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A mixed methods approach towards understanding key disease characteristics associated with the progression from RRMS to SPMS: Physicians’ and patients’ views
The mechanisms of transition from RRMS to SPMS are poorly understood.
•
This was the first stage of development of a novel tool to assess the signs of progression.
•
Both qualitative and quantitative methods were used to determine tool content.
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Physicians confirmed the usefulness of this tool in clinical practice.
Abstract
Objectives
The transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive multiple sclerosis (SPMS) evolves over time and it can be challenging for physicians to identify progression early. Typically, SPMS is diagnosed retrospectively with a significant delay, based on a history of gradual worsening, independent of relapses, following an initial relapsing-remitting disease course. As such, SPMS is often associated with a considerable period of diagnostic uncertainty. This study aimed to explore and characterize key symptoms and impacts associated with transitioning from RRMS to SPMS and inform the content for a tool to support evaluation of early subtle signs suggestive of progressive disease.
Methods
The qualitative study involved 60-min, face-to-face, concept elicitation (CE) interviews with 32 patients with MS (US = 16 and Germany = 16); and 30-min, telephone, CE interviews with 16 neurologists (US = 8 and Germany = 8). Multivariate analysis on data from a real-world observational study of 3294 MS patients assessed the differences between early-RRMS and early-SPMS, and identified factors that were significant drivers of this difference. These studies informed selection of the key variables to be included in a pilot tool. Sixteen physicians used the pilot tool, presented as a paper questionnaire, with a sample of patients whom they suspected were progressing to SPMS (n ≥ 5). Following this, the physicians participated in a 30-min cognitive debriefing (CD) interview to evaluate the relevance and usefulness of the tool. Qualitative analysis of all anonymized, verbatim transcripts was performed using thematic analysis.
Results
Patients and physicians reported signs that indicated progression to SPMS including gradual worsening of symptoms, lack of clear recovery, increased severity and presence of new symptoms. No specific symptoms definitively indicated progression to SPMS, however a number of potential symptoms associated with progression were identified by SPMS patients and physicians, including worsening ambulation, cognition, balance, muscle weakness, visual symptoms, bladder symptoms and fatigue. Quality of life domains reported to be more severely impacted in SPMS than MS in general included: physical activity, work, daily activities, emotional and social functioning. Multivariate analysis of the observational study data identified several variables strongly associated with progression to SPMS including, requirement of assistance in daily living, presence of motor symptoms, presence of ataxia/coordination symptoms, and unemployment. Physicians reported that items included in the tool were easy to understand and relevant. Physicians also reported that there is an unmet need for a tool to help identify signs of SPMS progression and so the tool would be useful in clinical practice.
Conclusions
This was the first stage of development of a novel, validated, physician-completed tool to support physician–patient interactions in evaluating signs indicative of disease progression to SPMS. Qualitative and quantitative methods (involving physician and patients) were used to determine tool content. The usefulness and unmet need for such a tool in clinical practice was confirmed via CD interviews with physicians. Further work is now warranted to develop a scoring algorithm and validate the tool so that it can be reliably implemented in clinical practice.
Multiple sclerosis (MS) is a chronic neurological disorder of the central nervous system (CNS) which affects approximately 2.3 million individuals worldwide (
GBD 2016 Multiple Sclerosis Collaborators Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016..
). At diagnosis, approximately 85% of patients have relapsing-remitting MS (RRMS) and with time, a proportion of patients enter a secondary progressive form of the disease, secondary progressive MS (SPMS), however large variations in time to onset of SPMS are observed. Generally, after 6–10 years from disease onset, approximately 25%–40% of patients with RRMS have progressed to SPMS, with a median time to transition ranging from 10 to 23 years (
). Disability progression in SPMS typically occurs as a steady deterioration of functional ability independent from relapses, whereby patients can still experience relapses followed by complete or incomplete recovery. The revised “Lublin Criteria” defined MS phenotypes considering two aspects reflecting inflammatory or neurodegenerative processes. According to those criteria, patients are described as having relapsing MS that is active or inactive, with or without worsening of disability, or progressive MS. Progressive MS can either be primary progressive MS (progressive accumulation of disability from onset) or secondary progressive (progressive accumulation of disability after the initial relapsing course), that is active or inactive, with or without disability progression whereby activity is determined by clinical relapse and/or magnetic resonance imaging [MRI] activity) (
The mechanisms of transition from RRMS to SPMS are not clearly understood and the disease seems to evolve as a continuum, so it is challenging for physicians to recognize when a patient has started to progress. Diagnosis is also difficult due to the lack of clear diagnostic criteria in the most recent McDonald update (2017) and absence of reliable imaging and biological markers for transition to SPMS (
). As such, SPMS is diagnosed after a period of retrospective analysis following an initial relapsing remitting course of the disease, whereby neurologists look for at least six to twelve months of clear progression before using the term secondary progressive (
), however to date, none have used a qualitative approach, which can provide an in-depth understanding of patient and physician experiences and identify relationships and trends that are not necessarily observable.
To our knowledge, this is the first study to use a mixed-methods approach to develop a tool for use in clinical practice to help sensitize about the risk of progressing from RRMS to SPMS and support evaluation of subtle signs suggestive of progression. Multivariate analysis of observational study data aimed to identify key variables that differentiate RRMS from early SPMS. Qualitative interviews with patients diagnosed with RRMS/SPMS and MS physicians aimed to identify and characterize the key symptoms and impacts associated with RRMS and SPMS, to further understand the experience of progression to SPMS and to confirm which variables are routinely assessed in clinical practice. Furthermore, interviews with physicians were designed to explore the clinical relevance of the pilot tool, presented as a paper questionnaire, and determine whether a digital version of the tool would be considered useful by physicians to help discuss and evaluate early signs of progression and feasible for use in clinical practice.
2. Methodology
2.1 Quantitative analysis
Retrospective analysis was conducted on data from a global cross-sectional study that collected information from physicians (neurologists) and their consulting MS patients on demographics, clinical history, current symptomatology, treatment history, and quality of life (
). The study collected data from 3294 MS patients in the US including 2003 patients diagnosed with RRMS and 401 diagnosed with SPMS Fig. 1.
Multivariate regression analysis was run on the clinical variables collected in an observational, disease specific program (DSP) from 1010 early RRMS (defined as RRMS diagnosis and EDSS <3) and 67 early SPMS patients (defined as SPMS diagnosis, EDSS ≥3, diagnosed with SPMS <3 years ago, diagnosed with MS > 4 years ago). Lasso penalized logistic regression was used to determine variables associated with being early RRMS or early SPMS. Covariates included in the regression were age, unemployment, requirement for assistance in daily living, number of T2 lesions, and the presence of motor, paresthesia/sensory, ataxia/coordination, micturition/bladder, mood/depression, and concentration/cognition symptoms. Bootstrap-based 95.0% confidence intervals were produced. Regression coefficients were used to generate the predicted probability of being early SPMS for the late RRMS patients (defined as RRMS diagnosis, EDSS ≥3, EDSS <6, diagnosed with MS ≥4 years ago) to assess potential misclassification of late RRMS patients.
2.2 Qualitative study
Face-to-face, semi-structured interviews were conducted with RRMS/SPMS patients and telephone interviews and pilot testing of a draft tool was conducted with physicians. Ethical approval was obtained from independent ethical review boards in Germany and the US (ADE1-14-506). Written informed consent was obtained prior to any research activities being conducted and before any confidential information was shared with the study team. All patients and physicians were recruited via recruitment agencies in the US and Germany. Patients were recruited via referrals from practicing physicians.
The target sample of 32 MS patients was stratified to include patients with differing disability status (EDSS 3.0–6.0 and EDSS > 6.0), RRMS or SPMS diagnosis, and across locations (US or Germany). Eligibility criteria for participation in the study are provided in Supplement 1. Patient interviews consisted of broad open-ended questions designed to elicit information regarding the patients’ disease experience.
The physician sample consisted of 16 experienced MS neurologists, recruited in the US (n = 8) and Germany (n = 8). Eligibility criteria for participation in the study are provided in Supplement 1. Initial interviews with MS physicians consisted of open-ended questions to explore physicians’ experience of treating patients with RRMS and SPMS, the differences between the two stages of disease and key concepts associated with progression from RRMS to SPMS. Interviews also explored the unmet need for a tool to help evaluate and discuss early signs of progression.
