Health-related quality of life in ANCA-associated vasculitis and item generation for a disease-specific patient-reported outcome measure

Introduction

Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) are organ- and life-threatening multisystem diseases of small arteries, known as the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs).¹ Patients present with inflammation in multiple body areas, including the lungs, ear, nose, kidneys, joints, and nerves,² with fevers, weight loss, and fatigue.³ Treatment is with glucocorticoids and other immunosuppressants.⁴ A third of patients will have irreversible damage at diagnosis,⁵ and 40% will suffer relapse.⁶ One-year mortality in AAV has been >15%,⁷ a poorer survival rate than breast or prostate cancer;⁸ however, mortality in AAV has improved, likely due to the adoption of newer treatment regimens.^9,10 Surveys have demonstrated impairments in health-related quality of life (HRQoL) in AAV, in particular fatigue.^3,11–18 A clinician-derived survey to assess patient perspectives in granulomatosis with polyangiitis was developed in 1998;¹⁹ however, there have been no in-depth qualitative studies to capture patient perspectives on the full range of HRQoL in the AAVs as a whole.

Due to the relative rarity of AAV, with three overlapping disease phenotypes, patients with AAV are frequently considered together,⁴ with patients with GPA and MPA included within the same randomized controlled trials (RCTs).^20–22 Primary outcomes are based on the physician-based Birmingham Vasculitis Activity Score,^23,24 which records the presence or absence of disease activity.^20–22,25 Patients with AAV, however, often have different perceptions of what is important to their physicians, for example, they rank fatigue as more important than dialysis or oxygen dependence.¹¹ To guage the efficacy of treatments within RCTs, validated measurement of both physician- and patient-focused outcomes is key.^11,26

The Outcome Measurement in Rheumatology (OMERACT) Vasculitis Working Group has consistently highlighted the need for a disease-specific patient-reported outcome (PRO) measure for patients with AAV,^25,27 due to concern that the generic Medical Outcomes Short Form-36 (SF-36) may not capture all themes of importance. Since OMERACT 2012,^27,28 an international collaboration (the UK, the USA, and Canada) has been developing an AAV disease-specific PRO measure, in line with the US Food and Drug Administration (FDA) guidelines for the development of PROs.²⁹ The development of a new PRO instrument involves three distinct stages with patient involvement at each step: 1) item generation and piloting, 2) item reduction and scale generation, and 3) testing reliability and validity.

This paper describes the themes of importance in HRQoL in relation to AAV, identified through in-depth qualitative analysis in three countries in order to produce candidate questionnaire items for a new disease-specific PRO for AAV.

Methods

The study steering committee included members from the UK, USA, and Canada: four patient partners; medical sociologists with extensive experience in PROM development, testing, and application; qualitative researchers; and clinical researchers with an interest in vasculitis. An initial conceptual framework was developed, through literature review and steering committee input, to explore domains of interest, and this framework evolved during the study.

A core qualitative working group (CQWG), comprising researchers from the three countries, performed the qualitative analysis, developed a collaborative code book of themes, and produced and refined candidate items. The steering committee gave critical feedback throughout on developing themes and items and the project received critical scrutiny at three successive Vasculitis Workshop sessions at Outcome Measures in Rheumatology (OMERACT) conferences.^27,28

Patient study sample

Patients diagnosed with AAV were recruited from three rheumatology centers in the UK, USA, and Canada. Inclusion criteria were age ≥18, ability to give informed consent, and a clinically verified diagnosis of GPA, MPA, or EGPA. Patients were purposively sampled to assure adequate representation of all three diseases, chronicity of disease, different age ranges, sex, and organ involvement. Study approvals were given by the NHS Research Committee South West-Central Bristol, the University of Pennsylvania Office of Regulatory Affairs, and the Ottawa Hospital’s Research Ethics Board. All patients provided written informed consent.

In-depth interviews

Exploratory semi-structured patient interviews were conducted to identify the range of salient aspects of HRQoL affected by AAV and its treatment. An interview guide of prompts and cues was developed by the steering committee. Interviews were performed by a qualitative researcher in the US (KK) and two clinical research fellows trained in qualitative interview techniques in the UK (JCR) and Canada (NM).

