Sex differences in adverse drug reactions from Adalimumab and etanercept in patients with inflammatory rheumatic diseases

ABSTRACT Background We examine sex differences in relation to the nature, frequency, and burden of patient-reported adverse drug reactions (ADRs) in patients with inflammatory rheumatic diseases. Research design and methods Rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis patients using etanercept or adalimumab from the Dutch Biologic Monitor were sent bimonthly questionnaires concerning experienced ADRs. Sex differences in the proportion and nature of reported ADRs were assessed. Additionally, 5-point Likert-type scales reported for the burden of ADRs, were compared between sexes. Results In total 748 consecutive patients were included (59% female). From the women 55% reported ≥1 ADR, which was significantly higher than 38% of the men that reported ≥1 ADR (p < 0.001). A total of 882 ADRs were reported comprising 264 distinct ADRs. The nature of the reported ADRs differed significantly between both sexes (p = 0.02). Women in particular reported more injection site reactions than men. The burden of ADRs was similar between sexes. Conclusions Sex differences in the frequency and nature of ADRs, but not in ADR burden, exist during treatment with adalimumab and etanercept in patients with inflammatory rheumatic diseases. This should be taken into consideration when investigating and reporting results on ADRs and when counseling patients in daily clinical practice.


Introduction
Attention to sex differences in relation to treatment differences has increased over the past decade. Sex is already known to play a role in the development, etiology [1,2], disease severity, and treatment outcome in inflammatory rheumatic diseases [3][4][5][6]. For example, more women suffer from rheumatoid arthritis (RA) (3:1), while psoriatic arthritis [7] and ankylosing spondylitis are more prevalent in men. Despite these known differences and the fact that female sex is considered a risk factor for a delay in early referral and adequate treatment for ankylosing spondylitis [8], sex differences are not considered in RA [9], psoriatic arthritis (PsA) [10] or ankylosing spondylitis treatment recommendations.
The terms sex and gender are often used interchangeably but have different meanings. The term sex is used to indicate biological differences, and gender is used to describe socially constructed characteristics of women and men. In 2019, the Dutch Institute for Research and Healthcare, Nivel, published a report on sex and gender differences in rheumatic care. The authors emphasized that sex and gender differences play an important role during all stages of rheumatic care, which should be addressed more often in clinical practice, as these could have consequences in therapeutic outcomes [11,12]. A similar message came from Klein et al. who reviewed the relationship between sex and gender differences in relation to treatment with biologics and stated that there is a need for personalized care to achieve better clinical outcomes, since men and women react differently to biologics, which could for instance affect treatment compliance [13].
Besides differences in disease etiology and treatment outcomes, it is known that sex may play a role in experiencing adverse drug reactions (ADRs) [14,15]. An increasing body of evidence already shows that women generally report more ADRs than men [16][17][18][19][20] and women more often reported ADRs that lead to more hospital admissions [21]. Underlying mechanisms are still not fully understood, but differences have thus far been attributed to a mixture of sex (genetics, pharmacokinetics/pharmacodynamics, and hormones) and gender differences (e.g. social roles, behaviors, and traits) [22,23]. Furthermore, data on differences in the nature and frequency of ADRs in relation to sex are still limited. The main reason for this could be that sex differences are often not considered in research on ADRs. From the Nivel literature review, only 25 out of 99 included studies could be used to compare sex differences as the majority of the studies did not report sex differences or were not able to report differences because the patient male/female subgroups were too small [11]. In addition to potential differences in the nature and frequency of ADRs between male and female patients, men and women may also experience burden from ADRs differently [24]. However, data on the burden of experienced ADRs is even more scarce as it is rarely assessed.
The aim of this study was to examine whether there are sex differences in the nature, frequency, and burden of reported ADRs in patients with inflammatory rheumatic diseases treated with adalimumab or etanercept.

Dutch Biologic Monitor
The Dutch Biologic Monitor (DBM) is a prospective cohort event monitoring system for patient-reported ADRs attributed to biologics, which has been described previously [24,25].
Patients that were 18 years or older and used one of the pre-defined monitored biologics for an immune-mediated inflammatory disease (IMID) were invited to participate in the DBM. Patients were included between 1 January 2017 and 2 November 2020 by health-care professionals of nine participating Dutch hospitals using consecutive sampling.

Patient selection
The DBM consists of patients with a wide variety of indications for biologic use. To be able to compare sex differences in relation to reported ADRs that were not attributed to differences in biologic use or indications, we only included patients with at least one of the three most common indications (RA, PsA, and ankylosing spondylitis/axial SpA) and the two most common biologics (adalimumab and etanercept) in this study. For this study, no distinction was made between originators and biosimilars. The DBM received a waiver for the Dutch Medical Research Involving Human Subjects Act by the Dutch Medical Research Ethical Committee of Brabant (file number: NW2016-66). Moreover, the Dutch Biologic Monitor was approved by the medical ethics committees of the participating hospitals. Patients received information concerning the study prior to participation and digital informed consent was obtained for all patients.

Reporting of ADRs
Digital questionnaires were filled out every 2 months. The questionnaires contained open-ended questions where patients could specify in free-text fields, which ADR they experienced. The translated questionnaire can be found in Supplementary File S2. Patients were also asked whether ADRs resulted in hospital admissions. Other specifications of the seriousness of ADRs were not asked. The reported ADRs were coded according to Medical Dictionary for Regulatory Activities (MedDRA ® ) terminology (version 21.0) [26] by qualified pharmacovigilance assessors. 'Preferred Terms' (PT) were used in the ADR analyses. When an ADR was reported multiple times in more than one questionnaire by the same person, the ADR was only counted once. When the same ADR occurred after a switch in biologic, the ADR was counted once for both biologic treatments.

Reporting burden
The burden of ADRs was reported on a 5-point Likert-type scale, representing 'no burden' (1), 'little burden' (2), 'quite burdensome' (3), 'high burden' (4), and 'very high burden' (5). If the same ADR was reported multiple times in more than one questionnaire by the same person, only the burden that was reported the first time was included in the analysis, since changes over time could be due to the duration of the ADR, which was not assessed for patients that mentioned an ADR only once.

Statistical analyses
Baseline characteristics for both male and female patients were presented in mean ± standard deviation (SD) or frequencies with proportions when appropriate. Differences in the proportion of the total number of ADRs were assessed using the chi-square test.
Differences in the distribution of reported nature of ADRs between male and female patients were assessed using Fisher-Freeman-Halton with Monte Carlo simulation. To allow replication of the analysis, a fixed seed was used. Post-hoc analyses were performed to assess sex differences in the proportional frequencies of ADRs that were reported at least times by either sex using Fisher's Exact test. The tests were adjusted for multiple testing using Bonferroni correction [27].
Likert-type scales reported for the ADR burden were compared between male and female patients for ADRs that were reported at least four times by male and female patients, using the Cochran-Armitage test for trend, which considers the ascending order of the Likert-type scale values [28].

Results
In this study, 748 patients were included, of which the majority was female (59%) (Figure 1, Table 1). The number of questionnaires answered by male and female patients was comparable, with a median of 5 questionnaires and interquartile range of 2-10 for males and females (Supplementary Figure S1).
The most prevalent indication for biologic therapy was RA, followed by PsA, for both male and female patients. Ankylosing spondylitis/axial SpA, on the other hand, was more prevalent in male patients. The distribution of etanercept and adalimumab use was comparable for male and female patients. From the female patients 43.7% received methotrexate as co-medication, while 35.2% of the male patients used methotrexate.

Sex differences in reported ADRs
During the study, 362 participants (48%) reported at least one ADR. From the female patients, 55% reported at least one ADR. This relative proportion was significantly higher as compared to 38% of the male patients that reported at least one ADR (p < 0.001). A total of 891 ADRs were reported. After the exclusion of sex-specific ADRs, 882 reported that ADRs remained. Female patients reported the majority of ADRs (74%). 1.4% of the total ADRs that were reported by females resulted in hospital admissions as compared to 3.9% of the total ADRs that were reported by males. These serious ADRs mostly belonged to the System Organ Classes (SOC): Cardiac disorders (n = 2 males, n = 1 female), Infections and infestations (n = 1 male, n = 2 females), Neoplasms benign, malignant and unspecified (incl cysts and polyps) (n = 2 males), Respiratory, thoracic and mediastinal disorders (n = 2 females).
The total of 882 ADRs comprised 264 distinct types of ADRs, and 71 (27%) distinct ADRs were mutually reported by both sexes (Figure 2).
Burden was assessed for ADRs that were reported at least four times by both sexes, which included 12 (5%) distinct ADRs (Figure 4). Pneumonia imposed the highest burden of the mutually reported ADRs. 'Arthralgia' (p = 0.052) showed the largest difference in ADR burden scores between male and female patients, however, this difference was not statistically significant (Supplementary Table S2).

Discussion
In this study, we examined the relationship between sex differences and the nature, frequency and burden of perceived and reported ADRs attributed to biologics in rheumatic diseases. Overall, the proportion of female patients reporting ADRs was higher than the proportion of male patients. This was also observed in previous studies on ADRs attributed to biologics in inflammatory bowel disease patients and patients with psoriasis [19,31]. Of all types of ADRs, 'injection site pain' was most frequently reported, with similar reporting rates between male and female patients. Regardless of the high frequency, 'injection site pain' was generally experienced with low burden by both male and female patients. Female patients did not only report more ADRs but also reported a wider variety of types of ADRs, hence the distribution of the nature of reported ADRs differed significantly between male and female patients. Differences in frequencies between male and female patients due to a longer duration of study participation were ruled out as the median number of completed questionnaires was similar between males and females. Post-hoc analyses showed that sex differences were particularly present for injection site reactions. When combining all injection site reactions, 56% of the women reported injection site reactions compared to 28% of the men. Besides the higher frequency of reported ADRs, female patients reported a wider variety of injection site reactions, such as: 'injection site haematoma,' 'injection site erythema,' 'injection site pruritus', and 'injection site inflammation' as compared to male patients. These findings are in line with a study by Curtis, et al. (2010) where female RA patients using etanercept or adalimumab reported more 'injection site burning' and 'stinging' than Age was missing for 1 male and 1 female patient. b Patients could report multiple indications. 5 male and 14 female participants also reported other indications, such as (Crohn's disease (male n = 3, female n = 2), peripheral spondyloarthritis (male n = 1, female n = 1), uveitis (male n = 2, female n = 1), rheumatoid related lung disease (female n = 1), arthrosis (female n = 1) Sjögren's syndrome (female n = 1), remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome (female n = 1), sarcoidosis (female n = 2), (systemic) scleroderma (female n = 4), systemic lupus erythematosus (female n = 1), ulcerative colitis (female n = 1). c Some patients switched to or from adalimumab or etanercept during the study. d Reported comedication is derived from the moment of inclusion. Eleven patients (male = 3, female = 8) did not start with etanercept or adalimumab at the moment they were included. For these patients, comedication is derived from the moment they reported to be treated with adalimumab or etanercept for the first time. e Corticosteroids include: predniso(lo)ne, methylprednisolone, and hydrocortisone. f Thiopurines include: azathioprine, mercaptopurine, and thioguanine. g Aminosalicylates include: sulfasalazine and mesalazine (female n = 1). male RA patients [32]. Other ADRs associated with female sex that have been previously attributed to the use of biologics, such as 'fungal and herpes simplex infections' in psoriasis and psoriatic arthritis patients [31,33], or 'allergic reactions' in inflammatory bowel disease were not reported in our study [19].
Sex-specific ADRs were excluded from our study. 'Cystitis' was not considered sex specific as both sexes can theoretically experience cystitis, although the incidence of cystitis in females is higher than in men due to anatomical differences [34]. It was therefore not surprising that cystitis was reported more often by female patients.
In spite of the higher frequency of ADRs that was reported by female patients, there was no difference in reported burden.
The strengths of this study are that ADRs were patientreported and collected using structured questionnaires, including the burden of experienced ADRs. Also, the group of male and female patients included in this study was rather large compared to other studies. There were also some limitations to our study. First, other causes of ADRs, such as comedication (for example, methotrexate), could have influenced the reporting of ADRs. More female patients were using methotrexate, because of the high number of females  with RA. Also, comorbidities could have played a role in reporting ADRs. In particular, cardiovascular disease is an important comorbidity in patients with rheumatic disease [35], and clinical expression of cardiovascular manifestations has been shown to be sex related in patients with inflammatory joint disease [36]. Unfortunately, the limited data per distinct ADR withheld us from formal statistical correction for these potential confounders. Also, the causal relationship of reported ADRs was not assessed. Therefore, ADRs (such as 'arthralgia' and 'therapeutic product effect decreased') may have been related to the disease rather than an ADR. On the other hand, we consider unfiltered patient-reported data on ADRs as a strength since it reflects the patient perspective on experienced ADRs. Secondly, burden was only assessed at one time point per person (i.e. the time the ADR was first reported as a 'new ADR'), since some patients reported ADRs over longer periods than others. For future studies, it is suggested to consequently assess burden over a longer period of time and to consider the duration of the ADR as well, as the burden may change over time for every patient.
In future studies, it would also be interesting to include the reasons why ADRs were or were not reported as burdensome. In the current cohort, patients elucidated on ADR burden in an open-ended text field. For a better understanding of differences in the experienced ADR burden between women and men, these explanations could be further investigated. This may provide insights if, and which sex or gender differences in burden perspective exist, and how to address these in clinical practice.

Conclusions
Sex differences in the frequency and nature of ADRs, but not in ADR burden, exist during treatment with adalimumab and etanercept in patients with inflammatory rheumatic diseases. This should be taken into consideration when counseling patients in daily clinical practice. Furthermore, these differences should be taken into account when investigating and reporting results on ADRs.

Funding
The Dutch Biologic Monitor work was supported by the Netherlands Organisation for Health Research and Development (ZonMw) [36]. No specific funding was received from any bodies in the public, commercial, or not-for-profit sectors to carry out the work described in this article.