAR and the new 2019 JIA diagnostic criteria consensus from the Pediatric Rheumatology International Trials Organization (PRINTO) [4]. The incidence of pleurisy varies among ethnic groups. The incidence of pleurisy has been reported to be about 3.6% in sJIA in Italy [5], 1.9% in North America and Canada [6], and 1.2% in France [7], while the incidence of pleurisy in various subtypes of JIA in China is about 4.4% [8]. Macrophage activation syndrome (MAS) is a potentially life-threatening complication of JIA, which is complicated by the combination of MAS in about 10% of sJIA patients, and the prevalence of subclinical forms is as high as 30% and 40% [9]. A multicenter study in China found that sJIA patients with combined MAS were more likely to present with pleurisy, with a rate of 7.5% [10]. JIA-associated pleurisy mostly has no obvious clinical symptoms, but some may present with chest pain, dry cough, fever, and in severe cases, respiratory distress. Imaging examination reveals unilateral or bilateral pleural effusion and pleural thickening as aseptic exudate with increased lymphocytosis, low glucose, elevated lactate dehydrogenase and protein [11], with attention to exclude infection, pulmonary embolism, and heart failure.

Treatment for pleurisy depends on the severity of the condition and the amount of pleural effusion. No specific treatment may be necessary for those with mild symptoms, and pleurisy should resolve itself when the primary disease is controlled. Those with chest pain may be prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) as recommended by the American College of Rheumatology (ACR) [12]. Anjali Sura et al. observed that those with plasmacytosis were less likely to use this approach [13]. For those with moderate-to-severe pleurisy, high-dose methylprednisolone shock (10–30 mg/kg day, up to 1–2 g/day for 1–3 days) followed by oral glucocorticoid therapy (up to 1–2 mg/kg day, up to 60 mg/day) may be advised [14]. Also, thoracentesis aspiration or closed chest cavity drainage may be considered for those with significant compression symptoms.

Diffuse Lung Disease

Diffuse lung disease (DLD) or diffuse parenchymal lung disease (DPLD), formerly known as ILD, is a broad term for a variety of heterogeneous diseases characterized by pathological changes in the distal lung units and impaired gas exchange [15]. In 2007, the Children’s Interstitial Lung Disease (chILD) proposed a classification system for DPLD in children under 2 years of age. In 2013, an extended classification was proposed, extending to children 18 years of age. This classification system is based on histological differences. It includes diffuse developmental and growth abnormalities, surface active substance abnormalities (such as pulmonary alveolar protein deposition, PAP), interstitial pneumonia, lymphoproliferative disorders, other typed of diffuse lung disease (such as iron-containing heme deposits and systemic disease-associated ILD), diseases resembling diffuse lung disease (such as small airway lesions like obliterative bronchiolitis (BO) and vascular lesions like pulmonary arterial hypertension (PAH), and specific types of disease of unknown etiology [16]. sJIA is associated with a combination of DLD, including interstitial pneumonia, alveolar protein deposition, iron-containing heme deposits, and pulmonary hypertension. RF + pJIA is less common and resembles adult rheumatoid arthritis, with the potential for rheumatoid nodules in addition to the manifestations mentioned above [25, 26, 52]. The typical manifestations of DLD and the possible treatment options for each subtype are outlined below. Table 1 outlines the typical clinical presentation of DLD and the primary treatment approaches for sJIA and RF + pJIA patients.

Table 1 Main clinical manifestations and treatment of JIA with diffuse lung diseasesJIA with DLD

It was observed that before 2010, sJIA combined with DLD was an extremely uncommon occurrence. Only a few cases had been reported [17, 18], exhibiting symptoms such as cough, dyspnea, and shortness of breath after physical activity. Lung high-resolution CT (HRCT) scans revealed ground-glass-like turbidity, eventually progressing to lobular septal thickening and fibrotic changes. However, since then, the number of cases of sJIA combined with DLD has increased. While some scholars have suggested that the use of biologics may be a contributing factor, it is unclear what is causing the increase in cases of sJIA combined with DLD. In 2011, a study involving 25 cases of sJIA combined with DLD revealed that 80% of patients were diagnosed after 2004, with 64% having PAH, 20% having PAP, and 28% having ILD. Moreover, the study highlighted a high mortality rate of about 68%, garnering the attention of the rheumatology community [19].

Lipoid pneumonia

Lipoid pneumonia (LP) is a rare form of DLD divided into two categories: endogenous and exogenous. Exogenous lipoid pneumonia (ELP) is linked to inhalation of mineral oil, gastroesophageal reflux, etc. Endogenous lipoid pneumonia, also known as cholesterol pneumonia, is predominantly obstructive and is caused by chronic pulmonary infections or abnormal lipid metabolism resulting in intra-alveolar lipid accumulation [20]. It is a scarce condition in sJIA, with only two cases reported.

