Abstract
Inclusion body myositis (IBM) is a slowly progressive and heterogeneous disorder that is a challenge for measuring clinical trial efficacy. The current methods of measuring progression of the disease utilizes the Inclusion Body Myositis Functional Rating Scale, grip strength by dynamometer, and finger flexor strength. One of the hallmarks of the disease is selective deep finger flexor weakness. To date, no adequate data has been available to determine how well the Functional Rating Scale relates to this hallmark physical exam deficit. Our study is the first to investigate the degree of correlation between items pertaining to hand function in the Functional Rating Scale with measured grip and finger flexor strength in IBM patients. We have found a lower than expected correlation with finger flexor strength and even lower with grip strength. The current Functional Rating Scale will benefit from optimization to measure clinical progression more accurately.
Keywords: Inclusion body myositis, Functional rating scale
1. Introduction
Sporadic inclusion body myositis (IBM) is the most common acquired myopathy after the age of 45. IBM has failed many potential therapeutics; [1-4] possibly attributable to the lack of a reliable outcome measures that have the sensitivity to assess changes in a slowly progressive disorder. A commonly used measure is the Inclusion Body Myositis Functional Rating Scale (IBM-FRS), [5] a 10-item questionnaire that assesses self-reported functional difficulties of different regional modalities, such as swallowing, upper extremity/hand function, lower extremity function, and ability to turn in bed (a measure of axial strength that also encompasses upper and lower extremity function). The benefit of IBM-FRS includes its ease of administration and a low inter-rater discrepancy; both rationales that have led to its use as a clinical end-point in multiple clinical trials to date.
The IBM-FRS was adapted from the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS); [6,7] IBM-FRS was first used in a clinical study with interferon 1α in 30 patients with definite or probable IBM [5]. A post-hoc analysis found that the IBM-FRS was sensitive to functional changes after 24 weeks in both the placebo and treatment arms. Subsequent longitudinal studies have suggested that the IBM-FRS changes over time; [8,9] however, the degree of decline is quite variable with an unclear correlation to the decline of physical strength. Specifically, whether the decline in the hand-function domain of the FRS is reflected in decline of grip strength and manual muscle testing (MMT).
IBM is differentiated from other neuromuscular disorders in its selective pattern of deep finger flexor weakness with relative sparing of the intrinsic hand muscles [10-13]. In fact, finger flexor weakness is the single most reliable sign at the time of diagnosis, [10] and demonstrates the most notable change at one year post diagnosis compared to all other muscle groups evaluated by MMT [8]. When IBM-FRS was introduced, its authors report a correlation with hand-grip dynamometry (Pearson’s coefficient of 0.56 at the start of the trial and 0.62 at the end of the trial), but its correlation with IBM-specific finger flexor strength was not explored [5].
Herein, we present a cross-sectional study that attempts to address the following: (1) Degree of correlation between strength (grip strength and finger flexor strength) and items in the IBM-FRS pertaining to hand/fine motor function; and (2) how these variables (grip strength, finger flexor strength, IBM-FRS) change with the duration of symptoms.
2. Materials and methods
We performed a cross-sectional observational study of 81 IBM patients recruited at The Myositis Association 2018 Annual Patient Conference (Table 1). Diagnosis of IBM was based on patient self-report. Concurrently, 74 healthy subjects who reported lack of inflammatory myositis or arthritis were recruited.
Table 1.
Synopsis of demographic in our cohort.
| IBM | Healthy Control | |
|---|---|---|
| # of subjects | 81 | 74 |
| Female: Male | 31: 50 | 46: 28 |
| Age range (years) | 46 – 80 | 27 – 84 |
| Race (Female: Male) | Caucasian (28:44) | Caucasian (40:25) |
| African-American (1:2) | African-American (1:1) | |
| Hispanic (1:0) | Hispanic (0:0) | |
| Native American (1:2) | Native American (1:0) | |
| Asian/Pacific Islander (0:0) | Asian/Pacific Islander (1:0) | |
| Mixed Race (0:1) | Mixed Race (2:0) | |
| Years of symptoms | 2–39 | NA |
This study was approved by the Washington University institutional review board.
