Abstract
Background:
Treatment guidance and real-world data assessing the management and burden of isolated proctitis (IP) are limited.
Objective:
We aimed to understand disease burden in ulcerative colitis (UC) patients with different degrees of disease extension, focusing on IP.
Design:
A cross-sectional survey, with retrospective data collection, of physicians and their consulting patients was conducted in France, Germany, Italy, Spain, the United Kingdom, and the United States between January 2020 and March 2021.
Methods:
Data were drawn from the Adelphi Real World UC Disease Specific Programme™. Physicians reported clinical presentation and treatment history for patients with UC. Patients were stratified according to their disease extension into IP (non-refractory (never received an immunomodulator (IM)/advanced therapy (AT)) or refractory (received an IM/AT)) and more extensive UC (MEUC) groups. Analyses were descriptive.
Results:
Among patients with IP (n = 221) and MEUC (n = 1607), respectively, the most common symptoms were abdominal pain (33.8% and 26.0%), bowel urgency (22.7% and 23.6%), and fatigue (22.7% and 23.8%). Physicians also commonly reported passing mucus (19.0%), tenesmus (15.7%), and rectal bleeding (15.3%) among patients with IP. Following diagnosis, 21.3% of IP and 42.8% of MEUC patients had received an IM, and 33.5% of IP and 68.9% of MEUC patients had received an AT. According to derived total Mayo scores, at consultation, 40.3% (95% confidence interval: 33.7, 47.1) of IP and 50.4% (47.9, 52.9) of MEUC patients were in remission; the lowest proportion of patients in remission was among refractory IP patients (35.0% (25.8, 45.0)).
Conclusion:
Patients with IP experienced a range of symptoms, with many requiring treatment beyond the guideline-recommended first-line conventional therapies. In addition, the majority of IP patients with IM and/or AT experience were not in remission.
Introduction
Ulcerative colitis (UC) is an idiopathic immune-mediated disease characterized by chronic inflammation of the mucosal surface of the bowel. 1 Inflammation in UC usually begins in the rectum and can extend to incorporate the rest of the colon. 2 The extent of colorectal inflammation can be classified in the following ways: isolated proctitis (IP), also commonly referred to as ulcerative proctitis, where involvement is limited to the rectum (E1); left-sided UC (E2), where the disease extends to include the left side of the colon, encompassing E1; and extensive colitis (E3), where the disease extends beyond the splenic flexure, encompassing both E1 and E2. 3
Approximately 20%–30% of patients with UC present with IP. Symptoms of IP are often distressing and can include rectal bleeding, tenesmus, urgency, and fecal incontinence.4,5 The disease burden experienced by patients with IP as a result of these symptoms is significant, often leading to frequent discomfort, impaired quality of life, and the need for ongoing medical management to prevent relapses and maintain remission.6–8
Further disease extension is common, with a meta-analysis in patients with IP in North America and Europe reporting that 20%–38% of patients progressed to left-sided or extensive colitis.7,9 There are multiple risk factors associated with disease extension, which include disease severity at the time of diagnosis, uncontrolled disease, the need for corticosteroids at the time of diagnosis, and one or more flares within the first year after diagnosis. 10 Disease extension is clinically important, as progression beyond the rectum has been associated with an increased risk of treatment escalation, hospitalization, and colectomy. 11 Preventing disease extension, therefore, represents an important therapeutic goal in the treatment and management of IP. 7
Timely treatment of IP is important to reduce the risk of proximal disease extension.7,12 While there are a variety of advanced therapies (ATs) available for patients with moderate-to-severe UC, there remains limited guidance for patients with IP who are not responding to conventional treatment. The European Crohn’s and Colitis Organisation (ECCO) guidelines recommend that patients with IP are treated with topical (rectal) 5-aminosalicylic acid (5-ASA) at first line, and in cases where this does not control disease, the guidelines recommend escalating treatment to include topical corticosteroids, or systemic therapies such as oral 5-ASA or corticosteroids. 13 Rectal therapies are used extensively in the treatment of IP, with non-adherence a significant issue that can lead to suboptimal disease management and increased symptom burden. 14 In some cases, immunomodulators (IMs) or systemic ATs, such as biologics or small molecules, may be considered when symptoms persist despite standard treatment. In patients with refractory IP who have failed these treatment approaches, surgery may be required or, in some cases, chosen as a preferred option before AT. 8
Historically, there have been limited data on patients with IP, especially surrounding additional treatment guidance, as this population has been systematically excluded from phase III clinical trials for AT. 7 However, a phase III randomized trial investigating the efficacy of etrasimod, a sphingosine 1-phosphate receptor modulator, for the treatment of UC included a subgroup of patients with IP and found an increase in the proportion of patients with IP experiencing symptomatic and clinical remission after treatment with etrasimod, when compared with placebo.15,16 In addition, the retrospective real-world NIHR BioResource study in the United Kingdom of 198 patients with a confirmed diagnosis of ulcerative proctitis identified that vedolizumab exhibited the highest drug persistence compared to infliximab, adalimumab, tofacitinib, and golimumab. 17 However, there remains a paucity of data relating to how IP is being managed in the real world, as well as the burden of disease experienced by patients.