In 2001, Finland reported a case of refractory sJIA accompanied by lipoid pneumonia [21], which was characterized by a cough, dyspnea, detectable dry rales on pulmonary examination, presence of secondary mild PAH, nodular lattice-like changes in the central lobular region and pulmonary fibrosis on lung CT, restrictive lung disease on lung function, and lung biopsy suggesting cholesterol granuloma-like pathological changes in the interstitial and alveolar lung. Ultimately, the patient succumbed to respiratory failure due to a worsening lung infection. In 2010, Toronto reported a 21-year-old patient with sJIA who presented with nocturnal paroxysmal cough and progressive exertional dyspnea [22]. Pulmonary CT revealed thickened lobular septa and ground-glass turbidity at the base of the lung, pulmonary function was restrictive ventilation, bronchial lavage fluid was dominated by foamy macrophages containing large fatty vesicles, and pulmonary pathology suggested small airways. The final diagnosis of endogenous lipid-like pneumonia was made, with gastroesophageal reflux in both cases.

Treatment options for lipoid pneumonia are limited, but clinical improvement has been reported after using whole lung bronchoscopy lavage, hormones, and tumor necrosis factor-alpha antagonists. In some cases, lung transplantation has been used to treat secondary lung infection [22, 23]. Additionally, intensive immunosuppressive therapy, such as methylprednisolone shock and cyclophosphamide arthritis were used. Controlling the underlying disease activity may also be beneficial in managing lipoid pneumonia [24].

Highly Lethal Lung Disease-Alveolar Protein Deposition-like Features

Pulmonary alveolar proteinosis (PAP) is a DLD associated with sJIA since 2013. It is characterized by an accumulation of alveolar surface active substances and dysfunction of alveolar macrophages, leading to progressive dyspnea, secondary lung infections, and pulmonary fibrosis. This disorder can be divided into primary and secondary categories, with primary PAP caused by genetic or autoimmune disruption of granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling and secondary PAP primarily caused by impaired macrophage numbers or function [25]. Since 2015, sJIA combined with a highly lethal lung disease presenting with PAP-like pathological changes has been widely reported, with a prevalence of up to 6.8%. In 2019, a prospective cohort study from a single center in Cincinnati, OH, USA, summarized the clinical features of 18 patients [26]. A retrospective study of 61 cases reported by the Children’s Arthritis and Rheumatism Trial Alliance (CARRA) in the USA identified risk factors, including age at diagnosis < 2 years, recurrent MAS, high incidence of adverse reactions to biological agents (IL-1 or IL-6 inhibitors), and significantly elevated serum IL-18 levels. The trisomy 21 ratios were higher than in the sJIA cohort.

The majority of patients with the sJIA-LD present with an insidious onset and mild clinical manifestations, such as mild shortness of breath and pestilential fingers, as the primary manifestation. In addition, more than half of patients have an erythematous rash with pruritus, 37% eosinophilia, and a few have unexplained abdominal pain. Allergic reactions to biological agents are significantly more common in sJIA-LD, up to 38%. Laboratory tests reveal an increase in ferritin levels and a decrease in lymphocytes (absolute counts < 60% of the lower limit of normal). Krebs Von den Lungen-6 (KL-6) can be used as an effective biomarker for sJIA-LD [67]. HRCT scans show characteristic changes, including septal thickening, paving stone sign, peripheral solidity, solidity around the bronchovesicular wall, ground-glass turbidity, and enlarged lymph nodes. The most common of these is septal thickening involving multiple perihilar lobes with or without ground-glass shadowing, typically affecting the lower lung region, anterior upper lobe, perihilar or peri-mediastinal regions, and occurring in roughly 60% of cases. Additionally, pulmonary ultrasonography has been used to diagnose sJIA-LD, displaying focal or diffuse irregular pleural thickening with scattered or synthetic B-lines and subpleural solidity [27]. Pulmonary function tests are not currently available to detect signs of sJIA-LD. However, a 6-min walk test or a pulmonary function test for carbon monoxide lung diffusion capacity may be beneficial. Lung biopsies performed on patients with sJIA-LD revealed a combination of PAP and ELP with extensive lymphoplasmacytic infiltration. In contrast to autoimmune or hereditary PAP, sJIA-LD patients exhibited an increased presence of foamy macrophages, cholesterol lacunae, inflammation, and fibrosis. Bronchial lavage (BAL) did not display diagnostic PAP features but was predominantly composed of macrophages with high levels of IL-18 and interferon-γ-induced chemokines (CXCL) 9 and CXCL10; Lung tissue transcription analysis indicated a trend of upregulation of IFN II and T cell activation network.

