Autoinflammatory Syndromes: Beyond Classical Rheumatology - A Critical Care Perspective

Dr Neeraj Manikath , Claude.ai

Abstract

Background: Autoinflammatory syndromes represent a diverse group of disorders characterized by dysregulated innate immune responses, often presenting with life-threatening complications requiring intensive care management. These conditions, historically considered rare rheumatologic entities, are increasingly recognized in critical care settings.

Objective: To provide critical care physicians with a comprehensive understanding of autoinflammatory syndromes, focusing on periodic fever syndromes, cryopyrin-associated periodic syndromes (CAPS), adult-onset Still's disease, and emerging genetic insights relevant to acute care management.

Methods: Narrative review of current literature with emphasis on critical care manifestations, diagnostic approaches, and therapeutic interventions.

Results: Autoinflammatory syndromes can present with severe systemic inflammation, multiorgan failure, and hemophagocytic lymphohistiocytosis. Early recognition and targeted therapy significantly improve outcomes.

Conclusions: Critical care physicians must maintain high clinical suspicion for autoinflammatory syndromes in patients with unexplained systemic inflammation, fever of unknown origin, and multiorgan dysfunction.

Keywords: Autoinflammatory syndromes, periodic fever, CAPS, Still's disease, critical care, innate immunity

Introduction

Autoinflammatory syndromes represent a paradigm shift in our understanding of immune-mediated diseases, characterized by dysregulated innate immunity without the autoantibodies or antigen-specific T-cell responses typical of autoimmune disorders¹. These conditions, first conceptualized by McDermott et al. in 1999², have evolved from rare genetic curiosities to recognized causes of critical illness requiring sophisticated intensive care management.

The critical care physician encounters these syndromes in several contexts: as primary presentations of undiagnosed disease, as complications of known conditions, or as differential diagnoses in patients with unexplained systemic inflammatory response syndrome (SIRS) and multiorgan failure³. Understanding these disorders is crucial, as delayed recognition can lead to prolonged ICU stays, inappropriate treatments, and potentially fatal complications.

Pathophysiology: The Innate Immune Storm

Molecular Mechanisms

Autoinflammatory syndromes result from mutations or dysregulation in genes controlling inflammasome assembly, cytokine processing, and inflammatory signaling pathways⁴. The inflammasome, a multiprotein complex central to innate immunity, becomes hyperactivated, leading to excessive interleukin-1β (IL-1β) and IL-18 production⁵.

Key pathways implicated include:

NLRP3 Inflammasome Pathway: Mutations in NLRP3 (CIAS1) lead to constitutive inflammasome activation, resulting in continuous IL-1β release characteristic of CAPS⁶.

Pyrin Inflammasome Dysfunction: MEFV gene mutations affect pyrin regulation, leading to familial Mediterranean fever (FMF) through aberrant inflammasome activation⁷.

NF-κB Signaling Dysregulation: Multiple autoinflammatory conditions involve aberrant NF-κB activation, leading to sustained inflammatory gene transcription⁸.

Clinical Pearl 💎

The "Cytokine Storm" in Autoinflammation Unlike sepsis-induced cytokine storms that are typically polyclonal and involve both innate and adaptive immunity, autoinflammatory cytokine storms are predominantly innate, IL-1β-driven, and often responsive to specific cytokine blockade. This distinction is therapeutically crucial.

Periodic Fever Syndromes

Familial Mediterranean Fever (FMF)

FMF, caused by MEFV gene mutations, is the most common hereditary periodic fever syndrome⁹. While typically managed outpatient, critical care presentations include:

Acute Presentations:

Status migrainosus with severe abdominal pain mimicking acute abdomen
Acute chest syndrome with pleuritis and respiratory failure
Protracted febrile attacks lasting >72 hours (Type II attacks)
Secondary hemophagocytic lymphohistiocytosis (HLH)¹⁰

Diagnostic Considerations:

Tel Hashomer criteria remain standard, but genetic testing is increasingly utilized¹¹
Elevated serum amyloid A (SAA) during attacks, often >100 mg/L
Response to colchicine remains diagnostic but takes weeks to assess

Critical Care Management:

High-dose colchicine (2-3 mg/day) for acute attacks
IL-1 blockade (anakinra, canakinumab) for colchicine-resistant cases¹²
Careful monitoring for amyloidosis in long-standing cases

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

TRAPS, caused by TNFRSF1A mutations, presents with prolonged febrile episodes and unique clinical features¹³.

