Patient-centric care in primary immune thrombocytopenia (ITP): shared decision-making and assessment of health-related quality of life

ABSTRACT

Immune thrombocytopenia (ITP), an autoimmune disease characterized by low platelet counts and increased bleeding risk, can impair health-related quality of life (HRQoL), impacting patients’ daily lives and mental health. A number of patient-reported outcome (PRO) measures (both generic and specific to ITP) can be used to understand the impact of ITP on HRQoL and generate evidence to guide disease management. As well-developed PRO tools could help in HRQoL assessment, their optimization could help to solidify a patient-centric approach to ITP management. Shared decision-making is a collaborative process between a patient and their healthcare professional in making decisions about care. Treatment decisions based on this shared process between physician and patient are recommended by clinical guidelines. The goal of this narrative review is to discuss treatment decisions with regards to patient-centric ITP management, with a focus on the impact of PRO measures and the process of shared decision-making in practice.

KEYWORDS:

• Immune thrombocytopenia
• shared decision-making
• health-related quality of life
• patient-reported outcome measures
• patient education
• treatment decisions
• clinical guidelines‌
• platelet counts

1. Introduction

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts (<100 × 10⁹/L) and an increased risk of bleeding [1,2]. Though the pathogenesis of ITP has yet to be fully determined, antibody and/or T-cell-mediated platelet destruction plays a key role [2]. Bleeding manifestations in ITP can range from mild events, such as skin bruises to more serious occasionally life-threatening events, such as organ bleeding and intracerebral hemorrhage [2,3].

The primary aim of ITP treatment is to increase the platelet count to prevent and/or cease any active bleeding [4,5]. The American Society of Hematology (ASH) clinical guidelines (2019) and the International Consensus Report (ICR) (2019) provide practical guidance for the diagnosis, treatment and management of ITP [4,5]. These reports recommend that a target platelet count of >20–30 × 10⁹/L is maintained at least for symptomatic patients as the risk of major bleeding increases below this level [4,5]. The ASH and ICR guidelines recommend first-line treatment with corticosteroids, intravenous immunoglobin (IVIg) and anti-D immunoglobulins, followed by thrombopoietin-receptor agonists (TPO-Ras), immune-modulators such as rituximab (used off-label) and fostamatinib, or splenectomy for patients who do not respond to first-line treatment or who are dependent on corticosteroids [4–6]. The guidelines also recommend that treatment is individualized to the patient and the phase of the disease, and that treatment decisions should be based on shared decision-making between the physician and patient [4,5].

Health-related quality of life (HRQoL) relates to how overall quality of life is perceived in relation to health status, including physical health (energy, fatigue, pain and sleep), psychological health (anxiety and depression), independence (work and activities of daily living) and social relationships (social life and sex life) [7]. ITP is now well-known to negatively impact HRQoL across many of these areas, affecting daily living and mental health [5,8]. ITP patients most commonly report symptoms that impact on their HRQoL, such as unexplained fatigue, anxiety and depression [7,9]. While physicians primarily focus on addressing platelet counts in order to minimize bleeding, fatigue and symptoms related to mental health are of more concern for patients [5].

This discrepancy between patients’ and physicians’ perceptions of symptoms and treatment goals was highlighted by the ITP World Impact Survey (iWISh): an exploratory, cross-sectional survey that assessed the impact of ITP, and its treatments, on patients’ lives [10]. The perceptions of 1507 patients and 472 physicians from 13 countries on the diagnostic pathway and the incidence and severity of symptoms were reported [8]. Although only 30–37% of physicians reported hearing about fatigue at diagnosis, 58% of patients reported fatigue as the most frequent and 73% as among the most severe symptoms associated with ITP at diagnosis [8]. As with many chronic diseases, fatigue is one of the most debilitating aspects of ITP [11]. Despite its importance to both patients and physicians, systematic assessment of fatigue is not yet included in the clinical evaluation of ITP and there are to date only a few clinical trials, such as the TPO-RA trials RAISE, RISA and EXTEND, that include fatigue as an outcome [12–14]. Similarly, other HRQoL outcomes are also not systematically evaluated by most adult and pediatric ITP studies as demonstrated by a meta-analysis [15]. More studies and standardization efforts are needed to address this knowledge gap.

