Patients’ perspectives towards biologic dose reduction in psoriasis: a qualitative study

Dose reduction of biologics for psoriasis could contribute to more efficient use of these expensive medicines. Evidence on opinions of patients with psoriasis regarding dose reduction is sparse. The objective of this study was therefore to explore patients’ perspectives towards dose reduction of biologics for psoriasis. A qualitative study was conducted, comprising semi-structured interviews with 15 patients with psoriasis with different characteristics and treatment experiences. Interviews were analyzed by inductive thematic analysis. Perceived benefits of biologic dose reduction according to patients were minimizing medication use, lowering risks of adverse effects and lowering societal healthcare costs. Patients reported to have experienced a large impact of their psoriasis, and expressed concerns about loss of disease control due to dose reduction. Fast access to flare treatment and adequate monitoring of disease activity were among reported preconditions. According to patients, they should have confidence in dose reduction effects and should be willing to change their effective treatment. Moreover, addressing information needs and involvement in decision-making were deemed important among patients. In conclusion, addressing patients’ concerns, fulfilling information needs, providing the possibility of resuming standard dose, and involving patients in decision-making are important according to patients with psoriasis when considering biologic dose reduction.


Introduction
Biologics have allowed patients with psoriasis to achieve adequate disease control, or even complete clearance [2]. The possibility of achieving good treatment responses now poses the question how these patients should be treated over the long term. Sustainable use of the expensive biologics is important as healthcare costs are increasing and access to biologics is unequal on a global scale. Dose reduction (DR) of biologics by means of injection interval prolongation for patients with stable low disease activity enables more efficient use of biologics with decreasing healthcare costs [3,4,17].
DR is already performed in daily practice but not on a standard basis [6,22]. Striving for standardization is however important: it leads to consistent and safe practice, and better uptake in routine care. For adoption of DR into practice, insight in factors which hamper or facilitate implementation is needed. Barriers to implementation of DR may arise at the patients' level [10,11]. We previously showed that 'fear for psoriasis flares' was the most important reason among patients with psoriasis for unwillingness to start DR in a daily practice evaluation study on DR of adalimumab, etanercept or ustekinumab [5]. In rheumatology, several qualitative studies reported that fear of relapse was a main concern among patients with inflammatory arthritis when considering biologic DR [23]. Nevertheless, patients were willing to try DR after receiving information on DR, and if increasing the dose was possible when deemed necessary

Data collection
A semi-structured interview guide was developed by the research team (LS, LV, JR, EJ), and addressed experiences with biologic treatment and DR, opinions and beliefs regarding DR, willingness to try DR, perceived opinions of people in patients' environment, preconditions for biologic DR, and information needs. Patient representatives from the national patients' association (IE, FO) reviewed the interview guide.
Interviews were conducted between September 2021 and March 2022 by one researcher (LS). This researcher/ physician (LS) had no long-term treatment relationship with participants, but conducted consultations with some participants in the past 6 months. Recruitment of patients ended when data saturation was reached (no new subthemes emerged from the last three interviews). Interviews were held by telephone, were audio-recorded and transcribed verbatim. No formal member check was performed, but a summary was presented to the participant at the end of the interview to check for accuracy. Patient and treatment characteristics were collected from BioCAPTURE.

Data analysis
Transcribed interviews were analyzed by inductive thematic analysis using ATLAS.ti software. Thematic analysis comprises a flexible approach for identifying themes, without trying to fit data into any predetermined category [8]. Repeated transcript reading was conducted to maximize data familiarity. Analytical rigor was sought using multiple coders (investigator triangulation) [18]: two researchers (LS, LV) coded the first three transcripts independently (open coding), resulting in a list of initial codes. Based on initial codes, next transcripts were systematically coded (axial coding) by one researcher (LS), and reviewed by another researcher (LV). Differences were discussed until consensus was reached. Newly identified themes were added to the codebook, using an inductive approach. Analysis was concurrent with data collection, to explore emerging themes further on in later interviews. When necessary, the interview guide was adapted. Constant comparison was applied throughout the whole process of data analysis, by comparison of emerging themes with new data [18]. Results and saturation were discussed during the process. Analysis resulted in (sub)themes that play a role for patients with psoriasis regarding biologic DR. Corresponding illustrative quotes were selected from the interviews, and were translated into English by a professional translation service. Results were revised based on discussion with key researches (LS, LV, JR, and EJ). Patient representatives (IE, FO, and AP) reviewed results to check whether results were formulated in a way compatible to the patient perspective.

