Adult Still's Disease

 

Adult Still's Disease Presenting in the Intensive Care Unit: Recognition, Diagnosis, and Management Challenges

Dr Neeraj Manikath,Claude.ai

Abstract

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder that can present with life-threatening complications requiring intensive care unit (ICU) admission. The classic triad of high-spiking fever, arthralgia, and salmon-pink rash is often accompanied by hyperferritinemia, making differentiation from sepsis, hemophagocytic lymphohistiocytosis (HLH), and other hyperinflammatory syndromes challenging. This review examines the clinical presentation, diagnostic approach, and management of AOSD in critically ill patients, highlighting key diagnostic pearls and common pitfalls encountered in the ICU setting.

Keywords: Adult Still's disease, hyperferritinemia, intensive care, systemic inflammation, fever of unknown origin

Introduction

Adult-onset Still's disease (AOSD) is a rare systemic inflammatory disorder with an estimated annual incidence of 0.16-0.4 per 100,000 adults.¹ While most cases present with classic outpatient symptoms, approximately 15-20% of patients require ICU admission due to severe systemic complications.² The diagnosis becomes particularly challenging in the ICU setting, where the differential diagnosis includes sepsis, malignancy-associated fever, and other hyperinflammatory syndromes.

The condition was first described by Eric Bywaters in 1971 as the adult counterpart to systemic juvenile idiopathic arthritis (sJIA).³ Despite decades of research, AOSD remains a diagnosis of exclusion with no pathognomonic laboratory test or histological finding.

Clinical Presentation in the ICU

Pearl #1: The "Quotidian Fever" Pattern

The pathognomonic fever pattern in AOSD is quotidian (daily) with temperature spikes reaching 39-40°C, typically occurring in late afternoon or evening, followed by rapid defervescence to normal or subnormal temperatures.⁴ This pattern, when present, is highly suggestive of AOSD and differs from the sustained fever patterns commonly seen in sepsis.

Classic Manifestations

Systemic Features:

• High-spiking fever (>39°C) - present in 95% of patients
• Arthralgia/arthritis affecting knees, wrists, and ankles - 90%
• Characteristic salmon-pink, evanescent rash - 85%
• Sore throat (often the initial symptom) - 70%
• Lymphadenopathy - 65%
• Hepatosplenomegaly - 60%

Oyster #1: The Disappearing Rash

The salmon-pink, maculopapular rash of AOSD is notoriously evanescent, appearing with fever spikes and disappearing during afebrile periods. In the ICU, this rash may be missed during routine examinations if not specifically sought during febrile episodes. The rash demonstrates Koebner's phenomenon (appearing at sites of skin trauma) and is typically non-pruritic.⁵

Life-Threatening Complications Requiring ICU Care

1. Macrophage Activation Syndrome (MAS)

• Occurs in 10-15% of AOSD patients
• Presents with persistent fever, cytopenias, coagulopathy
• Mortality rate: 10-20%⁶

2. Acute Respiratory Distress Syndrome (ARDS)

• Pulmonary involvement in 20-30% of severe cases
• May present as acute pneumonitis or pleural effusions
• Often steroid-responsive⁷

3. Cardiac Complications

• Pericarditis (30-40% of cases)
• Myocarditis (rare but potentially fatal)
• Tamponade requiring immediate intervention⁸

4. Hepatic Dysfunction

• Acute hepatitis with transaminase elevation >1000 IU/L
• Fulminant hepatic failure (rare)
• Drug-induced liver injury from NSAIDs⁹

Laboratory Findings

Pearl #2: The Hyperferritinemia Clue

Serum ferritin levels are markedly elevated in AOSD, often exceeding 3000 ng/mL (normal: 15-300 ng/mL). More importantly, the glycosylated ferritin fraction is typically <20% in AOSD, compared to >50% in infectious or malignant causes of hyperferritinemia.¹⁰

Key Laboratory Parameters

Inflammatory Markers:

• ESR: typically >100 mm/hr
• CRP: markedly elevated (>100 mg/L)
• Leucocytosis: 15,000-20,000/μL with neutrophil predominance
• Thrombocytosis: common in active disease

