Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients.

Original Research

1.

Introduction

2.

Patients and methods

3.

Results

4.

Discussion

5.

Concluding remarks

Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients Kaarina Kowalec, Elaine Kingwell, Eric M Yoshida, Ruth Ann Marrie, Marcelo Kremenchutzky, Trudy L Campbell, Mia Wadelius, Bruce Carleton & Helen Tremlett† †

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Toronto on 12/30/14 For personal use only.

University of British Columbia, Neuroscience Program, Vancouver, Canada

Objective: To identify and characterize drug-induced liver injury (DILI) associated with IFN-b in multiple sclerosis (MS) using recommended criteria. Methods: This retrospective, mixed methods design included a cohort of IFN-b exposed MS patients from British Columbia (BC), Canada and a series of DILI cases from other Canadian provinces and two adverse drug reaction (ADR) networks (USA and Sweden). Associations between sex, age and IFN-b product, and DILI were explored in BC cohort using Cox proportional hazard analyses. Characteristics, including the time to DILI, were compared between sites. Results: In BC, 18/942 (1.9%) of IFN-b exposed MS patients met criteria for DILI, with a trend toward an increased risk for women and those exposed to IFN-b-1a SC (44 mcg 3 weekly) (adjusted Hazard Ratios: 3.15;95% CI:0.72 -- 13.72, p = 0.13 and 6.26;95%CI:0.78 -- 50.39, p = 0.08, respectively). Twenty-four additional cases were identified from other sites; the median time to DILI was comparable between BC and other Canadian cases (105 and 90 days, respectively), but longer for the ADR network cases (590 days, p = 0.006). Conclusions: Approximately 1 in 50 IFN-b exposed patients developed DILI in BC, Canada. Identification of DILI cases from diverse sources highlighted that this reaction occurs even after years of exposure. Keywords: adverse drug reactions, drug-induced liver injury, IFN-b, multiple sclerosis Expert Opin. Drug Saf. (2014) 13(10):1305-1317

1.

Introduction

A neurodegenerative disease of the central nervous system, multiple sclerosis (MS) is characterized by inflammation, demyelination and axonal injury. The IFN-b represent the first disease-modifying drugs ever to be licensed for MS, and they remain the most widely used worldwide [1]. While they are generally considered safer than the newer biological agents approved for MS, the IFN-b are nonetheless associated with a variety of adverse drug reactions (ADRs), requiring regular blood work, including biochemical liver enzyme tests. Post-marketing studies or reanalysis of clinical trial data suggests that 30 -- 60% of MS patients exposed to an IFN-b will experience elevations in their biochemical liver enzyme tests (typically alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) [2-4]. While the long-term implication of liver injury as indicated by liver enzyme elevations is unclear, around 1 -- 2% of IFN-b exposed MS patients [3,4] experience severe elevations. Fulminant liver failure requiring a transplant has been reported in MS patients exposed to IFN-b [5-7], highlighting 10.1517/14740338.2014.947958 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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the potential severity of this reaction. In addition, several of the new therapies for MS have also been implicated in liver injury, including natalizumab, fingolimod, teriflunomide and alemtuzumab [8-12]. Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United States [13], and is also the most common reason for drug withdrawal from the market [14]. A better understanding of serious ADRs such as DILI is extremely important, not just because of the associated morbidity and high socioeconomic costs borne by the patients and society [15], but also once a serious ADR occurs, that drug is no longer a therapeutic option for the affected patient, limiting future choice. DILI is a challenging condition, and attempts to predict and prevent this condition have fallen short in other clinical situations [16]; it also remains poorly understood in MS. Previous studies in MS have focused on describing the more common low-grade or transient elevations in ALT and/or AST [2-4]. Few studies have attempted to clinically characterize DILI or explore factors that might identify those at greatest risk of developing DILI in patients exposed to IFN-b [7]. We applied the recommended DILI laboratory criteria [17] to people with MS treated with an IFN-b and examined possible clinical factors associated with this severe ADR. 2.

Patients and methods

Study population and setting This was a retrospective observational study, using a mixed methodological approach. We primarily conducted a cohort study, which included IFN-b exposed MS patients who developed DILI as well as those who did not in British Columbia, Canada. As a secondary aspect of the study, we identified and characterized additional cases of IFN-b-associated DILI from other MS clinics in Canada, as well as from national ADR surveillance networks from the USA and Sweden and compared them to the BC cases.

measurement) within 180 days prior to starting IFN-b and completed at least one biochemical liver test within 13 months after initiation of IFN-b therapy, were selected (Table 1). Patients with primary-progressive MS were not included because no IFN-b has been licensed for use in this disease course. Data collection For all patients in the cohort study, the data were composed of biochemical liver test results (including ALT and when available, AST, ALP and TBILI with the corresponding normal ranges), demographics (age, sex), MS clinical data (MS disease course, MS symptom onset date, and start and stop dates of the IFN-b product used). In addition, for patients meeting the DILI criteria (as defined in Section 2.4), additional data collected included symptoms of liver injury (for determining the severity of liver injury [17]) and the outcome/management of liver injury. No restriction was placed on which laboratory the patients had chosen to complete their routine biochemical liver testing (i.e., local community lab, hospital lab, etc.). The schedule for liver testing in Canadian patients, as recommended by Health Canada, was modified over the study period (1995 -- 2013), with an increase in the frequency of tests from 2003 [21], although the actual frequency of testing was at the discretion of the treating physician. 2.3