Analysis

Interviews were recorded and transcribed, anonymized, and systematically analyzed using a modified framework method.^30–32 Coding was carried out using both an inductive (codes emerged during analysis) and deductive (codes anticipated) approach,³³ with NVivo computer software used to index transcripts.³⁴ Interviews continued until no new substantive themes arose indicating data saturation.³⁵ The CQWG defined the themes of interest, produced a common thematic framework, and ensured uniformity of coding across sites. A proportion of transcripts from each site was double coded, to ensure common approaches.

Candidate item development

Members of the CQWG recast themes as candidate items, using patients’ descriptions throughout. Items were amended, and sometimes deleted by the CQWG, to reduce ambiguity and duplication. Piloting and further item amendment was conducted following feedback from steering committee patient partners.

US participants were invited to participate in a free-listing activity, a semi-structured interview technique in which participants are given a question or statement and asked to identify words they associate with that phrase.³⁶ This method uncovers how groups of people with shared experiences create, associate, and categorize topics.^36,37

The following questions were asked: “Which words would you use to describe your symptoms when your vasculitis: 1) first started; 2) is under control; and 3) is starting to flare?” Patient partners on the study team performed pile-sorting of the responses independently, with disagreement resolved through consensus. Following free-listing and pile-sorting, the Smith’s Salience Index (SSI)^38,39 was used to identify the most salient terms. SSI scores were calculated using ARTHROPAC software. The identified salient terms were contrasted across interview themes to provide additional lens of validation for candidate item development.

Patient refinement

Three rounds of patient cognitive interviews were completed, in order to check understanding and interpretation of the candidate items.^40,41 This was an iterative process, with items refined or rejected by the CQWG between each round.

In parallel, a readability and translatability assessment was completed in collaboration with a specialist UK company (Pharmaquest – translation and linguistic validation company for PROs).⁴² A breakout session was also held at the Vasculitis Workshop at OMERACT 2014, which sought feedback about 1) inclusion of contextual factors within the PRO and 2) attribution within the stem (or lead in sentence), to vasculitis and/or its treatment. All proposed item changes were tested by further cognitive interviews and steering committee review.

Results

Fifty participants, 24 men and 26 women, were interviewed in the UK, USA, and Canada. Participants’ characteristics are shown in Table 1. Interview transcripts were analyzed, identifying 55 individual themes of interest, grouped into seven domains (definitions of individual themes within the codebook in Table S1). The domains identified were general health perceptions, impact on function, psychological perceptions, social perceptions, social contact, social roles, and symptoms (Box 1 shows domain structure and individual themes). The saturation table of emergent themes is shown in Table S2.

Table 1 Demographic and disease features of 50 patients with ANCA-associated vasculitis Abbreviations: ANCA, antineutrophil cytoplasmic antibody; EGPA, eosinophilic granulomatosis with polyangiitis; ENT, ear nose and throat; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis.

Box 1 Domains and individual themes from patients with ANCA-associated vasculitis

General health perceptions

Eighty-six percent of patients used descriptions of how their general sense of self and wellness had been affected by developing AAV. Concerns about the future and difficulties making long-term plans were prominent, as was a sense of vulnerability in one’s own body.

“If I compare to 3 years ago… I was the guy who was working 7 days a week, 16 hour days, never tired. Now… Ufff. It’s not the same guy anymore.” [47-year-old male with EGPA]

“I didn’t want to set foot outside the door. Simply because I thought … I can’t trust my body anymore”. [53-year-old female with EGPA]

Impact on function

Ninety percent of participants described difficulties with reduced levels of physical function, over 80% had a reduction in mobility, and 20% described difficulties in washing and dressing. These impairments led to frustration and impacted finances and work (82%), the ability to perform household tasks (72%), taking part in hobbies and interests (46%), and restricted travel (76%).

“Weakness, inability to walk, to use my arms, to bathe, to do anything – I just laid in bed”. [82-year-old male with MPA]

“TV was a no-no. I got a telephone with a light on it, because it [the deafness] was that bad… I felt very isolated and very stupid”. [57-year-old male with GPA]

Psychological

Concerns about the future were highlighted in 86% of interviews with over 70% reporting experiencing fear, anxiety, or stress, and 50% describing depression or low mood. Anger or irritation was reported by almost 50%. Difficulties in making plans and the potential for premature death were described by patients of all ages.

“For the first year after I was diagnosed, I did nothing, apart from cope with me, my illness and trying to live as normal a life as possible”. [67-year-old female with GPA]

“I was only [age], my first year of college – everything is falling apart and I think I’m dying”. [36-year-old female with GPA]

Social perceptions

Participants were aware of the visibility of the condition, and its treatment side-effects, particularly in relation to glucocorticoids; these issues were discussed in 64% of interviews. A lack of empathy from others was reported by around 60% of interviewees, as was being the source of worry to others.

