A secondary outcome was the use of ancillary medications for pain relief during each period. therapy or remaining off biologic brokers, citing injection reactions and lack of efficacy most frequently for discontinuation. However, patients remaining on etanercept had reduced symptoms at follow-up. Conclusion Etanercept reduces symptoms and serum inflammatory markers of TRAPS in a dose-dependent manner, but does not completely normalize symptoms or acute phase reactants. Although long-term adherence to etanercept is usually poor, remaining on etanercept may provide continued PSFL symptomatic benefit. INTRODUCTION Tumor necrosis factor (TNF) plays critical roles in inflammation and immunity. TNF is usually implicated in the pathogenesis of rheumatoid arthritis and Crohns disease, and TNF blockade is an effective treatment in these conditions (1). TNFR1 is usually believed to mediate most of the pro-inflammatory effects of TNF. The autosomal dominant periodic fever syndrome TNF receptorCassociated periodic syndrome (TRAPS) is usually associated with heterozygous missense mutations in the extracellular domain name of the gene encoding TNFR1 (2). TRAPS is an autoinflammatory disease characterized by recurrent episodes of fever accompanied by abdominal pain, migratory rash, myalgia, conjunctivitis, and arthralgias lasting from a few days to several weeks (3, 4). Although attacks are usually unprovoked, patients report triggers such as stress, trauma, exercise and hormonal changes. Acute phase proteins are elevated during attacks and also during asymptomatic periods. Chronic elevation in serum amyloid-A (SAA) can result in amyloidosis and life-threatening organ damage. Although Floxuridine initial studies suggested that inflammation in TRAPS might stem from reduced shedding of mutant TNFR1 from the cell surface (2), TNFR1 mutant proteins associated with TRAPS do not bind TNF. They are retained and accumulate in the endoplasmic reticulum, most likely as Floxuridine a result of protein misfolding, and are termed structural mutants (5). Two rare polymorphisms in the TNFR1 gene, R92Q and P46L, have also been associated with TRAPS, but behave normally in cell biological assays and lead to a less severe phenotype without progression to amyloidosis (6). Cells harboring heterozygous TNFR1 mutants exhibit increased responsiveness to TLR ligands in a manner dependent on the wild-type TNFR1, MAP kinases, and mitochondrial reactive oxygen species (7, 8). The dependence of hyper-inflammatory responses in TRAPS on interactions between TNF and the wild-type TNFR1 creates a rationale for TNF blockade in TRAPS. Before the discovery of the genetic lesion in TRAPS, patients were treated mainly with NSAIDS and/or corticosteroids. Colchicine is not an effective treatment for TRAPS. Case reports on the use of etanercept, a fusion protein of the extracellular domain name of TNFR2 and the Fc portion of human IgG1, have found variable results in TRAPS patients and rely primarily upon subjective patient reporting (4, 9, 10). Reports of the use of IL-1 receptor antagonist anakinra and tociluzimab, which targets the IL-6 receptor, in TRAPS patients have been limited but encouraging (7, 11, 12). PATIENTS AND METHODS Patients Fifteen patients were enrolled, all with features common of TRAPS, including abdominal pain, myalgia, arthralgia/arthritis, rash, and ocular involvement during attacks, a genetically confirmed mutation in associated with TRAPS, Floxuridine and age 4 years (Supplemental Table 1). A minimum of two attacks during the initial 12-week period was required for inclusion. Patients were screened for TB and those with a positive PPD were excluded from the study. Protocol 94-HG-0105 is usually registered in clinicaltrials.gov as “type”:”clinical-trial”,”attrs”:”text”:”NCT00001373″,”term_id”:”NCT00001373″NCT00001373. Study Design Patients in the protocol were assigned to equal periods (12 to 14 weeks) of: (1) baseline observation, (2) etanercept (25 mg for adults and 0.4 mg/kg for children) twice weekly, (3) etanercept three-times weekly if there was evidence of inflammation during period 2, and (4) drug washout. Patients recorded the frequency, duration, and severity of five TRAPS-related symptoms using an analog scale from 0 to 10 (10 being the most severe), and use of ancillary anti-inflammatory medications (i.e., NSAIDs and oral corticosteroids) in a standardized daily diary. At the conclusion of each study period, patients completed a questionnaire quantifying pain and ancillary medication use during attacks. Serum inflammatory markers were measured during attacks and intercritical periods. Primary outcome measures were a change in self-reported symptoms, standardized by summing the daily symptom scores in each period and dividing by the number of weeks in the respective period, and a change in mean acute phase reactants, obtained during symptomatic and asymptomatic time points in each period. A secondary outcome was the use of ancillary medications for pain relief during each period. Between seven and nine years after the initial study, patients completed the questionnaire and an oral survey to determine treatment, satisfaction with response, and medical history. Patients were then followed prospectively for the remainder of the ten-year follow-up period. Serum.