2.1

Study event Patients had to fulfill recognized criteria for DILI [17], defined as one of: i) ALT or AST ‡ 5 upper limit of normal (ULN); or ii) ALP > 2 ULN or iii) simultaneous ALT ‡ 3 ULN and bilirubin > 2 ULN. Competing etiologies associated with liver enzyme elevations (i.e., viral hepatitis, etc.) were excluded, when possible, for patients fulfilling the study event. 2.4

Follow-up All patients were followed from the start of their first IFN-b to the earliest of i) a documented liver test result that fulfilled criteria for DILI; ii) the last liver test result prior to end of drug exposure or the study end (June 2013) or iii) the last liver test result that fell within the ‘regular’ liver testing requirement. ‘Regular’ testing was broadly defined as evidence of at least one yearly liver test (with no gap greater than 13 months between tests). The end of drug exposure occurred if patients switched from their original IFN-b, or between low- and high-dose IFN-b-1a SC, or stopped IFN-b treatment (i.e., only the first IFN-b treatment period was considered). 2.5

2.2

Cohort study in British Columbia, Canada

The source population for the cohort study consisted of all MS patients in the British Columbia (BC) MS database who were prescribed their first IFN-b between July 1995 (the first IFN-b licensing date in Canada) and June 2013. The BC MS database [18,19] contains demographic and clinical data collected prospectively since 1980 on patients visiting the four core MS clinics in BC. Patient chart reviews were conducted in 2001 (all charts from all four clinics) [3,20], 2009 [4] and again in June 2013 (the latter two reviews included all charts at the main University of British Columbia clinic only) to generate study-specific data (ALT, AST, alkaline phosphatase [ALP], total bilirubin [TBILI], symptoms of liver injury, outcome/management of liver injury) that were not routinely collected in the BC MS database [3,4,20]. All patients with definite MS and a relapsing-onset disease course with a first prescription of any IFN-b, who had a normal baseline biochemical liver test (including an ALT 1306

Statistical analyses The following characteristics were described: sex, age at IFN-b initiation, age at MS onset, MS disease duration at IFN-b initiation, MS disease course at IFN-b initiation (relapsing-remitting vs secondary-progressive) and IFN-b 2.6

Expert Opin. Drug Saf. (2014) 13(10)

Characteristics associated with DILI from interferon beta in multiple sclerosis patients

Table 1. Inclusion criteria to identify multiple sclerosis patients who developed or did not develop drug-induced liver injury associated with IFN-b treatment in British Columbia, Canada. Inclusion criteria


(1) Registered in the BC MS database, and hence assessed by a neurologist (2) Definite MS (Poser [15] or McDonald criteria [16]) (3) Relapsing-remitting or secondary-progressive disease course (4) First prescription of an IFN-b (IFN-b-1b subcutaneous, SC; IFN-b-1a SC (high and low dose) or IFN-b-1a intramuscular, IM) for MS between July 1995 and June 2013 (5) Normal baseline liver test result* (within the normal range for the reporting laboratory) < 180 days prior to IFN-b start (6) Minimum of one liver test within 13 months after starting IFN-b* *Consists of at least an alanine aminotransferase (ALT) measurement. Each individual liver test result had to include the corresponding ‘normal range’, as reported by the relevant laboratory. BC: British Columbia; MS: Multiple sclerosis.

product. The time to DILI and patient characteristics that were possibly associated with DILI were explored using Kaplan Meier curves and Cox proportional hazard regression models. MS disease course was not included in the models because the majority of patients had a relapsing-remitting disease course at IFN-b initiation. A multivariable Cox regression model was developed, including sex, age at IFN-b initiation and IFN-b product (chosen a priori as independent variables based on the previous DILI literature that has identified both sex and age as factors influencing DILI [22]). Other potential covariates (MS disease duration at IFN-b initiation and age at MS onset) were added to the multivariable models if statistical significance was reached in univariate model (p < 0.05). Sensitivity analysis We assessed the sensitivity of our estimate by lowering the threshold of a ‘DILI’ event with the reasoning that potential DILI cases may have reached a lower threshold and the drug was stopped due to an elevated liver test result before the DILI threshold was reached. For the alternative study event definition, the threshold was lowered to ALT or AST ‡ 3 ULN. A Cox regression analysis was performed and findings were compared to the results from the main analysis. 2.7

Identifying additional cases of IFN-b-associated DILI

2.8

Two separate groups of DILI cases were identified from other Canadian MS clinics and from other nationwide ADR surveillance networks. These cases were assessed to identify similarities or differences to the BC cases of DILI. Other Canadian sites Retrospective medical chart reviews were conducted in three additional MS clinics across Canada: Dalhousie Multiple Sclerosis Research Unit (Halifax, Nova Scotia), London Health Sciences Centre (London, Ontario) and Winnipeg Health Sciences Centre (Winnipeg, Manitoba) to identify additional MS patients exposed to IFN-b from July 1995 2.8.1

up until October 2012 and who experienced DILI. Data collection and DILI criteria were the same as for the BC cohort study. Other nationwide ADR surveillance networks (USA and Sweden)

