Key Points
Question
What are the domains of health-related quality of life among adults living with cutaneous chronic graft-vs-host disease (GVHD)?
Findings
In this concept elicitation study of 31 adults with cutaneous chronic GVHD, participants with epidermal and sclerotic disease had many overlapping skin changes and symptoms, which led to reductions in social, psychological, and physical functioning, and general perceptions of health.
Meaning
Cutaneous chronic GVHD impairs health-related quality of life independent of extracutaneous disease; this information can be used to develop and select patient-reported outcome measures with good content validity for clinical trials and to guide clinical practice.
Abstract
Importance
Cutaneous chronic graft-vs-host disease (GVHD) is independently associated with morbidity and mortality after allogeneic hematopoietic cell transplant. However, the health-related quality-of-life (HRQOL) domains that are most important to patients are poorly understood.
Objective
To perform a concept elicitation study to define HRQOL in cutaneous chronic GVHD from the patient perspective and to compare experiences of patients with epidermal vs sclerotic disease.
Design, Setting, and Participants
A single-center qualitative analysis from open-ended, semistructured interviews and free-listing terms conducted between April and September 2023. Participants were 18 years or older with a diagnosis of active cutaneous chronic GVHD, purposefully sampled for epidermal and sclerotic disease features, with ongoing sampling until thematic saturation.
Main Outcomes
HRQOL domains and codes from patient perspectives of living with cutaneous chronic GVHD were identified by inductive analysis of semistructured interviews. Smith salience index (Smith S) score, a measure of saliency for each list term, was calculated from free-listing terms from deidentified patient interviews.
Results
A total of 31 adults with cutaneous chronic GVHD (median [IQR] age, 61.1 [52.9-68.7] years) participated in interviews; 17 participants (54.8%) were male and 14 (45.2%) were female. Nine participants (29.0%) had epidermal, 13 (41.9%) sclerotic, and 9 (29.0%) a combination of disease types. The study identified 40 codes of importance grouped within 5 HRQOL domains: skin changes and symptoms, social functioning, psychological and emotional functioning, physical functioning, and general health perceptions. The most frequent symptoms were dry skin (n = 20 [65%]), tight skin (n = 19 [61%]), itch (n = 15 [48%]), and discoloration (n = 14 [45%]), which were seen in all disease subtypes. Impairment in social functioning was noted by all participants. Psychological and emotional functioning, including frustration (Smith S score, 0.32) and worry or concern (Smith S score, 0.12), and symptoms including discomfort (Smith S score, 0.20) were the most salient to patients. Individual and environmental factors, such as social comparison, illness comparison with cancer, anatomic location of disease involvement, and disease duration, affected the relationship between skin changes and symptoms and downstream functioning and general health perceptions.
Conclusions and Relevance
This qualitative analysis demonstrated the direct relationship between cutaneous chronic GVHD and HRQOL domains and identified codes not represented in existing GVHD- and dermatology-specific patient-reported outcome measures. These results can guide patient-reported outcome development and instrument selection for clinical trials and improve clinical decision-making.
This concept elicitation study explores health-related quality-of-life domains from the perspective of patients with cutaneous chronic graft-vs-host disease, defining the domains most important to patients and comparing epidermal vs sclerotic disease manifestation.
Introduction
Chronic graft-vs-host disease (GVHD) is a multisystem syndrome and the leading cause of morbidity, mortality, and impaired health-related quality of life (HRQOL) following allogeneic hematopoietic cell transplant.1,2,3,4,5 Skin is the most common organ affected by chronic GVHD6,7 and is the indication for initiating or adding systemic therapy in up to 80% of patients.8 However, cutaneous chronic GVHD is refractory to treatment in the majority of cases,9,10,11 resulting in prolonged disease activity and cumulative adverse effects of immunosuppressive therapy.8,12
Cutaneous chronic GVHD can broadly be classified into epidermal and sclerotic disease manifestations according to the 2014 National Institutes of Health (NIH) Consensus Criteria.13 Epidermal chronic GVHD is characterized by rashes that resemble lichen planus, psoriasis, atopic dermatitis, and other chronic inflammatory skin conditions. Sclerotic chronic GVHD results in thickening and tightening of the superficial and deep skin structures and fascia, often resulting in impaired mobility. Cutaneous chronic GVHD has been associated with impaired HRQOL,14 defined as the aspects of quality of life that relate specifically to a person’s health,15 and patients with worse HRQOL at cutaneous chronic GVHD diagnosis have higher risk of nonrelapse mortality independent of clinical severity.16
Despite the immense burden on patients, the NIH skin score, a clinician-reported measure of disease activity that encompasses body surface area involvement and depth of sclerosis, is the current reference-standard outcome measure used in chronic GVHD clinical trials.13,17 However, patients often have different perceptions of what is important compared with their clinicians and patient- and clinician-reported disease severity can be discordant.18,19,20 To gauge the efficacy of treatments in clinical trials, validated measurement of both clinician- and patient-focused outcomes is imperative.