The 5-year survival rate for this highly lethal form of sJIA-LD is only 42%, and the best treatment option is currently unknown. There is a history of biological exposure in these patients, though it is not clear whether it is drug-related. Schulert et al. reported that all patients in their cohort were treated with biologics, and 50% saw stable and progressive improvement. In Thailand, one patient with sJIA-LD was treated with the IL -6 inhibitor tocilizumab, resulting in disease control [28]. Additionally, the upregulation of transcription of genes related to the IFNγ pathway and T-cell activation pathway in BAL fluid and lung tissue has led to the attempted application of the Janus kinase (JAK) 1/2 inhibitor ruxolitinib to block IFNγ signaling therapy with good efficacy [29]. The safety and efficacy of JAK inhibitors for sJIA-LD should be further studied. Other targeted T-cell drugs, such as cyclosporine and mycophenolate mofetil, may also be considered to control LD [30]. In some cases, LD has been associated with drug reaction with eosinophilia and systemic symptoms (DReSS), which is caused by severe delayed hypersensitivity reactions, hyperinflammatory state of the organism, and whole-blood cytopenia [31, 32]. Early discontinuation of the suspected drug is necessary to control disease progression. Sato et al. reported the successful treatment of a patient with sJIA-LD combined with MAS via plasma exchange [33]. Despite this, the exact pathogenesis of the highly lethal lung disease in patients with sJIA remains unknown. Further research is needed to uncover the pathogenesis and determine the best clinical treatment.

Hematoxylin Deposition

Pulmonary hemosiderosis (PH) is a rare form of DLD characterized by recurrent episodes of diffuse alveolar hemorrhage (DAH). This leads to large amounts of iron accumulation in alveolar macrophages, resulting in cellular necrosis, tissue remodeling with pulmonary fibrosis, and the stimulation of ferritin production by macrophages, leading to hyperferricemia [34]. The age of onset of PH ranges from the neonatal period to adulthood, with a prevalence of approximately 0.24–1.23 per million person-years and a mortality rate of up to 50%. Clinical manifestations of PH include recurrent dyspnea, cough, fever, and varying degrees of anemia, with hemoptysis present in about half of the patients [35]. Chest radiographs may show pulmonary edema and patchy shadows. In contrast, HRCT may show diffuse or patchy ground-glass opacity, as well as the “paving stone sign” and lobular thickening due to pulmonary ferritin deposition. Bronchial lavage fluid is hemorrhagic and is dominated by alveolar macrophages with the presence of hemosiderin [36]. There have been no cohort studies on sJIA-PH, and only two cases have been reported on a case-by-case basis, one with recurrent MAS and one with combined trisomy 21 [37, 38]. It is essential to be aware of the potential for PH in patients with sJIA presenting with recurrent MAS, as dyspnea, iron deficiency anemia, and diffuse changes suggested by lung imaging may be present. It is hypothesized that sJIA-PH is associated with highly elevated serum ferritin levels, although this does not represent the level of iron stores in the alveoli [39].

Treatment of PH typically involves the use of glucocorticoids either alone or in combination with other immunosuppressants. In acute alveolar hemorrhage accompanied by respiratory failure, vital signs can be maintained through mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and high-dose methylprednisolone shock therapy [34]. Liposteroid, a lipid-based dexamethasone palmitate with potent anti-inflammatory properties, has been developed and studied in Japan and used to treat rheumatic diseases in conjunction with MAS [40]. This drug is absorbed by activated pulmonary macrophages, thus preventing the breakdown of heme and hemosiderin accumulation, thus treating PH [41]. However, it has yet to be applied to the treatment of sJIA.

Pulmonary Hypertension

Pulmonary arterial hypertension (PAH) is a condition characterized by an elevated pulmonary artery systemic pressure (PAP) of more than 20 mmHg and an increased pulmonary vascular resistance (PVR) of more than 3 Wood units, with normal pulmonary venous pressure (pulmonary wedge pressure < 15 mmHg) [42]. A cohort study by Kimura et al. found that 64% (16/25 cases) of patients with sJIA had pulmonary hypertension with pulmonary complications. Still, only 25% had interstitial lung disease or alveolar protein deposition manifestations. Furthermore, the disease activity was higher in patients with sJIA (including combined MAS) when PAH with pulmonary complications was diagnosed, suggesting that the severity of systemic inflammation plays a vital role in the pathogenesis of PAH [19, 43]. Symptoms of severe PAH may include exertional dyspnea, fatigue, syncope, cyanosis, chest pain, and in rare cases, heart failure [44]. Physical examination may reveal a separation of second heart sound separation and pulmonary valve murmur, while echocardiography is a sensitive tool for identifying PAH. Physical examination may reveal a separation of the second heart sound and pulmonary valve murmur, while echocardiography is a sensitive tool for identifying PAH. Cardiac catheterization is the gold standard for diagnosis, and other tests such as cardiac magnetic resonance imaging (MRI), 6-min walk test, chest computed tomography (CT), and pulmonary function can also be used to assess cardiopulmonary function.

