What are the treatment options for TNF‑receptor associated periodic syndrome (TRAPS)?

Treatment Options for TRAPS

IL-1 blockade with anakinra or canakinumab is the first-line biologic therapy for TRAPS, with canakinumab being the only FDA-approved agent for this indication. 1, 2

First-Line Treatment Approach

Initial Management

• Short-term glucocorticoids can be used for acute flares, but responses often wane over time and patients require close monitoring for increased disease activity 1
• Glucocorticoids should not be used for long-term maintenance due to adverse effects, but remain useful during acute inflammatory attacks 1, 3

Biologic Therapy: IL-1 Inhibitors (Preferred)

Anakinra (IL-1 receptor antagonist)

• First IL-1 blocker successfully used in TRAPS patients in small series and observational registries 1
• Requires daily subcutaneous injections
• Effective for controlling systemic and organ-specific inflammatory manifestations 1

Canakinumab (anti-IL-1β monoclonal antibody) - FDA Approved

• Dosing: 150 mg subcutaneously every 4 weeks for patients >40 kg; 2 mg/kg for patients 15-40 kg 2
• Up-titration protocol: Patients with persistent disease activity (PGA ≥2 or CRP >10 mg/L without adequate reduction) can receive additional doses, with escalation to 300 mg (or 4 mg/kg) every 4 weeks if needed 2
• Efficacy data: In the pivotal TRAPS trial, 50% of patients randomized to canakinumab achieved complete response (resolution of index flare at Day 15 with no new flares through Week 16) compared to significantly lower rates with placebo 2
• Provides longer dosing intervals (monthly) compared to daily anakinra 2, 4

Second-Line and Alternative Options

TNF Inhibitors (Limited Efficacy)

• Etanercept may provide benefit in individual patients, but responses frequently wane over time 1, 5
• Patients on etanercept require vigilant monitoring for breakthrough disease activity 1
• Important caveat: Some patients do not respond to TNF inhibition at all, particularly those with structural TNFRSF1A mutations 5, 6

IL-6 Inhibition

• Tocilizumab has shown success in case reports and small series, particularly in patients who fail TNF inhibitors 6, 4
• One case series demonstrated sustained efficacy and good safety profile over 42 months of tocilizumab therapy 4
• Should be considered as an alternative when IL-1 blockade is unavailable or ineffective 1, 6

Treatment Algorithm

Step 1: Confirm genetic diagnosis with TNFRSF1A sequencing (deep sequencing may be needed for somatic mutations) 1

Step 2: Initiate IL-1 blockade (anakinra or canakinumab) as first-line biologic therapy 1, 2

Step 3: If IL-1 blockade unavailable or ineffective, switch to anti-TNF agents (etanercept preferred based on historical use) 1, 5

Step 4: For patients failing both IL-1 and TNF inhibition, consider IL-6 blockade with tocilizumab 6, 4

Monitoring Requirements

Inflammatory Markers (Every Visit)

• CRP and ESR to assess systemic inflammation 1
• Serum amyloid A (SAA) and S100 proteins where available 1
• Peripheral neutrophilia on CBC with differential 1

Amyloidosis Screening (Every 6 Months)

• Proteinuria evaluation is mandatory every 6 months in all TRAPS patients 1
• Particularly critical in patients with positive family history of amyloidosis or SAA1 genetic variants 1
• Chronic uncontrolled systemic inflammation predisposes to AA amyloidosis, which represents the most severe long-term complication 1, 3

Dose Adjustment Strategy

• Age-appropriate dose adjustments of IL-1 blocking treatment are required to maintain control of inflammatory manifestations and normalize laboratory markers 1
• Treatment goal is complete normalization of CRP/SAA, not just improvement 1, 2

Critical Clinical Pitfalls

Genetic variants that are NOT pathogenic (D41E, I57S, P75L, R121Q, N145S) do not cause true TRAPS, though patients may still have autoinflammatory symptoms requiring treatment with colchicine or biologics 1

Structural mutations (causing receptor conformation abnormalities) carry the highest risk of secondary amyloidosis and require the most aggressive monitoring and treatment 3, 7

Delayed treatment with IL-1 blockade increases risk of irreversible complications including amyloidosis, hearing loss, and vision loss 1

Inadequate inflammatory control despite subjective symptom improvement still places patients at risk for long-term organ damage—laboratory markers must normalize, not just improve 1, 2