Supplementary Appendix

Transcription

1 Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Hunt D, Kavanagh D, Drummond I, et al. Thrombotic microangiopathy associated with interferon beta. N Engl J Med 2014;370: DOI: /NEJMc

2 Supplementary appendix Thrombotic Microangiopathy Associated with Interferon-β Table of Contents Page 1. Title and Table of Contents Page 2. Summary of clinical features of 4 cases of thrombotic microangiopathy in South Scotland Page 3. Interferon-β-associated thrombotic microangiopathy has chronic features with an identifiable prodromal phase Page 4. Patterns of reporting of thrombotic microangiopathy and recombinant interferon-β therapy Page 5. Geographical and temporal distribution of cases of HUS/TTP associated with a different IFNβ1a product. Page 6. Supplementary methods 1

3 Table S1. Summary of clinical details of 4 cases of thrombotic microangiopathy in South Scotland associated with interferon-β therapy presenting between 2010 and

4 Fig. S1. Interferon-β-associated thrombotic microangiopathy has chronic features with an identifiable prodromal phase (A) Review of South Scotland cases. Renal biopsies of all four cases identified evidence of chronic injury in all four cases. Picrosirius red staining in renal biopsies from cases 1 and 2 demonstrate cortical interstitial fibrosis (black arrows, scale bar = 100µm). Electron microscopy and silver staining from cases 3 and 4 show subendothelial widening and reduplication of glomerular basement membrane (blue arrows) scale bar = 10µm. Cases were examined retrospectively for abnormalities in clinical parameters in the months prior to diagnosis. Three out of four cases (case 3 did not attend her doctor in the months prior to presentation) demonstrated evidence of a clinical prodrome in the months prior to acute presentation. (B) Review of fatal UK case demonstrating retrospective evidence of a similar prodrome in the months prior to acute presentation and diagnosis (Dr O Flossmann). 3

5 Fig S2. Patterns of reporting of thrombotic microangiopathy and recombinant interferon-β therapy (A) The patient exposure to different interferon-β preparations at disease modifying therapy clinics was evaluated (see supplementary methods). The association of thrombotic microangiopathy with Rebif compared to other interferon preparations was significant (p=0.02 Fisher s exact test). (B) In total, 10 reports of interferon-β - associated thrombotic microangiopathy in the UK were received by the MHRA between 1998-August 2013, all associated with Rebif and none with other interferon-β preparations. (C) Disproportionality analysis performed by the MHRA for thrombotic microangiopathy-related terms and all interferon-β, demonstrating late emergence of a UK safety signal (EBGM = Empirical Bayes Geometric Mean, see supplementary methods). Reports of medically-confirmed HUS/TTP cases from the manufacturer global safety database in (D) countries which use the original formulation of Rebif and (E) countries which, like Scotland, have introduced a new serum-free formulation. The new formulation was first launched in Europe in September 2007 (source: Merck Drug Safety). 4

6 Fig. S3. Geographical and temporal distribution of cases of HUS/TTP associated with a different IFNβ1a product. (A) Number of spontaneous reports of Avonex (IFNβ1a, Biogen-Idec)-associated HUS/TTP in countries (such as USA) which have not introduced the same Rebif formulation as used in Scotland. (B) Number of spontaneous reports of Avonex-associated HUS/TTP in countries (such as European countries) which have introduced the same Rebif formulation as used in Scotland. 5