2.8.2

Two ADR networks [7,23] contributed cases: the United States-based Drug-Induced Liver Injury Network (DILIN) and the Sweden-based SWEDEGENE. These networks are described elsewhere [7,23], and the clinical characteristics of the DILIN IFN-b cases have been reported [7]. The DILIN is an ongoing prospective study, which enrolls adults and children with suspected DILI. It enrolled eight subjects between September 2004 and July 2012 with MS who developed well-characterized DILI due to IFN-b [7]. Inclusion criteria matched the BC and other Canadian sites, except that two consecutive elevations of ALT, AST or ALP were required [7]. For SWEDEGENE, which is a national biobank for ADRs, adult MS patients were identified retrospectively from the Swedish Drug Information System (SWEDIS) ADR reports (time period: 1990 -- 2013 [23]). The case definitions were i) ALT or AST > 5 ULN; ii) ALP > 2 ULN or iii) ALT > 3 ULN and TBILI > 2 ULN. In addition, both the DILIN and SWEDEGENE employed causality assessments as part of their enrollment process (the Roussel Uclaf Causality Assessment Method [RUCAM] [24] and Naranjo ADR probability scale [25], respectively). Descriptive comparisons between the cases derived from BC and the other Canadian MS clinics, and between BC and the nationwide ADR networks were performed focusing on the following characteristics: sex, age at IFN-b initiation, time to DILI onset from IFN-b initiation, and IFN-b product (available for all cases); and age at MS onset, MS disease duration at IFN-b initiation and disease course at IFN-b initiation (available for the BC and other Canadian cases only). Characteristics were compared using the MannWhitney U test for continuous variables and the Pearson’s chi-squared test or Fisher exact test for categorical variables. Statistical significance was defined as p < 0.05, and all analyses were performed using SPSS 22.0 (SPSS, Inc.,


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Chicago IL, USA). The study was approved by each of the appropriate institutional ethics review boards.

Definite relapsing-remitting or secondary-progressive MS patients exposed to IFN-β between July 1995 and June 2013 (n = 1883)

3.

Results

The BC MS cohort In the BC cohort, a total of 1883 patients with relapsingremitting or secondary-progressive MS were exposed to their first IFN-b between July 1995 and June 2013, and 942 patients met the full inclusion criteria, as shown in Figure 1. There were no significant differences between those included (n = 942) and those excluded (n = 941) based on sex (p = 0.59), age at IFN-b start (p = 0.91), age at MS onset (p = 0.62), IFN-b product (p = 0.35), MS disease course (p = 0.85) or MS disease duration (p = 0.73). The baseline characteristics of the 942 patients are shown in Table 2. Overall, 72.6% were women. The mean age at the start of IFN-b was 39.9 years, and most patients were in the relapsing-remitting phase of disease. 3.1


Baseline liver test result available (n = 1314)

Normal baseline occurring < 180 days prior to starting IFN-β (n = 1218)

DILI and IFN-b exposure Among the 942 IFN-b exposed patients, 18 (1.9%) developed DILI. All cases developed DILI within 2 years (692 days) of starting IFN-b (Figure 2), and all were identified by the DILI criterion of ALT or AST ‡ 5 ULN. The clinical features of these 18 DILI cases are summarized in Table 3. All cases for which an R-value could be calculated (11/18) displayed the hepatocellular liver injury pattern (R ‡ 5). Three patients displayed symptoms of DILI, two of which had severity scores rated as ‘moderate.’ Most of the cases stopped their current IFN-b drug treatment in response to the elevated liver enzyme results, although two cases remained on therapy and four switched to a lower dosed IFN-b. Normalization of aminotransferases was observed for the majority of the cases at the last follow-up (Table 3). The remaining ‘non-DILI’ patients were censored at the last documented regular liver test result prior to the end of either: follow-up (n = 229) or drug exposure (n = 695). 3.2

≥ 1 liver test result available (including corresponding range of normal) within 13 months of starting IFN-β (n = 942)

Figure 1. Selection of relapsing-onset multiple sclerosis (MS) patients with first exposure to an IFN-b between July 1995 and June 2013 from British Columbia, Canada.

Table 2. Characteristics of MS patients exposed to IFN-b and fulfilling study inclusion criteria in British Columbia, Canada. Characteristic Sex, n (%) Female Male Unknown Age at MS onset, mean y (SD) Age at IFN-b start, mean y (SD) Disease course at IFN-b start, n (%) Relapsing-remitting Secondary-progressive Unknown MS disease duration at IFN-b start, mean y (SD) IFN-b product, n (%) 1a IM (30 mcg weekly) 1a SC (22 mcg 3 weekly) 1a SC (44 mcg 3 weekly) 1b (250 mcg every other day)

n = 942* 684 (72.6) 220 (23.4) 38 (4.0) 31.2 (9.10) 39.9 (9.68) 889 (94.4) 2 (0.2) 51 (5.4) 8.6 (8.12) 149 162 238 393

(15.8) (17.2) (25.3) (41.7)

*Date of birth, and therefore age at IFN-b start was unknown for 38 patients; age at MS onset, and therefore MS disease duration, was unknown for 86 patients. MS: Multiple sclerosis; SD: Standard deviation; y: Years.