In accordance with recommendations from the US Food and Drug Administration (FDA), concept elicitation using qualitative research is a critical first step to understand outcomes that are important to patients to develop and select patient-reported outcomes (PROs) with face validity.21 Qualitative data exploring chronic GVHD demonstrated multifaceted impacts on HRQOL domains,22,23 but a 2020 systematic review highlighted a lack of in-depth qualitative research exploring cutaneous chronic GVHD specifically.24 The objective of this study was to perform concept elicitation to define HRQOL in cutaneous chronic GVHD using patient input and compare the lived experience of disease between patients with epidermal and sclerotic disease manifestations.
Methods
Study Design
The study committee included 2 dermatologists (E.B., J.M.G.), 2 transplant physician-scientists with expertise in GVHD (S.J.L., A.W.L.), and 4 qualitative research experts (P.F.C., M.D.K., S.K., M.M.S.). We designed a cross-sectional concept elicitation study that included an in-depth, semistructured interview to understand HRQOL in cutaneous chronic GVHD followed by free-listing to identify salient words or phrases considered to define disease activity and remission. Free-listing is a standard, systematic interviewing method that allows one to demonstrate how groups of individuals with shared experiences (eg, cutaneous chronic GVHD) define, associate, and prioritize topics25,26 and has been used as a qualitative technique to inform PRO development.27 The study was approved by the institutional review board of the University of Pennsylvania. Written informed consent was obtained from all participants. The study is reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) guidelines.28
Patient Study Sample
Participants were recruited from the Department of Dermatology and the Cell Therapy and Transplant Program at the University of Pennsylvania between April and September 2023. Eligibility criteria included being 18 years or older and having active cutaneous chronic GVHD according to the NIH Consensus Criteria.13 Participants with a preferred language other than English were eligible; however, there were no non–English speakers who met the enrollment criteria. Participants were purposefully sampled29 to achieve approximately equal representation of epidermal and sclerotic disease features. Patients with combination disease were considered to meet sampling criteria for both disease features. A participant sample size of 30 was determined based on the literature for item stabilization (ie, no change in item frequencies for the most salient items with additional interviews) for free-listing,25 with ongoing sampling until thematic saturation (ie, no new themes identified with additional interviews) was reached, resulting in a final sample size of 31.30 Informed consent was obtained from all participants, including consent to audio-record interviews and publish deidentified patient quotes.
Data Collection
Patients underwent clinical activity scoring using the NIH organ-based assessment tool to classify cutaneous chronic GVHD types and identify extracutaneous organ involvement.13 Interviews were performed within 7 days of enrollment either in person or via teleconferencing; interview mode has not been shown to affect interview responses.31,32 Interviews were conducted in a quiet, private space in English by an interviewer trained in conducting semistructured interviews and free-listing (M.M.).
The study committee developed a preliminary conceptual framework grounded in the conceptual model of HRQOL proposed by Wilson and Cleary15 and informed by systematic review of PROs in GVHD,24 dermatology-specific PROs,33,34,35 and content expertise. The preliminary conceptual framework included 4 HRQOL domains: symptoms, social functioning, emotional functioning, and physical functioning. An open-ended interview guide was developed from the preliminary conceptual framework to ask participants about their experiences living with cutaneous chronic GVHD (eMethods in Supplement 1). The interview guide was revised by the study committee after 10 interviews in response to an evolving conceptual framework to add questions about an emergent general health HRQOL domain, which was administered for the remaining 21 interviews. For free-listing data collection, participants were asked the following questions: “Which words would you use to describe your skin GVHD when it (1) first started, (2) is under control, and (3) is starting to flare?” to elicit words and statements associated with distinct disease activity states.
Data Analysis
All interviews were audio-recorded, professionally transcribed, and transcripts were deidentified. For analysis of semistructured interviews, deidentified transcripts were uploaded into NVivo qualitative data analysis software version 20 (QSR International). We used inductive thematic analysis to develop a hierarchical coding structure of first- and second-level codes representing specific HRQOL symptoms, functions, and health perceptions. The final codebook was refined through an iterative process in NVivo and used to code the remaining transcripts. The transcripts were coded independently by 2 researchers and 20% were double coded with interrater reliability assessed until coding consensus was high (κ >.75). Codes were mapped to the 5 HRQOL domains. Codes described by patients to be explicitly a result of extracutaneous chronic GVHD or treatment effects were not included.