Liver Function:

• Transaminase elevation (ALT/AST 2-5x normal)
• Elevated alkaline phosphatase and bilirubin
• Hypoalbuminemia

Negative Studies:

• Rheumatoid factor: negative
• ANA: negative (low-titer positive in <10%)
• Blood cultures: persistently negative

Hack #1: The Ferritin-to-ESR Ratio

A practical bedside calculation: Ferritin (ng/mL) ÷ ESR (mm/hr) ratio >21.5 has 79% sensitivity and 46% specificity for AOSD diagnosis.¹¹ While not diagnostic, this simple calculation can raise suspicion in febrile ICU patients.

Diagnostic Criteria and Challenges

Yamaguchi Criteria (1992) - Most Widely Used

Major Criteria:

1. Fever ≥39°C lasting ≥1 week
2. Arthralgia/arthritis ≥2 weeks
3. Typical rash
4. Leucocytosis ≥10,000/μL with ≥80% neutrophils

Minor Criteria:

1. Sore throat
2. Lymphadenopathy/splenomegaly
3. Liver dysfunction
4. Negative RF and ANA

Diagnosis requires: ≥5 criteria including ≥2 major criteria, plus exclusion of infections, malignancies, and other rheumatic diseases.¹²

Pearl #3: The "Exclusion Diagnosis" Challenge

AOSD remains a diagnosis of exclusion. In the ICU setting, this requires systematic evaluation for:

• Bacterial, viral, and fungal infections
• Hematologic malignancies (especially lymphoma)
• Autoimmune diseases (SLE, vasculitis)
• Drug-induced fever
• Hemophagocytic lymphohistiocytosis

Oyster #2: AOSD vs. Sepsis Differentiation

Distinguishing AOSD from sepsis in critically ill patients is challenging. Key differentiating features:

Feature	AOSD	Sepsis
Fever pattern	Quotidian, spiking	Sustained or irregular
Rash	Salmon-pink, evanescent	Variable, often petechial
Sore throat	Non-exudative, prominent	Usually absent
Ferritin	>3000 ng/mL, low glycosylation	Elevated but <3000 ng/mL
Procalcitonin	Normal or mildly elevated	Markedly elevated
Blood cultures	Negative	Often positive

Advanced Diagnostic Modalities

Hack #2: The 18F-FDG PET-CT Advantage

18F-FDG PET-CT shows characteristic patterns in AOSD:

• Diffuse bone marrow uptake
• Splenic uptake
• Lymph node involvement
• Joint inflammation
• Absence of focal infectious foci¹³

This imaging modality is particularly valuable when differentiating AOSD from occult malignancy or infection.

Biomarkers Under Investigation

IL-18 and IL-1β:

• Markedly elevated in active AOSD
• May correlate with disease activity
• Not yet in routine clinical use¹⁴

S100A8/A9 (Calprotectin):

• Elevated in active disease
• May predict treatment response
• Commercially available assays emerging¹⁵

Management in the ICU Setting

Pearl #4: The Steroid Response Test

A dramatic response to corticosteroids within 24-48 hours is characteristic of AOSD. This "therapeutic trial" can be both diagnostic and therapeutic, but should only be undertaken after excluding active infection.¹⁶

First-Line Treatment

Corticosteroids:

• Prednisolone 0.5-1.0 mg/kg/day
• Higher doses (1-2 mg/kg/day) for severe complications
• IV methylprednisolone for critically ill patients
• Expect rapid improvement in fever and symptoms¹⁷

NSAIDs:

• Limited utility in ICU patients due to organ dysfunction
• Naproxen 500 mg BID or indomethacin 150 mg/day
• Avoid in renal dysfunction or bleeding risk

Hack #3: The "Bridge Therapy" Approach

For critically ill patients where infection cannot be completely excluded:

1. Start broad-spectrum antibiotics
2. Simultaneously begin moderate-dose steroids (0.5 mg/kg prednisolone)
3. Monitor response over 48-72 hours
4. Discontinue antibiotics if cultures negative and steroid response confirms AOSD

Second-Line and Biologic Therapies

Methotrexate:

• 15-20 mg weekly
• Steroid-sparing agent
• Monitor for hepatotoxicity¹⁸

IL-1 Inhibitors (Anakinra):

• 100 mg subcutaneous daily
• Particularly effective for refractory cases
• Rapid onset of action (24-48 hours)
• Preferred for MAS complication¹⁹

IL-6 Inhibitors (Tocilizumab):

• 8 mg/kg IV monthly
• Alternative for anakinra-refractory cases
• Monitor for infections²⁰

TNF-α Inhibitors:

• Reserved for refractory arthritis
• Less effective for systemic features
• Higher infection risk in ICU patients²¹

Pearl #5: Managing Macrophage Activation Syndrome

MAS is the most feared complication of AOSD. Management principles:

• High-dose corticosteroids (methylprednisolone 10-30 mg/kg)
• Early IL-1 inhibition with anakinra
• Consider etoposide for refractory cases
• Cyclosporine as alternative immunosuppression
• Avoid biologics that may worsen cytokine storm²²

Prognosis and Long-term Outcomes

Disease Patterns

Monocyclic (30-40%):

• Single episode lasting <1 year
• Complete remission possible
• Best prognosis

Polycyclic (25-30%):

• Recurrent flares with intervening remissions
• May evolve to chronic arthritis
• Intermediate prognosis

Chronic Articular (30-40%):

• Persistent arthritis with minimal systemic features
• Joint destruction possible
• Requires long-term management²³

Oyster #3: The Transformation Phenomenon

AOSD can evolve over time, with initial systemic features giving way to chronic arthritis resembling rheumatoid arthritis. This transformation affects treatment strategies and long-term prognosis.

ICU-Specific Prognostic Factors

Favorable:

• Early diagnosis and treatment
• Good steroid response
• Absence of MAS
• Monocyclic pattern

Unfavorable:

• Delayed diagnosis (>3 months)
• MAS development
• Requirement for mechanical ventilation
• Multi-organ failure²⁴

Special Considerations in ICU Management

Hack #4: The Infection Monitoring Protocol

AOSD patients on immunosuppression require enhanced infection surveillance:

• Daily procalcitonin monitoring
• Serial blood cultures
• Fungal biomarkers (galactomannan, β-D-glucan)
• CMV/EBV monitoring
• Prophylactic antimicrobials in high-risk patients²⁵

Drug Interactions and Complications

Steroid-Related:

• Hyperglycemia requiring insulin protocols
• Increased infection risk
• Peptic ulcer prophylaxis
• Psychiatric complications

Biologic-Related:

• Immunosuppression
• Reactivation of latent infections
• Infusion reactions
• Cytopenias²⁶

Future Directions and Emerging Therapies

Novel Therapeutic Targets

JAK Inhibitors:

• Tofacitinib and baricitinib showing promise
• Oral administration advantage
• Rapid onset of action²⁷

IL-18 Inhibition:

• Tadekinig alfa under investigation
• Targets key cytokine in AOSD pathogenesis
• Early trials promising²⁸

Precision Medicine Approaches

Genetic Markers:

• HLA associations being defined
• Pharmacogenomics for drug selection
• Personalized treatment algorithms²⁹

Biomarker-Guided Therapy:

• IL-18 levels for treatment monitoring
• Ferritin kinetics for response assessment
• Cytokine profiles for drug selection³⁰

Clinical Pearls Summary

1. Quotidian fever pattern with afternoon/evening spikes is pathognomonic
2. Hyperferritinemia >3000 ng/mL with low glycosylated fraction suggests AOSD
3. Evanescent salmon-pink rash appears with fever and demonstrates Koebner phenomenon
4. Dramatic steroid response within 24-48 hours supports diagnosis
5. MAS development requires immediate aggressive immunosuppression

Take-Home Messages for ICU Practitioners

• Maintain high index of suspicion in young adults with fever of unknown origin
• Systematic exclusion of infections and malignancy remains crucial
• Early diagnosis and treatment improve outcomes significantly
• Steroid therapy should be initiated promptly once infection is excluded
• IL-1 inhibitors are game-changers for refractory cases and MAS
• Long-term rheumatologic follow-up is essential for all patients

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