What is Still’s Disease?

Still’s disease is a rare systemic inflammatory disorder characterized by high spiking fevers, an evanescent salmon-colored rash, and inflammatory arthritis. It exists in two main forms: Systemic Juvenile Idiopathic Arthritis (SJIA) in children under 16 years and Adult-Onset Still’s Disease (AOSD) in adults. Rather than being distinct conditions, current research suggests they represent a disease continuum differentiated primarily by age of onset, with overlapping clinical features, pathogenesis, and treatment approaches.

Affected Body Parts/Organs

Still’s disease is a multi-system disorder that can affect numerous body parts and organs, including:

• Joints (commonly knees, wrists, and ankles)
• Skin (manifesting as the characteristic salmon-colored rash)
• Liver and spleen (hepatosplenomegaly)
• Lymph nodes (lymphadenopathy)
• Heart (pericarditis)
• Lungs (pleuritis, pneumonitis)
• Throat (pharyngitis)
• Blood cells (leukocytosis, anemia, thrombocytosis)
• Central nervous system (in severe cases)

Prevalence and Significance

Still’s disease is considered rare, with AOSD estimated to affect approximately 1-2 per 100,000 people. SJIA represents about 10-20% of all juvenile idiopathic arthritis cases. The disease affects men and women equally, with AOSD typically occurring in young adults between 16-35 years of age, though cases in older adults have been documented. The significance of Still’s disease lies in its potential severity, diagnostic challenges, and impact on quality of life. Without proper treatment, it can lead to long-term joint damage, disability, and potentially life-threatening complications such as macrophage activation syndrome (MAS).

2. History & Discoveries

First Identification and Discoverer

Still’s disease was first identified and described by Sir George Frederic Still, a British pediatrician, in 1896. In his landmark paper, he documented a distinct form of chronic joint disease in children that was different from other forms of arthritis known at that time. He described the characteristic features of fever, rash, lymphadenopathy, splenomegaly, and arthritis.

Adult-Onset Form Recognition

The adult form of the disease was not recognized until much later. In 1971, Eric Bywaters published his observations of 14 adult patients with symptoms similar to those described by Still in children. Bywaters coined the term “Adult-Onset Still’s Disease” (AOSD) to acknowledge the similarities with the pediatric condition.

Major Discoveries and Breakthroughs

Key milestones in Still’s disease research include:

• 1992: Development of the Yamaguchi criteria for diagnosing AOSD, which remains the most widely used diagnostic framework
• Early 2000s: Recognition of Still’s disease as an autoinflammatory disorder rather than an autoimmune disease
• 2000s-2010s: Identification of the central role of pro-inflammatory cytokines, particularly interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-18 (IL-18)
• 2016-present: Growing evidence supporting the concept of SJIA and AOSD as a disease continuum rather than separate entities
• Recent years: Development and FDA approval of targeted biological therapies, particularly IL-1 and IL-6 inhibitors

Evolution of Medical Understanding

Medical understanding of Still’s disease has evolved significantly over time:

• Initially classified as a variant of rheumatoid arthritis
• Later recognized as a distinct clinical entity
• Now understood as a polygenic, systemic autoinflammatory disorder
• Recent advances in understanding the pivotal role of innate immunity and cytokine dysregulation
• Recognition of two main phenotypic patterns: a systemic inflammatory pattern (driven by IL-1 and IL-18) and a chronic articular pattern (associated with IL-6 and TNF-α)
• Growing evidence for the involvement of inflammasome activation and macrophage/neutrophil dysfunction

3. Symptoms

Early Symptoms

The early manifestations of Still’s disease typically include:

• High, spiking fevers (≥39°C/102°F), often with one or two peaks daily
• Evanescent salmon-colored rash that often appears during fever spikes
• Severe fatigue and malaise
• Sore throat (pharyngitis)
• Myalgia (muscle pain)
• Arthralgia (joint pain) without obvious swelling
• Lymphadenopathy (swollen lymph nodes)
• Hepatosplenomegaly (enlarged liver and spleen)

