Conditions That Mimic Still's Disease
Still's disease must be carefully differentiated from malignancies, infectious diseases, other immune-mediated inflammatory diseases, and monogenic autoinflammatory disorders, as misdiagnosis can lead to potentially harmful immunosuppressive treatment, particularly when malignancy is the true underlying cause. 1
Major Categories of Mimics
Malignancies
- Hematologic malignancies are critical to exclude, including non-Hodgkin's lymphoma, acute leukemia, and Hodgkin's disease 1
- These can present with fever, lymphadenopathy, splenomegaly, and leukocytosis—overlapping significantly with Still's disease 2
- Peripheral blood smear, bone marrow biopsy, and occasionally lymph node biopsy are essential when lymphadenopathy and splenomegaly dominate the clinical picture 2
- Solid tumors including lung cancer and prostate cancer have been reported as mimics 1
Infectious Diseases
- Bacterial infections (both pyogenic bacteria and mycobacteria) must be systematically excluded 1
- Viral infections including HIV, hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus (EBV), cytomegalovirus (CMV), parvovirus B19, and rubella can cause lymphadenopathy, arthralgia, and constitutional symptoms mimicking Still's disease 1, 3
- Parasitic infections such as toxoplasmosis should be considered 1
- Sepsis specifically can present with markedly elevated inflammatory markers and fever patterns similar to Still's disease 1
Monogenic Autoinflammatory Disorders
- TRAPS (Tumor necrosis factor receptor-associated periodic syndrome) 1
- CAPS (Cryopyrin-associated periodic syndrome) including Muckle-Wells syndrome 1
- HIDS/MKD (Hyperimmunoglobulin D syndrome/Mevalonate kinase deficiency) 1
- PFAPA syndrome (Periodic fever, aphthous stomatitis, pharyngitis, and adenitis) 1
- Familial Mediterranean fever 1
- In adult patients specifically, VEXAS syndrome and CHIP (clonal hematopoiesis of indeterminate potential) should be considered 1
Other Immune-Mediated Inflammatory Diseases
- Systemic lupus erythematosus (SLE) can present with fever, arthritis, and systemic manifestations, though alopecia and specific autoantibodies help differentiate it 1, 4
- Rheumatoid arthritis, though typically lacking the systemic features and characteristic rash of Still's disease 1
- Vasculitides including polyarteritis nodosa, other systemic vasculitides, giant cell arteritis, and ANCA-associated vasculitis 1
- Kawasaki disease in the appropriate age group 1
- Behçet's disease 1
- Sarcoidosis 1
- Polymyalgia rheumatica 1
- Spondyloarthropathies 1
- Relapsing polychondritis 1
- Polymyositis and scleroderma 1
- Connective tissue diseases more broadly 1
Other Conditions
- Chronic recurrent multifocal osteomyelitis (CRMO) 1
- Reactive arthritis 1
- DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) 1
- Crystal arthropathies 1
- Specific liver diseases including Gaucher's disease and hemochromatosis 1
Critical Diagnostic Pitfalls
The Danger of Premature Immunosuppression
Glucocorticoids and immunomodulating agents can be potentially deleterious if Still's disease is misdiagnosed, particularly when malignancy is the underlying condition. 1 This creates a clinical dilemma requiring careful evaluation without inadequately delaying treatment when Still's disease is truly present 1
Macrophage Activation Syndrome (MAS) Overlap
MAS itself can complicate Still's disease but must be differentiated from primary hemophagocytic lymphohistiocytosis (HLH), which can present similarly 1, 5
Distinguishing Features to Aid Diagnosis
- Marked elevation of IL-18 and/or S100 proteins (such as calprotectin) strongly supports Still's disease diagnosis when available, though validated thresholds are still being established 1
- The characteristic salmon-pink evanescent rash of Still's disease, while not pathognomonic, is a helpful distinguishing feature 2, 5
- Negative tests for IgM rheumatoid factor and antinuclear antibodies are characteristic of Still's disease 2
- Extremely elevated ferritin levels (often >5 times normal) with low glycosylated ferritin fraction support Still's disease 1
Systematic Approach to Evaluation
When evaluating a patient with suspected Still's disease, the 2024 EULAR/PReS guidelines emphasize that alternative diagnoses must be carefully considered through a comprehensive differential diagnostic workup before initiating immunosuppressive therapy 1. This includes appropriate investigations based on specific clinical features: cultures and serologies for infections, imaging and biopsies for malignancies, genetic testing for monogenic disorders, and autoantibody panels for other autoimmune conditions 1.