Adult-onset Still's disease (AOSD) is a rare systemic autoinflammatory disorder of unknown etiology. The main clinical features include high fever, transient rash, arthritis, arthralgia, sore throat, hepatosplenomegaly, and lymphadenopathy, often accompanied by elevated white blood cell count and increased serum ferritin levels. The global incidence of AOSD is approximately 0.16–0.40 per 100,000 people, with a peak onset age of 20–40 years, accounting for about 70% of all cases. The prevalence is slightly higher in women than in men. AOSD can be classified into two types: systemic type and arthritis type. The systemic type is characterized by fever and systemic symptoms, while the arthritis type mainly presents with high fever and arthritis, with relatively mild systemic symptoms and a tendency to develop into chronic arthritis.
Pathogenesis
The etiology and pathogenesis of AOSD remain unclear, but it is generally thought to involve factors such as infection, genetic predisposition, and immune system abnormalities.
Studies suggest an association between AOSD and infections, with certain pathogens potentially triggering or contributing to the disease onset. The clinical manifestations often resemble bacterial sepsis, but repeated blood cultures are usually negative, and antibiotics are ineffective. Genetic studies indicate potential susceptibility genes for AOSD, including HLA-B17, HLA-B18, HLA-B35, HLA-DR2, and HLA-DR7. Overactivation of the innate immune system and excessive production of pro-inflammatory cytokines are crucial mechanisms in AOSD pathogenesis. High levels of cytokines such as IL-1β, TNF-α, IFN-γ, IL-6, and IL-18 have been identified in the serum of patients during active disease. IL-18 levels are significantly correlated with serum ferritin levels, serving as indicators for disease diagnosis and activity assessment.
Clinical Manifestations
Fever
Fever is the most prominent symptom of AOSD, occurring in nearly all patients and lasting for more than one week, often throughout the disease course. The maximum body temperature frequently exceeds 39°C, with 1–2 fever spikes per day. A remittent fever pattern is common, although sustained fever or irregular fever can also occur. In some cases, the fever may spontaneously resolve without treatment, and patients generally feel well after fever subsides.
Rash
The typical rash of AOSD is a transient salmon-colored maculopapular eruption, predominantly distributed on the proximal limbs, neck, and trunk. The rash often appears during febrile episodes and fades as the fever resolves, leaving no residual marks. A small proportion of patients may develop atypical persistent rashes, such as pigmentary papules, fixed linear urticaria, or plaque-like urticaria.
Sore Throat
Approximately 70% of patients experience sore throat during the early stages of the disease, primarily presenting as dry throat discomfort. In severe cases, there may be difficulty swallowing or drinking, which worsens during fever and improves after fever reduction. Physical examination may reveal pharyngeal hyperemia and reactive hypertrophy of lymphoid follicles on the posterior pharyngeal wall, with negative throat cultures.
Joint and Muscular Symptoms
More than two-thirds of patients exhibit joint involvement, often concomitant with fever. Symptoms include joint pain or tenderness, with minimal swelling. The most commonly affected joints are the knees, wrists, and ankles. Muscle pain is reported in approximately 80% of patients, typically without elevated muscle enzyme levels or abnormal electromyography findings.
Hepatosplenomegaly and Lymphadenopathy
Hepatosplenomegaly and generalized symmetrical lymphadenopathy are observed in AOSD patients. Lymph node biopsy usually reveals reactive hyperplasia or chronic nonspecific inflammation, but necrotizing lymphadenitis may also be found.
Other Manifestations
Approximately 80% of patients present with hepatomegaly or elevated liver enzyme levels, which typically resolve with treatment. Cardiac and pulmonary involvement may include pericarditis, pleuritis, organizing pneumonia, infiltrative pulmonary disease, alveolar damage, and pulmonary hypertension.
Complications
Macrophage activation syndrome (MAS) is a serious, life-threatening complication of AOSD, with an incidence of 12%–15%. MAS may be suspected in AOSD patients with persistent fever, progressive peripheral cytopenia, decreased fibrinogen levels, elevated triglycerides,
Laboratory Tests
In the active phase of AOSD, peripheral blood white blood cell counts are elevated, typically ranging between (10–20) × 109/L, with some cases reaching up to 50 × 109/L. The proportion of neutrophils exceeds 80%, which has higher diagnostic value compared to total white cell counts. Some patients may develop anemia or thrombocytosis. Elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are closely associated with disease activity. Serum ferritin levels in AOSD patients are significantly increased, often exceeding the normal reference value by more than five times, which serves as an important diagnostic indication. Ferritin levels can also be used to evaluate disease activity, monitor treatment efficacy, and predict the risk of macrophage activation syndrome (MAS). Bone marrow examination may show hyperactive granulopoiesis with a left shift in nuclear maturation and toxic granules in the cytoplasm. The majority of patients test negative for rheumatoid factor (RF) and antinuclear antibodies (ANA), although a few may show low-titer positivity.