Advanced-Stage Symptoms

As the disease progresses, patients may develop:

• Persistent inflammatory arthritis affecting multiple joints
• Joint destruction and deformity (in chronic cases)
• Chronic pain
• Serositis (inflammation of serous tissues), including pleuritis and pericarditis
• Pulmonary complications, including interstitial lung disease
• Myocarditis (inflammation of the heart muscle)
• Persistent hepatosplenomegaly

Common vs. Rare Symptoms

Common symptoms include:

• Fever (present in >95% of cases)
• Arthralgias and arthritis (60-100%)
• Rash (60-80%)
• Sore throat (50-75%)
• Lymphadenopathy (30-60%)
• Hepatosplenomegaly (30-50%)

Rare symptoms include:

• Neurological manifestations (seizures, aseptic meningitis)
• Renal involvement
• Abdominal pain
• Pulmonary hypertension
• Disseminated intravascular coagulation (DIC)
• Acute respiratory distress syndrome (ARDS)
• Thrombotic thrombocytopenic purpura

Symptom Progression

The pattern of symptom progression can vary significantly between individuals:

• Monophasic pattern: A single episode followed by complete remission
• Intermittent pattern: Recurrent flares with periods of remission
• Chronic pattern: Persistent symptoms, particularly arthritis
• Systemic-dominant course: Characterized by prominent systemic inflammation with minimal arthritis
• Articular-dominant course: Characterized by progressive destructive arthritis with fewer systemic features

In many cases, systemic symptoms predominate early in the disease course, while articular manifestations may become more prominent over time.

4. Causes

Biological and Environmental Causes

The exact cause of Still’s disease remains unknown, but it is considered a multifactorial disorder with several potential contributors:

Biological factors:

• Dysregulation of innate immunity
• Abnormal activation of macrophages and neutrophils
• Excessive production of pro-inflammatory cytokines (IL-1, IL-6, IL-18)
• Activation of the NLRP3 inflammasome
• Abnormalities in natural killer (NK) cell function

Environmental triggers:

• Viral infections (including rubella, mumps, Epstein-Barr virus, cytomegalovirus, parvovirus B19)
• Bacterial infections (including Yersinia enterocolitica, Mycoplasma pneumoniae)
• Recent reports of cases following COVID-19 infection or vaccination

Genetic and Hereditary Factors

While Still’s disease is not considered a classic hereditary disorder, genetic factors appear to play a role in susceptibility:

• No single causative gene has been identified
• Polygenic inheritance pattern more likely
• Associations with certain HLA alleles have been reported, though findings are inconsistent across populations
• Variants in genes involved in innate immunity may contribute to disease susceptibility
• Still’s disease is classified as a “complex genetic disease” with multiple genetic and environmental factors contributing to its development

Known Triggers

Reported triggers for Still’s disease flares include:

• Infections (viral and bacterial)
• Stress
• Pregnancy and postpartum period
• Medication reactions
• Surgical procedures
• Trauma

However, in many cases, no specific trigger can be identified.

5. Risk Factors

Who is Most at Risk

Still’s disease can affect individuals of any age, gender, or ethnicity, but certain patterns have been observed:

Age:

• SJIA: Typically affects children under 16 years, with peak incidence between 1-5 years
• AOSD: Most commonly affects young adults 16-35 years, though cases in older adults do occur

Gender:

• Equal gender distribution in both SJIA and AOSD
• Some studies suggest slightly higher prevalence in females with the articular form

Ethnicity:

• Reported in all ethnic groups
• No clear ethnic predominance, though incidence may vary by geographic region

Environmental, Occupational, and Genetic Factors

Environmental and occupational factors that may influence risk include:

• Exposure to certain infections
• Possible role of air pollution (limited evidence)
• No clear occupational risk factors identified

Genetic factors:

• Family history of autoimmune or autoinflammatory diseases may increase risk
• No clear Mendelian inheritance pattern
• Potential role for certain HLA types, though findings are inconsistent

Impact of Pre-existing Conditions

The relationship between pre-existing conditions and Still’s disease risk is not well-established. However:

• Prior history of autoimmune disorders may potentially increase risk
• Immune dysregulation from any cause could theoretically predispose to Still’s disease
• No strong evidence links specific medical conditions to increased Still’s disease risk

6. Complications

Potential Complications

Still’s disease can lead to various complications, including:

Acute complications:

• Macrophage Activation Syndrome (MAS): A potentially life-threatening hyperinflammatory state characterized by excessive activation of macrophages and T cells
• Disseminated Intravascular Coagulation (DIC)
• Myocarditis
• Pericarditis and cardiac tamponade
• Acute respiratory distress syndrome (ARDS)
• Fulminant hepatitis
• Thrombotic thrombocytopenic purpura

Chronic complications:

• Joint destruction and deformity
• Functional disability
• Growth retardation (in children)
• Amyloidosis (rare)
• Psychological issues (depression, anxiety)
• Chronic pain
• Drug-related adverse effects

Long-term Impact on Organs and Overall Health

The long-term impact varies depending on disease severity, pattern, and treatment response:

Musculoskeletal system:

• Joint destruction and ankylosis (particularly of wrists and carpal joints)
• Decreased range of motion
• Muscle atrophy
• Osteoporosis (partly related to long-term corticosteroid use)

Cardiovascular system:

• Chronic pericarditis
• Myocardial fibrosis
• Increased risk of cardiovascular disease

Respiratory system:

• Interstitial lung disease
• Pulmonary fibrosis
• Pulmonary hypertension

Neurological system:

• Cognitive impairment (rare)
• Peripheral neuropathy

General health:

• Chronic fatigue
• Decreased quality of life
• Psychological impact of chronic disease

Disability and Fatality Rates

Disability rates:

• Approximately 30-50% of patients with AOSD develop chronic arthritis
• Among these, a significant proportion may experience functional limitations
• Modern biologic therapies have substantially reduced disability rates

Fatality rates:

• Overall mortality is low with appropriate treatment
• Most deaths are associated with MAS, which occurs in 5-10% of Still’s disease cases
• MAS has a mortality rate of 10-20% if not promptly recognized and treated
• Other causes of mortality include severe infections (often related to immunosuppressive therapy) and severe organ involvement

7. Diagnosis & Testing

Common Diagnostic Procedures

Diagnosis of Still’s disease is challenging due to its rarity and the nonspecific nature of many symptoms. It is largely a diagnosis of exclusion, requiring the elimination of other potential causes of similar symptoms.

Clinical evaluation:

• Comprehensive medical history
• Detailed physical examination
• Documentation of fever patterns
• Evaluation of rash characteristics
• Joint examination

Medical Tests

Laboratory tests:

• Complete blood count (typically shows leukocytosis with neutrophil predominance, anemia, thrombocytosis)
• Inflammatory markers: Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically markedly elevated
• Serum ferritin: Often extremely elevated (>1000 ng/mL), with decreased glycosylated fraction
• Liver function tests: Often show abnormalities, particularly elevated transaminases
• Serum albumin: Often decreased
• Coagulation studies: May show abnormalities, particularly in cases with MAS
• Autoantibody testing: Rheumatoid factor (RF) and antinuclear antibodies (ANA) are typically negative (important for differential diagnosis)

Imaging studies:

• X-rays: May be normal early in the disease; can show joint space narrowing, erosions, or ankylosis in chronic cases
• Ultrasound: Can detect joint effusions and synovitis
• MRI: More sensitive for detecting early joint changes and soft tissue inflammation
• CT scan: May be used to assess lymphadenopathy or visceral involvement
• Echocardiography: To assess for pericarditis or myocarditis

Other procedures:

• Joint fluid analysis: Shows inflammatory characteristics but is nonspecific
• Bone marrow examination: May be performed if MAS is suspected
• Lymph node biopsy: Sometimes performed to exclude lymphoma
• Skin biopsy: May show nonspecific inflammation

Diagnostic Criteria

Several sets of classification criteria have been developed, with the Yamaguchi criteria (1992) being the most widely used for AOSD:

Yamaguchi criteria: Major criteria:

1. Fever ≥39°C lasting ≥1 week
2. Arthralgia or arthritis lasting ≥2 weeks
3. Typical salmon-colored rash
4. Leukocytosis (≥10,000/mm³) with ≥80% neutrophils

Minor criteria:

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

For diagnosis, 5 or more criteria are required, including at least 2 major criteria, after excluding infections, malignancies, and other rheumatic diseases.