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Patient characteristics associated with IFN-b DILI From the survival analyses, while none of the characteristics examined were significantly associated with an increased hazard of reaching DILI (Table 4, and online only, Figures 3 and 4 depicting sex and IFN-b product, respectively), some trends were observed. There was a trend toward an increased risk for women compared to men (adjusted hazard ratio [adjHR]: 3.15; 95% CI: 0.72 -- 13.72, p = 0.13) and for those exposed to IFN-b-1a SC (44 mcg) (adjHR: 6.26, 95% CI = 0.78 -- 50.39, p = 0.08) in comparison to IFN-b-1a SC (22 mcg). None of the 149 included patients who were exposed to IFN-b-1a IM developed DILI. 3.2.1

Sensitivity analysis There were 27/942 (2.9%) patients who reached the alternative outcome of ALT or AST ‡ 3 ULN during IFN-b 3.2.2



0.030

Proportion of patients with DILI


0.025

0.020

0.015

0.010

0.005

0.000 0

1000

2000

3000

4000

5000

6000

Time from interferon b start to DILI (days) Time (days)

0

50

100

150

200

350

400

700

Number of cumulative events (cases)

0

4

8

11

12

14

16

18

Number of remaining patients

942

862

802

751

678

496

445

300

Figure 2. Kaplan-Meier curve indicating the time from IFN-b initiation to drug-induced liver injury (DILI) in the British Columbian multiple sclerosis cohort. Of the 942 patients, 18 reached the outcome (DILI). The remaining ‘non-DILI’ patients were censored at the last documented regular liver test result prior to the end of either: follow-up (n = 229) or drug exposure (n = 695).

exposure. Findings from the Cox regression analysis (uni- and multivariable) were in the same direction to those seen in the main analyses, and as before, no patient characteristic was significantly associated with the outcome (data not shown). Additional cases of IFN-b associated DILI A total of 24 additional DILI cases were identified from the other sites; 14 from three other MS clinics in Canada, and 10 from the ADR surveillance networks (8 from the USA, which have previously been described as a case series [7], and 2 from Sweden reported in 2009 and 2010). While additional cases from the ADR surveillance networks were reported, only 10 cases were enrolled in the respective networks. 3.3

There was a high preponderance of females across all sites (Table 5). The average age at the start of IFN-b was similar between BC and the other Canadian sites, but the BC cases were younger (by around 10 years) compared to those identified through the ADR surveillance networks in the USA and Sweden. The BC and other Canadian sites were also comparable for the age at MS onset. The median time to DILI onset was comparable between BC and the other Canadian sites (105 and 90 days, respectively), but it was significantly longer for cases from the nationwide ADR networks compared to those from BC (p = 0.006). The longest time period from initiation of IFN-b to onset of DILI was 4900 days (around 13 years), as identified through one of the ADR surveillance


1309

1310 17

43

51

36

24

19

42

35

28

29

2

3

4

5

6

7

8

9

10


19

54

90

64

1a 44 mcg

126

1b 250 mcg 102

1a 44 mcg

1a 44 mcg

1b 250 mcg 25

1a 44 mcg

1a 44 mcg

1b 250 mcg 36

1b 250 mcg 91

11

6.3

6.1

5.5

5.1

6.8

12

8.3

7.4

5.5

0.9

0.7

0.7

0.4

0.5

ND

ND

0.8

ND

ND

0.5

0.4

0.4

0.1

0.5

ND

ND

0.3

ND

ND

12.2

9.0

8.7

13.8

10.2

ND

ND

10.4

ND

ND

299

146

54

141

1206

15

57

591

445

3665

1

Vomiting/ nausea

None

None

None

None

None

None

None

2

1

1

1

1

1

1

1

Remained on drug; ALT = 1.45 ULN at last follow-up (3665 days) Stopped drug; ALT = 1.6 ULN at last follow-up (445 days) Stopped drug; ALT normalized within 6 months Stopped drug; ALT normalized within 30 days Stopped drug; ALT normalized within 2 weeks Reduced dose (to unknown amount); ALT normalized within 11 months Reduced dose to -1a SC 22 mcg; ALT normalized within 3 months Reduced dose to -1a SC 22 mcg; ALT = 1.06 ULN at last follow-up (54 days) Stopped drug; ALT normalized within 3 months Stopped drug; AST normalized within 9 months

Severity Outcome/Management score#

Abdominal 1 pain/numbness

None

Initial ALT Initial ALK Initial BILI R-value§ Length of Symptoms ( ULN) ( ULN) ( ULN) follow up{

‘None’ indicates no symptomatology recorded by the treating physician, which was documented as being associated with the liver injury/elevated liver test results. All cases met criteria for DILI [1]; two remained on the original IFN-b at study end, and four switched to a lower dose. *Within 3 months of DILI. z Time from drug start to DILI (in days). § R is the ratio of serum activity of alanine aminotransferase to serum activity of alkaline phosphatase [(ALT/ULN)/(ALP/ULN)]. R ‡ 5 indicates a hepatocellular pattern of liver injury, R > 2 to < 5 indicates a mixed liver injury pattern and R £ 2 indicates a cholestatic pattern [17]. { Time from DILI to most recent ALT (or AST) measurement (in days). # Severity Score [17]: 1 = mild (meets DILI criteria but TBILI < 2 ULN), 2 = moderate (meets DILI criteria and i) TBILI ‡ 2 ULN or ii) symptomatic hepatitis). No patient was scored 3 or higher [3 = severe (meets DILI criteria and TBILI > 2 ULN and at least one of the following: i) international normalized ratio ‡ 1.5; or ii) ascites and/or encephalopathy, disease duration < 26 weeks and absence of underlying cirrhosis; or iii) other organ failure due to DILI), 4 = fatal or transplantation. **Aspartate aminotransferase level (ALT unavailable). zz Time to normalization unavailable. ALK: Alkaline phosphatase; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; DILI: Drug-induced liver injury; ND: Data unavailable; TBILI: Total bilirubin; ULN: Upper limit of normal.