Therefore, the objective of this study was to understand disease burden among UC patients in the real world with different degrees of disease extension, with a focus on IP, by describing clinical characteristics and treatment pathways.
Materials and methods
Study design
Data were drawn from the Adelphi Real World UC Disease Specific Programme (DSP)™, a cross-sectional survey with elements of retrospective data collection of patients and physicians (gastroenterologists) conducted in routine clinical practice in Europe (France, Germany, Italy, Spain, and the United Kingdom) and the United States between January 2020 and March 2021. The DSP methodology has been previously described,18,19 validated, 20 and demonstrated to be representative and consistent over time. 21
Following completion of a short screening questionnaire, physicians were recruited to participate by local fieldwork partners. Physicians were eligible to participate if they were actively involved in the management of patients with inflammatory bowel disease, which was defined as seeing at least five patients with UC and five patients with Crohn’s disease in a typical month. All data in this study were physician-reported, captured either at the time of the patient consultation or retrospectively from patient medical records, with no prospective follow-up. Each participating physician was asked to collect information from their next seven patients with UC, who presented consecutively in routine clinical practice, without pre-selection, provided they met the inclusion criteria. Data collected at the time of consultation included patient demographics, disease extension, symptom presentation, and components of the Mayo score (allowing the Mayo score to be derived for all patients). Historical data captured from patient medical records included disease extension at diagnosis and treatment history.
Patients were eligible for inclusion if they were 18 years of age or older and had a confirmed diagnosis of UC. Patients also had to meet any one of the following criteria to be included in the study: had received either a corticosteroid, IM (including thiopurines and methotrexate), biologic (anti-tumor necrosis factor, anti-integrin, or anti-interleukin), or a Janus kinase (JAK) inhibitor for their UC since diagnosis, had been considered moderate or severe at some point based on the physician’s evaluation, or had a derived total Mayo score of >4 at some point since diagnosis. Patients involved in clinical trials were excluded from the study.
This study was performed in full accordance with legislation at the time of data collection, including the European Pharmaceutical Marketing Research Association, 22 the US Health Insurance Portability and Accountability Act 1996, 23 Health Information Technology for Economic and Clinical Health Act, 24 and the Declaration of Helsinki and subsequent amendments. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 25
Patient groups
Disease extension was captured at two time points: at the time of the patient’s consultation with the physician and at diagnosis (extracted from the patient’s medical records).
Patients were split into seven groups according to the extent of their disease and the therapy they were receiving at the time of consultation or had received since diagnosis. One group included all patients with IP (E1) at both diagnosis and consultation; this group was further divided into two subgroups based on treatment experience since diagnosis: “non-refractory IP” (had never received an IM and/or AT) and “refractory IP” (had received an IM and/or AT). A second group included patients with “more extensive UC (MEUC)” defined as patients with E2 and/or E3 at both diagnosis and consultation. Patients in the MEUC group were further categorized into “MEUC IM/AT naïve” (had never received IM and/or AT) and “MEUC IM/AT” (had received an IM and/or AT). A final group comprised patients with “proctitis with proximal extension (PPE),” which included patients who were classified as E1 at diagnosis whose disease had progressed to E2 or E3 by the time of consultation (Figure 1). Results for the PPE and MEUC IM/AT-naïve groups are included in the Supplemental Material.
A schematic diagram of the seven groups of patients with ulcerative colitis included in this study.
Study measures
To allow for the classification of patient disease activity (in remission/mild/moderate/severe), the components of the derived total Mayo Score for patients were captured. The derived total Mayo score included the following four physician-reported components: stool frequency, rectal bleeding, physician global assessment, and a measure of mucosal inflammation by endoscopy. The score for each category ranges from 0 to 3, with 0 being normal and 3 being severe. 26 The scores for each of the components are summed to give a derived total Mayo score on a scale of 0–12, where 0–2 indicates remission, 3–5 is mild, 6–10 is moderate, and >10 is severe disease.
In this study, disease burden was defined as the overall impact of UC on the patient, as reflected by symptom frequency, disease activity, and treatment patterns.
Data analysis
All analyses were descriptive in nature, with numerical variables shown as means and standard deviations (SD) and categorical variables shown as frequency counts (n) and percentages of patients in each group. No bivariate tests were run on these data, so where comparative language has been used between cohorts, these comparisons are relevant only to our study sample, and further investigation may be needed to verify our study findings. Confidence intervals (CIs) were also reported, with CIs for all data points included in the Supplemental Material to provide a better sense of the underlying variability.
Analyses were conducted in Stata v17.0. 27 Missing data were not imputed; therefore, sample sizes could vary between analyses and thus were reported separately for each analysis.
Results
Patient demographics
A total of 333 physicians reported on 1828 patients included in the study, based on the extent of their disease at diagnosis and at consultation (Figure 1). Of all patients with IP (n = 221), 118 had non-refractory IP and 103 had refractory IP, mean (SD) patient age was 39.3 (13.7) years, 50.7% (95% CI: 43.9, 57.4) were female, and mean (SD) time since diagnosis of UC was 3.3 (4.6) years (Table 1). Mean age and time since diagnosis appeared to be similar across IP subgroups; however, 57.3% (47.2, 67.0) of refractory IP patients were female, whereas 44.9% (35.7, 54.3) of non-refractory IP patients were female.
Patient demographics, clinical characteristics, and healthcare resource utilization across patients with varying disease extension reported by physicians.
As part of the definition of the groups, patients in the non-refractory IP group had not received an IM or AT, and patients in the refractory IP and MEUC IM/AT groups had to have received IM or AT since diagnosis.
Includes patients with known data only.
CI, confidence interval; HCP, healthcare professional; IM/AT, immunomodulator/advanced therapy—advanced therapy includes biologics and Janus kinase inhibitor; IP, isolated proctitis; MEUC, more extensive ulcerative colitis; SD, standard deviation.
Physicians reported data for a total of 1607 MEUC patients, of whom 1308 had received an IM and/or AT. MEUC patients had a mean (SD) age of 40.2 (14.5) years, disease duration of 5.0 (6.0) years, and 44.6% (95% CI: 42.1, 47.0) were female. Patients with MEUC who had received an IM and/or AT appeared to have similar demographic characteristics to the overall MEUC population (Table 1).
Physician characteristics are presented in Supplemental Table 1.
UC symptom prevalence
Common symptoms reported by physicians included abdominal pain (33.8% (95% CI: 27.5, 40.5) of patients with IP and 26.0% (23.9, 28.3) of patients with MEUC), bowel urgency (22.7% (17.3, 28.9) with IP and 23.6% (21.5, 25.8) with MEUC), and fatigue (22.7% (17.3, 28.9) with IP and 23.8% (21.7, 25.9); Figure 2, Supplemental Table 2).
Most common physician-reported symptoms across patients with varying disease extent.
Anal discharge/passing of mucus was experienced by 19.0% (14.0, 24.9) with IP, and only 8.7% (7.4, 10.2) with MEUC. A similar trend was observed for tenesmus, seen in 15.7% (11.2, 21.3) with IP and 10.1% (8.6, 11.6) with MEUC. Anemia was experienced by 23.3% (21.3, 25.5) of those with MEUC and 17.6% (12.8, 23.3) of those with IP.
When looking across the subgroups, abdominal pain was reported by physicians for 41.7% (32.1, 51.9) of patients with refractory IP, 26.5% (18.7, 35.7) with non-refractory IP, and 24.8% (22.5, 27.2) with MEUC IM/AT. Rectal bleeding was most frequently observed among non-refractory IP patients (18.6% (11.9, 27.0)). This was experienced by 12.2% (10.4, 14.1) of MEUC IM/AT patients and 11.7% (6.2, 19.5) of refractory IP patients. Further information on symptom prevalence across subgroups can be found in Supplemental Table 2.
