What treatments are used for autoinflammatory disorders?

Treatments for Autoinflammatory Disorders

IL-1 blocking therapies are the cornerstone of treatment for most autoinflammatory disorders, with specific agents selected based on the underlying condition, disease severity, and patient characteristics. 1

Classification of Autoinflammatory Disorders

Autoinflammatory disorders are characterized by dysfunction of the innate immune system resulting in recurrent episodes of systemic inflammation. These can be broadly categorized into:

1. IL-1 mediated autoinflammatory disorders:

   • Cryopyrin-Associated Periodic Syndromes (CAPS)
   • Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)
   • Mevalonate Kinase Deficiency (MKD)/Hyperimmunoglobulin D Syndrome (HIDS)
   • Deficiency of IL-1 Receptor Antagonist (DIRA)
   • Familial Mediterranean Fever (FMF)

2. Other monogenic disorders:

   • Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) syndrome

3. Polygenic/complex disorders:

   • Adult-onset Still's disease (AOSD)
   • Systemic Juvenile Idiopathic Arthritis (SJIA)

Treatment Approach by Disorder Type

IL-1 Mediated Autoinflammatory Disorders

CAPS (NLRP3-AID)

• First-line therapy:
  • Canakinumab: 2-8 mg/kg every 8 weeks for pediatric patients; 150-600 mg every 8 weeks for adults >40 kg 1
  • Rilonacept: Loading dose 4.4 mg/kg followed by maintenance dose 2.2 mg/kg weekly for pediatric patients; loading dose 320 mg followed by 160 mg weekly for adults 1
  • Anakinra: 1-2 mg/kg/day 1

TRAPS

• First-line therapy:
  • Canakinumab: 2-4 mg/kg every 4 weeks for pediatric patients; 150-300 mg every 4 weeks for adults >40 kg 1
  • Anakinra can be used but has shown less sustained response 1

MKD/HIDS

• First-line therapy:
  • Canakinumab: 2-4 mg/kg every 4 weeks for pediatric patients; 150-300 mg every 4 weeks for adults >40 kg 1
  • On-demand treatment may be sufficient for milder phenotypes 1
  • Anti-TNF agents may be considered if IL-1 blockade is ineffective or unavailable 1

DIRA

• First-line therapy:
  • Anakinra: 1-8 mg/kg/day 1
  • Rilonacept: 4.4 mg/kg weekly for pediatric patients; 320 mg weekly for adults 1

FMF

• First-line therapy: Colchicine
• For colchicine-resistant cases: IL-1 blockers (canakinumab or anakinra) 2

Adult-onset Still's Disease (AOSD)

• First-line therapy:

  • NSAIDs and corticosteroids for mild cases 1
  • IL-1 inhibitors (anakinra, canakinumab) for moderate to severe disease 3
  • IL-6 inhibitors (tocilizumab) as alternative 1

• Second-line therapy:

  • Methotrexate, leflunomide, or other conventional DMARDs 1
  • TNF inhibitors may be considered in refractory cases 1

Systemic Juvenile Idiopathic Arthritis (SJIA)

• First-line therapy:
  • IL-1 inhibitors (anakinra, canakinumab) or IL-6 inhibitors (tocilizumab) as initial monotherapy 1
  • Canakinumab dosing: 4 mg/kg (maximum 300 mg) every 4 weeks for patients ≥7.5 kg 3

Treatment Monitoring and Considerations

Treatment Goals

• Early control of disease activity
• Prevention of disease and treatment-related damage
• Optimal health-related quality of life
• Ultimate goal: complete remission 1

Monitoring Parameters

• Clinical symptoms using daily symptom diary scores or Auto-inflammatory Diseases Activity Index (AIDAI)
• Physician global assessment (PGA) and patient/parent global assessment (PPGA)
• Inflammatory markers: CRP (<5-10 mg/L indicates adequate control), ESR, SAA where available 1

Vaccination Considerations

• Non-live vaccines can be safely administered regardless of immunosuppressive therapy 1
• Live-attenuated vaccines should be used with caution and generally avoided during periods of high immunosuppression 1
• Annual influenza and pneumococcal vaccination strongly recommended 1
• COVID-19 vaccines: Theoretical concerns about disease flares with RNA vaccines, but insufficient data for specific recommendations 1

Special Populations

Pregnancy

• Limited data on IL-1 treatment in pregnancy
• Benefit-risk discussion should occur before conception
• Current evidence supports anakinra over other IL-1 inhibitors during pregnancy 1

Pediatric to Adult Transition

• Continuous and developmentally appropriate care during and beyond adolescence
• Careful monitoring for complications like amyloidosis, hearing loss, and vision loss 1

Complications and Monitoring

• Amyloidosis: Evaluate proteinuria every 6 months, particularly in patients with positive family history 1
• Systemic JIA-associated lung disease: Monitor for digital clubbing, especially in younger patients with MAS, history of reactions to tocilizumab, or trisomy 21 1
• Infections: Monitor for increased risk, especially with biological therapies 3

Treatment Algorithm

1. Diagnosis confirmation based on clinical presentation, genetic testing, and exclusion of other causes
2. Assess disease severity and specific autoinflammatory syndrome type
3. For IL-1 mediated disorders: Start with appropriate IL-1 blocking agent based on specific diagnosis
4. For AOSD/SJIA: Consider IL-1 or IL-6 inhibitors as first-line therapy
5. Monitor response using clinical symptoms and inflammatory markers
6. Adjust therapy based on response:
   • If inadequate response to initial dose, increase dose or frequency
   • If failure with one class of biologics, switch to alternative mechanism (e.g., TNF inhibitors)
7. Long-term monitoring for complications and disease control

IL-1 blocking therapies have revolutionized the management of autoinflammatory disorders, dramatically improving outcomes and quality of life for these patients.