Cumulative Review of Thrombotic Microangiopathy, Thrombotic Thrombocytopenic Purpura, and Hemolytic Uremic Syndrome Reports with Subcutaneous Interferon β-1a

Abstract

IntroductionRare 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.MethodsSearch 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.ResultsNinety-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.ConclusionNo 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.FundingAres Trading SA, Aubonne, Switzerland, a subsidiary of Merck Serono SA.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0212-6) contains supplementary material, which is available to authorized users.

Brief Review and a Clinical Case of Hemolytic Uremic Syndrome Associated with Interferon β Treatment

“…Interestingly, some cases of HUS may occur after several years of treatment with IFNβ. Furthermore, renal prognosis with chronic kidney disease was reported in most of these cases, but the outcome and the time necessary for the recovery are not clear [25] . Our case confirms that INFβ is a possible triggering factor for the development of HUS.…”

“…Furthermore, 1-10% of patients have vasodilatation, hypertension, increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, <1% HUS and increased gamma-glutamyl transferase (GGT) [24,25] . Renal side effects are rare; however, AKI related to acute tubular necrosis, acute interstitial nephritis, focal segmental glomerulosclerosis, and minimal change disease have been described to be associated with this therapy.…”

Type I interferon causes thrombotic microangiopathy by a dose-dependent toxic effect on the microvasculature

“…6,7 However, a causal role for IFN remains to be demonstrated, and alternative confounding etiologies such as other drugs, complement mutations, and Escherichia coli exposure have been suggested. 6,8 Establishing causation in drug safety is a major challenge. Frameworks have been proposed to support evidence of a causal association between disease and environmental factors, the best known of which are the Bradford-Hill criteria.…”

Maintaining consistent quality and clinical performance of biopharmaceuticals

“…Importantly, due to the low number of reported incidents and lack of a controlled clinical investigation, the association of the Rebif reformulation and thrombotic microangiopathy remains anecdotal. More recent global evaluations of Rebif adverse event case reports reveal no apparent correlation between the Rebif formulation change and thrombotic microangiopathy [36]. However, true causal relationships between product changes and rare adverse events are very difficult to definitively establish due to patient variability and reporting inconsistencies [35,36].…”