2, Paolo Marzullo , Francesco Barone-Adesi Accepted Manuscript

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Methimazole treatment and risk of acute pancreatitis: a population-based cohort study.

Alessandro Pecere1, Marina Caputo2, Andrea Sarro1, Andrealuna Ucciero1, Angelica Zibetti1, Gianluca

Aimaretti2, Paolo Marzullo2,3, Francesco Barone-Adesi1

1 Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy

2 Endocrinology, Department of Translational Medicine, Università del Piemonte Orientale, Novara,

Italy

3 Division of General Medicine, Ospedale S. Giuseppe, I.R.C.C.S. Istituto Auxologico Italiano, Verbania

28921, Italy

Corresponding Author

Alessandro Pecere

Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy

Keywords: methimazole, acute pancreatitis, hyperthyroidism, administrative database

Conflict of interest: nothing to declare

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Abstract

Context: A warning has been recently issued by the European Medicine Agency (EMA)

regarding a potential increased risk of acute pancreatitis (AP) in methimazole (MMI) users.

Objective: To investigate the association between MMI and diagnosis of AP in a population-

based study.

Materials and methods: A retrospective analysis of administrative health databases was

conducted (2013-2018). Relevant data were obtained from: i) inhabitants registry, ii) hospital

discharge records (ICD-9-CM 577.0), iii) drug claims registry (ATC H03BB02). We

evaluated AP risk in MMI users in 18 months of treatment, stratifying results by trimester.

Poisson regression was used to estimate the age- and sex-adjusted Rate Ratios (RR), and the

relative 95% confidence intervals (CI), comparing rates of AP between MMI users and non-

users. The absolute risk of AP in MMI users was also calculated.

Results: A total of 23,087 new users of MMI were identified. Among them, 61

hospitalizations occurred during the study period. An increase in AP risk was evident during

the first three trimesters of therapy (RR 3.40 [95%CI 2.12-5.48]; RR 2.40 [95%CI 1.36-4.23];

RR 2.80 [95%CI 1.66-4.73]), but disappeared thereafter. The AP absolute risk in MMI users

during the first 18 months of treatment was less than 0.4% in all sex- and age-classes.

Conclusions: Our results support the EMA warning, suggesting an increased risk of AP associated

with MMI use. However, such an increase seems limited to the first months of MMI treatment.

Moreover, in absolute terms, the probability of AP is low among patients, well below 1%.

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Introduction

Hyperthyroidism is an endocrine disorder associated with thyroid hormone excess,

recognized as most commonly originating from Graves’ disease, toxic multinodular goiter,

and toxic adenoma [1]. Worldwide, reported incidence is 25-93 cases per 100,000 inhabitants

[2-4]. Clinical presentation ranges from subclinical manifestations to overt thyrotoxicosis

with potential cardiovascular complications [1].

Thionamide antithyroid drugs methimazole (MMI), its prodrug carbimazole (not available in

Italy) and propylthiouracil (PTU) are the cornerstone of the therapeutic management of

hyperthyroidism [1]. MMI is recommended as the favored drug while PTU is preferred

during the first trimester of pregnancy and in patients experiencing adverse events during

MMI therapy [1]. Severe adverse events are rare and include agranulocytosis (estimated

frequency, 0.1–1.2%) and cytolytic or cholestatic hepatitis (estimated frequency, 0.1–0.2%)

[1]. In January 2019, the European Medicine Agency (EMA), basing on the available

literature and a series of EudraVigilance safety signals, issued a recommendation, adopted by

its Pharmacovigilance Risk Assessment Committee (EMA/PRAC/826440/2018), warning

against the risk of acute pancreatitis (AP) following MMI treatment based on seven case-

reports published to date [5-11]. Recently, a Danish epidemiological study [12] reported a

56% higher risk of hospitalization for AP with ongoing use of MMI, while PTU effect was

apparently null.

In view of the potential impact of these warnings on the daily endocrine management of

hyperthyroidism, we carried out a population-based cohort study to evaluate the association

between MMI treatment and AP onset.

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Materials and methods

This retrospective cohort study was conducted using administrative health databases (AHDs)

of Piedmont, an Italian region with a population of around 4,400,000 inhabitants

(corresponding to 7.5% of the national Italian population). The time period encompassed in

this study was from January 1, 2013 to December 31, 2018. Data concerning only

individuals aged at least 18 years and residing in Piedmont during the aforementioned period

were considered. We used the following databases: i) inhabitants registry, containing

demographic information such as gender, birth date, death date, and other relevant

demographic information; ii) hospital information system, including hospital discharge

records (HDRs) from public and/or private hospitals; iii) drug claims registry, including

records of all outpatient drug prescriptions reimbursable by the National Health Service. As

previous studies suggest a rapid onset of AP following MMI initiation [5-11], we focused our

analysis on new users of MMI (ATC H03BB02). We used a look-back of one year to exclude

prevalent MMI users and we evaluated hospital admission rates for AP (ICD-9-CM 577.0)

during the first 18 months of treatment. In order to evaluate changes of AP risk over the

treatment course, we stratified the analysis by trimester. The general population of the region

was used as comparison group.

Multivariable Poisson regression was used to estimate Rate Ratios (RR), and their relative

95% confidence intervals (CI), adjusting the results by gender and age. We also estimated

age- and sex-specific absolute risk of AP in MMI users during the first 18 months of

treatment.

All statistical analyses were performed using Stata version 15 (StataCorp, College Station, TX).

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Results

In the period 2013-2018, a total of 23,087 MMI new users were identified in the Piedmont Region.

Among them, a total of 61 hospitalizations for AP were observed during the first 18 months of

treatment, with a number of 13 hospitalization occurring in the first trimester. About 7% of the cases

with pancreatitis died during hospital stay.

The hospital admission rate for AP in MMI users during the first trimester of treatment was 270 per

100,000 person-years [95% CI 170-428], compared to a rate of 60 per 100,000 person-year [95% CI

59-61] in the general population. An increase in the risk of AP was evident during the first three

trimesters of therapy, but disappeared thereafter. RRs in the different trimesters were 3.40 [95% IC

2.12-5.48], 2.40 [95% IC 1.36-4.23], 2.80 [95% IC 1.66-4.73], 1.20 [95% IC 0.54-2.68], 1.60 [95% IC

0.80-3.21] and 0.80 [95% IC 0.30-2.14], respectively.

The absolute risk of AP in the first 18 months of treatment ranged between 0.02% and 0.39% in the

different sex- and age-classes (Table 1).

Discussion

This is a retrospective population-based study based on administrative health databases conducted

to investigate the association between MMI treatment and risk of AP in Italy.

Like radioactive iodine (RAI) and surgery, antithyroid drugs (ATDs) are approved as first-line

treatment of patients affected by Graves’ disease and as second-line therapeutic option in patients

with toxic multinodular goiter who are poor candidates for surgery and RAI, or to

ameliorate symptoms of hyperthyroidism in preparation for definitive treatments [1]. In Italy,

licensed ATDs (i.e., MMI and PTU) are the preferred primary treatment for the management of

Graves’ disease *13-15]. MMI has several advantages over PTU, such as better efficacy, less severe

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side-effects, longer half-life and duration of action, and allows once-daily dosing compared with two

to three times daily dosing of PTU [1]. For this reason, a thorough knowledge of the side effects of

MMI is necessary to inform the clinical practice.

AP is increasingly considered an important and potentially fatal acute gastrointestinal condition [16].

While gallstones and alcohol consumption are recognized causes of AP, the impact of other

determinants such as specific therapeutic agents is increasingly acknowledged, and a spectrum of

drugs has been associated with AP development [17].