ITP treatments can have major impacts on patients’ HRQoL, either positively for those who respond successfully to treatment, or negatively for those who do not respond or who experience adverse side effects [14,16,17]. Over two-thirds of surveyed patients with ITP reported experiencing treatment-related side effects [18]. Even though corticosteroids are the most commonly used first-line therapy, most guidelines recommend limiting their use to a maximum of six to eight weeks since prolonged treatment leads to negative impacts on HRQoL, and high relapse rates [4,5,7,18–21]. One study found the most commonly reported severe side effects of steroid therapy to be weight gain (48%), moon face (46%) and mood swings (36%), and that 69% of patients would only consider steroids in the absence of any other treatments [22]. There are reports that state that more than 95% of ITP patients treated with corticosteroids experience such adverse side effects, leading to discontinuation in approximately a third of patients [18,23]. No data exist that suggest that corticosteroids improve HRQoL [20], and patients have expressed frustration at high likelihood of relapse following corticosteroid treatment as well as loss of their clinical efficacy before the side effects disappear [24].

Although corticosteroids generally have a high initial response rate, this does not continue over the long term. A sustained platelet response rate following corticosteroid treatment is observed in approximately 30% patients at ≥6 months follow up [23]. Most patients are therefore likely to need second-line therapies, such as surgical splenectomy or administration of medical therapies such as TPO-RAs or immunosuppressive agents [4,5]. Patient perceptions on outcomes of splenectomy were evaluated in the iWISh survey, which showed that 38% of patients were satisfied with this treatment overall and 15% reported feeling that, although effective, splenectomy was an undesirable treatment. However, 43% of patients regretted having undergone splenectomy due to inefficacy. Only 54% of patients felt they had been made aware of the long-term complications of splenectomy before surgery, and 56% of patients were worried about long-term side effects, highlighting the need for improved patient education [25]. As patients are likely to receive second line therapies over the long-term, their impact on a patients’ HRQoL needs to be carefully considered. Data from several clinical trials show that patients responding to TPO-RA treatment also have improved HRQoL. Eltrombopag was shown to improve HRQoL vs placebo in studies of chronic ITP patients, with HRQoL assessed across several different areas, including fatigue as previously mentioned [12,14]. Similarly, romiplostim treatment significantly improved HRQoL in patients with chronic ITP, including patients who had prior splenectomy and when compared against placebo or standard of care [17,26,27].

However, the impact of TPO-RAs on HRQoL remains poorly investigated in clinical practice [28]. To facilitate improved patient-centered ITP management, the Thrombopoietin-Receptor Agonist Patient experience survey (TRAPeze) assessed the treatment preferences of European ITP patients regarding TPO-RAs [29–31]. Available results from United Kingdom- and Ireland-based patients with chronic ITP treated with either romiplostim or eltrombopag between September 2020 and February 2021 indicated a preference for treatments that were orally administered and without food restrictions [29]. Patients were generally satisfied with their TPO-RA treatments, believing that they were effective in treating ITP symptoms, although only <20% felt that their fatigue had improved following treatment [29]. Similar findings were observed in the Dutch and Italian cohorts of the survey [30,31]. Results were similar in a survey of patients with primary ITP in clinical practice in Switzerland, Austria, and Belgium from 2018 to 2020, 41% of whom were receiving TPO-RAs [28]. Again, the majority of patients were satisfied with TPO-RA treatment, although a limited impact on fatigue was observed. Additionally, patients treated with TPO-RAs showed a more positive perspective regarding their clinical outcomes and psychosocial state than those not using TPO-RAs and reported better outcomes with regard to bleeding, and other disease aspects such as anxiety [28].

Despite available treatment options, people with chronic ITP continue to experience a significant burden on quality of life, which is manifested through fatigue, activity restrictions, anxiety and changes to daily life routines [8,10,29]. Greater awareness around the extent of this burden on daily life for ITP patients should be raised, with more open communication between doctor and patient regarding treatment options and greater access to the most appropriate treatment for patients’ needs [24]. Patients have expressed desire for treatments that are effective over the long-term, with minimal impacts on side effects [24]. The iWISh survey found patients’ top three goals for ITP treatment, beyond sustained remission or a cure for ITP were (1) achieving healthy platelet counts (64%), (2) preventing episodes of ITP from worsening (44%), and (3) increasing energy levels (41%) [9,10].

Shared decision-making is a collaborative process involving a patient and their healthcare professional working together in making decisions about current and future care [32]. Treatment decisions based on shared decision-making are recommended by clinical guidelines. A comprehensive understanding of the challenges of living with ITP is needed to establish shared decision-making and optimize treatment outcomes and goals. This narrative review will discuss treatment decisions with regards to patient-centric ITP management, with a focus on the impact of patient-reported outcome (PRO) measures and the process of shared decision-making in practice.

2. Health-related quality of life assessment in ITP

2.1. Patient-reported outcome measures

A patient-reported outcome (PRO) is defined as a report of the status of a patient’s health condition directly from the patient, without interpretation by healthcare professionals [33]. Measurement of PROs is a valuable method for evaluating the impact of disease burden, the benefits of treatment from a patients’ perspective and can support clinical decision-making [7,20,34]. Treatment decisions in ITP are complex and platelet count does not fully correlate with disease burden [20,35]. Therefore incorporation of PROs into assessment of patients with ITP is valuable, since symptoms are often only experienced subjectively and cannot be quantified during evaluations by clinicians [35].

Despite the availability of both generic and ITP disease-specific tools to capture HRQoL data, measurement of PROs is often limited to research settings rather than routine care [20]. Generic tools that have been used to measure PROs in adult patients with ITP include the 36-Item Short-Form Health Survey (SF-36), EuroQol 5-Dimension (EQ-5D) and the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue and a 6-item subset of the Thrombocytopenia subscale of the FACT-Th18 (FACT-Th6) [5] (Table 1). Generic tools have indicated a reduced quality of life in ITP patients compared with controls or the general population, in particular for physical activities, emotional issues and social activities [7]. However, though useful for exploring overall quality of life, they are not disease-specific and do not identify the key factors that have the greatest impact on HRQoL in patients with ITP [8,36].

Table 1. Key patient-reported outcome measures for ITP.