A final list of free-listing terms was developed by combining root words, synonyms, and words with similar meanings for each question. Lists were entered into R version 4.1.1 (R Foundation). For each question, the Smith salience index (Smith S) score36,37 for each term was calculated using the equation Smith S score = (( ∑ (L-Rj+1))/L) / N, where L was the number of items in the list, Rj was the rank of the term j in the list, and N was the number of lists (participants).25 Smith S scores were sorted from high to low and plotted as scree plots to identify terms with relatively higher salience at disease onset, remission, and flare.26 The plots were inspected for a natural breaking point, indicated by a flattening of the slope, with terms above the breaking point considered salient. The study committee developed a final conceptual framework of HRQOL informed by results of the qualitative analysis. For descriptive statistics, P values were 2-sided with a significance threshold of P = .05.
Results
Participants
A total of 31 adults with cutaneous chronic GVHD participated in interviews (median [IQR] age, 61.1 [52.9-68.7] years; 17 [54.8%] male and 14 [45.2%] female) (Table 1), with interviews lasting an average of 18 minutes (range, 7-39 minutes). Two participants (6.5%) self-identified as Asian and 1 (3.2%) self-identified as Hispanic, with the remainder identifying as non-Hispanic White. Race and ethnicity data were collected to examine whether the experience of living with cutaneous chronic GVHD differed between racial and ethnic groups. At the time of interview, 11 participants (35.5%) were working, 9 (29.0%) retired, and 8 (25.8%) self-identified as disabled and unable to work.
Table 1. Participant Characteristics.
| Characteristic | No. of patients (%)a | ||||
|---|---|---|---|---|---|
| Total (N = 31) | Epidermal (n = 9) | Sclerotic (n = 13) | Combination (n = 9) | P value | |
| Age at enrollment, median (IQR), y | 61.1 (52.9-68.7) | 58.7 (41.5-68.9) | 59.8 (51.5-62.8) | 66.7 (60.8-71.0) | .10 |
| Genderb | |||||
| Male | 17 (54.8) | 3 (33.3) | 9 (69.2) | 5 (55.6) | .25 |
| Female | 14 (45.2) | 6 (66.7) | 4 (30.8) | 4 (44.4) | |
| Raceb | |||||
| Asian | 2 (6.5) | 1 (11.1) | 0 | 1 (11.1) | .46 |
| White | 29 (93.5) | 8 (88.9) | 13 (100.0) | 8 (88.9) | |
| Ethnicityb | |||||
| Hispanic | 1 (3.2) | 0 | 1 (7.7) | 0 | |
| Not Hispanic | 30 (96.8) | 9 (100.0) | 12 (92.3) | 9 (100.0) | |
| Underlying disease | |||||
| Acute myeloid leukemia | 9 (29.0) | 5 (55.6) | 3 (23.1) | 1 (11.1) | .37 |
| Acute lymphoblastic leukemia | 7 (22.6) | 0 | 4 (30.8) | 3 (33.3) | |
| Chronic myelogenous leukemia | 2 (6.5) | 1 (11.1) | 1 (7.7) | 0 | |
| Chronic lymphocytic leukemia | 1 (3.2) | 0 | 1 (7.7) | 0 | |
| Myelodysplastic syndrome | 3 (9.7) | 1 (11.1) | 0 | 2 (22.2) | |
| Non-Hodgkin lymphoma | 1 (3.2) | 0 | 1 (7.7) | 0 | |
| Mycosis fungoides | 8 (25.8) | 2 (22.2) | 3 (23.1) | 3 (33.3) | |
| Employment statusb | |||||
| Working | 11 (35.5) | 3 (33.3) | 6 (46.2) | 2 (22.2) | .51 |
| Retired | 9 (29.0) | 2 (22.2) | 3 (23.1) | 4 (44.4) | |
| Medical leave | 3 (9.7) | 2 (22.2) | 1 (7.7) | 0 | |
| Disabled, unable to work | 8 (25.8) | 3 (33.3) | 3 (23.1) | 2 (22.2) | |
| Unemployed, not looking for work | 1 (3.2) | 1 (11.1) | 0 | 0 | |
| Other | 1 (3.2) | 0 | 0 | 1 (11.1) | |
| Family income, $b | |||||
| 50 000-74 999 | 7 (22.6) | 2 (22.2) | 3 (23.1) | 2 (22.2) | .35 |
| 75 000-99 999 | 7 (22.6) | 2 (22.2) | 1 (7.7) | 4 (44.4) | |
| ≥100 000 | 17 (54.8) | 5 (55.6) | 9 (69.2) | 3 (33.3) | |
| Education levelb | |||||
| Grade school | 1 (3.2) | 1 (11.1) | 0 | 0 | .38 |
| High school graduate | 7 (22.6) | 1 (11.1) | 4 (30.8) | 2 (22.2) | |
| Some college | 6 (19.4) | 1 (11.1) | 4 (30.8) | 1 (11.1) | |
| College graduate | 10 (32.3) | 5 (55.6) | 2 (15.4) | 3 (33.3) | |
| Postgraduate degree | 7 (22.6) | 1 (11.1) | 3 (23.1) | 3 (33.3) | |
| Duration of skin chronic GVHD, median (IQR), d | 507.5 (56.0-985.0) | 43.0 (0.0-315.0) | 744.0 (592.0-1342.0) | 543.0 (77.0-802.0) | .01 |
| NIH skin score | |||||
| 1 | 5 (16.1) | 5 (55.6) | 0 | 0 | <.001 |
| 2 | 6 (19.4) | 3 (33.3) | 1 (7.7) | 2 (22.2) | |
| 3 | 20 (64.5) | 1 (11.1) | 12 (92.3) | 7 (77.8) | |
| NIH global severity score | |||||
| Moderate | 9 (29.0) | 7 (77.8) | 0 | 2 (22.2) | <.001 |
| Severe | 22 (71.0) | 2 (22.2) | 13 (100.0) | 7 (77.8) | |
| Extracutaneous organ involvement | |||||
| Ocular | 25 (80.6) | 9 (100.0) | 9 (69.2) | 7 (77.8) | .19 |
| Oral | 14 (45.2) | 3 (33.3) | 6 (46.2) | 5 (55.6) | .64 |
| Genital | 4 (12.9) | 2 (22.2) | 1 (7.7) | 1 (11.1) | .60 |
| Joint/musculoskeletal | 21 (67.7) | 3 (33.3) | 12 (92.3) | 6 (66.7) | .01 |
| Gastrointestinal | 5 (16.1) | 1 (11.1) | 3 (23.1) | 1 (11.1) | .67 |
| Liver | 3 (9.7) | 2 (22.2) | 1 (7.7) | 0 | .27 |
| Lung | 13 (41.9) | 2 (22.2) | 5 (38.5) | 6 (66.7) | .15 |
| Treatment | |||||
| Systemic steroids | 13 (41.9) | 4 (44.4) | 6 (46.2) | 3 (33.3) | .82 |
| Ruxolitinib | 19 (61.3) | 3 (33.3) | 10 (76.9) | 6 (66.7) | .11 |
| Belumosudil | 12 (38.7) | 1 (11.1) | 8 (61.5) | 3 (33.3) | .05 |
| Extracorporeal photopheresis | 7 (22.6) | 0 | 7 (53.8) | 0 | .01 |
| Tacrolimus | 6 (19.4) | 3 (33.3) | 2 (15.4) | 1 (11.1) | .44 |
| Topical steroids/calcineurin inhibitors | 24 (77.4) | 8 (88.9) | 7 (53.8) | 9 (100.0) | .02 |
Abbreviations: GVHD, graft-vs-host disease; NIH, National Institutes of Health.
Unless otherwise indicated.
Data collected by patient self-report.
Nine participants (29.0%) had epidermal, 13 (41.9%) sclerotic, and 9 (29.0%) combination disease. Participants with epidermal disease had a median (IQR) duration of cutaneous chronic GVHD of 43 (0-315) days compared with sclerotic (744 [592-1342] days) and combination disease (543 [77-802] days; P = .01). The NIH skin score, a clinician-based measure of disease severity, was severe in 20 participants (64.5%), with more sclerotic (n = 12 [92.3%]) and combination (n = 7 [77.8%]) participants having severe disease compared with epidermal (n = 1 [11.1%]) participants (P < .001). Twenty-nine participants (93.5%) had extracutaneous chronic GVHD, 24 (77.4%) were using topical steroids and/or calcineurin inhibitors, and 13 (41.9%) were using systemic corticosteroids.
