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. 2024 Feb 20;19(2):e0296821. doi: 10.1371/journal.pone.0296821

Burden of non-serious infections during biological use for rheumatoid arthritis

Barbara Bergmans 1,2,*, Naomi Jessurun 3, Jette van Lint 3, Jean-Luc Murk 2,4, Eugène van Puijenbroek 3,5, Esther de Vries 1,2
Editor: Sreeram V Ramagopalan6
PMCID: PMC10878515  PMID: 38377117

Abstract

Introduction

Biologicals have become a cornerstone in rheumatoid arthritis (RA) treatment. The increased risk of serious infections associated with their use is well-established. Non-serious infections, however, occur more frequently and are associated with a high socioeconomic burden and impact on quality of life but have not received the same attention in the literature to date. The aim of this study was to gain insight into the various non-serious infections reported in RA patients using biologicals and their experienced burden.

Materials and methods

The Dutch Biologic Monitor was a prospective observational study that included adults with rheumatoid arthritis and biological use who answered bimonthly questionnaires on the adverse drug reactions (ADRs) they experienced from their biological and reported the associated impact score (ranging from 1, no impact, to 5, very high impact). ADRs were assigned a MedDRA code by pharmacovigilance experts and labeled as definite, probable, possible or no infection by infectious disease professionals. Descriptive statistics were performed using medians and interquartile ranges.

Results

A total of 586 patients were included in the final analysis. Eighty-five patients (14.5%) reported a total of 421 ADRs labeled as probable or definite infections by the experts. Patient-assigned burden was ADR-specific. Upper respiratory tract infections were most frequently reported and had a high rate of recurrence or persistence, with a median impact score of 3.0 (IQR 2.0–3.0) which remained stable over time.

Discussion

Non-serious infections significantly outnumbered serious infections in this real-life cohort of RA patients using biologicals (77.1 non-serious infections and 1.3 serious infections per 100 patient years, respectively). Infections in the upper respiratory tract were rated as having an average burden, which remained constant over a long period of time. Awareness of the impact of recurrent and chronic non-serious infections may enable healthcare professionals to timely treat and maybe even prevent them, which would lessen the associated personal and socioeconomic burden.

Introduction

Rheumatoid arthritis (RA) is an auto-inflammatory disease that primarily affects the joints. Its prevalence varies geographically and has been estimated to affect up to 1.5% of the population in some regions, with women being affected two to three times as often as men [1]. Its impact is significant, with reduced quality of life and increased morbidity and mortality among its patients [2–5]. Treatment of RA is often complex and may require use of multiple immunomodulatory drugs to achieve disease remission [6]. The advent of biological therapies has marked a significant turning point in the treatment of RA. Biologicals target specific components of the immune system involved in the pathogenesis of RA. For the therapy of RA, a number of biological classes are available; each has a unique mode of action, safety profile, and efficacy. Tumor necrosis factor alpha (TNF-alpha) inhibitors are the oldest and most commonly used biological class in RA. Drugs such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are examples of TNF-alpha inhibitors. They specifically target the pro-inflammatory cytokine of the same name. Sarilumab and tocilizumab are examples of interleukin-6 (IL-6) inhibitors, which specifically target the interleukin-6 molecule. Rituximab causes a depletion of B-cells by binding to the CD-20 molecule on their surface. With abatacept, T-cell costimulation is suppressed. Biologicals are highly effective, have an acceptable benefit-to-risk profile and are well-tolerated in the long term, and are therefore increasingly used in RA treatment. However, accessibility to and the cost of these drugs lead to an unequal distribution of their use across the world [7], with their use correlating positively with a country’s social-economic status. According to Grellmann et al, biologicals are currently used in 29% of German RA patients [8].

The use of biologicals is associated with an increased risk of serious infections, the occurrence of which has been extensively studied since they hit the market in the late nineties. Moreover, published randomized controlled trials (RCTs) reveal the frequency of non-serious infections to be even 10 times higher than of serious infections [9–13], and infections are among the most frequently reported adverse reactions in RA patients using biologicals. However, unlike serious infections, non-serious infections have not been given the same attention in the scientific literature [9,14–16]. Because patients generally do not seek the help of healthcare professionals for non-serious infections, such as the common cold, healthcare professionals may underestimate their incidence and importance.

This poses the question what the occurrence and impact of non-serious infections in RA patients using biologicals really is. The most frequently reported non-serious infections during trials and observational studies of biological use are respiratory tract and urinary tract infections [9,14]. Prior research shows that such infections have a high socioeconomic burden [17–21]. Unfortunately, there is currently no standardized definition of non-serious infections, making research on this topic challenging [9].

Self-reporting of adverse drug reactions (ADRs–defined as harm caused by the correct use of the drug in question) by patients is an important component of pharmacovigilance and can take place as part of a trial or an observational study or can be based on spontaneous reporting. In spontaneous reporting, patients tend to report upon more (both known and unknown) adverse events (AEs–defined as any harm that occurred during correct or incorrect use of the drug, not necessarily reflecting a causal relationship) than their treating physicians and do so more quickly and in more detailed terms [22,23]. This may therefore contribute to earlier ADR detection. Patients report more upon the impact of the ADR on their life and well-being than health care professionals (HCPs) [24]. However, symptoms reported by patients may be of lower medical quality than the reports of HCPs [22,23].

In self-reporting as part of a trial or cohort study, patients also report more ADRs than HCPs, and agreement between HCPs and patients on ADRs is varied and dependent on the specific ADR [25,26]. Patients report more general system disorders such as fatigue and malaise. However, they report fewer infections than HCPs. As in spontaneous reporting, self-reporting during trials and observational studies is more reflective on the impact on patients’ quality of life [26,27].

Patient-generated data provide an important addition to standard HCP-based ADR monitoring [26,28,29], particularly where quality of life is concerned. As self-reporting is the only means by which ADR burden can be estimated, registration of ADR impact on daily life and well-being is an essential addition to current pharmacovigilance strategies. Having more detailed information on this aspect of ADRs may enable HCPs and patients alike to construct better treatment strategies that consider their experienced burden.

The aim of this study was to gain more insight into the various serious as well as non-serious infections reported by RA patients using biologicals, and their burden as perceived by the patients themselves. To achieve this, we used self-reported ADRs in web-based ADR questionnaires as part of the Dutch Biologic Monitor [29]. In the questionnaires patients were asked if adverse drug reactions occurred. Of course this doesn’t necessarily imply the existence of a true causal relationship; for this reason we consider the reported events as “potential ADRs”.

Materials and methods

Data collection

We used data from all RA patients included in the Dutch Biologic Monitor that collects patients’ experiences using web-based questionnaires addressing the use of biologicals and potential ADRs attributed to these drugs [29]. The Medical Ethics Committee Brabant judged that the Dutch Biologic Monitor does not require specific ethical approval (METC Brabant NW2016-66) since it collects data by means of questionnaires and existing data sources only. The monitor was approved by the scientific committees and boards of directors of participating hospitals. Patients were consecutively recruited by HCPs in nine Dutch hospitals during outpatient visits and through letters sent by their pharmacy. Patients were eligible when they were ≥ 18 years of age and had an established RA diagnosis, were treated with a biological and were proficient in Dutch. All participants provided a digital informed consent form prior to enrolment. Enrolled patients were asked to complete an online questionnaire once every two months to register potential ADRs. Patients were asked to share any experiences they had with the medications under study. These events will henceforward be referred to as "potential ADRs" because the patient suggested a causal relationship between the recorded events and the drug, but this relationship could not be verified. A causality assessment between the reported potential ADRs and the medication could not be performed. The following patient characteristics were registered in the first questionnaire: age, weight, length, comorbidities, smoking status, biological (generic and brand name and its start date) and RA-related comedication use (conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), prednisone). There was no predefined maximum number of questionnaires that could be completed by the patients in the course of time. The study was conducted from January 1, 2017, until December 31, 2020. Patients stopped receiving questionnaires when informed consent was withdrawn or if a previous questionnaire was left unanswered for 21 days.

