Systemic juvenile idiopathic arthritis: Complications

INTRODUCTION — 

Systemic juvenile idiopathic arthritis (sJIA; formerly called Still's disease or systemic-onset juvenile rheumatoid arthritis) is considered a subset of JIA, although the pathophysiology is most consistent with an autoinflammatory disorder [1]. Adult-onset Still's disease (AOSD) is probably the same disease when it begins in patients ≥16 years of age, and guidelines issued by the European Alliance of Associations for Rheumatology (EULAR) and Pediatric Rheumatology European Society (PReS) in 2024 advocate for a unified approach for both conditions under the terminology "Still's disease" [2]. (See "Classification of juvenile idiopathic arthritis", section on 'Systemic arthritis'.)

Children with sJIA require close supervision and careful monitoring. Serious systemic complications, including macrophage activation syndrome (MAS) and pericarditis, are relatively common in sJIA and are associated with increased morbidity and mortality [3]. Chronic lung disease and other forms of internal organ involvement are less common, although they are seen with increasing frequency [4-6]. Patients may also develop complications related to adverse drug effects, such as infection in the setting of taking immunosuppressive medications, or osteoporosis from long-term use of systemic glucocorticoids.

The complications and prognosis of sJIA are discussed in this review. Other complications of various forms of JIA are reviewed elsewhere (see "Juvenile idiopathic arthritis: Immunizations and complications", section on 'Complications'). The classification of JIA and the clinical manifestations, diagnosis, clinical course, and treatment of sJIA are discussed separately:

●(See "Classification of juvenile idiopathic arthritis".)

●(See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)

●(See "Systemic juvenile idiopathic arthritis: Treatment and prognosis".)

The complications, treatment, and prognosis of AOSD are also presented elsewhere. (See "Adult-onset Still's disease: Clinical manifestations and diagnosis" and "Adult-onset Still's disease: Treatment".)

MACROPHAGE ACTIVATION SYNDROME — 

Macrophage activation syndrome (MAS) is a severe complication of systemic juvenile idiopathic arthritis (sJIA) that should be treated as a life-threatening emergency [7,8]. The clinical and histopathologic characteristics of MAS are similar to those of hereditary lymphohistiocytic hemophagocytosis (HLH), but the diagnostic criteria for HLH are often not useful to diagnose MAS in sJIA. Evidence suggests that there is a shared genetic component, in that some patients with sJIA and MAS also have hypomorphic protein-altering variants in HLH-associated genes [9]. The specifics of MAS as they relate to sJIA are briefly discussed here. An overview of the diagnosis and treatment of HLH/MAS is provided separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Epidemiology and risk factors — While data are limited, at least 7 percent of patients develop overt MAS at some stage of their illness [10], and another 30 to 40 percent may have subclinical MAS [11]. MAS typically occurs within the first few days or weeks of the onset of sJIA, although it can occur at any point over the course of the disease. Some patients develop recurrent or refractory, chronic MAS, which appears to be associated with an increased risk of complications such as lung disease [4-6]. (See 'Epidemiology and risk factors' below.)

Triggers may include viral or bacterial infections or new medications, but often no inciting event is identified. More information on infectious and genetic risk factors in HLH is provided separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Genetic abnormalities' and "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Infections'.)

Clinical presentation — Providers must maintain a high degree of suspicion for MAS in patients with sJIA. Many of the clinical signs and symptoms can overlap (eg, fever, rash, liver dysfunction, lymphadenopathy), and the robust autoinflammatory nature of sJIA may mask some early signs of MAS on laboratory testing, making the HLH diagnostic criteria less useful in sJIA patients.

●Signs and symptoms – Children with sJIA and MAS may present with fever, spontaneous bleeding, bruising, hepatic dysfunction, lethargy, seizures, coma, and/or shock. The fever and rash are persistent and unremitting, unlike the intermittent daily fever and evanescent rash typical of simple active sJIA. Lymphadenopathy and hepatosplenomegaly are also common findings.

●Laboratory testing – On laboratory evaluation, the ferritin level can climb to well over 1000 ng/mL and often is much higher. The white blood cell count (WBC), hemoglobin, platelet count, and serum fibrinogen typically drop precipitously. Since sJIA typically causes leukocytosis, thrombocytosis, and hyperfibrinogenemia, the WBC, platelet, and fibrinogen values in MAS may initially become deceptively "normal" rather than low. Additionally, due to the decrease in fibrinogen, there is a paradoxical drop in the erythrocyte sedimentation rate (ESR) despite ongoing severe inflammation [12]. There are rapid elevations in liver function tests and lactate dehydrogenase (LDH) and, somewhat later in the course, in triglycerides.