HRQOL Domains
Interviews yielded 40 codes of interest that were subsequently grouped into 5 HRQOL domains: skin changes and symptoms, social functioning, psychological and emotional functioning, physical functioning, and general health perceptions (Table 2). The saturation Table of emergent concepts is shown in eTable 1 in Supplement 1.
Table 2. Domains and Codes From Patients With Cutaneous Chronic Graft-vs-Host Disease (GVHD)a.
| Characteristic | No. of patients (%) | |||
|---|---|---|---|---|
| Total (N = 31) | Epidermal (n = 9) | Sclerotic (n = 13) | Combination (n = 9) | |
| Skin changes and symptoms | 31 (100) | 9 (100) | 13 (100) | 9 (100) |
| Dry, flaky, scaly skin | 20 (65) | 8 (89) | 5 (38) | 7 (78) |
| Tight skin | 19 (61) | 2 (22) | 11 (85) | 6 (67) |
| Itch | 15 (48) | 6 (67) | 4 (31) | 5 (56) |
| Discoloration | 14 (45) | 3 (33) | 3 (23) | 8 (89) |
| Painful skin | 10 (32) | 4 (44) | 2 (15) | 4 (44) |
| Redness | 10 (32) | 4 (44) | 3 (23) | 3 (33) |
| Rash | 10 (32) | 5 (56) | 4 (31) | 1 (11) |
| Dimpling or rippling under skin | 10 (32) | 1 (11) | 9 (69) | 0 |
| Bumpy, rough skin | 8 (26) | 3 (33) | 2 (15) | 3 (33) |
| Burning skin | 6 (19) | 4 (44) | 0 | 2 (22) |
| Sores | 6 (19) | 3 (33) | 0 | 3 (33) |
| Hard, thick skin | 6 (19) | 2 (22) | 1 (8) | 3 (33) |
| Shiny skin | 5 (16) | 0 | 3 (23) | 2 (22) |
| Fragile, thin skin | 5 (16) | 1 (11) | 3 (23) | 1 (11) |
| Difficulty breathing due to skin | 5 (16) | 1 (11) | 2 (15) | 2 (22) |
| Irritated skin | 2 (6) | 1 (11) | 1 (8) | 0 |
| Achy skin | 2 (6) | 0 | 0 | 2 (22) |
| Thin, fragile fingernails | 2 (6) | 1 (11) | 0 | 1 (11) |
| Hair loss, texture change | 2 (6) | 1 (11) | 1 (8) | 0 |
| Difficulty sleeping due to skin | 2 (6) | 1 (11) | 1 (8) | 0 |
| Difficulty speaking due to skin | 1 (3) | 1 (11) | 0 | 0 |
| Social functioning | 31 (100) | 9 (100) | 13 (100) | 9 (100) |
| Adaptations to facilitate social life (eg, sun protection) | 16 (52) | 5 (56) | 7 (54) | 4 (44) |
| Self-consciousness, appearance of condition | 16 (52) | 5 (56) | 7 (54) | 4 (44) |
| Ability to work | 9 (26) | 1 (11) | 5 (38) | 2 (22) |
| Avoidance of social activities and participation | 8 (26) | 2 (22) | 3 (23) | 3 (33) |
| Dependency on others | 8 (26) | 3 (33) | 3 (23) | 2 (22) |
| Sex and intimate relationships | 3 (10) | 2 (22) | 1 (8) | 0 |
| Psychological and emotional functioning | 23 (74) | 7 (78) | 8 (62) | 8 (89) |
| Frustration (anger, irritation, annoyance) | 12 (39) | 6 (67) | 3 (23) | 3 (33) |
| Uncertainty or concerns about the future | 9 (29) | 3 (33) | 1 (8) | 5 (56) |
| Depression (down, unmotivated, sad) | 8 (26) | 2 (22) | 2 (15) | 4 (44) |
| Anxiety (fear, worry) | 7 (23) | 3 (33) | 2 (15) | 2 (22) |
| Physical functioning | 18 (58) | 3 (33) | 8 (62) | 7 (78) |
| Activities of daily living (walking, dressing, stairs) | 12 (39) | 2 (22) | 7 (54) | 3 (33) |
| Personal mobility | 10 (32) | 0 | 7 (54) | 3 (33) |
| Exercise and physical hobbies | 5 (16) | 1 (11) | 2 (15) | 2 (22) |
| General health perceptions | 30 (97) | 9 (100) | 12 (92) | 9 (100) |
| Good response to treatment | 19 (61) | 7 (78) | 6 (46) | 6 (67) |
| Poor response to treatment | 16 (52) | 4 (44) | 7 (54) | 5 (56) |
| Disease knowledge and expectations | 10 (32) | 2 (22) | 4 (31) | 4 (44) |
| General sense of wellness | 6 (19) | 1 (11) | 2 (15) | 3 (33) |
| Vulnerability to flares (sun, infections, vaccines) | 6 (19) | 3 (33) | 2 (15) | 1 (11) |
First-level codes were mapped to 5 health-related quality-of-life domains. Second-level codes included specific functions within first-level codes, some of which are represented in parentheses.