All interviews were audio-recorded and transcribed verbatim. Transcripts were coded using a thematic analysis approach and ATLAS.ti software (
). Conceptual saturation (defined as the point at which no new relevant or important information emerges from interviews) was evaluated by comparing three consecutive sets of transcripts to identify any concepts and themes that were only elicited in the final set of interviews and therefore did not achieve saturation. A conceptual model, outlining the disease experience of RRMS and SPMS, was developed based on patient and physician interviews. A conceptual model is a visual representation of the concepts involved in a disease area and can help organize and visualize the key features of a condition (
Questions for inclusion in the pilot tool were developed based on the findings from both the qualitative and quantitative phases, to assess the key factors that indicate progression to SPMS. For the purpose of this initial testing, the pilot tool was presented in the form of a paper questionnaire. An inclusive approach was taken with regards to the key variables included to ensure that no concepts of importance were excluded.
The questionnaire was pilot tested by 16 neurologists as part of their normal clinical practice, with at least five patients who they suspected were progressing to SPMS. Following pilot testing, neurologists (n = 16) attended a second 30-min CD interview to provide feedback on the relevance, comprehensiveness and understanding of the questionnaire and explore the usefulness and value of the tool.
3. Results
3.1 Quantitative analysis
Lasso penalized logistic regression indicated that, in order of strength of association, the following variables were significantly associated with being classified as early SPMS (Fig. 2): requirement for assistance in daily living (OR 10.42, CI [5.54, 24.80]), presence of motor symptoms (OR 3.27, CI [1.58, 9.01]), presence of ataxia/coordination symptoms (OR 2.60, CI [1.41, 5.08]), unemployment (OR 2.36, CI [1.18, 5.56]) and presence of micturition/bladder symptoms (OR 1.96, CI [1.02, 3.81]); while presence of paresthesia/sensory symptoms did not reach statistical nominal significance (OR 1.10, CI [0.82, 2.20]).
Increasing age (OR 1.04, CI [1.01, 1.07]), and increasing number of T2 lesions (OR 1.06, CI [1.03, 1.10]) were also found to be significantly associated with being classified as early SPMS. Other tested variables were not seen to be significantly associated with being classified as early SPMS. When this predicted probability, based on the regression equation, was applied to the late RRMS sample, 58.0% were classified as being closer to early SPMS, rather than early RRMS.
3.2 Qualitative study
3.2.1 Patient sample characteristics
Thirty-two (16 RRMS and 16 SPMS) patients participated in a qualitative interview. The average age of patients was 46 years (range: 25–60). More female patients (68.8%) than male patients (31.3%) participated in an interview and the proportion of male patients was higher in the SPMS group (37.5% vs. 25.0%).
SPMS patients had a higher mean EDSS and longer mean timed 25-foot walk test score than RRMS patients (Table 1). Compared with RRMS patients, more SPMS patients were not working due to MS (SPMS patients, n = 6; RRMS patients, n = 2), rated their health as poor on a scale of poor to very good (SPMS patients, n = 3; RRMS patients, n = 1) and their MS as severe in a scale of very mild to severe (SPMS patients, n = 5; RRMS patients, n = 1).
Table 1Patient demographic and clinical characteristics.