Derived Mayo score
According to the derived total Mayo scores, at the time of consultation, 40.3% (95% CI: 33.7, 47.1) of IP and 50.4% (47.9, 52.9) of MEUC patients were in remission (Mayo score 0–2; Figure 3). Within subgroups, remission was observed in 35.0% (25.8, 45.0) of refractory IP patients and 44.9% (35.7, 54.3) of non-refractory IP patients. Among patients in the MEUC IM/AT group, 51.5% (48.7, 54.2) were in remission.
Physician-reported derived total Mayo scores at the time of consultation across patients with varying disease extension.
Moderate disease activity (Mayo score 6–10) was observed in 32.6% (26.4, 39.2) of patients with IP and 23.5% (21.5, 25.7) of patients with MEUC. In the refractory IP patients, 35.0% (25.8, 45.0) were categorized as moderate. Overall, severe disease activity (Mayo score >10) was not widely experienced in our patient populations (Figure 3).
Treatment class received and line of treatment
Following diagnosis, 5-ASA (oral and/or rectal) was commonly prescribed to both IP and MEUC patients (84.2% and 78.1%, respectively). Corticosteroids were prescribed to 58.6% of MEUC patients versus 48.4% of IP patients (Figure 4). Of all patients with IP, IMs and biologics were prescribed in 21.3% and 33.0% of patients, respectively, since diagnosis. For patients with MEUC, IMs and biologics were prescribed in 42.8% and 67.8% of patients, respectively. Since diagnosis, 33.5% of patients with IP had received an AT compared to 68.9% of MEUC patients (Figure 5). Among patients with IP, 27.1% had received one line of AT, and 6.4% had received two or more lines.
Physician-reported type of therapy received since diagnosis and at consultation across patients with varying disease extension.
Number of AT lines received at the time of consultation across patients with varying disease extension.
At the time of consultation, 5-ASA was prescribed to 66.1% of patients with IP and 50.7% of patients with MEUC (Figure 4). Similarly, corticosteroids were prescribed to 24.9% of IP patients and 19.9% of MEUC patients. IMs were prescribed to 14.5% of IP and 22.0% of MEUC patients, while biologic prescription in IP patients (31.7%) was half that of MEUC patients (61.9%). In addition, 0.9% of patients with IP and 4.3% of MEUC patients were receiving a JAK inhibitor (Figure 4 and Supplemental Table 2). Among patients who were receiving a biologic, 4.5% of IP and 14.5% of MEUC patients were receiving anti-integrin.
Across subgroups, almost all treatment types were prescribed to a numerically higher proportion of MEUC IM/AT patients compared to refractory IP patients, since diagnosis, including 5-ASA (74.8% vs 67.0%), corticosteroid (56.6% vs 45.6%), IM (52.5% vs 45.6%), biologic (83.3% vs 70.9%), and JAK inhibitors (5.7% vs 1.9%). This was also observed at consultation (5-ASA: 42.7% vs 32.0%, corticosteroid: 14.1% vs 13.6%, IM: 27.1% vs 31.1%, biologic: 76.1% vs 68.0%, JAK inhibitors: 5.3% vs 1.9%).
Healthcare resource utilization
Overall, patients with IP had a mean (SD) of 4.6 (4.4) visits to a healthcare professional in the 12 months prior to the time of consultation, while MEUC patients had 6.0 (5.2) visits (Table 1). In the 12 months prior to data collection, 10.3% (95% CI: 6.4, 15.5) of IP and 17.6% (15.6, 19.6) of MEUC patients had been hospitalized due to their UC. When looking across the subgroups, 18.8% (16.6, 21.2) of those with MEUC IM/AT, 15.1% (8.5, 24.0) of those with refractory IP, and 5.9% (2.2, 12.5) of those with non-refractory IP had been hospitalized due to their UC in the 12 months prior. Overall, 4.1% (1.9, 7.6) of IP patients had undergone UC-related surgery compared to 2.5% (1.8, 3.4) of patients with MEUC.