7 Supplementary Methods Analysis of patient records Individual patients consented for retrospective evaluation of their clinical notes and further clinical evaluation including genetic testing. The study was approved by Newcastle and North Tyneside 1 Research Ethics Committee (MREC/1/3/83) and informed consent obtained in accordance with the Declaration of Helsinki. Mutation screening of CFH, CFI, CFB, MCP, C3 and THBD was undertaken using Sanger sequencing. Collection of local prescribing data The patients who developed thrombotic microangiopathy were prescribed interferon-β through three different multiple sclerosis disease-modifying therapy clinics in South Scotland. Prescribing records from the three clinics were analysed to determine the total number of patients exposed to each recombinant interferon preparations over this timeperiod This was performed as part of a triggered audit (NHS Lothian DCN QIT Registration Number 417). Neurologists who prescribe recombinant interferon-β therapy in South Scotland were contacted to ensure ascertainment of interferon-β associated thrombotic microangiopathy within these Health Boards over this period. MHRA Adverse Drug Reaction Reports and disproportionality analysis Requests were submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK. We requested the total number of Adverse Drug Reaction (ADR) reports associated with all interferon beta products using thrombotic microangiopathy-related terms haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. A further search using a broader search term Standardised MedDRA Queries (SMQ) for renovascular disorders was performed which identified a case of malignant hypertension. We additionally requested the year of report and the manufacturing origin of the interferon preparation and the disproportionality statistic for the period of the first report to date 1. The following guide to interpretation of disproportionality statistics is provided by the MHRA: The Proportional Reporting Ratio (PRR) and Empirical Bayes Geometric Mean (EBGM) are statistical scores of disproportionality which aid our signal detection processes at the MHRA through automatic methods where case by case review is not possible given the large volumes of ADR reports received by the MHRA. An adjusted ratio of observed to expected frequencies is calculated which provides an indication on whether a particular Drug- Event Combination (DEC) is occurring more frequently than expected when compared against the whole database so assessment is focused on DECs of concern. This score is used to triage DECs for further assessment and thresholds are set based upon whether the EBGM exceeds a certain level. For drugs subject to intensive monitoring in the EU all DECs for every case are reviewed and a threshold for the EBGM is not applied. For UK ADR reports concerning established medicines the signal threshold is currently set to return DECs for review which are not currently listed in the product information and there are more than 3 cases, the EBGM score is 2.5 and the lower confidence interval EB05 is 1.8. A raised EBGM score does not necessarily indicate a signal of concern, as disproportionality scores do not take account of background disease, medical conditions and other confounding factors, nor do they give any indication of the quality of evidence available. Assessment of the cases is required to take account of the strength/ quality of the Yellow Card reports and other 6

8 factors such as time to onset. Other sources of information such as published literature are also reviewed as part of the signal assessment process before a signal is confirmed. As disproportionality scores are dependent on background rates of reported terms in the database, these scores cannot be used as a comparison against other databases. On top of the threshold based on the disproportionality score generated for UK DECs for established medicines, the MHRA also review all DECs arising from fatal cases, paediatric cases, parent-child cases (ADRs experienced by the child during pregnancy), cases containing an Alert Term reaction (a reaction of special interest), or where there is a change in the frequency of a DEC with more than 8% of all reports being received in last quarter. Manufacturer Global Safety Database Requests The manufacturer provided further details of HUS/TTP reports associated with Rebif (Merck Drug safety). The manufacturer global safety database was searched using a custom MedDRA query developed by the manufacturer for capturing TTP and HUS. The identified cases included all spontaneously reported, medically confirmed TTP and HUS cases up to February Thirty-five reports were identified. For each case, the manufacturer identified the formulation currently used in the country from where the report originated. Reports were divided into countries which currently use the same formulation as Scotland (Rebif new formulation) and those which use the original formulation, based on the manufacturer s assessment. The manufacturer additionally provided the date of onset of adverse event. A request for global safety data was made to the manufacturers of a similar widely used recombinant IFNβ1a product (Avonex, Biogen-Idec). The manufacturer conducted a cumulative search of the Biogen Idec Avonex Global Safety Database (GSD) for the reporting interval from 1996 through 17 May 2013 using the MedDRA (version 15.1) Preferred Terms (PT) of haemolytic uraemic syndrome, thrombotic thrombocytopenia purpura, and thrombotic microangiopathy. The search identified 11 cases. Reports were divided into those arising from countries which currently use the same Rebif formulation as Scotland and those which do not (see above). The manufacturer additionally provided the date of onset of adverse event. References 1. Bate A, Evans SJW. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiol Drug Saf 2009; 18: