Introduction
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by periods of remissions and exacerbations with an overall prevalence of 20% in childhood and 2–5% in adulthood [1], which significantly worsens the quality of patients’ life [2]. The treatment for AD includes emollients, which are a crucial part of the therapeutic process, no matter what the severity of the disease is. Other treatments for AD are topical anti-inflammatory drugs like corticosteroids (TCS), calcineurin inhibitors (TCI), systemic immunosuppressive and immunomodulatory drugs as well as phototherapy [3].
Before the era of novel treatments with biologics and small molecules in AD, systemic treatment for severe AD in Poland included corticosteroids (short pulses), cyclosporine A (registered for treating adults with severe AD), methotrexate (off-label), azathioprine (off-label) and mycophenolate mofetil (off-label).
Recent years were rich in the clinical trials focusing on suppressing the immune system involved in underlying inflammatory response in AD directly or indirectly. Understanding the mechanisms of AD has led to the discovery of two new therapeutic strategies for general treatment: monoclonal antibodies directed against interleukins or their receptors, and small molecule drugs that inhibit Janus kinases-signal transducer and activator of transcription protein (JAK-STAT) signaling pathways [4]. Some of these drugs have already been registered by the European Medicines Agency (EMA) and/or U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe AD. These new drugs are reimbursed in Poland too, if specific condition and requirements are fulfilled.
One of the key components of patient-centered healthcare is shared decision-making (SDM). It involves patients in decisions about their healthcare and allows for greater engagement in the therapeutic process. A study of Umar et al. established that adjusting therapy to patients’ preferences is associated with improved patient satisfaction with treatment. Physicians’ recommendations based on patients’ preferences were related to four subscales such as effectiveness, side-effects, convenience and global satisfaction [5]. A study on SDM in a group of individuals suffering from alopecia areata (AA) demonstrated that patients wanted to be included in the therapy selection process, it also resulted in less decisional regret [6]. A scoping review conducted by Morrison et al. regarding shared decision making in rheumatology showed improved patient satisfaction and treatment adherence [7]. Also in the treatment of asthma, taking patients’ therapeutic decisions into account significantly improved treatment outcomes [8].
With the influx of new treatment options for AD, it is important for the physicians to know patients most-valued treatment attributes, side effects that could keep patients from taking the drug and the most convenient route of administration of the drug.
There are very few studies giving answers for the questions above, and, to our knowledge, this is one of the first such study in Poland.
Material and methods
We conducted an original, anonymous questionnaire among patients aged over 18 years with AD. We used Google® Forms to design and generate the questionnaire and distributed it to the patients from the dermatology clinic in Gdansk (Poland) and online support groups for adults with AD. All respondents were given the same questionnaire. We measured the severity of AD by Patient-Oriented Scoring Atopic Dermatitis (PO-SCORAD). We analyzed questionnaires of patients with moderate to severe AD who could be possibly qualified for systemic therapy, as well as patients with mild AD symptoms as patients in possible remission.
The questionnaire was divided into three parts: demographics, preferences regarding the novel medications in AD and acceptability of potential side effects. The demographics section consisted of data regarding the patient (age, gender, residence, education), therapies that the patient has used so far in the treatment of AD (topical or/and systemic) and the level of satisfaction with the treatment so far. In the second section, patients were asked to choose the characteristics of the drugs and expectations regarding treatment outcomes (table 1).
The third part is based on the study of Boeri et al. [9] and data available in the literature on the frequency of individual adverse drug reactions. It refers to the degree to which patients are able to accept the potential risk of a given adverse reaction resulting from the use of the drug (table 2).
Respondents not diagnosed by a medical professional were excluded from the study.
Statistical analysis
Completed questionnaires were downloaded and prepared as tables in Microsoft Excel. In order to analyze the data, binary logistic regression and Pearson correlation were used in JASP 0.17.1.0 software. P-value equal to or less than 0.05 was considered statistically significant. Categorical data were summarized by percentages and frequencies.
Results
Demography
For the study we enrolled 174 respondents, however we excluded 14 of them as they were not diagnosed by medical professionals or provided an incomplete questionnaire. In the final data from 160 questionnaires, nearly half (46.6% (n = 74)) of the respondents were in the age between 26–35. The smallest group of our respondents comprised of patients aged over 46 years old (2.5% (n = 4)). The majority of the respondents (76.3% (n = 122)) were females, while the remaining 23.8% (n = 38) were males. Over 70% of respondents live in a city with population over 150 000. Up to 87.5% of the respondents were diagnosed with AD more than 2 years ago. The average PO-SCORAD was 53.675625 ±16.03275243 (min.: 0; max.: 89.5). Up to 63.3% of patients have PO-SCORAD greater than 50, which is equivalent to the severe form of the disease.
