Still's Disease: Differential Diagnosis, Mimicking Conditions, and Diagnostic Approach

What is a differential diagnosis of Still's disease?

A differential diagnosis of Still's disease involves systematically evaluating other conditions that present with similar symptoms, such as high fever, rash, joint pain, and elevated inflammatory markers, to ensure an accurate diagnosis and appropriate treatment.

Understanding Still's Disease

Still's disease, also known as Adult-Onset Still's Disease (AOSD) in adults and Systemic Juvenile Idiopathic Arthritis (sJIA) in children, is a rare, systemic inflammatory condition. It is characterized by a classic triad of high spiking fevers, a transient salmon-pink rash, and joint pain or arthritis. Other common features include sore throat, lymphadenopathy (swollen lymph nodes), hepatosplenomegaly (enlarged liver and spleen), serositis (inflammation of the lining of organs like the heart or lungs), and significantly elevated inflammatory markers like C-reactive protein (CRP) and ferritin. Due to its non-specific symptoms, diagnosing Still's disease can be challenging, necessitating a thorough process of differential diagnosis.

The Concept of Differential Diagnosis

Differential diagnosis is a systematic clinical process used by healthcare professionals to distinguish a particular disease or condition from others that present with similar signs and symptoms. It involves:

• Listing potential causes: Generating a list of all possible conditions that could explain the patient's symptoms.
• Gathering evidence: Collecting more information through detailed history, physical examination, laboratory tests, and imaging studies.
• Refining the list: Eliminating unlikely conditions and narrowing down the possibilities based on the evidence.
• Confirming the diagnosis: Arriving at the most probable diagnosis, often by excluding other conditions.

For Still's disease, this process is crucial because its symptoms overlap significantly with a wide array of infectious, malignant, and other inflammatory conditions.

Key Features Guiding the Diagnosis of Still's Disease

While Still's disease lacks a single diagnostic test, certain clinical and laboratory features are highly suggestive and help guide the differential diagnosis:

• Quotidian Fever Pattern: Daily temperature spikes, often reaching 102°F (39°C) or higher, typically occurring once a day, usually in the late afternoon or evening, and returning to normal or below normal without antipyretics.
• Evanescent Rash: A non-itchy, salmon-pink macular or maculopapular rash that often appears during fever spikes and fades as the fever subsides. It commonly affects the trunk and proximal extremities.
• Arthralgia/Arthritis: Joint pain is common, evolving into frank arthritis in many cases, often affecting wrists, knees, and ankles.
• Sore Throat: A common initial symptom, often preceding other manifestations.
• Leukocytosis: A marked increase in white blood cells (neutrophils).
• Elevated Ferritin: Extremely high serum ferritin levels (often >1000 ng/mL) are a hallmark, though not exclusive, of Still's disease. Glycosylated ferritin levels may be particularly helpful.
• Negative Autoantibodies: Absence of rheumatoid factor (RF) and antinuclear antibodies (ANA) is typical, helping to differentiate it from other autoimmune diseases.

Conditions Mimicking Still's Disease

The differential diagnosis of Still's disease is extensive and includes various categories of conditions:

• Infections:
  • Bacterial Infections: Sepsis, bacterial endocarditis, osteomyelitis, Lyme disease, tuberculosis. These can cause fever, elevated inflammatory markers, and sometimes joint pain. Differentiated by positive cultures, specific antibodies, or imaging.
  • Viral Infections: Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), Human Immunodeficiency Virus (HIV), Parvovirus B19, enteroviruses. These often cause fever, rash, lymphadenopathy, and arthralgia. Differentiated by specific viral serologies or PCR.
  • Parasitic Infections: Malaria, toxoplasmosis.
• Malignancies:
  • Lymphoma (especially Non-Hodgkin Lymphoma): Can present with fever, weight loss, night sweats, lymphadenopathy, and hepatosplenomegaly. Lymph node biopsy is critical for differentiation.
  • Leukemia: May cause fever, fatigue, bone/joint pain, and abnormal blood counts. Bone marrow biopsy is diagnostic.
  • Myelodysplastic Syndromes (MDS): Can cause fevers and cytopenias.
  • Other Solid Tumors: Rarely, some carcinomas can present with paraneoplastic syndromes mimicking inflammatory conditions.
• Other Rheumatic and Autoimmune Diseases:
  • Systemic Lupus Erythematosus (SLE): Shares fever, rash, arthritis, and serositis. Differentiated by positive ANA, anti-dsDNA, and specific organ involvement (e.g., kidney, CNS).
  • Rheumatoid Arthritis (RA): Still's disease can evolve into a chronic polyarthritis resembling RA. Differentiated by positive RF and anti-CCP antibodies, and different patterns of joint erosion over time.
  • Vasculitis Syndromes: Such as polyarteritis nodosa or ANCA-associated vasculitis, can cause fever, rash, and multi-organ involvement. Differentiated by specific serologies, biopsy, and organ-specific manifestations.
  • Familial Mediterranean Fever (FMF) and Other Autoinflammatory Syndromes: These genetic disorders cause recurrent episodes of fever, serositis, and arthritis. Genetic testing is key for differentiation.
  • Reactive Arthritis: Follows a specific infection (e.g., gastrointestinal or genitourinary).
• Drug Reactions:
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome): A severe hypersensitivity reaction to certain medications (e.g., anticonvulsants, allopurinol) that can cause fever, rash, lymphadenopathy, and internal organ involvement (e.g., hepatitis, nephritis). A detailed drug history is crucial.
• Other Inflammatory Conditions:
  • Inflammatory Bowel Disease (IBD): Crohn's disease or ulcerative colitis can have extra-intestinal manifestations like fever, arthritis, and skin lesions. Primary gastrointestinal symptoms are usually present.
  • Sarcoidosis: A granulomatous disease that can cause fever, arthritis, lymphadenopathy, and organ involvement. Diagnosis often relies on biopsy showing non-caseating granulomas.
  • Thyroiditis (Subacute): Can cause fever, malaise, and neck pain, sometimes mimicking systemic inflammation.

Diagnostic Approach and Challenges

The diagnosis of Still's disease is largely one of exclusion. There is no single definitive test. Clinicians rely on a combination of:

• Detailed Clinical History: Including fever patterns, rash characteristics, joint involvement, and other systemic symptoms.
• Thorough Physical Examination: Looking for lymphadenopathy, hepatosplenomegaly, and signs of serositis.
• Laboratory Tests:
  • Complete Blood Count (CBC): To assess leukocytosis.
  • Inflammatory Markers: ESR and CRP.
  • Serum Ferritin: Crucial for its often marked elevation.
  • Liver Function Tests (LFTs): To check for liver involvement.
  • Autoantibody Panel: ANA, RF, anti-CCP, ANCA to rule out other autoimmune conditions.
  • Blood Cultures and Viral Serologies: To exclude infectious causes.
  • Bone Marrow Biopsy and Lymph Node Biopsy: If malignancy is suspected.
• Imaging Studies: X-rays, MRI, or ultrasound may be used to assess joint damage or organ involvement.

The primary challenge in diagnosing Still's disease lies in its ability to mimic so many other conditions. This often leads to a delay in diagnosis, as extensive workups are required to rule out more common or life-threatening diseases.

Importance of Accurate Diagnosis

An accurate and timely diagnosis of Still's disease is paramount for several reasons:

• Appropriate Treatment: Initiating the correct treatment (often corticosteroids, NSAIDs, or biologic disease-modifying antirheumatic drugs like IL-1 or IL-6 inhibitors) can control inflammation, prevent joint damage, and manage systemic complications.
• Avoiding Inappropriate Therapies: Misdiagnosis can lead to unnecessary or harmful treatments for other conditions.
• Preventing Complications: Untreated Still's disease can lead to chronic arthritis, macrophage activation syndrome (a life-threatening complication), and other organ damage.
• Prognosis and Management: Understanding the diagnosis allows for proper long-term management, monitoring for complications, and patient education.

Conclusion

The differential diagnosis of Still's disease is a complex and often protracted process that requires a high index of suspicion, meticulous clinical evaluation, and a comprehensive battery of laboratory and imaging tests. By systematically ruling out a wide range of infectious, malignant, and other inflammatory conditions, healthcare providers can ultimately arrive at an accurate diagnosis, enabling the initiation of appropriate treatment and improving patient outcomes for this challenging systemic inflammatory disorder.