Fautrel criteria (2002) is another set of criteria that incorporates ferritin levels.

Early Detection Methods and Effectiveness

Early detection challenges:

• Initial symptoms often mimic common infections
• Lack of specific biomarkers
• Need to exclude numerous other conditions

Potential early indicators:

• Persistent fever unresponsive to antibiotics
• Characteristic fever pattern (1-2 daily spikes with return to normal)
• Rash coinciding with fever spikes
• Markedly elevated ferritin
• Neutrophilic leukocytosis without evidence of infection

Diagnostic delays are common, with many patients experiencing symptoms for months before diagnosis. Early recognition is facilitated by awareness of the characteristic symptom pattern and prompt testing for inflammatory markers and ferritin.

8. Treatment Options

Standard Treatment Protocols

Treatment approaches are tailored to disease severity, pattern, and individual patient factors. General strategies include:

First-line treatments:

• Non-steroidal anti-inflammatory drugs (NSAIDs): For mild cases, particularly with predominant joint symptoms
• Glucocorticoids (prednisone, methylprednisolone): Highly effective for controlling systemic features, used in moderate to severe disease
• Disease-modifying antirheumatic drugs (DMARDs): Methotrexate is most commonly used, particularly for articular disease

Second-line treatments:

• Biologic agents (detailed below)
• Calcineurin inhibitors (cyclosporine, tacrolimus): Sometimes used, particularly for cases with MAS

Medications, Surgeries, and Therapies

Medications:

• NSAIDs: Ibuprofen, naproxen, indomethacin
• Glucocorticoids: Prednisone, methylprednisolone (oral or intravenous)
• Conventional DMARDs: Methotrexate, leflunomide, hydroxychloroquine, sulfasalazine
• Biologic DMARDs:
  • IL-1 inhibitors: Anakinra, canakinumab, rilonacept
  • IL-6 inhibitors: Tocilizumab, sarilumab
  • TNF inhibitors: Infliximab, etanercept, adalimumab (generally less effective)
  • Others: Abatacept, rituximab (used in refractory cases)
• Janus kinase (JAK) inhibitors: Tofacitinib, baricitinib
• Calcineurin inhibitors: Cyclosporine, tacrolimus
• Intravenous immunoglobulin (IVIG): Used in severe cases, particularly with MAS

Surgeries:

• Joint replacement surgery: For patients with severe joint damage
• Synovectomy: Occasionally performed for chronic synovitis

Other therapies:

• Physical therapy: Important for maintaining joint function
• Occupational therapy: For adaptive strategies
• Psychological support: To address the mental health impact of chronic disease

Emerging Treatments and Clinical Trials

Recent and ongoing research has focused on targeted therapies:

Approved biological treatments:

• IL-1 inhibitors: Now considered first-line biological therapy for systemic AOSD
• IL-6 inhibitors: Particularly effective for the articular phenotype

Emerging treatments under investigation:

• IL-18 inhibitors: Tadekinig alfa (IL-18 binding protein)
• JAK inhibitors: Showing promise in early studies
• Selective sphingosine 1-phosphate (S1P) receptor modulators
• Granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors: Mavrilimumab
• Combination therapies with different biological agents

Recent trend toward earlier use of biological therapies, with some evidence suggesting better outcomes with earlier intervention.