Results
Patient characteristics are summarized in Table 1. Among participants, differences in current biologic treatment, number of previous biologics used and experience with DR were present. Saturation was achieved after 15 completed interviews. Mean duration of interviews was 28 min. After analyzing the first three interviews, minor changes were made to the interview guide including addition of questions regarding psoriatic arthritis (PsA), and preferences for timing and channeling of information.
In total, seven main themes were identified: disease control, attitudes towards medication and DR, healthcare access and organizational aspects, cost reduction, information needs, social aspects, and decision-making. Corresponding subthemes are described below. An overview of (sub)themes and illustrative quotes is presented in Table 2. Summarized clinical implications based on (sub)themes arising from the interviews are graphically presented in Fig. 1.

Impact of psoriatic disease
Disease control was brought up as an important issue. Patients reported to have experienced a large physical and/or psychosocial impact of their psoriasis, which also involved feelings of shame. Having psoriatic disease also had an impact on work and daily functioning. Causing itch, pain and scaling, psoriasis had a large impact on patients' wellbeing. In case of concomitant PsA, joint symptoms had a major impact on patients' lives as well. In contrast, patients mentioned that being free of psoriatic disease provided a feeling of freedom. As such, patients did not want to go back to the days when they had severe psoriasis. Participants expressed that healthcare providers should pay attention to the (past) impact of the disease within the context of DR.

Effort to reach low disease activity
Patients valued the option of the highly effective biologics. Participants reported to have used different treatment modalities over time, before qualifying for biologics. The effort to reach a state of low disease activity was therefore an identified barrier to DR. Initiation of DR after a long period of biologic treatment was reported as a factor to overcome this possible barrier, as this could gain patients' trust in DR effects and might prevent loss of effectiveness according to patients.

Fear of disease flares
Related to the past experiences of having severe psoriasis, fear of disease worsening was identified as an important theme among participants. It was reported that the risk of disease flares could result in unwillingness to start DR. Patients experienced with DR noted that concerns about disease flares may disappear after perceived maintained treatment effectiveness despite reducing the dose.

Treatment goals
Adequate disease control can be important for patients when starting or continuing DR. However, definitions of adequate disease control and the ideal duration of having good treatment effects before starting DR can differ between patients. The amount of psoriasis lesions and location of lesions could contribute to perceived disease activity. Treatment goals can change over time, depending on patients' life course and previous (un)successful treatment experiences. Hence, it was suggested that patients' goals should be addressed by healthcare providers. Although the accepted level of disease activity might differ between patients, participants mentioned that DR should preferably be initiated after adequate disease control is reached and maintained for a prolonged period.

Attitude towards possible adverse effects
Having experienced side effects or concerns regarding unknown risks of biologics may act as facilitators for DR. While some participants expressed these concerns, others did not fear the risk of side effects at all. Conversely, not experiencing side effects may act as a barrier for DR, as patients could see no reason why they would change their treatment.

Willingness to change effective treatment
Willingness to change effective treatment can play a role when considering DR. Participants expressed that (un)willingness to try DR depends on received information. Moreover, maintaining good treatment effects was deemed important for patients while reducing the dose, and confidence in effectiveness is needed before treatment alterations, according to patients. It was reported that the decision to start with DR could be based on a balance between willingness to try versus risking a flare. For patients experienced with DR, negative or positive experiences with DR could contribute to the willingness of reducing the dose again.

Use of concomitant topical treatment
Different views regarding the use of topical treatment were expressed. Some patients preferred to use topicals first before resuming the standard dose in case of increased psoriasis activity following DR. However, patients could also have experienced ineffectiveness of topicals or have negative feelings towards the use of topicals. As such, not having to use topicals again before resuming the standard dose was also mentioned as prerequisite before considering DR.

Confidence in DR
Participants expressed that there should be a level of confidence in the DR process. Confidence in DR effects and in reaching adequate treatment responses again after increasing the dose in case of psoriasis worsening were reported facilitators for DR.

Practical use of the biologic
As biologics are usually self-injected, administrating less injections was a perceived benefit of DR, specifically for patients who disliked self-injecting. Likewise, less pharmacy visits or less pharmacy delivery moments were expressed as possible advantages of DR. However, for other patients, self-injections were perceived to be convenient and thus less injections will not provide much benefits.

Minimizing medication use
Minimizing medication use was an important reported motivation for DR. Participants expressed that medication in general is not good for one's body and there could be unknown long-term risks. Besides, patients did not want to be dependent of medication. However, biologics are needed for disease control, but the lesser the use, the better.

