title: A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome.
abstract: OBJECTIVE
  Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin-1beta (IL-1beta), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS.
  
  
  METHODS
  Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values.
  
  
  RESULTS
  In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen.
  
  
  CONCLUSIONS
  In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA. goldbacr@mail.nih.gov <goldbacr@mail.nih.gov>
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: Sharukh D
authors.initials: SD
authors.lastname: Shroff
authors.forename: Mildred
authors.initials: M
authors.lastname: Wilson
authors.forename: Christopher
authors.initials: C
authors.lastname: Snyder
authors.forename: Sara
authors.initials: S
authors.lastname: Plehn
authors.forename: Beverly
authors.initials: B
authors.lastname: Barham
authors.forename: Tuyet-Hang
authors.initials: TH
authors.lastname: Pham
authors.forename: Frank
authors.initials: F
authors.lastname: Pucino
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wesley
authors.forename: Joanne H
authors.initials: JH
authors.lastname: Papadopoulos
authors.forename: Steven P
authors.initials: SP
authors.lastname: Weinstein
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Mellis
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kastner
mesh_terms: D000328:Adult; D018771:Arthralgia / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics; D003080:Cold Temperature / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005076:Exanthema / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005334:Fever / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010865:Pilot Projects; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013577:Syndrome; D016896:Treatment Outcome
chemical_list: D002352:Carrier Proteins; D007141:Immunoglobulin Fc Fragments; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; C531377:rilonacept