9. Prevention & Precautionary Measures

Preventive Strategies

Since the exact cause of Still’s disease remains unknown, primary prevention is limited. However:

• No specific preventive measures have been definitively established
• Early diagnosis and treatment can prevent complications
• Regular monitoring for complications, particularly MAS, is essential
• Addressing and managing potential triggers may help prevent flares

Lifestyle Changes and Environmental Precautions

While no specific lifestyle modifications have been proven to prevent Still’s disease, general recommendations include:

• Regular exercise (adapted to disease activity and joint involvement)
• Balanced nutrition
• Adequate rest and stress management
• Avoiding known trigger factors for individual patients
• Prompt treatment of infections
• Regular medical follow-up

Vaccines and Preventive Screenings

Regarding vaccines:

• No vaccines prevent Still’s disease
• Routine immunizations are generally recommended, with special considerations for patients on immunosuppressive therapies
• Live vaccines are typically contraindicated for patients on high-dose steroids or biologic agents
• Annual influenza vaccination is recommended
• COVID-19 vaccination is generally recommended, though a few case reports have described AOSD flares following vaccination

Preventive screenings:

• Regular monitoring of disease activity
• Screening for medication side effects
• Monitoring for complications
• Tuberculosis screening before initiation of biologic therapies
• Hepatitis B and C screening before immunosuppressive therapy
• Cardiovascular risk assessment

10. Global & Regional Statistics

Incidence and Prevalence Rates

Global incidence and prevalence:

• AOSD: Estimated incidence of 0.16-0.4 per 100,000 persons per year
• Prevalence of AOSD: Approximately 1-2 per 100,000 population
• SJIA: Represents about 10-20% of all juvenile idiopathic arthritis cases
• Prevalence of SJIA: Approximately 1-10 per 100,000 children

Regional variations:

• Limited data on regional differences in incidence and prevalence
• Some studies suggest higher rates in Asian populations, but this may reflect reporting bias
• Prevalence appears similar across most studied populations

Mortality and Survival Rates

Mortality rates:

• Overall mortality is relatively low with modern treatment
• Most deaths are associated with MAS (10-20% mortality in MAS cases)
• 5-year survival rates exceed 95% with appropriate treatment
• Long-term life expectancy may be reduced in severe cases with significant organ involvement

Country-wise Comparison and Trends

Limited data exists on country-specific prevalence, but available information suggests:

• Similar prevalence across North America, Europe, and Asia
• Potential underdiagnosis in regions with limited healthcare access
• Increasing recognition in recent decades, leading to apparent increases in prevalence that likely reflect improved diagnosis rather than true increases in disease occurrence
• Higher reported rates of AOSD complications in some developing regions, potentially due to delayed diagnosis and treatment

Recent global trends:

• Improved outcomes with earlier diagnosis and biological therapies
• Decreasing rates of severe complications and disability
• Growing recognition of the disease continuum concept across pediatric and adult rheumatology
• Increasing research focus on personalized treatment approaches based on disease phenotype

11. Recent Research & Future Prospects

Latest Advancements in Treatment and Research

Recent significant advancements include:

Pathophysiology understanding:

• Recognition of Still’s disease as an autoinflammatory syndrome
• Identification of key inflammatory pathways and cytokines
• Better understanding of the role of the inflammasome
• Recognition of different disease phenotypes with distinct cytokine profiles

Treatment advances:

• FDA approval and widespread adoption of IL-1 and IL-6 inhibitors
• Growing evidence for effectiveness of JAK inhibitors
• Development of treatment algorithms based on disease phenotype
• Emerging evidence on optimal timing and duration of biological therapy
• Recognition that early intervention with biologics may improve outcomes

Diagnostic advances:

• Refined understanding of ferritin’s role as a biomarker
• Development of new biomarkers, including IL-18
• Improved classification criteria for MAS
• Better differentiation between disease flares and MAS

Ongoing Studies

Current areas of active research include:

Clinical studies:

• Optimal timing and duration of biological therapy
• Comparative effectiveness of different biological agents
• Identification of predictors of treatment response
• Long-term safety of biological therapies
• Prevention and treatment of MAS