Discussion
This study investigated the burden among patients with UC experiencing different degrees of disease extension, with particular emphasis on patients with IP, including refractory IP, and reported on their clinical characteristics, symptoms, and treatment patterns. Patients with refractory IP represent a subgroup of patients with UC where further research is needed to supplement the limited existing knowledge on disease burden and treatment outcomes. Our study showed that 33.5% of all patients with IP and 36.0% of patients with refractory IP had a derived total Mayo score of 6–12, indicative of moderate or severe disease activity. This contrasts with the general perception that IP is a milder form of disease 28 and suggests that a substantial proportion of patients with IP in our sample had disease activity that may be more commonly associated with more extensive disease. These findings highlight the need for further research to better understand treatment approaches and the potential role of ATs for patients with refractory IP.
In this study, physicians reported abdominal pain, bowel urgency, and fatigue in both the IP and MEUC patient groups. These findings are consistent with existing literature describing similar symptom patterns among patients with IP, 28 with bowel urgency frequently identified as a prominent and burdensome symptom, supporting the symptom profile observed in this cohort.5,29,30 These physician-reported symptoms may also reflect the extent of disease, with tenesmus, rectal bleeding, and passing mucus reported among patients with IP, and anemia reported among patients with MEUC.
We found that rectal bleeding was most frequently observed among IP patients, which may reflect its role as an early marker of active rectal inflammation. In UC, inflammation typically begins in the rectum, and rectal bleeding is a common symptom of proctitis.2,4 In our cohort, rectal bleeding was more often reported in the non-refractory IP group (18.6%) than in the refractory group (11.7%). Differences in treatment exposure, symptom patterns, or disease behavior between refractory and non-refractory IP patients could potentially contribute to variations in reported bleeding prevalence, although this requires further investigation.
Abdominal pain is a commonly reported symptom in patients with UC, with previous studies showing that more than 58% experience this symptom. 31 Although abdominal pain is generally not considered characteristic of IP, 28 physicians in our study reported both abdominal pain and cramping, particularly among patients with refractory IP. Evidence on abdominal pain in IP remains limited; however, a prior study has similarly documented its occurrence, with affected patients experiencing a disease burden comparable to those with UC. 32 Taken together, these findings indicate that patients with IP may experience a broader range of symptoms than is often recognized.
According to ECCO guidelines, 5-ASA and corticosteroids, particularly in rectal formulations (suppository or foam), are recommended as first-line therapies for IP to directly target the site of inflammation. 8 However, for patients with active proctitis who do not respond to conventional treatment, ECCO recommends considering systemic steroids, an IM, or AT such as biologics, as additional treatment options.8,13 More than a quarter of patients with IP in this study were receiving IM/AT and thus had already escalated beyond current ECCO guidelines for first-line treatment. While our findings were similar to a previous study, which reported that just over a quarter of patients with IP were receiving biologic agents, 33 a different study reported that 11.0% of patients with IP were receiving IM and/or AT, which is a considerably lower rate than our findings. 34
Despite some patients with IP advancing beyond conventional treatment to IM and AT, our study showed that some of these patients continued to experience a high disease burden. The percentage of patients not in remission was 40.4% among patients with IP and 50.4% among patients with MEUC. These findings highlight a gap in effective treatment options for patients with IP, as even after progressing to more intensive therapies, patients remain symptomatic. These findings emphasize the need for treatments with proven efficacy in patients with IP, particularly those who do not respond to conventional treatment. Previous studies have shown the importance of achieving remission as patients with active disease experience a significant burden across most quality-of-life domains, including poor physical and mental health. 35 One prospective observational study demonstrated that achievement of clinical remission normalized health-related quality of life in 82% of patients with UC. 36
As patients with IP have historically been systematically excluded from phase III clinical trials of ATs, 37 there is limited evidence to support the efficacy of therapeutic interventions for patients with refractory IP. 28 A previous study conducted using the ENEIDA registry demonstrated that anti-TNF biologics were ineffective in half of patients with refractory IP, highlighting a lack of clarity regarding which AT would be most appropriate and efficacious in instances where patients need to escalate beyond conventional therapy. 34 However, the need for efficacious therapeutic options for patients with IP is becoming more widely recognized, as clinical trials for recently developed ATs, such as etrasimod, have included these patients and demonstrated efficacy in this patient population. 15
The Adelphi Real World DSP methodology has several key strengths, including that it is a large, multinational, cross-sectional survey providing valuable data on patient and physician populations in real-world clinical practice settings. The DSP has minimal participant eligibility criteria, allowing for the inclusion of a broader patient population than what is typically included in studies such as randomized controlled trials. However, there are some limitations to consider: the patient data may not reflect the general UC population and specifically, the entire IP population, as patients with more severe disease and/or those who visit their physicians more frequently may have a higher likelihood of being included. Specifically, inclusion criteria prioritized patients with a history of moderate to severe disease or total Mayo score >4, which may result in underrepresentation of patients with milder disease, who are likely to be well controlled on first-line therapies. Physicians provided data for a consecutive series of patients to avoid selection bias, but no formal patient selection verification procedures were in place. Identification of the target patient group was not based on a formalized diagnostic checklist, but rather the judgment of the respondent physician, as is representative of a physician’s real-world classification of the patient. While recall bias may have affected physician responses, the data for these analyses were collected at the time of each patient’s appointment or from patient medical records, to mitigate this. It is also possible that some patients with IP presenting for consultation represent a subgroup with intolerance or non-response to topical 5-ASA therapies, which may contribute to higher observed disease burden or disease activity; however, as data on treatment tolerance and side effects were not available in this study, we were unable to assess this directly. Future studies should explore this potential source of selection bias to better understand differences in disease burden across patient groups.