Name of tool	No. questions	Domains	Research or clinical practice	Fatigue included (yes/no), significance (high/low)
Generic Tools
SF-36 [5,36,63]	36	Assesses an individual’s general health status across eight areas that cover physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health over the past 4 weeks. Two summary scores, the ‘Physical Component Summary’ and ‘Mental Component Summary’, can be calculated. Higher scores reflect better function.	Clinical and research	Yes, low
EQ-5D [5,36,64]	5	EQ-5D-3L and later the EQ-5D-5L/EQ-5D-Y are multi-attribute preference-based measures. Individual’s report on five areas of their health status: Mobility, Self-Care, Usual Activities, Anxiety/Depression, and Pain/Discomfort. Individuals answer ‘no’, ‘some’, or ‘many problems’ on each area based on their health state ‘today’. Index scores are assigned by applying a formula that attaches weights to each level based on data from a general US population sample. EQ-5D index scores range from –0.11 to 1.00 with 0 representing death and 1 representing perfect health.	Clinical and research	No, low
Hamilton anxiety and expression rating scales and HARS-IG [5,65]	14	Assesses an individual’s psychological and somatic symptoms- anxious mood; tension (including startle response, fatigability, restlessness); fears (including of the dark/strangers/crowds); insomnia; ‘intellectual’ (poor memory/difficulty concentrating); depressed mood (including anhedonia); somatic symptoms (including aches, pains); sensory (including tinnitus, blurred vision); cardiovascular (including tachycardia, palpitations); respiratory (chest tightness, choking); gastrointestinal (including irritable bowel syndrome-type symptoms); genitourinary (including urinary frequency, loss of libido); autonomic (including dry mouth, tension headache) and observed behaviour during interview. Each item is scored on a numeric scoring of 0 (not present) to 4 (severe): > 17/56 is taken to indicate mild anxiety; 25–30 is considered moderate–severe.	Clinical and research	Yes, low
MEI-SF [14]	18	A measure of motivation and energy. Summary scale from 0 to 108, where higher numbers indicate better HRQoL measures.	Research	Yes, high
FACIT-Fatigue subscale [14,66]	13	Assesses self-reported fatigue and the impact of this fatigue upon daily activities and function with a 7-day recall period. Includes areas such as tiredness, weakness, listlessness, lack of energy, and the impact of these feelings on daily functioning. Items are scored on a Likert scale (0 = not at all to 4 = very much) with anchors ranging from ‘Not at all’ to ‘Very much so’. For scoring, all items are summed to create a single fatigue score with a range from 0 to 52. Higher scores represent better functioning or less fatigue.	Research	Yes, high
FACT-Th6 [5,14,67]	6	Used to measure worry and/or concern about bleeding and bruising, and the impact of this worry and/or concern on physical and social activity. It is a 6-item subset of the more detailed FACT-Th (an 18-item subscale of the validated FACT that specifically measures concerns related to thrombocytopenia in the past 7 days [68]). It is scored using a 5-level Likert scale (0 = not at all to 4 = very much) and is calculated by totalling scores for the 6-items Scores can range from 0-24; higher scores representing better HRQoL.	Research	No
Fatigue Impact Scale (FIS) [7,69]	40	Assesses the effect of fatigue on cognitive functioning, physical functioning in daily life. Patients rate the extent to which fatigue has affected their life in the past 4 weeks on a questionnaire consisting of 10 ‘physical’ items, 10 ‘cognitive’ items, and 20 ‘social’ items, with 0 indicating ‘no problem’ and 4 indicating ‘extreme problem’. The maximum possible score an individual can receive is 160. In addition to the original version, a shorter 21-item measure, the Modified Fatigue Impact Scale, has been developed and validated.	Research	Yes, high
Work and Productivity Activity Impairment (WPAI) [70]	6	Measures the effect of health problems on an individual’s ability to work and perform regular activities through assessing absenteeism, presenteeism and impairments in unpaid activity during the past 7 days. Each question in the WPAI-GH has six outcomes: 1 = currently employed; 2 = hours missed due to health problems; 3 = hours missed other reasons; 4 = hours actually worked; 5 = degree health affected productivity while working; 6 = degree health affected productivity in regular unpaid activities and uses a 0–10 Visual Analogue Scale for questions 5 and 6.	Research	No
MFI-20 [71,72]	20	Self-report instrument designed to measure fatigue covering the following 5 dimensions: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Motivation and Reduced Activity. MFI-20 has an even proportion of positively and negatively worded items that are rated on a 5-point Likert scale. Subscale scores (range 4–20) are calculated as the sum of item ratings and a total fatigue score (range 20–100) is calculated as the sum of subscale scores. Higher scores are indicative of a higher level of fatigue.	Research	Yes, high
Fatigue Severity Scale [73,74]	9	Investigates the severity of fatigue in different situations during the previous week. Scores each item from 1 to 7, where 1 indicates strong disagreement and 7 strong agreement, and the final score represents the mean value of the 9 items.	Research	Yes, high
ITP Disease Specific Tools
ITP Life Quality Index (ILQI) [8,10,49]	10	Measures aspects including work life or school, time taken off work or education, ability to concentrate, social life, sex life, energy levels, ability to undertake daily tasks, and to provide support, hobbies, and capacity to exercise. Response options were based on a 4-point scale that include responses ‘never’, ‘sometimes’, ‘more than half of the time’ and ‘all of the time’.	Research	Yes, low
ITP Patient Assessment Questionnaire (ITP-PAQ) [38,39]	44	Assesses health across ten scales: Symptoms, Fatigue, Physical Health–Bother, Physical Health–Activity, Emotional Health–Psychological, Emotional Health-Fear, Overall Quality of Life, Social Activity, Work, and Women’s Reproductive Health. The Women’s Reproductive Health domain also has two subscales: Menstrual Symptoms and Fertility. It has a 4-week recall period. Response options are on 4–7 point Likert-type scales. All items are equally weighted and totalled to score the questionnaire. Scale scores range from 0 to 100, with higher scores indicating better health status.	Research	Yes, low
Kids’ ITP Tools (KIT) [40,75]	25 (Child) 26 (Parent)	Involves 3 questionnaires; one version for the child (aged 7–18 years), one version for the parent proxy to complete on behalf of the child (aged 2–18 years), and one for the parent to complete to measure how the disease impacts the parent. Scale of 0 (worst) to 100 (best)	Research	Yes, low

Several ITP-specific tools have also been developed [5], including (1) The ITP Life Quality Index (ILQI), (2) the ITP Patient Assessment Questionnaire (ITP-PAQ) and (3) the Kids’ ITP Tools (KIT) (summarized in Table 1). These are able to explore issues related to ITP more precisely, for example the impact of bleeding [7,8].