Description
RRMS patients (N = 16)
SPMS patients (N = 16)
SPMS / RRMS patients – Total (N = 32)
Patient demographics
Age, years
Mean [median]
45.0 [47.0]
46.0 [46.5]
46.0 [47.0]
Min, Max
25.0, 53.0
31.0, 60.0
25.0, 60.0
Gender, % (n)
Male
25.0% (4.0)
37.5% (6.0)
31.3% (10.0)
Female
75.0% (12.0)
62.5% (10.0)
68.8% (22.0)
Disease history
Time since MS diagnosis, % (n)
Less than 5 years
6.3% (1.0)
25.0% (4.0)
15.6% (5.0)
5 to 10 years
25.0% (4.0)
12.5% (2.0)
25.0% (8.0)
More than 10 years
68.8% (11.0)
62.5% (10.0)
65.6% (21.0)
EDSS score – Current
Mean [median]
4.9 [5.5]
5.6 [6.25]
5.3 [6.0]
Min, Max
3.0, 7.5
3.0, 7.5
3.0, 7.5
EDSS score – at diagnosis of SPMS
Mean [median]
N/A
4.5 [3.5]
4.5 [3.5]
Min, Max
2.0, 7.0
2.0, 7.0
Timed 25-foot walk test (s)
Mean [median]
11.3 [11.0]
27.8 [25.0]
19.7 [13.0]
Min, Max
0, 28.0
0, 60.0
0, 60.0
Disease activity
Current number of T2 weighted lesions
Mean [median]
10.3 [8.5]
10.8 [10.0]
10.5 [10.0]
Min, Max
3.0, 25.0
0, 25.0
0, 25.0
Current number of Gadolinium enhanced weighted lesions
Mean [median]
1.7 [0.5]
3.6 [1]
2.5 [1.0]
Min, Max
0, 7.0
0, 12.0
0, 12.0
New lesions in past 12 months, % (n)
Yes
6.3% (1.0)
37.5% (6.0)
21.9% (7.0)
No
81.3% (13.0)
37.5% (6.0)
59.4% (19.0)
Not known
12.5% (2.0)
25.0% (4.0)
18.8% (6.0)
Relapses in total
Mean [median]
8.6 [6.5]
15.0 [10.0]
11.5 [8.5]
Min, Max
2.0, 24.0
3.0, 50.0
2.0, 50.0
Relapses in the last 12 months
Mean [median]
0.3 [0]
0.6 [0]
0.4 [0]
Min, Max
0, 2.0
0, 6.0
0, 6.0
Other
Ever hospitalized due to MS, % (n)
Yes
37.5% (6.0)
68.8% (11.0)
53.1% (17.0)
No
56.3% (9.0)
31.3% (5.0)
40.6% (13.0)
Not answered
6.3% (1.0)
–
3.1% (1.0)
Patient level of independence, % (n)
Complete independence
31.2% (5.0)
6.3% (1.0)
18.8% (6.0)
Modified independence
37.5% (6.0)
37.5% (6.0)
37.5% (12.0)
Supervision or set-up
–
6.3% (1.0)
3.1% (1.0)
Minimal assistance
12.5% (2.0)
18.8% (3.0)
15.6% (5.0)
Moderate assistance
12.5% (2.0)
18.8% (3.0)
15.6% (5.0)
Maximal assistance
–
12.5% (2.0)
6.3% (2.0)
Not answered
6.3% (1.0)
–
3.1% (1.0)
Patient reported work status, % (n)
Working full-time
25.0% (4.0)
18.8% (3.0)
21.9% (7.0)
Working part-time
12.5% (2.0)
12.5% (2.0)
12.5% (4.0)
Looking for work
6.3% (1.0)
6.3% (1.0)
6.3% (2.0)
Full time homemaker
6.3% (1.0)
–
3.1% (1.0)
Not working due to MS
12.5% (2.0)
37.5% (6.0)
25.0% (8.0)
Retired
25.0% (4.0)
25.0% (4.0)
25.0% (8.0)
Other: on disability
6.3% (1.0)
–
3.1% (1.0)
Other: Self-employed
6.3% (1.0)
–
3.1% (1.0)
Patient reported severity of MS, % (n)
Severe
6.3% (1.0)
31.2% (5.0)
19.0% (6.0)
Moderate
75.0% (12.0)
50.0% (8.0)
63.0% (20.0)
Mild
18.8% (3.0)
12.5% (2.0)
15.6% (5.0)
Very mild
–
6.3% (1.0)
3.1% (1.0)
Patient reported general health, % (n)
Very good
6.3% (1.0)
–
3.1% (1.0)
Good
43.8% (7.0)
37.5% (6.0)
40.6% (13.0)
Fair
43.8% (7.0)
43.8% (7.0)
43.8% (14.0)
Poor
6.3% (1.0)
18.8% (3.0)
12.5% (4.0)
Abbreviations: EDSS, Expanded Disability Status Scale; MS, multiple sclerosis; n, number of patients; N, total number of patients; N/A, not applicable; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis.
The demographic characteristics and clinical experience of the physicians who took part in CE interviews are shown in Supplement 2. All physicians were experienced neurologists, who worked in private practice (62.5%), hospital-based care (25.0%) and/or an academic setting (25.0%). Physicians had a mean of 15 years of experience treating MS patients (range: 1–40).