“To have a big puffy moon face [due to glucocorticoids] is really hard for me. Well, you’re not attractive anymore – it’s weird”. [33-year-old female with GPA]

“I think some people were more supportive than others, and it wasn’t always the people I expected to be”. [67-year-old female with GPA]

Social contact

Eighty percent of interviewees described an impact on their social life, because of fatigue, difficulties with joining in physical activities or communicating, or concerns about letting people down by having to break plans.

“If we had a dinner date on the weekend I had to rest coming up to that day just to be able to have enough energy. I got to a point where I just didn’t bother”. [51-year-old female with EGPA]

“Meetings were the worst. Because I found that I was lip-reading. In an open room with a number of people, it was a nightmare”. [57-year-old male with GPA]

Social role

Eighty-two percent of participants discussed their occupation or finances, specifically stemming from difficulties with concentration and fatigue. Roles beyond work were also discussed, within the family (70%), and changes to role and status when having to rely on others for help (64%).

“When I was getting sick in the beginning I gave up my position as the executive director of the organization and I moved into a position with less responsibility”. [52-year-old female with GPA]

“It was hard on my son as well, so he started goofing off in school. I felt like I wasn’t a good mom, I wasn’t a good wife, and I was isolated”. [51-year old female with EGPA]

Symptoms

All of the patients described symptoms due to disease and treatment in depth. Nineteen different sets of symptoms were identified, most frequently fatigue (88%), cardiorespiratory symptoms (76%), issues related to body weight (74%), and upper respiratory tract symptoms (70%). A full list of symptoms is given in Box 1, with quotes in Box 2.

Box 2 Patient descriptions of symptoms of ANCA-associated vasculitis and its treatment

Free-listing and pile-sorting items of importance to patients with AAV

All 17 US patients interviewed were invited to free-list terms they associated with the onset, remission, and flaring of their AAV (Figure 1). The most salient themes at onset were pain and discomfort (SSI=0.37), nasal and sinus problems (SSI=0.32), and fatigue and energy levels (SSI=0.27). Emotional effects were within the top three during flare (SSI=0.28) and remission (SSI=0.27). Themes identified were compared with the individual themes of interest and domains from the in-depth patient interviews and no new themes were identified (Box 1 for overview and Table S1 for detailed descriptions).

Figure 1 Smith’s Salience Indices of patient’s free-listed and ranked terms. Notes: (A) Terms at AAV diagnosis; (B) terms during AAV remission; (C) terms during AAV flare; (D) comparison across AAV activity states. Abbreviations: AAV, associated vasculitis; labs, laboratory tests.

Candidate item development

Fifty-five individual themes were identified from the qualitative work (Box 1), and these were recast into an initial list of 105 candidate items by members of the CQWG. Patient descriptions informed the design of the candidate questionnaire items and response options, resulting in different sections. Patients described the overall severity of their symptoms, rather than the frequency; pain was usually described in relation to specific body areas, such as joints or muscles; and ability to function was described in terms of the amount of difficulty with completing a specific task. The candidate items were scrutinized for duplication and ambiguity of items, reducing the item pool to 42 items. Patients made it clear that it was difficult to tease apart symptoms caused by AAV versus its treatment, so both were included within the stem of the question. Items related to contextual factors (eg, support and self-efficacy – Box 1 and Table S1) were not included within the PRO itself, after discussion at an OMERACT 2014 breakout session with patient participants.²⁸

Three rounds of cognitive interviews were conducted in the UK and USA, using the 42-item version of the questionnaire, with amendments after each round. Word changes were suggested by patients, for example, clarification of the word essential in relation to activities, and change to the period of recall from 7 days to 4 weeks. All participants reported that the questionnaire captured content relevant to them. Seven items were rejected because of ambiguity, repetition, or being contextual factors. Following the translatability assessment (Box S1), minor changes were made to a few items, and these revisions were piloted in the last round of interviews. The conceptual framework evolved in response to insights from the qualitative research, feedback from the steering committee, and breakout sessions at OMERACT, and the final version is shown in Figure 2. The resulting 35-item candidate pool is shown in Box 3.