●Bone marrow examination – On bone marrow examination, numerous benign macrophages typically exhibit hemophagocytosis. However, bone marrow may also appear normal.

Of note, patients who are treated with certain biologic disease-modifying antirheumatic drugs (bDMARDs) may have less typical clinical features of MAS that may make it even more challenging to recognize. In a systematic literature review of patients with sJIA who developed MAS while using interleukin 1 (IL-1) or IL-6 inhibitors, ferritin levels were lower than those observed in historical MAS cohorts [13]. The 49 patients treated with the IL-6 inhibitor tocilizumab were less likely to be febrile, but other features of MAS were more pronounced, including lower platelet counts, lower fibrinogen, and higher liver function tests.

More information on the clinical features and laboratory abnormalities of MAS in the setting of adult-onset Still's disease (AOSD) and of HLH in general is described separately. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'Clinical features' and "Adult-onset Still's disease: Clinical manifestations and diagnosis", section on 'Macrophage activation syndrome'.)

Evaluation and diagnostic testing — In patients suspected of having sJIA and MAS, we check the following studies [14]:

●Complete blood count (CBC) with differential

●Coagulation studies, including prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimer

●Basic metabolic panel

●Liver function tests, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), total bilirubin, albumin, and LDH

●Serum triglycerides

●Serum ferritin

●ESR and C-reactive protein (CRP)

●Soluble IL-2 receptor alpha (sCD25 or sIL-2R), IL-18, and CXCL9 if available

●Infectious studies, including blood culture and Epstein-Barr virus (EBV) and cytomegalovirus (CMV) polymerase chain reaction (PCR)

●Chest radiograph

Additional diagnostic testing in some patients may include the following:

●Bone marrow biopsy, particularly if new-onset sJIA or concern for malignancy

●Abdominal ultrasound

Patients with unexplained neurologic changes (eg, headache, altered mental status, focal neurologic findings on examination) require additional evaluation, including consideration of magnetic resonance imaging (MRI) of the brain and lumbar puncture with cerebrospinal fluid testing. If there is neurologic involvement, certain therapies may be more beneficial (eg, dexamethasone has better central nervous system penetration compared with other glucocorticoids). (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'CNS involvement'.)

Diagnosis — It can be very challenging to diagnose MAS in the setting of sJIA, despite many attempts to develop clinically useful diagnostic criteria and scoring tools [7,15,16]. In the authors' experience, we make the diagnosis of MAS based on a combination of clinical and laboratory findings, with guidance from the 2016 classification criteria for MAS issued by the European Alliance of Associations for Rheumatology (EULAR, formerly known as the European League Against Rheumatism)/American College of Rheumatology (ACR)/Pediatric Rheumatology International Trials Organization (PRINTO) (table 1) [16].

Other diagnostic criteria and scoring tools are available to help distinguish MAS from sJIA flares, and also from HLH, and are listed below:

●MAS/sJIA (MS) score – A diagnostic scoring tool to differentiate MAS in sJIA from active sJIA without MAS, called the MAS/sJIA (MS) score, was developed and validated in 2019 [17] using multinational patient data collected for the creation of MAS classification criteria in 2016 (table 2) [16]. Fever is a mandatory criterion for the diagnosis and is not included in the score, although, as stated above, fever may not be present in patients with sJIA treated with tocilizumab even when MAS is present. This score still requires validation in clinical practice and may need revisions that take into account the use of bDMARDs.

●MAS-HLH score – A diagnostic scoring tool to help distinguish MAS in sJIA from primary HLH based upon a few clinical parameters, called the MH (MAS-HLH) score, is also available (table 3) [18]. This score was validated using data from a large, multinational, retrospectively collected cohort of patients with sJIA and MAS compared with data from clinical trials of genetically confirmed patients with HLH. This tool was able to distinguish these two illnesses with high specificity and sensitivity. The MH score assigns points for age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. Age ≤1.6 years at onset and a neutrophil count ≤1.4 x 10⁹/L were the most important factors in favor of a diagnosis of HLH rather than MAS complicating sJIA.