3.2.3 Symptoms associated with MS
A wide range of symptoms were reported by patients regardless of RRMS or SPMS disease status. The most frequently reported symptoms were numbness (RRMS = 12, SPMS = 14), ambulation (RRMS = 10, SPMS = 13), balance (RRMS = 9, SPMS = 12), fatigue (RRMS = 9, SPMS = 12), cognition (RRMS = 8, SPMS = 11), muscle weakness (RRMS = 9, SPMS = 10) and dexterity (RRMS = 7, SPMS = 12). With the exception of visual symptoms, tingling and headache, all symptoms were reported by more SPMS patients than RRMS patients (Fig. 3).
Fig. 3Key MS symptoms reported by patients (grouped by RRMS/SPMS).
Physicians reported a similar range of symptoms and highlighted which were important in identifying disease progression to SPMS (Fig. 4). The symptoms most frequently reported by physicians were vision (n = 15), cognitive symptoms (n = 15) and ambulatory symptoms (n = 15), followed by balance (n = 13). Physicians reported some differences between RRMS and SPMS patients with regards to duration, frequency and severity of symptoms. Differences in severity of symptoms were described in terms of the impact on daily functioning.
Fig. 4Symptoms reported by clinicians and symptoms highlighted as important in identifying progression to SPMS.
Patients reported a wide range of ways in which their MS impacted on their life, most frequently impacts to physical activities (RRMS = 16, SPMS = 16), emotions (RRMS = 16, SPMS = 16), daily activities (RRMS = 15, SPMS = 16), work (RRMS = 14, SPMS = 16), social life (RRMS = 12, SPMS = 11) and finances (RRMS = 7, SPMS = 4). More SPMS than RRMS patients reported impacts on their daily activities and work, while all or nearly all patients reported physical, social and emotional impacts (Fig. 5). Qualitative differences were evident in the way RRMS and SPMS patients described impacts. For example, RRMS patients reported having to hold onto something for support in the shower, while SPMS patients reported needing greater help bathing or a chair to sit in the shower.
Fig. 5Impacts of MS. Patient and physician perspective.
Physicians reported that patients with SPMS experience more impacts than MS patients generally, particularly with regards to work (n = 11 vs 4), physical activity (n = 10 vs 5), social (n = 6 vs 3) and emotional domains (n = 6 vs 2) while all patients experience impacts on daily activities. No physicians discussed the financial impact of MS (Fig. 5).
3.2.5 Experience during transition from RRMS to SPMS
Patients who progressed from RRMS to SPMS (n = 16) reported to have experienced overall worsening of symptoms. Worsening ambulation (n = 10), muscle weakness (n = 8), impaired vision (n = 5), fatigue and bladder symptoms (each n = 4) were most frequently associated with progression, although each patient had a unique experience in terms of which symptoms declined with progression (Fig. 6). Physicians also highlighted which symptoms were associated with progression to SPMS, including vision (n = 10), cognitive symptoms (n = 10), balance (n = 8) and ambulatory symptoms (n = 7) (Fig. 4).
Fig. 6Worsening symptoms associated with progression, as reported by patients with SPMS.
Patients reported experiencing an increase in severity of existing symptoms (n = 13), a decrease in the frequency of relapses (n = 6) and presence of new symptoms (n = 5) during progression to SPMS. While physicians considered a wide range of factors to be associated with progression to SPMS, including gradual worsening of symptoms (n = 13), lack of clear recovery (n = 10), increased severity of symptoms (n = 9) and presence of new symptoms (n = 9) (Fig. 7).
Fig. 7Factors associated with progression, as reported by physicians and patients.
Conceptual saturation was achieved for almost all symptoms and impacts amongst German and US patients. The conceptual model (Supplementary Figure 1) provides a visual overview of the overall disease experience of RRMS and SPMS, as reported by patients and physicians. The model includes symptoms, impacts, factors associated with relapse and progression, triggers and coping mechanisms.
3.2.6 Diagnosis of SPMS
Physicians talked about the many challenges they face when diagnosing SPMS which included: making treatment decisions (n = 10), detecting changes to SPMS (n = 6), measuring the severity of symptoms (n = 3), the diagnosis time frame (n = 2) and managing the impact on patients’ emotions (n = 2). Physicians’ explained that their diagnosis of SPMS was typically based on MRI scans (n = 11), EDSS scores (n = 8), relapse frequency and recovery (n = 8) and physical examinations (n = 6). Physicians reported that it took up to three years to confirm an SPMS diagnosis, however time to diagnosis varied. There was limited consistency between physicians in the methods used for diagnosis and the length of time taken to diagnose a patient, both within and between countries.