The ILQI is a 10-item PRO measure developed for clinical practice that contains questions that assess the impact of ITP over the past month on work or education, ability to concentrate, social life, sex life, energy levels, ability to undertake daily tasks, ability to support others, hobbies, and capacity to exercise, with responses ranging from ‘never’ to ‘all the time’ [37]. The ILQI was included in the iWISh survey and further analysis of the psychometric properties of the ILQI supports its validity and reliability in assessing HRQoL in patients with ITP [37].

Another questionnaire developed specifically for assessing HRQoL in adults with ITP is the ITP-PAQ, a 44-item questionnaire that includes ten scales: symptoms, fatigue/sleep, physical health–bother, physical health–activity, emotional health–psychological, emotional health–fear, overall quality of life, social activity, work, and women’s reproductive health [38]. Each scale is scored from 0 to 100 and higher scores indicate better HRQoL [38]. Data from literature reviews, focus groups of patients with ITP, and clinical input were used for the development of the ITP-PAQ and its psychometric properties including reliability, validity, and responsiveness have already been established [38]. The ITP-PAQ is also available in many languages. Further analyses using the ITP-PAQ score have calculated minimally important differences (MID) for each of the scales, in order to determine what is a clinically significant change and to help physician and patient interpretation of the scores (Table 1, [39]). The ITP-PAQ has been used in phase 3 clinical trials of ITP patients, comparing the effect of the TPO-RA romiplostim vs placebo or standard of care on HRQoL [17,27].

The KIT is a disease-specific measure of HRQoL for children with ITP, comprising three sections: one for the child to self-report (≥7 years), one for the parent proxy to complete on behalf of the child and one for the parent to complete [40]. The KIT shows an acceptable correlation to generic pediatric HRQoL measures such as the PedsQL and KINDL [40,41] and has been validated for international use in multiple languages [41]. It has been utilized in multiple studies to assess HRQoL in children with ITP [7]. MIDs have also been estimated, which can further aid the interpretation of its scores and its implementation in clinical practice [7,42].

Clinicians have stated that measuring PROs is important to understand the true burden of disease for patients with ITP [20,35]. However there are concerns regarding the integration of these instruments into the clinical workflow and their subsequent interpretation [35]. The ITP-PAQ, for example, provides a very comprehensive measure of a patient’s HRQoL and is recommended by the authors for research purposes; however, its implementation in routine clinical practice may be difficult due to its length. On the other hand, the ILQI consists of only 10 questions that focus on assessment of functional status but lack assessment of important aspects related to ITP, such as psychological and bleeding effects.

Integration of PRO data into clinical practice has been emphasized as a way to increase patient satisfaction with care and improve communication between patients and health-care professionals (HCPs), thus promoting patient-centered care [34,43]. PROs are increasingly accepted in numerous clinical settings [43]. The implementation of PROs in clinical practice has also been facilitated by the progression of technology in communicating with patients and collecting data (e.g. widely available internet access, smartphone/ tablet availability and electronic health records) as well as greater demands for PROs from a wide variety of stakeholders such as payers, regulators and professional organizations [43]. Currently, there is no one standardized measure that has been adopted for clinical trials, though the ITP-PAQ is the only comprehensive HRQoL questionnaire available for adults with ITP. This tool is likely more comprehensive than would be feasible for administration in clinical use but assessment of mood, ability to exercise or participate in sports, limitations in job performance or ability to complete household chores would give practitioners a sense of functional limitations in the setting of ITP.