Figure 2 Conceptual framework for the AAV-PRO. Notes: The scope of the developing measure was defined by the steering committee and evolved during development to include symptom severity, the impact of problems and limitations imposed by patients’ ANCA-associated vasculitis and treatment on their work and domestic roles, family and social interactions (including activities and interests outside the home), and psychological state. Abbreviations: AAV, ANCA-associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; PRO, patient-reported outcome.

Box 3 Candidate item pool for the questionnaire

Discussion

This is the most comprehensive evaluation of the patient perspective in AAV to date. Patients have been an integral part of this work as key members of the steering committee and qualitative interview participants, reflecting all three diseases, differing disease manifestations, a wide demographic range, and three different countries. The item generation for a novel, disease-specific PRO measure is underpinned by this qualitative research, which should ensure that the final candidate items have good face validity within each country. Themes identified in previous quantitative studies are confirmed, for example, fatigue,¹³ anxiety, and depression,¹⁶ and the impact on everyday function and employment.^17,43 Newer themes include difficulties in making plans, from short-term social engagements to life planning, previously reported in patients with systemic lupus erythematosus, rheumatoid arthritis, and GPA.^19,44,45

The strengths of this study include a high level of patient involvement, and ongoing critical review through OMERACT Workshops, which have helped to ensure that each stage was consistent with best practice. Patients were purposively sampled to include a range of disease features and demographics, including a high proportion of patients with recent active disease. This was to ensure a focus on themes (and then items), which would exhibit greatest change in the context of a RCT. A third of patients had longer-standing disease, and saturation of themes was also reached within this patient group. The high rate of relapsing disease may also be a reflection of the fact that patients with GPA, who have a higher rate of relapse,⁴⁶ were slightly over-represented compared with patients with MPA; this may be a potential bias of the sample. That only English-speaking participants were included is a limitation of this study. However, a translatability assessment was performed for the questionnaire items, to ensure that any future translation into a range of languages should be straightforward.⁴⁷ In addition, care was taken to develop items that were not overly culture-specific, for example, describing “difficulties with traveling far from home,” rather than “going on holidays.” Interviews were performed by clinical fellows in the UK and Canada, and this may have changed the way that patients described problems in relation to their disease or treatment. Training was, therefore, provided by experienced social scientists, who also evaluated all interview transcripts.

The OMERACT Vasculitis Working Group has highlighted the lack of a disease-specific PRO for AAV.²⁷ As per FDA guidance, the development of a PRO instrument should start with qualitative analysis involving patients with the disease, in order to identify themes of importance. However, generic PRO instruments, such as the SF-36,⁴⁸ can be used to measure and compare HRQoL between patients with different chronic conditions, and population norms. A combined approach of using disease-specific and generic PRO measures may, therefore, be the optimum way of comprehensively measuring HRQoL in AAV.⁴⁹

The 35-item candidate questionnaire will need to be shortened to reduce responder burden and optimize feasibility within RCTs. The next stage of development will involve a large-scale survey to facilitate further item reduction, and determine the underlying scale structure and measurement properties (reliability, validity, and responsiveness) of the final AAV-PRO instrument.

Acknowledgments

Sponsored by the University of Oxford, the Vasculitis Clinical Research Consortium and the University of Ottawa. With support from the Medical Research Fund, Oxford, the Oxfordshire Health Services Research Committee (Ref 1098), the US National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319 and U01 AR51874), the National Center for Research Resources (U54 RR019497), and the Office of Rare Diseases Research. Oxford University Innovation funded the translatability exercise. Additional support received by a Patient-Centred Outcomes Research Institute Pilot Project Grant.

Disclosure

Dr Robson and Professor Luqmani were supported in part by the National Institute for Health Research Musculoskeletal Biomedical Research Unit, Oxford, UK. Dr Robson was supported by a National Institute for Health Research (NIHR) clinical lectureship. Dr Milman was supported by a UCB/Canadian Rheumatology Association/Arthritis Society postgraduate rheumatology fellowship award and a research fellowship from the Department of Medicine at the Ottawa Hospital. The authors report no other conflicts of interest in this work.

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Supplementary materials

Table S1 Codebook descriptions of individual themes. Collaborative codebook by core qualitative group using consensus methods Abbreviations: AAV, antineutrophil cytoplasmic antibody-associated vasculitis; ADL, activities of daily life.

Table S2 Saturation table: domains and subcodes of emergent themes from 50 in-depth individual patient interviews within the US, Canada (CAN), and UK. 0 = theme not present; 1 = theme present

Box S1 Translatability of the questionnaire

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