Diagnosis
There are no specific serological or pathological markers for diagnosing AOSD, so the diagnosis largely relies on clinical evaluation. Commonly used classification criteria include the Japanese Yamaguchi criteria, the American Cush criteria, and the French Fautrel criteria.
The Japanese Yamaguchi criteria are widely applied in clinical practice and are as follows:
Major criteria:
- Fever ≥ 39°C persisting for at least one week
- Arthritis/arthralgia persisting for at least two weeks
- Typical rash
- White blood cell count ≥ 10 × 109/L with neutrophils ≥ 80%
Minor criteria:
- Sore throat
- Lymphadenopathy and/or hepatosplenomegaly
- Abnormal liver function
- Negative rheumatoid factor and antinuclear antibodies
Exclusion criteria:
- Exclusion of malignant diseases, infectious diseases, and other rheumatic diseases.
A diagnosis of AOSD can be considered when a patient meets at least five criteria, including at least two major criteria.
Differential Diagnosis
The diagnosis of AOSD requires differentiation from infections, autoimmune or autoinflammatory diseases, tumors, and other conditions.
Infectious Diseases
Possible infectious pathogens include bacteria, viruses, fungi, and parasites. Investigations should not only focus on common sites such as the respiratory and urinary tracts but also less obvious sites like the subphrenic region, perirenal area, and heart valves.
Autoimmune/Autoinflammatory Diseases
Autoimmune diseases like systemic lupus erythematosus, inflammatory myopathies, and vasculitis, as well as autoinflammatory diseases like familial Mediterranean fever and tumor necrosis factor receptor-associated periodic syndrome, may present with fever, rash, and joint pain. Differentiation can be achieved by analyzing rash characteristics, accompanying symptoms, autoantibodies, and genetic testing.
Malignancies
Hematologic malignancies, such as lymphomas, leukemia, and myeloproliferative diseases, often need to be ruled out. Physical examination should check for superficial lymphadenopathy and sternal tenderness. Lymphomas, in particular, can mimic many features of AOSD. Pathological biopsies of lymph nodes or bone marrow are often helpful for differentiation. Other malignancies, such as solid tumors, atrial myxomas, and paraneoplastic syndromes, can also present with symptoms resembling AOSD.
Other Diseases
Conditions such as acute febrile neutrophilic dermatosis, subacute thyroiditis, histiocytic necrotizing lymphadenitis, and drug-induced hypersensitivity reactions may also need to be considered.
Treatment
The primary medications for treating AOSD include nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, immunosuppressants, biologics, and JAK inhibitors. For mild cases, NSAIDs may be used as first-line treatment, with about one-quarter of patients achieving remission and favorable outcomes. Corticosteroids are the cornerstone of AOSD treatment, with a commonly used dose of prednisone at 0.5–1.0 mg/(kg·d). For patients who do not respond to conventional corticosteroid doses or develop severe complications, intravenous methylprednisolone at 500–1,000 mg/day for three consecutive days may be administered, with repeat courses as necessary.
Immunosuppressants like methotrexate can act synergistically with corticosteroids to control the disease. Calcineurin inhibitors are more suitable for patients with liver dysfunction and/or MAS, while other immunosuppressants, such as leflunomide and azathioprine, have also shown effectiveness in some reports. Biologic agents, including IL-6 inhibitors and IL-1 inhibitors, can alleviate symptoms by targeting pathogenic cytokines and are indicated for severe, refractory, recurrent, or highly active disease. Some patients with chronic arthritis-dominant AOSD may benefit from TNF-α inhibitors. JAK inhibitors are effective in refractory cases, aiding in disease remission and steroid reduction. Severe cases may also involve treatments like high-dose intravenous immunoglobulin (IVIG), plasma exchange, or immunoadsorption, though their efficacy requires further validation.
Prognosis
The clinical course of AOSD is highly variable, exhibiting significant heterogeneity. Most patients have a favorable prognosis. However, some may experience recurrent systemic symptoms or arthritis, making it difficult to reduce corticosteroid doses. Poor prognosis and a high risk of mortality are associated with severe liver damage, cardiac or pulmonary involvement, or complications such as MAS.