Access to treatment in case of disease flares
The possibility to re-increase the dose in case of psoriasis worsening following DR was a very important condition for patients. Fast access to dose alterations or alternative treatments was deemed essential. In addition, information about alternative treatment options in case of ineffectiveness of resumption of the standard dose should be available at DR start.

Access to the outpatient clinic
Patients appreciated the option to contact the outpatient clinic by telephone or digitally in case of questions or increased psoriasis activity, as this could be trust-gaining.

Acknowledge patients' impact of the disease
Discuss patients' treatment goals and satisfaction.

Address patients' concerns and perceived advantages of DR
Explore patients' motivations and concerns, including fear of losing disease control.

Provide healthcare access in case of loss of disease control
Including access to consultations and to dose alterations or alternatives.

Give patients time to think about DR
Let them discuss the option with others when preferred.

Perform shared decision-making
Provide a personalized approach and follow previously made agreements.

Fulfill information needs
Address expected effects of DR, risks, and options in case of losing disease control. Provide written and orally presented information. Fig. 1 Summary of clinical implications based on identified (sub)themes arising from the interviews After starting DR, a certain level of support should be available, for example through a digital app or a dedicated healthcare provider. This facilitates prompt access to care and generates feelings of being supported.

Importance of monitoring
Different opinions related to the frequency and importance of monitoring in the context of DR were expressed. Some patients wanted to have frequent outpatient visits after starting DR, while others did not. It was reported that live visits including skin-checks and blood monitoring could give feelings of being looked after. When starting DR, monitoring disease activity was mentioned as an important factor. More generally, laboratory checks were valued due to possible risks of biologics.

Barriers at the healthcare providers' level
According to patients, possible barriers could lie at the healthcare providers' level as well. It was indicated that the treating healthcare provider should be aware of DR as treatment option. For them, continuing the standard dose might be the easiest way to go. Additionally, participants suggested that involvement of different healthcare providers might limit application of DR, as the treating clinician should know the patients history to make an estimation of eligibility for DR.

Contribution to lowering costs of the national healthcare budget
Lowering costs was mentioned as an advantage of DR, as biologics are expensive. However, for individual patients there was no direct financial advantage, as they pay a fixed amount for their healthcare insurance in the Netherlands which covers their treatment costs. Still, it was reported that patients could contribute to lowering societal healthcare costs too. By contrast, patients mentioned that this would not be the case anymore when less expensive alternatives would become available (e.g., biosimilars).

Availability of biologics to more patients
Besides contributing to lowering societal healthcare costs, patients expressed the hope that biologics might become available for more patients due to decreased costs resulting from DR.

Content of information about DR
Participants emphasized the need for information on DR, including the rationale and evidence, expected effectiveness and potential risks of DR. Study results or previous experiences could help to gain realistic expectations. Furthermore, it was reported that information on treatment options in case of loss of disease control during DR should be provided. Some patients reported that they wanted as much information as possible. However, it was also mentioned that it could differ between patients how much information is needed or preferred to agree to DR.

Preferences for timing and channel of information
Participants suggested that information should be presented by the treating healthcare provider during a face-toface consultation as this promotes direct communication.
As such, the healthcare provider can accurately estimate DR eligibility. Written information could add to orally presented information, could help patients to think about DR, and could provide more time for consideration. It was reported that the option of DR could be presented at the start of biologic treatment or alternatively when patients have sustained low disease activity and would be thus eligible for DR.

What others in patients' environment think of DR
Patients were asked about factors that may influence their decision to start DR. Consequently, they reported that discussing the option of DR with relatives or other close contacts is important, as the impact of having psoriasis also affects them.
Other people can have other opinions or questions which might aid in the decision-making process. On the other hand, it was mentioned that patients would want to take the decision to start with DR themselves, as it concerns their own body and treatment.

Healthcare provider-patient relationship
Participants mentioned that healthcare providers should follow previously made agreements, for example regarding the option to resume the standard or previous dose after DR failure. Likewise, it was deemed important that healthcare providers listen, take patients seriously, and take time, as this is trust-gaining.

Expertise of the treating healthcare provider
A certain level of expertise of the involved healthcare provider with DR could give confidence according to patients. Moreover, some patients rely on advice of their physician. According to patients, physicians' experience with DR would imply that DR eligibility will be adequately estimated.

Personalized approach
As described before, impact of psoriasis and treatment history can differ between patients. Therefore, it was noted that a personalized approach is important when considering DR. Some patients are willing to try DR and others are not, and this should be respected. Moreover, it was reported that both patients' physical and mental health need to be addressed.

