Patient Perceptions in Mast Cell Disorders

The ability of health care professionals and industry representatives to understand the experiences, perceptions, and perspectives of patients plays a vital role in successful care, treatment, and informed development of novel therapies. Regulators increasingly recognize the patient’s voice as critical to drug development, with the US Food and Drug Administration’s 2009 Guidance on Patient-reported Outcomes, patient-focused drug development meetings, and the 21st Century Cures Act. Patients with a mast cell disorder (MCD), including mastocytosis, mast cell activation syndromes (MCAS), and hereditary α-tryptasemia, may experience daily physical, emotional, and social stressors, and awareness of these factors can help medical professionals provide more comprehensive care. Recognition that patient perceptions of their illness may differ from perceptions of treating physicians, especially related to quality of life, degree of disability, and chronicity of symptoms, is essential.

MCDs, considered rare diseases, affect newborns to adults and are divided into clonal and nonclonal disorders. Clonal disorders include cutaneous mastocytosis (CM), systemic mastocytosis (SM), and monoclonal MCAS.^{,  ,  ,  ,  ,}  Nonclonal disorders include forms of MCAS that are secondary or idiopathic.^{,  ,}  CM often presents in children less than 2 years old, and variants, most commonly maculopapular CM (urticaria pigmentosa), differ in size, shape, and pattern of skin rash, percentage of skin affected, and frequency of persistence into adulthood. Cutaneous mastocytoma or mastocytomas, usually present at birth, may spontaneously regress during childhood.^{,  ,}  SM, which may be associated with cutaneous lesions, is divided into indolent SM (ISM), smoldering SM (SSM), and the more advanced SM (AdvSM) categories: SM with associated hematologic neoplasm (SM-AHN), aggressive SM (ASM), and mast cell leukemia (MCL).^{,  ,  ,}  A separate category exists for mast cell (MC) sarcoma.^,  Progression from indolent to more aggressive disease is defined by strict diagnostic criteria.^{,  ,  ,}  A more recently described entity, hereditary α-tryptasemia, is associated with MC mediator release symptoms, dysautonomia, and connective tissue disorders, especially joint hypermobility. Potential triggers of MC mediator release,^{,  ,}  and resulting symptoms,^{,  ,  ,}  vary for each MCD patient (Boxes 1 and 2). Patients with AdvSM can present with cytopenias and organ enlargement/dysfunction from MC infiltration.^{,  ,  ,} 

Patients’ perceptions, experiences, and perspectives have been reported using a variety of data-gathering mechanisms, including patient-related observations, quality-of-life measurements, and patient-reported studies. A limited number of articles related to or containing responses from MCD patients are currently available (Table 1).

Two studies that yielded critical insight resulted from questionnaire validation processes, both of which reported mean importance (MI) scores.^,  The Mastocytosis Quality-of-Life Questionnaire (MQLQ) and Mastocytosis Symptom Assessment Form (MSAF) validations noted the percent of patients reporting an item, along with an item’s MI score, noted herein as MQLQ-MI and MSAF-MI, respectively. The Mastocytosis Quality of Life Questionnaire (MC-QoL) validation of a different set of questions developed by a separate group, noted the frequency of patients reporting an item experienced over the previous 2 weeks, along with an item’s MI score, noted herein as MC-QoL-MI. An MI score denotes the average importance rating level chosen for a given item. Each questionnaire validation reported MI scores based on a different scale:

• •
  MQLQ validation (importance range, 0–6) included an MQLQ-MI score that ranged from 1.5 to 3.4;
• •
  MSAF validation (importance range, 0–10), included an MSAF-MI score that ranged from 3.25 to 5.42;
• •
  MC-QoL validation (importance range, 1–5) included an MC-QoL-MI score that ranged from 2.20 to 3.51.

  ¹⁶

  • van Anrooij B.
  • Kluin-Nelemans J.C.
  • Safy M.
  • et al.

  Patient-reported disease-specific quality-of-life and symptom severity in systemic mastocytosis.

  Allergy. 2016; 71: 1585-1593

  • Crossref
  • PubMed
  • Scopus (31)
  • Google Scholar

  ^, 

  ¹⁷

  • Siebenhaar F.
  • von Tschirnhaus E.
  • Hartmann K.
  • et al.

  Development and validation of the mastocytosis quality of life questionnaire: MC-QoL.

  Allergy. 2016; 71: 869-877

  • Crossref
  • PubMed
  • Scopus (31)
  • Google Scholar

Higher MI scores and items with higher frequency are generally noted in this article.

Online surveys, including patient-reported diagnoses, have facilitated wider-based data collection, albeit with the limitation that actual diagnoses may differ from those reported. Also, given general unfamiliarity with MCDs, in some cases physician diagnoses may not necessarily be accurate. Nevertheless, online surveys provide a collective voice and picture of patients seen by physicians for diagnosis or treatment. The Mastocytosis Society, Inc (TMS) Patient Survey (TMS Survey) (Russell N, Jennings S, Jennings B, et al. The mastocytosis society survey on mast cell disorders: part 2—clinical experiences and beyond, manuscript submitted.) evolved from a pilot project, presented independently but in parallel to US and European Union (EU) MCD patients, that yielded a list of “Top 10 issues raised by patients in the US and EU.” In addition, some commentary herein derives from more than 20 years of TMS direct experience supporting patients affected by MCDs, their families, caregivers, and physicians.

Mast Cell Connect (MC Connect; NCT02620254, www.mastcellconnect.org), a patient-reported registry, was developed to advance understanding of mastocytosis and its impact on patients, and to facilitate development of new therapies. Participants register on a secure online portal and complete a 25-item survey to provide demographic, disease, and treatment information. Enrollment began December 1, 2015 and has been enabled by TMS, expert physicians, and media coverage. The registry includes participants with SM or CM. Diagnoses are self-reported, and participants are asked to provide medical reports that can be used to confirm diagnoses in the future. The study is institutional review board–approved (Chesapeake), and informed consent is required. At time of data cutoff (July 31, 2017), 264 participants had consented to join MC Connect, of whom 251 participants had completed the survey (Table 2). Participant-reported disease subtypes are shown in Fig. 1. Subsequent analyses focus on participants who reported a diagnosis of SM or CM.

Multiple challenges for diagnosis, care, and treatment of MCD patients exist. Heterogeneous presentation, unfamiliarity with MCDs, and evolution of newly recognized variants may prolong time from symptom onset to diagnosis. Considering reported average durations of 4 to 12 years (Table 3),^{,  ,}  it is important to consider patient perceptions of the diagnostic process. Frustration with this process is a major topic during support group discussions.

Mastocytosis patients visited a median of 3 specialists before a diagnosis was made, and nearly half consulted 3 to 6 physicians while seeking a diagnosis. Slightly more than one-third noted more than one specialist type, with dermatology, allergy/immunology, hematology/oncology, and general practice/internal medicine physicians most commonly involved in MCD diagnosis (Russell N, Jennings S, Jennings B, et al. The mastocytosis society survey on mast cell disorders: part 2—clinical experiences and beyond, manuscript submitted.)

Challenges for patients seeking an evaluation for an MCD include the following:

• •
  Obtaining a bone marrow biopsy, evaluated by pathologists familiar with mastocytosis
• •
  Obtaining KIT mutation testing in bone marrow samples and/or peripheral blood, with appropriate test sensitivity
• •
  Obtaining accurate mastocytosis disease subtyping
• •
  Capturing an MC mediator rise (serum tryptase, for SM minor criterion, along with other urinary mediators for nonclonal MCDs)

  ²

  • Valent P.
  • Akin C.
  • Arock M.
  • et al.

  Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.

  Int Arch Allergy Immunol. 2012; 157: 215-225

  • Crossref
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• •
  Developing an ongoing plan to seek a cause for symptoms of MC activation, and to treat symptoms,

  ²

  • Valent P.
  • Akin C.
  • Arock M.
  • et al.

  Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal.

  Int Arch Allergy Immunol. 2012; 157: 215-225

  • Crossref
  • PubMed
  • Scopus (443)
  • Google Scholar

  ^, 

  ²³

  • Cardet J.C.
  • Castells M.C.
  • Hamilton M.J.

  Immunology and clinical manifestations of non-clonal mast cell activation syndrome.

  Curr Allergy Asthma Rep. 2013; 13: 10-18

  • Crossref
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  while ruling out other diagnoses, if mediator testing is negative

Patients in the US and EU endure difficulties identifying and accessing health care professionals knowledgeable about MCDs. ISM patients (82%) were troubled by some physicians’ lack of mastocytosis knowledge (MQLQ-MI, 2.9). Nearly two-thirds of TMS Survey respondents receiving care in the US reported that it was not easy to access good care locally, and 37% had been denied care by a physician because of their MCD (Russell N, Jennings S, Jennings B, et al. The mastocytosis society survey on mast cell disorders: part 2—clinical experiences and beyond, manuscript submitted.) Although 39% were being treated by an MCD specialist, 80% noted the number of US MCD centers was insufficient; 83% reported comfort with the possibility of care managed locally, in conjunction with an MCD specialist (Russell N, Jennings S, Jennings B, et al. The mastocytosis society survey on mast cell disorders: part 2—clinical experiences and beyond, manuscript submitted.)

Although some patients are assertive in obtaining information and quality care, others are reluctant to “bother” their physicians. Sixty-six percent of US-treated TMS Survey respondents felt at least somewhat well informed by their physicians regarding diagnostic procedures, but fewer felt this way regarding follow-up investigations (58%), prognosis/future health (47%), and therapy options (53%) (Russell N, Jennings S, Jennings B, et al. The mastocytosis society survey on mast cell disorders: part 2—clinical experiences and beyond, manuscript submitted.)

Various terminologies have been used to describe forms of MCDs, including mast cell disorders/diseases, clonal/monoclonal (primary), nonclonal (idiopathic or secondary), with MC activation disorders (MCAD) and MCAS originally used interchangeably. Patients report confusion regarding these terms, compounded conceptually by occurrence of mastocytosis with or without MCAS.^,  Despite the availability of proposed diagnostic criteria developed by expert consensus, confusion and disagreement regarding MCAS diagnosis exist among patients and physicians, with some physicians following alternate diagnostic criteria. Patients often report to TMS resistance from physicians in accepting an MCAS diagnosis and that for any form of MCD, accurate diagnosis is essential for effective treatment. Studies suggest that most adults with mastocytosis skin lesions have SM, a diagnosis which requires a bone marrow biopsy.^,  However, only 40% of TMS Survey adults reporting a CM diagnosis recalled this assessment.

More than half of patients in several studies reported foods and/or beverages as allergies, intolerances, or triggers, and the causative types varied considerably.^{,  ,}  Alcohol, reported by 34% to 60%, posed a particular problem.^{,  ,}  Obtaining adequate nutrition concerned approximately one-fifth of TMS Survey respondents (Russell N, Jennings S, Jennings B, et al. The mastocytosis society survey on mast cell disorders: part 2—clinical experiences and beyond, manuscript submitted.) Mastocytosis patients felt their nutrition was impacted (77%; MC-QoL-MI, 3.30) and 73% altered food/beverage choices (MC-QoL-MI, 3.14). Allergies/intolerances to drugs were reported by roughly one-third to more than one-half of survey/study participants and to environmental substances and/or inhalants by more than half.^{,  ,}  Nearly 38% of TMS Survey respondents noted insect venom (“stings”) as an allergy, trigger, or problem, reported for 18% of mastocytosis patients in another study. Fear upon seeing a bee or wasp troubled 86% (MQLQ-MI, 3.4; highest MQLQ-MI in study).

Heat (82%), stress (81%), and exercise (63%) were the most common triggers reported by TMS Survey respondents. Temperature changes (76%; MQLQ-MI, 2.7) and cold (40%) were also problematic.^,  Stress is a potent trigger of MC activation and a constant companion of living with an MCD. Managing physical symptoms of nausea, diarrhea, acute pain, bloating, or brain fog, while performing the most essential daily living activities, can be extremely stressful. Mental stress was a trigger for 71%. Physical stresses (67%), such as friction, vibration, and environmental noise, while innocuous to others, can be significant threats.^{,  ,} 

Patients struggle to identify triggers, especially those less commonly reported. Others may be less willing to accept the concept of a physical, emotional, or temperature-related trigger, as opposed to more commonly known allergens. Patients and caregivers may feel the need to prove that the patient's reaction has a biological basis.

A common denominator for many MCD patients is the unpredictable onset of symptoms arising from the cascade of MC mediator release, including life-threatening anaphylaxis. This concern was the greatest single cause of distress for one-quarter of TMS Survey respondents and affected more participants moderately/extremely (70.9%), or extremely (43.5%), than any other queried aspect of life related to having an MCD; however, no other studies were found to address this issue in MCD patients.

There is a wide range in the frequency and intensity of any given symptom, individually and collectively^,  ; some MCD patients are chronically disabled, whereas others may lead relatively normal lives. Symptoms reported by registry participants are shown in Table 4, and by others, in Table 5. Patients commonly question whether a particular symptom is due to their MCD; this uncertainty troubled 89% of ISM patients (MQLQ-MI, 3).

Consideration of prognostic indicators can help prepare families of pediatric patients for the possibility of disease persisting into adulthood. No data were identified regarding patient and family perceptions related to future disease status in children with MCDs. In TMS support groups, parents whose children demonstrate extensive skin or systemic symptoms often report extreme fear of disease progression for their child. Adult mastocytosis patients report fear of “worsening disease” (84%; MC-QoL-MI, 3.37) and fear of “disease progression” (91%; MQLQ-MI, 2.6). No data were identified on this topic for patients with other MCD forms.

US and EU patients highlighted a need to develop improved MCD therapies, including curative rather than symptom-targeted, and to increase focus on holistic care approaches; these concerns persist. US patients also continue to report to TMS needing assistance, including financial, to obtain medications. Mastocytosis patients were frustrated by the absence of curative therapy (83%; MQLQ-MI, 2.5), noted fear of anaphylaxis triggered by prescribed medication (75%), and were afraid inappropriate treatment might be given if they were unresponsive (70%; MC-QoL-MI, 3.27). Patients and caregivers report concern to TMS regarding drug interactions and identifying which medications are most efficacious while minimizing side effects. Some patients use compounding pharmacies to eliminate reactions to unnecessary fillers. MCD patients may be triggered by nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid narcotics, making pain management challenging.

Despite articles outlining various MCD treatments supported by consensus,^{,  ,  ,}  some patients reported to TMS having a confirmed ISM diagnosis and being offered aggressive treatment not recommended for indolent disease. Although not widely discussed in literature, approximately 10 SSM patients stated to TMS that they had signs of improvement with chemotherapy to reduce MC burden and slow disease progression, resulting in decreased tryptase and symptoms. Patients may tend to receive improved diagnosis and treatment at MCD centers, and some reported to TMS being offered stem cell transplants for nonadvanced variants at nonspecialized centers and this treatment as the only option for SSM, SM-AHN, and ASM, without attempting chemotherapy.

In contrast to current recommendations, some MCD patients with nonclonal disease who have symptoms resistant to antimediator therapy have been offered tyrosine kinase inhibitors (TKIs), and have reported varying results. The authors are unaware of controlled studies involving large numbers of nonclonal MCD patients on TKIs. Another option reported by such patients seeking symptom relief is continuous diphenhydramine drip, with select patients self-reporting stabilization. Significant concerns exist regarding long-term effects of antihistamine use on cognition; adding a continuous intravenous delivery route elevates concerns. Both clonal and nonclonal MCD patients report to TMS success using omalizumab, an anti-immunoglobulin E monoclonal antibody, to control unprovoked anaphylaxis.

Mastocytosis resulted in a moderate to extremely severe reduction in quality of life for 64% of patients and impacted daily living for registry participants (Fig. 2). TMS Survey respondents (76%) reported moderate/extreme emotional impact on their life, and 72% of mastocytosis patients reported psychological impact. Disability experienced by mastocytosis patients due to symptoms occurred independent of diagnosis type, KIT mutation status, and elevated tryptase level. Registry participants worried and felt irritable and depressed (see Fig. 2); more than 50% of AdvSM patients also reported worrying and feeling nervous. Feelings of sadness, concern, lack of motivation, discouragement, frustration, or reduced capability were identified for approximately two-thirds of mastocytosis patients. Fear of being a burden to others (62%) and fear of the future (78%; MC-QoL-MI, 3.07) were also concerns. ISM patients reported being troubled by lack of cosmetic appeal, embarrassment, and increased visibility over time of their skin abnormalities (64%–71%). In TMS’s experience, there is great variability in how bothersome visibility of skin lesions is to patients; personality, age, and culture may be influencing factors.

Although progress has been made on some issues raised by patients, such as publication of international working group–derived definitions and criteria for MCAS, more specific disease classifications,^{,  ,  ,}  development of a proposed mastocytosis diagnostic algorithm, improved diagnostic methods, and advances in treatment,^,  unmet needs exist (Box 4).