Key Points

  • Collaboration among clinical experts, behavioral research methodologists, and patients can yield valuable symptom-assessment tools.

  • Patients with ECD possess widely varied and unappreciated symptomatology.

Abstract

Erdheim-Chester disease (ECD) is an ultra-rare hematologic neoplasm characterized by somatic mutations of the MAPK pathway and by accumulation of lesional histiocytes within tissues. Clinical phenotypes and sites of disease involvement are heterogenous in ECD, and no tool exists for systematic and comprehensive assessment of ECD symptomatology. We describe a collaborative effort among ECD specialists, patient-reported outcome (PRO) methodologists, and ECD patients to develop the Erdheim-Chester Disease Symptom Scale (ECD-SS): a symptom inventory for clinical ECD care and evaluation of ECD therapies. Methodologically rigorous focus groups led to the identification of 63 ECD symptoms in 6 categories, incorporated into the ECD-SS with respect to both severity and frequency. Among 50 ECD patients participating in a prospective registry study completing the ECD-SS, 46 (92%) reported neurological/psychological symptoms, 29 (58%) reported pain, and at least one-half reported mood symptoms, memory problems, or fatigue. Symptoms were highly frequent or almost constant regardless of their severity. The ECD-SS is a rigorously developed, patient-centered tool that demonstrates the wide and previously unappreciated burden of symptomatology experienced by ECD patients. Further studies will refine the symptom inventory and define its psychometric properties and role in clinical care and investigation in the context of ECD.

Introduction

Erdheim-Chester disease (ECD) is an inflammatory hematologic neoplasm, marked by recurrent somatic mutations in the MAPK pathway whereby histiocytes accumulate in tissues and cause illness.1  ECD lesions can infiltrate any organ system2,3  and cause pain, organ dysfunction, and disfigurement from tumoral infiltration. Additionally, clinical disease is mediated by cytokine elevations and perturbations,2,4,5  causing constitutional symptoms of fever, sweats, and fatigue. Despite the array of symptoms that characterize ECD, there are no standardized disease-specific assessments to measure symptom burden within this heterogeneous population. Patient-reported outcomes (PROs) are data elements directly reported by patients about symptoms and quality of life. There is increasing evidence that rigorous collection and analysis of PROs improves patient-centered care, especially for rare diseases.6-8  To create an informative PRO tool across the phenotypic spectrum of ECD, both for clinical care and for evaluating ECD therapies in clinical trials, we organized a collaboration among ECD clinicians, PRO methodologists, and ECD patients. Here, we describe the process of establishing the content validity of the Erdheim-Chester Disease Symptom Scale (ECD-SS) using state-of-the-art focus-group methodology, and we present the first prospective data on frequency and severity of symptoms in a cohort of ECD patients.

Methods

Institutional review board (IRB) approval was obtained to conduct focus groups and to analyze transcripts of audio-recorded data. The discussions described herein took place at the Patient and Family Gathering hosted by the Erdheim-Chester Disease Global Alliance on 10 October 2015 during the Fourth Annual International ECD Medical Symposium in Houston, TX. Because focus-group data were collected anonymously and without protected health information, the requirement for written informed consent was waived. ECD patients or caregivers could partake in the discussions.

The format (setting, duration), content (wording of questions and prompts), and execution (sequence of discussions, techniques for facilitation) of focus groups was designed by the Patient-Reported Outcomes, Community-Engagement and Language (PRO-CEL) Core at Memorial Sloan Kettering Cancer Center based on methodological best practices for PRO measure design.9,10  Focus groups (conducted by E.L.D. and J.J.B.) with 7 to 9 participants each were planned to last 60 to 90 minutes. Focus-group discussions were iterative in their design and execution with 3 phases as follows.

Concept elicitation: phase 1

Facilitators asked open-ended questions about ECD symptoms, allowing participants to describe their experiences fully and without interruption. Participants were also asked their opinions about how ECD symptoms should best be measured. Facilitators interpreted and reflected responses to the group to generate a list of specific symptoms from the discussion.

Integration of expert suggestions: phase 2

Prior to the focus groups, clinicians with expertise in ECD (E.L.D., D.M.H., O.A.-W., F.J.) created a list of symptoms synthesized from ECD literature, guidelines,11  and clinical experience. This proposed symptom list was presented to participants, who were invited to reflect upon the items for inclusion in or exclusion from the list created in phase 1.

Refinement: phase 3

Participants reviewed and appraised the aggregated list of participant- and clinician-generated symptoms to refine and reconsider the entire inventory. Participants were invited to share further thoughts about the discussion, and, in the process, to further add, remove, or modify symptom items. Aspects of symptomatology (eg, frequency, severity) most relevant to measurement were discussed. At the conclusion of the discussion, there was consensus that all participants’ symptoms were represented on the list and that, conversely, there were no extraneous items on the list (ie, applicable to no one in the group). Transcripts of the discussion were subsequently reviewed by the PRO methodologists to develop the ECD-SS.

Pilot data collection and analysis

The ECD-SS was administered to participants in a prospective, IRB-approved ECD registry study (NCT03329274). All patients provided informed consent to the study per the Declaration of Helsinki. Participants completed the ECD-SS via a secure web-based platform implemented frequently in PRO research. Symptom frequency and severity were analyzed descriptively using SAS version 9.4 (Cary, NC).

Results

Focus groups and ECD-SS

Three focus-group discussions were conducted, each with 8 participants. Of the 24 participants, 16 were ECD patients and 8 were caregivers. Each focus-group discussion was 45 to 60 minutes in length.

The process of generating the ECD-SS symptom inventory is schematized in Figure 1. Six categories of symptoms were identified: neurologic or psychological, gastrointestinal, pain-related, vision-related, respiratory or breathing, and a broad category of constitutional and other symptoms. Following phase 2 of the discussions, 69 symptoms were identified. Six symptoms were removed during refinement, yielding 63 ECD symptoms.

Figure 1.

ECD-SS. (A) The collaborative process of generating the ECD-SS symptom inventory. (B) The distributions of symptom categories and frequencies are presented by each level of symptom severity. Mean symptom severity is presented between each stacked bar chart.

Figure 1.

ECD-SS. (A) The collaborative process of generating the ECD-SS symptom inventory. (B) The distributions of symptom categories and frequencies are presented by each level of symptom severity. Mean symptom severity is presented between each stacked bar chart.

The scale was designed to measure both symptom frequency and severity. ECD-SS respondents check off all experienced ECD symptoms and rank the severity of their 5 most severe symptoms. Each symptom is rated on a numeric severity scale from 0 to 10. Frequency is rated for each symptom on a 5-point Likert scale (never, rarely, occasionally, frequently, almost constantly).

ECD symptoms

We present ECD-SS data from 50 ECD patients, a separate cohort from focus-group participants; patient characteristics and reported symptoms are summarized in Table 1. Sixty-two of 63 symptoms in the inventory were endorsed by a least 1 participant. Neurologic or psychologic symptoms were reported by 92%, with 50% or more of participants reporting depression or sadness, stress/anxiety, or memory problems, and 72% reporting fatigue or sleepiness. Aching bones or joints was reported by 56%, generalized pain by 36%, and aching muscles by 28%. Symptoms related to balance and dexterity, as well as those related to cognition were frequently reported. The distribution of symptom categories and their frequency, according to symptom severity, is presented in Figure 1. For the most severe symptom reported, the mean severity was 7.08 (standard deviation, 2.02). This most severe symptom reported was neurologic/psychological for 24 (48%) of participants, constitutional/other for 14 (28%), gastrointestinal for 1 (2%), pain for 8 (16%), visual for 2 (4%), and respiratory for 1 (2%). Symptoms were reported to be highly frequent, irrespective of severity: the most severe symptom was reported to be either frequent or almost constant for 43 participants (86%) and was frequent or almost constant for 29 (58%) for the least severe symptom. Of note, 37 participants (74%) were undergoing active treatment at the time of completing the ECD-SS.

Table 1.

Clinical characteristics and prevalence of symptoms as reported on the ECD-SS

CharacteristicN*%*
Age, y 56.1 (median) 18-77 (range) 
Sex   
 Male 28 56 
 Female 21 42 
 Unknown 
Race   
 White 46 92 
 African American 
 Asian 
 Unknown 
Self-reported disease locations   
 Bone 36 72 
 Skin 16 
 Brain 23 46 
 Lungs 16 
 Heart 14 28 
 Kidneys 23 46 
 Eyes 16 32 
 Spine 18 
Treatment at time of completing ECD-SS   
 Targeted therapy 27 54 
 Conventional therapy 18 
 Targeted and conventional therapy 
 No current treatment 18 
 Unknown 
Neurologic or psychological symptoms   
 Memory problems (forgetfulness, repeating questions or statements) 26 52 
 Depression or sadness 25 50 
 Stress/anxiety 25 50 
 Trouble with balance or walking 25 50 
 Short-tempered 21 42 
 Discouragement 19 38 
 Weakness of the arms or legs 18 36 
 Mood swings 17 34 
 Trouble with dexterity/coordination 17 34 
 Difficulty concentrating or paying attention 17 34 
 Numbness or tingling in hands or feet 15 30 
 Ringing in the ears (tinnitus) 14 28 
 Speech difficulties 13 26 
 Choking (while eating or drinking) 11 22 
 Difficulty swallowing 11 22 
 Dizziness 11 22 
 Head rush or light headedness or spinning sensation (vertigo) 10 20 
 Headache 16 
 Inappropriate crying 
 Inappropriate behavior 
 Personality changes 
 Inappropriate laughter 
Constitutional or other symptoms   
 Fatigue or sleepiness 36 72 
 Decreased sexual interest 16 32 
 Frequent or excessive urination 15 30 
 Insomnia or difficulty sleeping 14 28 
 Sudden urge to urinate 13 26 
 Night sweats 12 24 
 Inability to sleep due to pain 11 22 
 Itchy skin 11 22 
 Rash or skin problems 11 22 
 Frequent napping 10 20 
 Swelling of the arms or legs (edema) 10 20 
 Inability to drive 16 
 Hot flashes 14 
 Inability to sleep lying down 14 
 Problems tasting food 
 Changes in smell 
 Pounding or racing heart (palpitations) 
 Other problem that was not listed or I do not have any symptoms. 
 Fever 
 Hyperhidrosis (excessive sweating) 
 Urinary incontinence 
 Urinary tract pain 
Gastrointestinal symptoms   
 Dry mouth 15 30 
 Diarrhea 13 26 
 Abdominal pain 10 20 
 Decreased appetite 14 
 Nausea 14 
 Dental problems 
 Ulcers or other stomach problems 
 Vomiting 
Pain   
 Aching bones or joints 28 56 
 Pain 18 36 
 Aching muscles 14 28 
Visual symptoms   
 Blurred vision 11 22 
 Changes in vision 12 
 Double vision 10 
Respiratory symptoms   
 Cough 18 
 Shortness of breath (in general) 14 
 Trouble breathing at night 
 Trouble breathing/shortness of breath (in general) 
 Hypoxia (air hunger from low oxygen) 
Most common in patients on no treatment (N = 9)   
 Stress/anxiety 89 
 Fatigue or sleepiness 78 
 Memory problems 78 
 Depression or sadness 67 
 Aching bones or joints 67 
Most common in patients on conventional therapy (N = 9)   
 Short-tempered 56 
 Difficulty concentrating or paying attention 56 
 Aching bones or joints 56 
 Pain 56 
 Fatigue or sleepiness 56 
Most common in patients on targeted therapy (N = 27)   
 Fatigue or sleepiness 19 70 
 Depression or sadness 13 48 
 Trouble with balance or walking 13 48 
 Memory problems 13 48 
 Aching bones or joints 13 48 
CharacteristicN*%*
Age, y 56.1 (median) 18-77 (range) 
Sex   
 Male 28 56 
 Female 21 42 
 Unknown 
Race   
 White 46 92 
 African American 
 Asian 
 Unknown 
Self-reported disease locations   
 Bone 36 72 
 Skin 16 
 Brain 23 46 
 Lungs 16 
 Heart 14 28 
 Kidneys 23 46 
 Eyes 16 32 
 Spine 18 
Treatment at time of completing ECD-SS   
 Targeted therapy 27 54 
 Conventional therapy 18 
 Targeted and conventional therapy 
 No current treatment 18 
 Unknown 
Neurologic or psychological symptoms   
 Memory problems (forgetfulness, repeating questions or statements) 26 52 
 Depression or sadness 25 50 
 Stress/anxiety 25 50 
 Trouble with balance or walking 25 50 
 Short-tempered 21 42 
 Discouragement 19 38 
 Weakness of the arms or legs 18 36 
 Mood swings 17 34 
 Trouble with dexterity/coordination 17 34 
 Difficulty concentrating or paying attention 17 34 
 Numbness or tingling in hands or feet 15 30 
 Ringing in the ears (tinnitus) 14 28 
 Speech difficulties 13 26 
 Choking (while eating or drinking) 11 22 
 Difficulty swallowing 11 22 
 Dizziness 11 22 
 Head rush or light headedness or spinning sensation (vertigo) 10 20 
 Headache 16 
 Inappropriate crying 
 Inappropriate behavior 
 Personality changes 
 Inappropriate laughter 
Constitutional or other symptoms   
 Fatigue or sleepiness 36 72 
 Decreased sexual interest 16 32 
 Frequent or excessive urination 15 30 
 Insomnia or difficulty sleeping 14 28 
 Sudden urge to urinate 13 26 
 Night sweats 12 24 
 Inability to sleep due to pain 11 22 
 Itchy skin 11 22 
 Rash or skin problems 11 22 
 Frequent napping 10 20 
 Swelling of the arms or legs (edema) 10 20 
 Inability to drive 16 
 Hot flashes 14 
 Inability to sleep lying down 14 
 Problems tasting food 
 Changes in smell 
 Pounding or racing heart (palpitations) 
 Other problem that was not listed or I do not have any symptoms. 
 Fever 
 Hyperhidrosis (excessive sweating) 
 Urinary incontinence 
 Urinary tract pain 
Gastrointestinal symptoms   
 Dry mouth 15 30 
 Diarrhea 13 26 
 Abdominal pain 10 20 
 Decreased appetite 14 
 Nausea 14 
 Dental problems 
 Ulcers or other stomach problems 
 Vomiting 
Pain   
 Aching bones or joints 28 56 
 Pain 18 36 
 Aching muscles 14 28 
Visual symptoms   
 Blurred vision 11 22 
 Changes in vision 12 
 Double vision 10 
Respiratory symptoms   
 Cough 18 
 Shortness of breath (in general) 14 
 Trouble breathing at night 
 Trouble breathing/shortness of breath (in general) 
 Hypoxia (air hunger from low oxygen) 
Most common in patients on no treatment (N = 9)   
 Stress/anxiety 89 
 Fatigue or sleepiness 78 
 Memory problems 78 
 Depression or sadness 67 
 Aching bones or joints 67 
Most common in patients on conventional therapy (N = 9)   
 Short-tempered 56 
 Difficulty concentrating or paying attention 56 
 Aching bones or joints 56 
 Pain 56 
 Fatigue or sleepiness 56 
Most common in patients on targeted therapy (N = 27)   
 Fatigue or sleepiness 19 70 
 Depression or sadness 13 48 
 Trouble with balance or walking 13 48 
 Memory problems 13 48 
 Aching bones or joints 13 48 
*

Columns 2 and 3 represent number and percent of patients, respectively, except as noted in row 1.

Vemurafenib, dabrafenib, cobimetinib, trametinib, or dual BRAF/MEK therapy.

Corticosteroids, interferon, anakinra, tocilizumab, methotrexate.

Discussion

We describe here the collaborative and patient-centered methodologic process of developing a comprehensive symptom inventory for ECD. The disease symptomatology captured from the ECD-SS suggests an extensive burden of symptoms in ECD patients, exceeding that which has been described in the literature.11-14  All symptoms on the inventory except for 1 were endorsed by at least 1 of the 50 ECD patients completing the assessment, supporting the content validity of the ECD-SS items as resonant with real-world patient experience. These pilot data further illustrated that frequent symptoms such as impaired cognition, psychological distress, pain, and constitutional symptoms are those that do not have a correlate on imaging scans. Moreover, these symptoms are present in a largely treated population, suggesting inadequate supportive management even in the setting of controlled disease. Therefore, these symptoms are not measured, or evaluated with respect to therapeutic response, by traditional radiologic assessments. This highlights an important gap, and opportunity for meaningful improvement, within the clinical assessment of ECD patients. A limitation of this kind of assessment, particularly when performed cross-sectionally, is that disease-related symptoms are not distinguished from treatment side effects. Further study of the ECD-SS will involve investigation of its psychometric properties, including methods such as internal consistency, factor analysis, and principal components analysis, which could provide quantitative insights into reconsidering the symptom categories and refining the inventory by removing redundant items. Other avenues of future inquiry will involve methods of composite scoring and of changes in symptom scores across time points. Continued implementation and evaluation of the ECD-SS within clinical care and investigational studies will help to define its role in comprehensive ECD assessment.

Acknowledgments

This work was supported by funding from the Erdheim-Chester Disease Global Alliance, the Frame Fund, and the Joy Family West Foundation. This research was also funded in part through National Institutes of Health, National Cancer Institute Cancer Center Support grant P30 CA008748.

Authorship

Contribution: E.L.D., J.J.B., T.M.A., F.J., K.B., and J.C. collected the data; E.L.D., A.S.R., J.J.B., E.S., A.J.A., R.R., K.B., J.C., J.J.M., T.M.A., and K.S.P. analyzed and interpreted the data; E.L.D., A.S.R., J.J.B., E.S., A.J.A., D.M.H., O.A.-W., R.R., F.J., K.B., J.C., J.J.M., T.M.A., and K.S.P. wrote the manuscript; and all authors approved the final manuscript.

Conflict-of-interest disclosure: D.M.H. reports personal fees from Atara Biotherapeutics, Chugai Pharma, Boehringer Ingelheim, AstraZeneca, Pfizer, Bayer, Debiopharm Group, and Genetech; and grants from AstraZeneca, Puma Biotechnology, and Loxo Oncology, outside of the submitted work. O.A.-W. reports grants from the National Cancer Institute, National Institutes of Health; grants and personal fees from H3B Biomedicine and Foundation Medicine Inc; and personal fees from Merck, outside of the submitted work. R.R. reports personal fees from Incyte, outside of the submitted work. F.J. reports research support from Novartis, Genentech, BioMed Valley Discoveries, Plexxikon, Deciphera, Piqur, Symphogen, Bayer, FujiFilm Corporation, and Upsher-Smith Laboratories; is on the scientific advisory boards of IFM Therapeutics, Synlogic, Guardant Health, and Deciphera; is a paid consultant for Trovagene and Immunomet; and has ownership interests in Trovagene; all are outside of the submitted work. K.S.P. reports stock ownership in Johnson & Johnson, Viking Therapeutics, Catalyst Biotech, and Pfizer, outside of the submitted work. The remaining authors declare no competing financial interests.

Correspondence: Eli L. Diamond, Department of Neurology, Memorial Sloan Kettering Cancer Center, 160 East 53rd St, 2nd Floor Neurology, New York, NY 10022; e-mail: diamone1@mskcc.org.

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Author notes

*

E.L.D. and A.S.R. contributed equally to this work.

T.M.A. and K.S.P. contributed equally to this work.