●2004 HLH diagnostic criteria – The 2004 HLH diagnostic criteria often cannot be applied to MAS in patients with sJIA, even though the clinical syndromes are similar, because the HLH criteria are too stringent to be able to identify sJIA patients in early MAS, when they are most responsive to treatment [15]. However, it is useful to be familiar with these criteria, especially when trying to differentiate MAS in sJIA from HLH. The differences between the diagnostic criteria for HLH and the classification criteria for MAS are shown in the table (table 1). The use of the 2004 HLH diagnostic criteria is discussed in more detail elsewhere. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis", section on 'HLH-2004 criteria'.)

Treatment

Urgency of treatment — Treatment should be urgently initiated once MAS is diagnosed or suspected with the guidance of a pediatric rheumatologist, given the complexity of these patients and the speed with which their clinical status can deteriorate. Ideally, superimposed infection should be ruled out prior to starting therapy. However, if patients are critically ill, we start empiric therapy for MAS as below, while the infectious evaluation is ongoing.

Initial treatment — In most patients with sJIA and MAS, we treat with high-dose systemic glucocorticoids and anakinra, rather than using either therapy alone. Drug dosing is provided in the table (table 4) and evidence to support individual agents is described in detail below. There are no data to directly compare treatment strategies in sJIA and MAS. Our approach is generally consistent with that outlined in the 2021 ACR guideline for treatment of sJIA [19], although we favor the short-acting anakinra over other IL-1 inhibitors or IL-6 inhibitors given the relatively greater amount of supportive data and ability to adjust therapy.

●Systemic glucocorticoids – Systemic glucocorticoids are typically started at "pulse" dosing of methylprednisolone 30 mg/kg (maximum dose 1 g) given intravenously once a day for three days [12]. The subsequent taper of glucocorticoids depends on the clinical response, but patients are often transitioned to high-dose methylprednisolone 1 mg/kg given intravenously twice a day. Adverse effects and monitoring of glucocorticoids are described in detail separately. (See "Major adverse effects of systemic glucocorticoids".)

●Anakinra – Anakinra is an IL-1 inhibitor that is given by subcutaneous injection and has a short half-life, which therefore allows for more fine-tune adjustment of immunosuppression if needed. Patients typically need higher doses when MAS is present (ie, 5 to 10 mg/kg, divided two to four times daily). Intravenous dosing may be needed in critically ill patients. Information about adverse effects and monitoring of anakinra is provided elsewhere. (See "Interleukin 1 inhibitors: Biology, principles of use, and adverse events".)

Direct evidence to support the use of bDMARDs in sJIA complicated by MAS is promising but very limited [20-23]. As an example, in a retrospective study of 44 children with secondary HLH or MAS who were treated with anakinra, there was a 57 percent decrease in ferritin within 15 days of initiating therapy [22]. The 13 patients with underlying sJIA had the lowest mortality rate (0 percent, versus 100 percent of the three patients with underlying hematologic malignancy).

In addition to adding the therapies above, certain baseline immunosuppressive medications for sJIA may need to be substituted or held (eg, methotrexate should be held if there is a concern for liver dysfunction).

Patients should be monitored closely for evidence of improvement in their temperature, physical examination (eg, rash, lymphadenopathy, organ-specific findings), and laboratory abnormalities (eg, cytopenias, transaminitis, hyperferritinemia). IL-18 and CXCL9 levels can be helpful in the diagnosis and monitoring of MAS, although IL-18 may remain persistently elevated in patients with inactive disease [24]. Since all of these medications have a relatively quick onset of action, we generally expect some improvement in clinical and laboratory features within a few days of initiating therapy.

Treatment of refractory disease — The following therapies should be considered in patients who continue to worsen despite glucocorticoids and anakinra and do not show rapid improvement:

●Emapalumab – Emapalumab is an anti-interferon (IFN) gamma monoclonal antibody that is approved by the US Food and Drug Administration (FDA) for the treatment of pediatric and adult patients with refractory HLH. In a single-arm clinical trial of 15 patients with sJIA-associated MAS, 94 percent achieved resolution of MAS in a median of 25 days [25]. More information on the use of emapalumab for primary HLH is provided elsewhere. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Relapsed or refractory disease'.)

●Ruxolitinib – Ruxolitinib is a type of Janus kinase (JAK) inhibitor. In a retrospective review that compared 11 children with secondary HLH who received ruxolitinib with 11 age-matched controls who did not, those who received ruxolitinib had more rapid resolution of fever and required lower glucocorticoid doses compared with the control group [26]. Treatment appeared to be well-tolerated. Data supporting the use of ruxolitinib for primary HLH are described separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis", section on 'Relapsed or refractory disease'.)

●Tocilizumab – Tocilizumab is an IL-6 inhibitor that is often used to treat sJIA without MAS. Limited observational data suggest that some patients with MAS related to AOSD or sJIA respond well to treatment with tocilizumab [27-29].