Patients with ITP would benefit from physicians and other healthcare providers receiving further education on the importance of using PROs to measure HRQoL. More widespread use of PROs to measure HRQoL in both research and clinical practice settings would further drive understanding of how ITP impacts patients’ HRQoL and how treatment can be optimized to manage this. This could be achieved by developing shorter versions of ITP-specific tools, such as the ITP-PAQ, that are less burdensome to complete during routine clinical visits or by developing versions of the questionnaires that could easily be integrated into smartphone applications (apps). However, this comes with the caveat that such shortened versions might not cover all elements important for assessment of ITP patients.

3. Shared decision-making in clinical practice

3.1. Patient education, communication, and collaboration

Shared decision-making is a collaborative process involving a patient and their HCP working together to make joint decisions regarding care (Figure 1). This brings together the expertise of the physician, regarding the disease, its diagnosis and treatment options, and the expertise of the patient regarding their experience of the disease and preferences [44]. This joint process ensures patients’ understanding of the risks, benefits and consequences of different treatment options as well as the characteristics and risks of their disease [32]. Patients will therefore be empowered to participate in decisions about the care that is right for them, meaning that procedures and treatments can be chosen based not only on evidence but also patients’ preferences, beliefs and values [32]. For example, a patient who prefers a finite duration of therapy may choose to start rituximab as a first line after failure of steroids rather than a TPO-RA.

Figure 1. Patient journey and collaborative decision-making in patient-centric ITP care [24,47]. Due to occasional delays in diagnosis and the need for multiple lines of therapy, the patient journey of ITP patients can be long and extensive. This journey chart highlights the need for a close patient-provider relationship, as well as exchange between and the involvement of a multi-disciplinary team and other stakeholders such as family and carers.

Shared decision-making should be treated as an ongoing process throughout a patient’s disease journey and can be applied to most aspects of care: screening/diagnostic tests, medical procedures, medications, self-management, psychological/educational interventions and undertaking other lifestyle changes [32,44]. Importantly, medication side effects should be carefully examined. For example, a patient with severe anxiety and sleeplessness while on steroid therapy may wish to avoid future steroid treatment in favour of early initiation of second-line TPO-RA. An effective shared decision-making process can offer patients the following: balanced, evidence-based information on the decision and its potential outcomes, supportive counselling with an HCP to resolve uncertainties and clarify preferences, and a system for recording and implementing the patient’s preferences [44]. Involving patients more directly in the management of their disease can lead to greater satisfaction with any decisions made, better communication and trust between patient and HCP, improved adherence to treatment plans and an overall optimal experience of care [32]. Several published guidelines and guidance documents are available to communicate the importance and benefits of shared decision-making to physicians and patients, providing frameworks for the process and tools and decision aids for use with patients such as the ‘Shared Decision Making Toolkit’ developed by the ITP Support Organization and UK ITP Forum [32,44–47].

Informed and engaged ITP patients can be instrumental for shared decision-making and treatment optimization as well-informed patients will be better able to actively discuss their medical care and treatment options. Comprehensive patient education is therefore necessary for effective patient-centered healthcare approaches [48]. For ITP patients, this will involve providing information about all issues relating to ITP, including disease characteristics, symptoms, treatments, and what the patient care pathway looks like [47]. Benefits of patient education include a greater understanding of the needs of medication along with a reduced perception of potential harm from treatment [48]. As well as including patients, an effective education programme should also extend to other stakeholders such as families and carers [24]. A diverse medical care team is required for the management of ITP and they would also benefit from being included in educational efforts. Patients have highlighted a need for their HCPs to have current knowledge of ITP and any updates to treatment guidelines [24]. Data from the iWISh survey also highlighted the need for further training of physicians and HCPs on ITP disease management [49].