Overall 96% of respondents used some form of topical treatment and 28% of respondents were already treated with systemic treatment in the past.
Preferences of systemic treatment in AD
What attribute (improving skin appearance or itch reduction) is more important?
For 55.6% (n = 89) of respondents, itch reduction was a more important attribute of the drug than improving skin appearance. We found that there is no significant relation between gender and preferable treatment effect. Furthermore, we found no significant correlation between age and particular treatment effect as well. There was, however, a correlation between the level of pruritus and preferable effect. Patients with a higher level of pruritus on a scale 0–10 tend to choose itch reduction over improving skin appearance (p < 0.05).
88.8% (n = 142) of patients would prefer a delayed onset of action, if the treatment effect remained for a longer period of time.
Route of administration (Figure 1)
With the same effectiveness of the drug, up to 68.8% (n = 110) of respondents prefer to take one tablet every day, whereas the remaining 31.3% (n = 50) of the respondents prefer an injection every 2 weeks. If the injectable form of the drug was more effective, 87.2% (n = 140) of the respondents would choose it instead of the tablet form. Furthermore, 12.8% (n = 20) of the respondents claim that they would never use drug in the injectable form.
A total percentage of 91% (n = 146) of the respondents would rather take the drug on their own, 9% (n = 14) at the clinic or hospital. Moreover, 61.5% (n = 98) of the patients prefer continuous treatment and 38.5% (n = 62) – on-demand treatment. Up to 72.4% (n = 115) prefer check-ups every 6 months, 27.6% (n = 45) every month.
The χ2 test was used to check whether there was a relationship between patients already taking dupilumab (12.5% (n = 20)), whether they preferred to take the drug in the injectable form every 2 weeks or a tablet form every day. The relationship was not statistically significant (p > 0.05), however, it is worth noting that patients already treated with dupilumab would be just as likely to choose an injection (50% (n = 10)) or a tablet (50% (n = 10)), while the others without any history of dupilumab treatment would be significantly more likely to choose a tablet (70% (n = 98)).
Safety vs. effectiveness of the drug
Up to 80% (n = 128) of the respondents prefer a less effective but safer drug. The more severe the disease as assessed by PO-SCORAD, the greater the chance that patients will choose a less safe but more effective drug (p = 0.006).
Patients who were treated with a sort of systemic treatment in the past are also more likely to choose a less safe but more effective drug (p = 0.008).
Patients with a higher level of pruritus (measured on a numeric scale from 0 to 10) have a tendency to choose a more effective drug, despite the higher chance of side effects (p < 0.001).
Maximum acceptance risk of potential side effects of the drug
Side effects the respondents are mostly concerned about are malignancy (80.6% (n = 129)), thromboembolism (15.6% (n = 25)), and the risk of serious infection (3.9% (n = 6)). For each age group, the risk of malignancy was the least acceptable side effect.
We asked patients about the tolerance of yearly risk of a serious infection, cancer and venous thromboembolism of 0.1%, 0.5% and 1.5%. We found out that the most tolerable side effect was the 0.1% risk of developing a serious infection, where 85% (n = 136) of the patients could accept it. The yearly 1.5% risk of developing cancer was the least tolerable adverse effect, with only 5% (n = 8) of patients able to accept it.
Discussion
To the best of our knowledge, this was one of the first studies in Poland to establish the novel systemic treatment preferences in adult patients suffering from AD. Analyzed questionnaires of 160 Polish citizens showed some interesting facts about preferable features of systemic drugs in AD.
Most of the studies on systemic treatment preferences in AD available in the literature are in the form of Discreet Choice Experiments (DCE). Our study had a more simplified form. However, it has provided interesting data.
The route of administration of the drug is one of the most important factors determining compliance. If it is convenient for the patient, it may translate to improved adherence, and, finally better treatment outcomes. If patients in our study had a choice of two drugs with the same effectiveness, one as a tablet taken daily and the other as an injection taken every two weeks, the vast majority would choose the drug in a tablet form. However, in order to achieve better treatment outcomes and effectiveness, the majority would opt for a drug in the form of injections. Only a small group of respondents would not decide to have injectable treatment. However, for those who were previously treated with a subcutaneous injection medication like dupilumab, the form of the medication may not have been so significant. The possible reason for that is the benefits of using dupilumab outweigh the inconvenience associated with taking the medication in the injectable form. It may also suggest that the act of administering an injection in the past, reduces the fear associated with its use.