●Cyclosporine – Cyclosporine is a type of calcineurin inhibitor. Multiple case reports support its use in patients with MAS related to sJIA [30,31]. Tacrolimus has been proposed as an alternative calcineurin inhibitor [32].

●Etoposide – Etoposide is an antineoplastic agent and part of the HLH-2004 protocol for the treatment of HLH. A case series has described the successful use of lower-dose etoposide (50-100 mg/m² weekly) in refractory MAS [33].

●Other therapies – There are case reports of successful treatment with cyclophosphamide [4,8]. Intravenous immunoglobulin (IVIG) can also be used for MAS/HLH, especially if there is concern for a concomitant infection, but is rarely sufficient to control inflammation [34,35].

●Investigational approaches – High levels of IL-18 are correlated with severe systemic disease, MAS, and HLH. A recombinant IL-18 binding protein (rIL-18BP; called tadekinig alfa) and a bispecific IL-1 and IL-18 antibody (MAS825) have been or are under investigation for use in primary forms of HLH [36].

LUNG DISEASE — 

An unusual form of incompletely defined and characterized chronic lung disease with a high fatality rate is increasingly seen and has been termed systemic juvenile idiopathic arthritis-associated lung disease (sJIA-LD) [4-6].

Epidemiology and risk factors — There is no consensus definition for sJIA-LD, and its incidence is rare and not well defined. The reasons for the increased frequency of lung disease in sJIA are unclear, although there is a temporal association coincident with the more widespread usage of biologic disease-modifying antirheumatic drugs (bDMARDs) in sJIA. Reported risk factors for development of sJIA-LD include a younger age of sJIA onset (under two years of age), severe adverse drug reactions (including anaphylactic reactions to tocilizumab), extremely high levels of interleukin 18 (IL-18), and trisomy 21 [5]. In addition, some children who develop sJIA-LD while on IL-1 or IL-6 inhibitors demonstrate features of suspected delayed hypersensitivity responses, including eosinophilia and atypical rashes, with a possible link to human leukocyte antigen (HLA)-DRB1*15 [37]. However, a further study of HLA typing in a prospective single-center cohort of new-onset sJIA patients did not reveal a definite association of HLA haplotype with sJIA-LD, drug reactions, overall treatment responses, or eosinophilia [38].

Clinical presentation — Typically, patients with sJIA-LD have severe systemic disease that is difficult to control, many with features of macrophage activation syndrome (MAS; acute and chronic). Clinically patients often display subtle respiratory signs and symptoms at diagnosis, but some have more obvious early physical signs such as acute erythematous clubbing.

The pathology of lung disease in sJIA is unusual, with predominant pulmonary alveolar proteinosis (PAP) and/or endogenous lipoid pneumonia (ELP). Septal thickening of peripheral lobes with ground glass opacities are the most common lung computed tomography (CT) findings. Higher levels of IL-18 were seen in the serum of these patients as well as in the bronchoalveolar lavage (BAL) fluid, which also contained high levels of the interferon (IFN) gamma-induced chemokines CXCL9 and CXCL10 [6].

Evaluation and diagnostic testing — We monitor all patients with sJIA for the development of sJIA-LD as outlined in the algorithm (algorithm 1), which is adapted from a published approach [35,39].

Diagnosis — We make the diagnosis of sJIA-LD in patients who present with signs and symptoms of lung disease that correlate with typical abnormalities on their diagnostic testing, in the absence of another alternative diagnosis (eg, active infection).

Treatment — We recommend a threefold approach to treatment of sJIA-LD, which is based on the authors' expertise given the very limited evidence to guide treatment of this condition:

●Control of sJIA – First, it is important to attempt to control the underlying sJIA, as high disease activity appears to drive disease progression. Of note, development of lung disease does not necessarily preclude the continued use of IL-1 or IL-6 inhibitors, as per the guidelines issued in 2024 on the treatment of Still's disease [2]. Treatment of sJIA is described in detail elsewhere. (See "Systemic juvenile idiopathic arthritis: Treatment and prognosis".)

●Treatment of interstitial inflammation – Second, for most patients, we add medications that target the interstitial inflammation in sJIA-LD such as mycophenolate mofetil, cyclosporine, or a Janus kinase (JAK) inhibitor. The choice of a specific agent should be made based on the provider's experience, patient and family preference, overall disease control, and baseline immunosuppressive regimen. As examples, mycophenolate mofetil and cyclosporine are types of conventional synthetic DMARDs (csDMARDs) that are often combined with another csDMARD or bDMARD, while JAK inhibitors are a type of targeted synthetic DMARD (tsDMARD) and caution should be used if combining these agents with other bDMARDs.