Grip strength of the dominant hand was measured two times consecutively by a Jamar hydraulic hand dynamometer and averaged for analysis. Finger flexor strength was assessed by board-eligible or board-certified neuromuscular physicians and described as complete inability to flex fingers (graded 0/5), severe weakness (no resistance, graded 1/5), moderate weakness (very little resistance, graded 2/5), mild weakness (breakable resistance, graded 3/5), subtle weakness (resistance that is near unbreakable, graded 4/5), and full strength (graded 5/5). This qualitative scale was used instead of the Medical Research Council (MRC) Muscle Grading Scale because of the difficulty in implementing the MRC scale in the finger flexors, particularly in assessing antigravity strength in this population, and the goal of having a finer gradation for strength assessment. If discrepancies occurred in the finger flexor strength score between digits within a subject, the weakest score was used for analysis.
The IBM-FRS [5] was filled out by each subject with IBM. Patients scored each of the ten items from 0 (complete inability to perform task) to 4 (normal). The maximum possible score is 40. In instances that the subject chose two concurrent functional states, the lower score that conveyed the more severe functional loss was selected for analysis.
The correlation of grip strength or graded finger flexor strength with the hand function domain questions of the IBM-FRS was analyzed by Pearson correlation and the corresponding p-values were obtained. Additionally, grip strength measured by the handgrip dynamometer were normalized by age and sex according to data collected from the NIH Toolbox project [14] (Table 2).
Table 2.
Pearson correlation of IBM-FRS sum and scores of individual items #2 to 4 compared to grip strength normalized to published values according to age and sex, [14] as well as finger flexor strength score.
| % Grip normalized by population age and sex |
Finger flexor strength |
|
|---|---|---|
| #2 Handwriting | 0.26 (p = 0.02) | 0.37 (p < 0.001) |
| #3 Cutting food/Utensil | 0.54 (p < 0.001) | 0.50 (p < 0.001) |
| #4 Fine motor | 0.33 (p = 0.03) | 0.40 (p < 0.001) |
| IBM-FRS sum | 0.49 (p < 0.001) | 0.45 (p < 0.001) |
3. Results
3.1. Demographics
We compared 81 IBM patients to 74 healthy controls. The IBM patients had a male predominance (1.6 male:1 female), while the control subjects had reverse female predominance (1 male:1.6 female) as befitting a disease that has a male predominance with the healthy controls most likely partners of the patients.
The healthy control population included slightly younger patients: The IBM cohort had a median age of 68 with interquartile range [IQR] spanning 63 to 72, while the healthy controls had a median [IQR] age of 64 [56, 71]. The distribution of self-described racial categories of the two cohorts was similar—predominantly white non-Hispanic patients (Table 1).
3.2. IBM-FRS sum score was not correlated with disease duration
The mean IBM-FRS sum score for our cohort was 27.9 ± 6.3. This is comparable to the cohort of 27 patients in the initial paper introducing this scale (26.8 ± 7.1) and the two longitudinal studies (27 and 28.9 ± 9.0 respectively) [5,8,9].
Past longitudinal studies with IBM-FRS suggest that it is sensitive enough to detect change over a period of time as short as one year. The IBM-FRS sum score in the 23-patient British IBM-Net cohort declines by 13.8% ± 10.4 over one year (3.8 ± 3.2 points per year) [8]. A second French cohort did not show significant decline in the IBM-FRS over nine months, but did decline by 22.3% ± 17.3 over four years [9].
In our cross-sectional study, the IBM-FRS sum score did not correlate with patient-reported disease duration (Fig. 1). Linear regression analysis showed a correlation coefficient of −0.07 and a p-value of 0.54. These results are consistent with the heterogeneity of the IBM natural history—each individual progresses at their own variable rate. Furthermore, this is most likely reflected in the large standard deviation of the change in the IBM-FRS sum scores of the British and French cohorts [8,9].
Fig. 1.
Sum of IBM-FRS did not demonstrate a clear decline over duration of patient-reported symptoms (correlation coefficient −0.07, p-value 0.54).
3.3. Each individual IBM-FRS question was not correlated with disease duration
A comparison of each IBM-FRS question against self-reported disease duration also showed no correlation. (Supplemental Table 1 & Supplemental Fig. 1) Summing the questions focused on hand function (questions #2 handwriting, #3 cutting food/utilizing utensil, and #4 fine motor) similarly found no correlation with disease duration (Fig. 2). Linear regression analysis showed a correlation coefficient of −0.04 and a p-value of 0.74.
Fig. 2.
Items pertaining to hand function did not decline as anticipated with duration of patient-reported symptoms (correlation coefficient −0.04, p-value 0.74).