Patient associations can also play a vital role in providing patient education and educational materials. The Platelet Disorder Support Association (PDSA) is one such association, founded in the US in 1998 with the intention of providing a source of education, advocacy, and support for patients with ITP and other platelet disorders [24]. In 2017, the ITP Natural History Study Patient Registry was launched by the PDSA to better understand ITP patient characteristics, disease management and quality of life, as well as help to further the use of PROs and encourage involvement of ITP patients in research [24]. Experience from the PDSA indicates that patients want to take a role in their disease management and engage in a partnership with their healthcare providers. This includes involvement in treatment decisions and education on all of the available treatment options [24]. The ITP Support Association is a UK-based charity with a focus on promoting the welfare of ITP patients and their families. A recent patient survey highlighted concerns from patients that their preferences were not considered in their disease management [50]. Based on this, the ITP Support Association, in collaboration with the UK ITP Forum, developed a shared decision-making toolkit for patients [47]. This outlines what collaborative decision-making in ITP management looks like and provides practical advice for patients and physicians to work towards this [47].

In addition, there are numerous tools available, such as apps and logbooks, that can aid in patient education and support [51–54]. These include the ITP Pocket Log, an app launched by Novartis in association with the ITP Support Association to help patients manage their ITP in daily life, allowing to track symptoms, test results and medications [53]. A similar app is the florioITP, which also allows patients to track their symptoms and platelet counts and log their treatments [52]. Both apps can generate reports that patients can discuss with their physicians, which can help to identify any changes or trends in their disease over time. For example, apps can aid the patient in providing evidence of possible association between platelet counts and various symptoms, such as fatigue and bleeding, as well as providing reports on treatment compliance, frequency of side effects and frequency of routine tests such as blood tests.

Other sources of patient information include web-based repositories of information, such as the International ITP alliance [55] This provides an easily accessible, comprehensive overview of information about the disease, sources of patient support and updates on global studies [55] Increased availability of such mobile health apps and resources could help to increase health awareness and patient engagement, as well as contribute to behavioural change in patients.

Patient-centric approaches to healthcare have been increasingly promoted over recent decades [56]. A patient centric approach covers multiple components, such as exploring the disease experience, understanding the patient as a whole (including any personal limitations related to time / resources) and enhancing the patient-doctor relationship [56]. Evidence suggests that such approaches may have better outcomes than simply providing advice [57]. Motivational interviewing, which helps patients to explore and resolve uncertainties or resistance towards the behaviour changes suggested by their physicians, is one such approach that has gained interest in healthcare settings. In addition to, focusing on behavioural changes, a physician taking a patient-centric approach will also be aware of any personal, familial or medication changes that the patient might be undergoing, with regular assessment of patient’s status and expectations [56].

As ITP management requires a diverse team, a multi-disciplinary approach to support patient-centric care and shared decision-making should include, in addition to the hematologist, social workers, psychologists, nurse specialists, and pharmacists. Social workers in particular could be instrumental in helping patients to implement lifestyle and behavioural changes. It is important to acknowledge however that in clinical practice, not every hematologist will have access to support from such a multidisciplinary team, emphasizing the need for centralized care. Further discussions with healthcare authorities on how to provide patients with access to these non-pharmacologic treatments for ITP are therefore needed. Furthermore, hematologists and other HCPs will need additional training to help the development of skills in patient-centric care.

3.2. Complementary, non-pharmacologic management of ITP (fatigue-directed strategies)

Both physicians and patients have highlighted resolution of fatigue as one of the most important treatment goals in ITP [9]. Fatigue, as one of the most common symptoms of ITP with debilitating effects on daily life, may impact on a patients’ willingness and/or ability to make behavioural changes [24]. One study of patients experiencing chronic illnesses (fibromyalgia, arthritis and inflammatory bowel disease) found that patients experiencing more hopefulness experienced less fatigue [58]. Patients who can identify a personally meaningful goal and work towards achieving it may perceive less stress and fatigue [58]. Hopefulness may allow a patient experiencing chronic illness to plan achievement of their goals within the constraints of their symptoms, helping them to become more engaged in their disease management [58].

Although administration of ITP-specific therapy is the best-studied route to improving fatigue [12,16,59], these treatments may cause adverse effects and increase rather than reduce fatigue [11]. Furthermore, although ITP treatments have shown positive effects on HRQoL in general in clinical trials, few significant improvements in fatigue have been shown [11,12,16,60]. Incorporation of assessment of fatigue into future trials would be valuable, to gain further insights into patients’ experience with fatigue and the potential impacts of treatment.