F

F

F

F

F

F

F

F

M

1a 22 mcg

47

1

M

Latency‡

Patient No. Age* (y) Sex Product

Table 3. Clinical features of the 18 cases of IFN-b-associated liver injury in British Columbia, Canada.


K. Kowalec et al.


49 47

35

36 20

40

45

12 13

14

15 16

17

18

F

F

F F

F

F F

F

343 679

1b 250 mcg 379

1b 250 mcg 692

1b 250 mcg 362 1a 44 mcg 109

1b 250 mcg 289

1a 44 mcg 1a 44 mcg

1b 250 mcg 169

Latency‡

7

5.2**

12** 6.2

8.2

5.7 6.5

5.8

0.5

ND

ND 0.7

ND

0.5 0.8

0.9

0.7

ND

1.1 0.4

ND

0.4 0.5

0.1

14.0

ND

ND 8.9

ND

11.4 8.1

6.4

2037

2408

657 654

872

341 477

349

None

None

ND None

Pruritus

ND None

None

Initial ALT Initial ALK Initial BILI R-value§ Length of Symptoms ( ULN) ( ULN) ( ULN) follow up{

1

1

ND 1

2

ND 1

1

Stopped drug; ALT normalized within 1 year; abdominal ultrasound showed slightly coarse texture and increase echogenicity of liver, but no focal lesion; other structures normal ND Switched drug to 1a IM; ALT normalized within 15 months Stopped drug; ALT normalized within 4 months ND Remained on drug; ALT normalized within 1 year Stopped drug; AST normalized within 2 weeks ALT normalizedzz

Severity Outcome/Management score#

‘None’ indicates no symptomatology recorded by the treating physician, which was documented as being associated with the liver injury/elevated liver test results. All cases met criteria for DILI [1]; two remained on the original IFN-b at study end, and four switched to a lower dose. *Within 3 months of DILI. z Time from drug start to DILI (in days). § R is the ratio of serum activity of alanine aminotransferase to serum activity of alkaline phosphatase [(ALT/ULN)/(ALP/ULN)]. R ‡ 5 indicates a hepatocellular pattern of liver injury, R > 2 to < 5 indicates a mixed liver injury pattern and R £ 2 indicates a cholestatic pattern [17]. { Time from DILI to most recent ALT (or AST) measurement (in days). # Severity Score [17]: 1 = mild (meets DILI criteria but TBILI < 2 ULN), 2 = moderate (meets DILI criteria and i) TBILI ‡ 2 ULN or ii) symptomatic hepatitis). No patient was scored 3 or higher [3 = severe (meets DILI criteria and TBILI > 2 ULN and at least one of the following: i) international normalized ratio ‡ 1.5; or ii) ascites and/or encephalopathy, disease duration < 26 weeks and absence of underlying cirrhosis; or iii) other organ failure due to DILI), 4 = fatal or transplantation. **Aspartate aminotransferase level (ALT unavailable). zz Time to normalization unavailable. ALK: Alkaline phosphatase; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; DILI: Drug-induced liver injury; ND: Data unavailable; TBILI: Total bilirubin; ULN: Upper limit of normal.

50

11

Patient No. Age* (y) Sex Product

Table 3. Clinical features of the 18 cases of IFN-b-associated liver injury in British Columbia, Canada (continued).



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Table 4. Univariable and multivariable Cox proportional hazards regression analyses of potential predictors of drug-induced liver injury in MS patients exposed to IFN-b. Variable

No. of patients*

Univariable HR (95% CI)

904 856 904 856 793

p-value

HR (95% CI)

p-value

9.96) 1.05) 1.01) 1.00)

0.28 0.99 0.11 0.06

3.15 (0.72 -- 13.72)

0.13

0.97 (0.92 -- 1.02)

0.23

Ref. 4.55 (0.57 -- 36.4) 2.94 (0.37 -- 23.2)

0.15 0.31

Ref. 6.26 (0.78 -- 50.39) 3.71 (0.47 -- 29.59)

0.08 0.22

2.26 1.00 0.95 0.92

(0.51 (0.95 (0.91 (0.85

-----

*Number of patients included, per variable for univariable analysis. For the multivariable model, n = 793. z Hazard ratio expressed as per 1-year increase. § None of the patients who were exposed to IFN-b-1a IM (30 mcg) reached the event (developed DILI); these patients were not included in the models that included IFN-b product. DILI: Drug-induced liver injury; HR: Hazard ratio; MS: Multiple sclerosis.