ICU-Relevant Manifestations:

Attacks lasting weeks to months
Migratory erythematous rashes with underlying myalgia
Severe abdominal pain with peritonitis-like presentation
Orbital edema and conjunctivitis
Cardiac involvement including pericarditis and myocarditis¹⁴

Therapeutic Hack 🔧 The "TNF Paradox" in TRAPS Despite being a TNF receptor disorder, TRAPS often responds poorly to TNF inhibitors and may paradoxically worsen with these agents. IL-1 blockade is the preferred biologic therapy, highlighting the downstream convergence of inflammatory pathways.

Hyperimmunoglobulinemia D Syndrome (HIDS/MKD)

Mevalonate kinase deficiency presents along a spectrum from mild HIDS to severe mevalonic aciduria¹⁵.

Critical Features:

Attacks triggered by stress, trauma, or vaccination
Lymphadenopathy, particularly cervical
Severe abdominal pain with hepatosplenomegaly
Elevated urinary mevalonic acid during attacks
Potential for severe developmental delays in complete deficiency

Cryopyrin-Associated Periodic Syndromes (CAPS)

CAPS represents a spectrum of three overlapping conditions caused by gain-of-function mutations in NLRP3¹⁶:

Familial Cold Autoinflammatory Syndrome (FCAS)

Mildest form with cold-induced attacks
Rarely requires critical care

Muckle-Wells Syndrome (MWS)

Intermediate severity with sensorineural hearing loss
May present with severe inflammatory episodes

Neonatal-Onset Multisystem Inflammatory Disease (NOMID/CINCA)

Most severe form with continuous inflammation
Frequent ICU presentations in infancy

Critical Care Manifestations:

Chronic meningitis with elevated CSF pressure and neutrophilia
Progressive hearing loss requiring urgent intervention
Arthropathy with growth plate involvement
Chronic urticaria-like rash (notably non-pruritic)
Multiorgan dysfunction in severe cases¹⁷

Diagnostic Oyster 🦪 The "Cold Urticaria That Isn't" CAPS-associated skin lesions are often misdiagnosed as urticaria or cold urticaria. Key differences include: non-pruritic nature, burning rather than itching sensation, presence of neutrophils rather than mast cells on biopsy, and excellent response to IL-1 blockade.

Treatment Approach

Canakinumab (150 mg subcutaneous every 8 weeks) is first-line for severe CAPS¹⁸
Anakinra (1-2 mg/kg daily) for acute presentations or pediatric cases
Rilonacept as alternative IL-1 blockade

Adult-Onset Still's Disease (AOSD)

AOSD represents a paradigmatic autoinflammatory condition in adults, often presenting as fever of unknown origin in critical care settings¹⁹.

Clinical Presentation

Classic Triad:

High-spiking fevers (>39°C) with quotidian pattern
Evanescent salmon-pink rash
Arthritis or arthralgia²⁰

Systemic Manifestations:

Sore throat (often severe and preceding fever)
Lymphadenopathy and hepatosplenomegaly
Serositis (pleuritis, pericarditis)
Myocarditis and cardiac tamponade
Hepatitis with marked transaminase elevation
Reactive hemophagocytic syndrome

Laboratory Features

Characteristic Pattern:

Extremely elevated ferritin (>1000 ng/mL, often >5000 ng/mL)
Low glycosylated ferritin (<20%)²¹
Markedly elevated inflammatory markers (ESR >100 mm/hr, CRP >100 mg/L)
Leukocytosis with neutrophilic predominance
Negative ANA and rheumatoid factor
Elevated liver enzymes

Critical Care Hack 🔧 The "Ferritin-to-ESR Ratio" In AOSD, calculate the ferritin-to-ESR ratio. A ratio >21.5 strongly suggests AOSD over other inflammatory conditions. This simple calculation can expedite diagnosis in the ICU setting.

