The Role of Interleukin 18/Interleukin 18-Binding Protein in Adult-Onset Still’s Disease and Systemic Juvenile Idiopathic Arthritis

Interleukin 18 (IL-18) is a pro-inflammatory cytokine of the IL-1 family, whose activity is tightly controlled at the level of production, as well as signalization. Notably, it is buffered by its natural inhibitor, IL-18 binding protein (IL-18BP), which is massively present in circulation in normal and in most pathological conditions, thus preventing harmful pro-inflammatory systemic effects of IL-18. IL-18 has long been considered to be involved in the pathophysiology of various inflammatory diseases. However, a first clinical trial using recombinant IL-18BP for the treatment of rheumatoid arthritis and psoriasis gave disappointing results. Direct measurements of unbound, bioactive, free form of circulating IL-18 demonstrated that IL-18 was more specifically involved in adult-onset Still’s disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) but also in their most severe complication, macrophage activation syndrome (MAS). More importantly, administration of recombinant IL-18BP to patients with AOSD, and sJIA with MAS, showed promising results. This review summarizes available data regarding IL-18 and IL-18BP in AOSD and sJIA in mouse models and humans and shows the importance of IL-18/IL-18BP imbalance in these conditions, leading to the conclusion that IL-18, particularly free IL-18, may be a useful biomarker in these diseases and an interesting therapeutic target.

An Adult-Onset Still’s Disease During Pregnancy that Delivered a Neonate with Hemophagocytic Lymphohistiocytosis and Severe Liver Failure Requiring Liver Transplantation: A Case Report and Literature Review

Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology that is categorized as a non-hereditary disease. Neonatal hemophagocytic lymphohistiocytosis (HLH) is also a rare, but potentially fatal condition. Neonatal HLH is one of the causes of neonatal acute liver failure that often requires urgent liver transplantation. The relationship between AOSD during pregnancy and neonatal HLH currently remains unclear. We encountered a case of AOSD that developed during pregnancy, and an offspring was born with neonatal HLH resulting in severe liver failure. The mother with AOSD only presented with liver dysfunction during pregnancy; however, disease activity was exacerbated after delivery. The maternal clinical course was quite severe and refractory that she required biological therapy in addition to high-dose corticosteroids and immunosuppressants. Additionally, the severe condition of the neonate with HLH and acute liver failure required intensive care with the administration of steroids and intravenous immunoglobulin treatments, and ultimately liver transplantation. This is the first case that severe maternal AOSD associated with a neonatal HLH resulted in severe clinical courses. Physicians need to be aware of the risk of a mother with AOSD delivering an offspring with neonatal HLH with potentially acute liver failure.

Adult-Onset Still’s Disease: Novel Biomarkers of Specific Subsets, Disease Activity, and Relapsing Forms

Adult-onset Still’s disease (AOSD) is a systemic inflammatory disease of unknown etiology. Recent studies have demonstrated that the hallmark of AOSD is a cytokine storm, which is characterized by the excessive production of interleukin (IL)-1, IL-6, IL-18, tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ), suggesting how pro-inflammatory cytokines play an important role in the pathogenesis of this disease. Actually, a certain proportion of patients (around 17–32%) with severe clinical symptoms achieves only partial remission or is resistant to both first-line corticosteroids and second-line DMARDs. These patients are defined as refractory AOSD patients, requiring higher dosage glucocorticoids, longer treatment duration, or the simultaneous introduction of immunosuppressive drugs, further leading to AOSD relapses. In this narrative review, we will analyze the latest literature data to unravel potential pathogenetic factors associated with specific patterns of AOSD disease or relapses in order to identify biomarkers that may guide clinical decisions, eventually leading to new therapeutic options.

Short-term, Low-Dose Etoposide in Refractory Adult-Onset Still’s Disease-Associated Macrophage Activation Syndrome, a Case Series Study

Objectives:In this study, we modified the classical regimen of the hemophagocytic lymphohistiocytosis-04 protocol and evaluated the efficacy and safety of short-term, low-dose etoposide in patients with refractory macrophage activation syndrome (MAS) associated with adult-onset Still’s disease (AOSD).Methods:A total of 17 patients with refractory AOSD-associated MAS were enrolled and received short-term, low-dose etoposide (100 mg twice a week for four times). Another 11 patients, who were not treated with etoposide, were included as historical controls. Patient information, such as clinical manifestations, laboratory results, treatments, and short-term prognosis, were recorded and analyzed.Results:In this case series, 88.24% of the patients with MAS who were treated with short-term, low-dose etoposide had a favorable response in 3 weeks, which was significantly higher (p = 0.017) than that in the patients with MAS who were treated without etoposide (45.45%). The 90-day survival rate after the onset of MAS was significantly higher (p = 0.0029) among the patients in the short-term etoposide group (16/17, 94.12%) than in the control group (5/11, 45.45%). Conclusion:The regimen of short-term (2-week), low-dose etoposide was highly effective in the treatment for patients with refractory AOSD associated MAS with an acceptable safety profile.

Case Report: Adult Onset Still’s Disease after vaccination against Covid-19

Vaccination against the virus responsible for COVID-19 has become a key in preventing mortality and morbidity related to the infection. Studies have shown that the benefits of vaccination outweigh the risks. However, there are concerns regarding serious adverse events of some vaccines, although they are fortunately rare. Here, we report a case of a 47-year-old female from Kathmandu who presented with high grade fever, dry cough and erythematous rash a week after exposure to the Oxford-AstraZeneca vaccine. She had hepatosplenomegaly, persistent leucocytosis, anaemia and thrombocytosis along with markedly raised inflammatory markers. Her tests for infectious causes and haematological malignancies was negative and she showed no response to multiple antibiotics. Finally, she had a dramatic response to steroids with disappearance of fever and normalization of other laboratory parameters. Hence, she was diagnosed with Adult-onset Still’s Disease (AOSD). She was under methotrexate and prednisolone tapering dose and doing well as at time of writing. The trigger for the disease was hypothesized to be the vaccine because of the strong temporal association.