This is an example of a different perspective than that shown in two different publications. In the Okubo et al. publication, only half of respondents would opt for injectable treatment [10]. In this particular study, patients had the option to choose only two drugs with different features, weighing the pros and cons of different therapies, whereas in our study, individuals were choosing only between different features. In our study, it was relatively easy to immediately pick a tablet over an injection, whereas in the study of Okubo et al., the drug in the tablet form had, for instance, more adverse events in comparison to the drug in the injectable form, so the decision was not that simple.
However, it is important to emphasize that other studies also suggest that route of administration is an important feature of the drug for many patients. For instance, respondents from Thomas et al. publication were willing to choose less effective drugs in order to have a more convenient route of administration (for example tablet form) [11]. However, interestingly, those patients who had previous experience with medications in the injectable form were more willing to accept these form of administration.
When asked which effect was more important to them - skin appearance improvement or itch improvement, the majority of patients opt for itch improvement. Although it would seem that women or younger people would rather prefer an improvement in the appearance of their skin, our study did not show such a relationship. Patients with a higher severity of itching on a scale of 0 to 10, not surprisingly, would opt for itch improvement as the main outcome.
Our results remain consistent with similar ones, especially the study conducted by Kwatra et al. [12]. In their publication, respondents prioritized itch reduction over other attributes, and they were willing to have less safe but more effective treatment. The results point out the intense pruritus experienced by individuals with moderate-to-severe AD, who were the only participants in this study. That was not the case in our study, where we also included patients with mild AD.
In a DCE study of 213 patients in the United States (US) the most important feature that would discourage patients from taking the drug, even at the cost of good effectiveness, was malignancy risk [9]. In our study, malignancy risk was also not acceptable for most of the patients.
An interesting point of reference is publications regarding prescribers’ perspectives on treatment choice. In a study conducted in Spain by Carrascos Carrillo et al. [13] and in Japan by Okubo et al. [10], the most important feature of the drug was objective efficacy. Experts from Spain were also willing to accept the increased risk of side effects in exchange for more effectiveness in treatment. Additionally, the form of the medication is not as important as for their patients.
The possible clinical implications for our study in everyday clinical practice would undoubtedly be the fact that patients in general have their own opinions about the drugs prescribed by the doctor. Considering these viewpoints can facilitate the treatment process as there is a constant possibility that patients may not comply with the recommended treatment, considering it insufficiently safe, for instance. It is crucial to recognize that doctors occasionally have limited time to dedicate to individual patients. One potential future approach is to use questionnaires to determine the most significant factors for patients, identify less important features, and automatically include them in the doctors’ medical documentation. Another potential approach involves recognizing the findings of research like ours to determine the specific preferences of different patient groups and showing these results to doctors. To improve patients’ adherence to therapy, organizing educational activities that explain the disease’s pathogenesis and the impact of the drug on the disease’s course may be beneficial.
In terms of potential future study directions, we strongly believe that creating some multicenter research with patients’ opinions on medications may be extremely helpful. Standardizing the methodologies across all studies could potentially simplify comparisons. Grouping patients into clusters may also potentially help shape/determine future directions in pharmacology. It would be valuable to repeat this type of study in the future when clinical experience with a broad range of medications is greater. At that time, the opinions will be expressed exclusively by patients who have actually undergone treatment with these drugs rather than by those who might potentially be treated. AD is a chronic disease, and patients suffering from it remain under the care of a doctor for many years, using long-term treatment. A good patient-doctor relationship and shared decision-making regarding therapy, based on patients’ preferences are crucial in dermatological diseases, where the range of therapeutic options is large and therapeutic success strictly depends on compliance with treatment principles [14].
This study has some limitations. A greater group of respondents could provide wider perspective on the topic. It may be interesting to learn about the viewpoints of parents of patients or adolescents as they might vary greatly. Additionally, it may be important to take into account the differences in attitudes that can exist between different countries, cultural factors, and other elements that are not addressed in our study as our group consists solely of Polish nationals. We are aware of the fact that our study group is quite homogeneous.
Another limitation is accuracy of the assessments of extent and severity of eczema by patients, which may result in some discrepancies between the real, professionally assessed severity of the disease. In the group of patients receiving the medication in the form of injections, only dupilumab was administered. At the time of the study, reimbursement for other biologic drugs was not yet available. Also, the study included a group of patients who had not received systemic therapy, so these are partly theoretical considerations.