The underlying pathophysiologic nature of fatigue in ITP remains unknown [20,60]. Whilst in other chronic disorders, and cancer, fatigue appears to be driven by immune activation and pro-inflammatory processes, the causes in ITP have not been fully elucidated and the level of fatigue does not appear to correlate with platelet count [11]. Evidence supports the presence of a pro-inflammatory environment in ITP and suggests a role for pro-inflammatory cytokines in fatigue [11]. Causes of fatigue are thought to be multifactorial; alongside the disease itself, underlying comorbidities, ITP therapies, depression and other behavioural/psychological factors and lack of physical activity are possibilities [11,60]. Therefore, therapeutic interventions known to be effective for fatigue in other disease, such as chronic fatigue syndrome, have not been studied in ITP based on the differing etiology [59].

Non-pharmacological methods may complement medical therapies for managing fatigue in ITP patients. Whilst their effectiveness has not been studied specifically in ITP patients, they have proven beneficial in patients with other causes of chronic fatigue, such as cancer [11]. There is a wide range of such interventions, including cognitive behavioural therapy (CBT) promoting exercise/physical activity, yoga, complementary therapies such as massage and acupuncture, energy conservation and psychosocial therapies [11]. In the management of chronic fatigue syndrome, the effectiveness of education, CBT and exercise are associated with Grade 1A evidence [11]. In cancer-associated fatigue, both yoga and CBT have been shown to reduce inflammation activity, including a decrease in NF-kB, an inflammatory transcription factor [61]. As fatigue remains present in untreated patients with low disease activity, other factors are likely contributing to persistent fatigue in ITP [62]. A study into factors contributing to fatigue in ITP patients identified several non-disease-specific factors that may play a role, including physical and functional well-being, physical activity and vitamin D levels [62]. We therefore would suggest that all ITP patients be screened for vitamin D deficiency. Though data is limited, referral to physical therapy for the development of a graded-intensity exercise programme and CBT may be helpful. Further exploration of non-pharmacological interventions in ITP may provide additional options for addressing the important issue of fatigue. In addition to fatigue, other factors affecting ITP patients’ quality of life include pain, sleep disturbances, depression, and side effects from therapies such as corticosteroids [24]. These are all potentially treatable factors, and an effective patient-centric approach can involve physicians identifying which of these issues are impacting their patients’ quality of life and exploring their treatment options, such as limiting steroid use and duration particularly in patients experiencing more severe adverse effects.

4. Expert opinion and conclusion

Evidence has shown that patient-centered approaches can lead to improved outcomes in treatment of chronic diseases. Patients and physicians should aim to consider both the impact of symptoms of ITP as well as the impact of treatment side effects when making decisions regarding disease management. A need for brief, validated instruments that can identify clinically significant PROs while also being able to be feasibly incorporated into the routine clinical care of ITP has been identified. These instruments are needed to properly assess the impact of ITP and therapies on fatigue and HRQoL, and ultimately optimize ITP treatment. Inclusion of HRQoL and fatigue as outcomes in future studies may help to optimize management of HRQoL issues in clinical practice.

To improve the management of ITP, it is important to move from a generic approach that treats all patients in the same way to individualized treatment based on the probability of response, the likely effect on the patient’s most bothersome symptoms and risks of adverse effects or complications. In the future, establishing research models to understand, assess, and support patients’ values and preferences will be crucial to allow patient-centric care and shared decision-making in ITP.

Conflicts of interests

Hillary Maitland has participated on speaker boards for Sobi and Sanofi. Catherine Lambert has participated on advisory boards for Sobi, Sanofi, CSL, Roche and Amgen and has received lecture honoraria from Bayer, Sobi, Sanofi, Roche and Amgen. Waleed Ghanima reports fees for participation in Advisory board from Amgen, Novartis, Pfizer, Principia Biopharma Inc- a Sanofi Company, Sanofi, SOBI, Grifols, UCB, Argenx, Cellphire, Alpine, Kedrion, HiBio. Lecture honoraria from Amgen, Novartis, Pfizer, Bristol Myers Squibb, SOBI, Grifols, Sanofi and Bayer. Research grants from Bayer, BMS/Pfizer and UCB.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

Medical writing support was provided by Laura Corbett, nspm ltd (Meggen, Switzerland) and was funded by Sobi.