More information about specific immunosuppressive agents is provided below:

•Mycophenolate mofetil – Mycophenolate mofetil has been successfully used for lung disease related to other types of rheumatic disease, such as interstitial lung disease [40], but is not typically used for other manifestations of sJIA. In a cohort of patients with sJIA-LD, 12 of 37 patients were treated with mycophenolate mofetil after their diagnosis [41]. The dosing, adverse effects, and monitoring of mycophenolate mofetil are described in detail elsewhere. (See "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases".)

•Cyclosporine – Cyclosporine is a calcineurin inhibitor that is sometimes used to treat refractory systemic manifestations of sJIA, including MAS. (See 'Treatment of refractory disease' above.)

•JAK inhibitors – The use of various types of JAK inhibitors, including tofacitinib, ruxolitinib, and baricitinib, has been reported in patients with sJIA and sJIA-LD. In the same cohort of patients with sJIA-LD described above, 22 of 37 patients started a JAK inhibitor after their diagnosis [41]. (See "Systemic juvenile idiopathic arthritis: Treatment and prognosis", section on 'JAK inhibitors'.)

●Azithromycin for selected patients – Third, for patients with hypoxia or clinical concern for airway inflammation (eg, chronic cough), we consider adding azithromycin, which has antiinflammatory effects and can prevent flares in other pediatric lung diseases [42].

●Consideration of Pneumocystis jirovecii pneumonia (PJP) prophylaxis – Prophylactic therapy to prevent Pneumocystis pneumonia (PCP) may be required for patients with significant immune suppression, including taking prolonged courses of prednisone (eg, in adults, ≥20 mg of prednisone a day or the equivalent for ≥1 month) along with other immunosuppressive agents. (See "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Indications'.)

OTHER COMPLICATIONS

Growth retardation — Historically, when systemic glucocorticoids were one of the primary treatments for systemic juvenile idiopathic arthritis (sJIA), patients commonly developed profound growth abnormalities with obesity and short stature due to a combination of adverse drug effects and incomplete suppression of systemic inflammation. Following the introduction of more effective biologic disease-modifying antirheumatic drugs (bDMARDs), growth abnormalities have become less frequent [43]. However, short stature and failure to thrive may still be seen in patients with chronic unremitting disease, even in those who do not receive glucocorticoids [44-46]. Short stature can also complicate other types of JIA. (See "Juvenile idiopathic arthritis: Immunizations and complications", section on 'Short stature'.)

Uveitis — While patients with sJIA are at relatively lower risk for developing uveitis compared with other types of JIA, patients still require regular annual screening (algorithm 2). The approach to screening and treatment of uveitis in JIA is described separately. (See "Oligoarticular juvenile idiopathic arthritis" and "Juvenile idiopathic arthritis: Immunizations and complications", section on 'Chronic anterior uveitis'.)

Inflammatory bowel disease — There are case reports and one case series of children with sJIA subsequently diagnosed with inflammatory bowel disease (IBD) [47,48]. These children were distinct from the broader population of sJIA patients in that they were often older at diagnosis, had a more persistent disease course, and responded well to tumor necrosis factor (TNF) inhibitors after discontinuing anti-interleukin 1 (IL-1) or IL-6 bDMARDs. In addition, a monogenic disease caused by LACC1 deficiency can mimic sJIA and also cause prominent colitis, suggesting that the finding of IBD is not incidental but represents a unique disease phenotype [49-51].

Other complications — A few cases of atypical kidney, cardiac, hepatic, endocrine, or other complications have been reported in every large series, but the extent to which these represent incidental findings or complications of sJIA is uncertain [3].

UNANSWERED QUESTIONS — 

The pathogenesis of systemic juvenile idiopathic arthritis (sJIA) and its complications, including macrophage activation syndrome (MAS) and associated lung disease (sJIA-LD), are still active areas of investigation. Some researchers have raised a concern that the increase in sJIA-LD may be related to the more widespread use of bDMARDs [4] and that this potential relationship may be mediated by a process similar to drug reaction with eosinophilia and systemic symptoms (DRESS) [37]. However, others have reported improvement in some patients with sJIA-LD despite continuing bDMARDs [6] and alternative hypotheses have been proposed to explain the clinical presentation of sJIA-LD [52]. As such, our practice is early initiation of bDMARD therapy to achieve rapid disease control, together with close surveillance for both potential drug reactions and the development of complications such as sJIA-LD [39,42]. More robust prospective and mechanistic studies are needed to further investigate this important issue. (See 'Epidemiology and risk factors' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Juvenile idiopathic arthritis".)