Conclusions
The study revealed some interesting facts about patients’ perspective on treatment choice. The route of administration in the form of injection would be acceptable for most patients in exchange for effectiveness. Reduction of itch was a favorable treatment effect. Additionally, for patients previously treated with injections, the route of administration was indifferent compared to respondents with no history of injection treatment. Patients with a prior history of systemic treatment would likely demonstrate greater acceptance of potential adverse effects associated with the therapy as opposed to the cohort without a history of systemic atopic dermatitis treatment. More studies are needed to fully understand the preferences of the patients overall, and yet, each patient should be treated individually despite the statistics.
Funding
No external funding.
Ethical approval
The questionnaire and research materials were reviewed and accepted by the Independent Bioethics Committee for Scientific Research at the Medical University of Gdansk (NKBBN/335/2022/).
Conflict of interest
Trzeciak M. has been a speaker for Abbvie, Bioderma, BauschHealth, Leo Pharma, Eli Lilly, Loreal/LaRoche, Pfizer, Pierre Fabre, Sanofi, Mead Johnson and consulting or advisory board for Abbvie, Sanofi, Leo Pharma, BauschHealth, LaRoche, but not in connection to this manuscript. The others authors declare no conflict of interest.
References
1. Mortz C.G., Andersen K.E., Dellgren C., Barington T., Bindslev-Jensen C.: Atopic dermatitis from adolescence to adulthood in the TOACS cohort: prevalence, persistence and comorbidities. Allergy 2015, 70, 836-845.
2.
Blome C., Radtke M.A., Eissing L., Augustin M.: Quality of life in patients with atopic dermatitis: disease burden, measurement, and treatment benefit. Am J Clin Dermatol 2016, 17, 163-169.
3.
Wollenberg A., Kinberger M., Arents B., Aszodi N., Avila Valle G., Barbarot S., et al.: European guideline (EuroGuiDerm) on atopic eczema - part II: non-systemic treatments and treatment recommendations for special AE patient populations. J Eur Acad Dermatol Venereol 2022, 36, 1904-1926.
4.
Bieber T.: Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov 2022, 21, 21-40.
5.
Umar N., Schaarschmidt M., Schmieder A., Peitsch W.K., Schöllgen I., Terris D.D.: Matching physicians’ treatment recommendations to patients’ treatment preferences is associated with improvement in treatment satisfaction. J Eur Acad Dermatol Venereol 2013, 27, 763-770.
6.
Reyes-Hadsall S., Drake L., Han J.J., Lee K.J., Zhou G., Mostaghimi A., et al.: Shared decision-making, therapeutic choice, and decisional regret in patients with alopecia areata. JAMA Dermatol 2022, 158, 1187-1191.
7.
Morrison T., Foster E., Dougherty J., Barton J.: Shared decision making in rheumatology: a scoping review. Semin Arthritis Rheum 2022, 56, 152041.
8.
Wilson S.R., Strub P., Buist A.S., Knowles S.B., Lavori P.W., Lapidus J., et al.: Shared treatment decision making improves adherence and outcomes in poorly controlled asthma. Am J Respir Crit Care Med 2010, 181, 566-577.
9.
Boeri M., Sutphin J., Hauber B., Cappelleri J.C., Romero W., Di Bonaventura M.: Quantifying patient preferences for systemic atopic dermatitis treatments using a discrete-choice experiment. J Dermatolog Treat 2022, 33, 1449-1458.
10.
Okubo Y., Ho K.A., Fifer S., Fujita H., Oki Y., Taguchi Y.: Patient and physician preferences for atopic dermatitis injection treatments in Japan. J Dermatolog Treat 2020, 31, 821-830.
11.
Thomas C., Raibouaa A., Wollenberg A., Capron J.P., Krucien N., Karn H., et al.: Patient preferences for atopic dermatitis medications in the UK, France and Spain: a discrete choice experiment. BMJ Open 2022, 12, e058799.
12.
Kwatra S.G., Lio P., Weidinger S., Calimlim B., Ladizinski B., Vigna N., et al.: Patient preferences for atopic dermatitis treatments: a discrete choice experiment. J Dermatol Treat 2023, 34, 2222201.
13.
Carrascosa Carrillo J.M., Baselga Torres E., Gilaberte Calzada Y., Jurgens Martínez Y.N., Roustan Gullón G., Yanguas Bayona J.I., et al.: Quantifying physician preferences for systemic atopic dermatitis treatments using a discrete-choice experiment. Dermatol Ther (Heidelb) 2022, 12, 1197-1210.
14.
Morrison T., Johnson J., Baghoomian W., Hamilton A., Simpson E., Greiling T., et al.: Shared decision-making in dermatology: a scoping review. JAMA Dermatol 2021, 157, 330-337.