0.04 Female Proportion of patients with DILI


Female sex Age at MS onsetz Age at IFN-b start§ MS disease duration at IFN-b start* IFN-b product§ 1a SC (22 mcg 3 weekly) 1a SC (44 mcg 3 weekly) 1b (250 mcg every other day)

Multivariable

0.03

0.02

Male 0.01

Log-rank test p = 0.189

0.00 0

1000 2000 3000 4000 5000 Time from interferon b start to DILI (days)

6000

Figure 3. Kaplan-Meier curve indicating the time from IFN-b initiation to drug-induced liver injury (DILI) in the British Columbian multiple sclerosis patients, by sex.

networks. Of note, this patient experienced normalization of liver aminotransferases 4 months after stopping IFN-b. The longest time period to onset of DILI among the cases from Canada was 2639 days (~ 7 years); this patient experienced a positive rechallenge and subsequently stopped IFN-b therapy. At the last follow-up (3 months after meeting DILI criteria), ALT levels had not yet normalized. 4.

Discussion

We applied standardized DILI laboratory parameters and inclusion criteria to people with MS who were treated with an IFN-b. In British Columbia, Canada, we found ~ 1 in 1312

50 MS patients treated with an IFN-b reached criteria for DILI. In comparison, a previous Icelandic population-based study of the incidence of DILI (defined as AST > 3 ULN or ALT > 2 ULN) reported rates that were considerably lower; the highest observed incidence rate was 1 in 133 treated patients (for azathioprine) [26], although this estimate was based on only 4 cases and the 95% CI included 1 in 50. The difference may also be due to differences in the case ascertainment methods and a potential underestimation of cases in the Icelandic study, as acknowledged by the authors [26]. We were unable to find another study using the same explicit criteria in a population of MS patients. One study using data from clinical trials found a higher proportion of cases when



0.05

Proportion of patients with DILI


IFNβ-1a SC 44 mcg 0.04

IFNβ-1a SC 22 mcg

0.03

0.02 Log-rank test p = 0.089 0.01 IFNβ-1b SC 0.00

IFNβ-1a IM 0

1000

2000

3000

4000

5000

6000

Time from interferon b start to DILI (days)

Figure 4. Kaplan-Meier curve indicating the time from IFN-b initiation to drug-induced liver injury (DILI) in the British Columbian multiple sclerosis patients, by IFN-b product.

Table 5. Characteristics of MS patients reaching criteria for DILI during IFN-b exposure from the different sites -- British Columbia, rest of Canada and the nationwide (USA/Sweden) adverse drug reaction surveillance networks. Characteristic

BC (n = 18) [1]

Rest of Canada (n = 14) [2]

p-value [1] vs [2]

USA and Sweden (n = 10) [3]

p-value [1] vs [3]

Female sex, n (%)* Age at MS onset, mean y (SD)z Age at IFN-b start, mean y (SD)z Disease course at IFN-b start, n (%)* Relapsing-remitting Secondary-progressive Disease duration at IFN-b start, mean y (SD)z Days to DILI onset, median (range)z

16 (88.9) 31.4 (9.14) 36.8 (10.0)

14 (100) 31.5 (7.53) 39.0 (11.9)

0.20 0.78 0.55

9 (90.0) NA 46.6 (9.81)

0.93

16 (88.9) 2 (11.1) 5.17 (7.80) 105.5 (17 -- 692)

13 (92.9) 1 (7.1) 8.64 (7.85) 90.5 (31 -- 2639)

0.70

NA

0.14 0.84

NA 590.5 (101 -- 4900)

0 1 (5.6) 8 (44.4) 9 (50.0)

1 2 6 5

0.58

3 (30) 0 3 (30) 4 (40)

IFN-b product, n (%)§ 1a IM (30 mcg weekly) 1a SC (22 mcg 3 weekly) 1a SC (44 mcg 3 weekly) 1b (250 mcg every other day)

(7.1) (14.3) (42.9) (35.7)

0.03

0.006

0.11

*Comparison using Pearson’s chi-squared test. z Comparison using the Mann-Whitney U test. § Comparison using the Fisher’s exact test. BC: British Columbia; DILI: Drug-induced liver injury; MS: Multiple sclerosis; NA: Data not available; SD: Standard deviation.

investigating only those treated with IFN-b-1a SC 44 mcg (1 in 35, or 2.8%) [2]; however, this study was not able to employ the more recently published DILI criterion [17]. Our current study applies internationally recommended DILI criteria [17] to a population of MS patients; it uses a more stringent cutoff to define ‘liver injury’ than has been used in previous studies of DILI in MS and includes a

minimum frequency of liver testing. These methods could provide a standardized approach to identifying and characterizing DILI in future studies of MS. Similar case definitions to the one used here have been employed by other research groups to investigate predictive factors in clinical and pharmacogenomic studies in non-MS, clinical populations [27,28]. Utilization of a recommended


