Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study

Abstract

Objective: To investigate the efficacy of etanercept in improving the symptoms and underlying inflammation in patients with tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

Methods: Fifteen patients with TRAPS were enrolled in a prospective, open-label, dose-escalation study. Patients recorded attacks, symptom severity, and use of ancillary medications in a daily diary. Blood samples were collected during each period and measured for levels of acute-phase reactants. Between 7 years and 9 years after the conclusion of the initial study, patients completed a followup survey and were evaluated to determine the long-term outcome of etanercept treatment.

Results: Etanercept treatment significantly attenuated the total symptom score and reduced the frequency of symptoms. Etanercept also reduced levels of acute-phase reactants, particularly during asymptomatic periods. During a 10-year followup period, patients continued to receive etanercept for a median of 3.3 years, with a number of patients switching to anti-interleukin-1β receptor therapy or not receiving biologic agents, most frequently citing injection site reactions and lack of efficacy as reasons for discontinuation. However, patients continuing to receive etanercept had reduced symptoms at followup.

Conclusion: Etanercept reduces symptoms and serum levels of inflammatory markers of TRAPS in a dose-dependent manner, but does not completely normalize symptoms or acute-phase reactant levels. Although long-term adherence to etanercept is poor, continuing to receive etanercept may provide continued symptomatic benefit.

Trial registration: ClinicalTrials.gov NCT00001373.

Figure 1. Effect of etanercept on symptom scores and symptom-free days in TRAPS

Average weekly symptom scores (A) and symptom-free days per week (B) were measured in TRAPS patients (n=14) over the four study periods. Individual symptom scores (rash, eye redness/swelling, abdominal pain, muscle pain, and joint pain) are shown (C). Symptom score is from 0–10; 10 is most severe, 0 is least. P = period. Error bars represent mean ± SEM. *, p ≤ 0.05; **, p < 0.01, relative to period 1. ‡, p ≤ 0.05; ‡‡, p < 0.01, relative to period 3.

Figure 2. Reduction in serum acute phase reactants with etanercept therapy in TRAPS

CRP, SAA, and ESR levels were measured in TRAPS patients (n=14) during asymptomatic periods (A, B, C) and during attack periods (D, E, F) over the four study periods. The box limits represent 25^th and 75^th percentiles, the line within the box shows the median, and the whiskers end at 1^st and 99^th percentiles. P = period. *, p ≤ 0.05; **, p < 0.01, relative to period 1. ‡, p ≤ 0.05; ‡‡, p < 0.01, relative to period 3.

Figure 3. Biologic therapy decreases attack severity in the short- and long-term

Maximum and average attack-associated pain scores (A) and attack ancillary anti-inflammatory medication use (B) were recorded at the conclusion of each study period (n=14) and at the long-term follow-up (off etanercept, n=10; on etanercept, n=4). Pain score is from 0–10; 10 is most severe, 0 is least. Ancillary medication use is scored from 0–3; 3 is most use, 0 is least. (C) TRAPS patient medication use over a ten-year follow-up period is shown. Letters correspond to reason for discontinuation of etanercept therapy. *, time of completion of study questionnaire (patient 6 and 7 completed questionnaire twice). GC PRN = corticosteroids as needed. P = period. Error bars represent mean ± SEM. *, p ≤ 0.05; **, p < 0.01, relative to period 1. ‡, p ≤ 0.05, relative to period 3. ††, p ≤ 0.01, relative to off etanercept at follow-up.