SUMMARY AND RECOMMENDATIONS

●Macrophage activation syndrome (MAS) – MAS is a severe complication of systemic juvenile idiopathic arthritis (sJIA) that should be treated as a life-threatening emergency. (See 'Macrophage activation syndrome' above.)

•Epidemiology and risk factors – At least 7 percent of patients with sJIA develop overt MAS at some stage of their illness, and another 30 to 40 percent may have subclinical MAS. Although triggers may include viral or bacterial infections or new medications, often no inciting event is identified. (See 'Epidemiology and risk factors' above.)

•Clinical presentation – Many clinical signs and symptoms of MAS overlap with those of active sJIA (eg, fever, rash, liver dysfunction, lymphadenopathy). The fever and rash are persistent and unremitting in MAS, unlike the intermittent daily fever and evanescent rash typical of simple active sJIA. The robust autoinflammatory nature of sJIA may mask some early signs of MAS on laboratory testing, making the hereditary lymphohistiocytic hemophagocytosis (HLH) diagnostic criteria less useful in sJIA patients. (See 'Clinical presentation' above.)

•Evaluation and diagnostic testing – For patients suspected of having MAS, we obtain a chest radiograph and laboratory testing including a complete blood count (CBC) with differential, coagulation studies, a complete metabolic panel, triglycerides, ferritin, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), infectious studies (eg, blood culture, Epstein-Barr virus [EBV], and cytomegalovirus [CMV] polymerase chain reaction [PCR]), and, when available, soluble IL-2 receptor alpha (sCD25 or sIL-2R), interleukin 18 (IL-18), and CXCL9.

•Diagnosis – Diagnosing MAS in the setting of sJIA is challenging and requires maintaining a high index of suspicion. We diagnose MAS in sJIA based on a combination of clinical and laboratory findings, with guidance from the 2016 MAS classification criteria (table 1). (See 'Diagnosis' above.)

•Treatment

-Urgency of treatment – Treatment should be urgently initiated once MAS is diagnosed or suspected. Ideally, superimposed infection should be ruled out prior to starting therapy; however, if patients are critically ill, we start empiric therapy while the infectious evaluation is ongoing. (See 'Urgency of treatment' above.)

-Initial treatment – In most patients with sJIA and MAS, we treat with high-dose systemic glucocorticoids and anakinra, rather than using either therapy alone or alternative immunosuppressive agents (Grade 2C). If patients do not improve, we rapidly escalate to other agents. Drug dosing is in the table (table 4). (See 'Initial treatment' above.)

●Lung disease – sJIA-associated lung disease (sJIA-LD) is an unusual form of incompletely defined and characterized chronic lung disease with a high fatality rate. (See 'Lung disease' above.)

•Clinical presentation – Typically, patients have severe systemic disease that is difficult to control, many with features of MAS. While patients often display subtle respiratory signs and symptoms at diagnosis, some may have acute erythematous clubbing. On CT, pleural and/or septal thickening of peripheral lobes with ground glass opacities are the most common findings. (See 'Clinical presentation' above.)

•Evaluation and diagnostic testing – We monitor all patients with sJIA for the development of sJIA-LD as outlined in the algorithm (algorithm 1). (See 'Evaluation and diagnostic testing' above.)

•Diagnosis – We diagnose sJIA-LD based on the presence of signs and symptoms of lung disease that correlate with typical abnormalities on diagnostic testing, in the absence of alternative diagnoses (eg, active infection). (See 'Diagnosis' above.)

•Treatment – For most patients with sJIA-LD, we suggest adding a medication that targets the interstitial inflammation in sJIA-LD such as mycophenolate mofetil, cyclosporine, or a Janus kinase (JAK) inhibitor, rather than using alternative forms of immunosuppression (Grade 2C). The choice of a specific agent is based on the provider's experience, patient and family preference, overall disease control, and baseline immunosuppressive regimen. The risks and benefits of discontinuing anti-IL-1 or IL-6 bDMARD therapy are unclear. We also optimize control of the underlying sJIA and, for patients with hypoxia or signs of airway inflammation, we add azithromycin. (See 'Treatment' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Thomas JA Lehman, MD, who contributed to an earlier version of this topic review.