Basic science research:

• Genetic factors influencing disease susceptibility and severity
• Detailed mechanisms of innate immune dysregulation
• Role of specific inflammasome components
• Environmental triggers and their interaction with genetic factors
• Biomarker development for personalized medicine approaches

Potential Cures or Innovative Therapies

While a definitive cure remains elusive, innovative approaches under investigation include:

Targeted therapies:

• Next-generation cytokine inhibitors with improved efficacy and convenience
• Combined cytokine blockade approaches
• IL-18 inhibition strategies
• Small molecule inhibitors of specific inflammatory pathways
• Cell-based therapies, including mesenchymal stem cells

Predictive medicine:

• Genetic and biomarker profiling to guide personalized treatment
• Early intervention strategies to prevent chronic disease
• Risk stratification tools to identify patients at risk for severe complications

Future directions:

• Better understanding of disease heterogeneity to guide precision medicine
• Development of curative approaches targeting the root causes of immune dysregulation
• Improved strategies to prevent and treat MAS
• Novel drug delivery systems for improved treatment adherence and reduced side effects

12. Interesting Facts & Lesser-Known Insights

Uncommon Knowledge

Lesser-known aspects of Still’s disease include:

• The “Still’s rash” often intensifies with heat or friction (Koebner phenomenon)
• Ferritin levels in Still’s disease can reach extraordinarily high levels (>10,000 ng/mL), higher than almost any other condition
• Still’s disease can mimic certain malignancies, particularly lymphoma
• Sir George Still, who first described the disease, was also known for describing attention deficit hyperactivity disorder
• The disease shows a remarkable response to IL-1 blockade, often with dramatic improvement within hours to days
• The salmon-colored rash is often transient and may be missed if not specifically looked for during fever spikes

Myths and Misconceptions vs. Medical Facts

Common misconceptions:

• Myth: Still’s disease is a form of rheumatoid arthritis Fact: It is a distinct autoinflammatory disorder with different pathophysiology
• Myth: Still’s disease only affects children Fact: It can occur at any age, with adult-onset cases being well-documented
• Myth: Still’s disease always causes arthritis Fact: Some patients, particularly those with the systemic phenotype, may have minimal joint involvement
• Myth: Still’s disease is always a lifelong condition Fact: Some patients have a monophasic course with complete recovery
• Myth: High-dose steroids are always necessary for treatment Fact: With modern biological therapies, steroid doses can often be minimized or eliminated

Impact on Specific Populations

Unique considerations for specific populations:

Pregnancy:

• Disease often improves during pregnancy but may flare postpartum
• Some medications require modification or discontinuation during pregnancy
• Successful pregnancies are possible with proper disease management

Elderly patients:

• AOSD in elderly patients (>65 years) may present with less typical features
• Higher risk of medication-related complications
• Often requires more careful monitoring

Pediatric patients:

• Growth and development considerations
• School and social impact
• Transition of care from pediatric to adult providers

Professional impact:

• Can affect educational and career trajectories
• Some occupations may be challenging with joint limitations
• Workplace accommodations may be necessary

With modern treatments, especially biological agents targeting specific cytokines, the long-term outlook for patients with Still’s disease has improved significantly. Many patients can achieve remission or low disease activity with appropriate therapy, allowing them to lead fulfilling lives with minimal disability.

References

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3. Giacomelli R, et al. (2021). International consensus on the clinical approach to adult-onset Still’s disease. Rheumatology (Oxford), 60(7):3052-3063.

4. Jamilloux Y, et al. (2019). Adult-onset Still’s disease. Autoimmunity Reviews, 18(9):102364.

5. Ruscitti P, et al. (2024). Recent advances and evolving concepts in Still’s disease. Nature Reviews Rheumatology, 20(2):116-132.

6. Nirmala N, et al. (2015). Gene-expression analysis of adult-onset Still’s disease and systemic juvenile idiopathic arthritis is consistent with a continuum of a single disease entity. Pediatric Rheumatology, 13:50.

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