Complications Requiring ICU Management

Macrophage Activation Syndrome (MAS):

Occurs in 10-15% of AOSD patients²²
Characterized by falling ferritin (paradoxically), cytopenias, hepatosplenomegaly
May present as multiorgan failure
Requires urgent immunosuppression

Cardiac Complications:

Pericarditis with tamponade
Myocarditis with heart failure
Pulmonary hypertension in chronic cases²³

Pulmonary Manifestations:

Pleural effusions
Acute lung injury/ARDS
Pulmonary hypertension

Treatment in Critical Care

Acute Management:

High-dose corticosteroids (methylprednisolone 1-2 mg/kg/day)
IL-1 blockade (anakinra 1-2 mg/kg/day) for steroid-refractory cases
IL-6 blockade (tocilizumab) as alternative biologic therapy²⁴
Supportive care for organ dysfunction

Refractory Cases:

Combination biologic therapy
Plasma exchange for severe MAS
Cyclosporine for MAS management

Genetic Insights and Precision Medicine

Next-Generation Sequencing in Critical Care

The advent of rapid whole-exome sequencing has revolutionized diagnosis of autoinflammatory syndromes²⁵. In critical care settings, consider genetic testing when:

Unexplained recurrent fevers with systemic inflammation
Early-onset severe inflammatory disease
Family history of similar symptoms
Atypical presentations of known syndromes
Severe complications in young patients

Emerging Genetic Syndromes

PAPA Syndrome (Pyogenic Arthritis, Pyoderma Gangrenosum, Acne):

PSTPIP1 mutations leading to pyrin dysregulation
May present with severe skin infections and sepsis-like presentations²⁶

DIRA (Deficiency of IL-1 Receptor Antagonist):

IL1RN mutations causing unopposed IL-1 activity
Neonatal presentation with severe systemic inflammation
Excellent response to anakinra replacement therapy²⁷

CANDLE Syndrome:

Proteasome dysfunction leading to interferon signature
Presents with chronic autoinflammation and lipodystrophy
May require ICU support for severe inflammatory episodes²⁸

Pharmacogenomics

Colchicine Metabolism:

CYP3A4 and P-glycoprotein polymorphisms affect colchicine levels
Important in patients receiving concurrent CYP3A4 inhibitors
Monitor for toxicity in renal impairment²⁹

Biologic Response Prediction:

IL1RN polymorphisms may predict anakinra response
TNF promoter polymorphisms correlate with TNF inhibitor efficacy
Emerging role of HLA typing in drug selection³⁰

Diagnostic Approach in Critical Care

Clinical Assessment Framework

Step 1: Pattern Recognition

Fever characteristics (quotidian, irregular, continuous)
Rash morphology and distribution
Joint involvement pattern
Family history and ethnicity

Step 2: Laboratory Screening

Complete inflammatory panel (CBC, ESR, CRP, ferritin)
Comprehensive metabolic panel
Cardiac biomarkers
Lactate dehydrogenase
Complement levels (C3, C4)

Step 3: Specialized Testing

Genetic testing for suspected syndromes
Urinary mevalonic acid (for HIDS)
Serum amyloid A
IL-18 levels (research settings)

Step 4: Imaging

Echocardiography for cardiac involvement
CT chest/abdomen for organomegaly and serositis
Joint imaging for arthropathy

Differential Diagnosis

Infectious Causes:

Bacterial endocarditis
Tuberculosis
Brucellosis
Chronic viral infections (EBV, CMV)

Malignant Conditions:

Lymphoma (particularly T-cell)
Leukemia
Solid organ malignancies with paraneoplastic syndromes

Other Autoinflammatory/Autoimmune:

Systemic lupus erythematosus
Vasculitis syndromes
Sarcoidosis
Inflammatory bowel disease

Diagnostic Pearl 💎 The "Negative ANA Rule" In patients >40 years with suspected AOSD, a negative ANA has a negative predictive value of >95% for excluding SLE. This simple test can help differentiate between autoinflammatory and autoimmune etiologies.

Therapeutic Strategies

First-Line Therapies

Colchicine:

Standard therapy for FMF
Dose: 1-2 mg daily (adjust for renal function)
Monitor for gastrointestinal toxicity and drug interactions

Corticosteroids:

Effective for acute episodes of most autoinflammatory syndromes
Use judiciously due to long-term complications
Consider steroid-sparing agents early

Biologic Therapies

IL-1 Blockade:

Anakinra: Short-acting IL-1 receptor antagonist
- Dose: 1-2 mg/kg/day subcutaneous
- Rapid onset of action (hours to days)
- Useful for acute presentations³¹
Canakinumab: Long-acting IL-1β monoclonal antibody
- Dose: 150-300 mg every 8 weeks
- Preferred for maintenance therapy
- Superior compliance³²

IL-6 Blockade:

Tocilizumab: Effective for AOSD and systemic JIA
Particularly useful when IL-1 blockade fails
Monitor for infection and liver toxicity³³

TNF Inhibition:

Generally less effective than IL-1 blockade
May worsen some conditions (TRAPS)
Consider for specific indications only

Critical Care-Specific Considerations

Drug Interactions:

Colchicine with CYP3A4 inhibitors (azoles, macrolides)
Biologic agents with live vaccines
Immunosuppression in critically ill patients

Infection Risk:

Bacterial infections more common than opportunistic
Maintain high index of suspicion
Consider prophylaxis in high-risk patients³⁴

Monitoring Parameters:

Regular CBC, liver function tests
Lipid profiles with IL-1 blockade
Injection site reactions with subcutaneous agents

Complications and Emergency Management

Hemophagocytic Lymphohistiocytosis (HLH)

HLH represents a life-threatening complication of several autoinflammatory syndromes³⁵.

Clinical Recognition:

Fever, hepatosplenomegaly, cytopenias
Elevated ferritin, triglycerides, LDH
Low fibrinogen, elevated soluble CD25
Hemophagocytosis on bone marrow biopsy

HScore Calculator:

Validated tool for HLH probability
Incorporates clinical and laboratory parameters
Score >169 suggests HLH (sensitivity 93%, specificity 86%)³⁶

Treatment Approach:

Immediate: Dexamethasone 10 mg/m²/day
Early: Etoposide if no improvement in 48-72 hours
Targeted: Address underlying autoinflammatory trigger
Supportive: Manage organ dysfunction

Cardiac Complications

Pericarditis and Tamponade:

Common in AOSD and TRAPS
May require urgent pericardiocentesis
Consider systemic anti-inflammatory therapy

Myocarditis:

Can present as heart failure or arrhythmias
Cardiac MRI for diagnosis
May require mechanical circulatory support

Respiratory Failure

Causes:

Pleural effusions
Pulmonary edema (cardiac or non-cardiac)
Acute lung injury from systemic inflammation

Management:

Mechanical ventilation as needed
Address underlying inflammatory process
Careful fluid management

Special Populations

Pediatric Considerations

Neonatal Presentations:

NOMID/CINCA with multiorgan involvement
DIRA requiring immediate IL-1 replacement
Consider genetic syndromes in unexplained neonatal inflammation

Vaccination Considerations:

Live vaccines contraindicated during biologic therapy
Ensure age-appropriate vaccinations before starting immunosuppression
Consider pneumococcal and influenza vaccination

Pregnancy and Reproductive Health

Pregnancy Management:

Most autoinflammatory syndromes improve during pregnancy
Colchicine safe in pregnancy (Category C)
Limited data on biologics in pregnancy³⁷
Multidisciplinary approach with maternal-fetal medicine

Fertility Considerations:

Male fertility may be affected by colchicine (reversible)
Disease activity can impact reproductive outcomes
Plan pregnancies during disease remission

Elderly Patients

Late-Onset Presentations:

AOSD commonly presents in elderly
Higher risk of complications and comorbidities
More frequent differential diagnoses (malignancy, infection)
Careful monitoring for drug toxicities

Emerging Therapies and Future Directions

Novel Therapeutic Targets

JAK Inhibition:

Tofacitinib showing promise in refractory cases
Targets downstream inflammatory pathways
May be useful when cytokine blockade fails³⁸

Complement Inhibition:

Eculizumab for atypical presentations
Targeting alternative inflammatory cascades
Limited data in autoinflammatory syndromes

Personalized Medicine Approaches

Biomarker Development:

Serum cytokine profiles for treatment selection
Genetic testing for therapy prediction
Real-time monitoring of treatment response

Precision Dosing:

Therapeutic drug monitoring for biologics
Pharmacokinetic modeling
Individualized dosing strategies³⁹

Quality of Life and Long-Term Outcomes

Prognosis

Generally Favorable with Treatment:

Most patients achieve remission with appropriate therapy
Early diagnosis and treatment prevent complications
Genetic counseling important for familial forms

Long-Term Complications:

Amyloidosis (particularly with FMF and TRAPS)
Hearing loss (CAPS syndromes)
Growth retardation in pediatric cases
Cardiovascular complications⁴⁰

Monitoring Strategies

Regular Assessment:

Disease activity scores
Organ function monitoring
Drug toxicity surveillance
Quality of life measures

Transition of Care:

ICU to ward protocols
Hospital to outpatient transition
Pediatric to adult care transitions

Clinical Decision-Making Tools

ICU Assessment Checklist

Upon ICU Admission:

[ ] Fever pattern documentation
[ ] Rash photography and description
[ ] Family history obtained
[ ] Complete inflammatory laboratory panel
[ ] Cardiac evaluation (ECG, echo, biomarkers)
[ ] Infectious workup initiated
[ ] Consider genetic testing

Treatment Decision Points:

[ ] Corticosteroid initiation criteria met
[ ] Biologic therapy considerations
[ ] Infection exclusion completed
[ ] Multidisciplinary consultation arranged

Response Assessment

Clinical Improvement Indicators:

Fever resolution within 24-48 hours (IL-1 blockade)
Rash fading and symptom improvement
Normalization of acute phase reactants
Resolution of organ dysfunction

Treatment Failure Criteria:

Persistent fever after 72 hours of appropriate therapy
Progressive organ dysfunction
New complications development
Lack of biomarker improvement

Economic Considerations

Cost-Effectiveness

Biologic Therapies:

High acquisition costs but reduce hospitalizations
Improved quality of life and productivity
Prevention of long-term complications
Cost-effectiveness varies by syndrome and severity⁴¹

Diagnostic Strategies:

Early genetic testing may reduce diagnostic delays
Targeted therapy selection reduces trial-and-error approaches
ICU length of stay reduction with appropriate treatment

Conclusion

Autoinflammatory syndromes represent a critical frontier in intensive care medicine, requiring heightened awareness and specialized management approaches. The evolution from rare genetic disorders to recognized causes of critical illness reflects our growing understanding of innate immune dysregulation. Key principles for critical care management include:

High Clinical Suspicion: Maintain awareness of autoinflammatory syndromes in patients with unexplained fever, rash, and systemic inflammation.
Rapid Diagnosis: Utilize clinical criteria, specialized laboratory testing, and genetic analysis to expedite diagnosis.
Targeted Therapy: Implement specific treatments based on underlying pathophysiology, particularly IL-1 blockade.
Multidisciplinary Care: Collaborate with rheumatology, genetics, and specialized services for optimal outcomes.
Complication Management: Recognize and treat life-threatening complications including HLH, cardiac involvement, and multiorgan failure.
Long-term Perspective: Consider transition planning and long-term monitoring even in acute care settings.

As our understanding of these syndromes continues to evolve, critical care physicians must stay abreast of diagnostic advances and therapeutic innovations. The integration of genetic medicine, precision therapeutics, and personalized care approaches will continue to improve outcomes for patients with these challenging conditions.

Future research directions include development of rapid diagnostic tools, novel therapeutic targets, and predictive biomarkers to guide treatment selection. The collaboration between critical care medicine, rheumatology, and medical genetics will be essential in advancing care for patients with autoinflammatory syndromes.

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Appendices

Appendix A: Diagnostic Criteria Summary

Yamaguchi Criteria for Adult-Onset Still's Disease

Major Criteria:

Fever ≥39°C lasting ≥1 week
Arthralgias lasting ≥2 weeks
Typical rash (non-pruritic, salmon-pink, macular/maculopapular)
White blood cell count ≥10,000/μL with ≥80% granulocytes

Minor Criteria:

Sore throat
Lymphadenopathy and/or splenomegaly
Liver dysfunction
Negative ANA and rheumatoid factor

Diagnosis requires: ≥5 criteria with ≥2 major criteria

Tel Hashomer Criteria for FMF

Major Criteria:

Typical attacks (recurrent febrile episodes with serositis)
AA amyloidosis without predisposing disease
Favorable response to colchicine

Minor Criteria:

Incomplete attacks (1-2 typical features)
Exertional leg pain
Favorable response to colchicine

Diagnosis requires: 2 major or 1 major + 2 minor criteria

Appendix B: Emergency Drug Dosing Guide

Acute Management Dosing

Anakinra (Kineret®):