Decision-making process
Participants emphasized the need for clear agreements on DR processes. After receiving information, time should be offered to think about DR. Patients mentioned that the healthcare provider should initiate the conversation on biologic DR, but patients should be involved in the actual decision-making. Giving patients a choice is trust-gaining. Participants also reported that in case of psoriasis worsening, the next step should be discussed with the patient and decisions should be made with the patient as well.

Discussion
This qualitative study explored perspectives of patients with psoriasis towards biologic DR. Inductive thematic analysis of interviews with 15 patients with psoriasis uncovered seven main themes and 23 subthemes that play a role for patients when considering DR. Among concerns of patients was the risk of disease flares due to DR. Fast access to flare treatment and adequate monitoring of disease activity were among reported preconditions. By contrast, motivations for DR could be minimization of medication use, less injections, and a lower risk of adverse effects. Patients valued a good relationship with, and expertise of, their treating healthcare provider. Moreover, addressing information needs together with patient involvement in decision-making were deemed important. To our best knowledge, this is the first study providing a broad exploration of perspectives of patients with psoriasis on biologic DR. In the context of DR, patients reported fear of disease worsening. This might be related to the reported (past) impact of the disease on patients' lives, which has been described before [1,14,20,25]. A previous interview study among patients with psoriasis indicated having less impact of psoriasis as an important treatment goal, and the fear that treatment would not be effective (anymore) was reported as well [15]. In line with our results, fear of biologic discontinuation and the struggle to receive biologics were among reported issues by psoriasis patients before [15,20]. These issues should be addressed by healthcare professionals to reduce patients' uncertainties [20]. A recent review showed that symptom control, treatment safety, confidence in care, communication with healthcare professionals and costs were among frequently reported patient-relevant outcomes in psoriasis [13]. These findings correspond with our data and indicate that addressing concerns and needs of patients is of great importance when adjusting treatment.
We identified several factors influencing patients' willingness to try DR. Among patients' reported barriers was the fear for delayed access to consultations or to the previous dose in case of psoriasis worsening. Some participants reported the importance of monitoring disease activity during consultations, but actual preferences for frequency of monitoring were not provided. Preferences might depend on past experiences with received care and its quantity. Moreover, we believe that DR should be aimed at patients with low disease activity, with the goal to strive for the lowest effective dose. When educating patients and providing healthcare access in case of diminishing treatment effects, patients' whish for sufficient monitoring could be accommodated.
Previous studies among patients with inflammatory arthritis have found similar patient-reported factors towards biologic DR [9,12,16,23,24]. Of note, DR strategies for inflammatory arthritis have been incorporated in guidelines and patients might consequently be used to the concept of DR as part of standard care [19]. It has also been suggested in rheumatological literature that by informing patients about possible future DR at treatment start, awareness and confidence could be created [9,12,16]. For psoriasis, guidance of patients toward DR could as such be improved with incorporation of DR strategies into clinical practice and treatment guidelines.
This study has several strengths. First, we included a variety of patients with different treatments and experiences with DR, which allowed us to explore relevant perspectives of patients with psoriasis. Second, using a qualitative approach, a comprehensive exploration of patient-relevant factors could be accomplished. Results could contribute to further implementation of DR strategies by incorporating the patient perspective.
Limitations can be found in the study design. Data interpretation could have been influenced by possible framing of questions during interviews, and there might have been other relevant factors of which patients were unaware or which were not mentioned due to social desirability. Due to the qualitative design, interpreting exact numbers and drawing conclusions on most important patient-related opinions was not possible. Reported experiences might be culturally dependent and different findings could be found in other settings. Therefore, replication of this study in other settings would be of added value.
Results of this study show that patients' impact of their disease and concerns related to DR should be acknowledged when further implementing DR. According to patients, information on and access to flare treatment should be incorporated in DR strategies, as well as information on DR rationale, expected effects and potential risks. Development of clear patient information and incorporation of patientrelevant factors into clinical guidelines on DR could enhance shared decision-making. Standardization of DR strategies and uptake in regular care may gain trust with patients. However, addressing individual treatment goals and satisfaction, and give each patient a choice remains important.
In conclusion, perceived benefits of biologic DR according to patients with psoriasis were minimizing medication use, lowering risks of adverse effects, and lowering societal healthcare costs. However, patients could have concerns related to loss of disease control following DR. Patient interviews indicated that this barrier needs to be addressed by providing adequate information, involving patients in decision-making, offering patients time to think about DR, and providing fast access to healthcare in case of disease flares. By acknowledging these patient-relevant factors when considering DR, further implementation of biologic DR strategies into clinical practice can be facilitated.