Currently available evidence on an increased risk of AP in patients treated with MMI is based

on seven case-reports [5-11] and one case-crossover study [12]. Four of these cases prompted

suggestive evidence of a causal relationship between AP and MMI use, as based on

recurrence after a re-challenge drug test [5, 6, 8, 9]. Conversely, two retrospective analyses

conducted in Taiwan and based on the use of the same database [18-19], failed to

demonstrate a relationship between MMI use and AP. These studies were probably hampered

by the inclusion of "ever used" MMI, which would miss cases of AP that occurred close to

MMI initiation.

In this analysis, we found that risk of AP was raised among new MMI users. The estimated

absolute risk during the first 18 months of treatment ranged between 0.02% and 0.08% in the

group of patients aged 18-59 years, while it increased to 0.16%-0.39% among patients aged

60 or more. These findings suggest that the risk of AP is increased in MMI users, but it

should be considered as a rare adverse event in the younger population, while being slightly

more frequent in the older groups. In general, data reported in a recent systematic review

contributed in demonstrating the overall safety profile of ATDs, when used in long-term

treatments as well [20].

In our analysis we also observed that the risk of AP was raised during the first three

trimesters of treatment and declined thereafter. This temporal pattern parallels that reported in

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previous case reports, where the onset of AP was identified between 4 days and 12 weeks

after commencing MMI therapy with no evidence of cumulative dose-response effect [5-11].

A number of hypothetical factors could be involved in the observed association between

MMI use and AP, including reactive metabolites and intermediates formation, oxidative

stress induction, intracellular targets dysfunction and immune-mediated toxicity [21]. The

MMI reactive intermediates sulfenic and sulfinic acids are capable of interacting with

intracellular targets and are involved in liver injury [20]. Whether these metabolites play a

similar role for pancreatic injury remains to be demonstrated. Some authors previously

reported a rapid onset of AP shortly after commencing MMI treatment and AP relapse after a

second MMI challenge [5, 6, 8, 9]. This could suggest, like for liver injury, an immune-

mediated mechanism involving, through a cytokine-induced response, an immunogenic drug-

protein complex or auto-antibodies [22].

A limitation of using administrative health data is the lack of clinical information. For example, as we

did not have information on the severity of the hyperthyroidism for which therapy with MMI was

started, we were not able to directly disentangle the possible effects of the underlying condition

from that of the treatment. This could be relevant, as thyroid hormones play a pivotal role in

pancreas physiology and pathology [23], and studies in rodents found that hyperthyroidism

promotes gallstone formation in vivo, which predisposes to AP [24-25]. We note, however, that the

early onset of AP after MMI commencement and the positive re-challenge drug tests reported by

other authors suggest that most of the effect is due to the treatment. Another relevant limit in our

data is that the actual dose of the drug prescribed to patients was not collected. Hence, future

studies are warranted to evaluate whether AP following MMI treatment has specific features, or if

specific subgroups of population have an especially higher risk. In particular, it should also be

investigated whether high or low doses of MMI entail the same risk of AP.

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Our results confirm and further expand previous evidence relating the use of MMI to the

development of AP, providing new insights on the risk profile of MMI users. On the other

side, the observed risk seems limited to the first three trimesters of MMI treatment. In

absolute terms, the probability of AP is low among patients, well below 1%. These aspects

should be taken into account when balancing risk and benefits of starting MMI treatment.

Thus, it could be important to resume on previous patients’ history with regards to pancreatic

health. Subsequently, particularly elderly patients should be informed on the possible risk of

acute pancreatitis during MMI treatment. Further studies are necessitated to investigate on the

individual determinants of AP risk in MMI users.

Acknowledgements

This study was partially funded by the AGING Project – Department of Excellence –

Department of Translational Medicine, Università del Piemonte Orientale and the FAR-2019

Grant issued by Università del Piemonte Orientale.

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Table 1. Absolute risk of AP in the 18 months following MMI treatment initiation

Age (years) Men Women

18-39 0.02% 0.05%

40-59 0.09% 0.08%

60-79 0.16% 0.17%

At least 80 0.37% 0.39%

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2, Paolo Marzullo , Francesco Barone-Adesi Accepted Manuscript