1313


K. Kowalec et al.

case definition and accurate phenotyping of patients are considered of primary importance in reliably determining whether clinical risk factors are associated with the ADR [29]. All cases identified here met the case definition [17], including the six patients who either continued treatment or switched to a lower dose; likely representing a balance between risk versus possible benefit from IFN-b. This case definition is known to represent patients experiencing a severe or medically significant and potentially disabling event, as per the Common Terminology Criteria for Adverse Events (v4.0) [30]. The employment of stricter criteria to define DILI comes at a cost, as it results in a relatively small group of cases within which to explore potential clinical characteristics that might be useful as predictors of DILI in IFN-b exposed individuals. Although no single characteristic reached statistical significance in our analyses, we observed some interesting trends. Women had an approximately threefold greater risk than men (albeit not significant). Using a lower threshold to define liver injury (i.e., any elevation in ALT or AST), others have reported the reverse; that men with MS are at a greater risk than women with MS [31,32]. These seemingly contradictory findings actually concur with the broader literature indicating that men in general are at an increased risk of low-grade elevations in their liver test results [32], while women are more susceptible to the more severe reaction of DILI, especially when it is autoimmune related [33,34]. This higher than expected preponderance of women observed among the BC cases was also evident in the DILI cases from the other MS clinics in Canada, and the national ADR surveillance networks (USA and Sweden). Similarly, others have reported that 90% of IFN-b exposed MS patients with symptomatic and ‘severe hepatic dysfunction’ are women [2], as compared to the expected 64 -- 76% of women in an IFN-b-treated MS population [35,36]. There was also a trend (nonsignificant) toward a greater risk of DILI for the higher-dose IFN-b product. This observation concurs with other studies [2], (including that of a smaller sample of the BC MS cohort) [4] even when using a lower threshold to identify liver injury (i.e., any elevations in ALT or AST) [2-4]. Younger age has previously been reported as a risk factor for de novo ALT elevations in IFN-b exposed MS patients [2,4]. Although the association was not statistically significant, the direction of our hazard ratio for age concurred with these previous observations [2,4]. Younger age has similarly been reported to be associated with hepatocellular DILI from other therapies used to treat other conditions [22]. However, serum ALT levels decrease with age in healthy untreated individuals [37], which may lower the probability that older adults will reach the threshold for DILI as currently defined. DILI cases from BC, other Canadian and international sites were not only ascertained from different populations, but they were collected during different time periods, utilizing different methods. However, this approach enabled us to identify a broad range of DILI patients, and the age at MS onset, 1314

age at IFN-b start and sex distribution were all similar between the cases from BC and from the rest of Canada. Even so, an understanding of the main differences between the sites is important to contextualize findings. For instance, findings might be affected by local prescribing practices [38] or even the licensing (hence availability) or the local cost of specific drugs. These factors may alter the number of DILI cases attributed to one IFN-b product versus another. DILI in the BC and other Canadian MS patients developed fairly early during the course of IFN-b treatment (medians of 90.5 and 105.5 days, respectively) and differed from the ADR surveillance network cases (median of 590.5 days). This might relate to the types of patients clinicians refer to a surveillance network. For instance, the rates of DILI in clinical practice may be up to 10-fold higher than that reported to any centralized data registry or to regulatory bodies [39,40], indicating only select, and perhaps more unusual, cases are reported to surveillance networks. A relatively short time to event was also observed in clinical trial data (trial participants are typically monitored more frequently than patients in clinical practice), where 75% of ALT or AST elevations occurred within the first 6 months among those exposed to IFN-b-1a SC (44 mcg) [2]. A wide range in time to onset of idiosyncratic hepatotoxicity is not uncommon among other drugs [41]. In this patient cohort, cases typically displayed a hepatocellular liver injury pattern, as evidenced by the R-value > 5, which is associated with worse prognosis in the presence of jaundice, than the other two patterns [42]. The three patterns of liver injury associated from drugs (hepatocellular, cholestatic and mixed) are associated with different prognoses [43]. However, only 60% of BC cases had ALP tests, so the other patterns of liver injury were less likely to be detected. This study employed an internationally recommended and rigorous definition of DILI [17], facilitating a standardized approach and potential replication of findings [44]. We also purposely selected individuals from the BC cohort with a previous ‘normal’ liver test result (in the 6 months prior to IFN-b initiation) who maintained a regular frequency of testing. While this resulted in the exclusion of a number of the treated BC patients, this minimum data requirement was a strength of the study, as it reduced the likelihood of misclassification of cases, and minimized the inclusion of individuals with a prior history of liver comorbidity. Reassuringly, we found that excluded patients did not differ demographically from those that were included; however, we do not know if they were more or less at risk of DILI than the included patients due to differences in unmeasured factors. We were unable to consider certain potential confounders, such as body mass index. DILI is more frequent in obesity-related nonalcoholic fatty liver disease (NAFLD) [45] and an increase in ALT/ AST could be caused or amplified by NAFLD. However, ensuring that all individuals had an ALT/AST within the normal range pretreatment would have helped to mitigate this by potentially screening out people with NAFLD at baseline.




It is known that the application of retrospective causality assessments such as the RUCAM scale [17] is problematic, if not impossible, unless exhaustive clinical data are collected at the time of the acute injury [46]. This is largely because the confidence in the diagnosis increases as other potential causes are excluded (such as viral hepatitis, biliary obstruction, hypotension, etc.) [17]. The Canadian MS patients who met the DILI case definition with biochemical liver enzyme parameters were not subject to expert panel causality assessments [47] (in contrast to the international cases), which might have contributed to qualitative differences between the DILI cases among the IFN-b exposed Canadian patients and those identified by the surveillance networks. 5.