The primary treatment for sJIA in combination with PAH is to manage the active state of the primary disease and provide medical support such as oxygen therapy, cardiac strengthening, diuresis, and anticoagulation. Targeted therapies for PAH have been studied, with the only clinical trial data relevant to children for phosphodiesterase inhibitor type 5 -sildenafil [45]. A case study by Luciana et al. reported the use of IL-1 inhibitor canakinumab to treat a patient with sJIA combined with MAS and severe pulmonary hypertension [46], offering a potential new treatment option for patients with MAS and PAH-related sJIA.

pJIA with DLD

RF + pJIA is analogous to adult rheumatoid arthritis, and rheumatoid nodules, as well as interstitial lung disease, and can be seen in association with DLD, which may present as interstitial pneumonia, diffuse pulmonary hemorrhage, and mechanized pneumonia due to fine occlusive bronchitis [47, 48].

Pulmonary rheumatoid nodules are a rare extra-articular manifestation of rheumatoid arthritis, with a prevalence ranging from 0.4 to 32% [49]. Generally, they do not cause any clinical symptoms; however, some individuals may experience cough, usually in the interlobular septum or subpleural lung areas [50]. Around half of these nodules can later form cavities or lead to pleural effusion and spontaneous pneumothorax [51]. In children with RF + pJIA, the nodules are similar to those of adults, and methotrexate treatment may accelerate their appearance, necessitating dynamic monitoring [52]. The IL-6 inhibitor tocilizumab has been found to improve pulmonary rheumatoid nodules in adult patients [53], and its efficacy in patients with pJIA needs further study.

Patients with RF + pJIA combined with ILD typically present with no obvious respiratory symptoms, patchy ground-glass changes on high-resolution CT of the lungs, and no specific changes in bronchial lavage fluid. Elevated salivated glycocalyx antigen KL-6 has been reported in isolated cases [54]. Maruyama et al. reported that KL-6 levels decreased to normal and intrapulmonary lesions improved significantly after the application of the IL-6 inhibitor tocilizumab for pJIA, which was attributed to the inhibition of IL-6 production and reduction of its pro-fibrotic effect on lung fibroblasts. However, drug-induced lung injury must be considered during the application, as one case of acute interstitial lung disease after applying tocilizumab for pJIA was reported in 2021 [55]. Additionally, patients with RF + pJIA in combination with ILD should be monitored for auto-inflammatory diseases, such as mutations in the COPα gene, which can lead to excessive production of type I interferon and present as RF + recurrent arthritis and interstitial lung lesions [56, 57]. Similarly, STING-associated vasculopathy with onset in infancy (SAVI) has been reported to have early onset RF + polyarthritis combined with an ILD clinical phenotype [58]. Therefore, genetic testing should be conducted to exclude auto-inflammatory diseases in RF + polyarthritis combined with ILD with a positive family history.

Secondary Pulmonary Infections

A study involving 365 patients with JIA revealed that a significant number (24%) had developed nosocomial infections, particularly bacterial pneumonia, a rate higher than that in control children [59]. A comparative cohort study found that procalcitonin (PCT) could be used as a marker to differentiate between active JIA and bacterial infection [60]. Additionally, Mycoplasma pneumonia infection was observed in 21.2% of JIA patients, particularly those with oligoarticular JIA, and was associated with an elevation in serum IgE levels [61]. These high-rated respiratory tract infections in JIA patients may be attributed to the dysfunctional immune function of the body, the low antimicrobial activity of alveolar macrophages, and the use of immunosuppressive agents in JIA patients.

Studies from Brazilian and Portuguese registries have revealed that approximately 10.6% of children are infected with tuberculosis [62]. Therefore, it is essential to actively exclude TB infection when children with JIA present with symptoms such as hypothermia, wasting, and night sweats. The 2021 ACR guidelines recommend screening for Mycobacterium tuberculosis before the initiation of biologic-based disease-modifying anti-rheumatic drugs (DMARDs) and after treatment, if there is suspected exposure to Mycobacterium tuberculosis [12]. A study by Hügle et al. using the German Center for Pediatric and Young Adult Rheumatology database found no significant disease activity in JIA patients with SARS-CoV-2 infection. Additionally, Haşlak et al. compared seropositivity rates between JIA patients and healthy controls with asymptomatic SARS-CoV-2 infection without substantial differences. However, SARS-CoV-2 infection-induced cytokine changes may lead to outbreaks of JIA in more susceptible populations. Therefore, further research is needed to understand better the potential relationship between necrobiosis and JIA in children with JIA and pneumoconiosis to determine the long-term prognosis after infection [63, 64].