title: Cumulative Review of Thrombotic Microangiopathy, Thrombotic Thrombocytopenic Purpura, and Hemolytic Uremic Syndrome Reports with Subcutaneous Interferon β-1a.
abstract: BACKGROUND
  Rare cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), have been reported with interferon β products. We performed a cumulative review of TMA cases recorded in a Global Safety Database for patients with multiple sclerosis who received subcutaneous interferon β-1a treatment.
  
  
  METHODS
  Search criteria were: all reported cases, serious and non-serious, from all sources (including non-health care professionals and clinical trial reports), regardless of event ranking and causality assessment by reporter or company. Data lock was May 3, 2014, with additional analysis of cases reported between August 1, 2014-November 30, 2014.
  
  
  RESULTS
  Ninety-one patient cases (76.9% female) with 105 events were retrieved. Time to onset varied from 2 months to 14 years, and in 31.9% of patients the event occurred within 2 years of treatment initiation. Seven patients had a fatal outcome (five were secondary to other causes and two reported insufficient information). Forty-four patients recovered, 32 patients had not recovered at the time of the report, and in eight cases outcome was either not reported or unknown. Treatment was discontinued in 84.6% (77/91) of patients. In 67% (61/91) of patients, the reporter suspected a causal association between treatment and TMA/TTP-HUS. Risk factors and/or confounding factors were present in 45.1% (41/91) of patients. Early prodromal syndrome or specific patterns were not detected, although 54.9% (50/91) of cases contained insufficient information. Overall reporting rate of TMA/TTP-HUS was estimated as 7.2 per 100,000 patient-years. Reporting rates for human serum album (HSA)-containing and HSA-free formulations were 5.72 and 7.68 per 100,000 patient-years, respectively.
  
  
  CONCLUSIONS
  No new signal relating specifically to increased frequency of TMA/TTP-HUS with HSA-free subcutaneous interferon β-1a was detected and no additional risk mitigation measures are required regarding the different formulations. The benefit-risk balance of subcutaneous interferon β-1a remains positive, and routine pharmacovigilance monitoring is appropriate.
  
  
  BACKGROUND
  Ares Trading SA, Aubonne, Switzerland, a subsidiary of Merck Serono SA.
authors.affiliation: Merck Serono, Ares Trading SA, Aubonne, Switzerland, ali-frederic.ben-amor@merckgroup.com.
authors.forename: Ali-Frédéric
authors.initials: AF
authors.lastname: Ben-Amor
authors.forename: Anton
authors.initials: A
authors.lastname: Trochanov
authors.forename: Tanya Z
authors.initials: TZ
authors.lastname: Fischer
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects*; D000328:Adult; D000368:Aged; D005260:Female; D006463:Hemolytic-Uremic Syndrome / Q000139:chemically induced* / Q000517:prevention & control; D006801:Humans; D007279:Injections, Subcutaneous; D000068556:Interferon beta-1a / Q000008:administration & dosage / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000139:chemically induced* / Q000517:prevention & control; D013557:Switzerland
chemical_list: D000276:Adjuvants, Immunologic; D000068556:Interferon beta-1a