Physicians felt that the development of a tool supporting evaluation of early signs of progression would be useful for clinical practice. They reported that they would not make an SPMS diagnosis based on the tool, but that the tool would encourage them to conduct additional assessments to further evaluate and confirm progression. Physicians reported a preference for a validated, electronic tool which generates a score, percentage, or a graphical output.
3.2.7 Development and initial feasibility testing
The questionnaire was developed based on findings from both the quantitative and qualitative research and split into three sections to address relapse and recovery, symptoms and impacts (Fig. 8).
Overall, physicians found the content of the questionnaire relevant and appropriate and reported that a digital tool would be useful in clinical practice (Table 2).
Table 2Physician feasibility testing and cognitive debriefing findings.
Aspect of the tool
Discussed by n/N (%)
Findings
Questionnaire content
12/16 (75.0)
• 8/12 physicians were positive about the tool content
• 2/12 physicians felt the tool was too long
• 2/12 physicians were unclear when discussing the tool content
Questionnaire usability
11/16 (69.0)
• 11/11 physicians reported the tool was easy and simple to complete
Usefulness of a tool
15/16 (94.0)
• 13/15 physicians commented positively on the value of the tool in clinical practice and described it as “comprehensive” and “useful”
• 2/15 felt the tool would be useful for research by primary care physicians
Tool format
16/16 (100.0)
• 11/16 physicians would prefer a digital tool
• 3/16 physicians would prefer a paper tool
• 2/16 physicians had no preference
Use in clinical practice
8/16 (50.0)
• 7/8 physicians had a positive opinion on implementing the tool in clinical practice
• 1/8 physician suggested it would be useful if completed by a patient or primary care physician
Abbreviations: n, number of patients; N, total number of patients.
All 16 physicians confirmed that they understood the instructions provided and demonstrated their understanding by completing the questionnaire correctly. Thirteen of the 20 items included in the questionnaire were understood by all physicians, however there were five instances where one physician did not demonstrate a clear understanding of the item (ambulation, balance, bladder and bowel, pain and speech symptoms).
Eight items (assessing presence of a patient relapse, number of relapses, MRI indication of new activity, motor symptoms, pain, sensory symptoms, bladder and bowel symptoms and impacts to patient's mobility) were reported to be relevant by all 16 physicians. For three items (recovery from relapse, visual and speech symptoms), at least one physician reported that it was not relevant to identifying progression to SPMS. Additionally, for nine items (MRI performed, visual, ambulatory, coordination and balance, cognitive and fatigue symptoms in addition to impacts on self-care, hobbies and leisure time and paid and unpaid work) at least one physician reported that they were unsure whether the item was relevant.
4. Discussion
MS is a complex and heterogeneous disease which makes it very difficult to predict its individual course, including identifying signs of progression to SPMS. Lack of consistency in diagnosis of SPMS further complicates assessment in daily practice. As part of the personalized medicine approach, MS patients should be characterized by a detailed clinical profiling which is the base of all long-term documentation. The patient experience and disease history should be documented throughout the course of the disease to understand treatment response, relapses and disease progression as well as quantitative inflammatory and neurodegenerative MRI markers (
). The common definition of SPMS, including the gradual progression of disability independent of relapses over at least 6 to 12 months following an initial RRMS course, is not easily applied in clinical practice leaving the analysis of patient documentation open to interpretation. In line with previous studies, physicians in this study confirmed that: the transition from RRMS to SPMS is difficult to diagnose; “progression” is not clear or easy to be recognized and there is only limited consistency in how patients are diagnosed with SPMS and how long the diagnostic process takes i.e. up to 3–4 years until diagnosis confirmation (
Previous natural history studies have investigated predictors of conversion to SPMS with the objective of understanding disease evolution and identifying patients at higher risk of progression early in the disease course (
). More recently, the accuracy and feasibility of an objective data-derived definition for SPMS has been evaluated using the observational cohort MSBase, an online neuro-immunology registry, primarily to enable comparability of future research studies. The best definition of SPMS relies on changes detected by EDSS, the pyramidal functional score, and information about preceding relapses which may reduce sensitivity to more subtle forms of progression in other functional domains. Applicability for clinical practice may be limited due to its reliance on EDSS score, which might not be regularly assessed in routine practice (
). In addition, an only semi-standardized neurological examination as the Neurostatus at different timepoints is probably not as sensitive as a detailed adaptive neurological history which would be used by a progression discussion tool.