Patient-reported ADRs

In every questionnaire, patients were asked to report on whether they experienced potential ADRs since the last questionnaire. If potential ADRs were reported, the following information was requested: a patient’s description of the potential ADR, its start date, and its burden on a five-point Likert scale [30], being 1, no burden, and 5, a very high burden. When a potential ADR was mentioned, patients were requested to report its status in each subsequent questionnaire until a stop date for the potential ADR was provided. In this way, the development of the potential ADR (getting better, getting worse, staying the same, or resolved, and if so, a stop date) was recorded, and whether the patient had contacted HCP(s) because of the ADR and which type of HCP was contacted, whether treatment of the potential ADR was provided (if applicable), whether the patient was hospitalized and what actions were taken by the patient. A potential ADR was considered serious when treatment involved hospitalization, was life-threateming or resulted in death or a significant disability [31].

Patient-reported descriptions of potential ADRs, provided as free text, were interpreted by trained assessors at the Dutch Pharmacovigilance Centre Lareb and coded using the Medical Dictionary for Regulatory Activities Terminology (MedDRA version 23.1) [32]. The MedDRA system encompasses a hierarchal structure in which individual potential ADRs can be classified according to, first, the System Organ Class (SOC), then, the High-Level Group Terms (HLGT), then, the High-Level Terms (HLT), then, the Preferred Terms (PT) and, finally, the Lower Level Terms (LLT).

Assigning infection probability and recoding by medical professionals

Since it was not always clear to what extent a reported potential ADR could be considered an infection, all reported potential ADRs were rated on the probability of being an infection by physicians specialized in infectious diseases (BB, JLM, EdV). As potential ADRs were patient-reported, generally little to no information about additional diagnostics was provided (for example, when herpes zoster was reported as a potential ADR, there was no information on whether a polymerase chain reaction (PCR) was positive for varicella zoster virus). Currently, no standardized method of assigning infection probability exists, therefore we made use of clinical judgement. Predefined options were “definite”, when infection was considered certain (for example, “herpes zoster”); “probable”, when infection was considered likely, but the description did not allow for a definitive confirmation (for example, “infection susceptibility increased”); “possible” when infection was considered unlikely but could not be ruled out (for example, “malaise”); “noninfectious” when the potential ADR was considered as definitely not an infection (for example, “hematoma”). This physician’s label did not imply any sort of causal relationship between the potential ADR and the drug. Reported potential ADRs were independently reviewed by BB, EdV and JLM (physicians specialized in infectious diseases), with BB reviewing all potential ADRs and EdV and JLM each reviewing another half, so that every potential ADR was reviewed twice. Discrepancies in rating decisions were resolved by discussion between BB, EdV, JLM and EvP (physician specialized in pharmacovigilance and general practice) until consensus was reached. Because initial MedDRA coding, as interpreted by trained MedDRA assessors at pharmacovigilance centre Lareb, showed discrepancies between the assigned coding and the expert opinion of the physicians in some cases, potential ADRs deemed definite, probable or possible infections were recoded to a more appropriate MedDRA-term by the authors when needed. For example, if the original MedDRA coding specified “inflammation of wound” under PT, the PT was recoded to “wound infection”, to align with the judgment of the potential ADR being a “definite” infection. When recoding, we decided to code only from the SOC level to PT level, since LLT’s tend to be too detailed or are synonyms of the overarching PT. The MedDRA system lacks specific information on the organ system in which infections occur. Although each PT is formally linked to a single MedDRA primary System Organ Class, it could not always be ruled out that the infection may have occurred in another organ system. Insufficient information was available to adequately reflect where in the body infections took place. To solve this, PTs were assigned a “system organ category” predefined by the authors in which the potential ADR had most likely occurred by BB. Definite, probable and possible infections were categorized into the following predefined categories: bone and joint, ear, eye, gastro-intestinal, genital, respiratory tract (divided into upper respiratory tract, lower respiratory tract), lymphatic tissue, neurological, oral, skin/soft tissue, systemic, urinary tract, other, or unknown. For a list of PTs corresponding to each category, see Table 1 in S1 Appendix. Definite infections were assigned a most likely pathogen type by BB, EdV, JLM and EvP through independent review and consensus discussion where needed (bacterial, viral, fungal or unknown, see Table 2 in S1 Appendix).

Database cleaning

Start and stop dates and age, weight and length were entered into date or numerical fields. However, no automated validation of these fields was carried out upon entering the data in the system. Consequently, we identified several inconsistencies in age, weight, length and start and stop dates of both biologicals and potential ADRs that we dealt with based on discussion among all authors until consensus was reached. See Table 3 in S1 Appendix.

Statistical analysis

Statistical analysis was performed in R version 4.2.2 [33]. The packages dplyr [34], summarytools [35] and ggplot2 [36] were used for data analysis and visualization.

Medians and interquartile ranges (IQRs) were calculated when data was not normally distributed. Outcomes were calculated for the total number of potential ADRs labeled as definite or probable infections by our team (whenever a potential ADR was reported in multiple questionnaires, it was counted multiple times). We used bar charts to visualize the distribution of probable and definite infections across various organ systems, and box plots to visualize the median impact score and percentile ranges of probable and definite infectious events in subsequent questionnaires. To achieve this, we plotted the median impact score for every questionnaire in which a probable or definite potential infectious ADR was sequentially reported (the first questionnaire in which a potential ADR was reported being “1”, the second one being “2”, etc). This was irrespective of the potential ADR reporting timeline: if a potential ADR was reported by a patient for the first time in for example the 15th questionnaire, it was plotted as questionnaire number 1 in this visualization.

Results

A total of 586 RA patients were included in the cohort, who together completed 5,388 questionnaires. See Table 1 for baseline patient characteristics. Of all patients, 30 (5.1%) also suffered from another autoimmune disease and 353 (60.2%) reported one or more other comorbidities. TNF-alpha inhibitors were the most frequently used biologicals (495 patients, 84.5%), followed by interleukin-6 antagonists (41 patients, 7.0%), T-cell costimulation inhibitors (31 patients, 5.3%), CD-20 inhibitors (16 patients, 2.7%) and other interleukin antagonists (3 patients, 0.5%).

Table 1. Baseline patient characteristics at the first questionnaire.

Characteristics (n = 586) n (%)
Female 414 (70.6)
Male 172 (29.4)
Age (mean years, SD) 59.3 (12.1)
Length (mean cm, SD) 171.9 (9.4)
Weight (mean kg, SD) 76.5 (14.9)
Concurrent autoimmune diseases (n, %)
Ankylosing spondylitis 12 (2.0)
Crohn’s Disease 6 (1.0)
Colitis ulcerosa 3 (0.5)
Remitting Seronegative Symmetrical Synovitis with Pitting Edema (RS3PE) 1 (0.2)
Sarcoidosis 1 (0.2)
Scleroderma 4 (0.7)
Sjögren 1 (0.2)
Systemic Lupus Erythematosus 1 (0.2)
Unknown 1 (0.2)
Comorbidities (n, %) a
Respiratory disorder 77 (13.1)
Cardiovascular disorder 172 (29.4)
Hypercholesterolemia 123 (21.0)
Psychiatric disorder 31 (5.3)
Cancer 13 (2.2)
Nervous system disorder 19 (3.2)
No comorbidity 179 (30.6)
Not specified 53 (9.0)
Smoking status (n, %)
Daily 63 (10.8)
Weekly 9 (1.5)
Monthly or less 21 (3.6)
Never 490 (83.6)
Not specified 3 (0.5)
RA-related comedication (n, %) a
Azathioprine 18 (3.1)
Hydroxychloroquine 61 (10.4)
Hydrocortisone 3 (0.5)
Leflunomide 39 (6.6)
Methotrexate 291 (49.5)
Prednisone 78 (13.3)
Sulfasalazine 38 (6.5)
No comedication 123 (21.0)
Not specified 32 (5.5)
Biological use (n, %)
Abatacept (T-cell costimulation inhibitor) 31 (5.3)
Adalimumab (TNF-alpha inhibitor) 184 (31.4)
Anakinra (IL-1 inhibitor) 1 (0.2)
Certolizumab pegol (TNF-alpha inhibitor) 19 (3.2)
Etanercept (TNF-alpha inhibitor) 262 (44.7)
Golimumab (TNF-alpha inhibitor) 14 (2.4)
Infliximab (TNF-alpha inhibitor) 16 (2.7)
Rituximab (anti-CD20) 16 (2.7)
Sarilumab (IL-6 inhibitor) 1 (0.2)
Secukinumab (IL-17A inhibitor) 2 (0.3)
Tocilizumab (IL-6 inhibitor) 40 (6.8)
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IL = interleukin, RA = rheumatoid arthritis; SD = standard deviation, TNF = Tumor Necrosis Factor.

aAn individual patient could have no, one or multiple comorbidities and/or comedications.

Participants answered a median of five questionnaires (range 1 to 22). One fifth of participants (n = 121, 20.6%) only completed one questionnaire, and more than half (n = 326, 55.6%) stopped participating after the fifth questionnaire (see Fig 1 in S1 Appendix). There were no significant differences in patient characteristics between patients completing only the first questionnaire and patients completing more questionnaires (see Table 4 in S1 Appendix). Together all questionnaires encompass a follow up duration of 546 patient years, with a median duration of 8.0 months per patient (IQR 2.0–20.0). More than half of the respondents (n = 311, 53.1%) had used their biological for less than three years at inclusion, the median number of months between start of the biological and start of the questionnaires being 30.0 (IQR 13.0–81.0). See Fig 2 in S1 Appendix. Fig 3 in S1 Appendix shows questionnaires were distributed and filled out around the same time every two months, therefore a cyclical pattern can be observed in the total number of filled in questionnaires per calendar week throughout the year.

More than half of the participants (n = 305, 52.0%) reported one or more potential ADRs, with a total of 2,817 potential ADRs being reported across 4,015 questionnaires. Of these, 1,950 (69%) were considered non-infectious in nature, and 867 (31%) potential ADRs were considered either possible (446, 15.8%), probable (63, 2.2%) or definite (358, 12.7%) infections. 156 (26.7%) participants reported one or more possible, probable or definite potential infectious ADRs. Overall, most potential ADRs were classified as related to the upper respiratory tract, skin and soft tissue, and systemic symptoms by our team. See Fig 1. More than half of all potential infectious ADRs were labeled as “possible infection” by our team, meaning an infection was unlikely, but could not be excluded. For example, nearly all (n = 101, 75.4%) possible skin- and soft tissue related infections were coded as SOC “General disorders and administration site conditions”, making injection site reaction the most likely explanation. We therefore describe probable and definite infections in the main text and possible infections separately in Figs 4 and 5 in S1 Appendix and Table 5 in S1 Appendix.

Fig 1. Affected organ system classes.

Fig 1

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NOS = not otherwise specified. Distribution of all infection-related potential ADRs across the various organ systems. Infection labels are shown for each organ system. One patient could contribute multiple potential ADRs.

Overall, 85 (14.5%) patients reported a total of 421 probable and definite infection ADRs, corresponding to 136 unique probable and definite potential infectious ADRs per patient. The median time between start of the biological and a reported probable or definite infection was 18.0 months (IQR 2.0–72.0). The median reported duration of probable and definite infections was 31.0 days (IQR 13.0–64.0). Overall, these potential ADRs were assigned a median impact score of 3.0 (IQR 2.0–4.0) by participants. See Table 2. Table 6 in S1 Appendix shows all potential ADRs subdivided according to organ system and experts’ infection label. See Fig 6 in S1 Appendix for an analysis of probable and definite upper respiratory tract infections throughout different seasons. There was high variability considering the duration of potential ADRs: most patients reported relatively short durations, however, incidentally, exceedingly long durations were reported. Overall, we classified most definite potential infectious ADRs as being bacterial in nature (Fig 7 in S1 Appendix).

Table 2. Characteristics of probable and definite infections in the cohort.

Number of potential ADRs (n, %) N of occurrences per patient (median, IQR)a Impact score (median, IQR) Time between start biological and potential ADR (months) (median, IQR)b Duration (days)
(median, IQR)b 		Contact HCP (n, %) Hospitalization (n, %)
All definite and probable potential infectious ADRsc
 421 3.0 (2.0–8.0) 3.0 (2.0–4.0) 18.0 (2.0–72.0) 31.0 (13.0–64.0) 207 (49.3) 8 (1.9)
All definite potential infectious ADRsc
 358 (41.29) 3.0 (2.0–5.0) 3.0 (2.0–4.0) 20.0 (4.0–69.0) 31.0 (12.5–52.3) 173 (48.3) 8 (2.2)
All probable
potential infectious ADRsc
 63 (7.27) 2.0 (1.0–5.0) 3.0 (2.0–3.0) 6.0 (0.0–80.0) 28.0 (16.0–48.0) 34 (54.0) 0 (0)
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ADR = adverse drug reaction, HCP = Healthcare provider, IQR = interquartile range, PT = MedDRA Preferred Term.

aIn a total of 156 patients reporting a possible, probable or definite infection ADR.

bWhen calculating the time between the start of the biological and the first occurrence of the potential ADR and the duration of the potential ADR, we used start dates provided by the participants. However, in a large proportion of cases, stop dates for potential ADRs were missing because of loss to follow-up or a constantly recurring/chronic infection without a stop date. For the purposes of calculating potential ADR duration in this table, we only used potential ADRs that had an available stop date.

cAll potential ADRs: The total number of probable or definite potential infectious ADRs mentioned by all patients in all questionnaires (potential ADRs are counted each time when mentioned in a questionnaire by a patient).

Impact assigned by patient

Fig 2 shows the potential ADRs’ impact scores per each questionnaire for probable and definite infections across various organ systems. Infections in skin and soft tissues and the urinary tract had comparatively high impact scores. Impact scores and the number of questionnaires in which infections were sequentially reported varied substantially depending on the affected organ system. Upper respiratory infections, in particular, had a high rate of recurrence or persistence: more than half (n = 15) of the patients who reported an upper respiratory tract infection at least once, reported it in up to three subsequent questionnaires (six months). When separating probable and definite upper respiratory tract infections into individual potential ADR-PTs (see Fig 8 in S1 Appendix), nasopharyngitis accounts for the majority of potential ADRs, followed by sinusitis. Contrary to upper respiratory tract infections, urinary tract infections were not reported for more than three consecutive questionnaires, indicating these infections may not recur as frequently. Patients with skin and soft tissue infections, lower respiratory tract infections and urinary tract infections reported a relatively high initial burden, that subsided relatively quickly over time as opposed to upper respiratory tract infections (Fig 2).

Fig 2. Impact scores per questionnaire for probable and definite infections in various organ systems.

Fig 2

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LRT = lower respiratory tract, URT = upper respiratory tract. Data are presented as patients reporting a probable or definite infection once or multiple times (x-axis) and the patient-assigned impact score (y-axis). The numbers in red represent the number of patients that reported an infection. The questionnaire in which a potential ADR was reported for the first time is indicated as “1” on the x-axis, the questionnaire in which a potential ADR in the same organ system was reported for the second time by that patient is indicated as “2” on the x-axis, etc.. In some organ systems, e.g., systemic infections, a single patient is observed that continues to mention a potential ADR in this organ system for an extended period of time.

Patients using biologicals are specifically instructed to contact their HCP in case of an infection. Out of all probable and definite potential infectious ADRs, 207 (49.3%) were followed by contact with an HCP. There was a higher rate of consultation in lower respiratory tract infections (79.4%), eye infections (72.2%) and urinary tract infections (70.4%). Conversely, an HCP was only consulted 32.6% of the time in upper respiratory tract infections. 41.8% of skin- and soft tissue infections were followed by contact by an HCP. When subdividing probable and definite skin- and soft tissue infections into individual potential infectious ADRs, 29 (36.7%) were coded as “skin infection” and not otherwise specified. At the same time, this potential ADR had a low rate of HCP consultation. See Fig 9 in S1 Appendix. Overall, the general practitioner was the most frequently consulted HCP, with a total of 122 visits. A medical specialist was consulted 99 times. For details, see Table 7 in S1 Appendix.

There were eight hospitalizations in seven patients due to definite or probable infections, corresponding to an incidence of 1.3 hospitalized patients per 100 patient years of follow-up. Three patients reported hospitalization for pneumonia, one for a fungal lower respiratory tract infection, one for an upper respiratory tract infection (which was however most likely a hospitalization because of a tonsillectomy to resolve recurrent throat infections), one for erysipelas, and one for oral herpes. Potential ADRs that led to hospitalization had a high median impact score of 5.0 (IQR 4.50–5.00).

Discussion

In this study, we evaluated the occurrence and self-reported burden of non-serious infections as reported by RA-patients using biologicals. Because it was sometimes uncertain to what extent reported potential ADRs were infections, each potential ADR was rated by four physicians specialized in infectious disease or pharmacovigilance and general practice as definite, probable or possible infection or as potential non-infectious ADR. We found 14.5% of patients reported any kind of likely (i.e., definite or probable) infection at least once during the course of their treatment; only 1.2% of patients reported the occurrence of a serious infection. Non-serious infections had a median impact score of 3.0 (IQR 2.0–4.0), which remained stable over time in upper respiratory tract infections during several months of follow-up.

In our cohort of 586 patients, only seven (1.2%) patients experienced an infection leading to hospitalization, corresponding to 1.3 serious infections per 100 patient years of follow-up. However, 85 (14.5%) patients reported a potential ADR that was considered a probable or definite infection by our team (logically, most of them being non-serious) corresponding to an incidence rate of 15.6 infected patients per 100 patient years and an event rate of 77.1 events per 100 patient years of follow-up. Non-serious infections have not been the focus of most literature on biological safety to date. Estimates of the incidence of non-serious infections in RA patients treated with biologicals have been highly variable (ranging between anywhere between 13 and 147 infectious events per 100 patient years of follow-up) [37,38]. This high variability is likely the effect of heterogeneity, bias and incomplete reporting that is inherent to harm-reporting in RCTs [39,40], aggravated by the absence of a standardized definition of non-serious infection [37–42]. The incidences we found in this study are similar to those in RCT’s and registry studies, which have a similar follow-up frequency (once every two or three months). The literature on serious infections, on the other hand, has been more consistent, reporting event rates of 2 to 10 events per 100 patient years of follow-up [43,44]. As opposed to non-serious infections, there is a standardized definition of a serious infection, and any occurrence is consistently registered and reported. It should be noted that the event rate for serious infections we found using patient-generated data falls within the previously reported range.

Infections have previously been described as especially burdensome by patients receiving biological therapies and are a frequent cause of treatment discontinuations [45,46]. In line with previous literature, the majority of these infections are non-serious in nature and are mostly related to the upper respiratory tract [9,14,47]. As for the non-serious infections in our dataset, upper respiratory tract infections were reported by the highest number of patients and in the highest number of sequential questionnaires, indicating a high rate of either recurrence or persistence of such infections. Upper respiratory tract infections were attributed an initial median impact score of 3 (IQR 2.0–3.0) by patients and remained relatively stable over several months of follow-up. The high incidence of upper respiratory tract infections is in line with existing literature [9,14]. Stjärne et al have previously established that acute rhinosinusitis, though usually self-limiting and with a very low rate of complications, in general reduces a patient’s quality of life [48]. Patients with chronic rhinosinusitis with nasal polyps also experience this as a high burden [49]. Rhinosinusitis and other upper respiratory tract infections come at considerable socioeconomic costs and work absenteeism [19,21,50–53], lead to an increase in (often unnecessary) antibiotic use and may therefore stimulate bacterial resistance [54,55]. In our dataset, only 32% of participants sought help from a HCP for upper respiratory tract infections, meaning a large proportion of these infections likely go unnoticed in regular practice, and they may be underreported in the literature to date. Considering the high burden that is attributed to these infections, and their high rate of recurrence or persistence, it is of paramount importance to create more awareness surrounding this phenomenon as the information that is currently available is likely only the tip of the iceberg.

Lower respiratory tract infections, skin and soft tissue infections and urinary tract infections were rated with higher impact scores by RA patients than upper respiratory tract infections, but interestingly impact scores dropped after the first questionnaire where they were reported. A possible explanation may be that these infections are taken more seriously and therefore more readily treated. These infections also had a markedly shorter reported duration than upper respiratory tract infections. Prior literature shows that recurrent urinary tract infections have a negative effect on patients’ experienced quality of life and also lead to significant direct and indirect economic costs [56–59]. Not surprisingly, infections leading to hospitalization (four of which were lower respiratory tract infections) were experienced as very burdensome (median impact score 5.0, IQR 4.5–5.0).

This study has several limitations. Firstly, the frequency of questionnaires (bimonthly) is not ideal for the purpose of evaluating potential infectious ADRs, as most infections have a shorter duration and can be forgotten in the course of two months, leading to recall bias. As data were provided by a third party and no changes could be made to the methodology in this study. Participants self-reported exceedingly long durations of infections, which is most likely also the result of recall bias or a different interpretation of recurrence versus persistence of infection. As illustrated in Table 2, some patients may interpret recurrent infections as a single infection that is “always present” while others may view them as multiple infections of shorter duration. Alternatively, upper respiratory tract infections may be followed by an exacerbation of chronic obstructive pulmonary disease (COPD) or asthma (13.1% of participants having reported a comorbid pulmonary condition), the symptoms of which may have been mistakenly identified as upper respiratory tract infection. Due to the absence of detailed information and the previously mentioned factors, it was impossible to discern whether an infection was recurrent or chronic. Lastly, data were obtained by using patient-reported outcomes. While patient-reported outcomes may provide valuable additional information on ADRs, they are prone to bias and underestimation, as patients often fail to recognize the causal relationship with their therapy or report (multiple) symptoms instead of an infectious disease diagnosis [26]. The same applies to the potential infectious ADRs in this database. This is illustrated by participants in this study reporting skin infections that are not otherwise specified, but did not require any medical care, meaning patients may not be able to correctly identify a skin infection. Working with patient-reported data also meant having to exclude several patient-provided start and stop dates of potential ADRs that were improbable or impossible (see Table 3 in S1 Appendix). Because of high attrition rate, stop dates of ADRs were often missing as patients left the study while the potential ADR persisted or before a stop date was registered. Nevertheless, patient-reported potential ADRs are of great additional value to pharmacovigilance, as patients generally report different aspects of ADRs than HCPs would [24]. ADR burden can only be reported by patients themselves. Limited data has been obtained so far regarding the impact of infections on a patient’s quality of life during biological therapy, which is where patient-reported outcomes using an impact score provide a high additional value. Furthermore, patient-reported outcomes provide a unique point of view: that of the patient, and not the HCP. This information is of added value for general practitioners and medical specialists alike, as a large proportion of patients will contact their HCP when they have an infection.

This study provides an overview of the patient-experienced burden of non-serious infections in biological treatment in RA. Though not life-threatening, it is clear that a significant proportion of patients (14.5%) suffers from an infection at some point during their treatment, and our data show that even such non-serious infections have a significant impact on patients’ quality of life, with a median impact score of 3.0 (out of 0 to 5). Creating more awareness of the affected organ systems and the burden of non-serious infectious ADRs may enable HCPs to timely treat and maybe even prevent them, lessening both their associated personal as well as socioeconomic burden. Future research should focus more on the occurrence and burden of non-serious infections and include multiple methods of assessing impact on quality of life.

Supporting information

S1 Appendix

(DOCX)

pone.0296821.s001.docx (920.7KB, docx)

Data Availability

A de-identified dataset cannot openly be shared because it contains potentially sensitive or identifying information. These legal restrictions logically follow from the European EU general data protection regulation (GDPR) that clarifies that information is considered personal data whenever an individual can be identified, directly or indirectly, "by reference to an identifier such as a name, an identification number, location data, an online identifier or to one or more factors specific to the physical, physiological, genetic, mental, economic, cultural or social identity of that natural person". Data requests may be sent to Pharmacovigilance Centre Lareb, Dr. A.C. Kant, PhD, Director (a.kant@lareb.nl).

Funding Statement

We confirm this is original work that has not been published elsewhere, nor is it under consideration for publication elsewhere. All authors confirm having no conflicts of interest to disclose. The Dutch Biologic Monitor was supported by the Netherlands Organisation for Health Research and Development (ZonMw) [grant number 848050005]. There was no additional external funding received for this study.

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PONE-D-23-19279Burden of non-serious infections during biological use for rheumatoid arthritisPLOS ONE

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Reviewer #2: Partly

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Reviewer #2: N/A

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Reviewer #2: Yes

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Reviewer #1: I appreciate the underlying intent of the authors in their approach, although I have reservations regarding the implementation of the bi-monthly survey. This method seems to have potentially resulted in an inaccurate representation of the actual duration of nonserious infections. This concern is particularly pronounced in cases of upper respiratory tract infections and skin and soft tissue infections, as explicitly mentioned in the manuscript.

As a general note I found the terminology of adverse drug reaction misleading when talking about nonserious infections.

More detail is needed in the methodology section regarding the process of stratifying each patient episode. The authors have separated infections into definite and probable, however there is no example of what would classify a definite infection. For example the patient stated they went to their GP and got a herpes swab or got a rapid antigen covid test and this was positive. An explanation of how the authors put episodes into each category would have been appreciated to understand how the data was sorted.

Some of the language used in the manuscript is very confusing. There was also a lot of interpretation in the results section. For example "Remarkably, only 41.8% of skin- and soft tissue infections were followed by

contact by an HCP, even though their occurrence was relatively high at a total of 79 ADRs, and such infections would normally require medical intervention." I feel like this interpretation belongs in the discussion. The authors quote the number of infection per 100 patient years. It would be nice to reference general population figures for infections as well - was this above the rate seen in the general population?

The authors state accurately in the conclusion that the study design leads to significant recall bias for patients. The impact on patients is I think worth looking into more and whether or not patients withheld medications because of it would have been interesting to divulge into.

Reviewer #2: Comments and observations to the authors on the Article “Burden of non-serious infections during biological use for rheumatoid arthritis

GENERAL COMMENTS:

I revised the paper based on suggested recommendations. I want to extend my appreciation for taking the time and effort necessary to satisfy my comments. I found a merit in your paper, otherwise I identified some concerns. I think you bring up some important issues that will spark considerable debate, both in terms of what you have actually found and in terms of the medical implications. My comments are mainly aimed at tightening up the logic and the clarity of what you have communicated and tested. The article is well written and logically structured. The originality is the theme of non-serious infections that have not been given the same attention in the literature as the serious infections had. The raise of this theme is astute and it serve very well to highlight creative and different ways of thinking about the safety of these drugs. My first claim is to accept the article with minor revisions, but I also suggest to the authors to write a more convincing reasons in support of their methodology.

SPECIFIC COMMENTS

Comment_ introduction: starting with the introduction, and wherever you say “the biologicals”, please say what you actually found, not just that there are “the biologicals”. Rheumatoid arthritis is a disease characterised by inflammation of synovial joints. Please add more detailed information about this disease (epidemiology and etc….). One of the most significant land in the RA therapeutic landscape has occurred with the introduction of biological disease modifying anti-rheumatic drugs. Please add epidemiology data on RA and biologicals drugs. There are many classes of biological drugs currently available, each with a different molecular target and differences in their efficacy and safety profile. Please describe the real-world use of your biological drugs and how they fit into your analysis.

Line 67: please add some more references to support your statement: “unlike serious infections, non-serious infections have not been given the same attention in the scientific literature”. Please add the reason why the literature did not pose so much attention to this issue: perhaps, because it has been greatly reassuring to the rheumatology community that they have been found to have an acceptable benefit-to-risk profile and are well tolerated in the long term?

Line 73: “Prior research shows that such infections have a high socioeconomic burden”: this is a crucial point in your paper, since for the clinician the most important ADRs are usually the most serious ones, but for the patient even an itching (non-serious reaction) that has been going on for years can be very disabling and annoying. A good quality of life is very important for the patient.

Line 79 and line 85: “patient tend”: in your paper it is crucial the patient view. Please stress this point, because the patient reporting is very, very important and it raised some different aspects in comparison to the physician reporting.

Line 155: I do not really understand what you mean. Why did you not report/use the causality assessment that is usually used in pharmacovigilance (I mean WHO-UMC) system, Naranjo algorithm or other updated Logistic method)? I think that a causality assessment evaluation would be important. I mean it would be important to follow these steps: “All non-serious ADR reports, not related to vaccines and with a "definite", "probable" or "possible" causality assessment, inserted into the database (period- time) were analyzed”. Please also add the criteria of non -seriousness events. Otherwise, if you would like to follow these “assigning infection probability and recoding by medical professionals” please describe better your method and especially explain you have followed a standard method recognized by the scientific literature.

Line 166: “Because MedDRA coding showed discrepancies between the assigned coding and the expert opinion of the infectious disease professionals, ADRs deemed definite, probable or possible infections were MedDRA-recoded by the authors when needed”: I do not really understand your methods. Did you change the coding assigned/identified by the patient?

Line 214: TNF-alpha inhibitors were the most frequently used biologicals (495 patients, 215 84.5%. And what about the others? And which TNF-inhibitors did you include? Can you also provide a list of PT terms related to each drug, please?

Line 342: Because it was sometimes uncertain to what extent reported ADRs were infections, each ADR was rated by four medical professionals specialized in infectious disease or adverse event registration as definite, probable or possible infection or as non-infectious ADR. This is a crucial point in your paper and this is the main point I do not really understand. I mean when an ADR is reported by a healthcare professional/citizen it is then coded via MedDRA. If the ADR is not clear, the health operators/patient is called and explanations are asked. Then a causality assessment (rating with definite, probable, etc…) is assigned to each drug-ADR pair and a severity level to each event. Which method did you use for you analysis? Just other two comments: among the limitations it would be important to also stress those of spontaneous reporting system and among the discussion to include the patient reporting system. I do not make other important requests to the other parts of the article, because, in my opinion, the line 342 is a fundamental point.

Line 423: “To the best of our knowledge, this is the first study giving an overview….” In the literature some articles describing also these non- serious ADRs. I think it would be good to cite these articles and to compare your results with their results.

General comments to the Editor:

Thank you for giving us me the opportunity to review this article. I raised some comments. The crucial point of this article is the methodology. Thank you

**********

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PLoS One. 2024 Feb 20;19(2):e0296821. doi: 10.1371/journal.pone.0296821.r002

Author response to Decision Letter 0

6 Dec 2023

Response to the reviewers “Burden of non-serious infections during biological use for rheumatoid arthritis [PONE-D-23-19279]”

Dear Editor,

We thank you for considering our manuscript for publication in PLOS ONE and for the helpful comments raised by the reviewers. Please find attached a revised version of the manuscript and the detailed list of the point-to-point responses to the reviewer questions depicted below.

We thank all reviewers for their extensive and thorough review of our manuscript and the useful comments and questions, which have improved our manuscript considerably.

Sincerely,

Barbara Bergmans et al.

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Author’s response: Thank you for bringing this to our attention. We have renamed the supplementary materials, changed figure and table legends to the upright font and adjusted table footnotes and title formats. The manuscript now meets PLOS ONE’s style requirements.

2. Thank you for stating in your Funding Statement:

“The Dutch Biologic Monitor work was supported by the Netherlands Organisation for Health Research and Development (ZonMw)

[grant number 848050005]. No funding was received for this study.”

Please provide an amended statement that declares *all* the funding or sources of support (whether external or internal to your organization) received during this study, as detailed online in our guide for authors at http://journals.plos.org/plosone/s/submit-now. Please also include the statement “There was no additional external funding received for this study.” in your updated Funding Statement.

Please include your amended Funding Statement within your cover letter. We will change the online submission form on your behalf.

Author’s response: Only the Dutch Biologic Monitor received funding. This study used data generated in this monitor but was in itself entirely unfunded. We have added the suggested sentence to the Funding Statement and amended the cover letter to include the additional funding information.

3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match.

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

Author’s response: Thank you for bringing this to our attention, this has been corrected in the version that has been resubmitted.

Reviewer #1:

1. I appreciate the underlying intent of the authors in their approach, although I have reservations regarding the implementation of the bi-monthly survey. This method seems to have potentially resulted in an inaccurate representation of the actual duration of nonserious infections. This concern is particularly pronounced in cases of upper respiratory tract infections and skin and soft tissue infections, as explicitly mentioned in the manuscript.

Author’s response: We genuinely appreciate your thoughtful evaluation of our manuscript. Your concerns regarding the bi-monthly questionnaire are well noted. While we understand and acknowledge the limitations of this approach in identifying precise timelines, the data was provided by a third party and collected through an already established methodology, which we were not able to change. We have, however, elaborated more on this point in the discussion.

Lines 438 to 449 in the manuscript (without track changes) now read:

“This study has several limitations. Firstly, the frequency of questionnaires (bimonthly) is not ideal for the purpose of evaluating potential infectious ADRs, as most infections have a shorter duration and can be forgotten in the course of two months, leading to recall bias. As data were provided by a third party, no changes could be made to the methodology in this study. Participants self-reported exceedingly long durations of infections, which is most likely also the result of recall bias or a different interpretation of recurrence versus persistence of infection. As illustrated in table 2, some patients may interpret recurrent infections as a single infection that is “always present” while others may view them as multiple infections of shorter duration. Alternatively, upper respiratory tract infections may be followed by an exacerbation of chronic obstructive pulmonary disease (COPD) or asthma (13.1% of participants having reported a comorbid pulmonary condition), the symptoms of which may have been mistakenly identified as upper respiratory tract infection.”

2. As a general note I found the terminology of adverse drug reaction misleading when talking about nonserious infections.

Author’s response: Thank you for your feedback. Though we have stated in the manuscript a causal relationship between the patient’s symptoms and the drug cannot be confirmed nor denied, we agree it is confusing to use the term ADR for the events in this study. The term “adverse events”, however, does not entirely cover the load as it implies a causal relationship does not necessarily exist, and patients were explicitly asked to report upon symptoms they themselves related to the use of the drug. We therefore now use “potential ADRs” throughout the manuscript and explain this issue in the introduction and methods sections.

Lines 126 to 129 in the manuscript (without track changes) now read:

“In this study, patients were asked to report upon events they themselves related to the drugs under study. As a causal relationship between the reported events and the drug was attributed by the patient but could not be verified, these events will henceforward be referred to as “potential ADRs”.”

Lines 143 to 147 in the manuscript (without track changes) now read:

“Enrolled patients were asked to complete an online questionnaire once every two months to register potential ADRs. Patients were asked to share any experiences they had with the medications under study. These events will henceforward be referred to as "potential ADRs" because the patient suggested a causal relationship between the recorded events and the drug, but this relationship could not be verified.”

3. More detail is needed in the methodology section regarding the process of stratifying each patient episode. The authors have separated infections into definite and probable, however there is no example of what would classify a definite infection. For example, the patient stated they went to their GP and got a herpes swab or got a rapid antigen covid test and this was positive. An explanation of how the authors put episodes into each category would have been appreciated to understand how the data was sorted.

Author’s response: Thank you for your thorough review of our manuscript. Your observation regarding the need for additional detail in the methodology section is helpful. We concur the assignment of infection probability to individual potential ADRs needs further clarification and examples and have provided these in the methods section.

Lines 182 to 207 in the manuscript (without track changes) now read:

“Since it was not always clear to what extent a reported potential ADR could be considered an infection, all reported potential ADRs were rated on the probability of being an infection by physicians specialized in infectious diseases (BB, JLM, EdV). As potential ADRs were patient-reported, generally little to no information about additional diagnostics was provided (for example, when herpes zoster was reported as a potential ADR, there was no information on whether a polymerase chain reaction (PCR) was positive for varicella zoster virus). Currently, no standardized method of assigning infection probability exists, therefore we made use of clinical judgement. Predefined options were “definite”, when infection was considered certain (for example, “herpes zoster”); “probable”, when infection was considered likely, but the description did not allow for a definitive confirmation (for example, “infection susceptibility increased”); “possible” when infection was considered unlikely but could not be ruled out (for example, “malaise”); “non-infectious” when the potential ADR was considered as definitely not an infection (for example, “hematoma”). This physician’s label did not imply any sort of causal relationship between the potential ADR and the drug. Reported potential ADRs were independently reviewed by BB, EdV and JLM (physicians specialized in infectious diseases), with BB reviewing all potential ADRs and EdV and JLM each reviewing another half, so that every potential ADR was reviewed twice. Discrepancies in rating decisions were resolved by discussion between BB, EdV, JLM and EvP (physician specialized in pharmacovigilance and general practice) until consensus was reached. Because initial MedDRA coding, as interpreted by trained MedDRA assessors at pharmacovigilance center Lareb, showed discrepancies between the assigned coding and the expert opinion of the physicians in some cases, potential ADRs deemed definite, probable or possible infections were recoded to a more appropriate MedDRA-term by the authors when needed. For example, if the original MedDRA coding specified “inflammation of wound” under PT, the PT was recoded to “wound infection”, to align with the judgment of the potential ADR being a “definite” infection.“

4. Some of the language used in the manuscript is very confusing. There was also a lot of interpretation in the results section. For example "Remarkably, only 41.8% of skin- and soft tissue infections were followed by contact by an HCP, even though their occurrence was relatively high at a total of 79 ADRs, and such infections would normally require medical intervention." I feel like this interpretation belongs in the discussion.

Author’s response: We appreciate your perspective on the distinction between interpretation and factual presentation within the results section. We have moved all text including interpretations from the results section to the discussion.

5. The authors quote the number of infection per 100 patient years. It would be nice to reference general population figures for infections as well - was this above the rate seen in the general population?

Author’s response: Thank you for your suggestion. This study made use of bi-monthly questionnaires and patient self-reporting. This makes it difficult to compare the incidence rate of infections in this study to prior literature, as studies to date were either clinical trials or registries that had follow-up intervals of three to six months, or a very limited number of dated studies examining the frequency of self-reported infections in the general population utilizing a higher frequency of questionnaires. We now elaborate some more upon this in the discussion section.

Lines 390 to 397 in the manuscript (without track changes) now read:

“Estimates of the incidence of non-serious infections in RA patients treated with biologicals have been highly variable (ranging between 13 and 147 infectious events per 100 patient years of follow-up)[32, 33]. This high variability is likely the effect of heterogeneity, bias and incomplete reporting that is inherent to harm-reporting in RCTs[34, 35], aggravated by the absence of a standardized definition of non-serious infection. The incidences we found in this study are similar to those found in RCTs and registry studies, which have a similar follow-up frequency (once every two or three months).”

6. The authors state accurately in the conclusion that the study design leads to significant recall bias for patients. The impact on patients is I think worth looking into more and whether or not patients withheld medications because of it would have been interesting to divulge into.

Author’s response: We value your insight regarding the impact on patients and your suggestions are important ones to consider. Unfortunately, no additional information on impact or discontinuation of immunosuppression was included in this dataset. We agree that it is essential for future research to employ methodologies that reduce recall bias and include multiple methods of assessing impact on quality of life.

Lines 476 to 480 in the manuscript (without track changes) now read:

“Creating more awareness of the affected organ systems and the burden of potential non-serious infectious ADRs may enable HCPs to timely treat and maybe even prevent them, lessening both their associated personal as well as socioeconomic burden. Future research should focus more on the occurrence and burden of non-serious infections and include multiple methods of assessing impact on quality of life.”

 

Reviewer #2:

Comments and observations to the authors on the Article “Burden of non-serious infections during biological use for rheumatoid arthritis

GENERAL COMMENTS:

1. I revised the paper based on suggested recommendations. I want to extend my appreciation for taking the time and effort necessary to satisfy my comments. I found a merit in your paper, otherwise I identified some concerns. I think you bring up some important issues that will spark considerable debate, both in terms of what you have actually found and in terms of the medical implications. My comments are mainly aimed at tightening up the logic and the clarity of what you have communicated and tested. The article is well written and logically structured. The originality is the theme of non-serious infections that have not been given the same attention in the literature as the serious infections had. The raise of this theme is astute and it serve very well to highlight creative and different ways of thinking about the safety of these drugs. My first claim is to accept the article with minor revisions, but I also suggest to the authors to write a more convincing reasons in support of their methodology.

Author’s response: We are sincerely grateful for your dedicated effort in reviewing and offering recommendations for the revision of our paper. We especially appreciate your positive comment regarding the originality of our topic, as we agree to the importance of recognizing the patient’s perspective in assessing drug safety. We also acknowledge your concerns regarding the clarity of the methodology, and we have amended the methods section based on your suggestions.

Lines 182 to 207 in the manuscript (without track changes) now read:

“Since it was not always clear to what extent a reported potential ADR could be considered an infection, all reported potential ADRs were rated on the probability of being an infection by physicians specialized in infectious diseases (BB, JLM, EdV). As potential ADRs were patient-reported, generally little to no information about additional diagnostics was provided (for example, when herpes zoster was reported as a potential ADR, there was no information on whether a polymerase chain reaction (PCR) was positive for varicella zoster virus). Currently, no standardized method of assigning infection probability exists, therefore we made use of clinical judgement. Predefined options were “definite”, when infection was considered certain (for example, “herpes zoster”); “probable”, when infection was considered likely, but the description did not allow for a definitive confirmation (for example, “infection susceptibility increased”); “possible” when infection was considered unlikely but could not be ruled out (for example, “malaise”); “non-infectious” when the potential ADR was considered as definitely not an infection (for example, “hematoma”). This physician’s label did not imply any sort of causal relationship between the potential ADR and the drug. Reported potential ADRs were independently reviewed by BB, EdV and JLM (physicians specialized in infectious diseases), with BB reviewing all potential ADRs and EdV and JLM each reviewing another half, so that every potential ADR was reviewed twice. Discrepancies in rating decisions were resolved by discussion between BB, EdV, JLM and EvP (physician specialized in pharmacovigilance and general practice) until consensus was reached. Because initial MedDRA coding, as interpreted by trained MedDRA assessors at pharmacovigilance center Lareb, showed discrepancies between the assigned coding and the expert opinion of the physicians in some cases, potential ADRs deemed definite, probable or possible infections were recoded to a more appropriate MedDRA-term by the authors when needed. For example, if original MedDRA coding specified “inflammation of wound” under PT, the PT was recoded to “wound infection”, to align with the judgment of the potential ADR being a “definite” infection. “

SPECIFIC COMMENTS

2. Comment_ introduction: starting with the introduction, and wherever you say “the biologicals”, please say what you actually found, not just that there are “the biologicals”. Rheumatoid arthritis is a disease characterised by inflammation of synovial joints. Please add more detailed information about this disease (epidemiology and etc….). One of the most significant land in the RA therapeutic landscape has occurred with the introduction of biological disease modifying anti-rheumatic drugs. Please add epidemiology data on RA and biologicals drugs. There are many classes of biological drugs currently available, each with a different molecular target and differences in their efficacy and safety profile. Please describe the real-world use of your biological drugs and how they fit into your analysis.

Author’s response: Thank you for your detailed recommendations regarding the enhancement of the introduction. We made substantial revisions to the introduction section, incorporating all your suggestions.

Lines 59 to 80 in the manuscript (without track changes) now read:

“Rheumatoid arthritis (RA) is an auto-inflammatory disease that primarily affects the joints. Its prevalence varies geographically and has been estimated to affect up to 1.5% of the population in some regions, with women being affected two to three times as often as men [1]. Its impact is significant, with reduced quality of life and increased morbidity and mortality among its patients[2-5]. Treatment of RA is often complex and may require use of multiple immunomodulatory drugs to achieve disease remission[6]. The advent of biological therapies has marked a significant turning point in the treatment of RA. Biologicals target specific components of the immune system involved in the pathogenesis of RA. For the therapy of RA, a number of biological classes are available; each has a unique mode of action, safety profile, and efficacy. Tumor necrosis factor alpha (TNF-alpha) inhibitors are the oldest and most commonly used biological class in RA. Drugs such as adalimumab, etanercept, certolizumab pegol, golimumab, and infliximab are examples of TNF-alpha inhibitors. They specifically target the pro-inflammatory cytokine of the same name. Sarilumab and tocilizumab are examples of interleukin-6 (IL-6) inhibitors, which specifically target the interleukin-6 molecule. Rituximab causes a depletion of B-cells by binding to the CD20 molecule on their surface. With abatacept, T-cell co-stimulation is suppressed. Biologicals are highly effective, have an acceptable benefit-to-risk profile and are well-tolerated in the long term, and are therefore increasingly used in RA treatment. However, accessibility to and the cost of these drugs lead to an unequal distribution of their use across the world[7], with their use correlating positively with a country’s socioeconomic status. According to Grellmann et al, biologicals are currently used in 29% of German RA patients[8].”

3. Line 67: please add some more references to support your statement: “unlike serious infections, non-serious infections have not been given the same attention in the scientific literature”. Please add the reason why the literature did not pose so much attention to this issue: perhaps, because it has been greatly reassuring to the rheumatology community that they have been found to have an acceptable benefit-to-risk profile and are well tolerated in the long term?

Author’s response: We agree we should elaborate more on why the various reasons non-serious infections have not been given the same attention in the scientific literature and have done so in the introduction. We feel the principal reason for this is that patients generally do not seek the help of healthcare professionals for non-serious infections, such as the common cold, and healthcare professionals therefore may underestimate their occurrence and importance. We have added several references to support our statement.

Lines 82 to 90 in the manuscript (without track changes) now read:

“The use of biologicals is associated with an increased risk of serious infections, the occurrence of which has been extensively studied since they hit the market in the late nineties. Moreover, published randomized controlled trials (RCTs) reveal the frequency of non-serious infections to be even 10 times higher than of serious infections[9-13], and infections are among the most frequently reported adverse reactions in RA patients using biologicals. However, unlike serious infections, non-serious infections have not been given the same attention in the scientific literature[9, 14-16]. Because patients generally do not seek the help of healthcare professionals for non-serious infections, such as the common cold, healthcare professionals may underestimate their incidence and importance.”

4. Line 73: “Prior research shows that such infections have a high socioeconomic burden”: this is a crucial point in your paper, since for the clinician the most important ADRs are usually the most serious ones, but for the patient even an itching (non-serious reaction) that has been going on for years can be very disabling and annoying. A good quality of life is very important for the patient.

Author’s response: Thank you for highlighting this point. We share your view that the patient’s perspective in assessing the importance of non-serious infections is essential.

5. Line 79 and line 85: “patient tend”: in your paper it is crucial the patient view. Please stress this point, because the patient reporting is very, very important and it raised some different aspects in comparison to the physician reporting.

Author’s response: Thank you for your insightful comment. We agree recognizing the unique vantage point of patients in reporting adverse reactions is crucial, and we further emphasized this point within our manuscript.

Lines 116 to 121 in the manuscript (without track changes) now read:

“Patient-generated data provide an important addition to standard HCP-based ADR monitoring[9-11], particularly where quality of life is concerned. As self-reporting is the only means by which ADR burden can be estimated, registration of ADR impact on daily life and well-being is an essential addition to current pharmacovigilance strategies. Having more detailed information on this aspect of ADRs may enable HCPs and patients alike to construct better treatment strategies that consider their experienced burden.”

6. Line 155: I do not really understand what you mean. Why did you not report/use the causality assessment that is usually used in pharmacovigilance (I mean WHO-UMC) system, Naranjo algorithm or other updated Logistic method)? I think that a causality assessment evaluation would be important. I mean it would be important to follow these steps: “All non-serious ADR reports, not related to vaccines and with a "definite", "probable" or "possible" causality assessment, inserted into the database (period- time) were analyzed”. Please also add the criteria of non -seriousness events. Otherwise, if you would like to follow these “assigning infection probability and recoding by medical professionals” please describe better your method and especially explain you have followed a standard method recognized by the scientific literature.

Author’s response: We appreciate your insight and comments regarding the methodology of our manuscript. We acknowledge we should formulate the methods section more clearly. This study made use of patient-reported data. Participants were prompted bi-monthly to answer a series of questions regarding potential ADRs they experienced which they themselves deemed a result of the medication they were using. For the purpose of this study, we were only interested in the potential ADRs that could signify an infection. Unfortunately, no standardized method of assigning infection probability currently exists. Neither the Naranjo algorithm nor the WHO-UMC algorithm have been validated for non-serious infections specifically. We therefore used our own criteria as described below. This approach is based on clinical judgement and was considered the optimal approach for this study. Every potential ADR in the dataset was independently rated by three medical professionals specialized in infectious disease or pharmacovigilance and general practice on the probability of the potential ADR being an infection. Since no standardized rating exists, we devised the following rules: a potential ADR was considered a “definite” infection when infection was considered certain (for example, herpes zoster); “probable”, when infection was considered likely, but the description lacked definitive confirmation (for example, “infection susceptibility increased”; “possible” when infection was considered unlikely but could not be ruled out (for example, “malaise”); “non-infectious” when the potential ADR was considered as definitely not an infection (for example, “hematoma”). Discrepancies in rating were resolved by discussion until consensus was reached.

We agree our manuscript needs a more thorough and detailed explanation of our methodology. We amended the relevant section and included examples.

Lines 182 to 207 in the manuscript (without track changes) now read:

“Since it was not always clear to what extent a reported potential ADR could be considered an infection, all reported potential ADRs were rated on the probability of being an infection by physicians specialized in infectious diseases (BB, JLM, EdV). As potential ADRs were patient-reported, generally little to no information about additional diagnostics was provided (for example, when herpes zoster was reported as a potential ADR, there was no information on whether a polymerase chain reaction (PCR) was positive for varicella zoster virus). Currently, no standardized method of assigning infection probability exists, therefore we made use of clinical judgement. Predefined options were “definite”, when infection was considered certain (for example, “herpes zoster”); “probable”, when infection was considered likely, but the description did not allow for a definitive confirmation (for example, “infection susceptibility increased”); “possible” when infection was considered unlikely but could not be ruled out (for example, “malaise”); “non-infectious” when the potential ADR was considered as definitely not an infection (for example, “hematoma”). This physician’s label did not imply any sort of causal relationship between the potential ADR and the drug. Reported potential ADRs were independently reviewed by BB, EdV and JLM (physicians specialized in infectious diseases), with BB reviewing all potential ADRs and EdV and JLM each reviewing another half, so that every potential ADR was reviewed twice. Discrepancies in rating decisions were resolved by discussion between BB, EdV, JLM and EvP (physician specialized in pharmacovigilance and general practice) until consensus was reached. Because initial MedDRA coding, as interpreted by trained MedDRA at pharmacovigilance center Lareb, showed discrepancies between the assigned coding and the expert opinion of the physicians in some cases, potential ADRs deemed definite, probable or possible infections were recoded to a more appropriate MedDRA-term by the authors when needed. For example, if original MedDRA coding specified “inflammation of wound” under PT, the PT was recoded to “wound infection”, to align with the judgment of the potential ADR being a “definite” infection. “

7. Line 166: “Because MedDRA coding showed discrepancies between the assigned coding and the expert opinion of the infectious disease professionals, ADRs deemed definite, probable or possible infections were MedDRA-recoded by the authors when needed”: I do not really understand your methods. Did you change the coding assigned/identified by the patient?

Author’s response: Thank you for highlighting the need to further clarify this section. The patient-reported data was coded by pharmacovigilance professionals using MedDRA. Only after assigning an infection probability ranging from possible to definite, did we analyze this MedDRA code. Initial coding was performed by pharmacovigilance assessors, not necessarily with a clinical background. Review of the cases for this study was done by four physicians specializing in infectious diseases or pharmacovigilance, which has led in a limited number of cases to recoding to a more appropriate MedDRA term. When necessary, we recoded the potential ADR using MedDRA. For example, a potential ADR was considered a “definite” infection. Original MedDRA coding specified “inflammation of wound” under PT. We recoded this PT to “wound infection”, to align with our judgement of the potential ADR being a “definite” infection. Recoding occurred in a minority of cases (22.8% of potential ADRs deemed a possible, probable or definite infection).

8. Line 214: TNF-alpha inhibitors were the most frequently used biologicals (495 patients, 215 84.5%. And what about the others? And which TNF-inhibitors did you include? Can you also provide a list of PT terms related to each drug, please?

Author’s response: Thank you for your suggestions. A list of the various included biologicals at the time of the first questionnaire can be found in Table 1 in the main text; patients used abatacept, adalimumab, anakinra, aertolizumab pegol, etanercept, golimumab, infliximab, rituximab, sarilumab, secukinumab or tocilizumab at inclusion. Some patients switched from biological during the course of the study. In line with your suggestion, we provided an overview of PTs that we considered a possible, probable or definite infection per biological class in S1 Appendix Table 8.

9. Line 342: Because it was sometimes uncertain to what extent reported ADRs were infections, each ADR was rated by four medical professionals specialized in infectious disease or adverse event registration as definite, probable or possible infection or as non-infectious ADR. This is a crucial point in your paper and this is the main point I do not really understand. I mean when an ADR is reported by a healthcare professional/citizen it is then coded via MedDRA. If the ADR is not clear, the health operators/patient is called and explanations are asked. Then a causality assessment (rating with definite, probable, etc…) is assigned to each drug-ADR pair and a severity level to each event. Which method did you use for you analysis?

Author’s response: We agree the methods section was unclear in this respect. We kindly refer to our response to the comment on line 155 (the sixth comment by reviewer #2).

10. Just other two comments: among the limitations it would be important to also stress those of spontaneous reporting system and among the discussion to include the patient reporting system. I do not make other important requests to the other parts of the article, because, in my opinion, the line 342 is a fundamental point.

Author’s response: Thank you for your insightful comment. We have included a section on the limitations of patient-reported data in the discussion. However, this study was a prospective cohort study, and we feel the limitations of traditional spontaneous reporting do not apply to this study design.

Lines 442 to 460 in the manuscript (without track changes) now read:

“Participants self-reported exceedingly long durations of infections, which is most likely also the result of recall bias or a different interpretation of recurrence or persistence of infection. As illustrated in table 2, some patients may interpret recurrent infections as a single infection that is “always present” while others may view them as multiple infections of shorter duration. Alternatively, upper respiratory tract infections may be followed by an exacerbation of chronic obstructive pulmonary disease (COPD) or asthma (13.1% of participants having reported a comorbid pulmonary condition), the symptoms of which may have been mistakenly identified as upper respiratory tract infection. Due to the absence of detailed information and the previously mentioned factors, it was impossible to discern whether an infection was recurrent or chronic. Lastly, data were obtained by using patient-reported outcomes. While patient-reported outcomes may provide valuable additional information on ADRs, they are prone to bias and underestimation, as patients often fail to recognize the causal relationship with their therapy or report (multiple) symptoms instead of an infectious disease diagnosis [26]. The same applies to the potential infectious ADRs in this database. This is illustrated by participants in this study reporting skin infections that are not otherwise specified, but did not require any medical care, meaning patients may not be able to correctly identify a skin infection. Working with patient-reported data also meant having to exclude several patient-provided start and stop dates of potential ADRs that were improbable or impossible (see S1 Appendix Table 3).”

11. Line 423: “To the best of our knowledge, this is the first study giving an overview….” In the literature some articles describing also these non- serious ADRs. I think it would be good to cite these articles and to compare your results with their results.

Author’s response: We appreciate your observation and have included references to studies focusing on ADRs in biological use.

Lines 404 to 407 in the manuscript (without track changes) now read:

“Infections have previously been described as especially burdensome by patients receiving biological therapies and are a frequent cause of treatment discontinuations[40, 41]. In line with previous literature, the majority of these infections are non-serious in nature and are mostly related to the upper respiratory tract[9, 14, 42].”

Attachment

Submitted filename: Response to Reviewers.docx

pone.0296821.s002.docx (64KB, docx)

Decision Letter 1

Sreeram V Ramagopalan

19 Dec 2023

Burden of non-serious infections during biological use for rheumatoid arthritis

PONE-D-23-19279R1

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Acceptance letter

Sreeram V Ramagopalan

9 Feb 2024

PONE-D-23-19279R1

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Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Appendix

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    pone.0296821.s001.docx (920.7KB, docx)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0296821.s002.docx (64KB, docx)

    Data Availability Statement

    A de-identified dataset cannot openly be shared because it contains potentially sensitive or identifying information. These legal restrictions logically follow from the European EU general data protection regulation (GDPR) that clarifies that information is considered personal data whenever an individual can be identified, directly or indirectly, "by reference to an identifier such as a name, an identification number, location data, an online identifier or to one or more factors specific to the physical, physiological, genetic, mental, economic, cultural or social identity of that natural person". Data requests may be sent to Pharmacovigilance Centre Lareb, Dr. A.C. Kant, PhD, Director (a.kant@lareb.nl).

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