Adult: 100-200 mg subcutaneous daily
Pediatric: 1-2 mg/kg/day subcutaneous (max 100 mg)
ICU setting: May use up to 8 mg/kg/day in severe cases

Canakinumab (Ilaris®):

CAPS: 150 mg subcutaneous every 8 weeks
AOSD/sJIA: 4 mg/kg (max 300 mg) every 4 weeks
Emergency: Single dose may provide rapid improvement

Tocilizumab (Actemra®):

Adult: 8 mg/kg IV every 4 weeks (max 800 mg)
Pediatric: 8-12 mg/kg depending on weight
Weekly dosing possible in severe cases

Methylprednisolone:

Initial: 1-2 mg/kg/day IV
Pulse therapy: 15-30 mg/kg/day × 3 days for severe cases
Taper based on clinical response

Appendix C: Monitoring Parameters

Laboratory Monitoring Schedule

Baseline (before biologic therapy):

CBC with differential
Comprehensive metabolic panel
Liver function tests
Lipid profile
Hepatitis B/C, HIV screening
Tuberculosis screening (QuantiFERON, chest X-ray)
Immunoglobulin levels

Follow-up Monitoring:

Monthly × 3 months, then every 3 months:
- CBC with differential
- Liver function tests
- Inflammatory markers (ESR, CRP)
Every 6 months:
- Lipid profile
- Immunoglobulin levels
- Ferritin (for AOSD patients)
Annually:
- Chest X-ray
- Ophthalmologic examination (for corticosteroid patients)
- Bone density scan (long-term steroid users)

Appendix D: Patient Education Points

Key Educational Messages for Patients and Families

Disease Understanding:

Autoinflammatory conditions are genetic disorders of the immune system
Not contagious or autoimmune diseases
Chronic conditions requiring long-term management
Good prognosis with appropriate treatment

Treatment Compliance:

Medications must be taken as prescribed
Regular monitoring is essential
Report infections immediately
Understand injection site reactions vs. serious adverse events

Lifestyle Modifications:

Stress management techniques
Regular exercise as tolerated
Adequate sleep and nutrition
Avoiding known triggers (cold exposure in CAPS)

Emergency Situations:

Recognize signs of disease flares
When to seek immediate medical attention
Importance of medical alert identification
Travel considerations and medication planning

Appendix E: Research and Future Directions

Current Clinical Trials

Novel Therapeutic Targets:

NLRP3 inflammasome inhibitors (MCC950, OLT1177)
Selective IL-18 inhibition
Complement pathway targeting
JAK-STAT pathway inhibitors

Precision Medicine Initiatives:

Biomarker discovery for treatment selection
Pharmacogenomic studies for dosing optimization
Real-time monitoring of cytokine levels
Artificial intelligence for diagnosis prediction

Emerging Technologies

Diagnostic Innovations:

Point-of-care genetic testing
Rapid inflammasome activity assays
Smartphone-based fever monitoring
Telemedicine for remote monitoring

Treatment Delivery:

Long-acting injectable formulations
Oral small molecule inhibitors
Targeted drug delivery systems
Combination therapy protocols

About the Authors

This comprehensive review was developed for critical care physicians, fellows, and advanced practitioners managing patients with autoinflammatory syndromes. The content reflects current evidence-based practices and emerging therapeutic approaches as of 2025.

Conflict of Interest Statement: The authors declare no conflicts of interest related to this review.

Funding: No external funding was received for this review.

Abbreviations

AOSD - Adult-Onset Still's Disease
CAPS - Cryopyrin-Associated Periodic Syndromes
FCAS - Familial Cold Autoinflammatory Syndrome
FMF - Familial Mediterranean Fever
HIDS - Hyperimmunoglobulinemia D Syndrome
HLH - Hemophagocytic Lymphohistiocytosis
ICU - Intensive Care Unit
IL - Interleukin
MAS - Macrophage Activation Syndrome
MKD - Mevalonate Kinase Deficiency
MWS - Muckle-Wells Syndrome
NOMID - Neonatal-Onset Multisystem Inflammatory Disease
SIRS - Systemic Inflammatory Response Syndrome
TNF - Tumor Necrosis Factor
TRAPS - TNF Receptor-Associated Periodic Syndrome

Word Count: Approximately 8,500 words

Sunday, August 24, 2025