Manouchehrinia et al. generated a nomogram which estimates the risk of conversion to SPMS over 10–20 years derived from a large national registry, identified gender, age, first recorded EDSS score and age at disease onset as the most relevant variables (
). The current study is unique as it employed both qualitative (involving both patients and physicians), and quantitative approaches to develop the content of a tool, with the objective to ultimately be used in clinical practice and provide an immediate indication of a patient's MS disease status. In this study, empirically derived real-world data provides insights into relationships and trends that are not necessarily observable, while theoretically derived, qualitative data is a rich source of information that ensures the tools’ content is reflective of real patient experiences and is of value to physicians.
The findings from this study indicate that no specific symptoms are exclusively associated with progression to SPMS and there is considerable overlap in symptoms experienced by RRMS and SPMS patients. The most frequently reported symptoms of SPMS, as reported by both patients and physicians, included worsening ambulation, cognition, balance, muscle weakness, visual symptoms, bladder symptoms and fatigue. Impacts to daily activities and work were more frequently reported by SPMS patients, while physicians appeared to focus on impacts related to physical activities and work. An important insight from the qualitative assessment indicated that SPMS patients experience more severe symptoms for a longer duration. This information is not routinely collected or reported in electronic medical records (EMR) hence approaches commonly used to characterize SPMS patients which are typically based purely on quantitative assessments (e.g. EMR, registries or observational studies), would miss this kind of information.
Physicians in this study highlighted a clear unmet need for an educational tool that could be used in routine clinical practice to aid disease management. The vast majority of physicians said that they would be likely to use the tool in their clinical practice to discuss and evaluate early signs of progression to SPMS. The output would be used to encourage the conduct of further assessments, such as an MRI or electrophysiological tests, which would further confirm progressive disease. Overall, the content of this pilot tool (presented to physicians in the form of a questionnaire) was well understood, relevant and of value to physicians for use in clinical practice. Physicians reported that they would like a well validated, electronic tool which produces a score, percentage or graphical output. Physicians were unsure of the relevance of some questions within the tool and future research will aim to evaluate question relevance and importance in identifying progression in more detail.
This study represents the first stage of comprehensive research aiming to develop a physician completed tool to support early evaluation of signs of progressive disease standardizing neurological history taken by the physician. Tool content has been developed, based on the qualitative (patient and physician) and quantitative insights, to ultimately support physician–patient discussions in assessing early and subtle signs of progressive disease in any neurological domain. The usefulness for such a tool in clinical practice was confirmed, via CD interviews with physicians. Further work is now warranted to develop a scoring algorithm for the pilot tool, followed by validation of the tool so that it can be reliably implemented in clinical practice.
Study funding
The study was funded by Novartis Pharma AG, Basel, Switzerland.
Conflict of Competing Interests
Tjalf Ziemssen has received personal compensation for participating on advisory boards, trial steering committees and data and safety monitoring committees, as well as for scientific talks and project support, from Almirall, Bayer, BAT, Biogen, Celgene, Sanofi Genzyme, Merck, Novartis, Roche, Vitaccess, and Teva.
Chloe Tolley, Sarah Kilgariff, Eddie Jones, and James Pike are employees of Adelphi Values Ltd. UK, a healthcare research consultancy. Bryan Bennett was an employee of Adelphi Values at the time of study conduct.
Davorka Tomic, Daniela Piani Meier, and Raquel Lahoz are employees of Novartis Pharma AG, Basel, Switzerland.
Acknowledgments
Funding support was from Novartis Pharma AG, Basel, Switzerland. We gratefully acknowledge all the participating physicians for their contribution and insights on the draft tool. We would like to acknowledge Elisabetta Verdun di Cantogno and Denis Simsek for their support during the initial stages of the study. We also acknowledge Sivaram Vedantam of Novartis Healthcare Pvt. Ltd., for medical writing support, which included literature search, drafting of sections of article and revising the article as per author comments and preparation of submission, and Uma Kundu of Novartis Healthcare Pvt. Ltd., for scientific editorial review support.
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