Autoinflammatory disorders

Autoinflammatory disorders are a group of rare conditions caused by an overactive innate immune system leading to recurrent or persistent systemic inflammation. These disorders are broadly categorized as either monogenic (e.g., inflammasomopathies, interferonopathies) or polygenic (e.g., adult-onset Still disease). They typically manifest with recurrent fever with other signs of inflammation (e.g., rash, arthritis). Diagnosis is based on characteristic clinical features and the exclusion of common causes of fever (e.g., infection, malignancy). Initial diagnostics involve a clinical evaluation and laboratory studies (e.g., CBC, CMP, inflammatory markers), while genetic testing may be used for confirmation. Management aims to control inflammation and prevent complications. Treatment is specific to each condition and may involve symptomatic relief for acute attacks (e.g., NSAIDs or corticosteroids) and long-term prophylactic therapy (e.g., colchicine or targeted biologics).

Definition

• Autoinflammatory disorders are a group of rare conditions caused by an overactive innate immune system leading to recurrent or persistent inflammation. ^[1]
• Unlike in autoimmune conditions, an adaptive immune response is not the primary driver of inflammation but may still be present. ^[1][2]

Types of autoinflammatory disorders ^[3]

Over 40 autoinflammatory disorders have been identified. The following list is not exhaustive. ^[4]

Monogenic ^[4][4]

• Inflammasomopathies and other disorders of IL-1 regulation
  • Familial Mediterranean fever (FMF)
  • NLRP3-associated autoinflammatory disease
  • Mevalonate kinase deficiency (MKD; previously known as Hyper-IgD syndrome)
  • Pyrin-associated autoinflammation with neutrophilic dermatosis
  • PSTPIP1-associated arthritis, pyoderma gangrenosum, and acne
  • NLRC4-associated autoinflammatory disease
  • LPIN2-chronic nonbacterial osteomyelitis (Majeed syndrome)
  • Deficiency of IL-1 receptor antagonist (DIRA)
  • Deficiency of the interleukin-36 receptor antagonist
• Type I interferonopathy
  • Aicardi-Goutières syndrome (AGS)
  • STING-associated vasculopathy with onset in infancy (SAVI)
  • Proteosome-associated autoinflammatory syndromes
  • Singleton-Merten syndrome
• Disorders of tumor necrosis factor (TNF) and/or NF-κB regulation
  • TNF receptor-associated periodic syndrome (TRAPS)
  • Deficiency of adenosine deaminase 2 (DADA2)
  • NOD2-associated granulomatous disease
  • A20 haploinsufficiency (HA20)
• Other
  • Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome
  • Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay

Polygenic ^[2]

• Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome
• Systemic juvenile idiopathic arthritis
• Adult-onset Still disease
• Gout ^[2]
• Behçet disease ^[3]

Patients with autoinflammatory disorders typically present with recurrent features of inflammation. Manifestations differ by disease and may include: ^[2][3][5]

• Recurrent fever
• Rash (e.g., urticaria, vasculitis)
• Abdominal pain
• Arthritis and/or arthralgia
• Clinical features of pericarditis
• Lymphadenopathy and/or organomegaly
• Oral lesions
• Eye inflammation

Approach ^[2]

• Suspect autoinflammatory disorders in patients with any of the following:
  • Characteristic clinical features, e.g., recurrent fevers with rash and/or joint pain
  • Diagnostics for fever of unknown origin
  • Poor response to standard therapy for febrile conditions
• Perform a clinical evaluation and initial laboratory studies to assess for features of inflammation.
• Order additional diagnostics as indicated, e.g.:
  • Targeted testing to exclude alternative diagnoses
  • Genetic testing to evaluate for specific autoinflammatory disorders

Clinical evaluation ^[2][3]

• Symptom characteristics
  • Age at symptom onset
  • Features of systemic inflammation (e.g., arthralgia, rash, conjunctivitis)
  • Timing and degree of fevers and/or other symptoms
  • Triggers (e.g., infection, emotional stress)
• Family history of similar symptoms or a known autoinflammatory disorder
• Signs of genetic disorders (e.g., characteristic facial features)
• Children: assessment of pediatric growth and pediatric developmental history

Initial testing ^[2][3]

Obtain the following in all patients:

• CBC
• CMP
• Inflammatory markers (e.g., ESR, CRP, serum amyloid A)

Measure inflammatory markers during both active flares and asymptomatic intervals. Consider alternative diagnoses in patients without laboratory evidence of inflammation during active flares. ^[3]

Additional testing ^[2][3]

Consider the following in select patients, with specialist consultation as needed.

• Diagnostics to exclude alternative diagnoses, e.g.:
  • Bacterial cultures, viral serologies, and imaging: to exclude infection
  • Imaging: for suspected malignancy
  • Autoantibodies: for suspected autoimmune disease
  • Immunoglobulins, vaccine titers: for suspected immunodeficiency
  • Biopsies of affected sites
• Genetic testing: to detect a specific underlying autoinflammatory disorder

• Infection
• Malignancy
• Autoimmune disease (e.g., systemic lupus erythematosus, differential diagnoses of inflammatory arthritis)
• Immunodeficiency and/or immune dysregulation (e.g., cyclic neutropenia, congenital immunodeficiency syndromes) ^[6]
• Drug hypersensitivity reaction
• See also:
  • Etiology of fever of unknown origin
  • Causes of pediatric fever

The differential diagnoses listed here are not exhaustive.

General principles ^[7]

• Management is driven by a specialist and determined by the underlying disorder and its manifestations.
• Goals of treatment include:
  • Control of inflammation and symptoms
  • Prevention of complications (e.g., organ damage)
  • Improved quality of life
• Pharmacological treatment is targeted to the specific molecular abnormality, when known. ^[2]
• Response to treatment and disease progression can be monitored using:
  • Symptom diaries
  • Validated instruments for measuring disease activity
  • Laboratory studies (e.g., inflammatory markers)
• Manage associated conditions and complications.
  • Assistive devices: for musculoskeletal, visual, and/or hearing impairment
  • Genetic counseling: for known genetic abnormalities
  • Management of neurodevelopmental disorders

Pharmacological treatment ^[2][5]

Targeted biologic agents

• IL-1 inhibitors: for inflammasomopathies and other disorders of IL-1 regulation (e.g., FMF, MKD, DIRA)
• JAK inhibitors: for interferonopathies (e.g., AGS, SAVI)
• TNF inhibitors: disorders of TNF and/or NF-κB regulation (e.g., DADA2, HA20)

Nontargeted agents

• Nonsteroidal anti-inflammatory drugs: for symptomatic relief during acute attacks
• Colchicine: first-line prophylactic agent for select conditions (e.g., gout, FMF, PFAPA syndrome)
• Glucocorticoids: abortive therapy for select conditions (e.g., PFAPA syndrome, VEXAS syndrome)

Familial Mediterranean fever is a type of monogenic autoinflammatory inflammasomopathy characterized by recurrent fever, serositis, and elevated inflammatory markers, leading to chronic systemic inflammation. ^[8]

Epidemiology

• Most common type of monogenic autoinflammatory inflammasomopathy ^[8]
• Most prevalent in individuals of Middle Eastern or Mediterranean descent ^[3]

Etiology

• Genetic mutation in the MEFV gene ^[4][8][9]
• Triggers for attacks ^[10]
  • Emotional stress
  • Physical stress (e.g., infection, starvation, fatigue, trauma)
  • Menstruation

Clinical features ^[2][4][8]

FMF usually manifests in childhood and continues into adulthood. ^[8]

• Recurrent episodic attacks, typically lasting < 3 days and including one or more of the following: ^[4]
  • Fever
  • Abdominal and/or chest pain
  • Joint pain with possible swelling
  • Rash on the lower extremities resembling erysipelas
• Protracted febrile myalgia syndrome (PFMS) ^[8][11]
  • Severe, disabling myalgia in combination with fever and elevated inflammatory markers, lasting days to weeks
  • Other manifestations include abdominal pain, diarrhea, and vasculitic rash

Severe abdominal pain in FMF often resembles acute appendicitis. ^[12]

Diagnosis

• Diagnosis is clinical and requires specialist consultation.^[8][13]
• Laboratory studies can support the diagnosis and exclude alternative diagnoses; findings include: ^[8][10]
  • ↑ WBC ^[8]
  • ↑ inflammatory markers
  • Findings that suggest complications (e.g., proteinuria and/or ↑ creatinine in patients with amyloidosis)
• Advanced diagnostics may be ordered by a specialist.
  • Genetic testing: recommended for all patients but results may not be confirmatory
  • Diagnostics of amyloidosis (e.g., renal biopsy): to follow-up abnormal urinalysis ^[10]

Creatine kinase is typically normal in patients with PFMS; if elevated, suspect other causes of muscle pain (e.g., drug toxicity). ^[10]

Management ^[8]

Management is typically lifelong and guided by a rheumatologist.

• Nonpharmacological management
  • Lifestyle modifications (e.g., regular physical activity, sleep hygiene)
  • Consider referral for therapies to improve symptoms and functional status (e.g., cognitive behavioral therapy, physiotherapy).
• Pharmacological management
  • All patients: Colchicine is the preferred initial therapy. ^[8]
    • Colchicine should be taken daily for long-term prophylaxis, and the dosage should be maintained during acute attacks.
    • Monitoring for treatment response and toxicity (e.g., transaminitis) is typically performed every 3–6 months. ^[10]
    • Dosage may be adjusted in patients with breakthrough attacks or evidence of inflammation on blood work.
  • Patients with inadequate response to colchicine or adverse effects: Disease-modifying antirheumatic drugs are an alternative or adjunctive option.
  • Patients with acute attacks: Consider NSAIDs in addition to the normal dose of colchicine for symptom relief. ^[8]
  • Patients with PFMS: Treatment options include glucocorticoids, NSAIDs, and IL-1 inhibitors.

Complications ^[8][10]

• Reactive amyloidosis (most commonly affects the kidneys) ^[4]
• Chronic arthritis
• Vasculitis
• Liver disease

Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome is a polygenic autoinflammatory disorder that most commonly occurs in children. ^[3][6]

Epidemiology

• Most common autoinflammatory disease in children ^[6]
• Typically manifests before 5 years of age and resolves by adolescence ^[12]

Clinical features

• Recurrent episodes of high fever every 2–8 weeks, lasting 3–7 days ^[6]
• Prodromal fatigue and/or chills ^[12]
• Associated features during febrile episodes: ^[6]
  • Pharyngitis
  • Aphthous stomatitis
  • Cervical lymphadenopathy

Diagnosis

• Diagnosis is primarily clinical, based on: ^[2][13][14]
  • Characteristic clinical features
  • Absence of symptoms between episodes
  • Exclusion of other causes of symptoms (e.g., infection, cyclic neutropenia)
  • Normal growth and development
• Laboratory studies: Inflammatory markers are elevated during episodes of fever, but normal between episodes. ^[2]

Treatment

Consider the following treatment options in consultation with a specialist. ^[6]

• Pharmacological treatment
  • Corticosteroids (e.g., prednisone ): for abortive therapy ^[6]
  • Cimetidine or colchicine: for daily prophylaxis
  • Antipyretics: as supportive care for pediatric fever
• Surgery: Tonsillectomy with or without adenoidectomy may stop symptom recurrence. ^[15]