Domain 1: Skin Changes and Symptoms
Skin changes and symptoms were spontaneously reported by all participants. Twenty-one codes were identified, with dry skin (n = 20 [65%]), tight skin (n = 19 [61%]), itch (n = 15 [48%]), and discoloration (n = 14 [45%]) reported most frequently (Table 2). Itch was described with consistent language, while severity was described by extent of involved body surface area, measures taken to alleviate itch (eg, medication), and impact on function (eg, sleep) (eTable 2 in Supplement 1).
A patient with epidermal disease said, “When it’s this intense with a breakout, it’s like it is on the front of my legs, my whole body is itching…I tend to be itchy all over” (patient 24).
Uncomfortable skin sensations were reported as pain (n = 10 [30%]), burning (n = 6 [19%]), aching (n = 2 [6%]), and irritation (n = 2 [6%]).
A patient with sclerotic disease commented, “When it all started, head to toe was just wracked with pain. I had no idea what was happening…I was getting flare-ups across my entire body and had to go back on steroids in order to reduce it” (patient 9).
Excluding patients with combination disease, shiny skin was reported only in sclerotic participants, while burning skin, sores, fingernail changes, and difficulty speaking were exclusive to epidermal participants. Additional participant descriptions of skin changes and symptoms and how they relate to other HRQOL domains are included in eTable 2 in Supplement 1.
Domain 2: Social Functioning
All participants reported that cutaneous chronic GVHD adversely affected social function. Six codes emerged, including feeling self-conscious regarding the appearance of the condition (n = 16 [52%]), lifestyle changes to facilitate social interactions (n = 16 [52%]), ability to work or maintain a career (n = 9 [26%]), avoidance of social activities (n = 8 [26%]), dependency on others (n = 8 [26%]), and impacts on intimacy (n = 3 [10%]).
Regarding social functioning, patients said, “I’m really self-conscious about it because sometimes I feel like people are looking at me trying to figure out what the heck is all that stuff on her face?” (patient 21, combination disease).
“I can’t really go swimming. Any kind of being in the sun outside, like in the summer…I feel like I get stuck in the house because I’m scared to make it worse and make it more painful” (patient 14, epidermal disease).
“The mobility difficulty causes a number of issues. It is very much more difficult to be intimate. It’s difficult just getting around, I have to plan how I’m going to manage my day. Just getting dressed is difficult, I usually have to have my wife help me put my socks on, which is, you feel really old” (patient 15, sclerotic disease).
Domain 3: Psychological and Emotional Functioning
Twenty-three participants (74%) described the impact of cutaneous chronic GVHD on psychological and emotional functioning, which was reported more frequently by epidermal (n = 7 [78%]) and combination (n = 8 [89%]) participants than participants with sclerosis (n = 8 [62%]). Participants felt frustration and anger (n = 12 [39%]), concern about the future (n = 9 [29%]), depression (n = 8 [26%]), and anxiety (n = 7 [23%]).
Patients with combination disease said, “We’re frustrated that we’re not seeing improvements and we’re a little scared of it progressing because if, for instance, the hardening of the skin continues to move and expand, I might have to go on oxygen. They might not be able to do anything, there’s really no treatment for it. And that’s frustrating” (patient 13).
“And during the day when I get a flare-up, it’s a matter of just not feeling motivated to do anything. Not wanting to move around, not wanting to go outside. So, it’s very inhibiting and isolating” (patient 16).
Domain 4: Physical Functioning
Eighteen participants (58%) discussed limitations in physical activity, which was seen more commonly in sclerosis (n = 8 [62%]) and combination (n = 7 [78%]) participants compared with epidermal (n = 3 [33%]) participants. Three codes emerged, including reduction in basic activities of daily living (n = 12 [39%]), general mobility (n = 10 [32%]), and exercise and physical hobbies (n = 5 [16%]).
Regarding physical functioning, patients commented, “The ability of getting dressed in the morning, just putting your socks on, getting your underwear on, it’s all limited” (patient 3, sclerotic disease).
“Sometimes it affects my ability to get up quickly because everything feels creaky and slow. Like the Tin Woodsman put out in the rain overnight” (patient 21, combination disease).
“Can’t play sports with the kids, can’t go on long walks, I don’t think I’ll ever be running again, you know, it affects everything” (patient 29, sclerotic disease).
Domain 5: General Health Perceptions
Thirty participants (97%) described how cutaneous chronic GVHD affected their general sense of health. Participants reported feeling confused and surprised by new symptoms (n = 10 [32%]). They identified as being in poor health (n = 6 [19%]) and vulnerable to exposures, including infection, the sun, or vaccines (n = 6 [19%]). They described both positive (n = 19 [61%]) and negative (n = 16 [52%]) perspectives regarding cutaneous chronic GVHD treatment.
A patient with combination disease said, “I used to—look, I was a real healthy guy and now I’m like this broken-down old man and it sucks” (patient 13).
Salient Free-Listing Terms
The most salient terms at onset were confusion (Smith S score, 0.30), worry or concern (Smith S score, 0.23), and frustration (Smith S score, 0.22) (Figure 1A), with the most salient terms in disease remission conversely relief (Smith S score, 0.39) and happiness (Smith S score, 0.32) (Figure 1B). Salient terms during flares were similar to those at disease onset with frustration (Smith S score, 0.32), discomfort (Smith S score, 0.20), and worry or concern (Smith S score, 0.12) having the highest salience (Figure 1C). Free-listing terms stratified by epidermal, sclerotic, and combination participants demonstrated similarity in salient terms (eFigure A-C in Supplement 1). Free-listing terms were compared with codes from semistructured interviews and no new themes were identified (eTable 3 in Supplement 1).
Figure 1. Smith Salience Index of Patients’ Free-Listed Terms.
Scree plots of the Smith salience index score of each term sorted from high to low. Terms reported by all patients at cutaneous chronic graft-vs-host disease (GVHD) diagnosis (A), during cutaneous chronic GVHD remission (B), and during cutaneous chronic GVHD flares (C).
The final conceptual framework of HRQOL for cutaneous chronic GVHD is shown in Figure 2, encompassing 5 domains with skin changes and symptoms upstream of physical functioning, psychological and emotional functioning, social functioning, and general health perceptions. Grounded in the HRQOL framework proposed by Wilson and Cleary,15 individual and environmental characteristics were observed to affect the relationship between skin changes and symptoms and downstream HRQOL domains in cutaneous chronic GVHD, including social comparison, illness comparison with cancer, anatomic location of disease involvement, and disease duration.
Figure 2. Conceptual Framework for Health-Related Quality of Life in Cutaneous Chronic Graft-vs-Host Disease (GVHD).
The scope of the conceptual framework was defined by the study committee and evolved during the study period to include skin changes and symptom severity, the impact of patients’ cutaneous chronic GVHD on their general perceptions of health and disease, physical functioning, psychological and emotional functioning, and social functioning.
Patients said, “I noticed a couple of people looking at my legs, but that didn’t bother me. Once you’re [age redacted], that sort of thing doesn’t bother you” (patient 28, epidermal disease).
“All this other stuff as far as I’m concerned, it doesn’t mean anything to me. I survived. Some discomfort is better than not being here” (patient 27, combination disease).
“I healed a patch of [GVHD] on my face, and when that initially happened, I was really scared about it, but now it’s not in an area for me where I feel it hinders my life in any way” (patient 2, sclerotic disease).
“This is 13 years now, so I’ve gotten so used to it. I’ve learned how to treat it, what to look for” (patient 8, sclerotic disease).
Discussion
In this concept elicitation study of patients with cutaneous chronic GVHD purposefully sampled for epidermal and sclerotic disease manifestations, participants reported impact on HRQOL across many domains. Although 29 of 31 participants had extracutaneous chronic GVHD, all participants reported skin symptoms and skin changes, many of whom experienced downstream social, psychological, and physical dysfunction and general health impairment because of their skin disease. Study findings align with prior studies that show an association between cutaneous chronic GVHD symptoms,7 general HRQOL,14 and disability 18 months after diagnosis.38 However, these studies are limited by the confounding effect of extracutaneous chronic GVHD on HRQOL. Patient perspectives provide valuable insight into these associations by highlighting the experiences (itch, pain, concerns about appearance, and limitations in mobility) that link skin disease to impaired HRQOL. The skin-specific concepts identified in this study highlight PROs as critical outcomes of therapeutic efficacy for cutaneous disease in chronic GVHD clinical trials.
Participants with epidermal- and sclerotic-only disease reported overlapping HRQOL domains and codes, despite clinical disease differences. Although these patients had distinct disease types at the time of interview, many experienced the other disease type previously during their disease course, which may contribute to shared experiences. A 2023 study demonstrated that 24% of patients who present with epidermal disease progress to sclerosis, while 15% of patients who present with sclerosis later develop epidermal disease.39 There were also many symptoms (eg, dry skin, itch, uncomfortable skin sensations) and functional impairments (eg, concerns about appearance, anxiety, depression, dependency) that were part of a shared lived disease experience among epidermal, sclerotic, and combination disease patients. Notably, there were symptoms (eg, sores, tight skin) classically associated with sclerosis that were reported by epidermal patients and resulted from epidermal skin changes. Clinical heterogeneity in cutaneous chronic GVHD makes estimation of disease activity difficult to standardize; however, these qualitative data suggest that a single PRO could be used for patients with epidermal and sclerotic disease.
Participants confirmed many concepts included in current generic, disease-specific, and dermatology-specific PROs, but also identified new concepts not represented in existing measures.24 The Lee Symptom Scale is a 30-item measure with a skin subscale comprising 5 symptoms (abnormal skin color, rashes, thickened skin, sores on skin, and itchy skin) and is the reference-standard PRO used in chronic GVHD clinical trials.40,41 This study identified skin changes and symptoms (eg, tight skin, dry or flaky skin, red skin, skin dimpling) not captured in the Lee Symptom Scale or other dermatology-specific measures.33,42 In addition to skin symptoms, participants described reductions in several functional HRQOL domains with particular saliency of the psychological and emotional domain, which is consistent with other inflammatory skin conditions, including atopic dermatitis, psoriasis, and acne.43,44 Reductions in physical functioning are less common to inflammatory skin conditions and not captured in dermatology-specific PROs. A novel PRO that includes symptoms, function, and general health perceptions is needed to adequately capture outcomes of importance to patients with cutaneous chronic GVHD. A cutaneous chronic GVHD PRO will overcome issues of content validity in existing PROs and be implemented in therapeutic trials as a coprimary or secondary end point to capture meaningful response to treatment.
Limitations
This study has limitations. First, patients were included only if they had active disease to ensure a focus on outcomes that would exhibit the greatest change in therapeutic clinical trials. Patients were purposefully sampled to include a range of clinical disease manifestations to better understand the lived experience across a heterogeneous disease. Second, patients with severe disease (NIH skin score, 3) were overrepresented and may bias the code frequencies reported. Third, participants were asked about experiences related to cutaneous chronic GVHD specifically; however, it is possible that some HRQOL impacts were difficult to isolate from effects of extracutaneous chronic GVHD, treatment, or other comorbid diseases. Fourth, this study was limited by small sample size, although patients were enrolled until thematic saturation according to best practices in qualitative research. Fifth, the study was performed at a single center with relative homogeneity of demographic characteristics with respect to race and ethnicity. Such sampling bias is particularly significant considering patients with skin of color may be differentially affected by epidermal disease.45 Accordingly, these findings will be extended in subsequent PRO development studies by purposefully including a more diverse sample.
Conclusions
PROs are important measures of therapeutic efficacy and are central components of the FDA’s patient-focused drug development program. According to FDA guidance, the development of a PRO must start with concept elicitation to understand patient perspectives and ensure content validity.21 This qualitative analysis identified symptoms, functions, and general health impacts relevant to patients with both epidermal and sclerotic chronic GVHD, many of which are not represented in existing PROs. Next steps will be to build on the present findings and the conceptual framework of HRQOL by developing a disease-specific PRO to use in clinical trials and as a clinical decision-making tool for cutaneous chronic GVHD.
eMethods. Free-listing exercise and semi-structured interview guide
eTable 1. Saturation table of domains and codes
eTable 2. Patient descriptions of skin changes and symptoms and relationship to other HrQOL domains
eTable 3. Free-listing terms and Smith’s Saliency Indices
eFigure. Smith’s Saliency Indices of free-listed terms reported by cutaneous chronic GVHD type
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Free-listing exercise and semi-structured interview guide
eTable 1. Saturation table of domains and codes
eTable 2. Patient descriptions of skin changes and symptoms and relationship to other HrQOL domains
eTable 3. Free-listing terms and Smith’s Saliency Indices
eFigure. Smith’s Saliency Indices of free-listed terms reported by cutaneous chronic GVHD type
Data Sharing Statement