As this study was cross-sectional, patients were at different stages of their disease journey at the time of the study, which meant that disease extension was only captured at two time points (diagnosis and consultation)—therefore, it is not known whether there was a change in disease extent between these two time points. In addition, the cross-sectional design of the study does not allow for identification of causal relationships. Disease activity was assessed using a derived Mayo score, which may limit the precision of disease activity assessment and should be considered when interpreting these findings. Data regarding the route of administration for prescribed treatments were not captured; therefore, this study did not include details about whether 5-ASA or steroid treatments were oral or topical. As the aim of this study was to explore disease burden and treatment patterns within UC subgroups, the data were reported descriptively, and this prevented any conclusions about causal relationships or significant associations. Future research building on these findings should further explore the differences between the UC subgroups using adjusted analysis. In addition, our study did not capture information on time to surgery or to initiation of biologic therapy. These factors could influence treatment outcomes and disease progression, highlighting the need for further research to explore their impact in patients with IP.
Conclusion
In this study, patients with IP were found to have a high disease burden, and a proportion of patients required treatment with IMs and ATs, beyond the guideline-recommended first-line conventional therapies. Furthermore, the majority of IP patients who had IM and/or AT experience were not in remission at the time of consultation. Given the limited available clinical trial and real-world data on assessing advanced treatments for IP patients, this suggests that novel therapies and/or treatment optimization may be needed for patients with IP.
Supplemental Material
sj-doc-1-tag-10.1177_17562848261448080 – Supplemental material for Clinical characteristics and treatment pathways of ulcerative colitis patients with isolated proctitis in Europe and the United States
Supplemental material, sj-doc-1-tag-10.1177_17562848261448080 for Clinical characteristics and treatment pathways of ulcerative colitis patients with isolated proctitis in Europe and the United States by Alessandro Armuzzi, Silvio Danese, Manuel Barreiro-de Acosta, Peter Hur, Lauren Bartolome, Karolina Wosik, Hannah Knight, Vanda Palace and Laurent Peyrin-Biroulet in Therapeutic Advances in Gastroenterology
Supplemental Material
sj-docx-2-tag-10.1177_17562848261448080 – Supplemental material for Clinical characteristics and treatment pathways of ulcerative colitis patients with isolated proctitis in Europe and the United States
Supplemental material, sj-docx-2-tag-10.1177_17562848261448080 for Clinical characteristics and treatment pathways of ulcerative colitis patients with isolated proctitis in Europe and the United States by Alessandro Armuzzi, Silvio Danese, Manuel Barreiro-de Acosta, Peter Hur, Lauren Bartolome, Karolina Wosik, Hannah Knight, Vanda Palace and Laurent Peyrin-Biroulet in Therapeutic Advances in Gastroenterology
Footnotes
Acknowledgements
The authors received assistance in the submission of this manuscript from Natasha Jones, an employee of Adelphi Real World, which was a paid consultant to Pfizer in connection with the development of this manuscript. All authors authorized the submission and have approved all statements and declarations included in the submission.
Declarations
Supplemental material
Supplemental material for this article is available online.
References
Supplementary Material
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