Concluding remarks

In summary, we found the risk of DILI in the IFN-b exposed BC MS cohort to be ~ 1 in 50. We did not identify any significant predictors of DILI associated with IFN-b exposure, although there was a trend toward a greater risk for women and those exposed to IFN-b-1a SC (44 mcg). The ‘at risk’ window appears wide; while the greatest risk appeared in the first few years after treatment initiation, the reaction can also occur over a decade after initiation of IFN-b therapy. It is recommended that MS patients undergo regular monitoring of ALT and/or AST during exposure to IFN-b [21]. However, regular liver testing by itself is not expected to prevent every case of acute liver failure [5,44]; the identification of additional risk factors, such as genetic determinants, that are predictive of this severe reaction would be of high clinical utility.

Acknowledgments We are grateful to Naga Chalasani, MD, for facilitating access to the DILIN case data and for helpful comments on the manuscript and to Pa¨r Hallberg, PhD, for access to the clinical data related to the SWEDEGENE samples. We thank Tom Duggan, Yinshan Zhao, PhD and Feng Zhu (Division of Neurology, University of British Columbia) for help with data handling and coding. We thank all multiple sclerosis clinic patients for sharing their clinical information. We also thank the BCMS Clinic neurologists who contributed to the study through patient examination and data collection (current members listed here): A. Traboulsee, MD, FRCPC (UBC Hospital MS Clinic Director and Head of the UBC

MS Programs); A-L Sayao, MD, FRCPC; V Devonshire, MD, FRCPC; S Hashimoto, MD, FRCPC; J Hooge, MD, FRCPC; L Kastrukoff, MD, FRCPC; J Oger, MD, FRCPC; D Adams, MD, FRCPC; D Craig, MD, FRCPC; S Meckling, MD, FRCPC; L Daly, MD, FRCPC; O Hrebicek, MD, FRCPC; D Parton, MD, FRCPC and K Pope, MD, FRCPC. KK was funded by the Canadian Institutes of Health Research (Doctoral award) and the University of British Columbia. HT is funded by the Multiple Sclerosis Society of Canada (Don Paty Career Development Award); is a Michael Smith Foundation for Health Research Scholar and the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. EK was funded by the Michael Smith Foundation for Health Research (Postdoctoral Fellowship). RAM was funded in part by a Don Paty Career Development Award from the MS Society of Canada. MW was funded by Swedish Research Council (Medicine 523-2008-5568). BC was funded by the Canadian Institutes of Health Research, Genome Canada and the Child & Family Research Institute (Vancouver, Canada).

Declaration of interest K Kowalec, E Kingwell, E Yoshida, M Kremenchutzky, M Wadelius and B Carleton report no conflicts of interest. H Tremlett has received research support from the National Multiple Sclerosis Society, Canadian Institutes of Health Research, and UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres (2013), the National MS Society (2012, 2014), Bayer Pharmaceutical (speaker, 2010, honoraria declined), Teva Pharmaceuticals (speaker 2011), ECTRIMS (2011, 2012, 2013), UK MS Trust (2011), the Chesapeake Health Education Program, US Veterans Affairs (2012, honorarium declined), Novartis Canada (2012), Biogen Idec (2014, honorarium declined), American Academy of Neurologists (annual meeting speaker, 2013, 2014, honorarium declined). Unless otherwise stated, all speaker honoraria are donated either to an MS charity or to an unrestricted grant for use by her research group. RA Marrie has conducted clinical trials for Sanofi-Aventis. T Campbell has previously received funding from Biogen Idec, Consultants fees from Biogen Idec, Genzyme, EMD Serono, Teva Canada Innovation, Novartis, Nurse Fellowship Biogen Idec Canada.


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Affiliation Kaarina Kowalec1,2,3 MSc, Elaine Kingwell4 PhD, Eric M Yoshida5 MD, Ruth Ann Marrie6,11 MD PhD, Marcelo Kremenchutzky7 MD, Trudy L Campbell8 NP, Mia Wadelius9 MD PhD, Bruce Carleton2,3,10 PharmD & Helen Tremlett†1,4 PhD † Author for correspondence 1 University of British Columbia (UBC), Neuroscience Program, Room S178, 2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada Tel: +1 604 822 0759; E-mail: [email protected] 2 Child & Family Research Institute, Vancouver, Canada 3 BC Children’s Hospital, Pharmaceutical Outcomes Programme, Vancouver, Canada 4 University of British Columbia, Division of Neurology, Faculty of Medicine, Vancouver, Canada 5 University of British Columbia, Division of Gastroenterology, Faculty of Medicine, Vancouver, Canada 6 University of Manitoba, Department of Internal Medicine, Winnipeg, Canada 7 Western University, Department of Clinical Neurological Sciences, London, Canada 8 Dalhousie University, Halifax, Canada 9 Uppsala University Hospital, Uppsala, Sweden 10 University of British Columbia, Division of Translational Therapeutics, Department of Pediatrics, Faculty of Medicine, Vancouver, Canada 11 University of Manitoba, Department of Community Health Sciences, Winnipeg, Canada

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Interferon beta augments suppressor cell function in multiple sclerosis.

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Preserved in vivo response to interferon-alpha in multiple sclerosis patients with neutralising antibodies against interferon-beta (REPAIR study).

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Beta-interferon exposure and onset of secondary progressive multiple sclerosis.

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Cognitive dysfunction in patients with multiple sclerosis treated with different types of interferon beta: a randomized clinical trial.

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