3.4. Cross-sectional analysis of handgrip strength showed a ceiling effect as disease progresses
In contrast, cross-sectional analysis of dominant grip strength showed a ceiling effect of the disease on maximal handgrip strength over 40 years (Fig. 3). The ranges of grip strength at earlier stages of the disease were more variable, slowly becoming less variable and more weak with disease duration. This is similar to the data that compared knee extension strength versus disease duration in the French cohort [15].
Fig. 3.
Distribution of grip strength across duration of patient-reported symptoms in IBM patients. (A) A clear decline was noted (linear regression correlation −0.21, p-value 0.06). This decline was more dramatic in males (blue) compared with females (orange) due to the larger distribution of strength earlier on in the course (p-value for two sample t-test < 0.001). (B) Grip strength when normalized to published population values by age and sex [14]. (C) Qualitative finger flexor strength score across duration of symptoms (linear regression correlation −0.10, p-value 0.39).
Furthermore, grip strength values distinguished the IBM patients and the healthy controls particularly when normalized to known population values based on age and sex. (Fig. 4 and Supplemental Fig. 2). The median [IQR] grip strength was 9 [5,12] kg for the IBM cohort versus 30 [25,36] kg for the control cohort. When normalized based on age and sex, the median grip strength (percentage of norm) for the IBM cohort (27% [19, 37]) was different from the control cohort (111% [99,122].
Fig. 4.
(A) The distribution of grip strength between healthy controls (grey) in our cohort compared with IBM patients (black). (B) Normalization of grip strength value to age and sex further distinguished the two populations [14].
3.5. Hand function IBM-FRS items were only moderately correlated with grip strength (Table 2)
Of the three questions on the IBM-FRS pertaining to hand function, question #3 asking about cutting food and handling utensils had the highest correlation with finger flexor strength as well as grip strength. However, the degree of correlation of the hand function items in the IBM-FRS were moderate, at best, (less than 0.6) for grip strength, even when normalizing for age and sex. Similarly, the finger flexor strength score had a Pearson’s coefficient of less than 0.5 for IBM-FRS questions pertaining to hand function.
3.6. Only severe loss of finger flexor strength correlated with subjective findings of loss of hand function in IBM-FRS
We stratified the IBM patients by finger flexor strength and compared their subjective perspective of hand function based on IBM-FRS. We found that, for the most part, patients with moderate weakness in the finger grips might not have felt that it subjectively affected their ability to write, to cut food, or to use fine motor control.
Handwriting ability (Fig. 5A) appeared to be relatively preserved with patients still rating their ability as quite high (3/4 or 4/4) with moderate strength loss (2/5 or greater) at best. Preservation of handwriting ability may be attributed to limited reliance on finger flexor strength compared to other intrinsic muscles of the hand or that patients were more adept at adapting to preserve this function.
Fig. 5.
Breakdown of the IBM-FRS rating according to finger flexor strength score. X-axis shows IBM subjects divided into 6 subgroups based on their measured finger flexor strength, which was graded on a scale of 0/5-5/5. Each bar represents the percent of patients within the subgroup reporting the same FRS score for (A) Handwriting (B) Cutting food/utensil (C) Fine motor (D) Dressing (E) Hygiene scored from 0 (cannot perform the function) to 4 (full function).
4. Discussion
Our study assessed hand function in a cross-sectional IBM cohort. The decline in IBM-FRS sum score was not associated with disease duration (Fig. 1); neither were the questions assessing hand function in the IBM-FRS (Fig. 2). This might have been confounded by the accuracy of the patient-reported duration of symptoms.
Longitudinal studies suggest that the IBM-FRS is sensitive to change over the course of one to four years, albeit the declines are associated with comparatively large standard deviations [8,9]. The 2013 British IBM-net study shows a decline of 13.8 ± 10.4% points over the course of one year, with the starting mean IBM-FRS value of 27. The 2014 French study based on 17 patients between the ages of 64 and 80, shows a four-year decline of 22.3 ± 17.3% from a starting IBM-FRS value of 28.9 ± 9.0. While our study was a cross-sectional study, our data suggests that the current IBM-FRS may not be able to determine the efficacy of a clinical trial therapies (Fig. 1).
It takes significant loss in finger flexor and grip strength to result in subjective patient complaint of hand function decline based on the current IBM-FRS (Fig. 5). Patients had to have virtually no handgrip strength before they subjectively complained of impairment of activities such as writing, cutting food, or fine motor problems. The current IBM-FRS lacked sensitivity to detect clinical changes. Despite this concern, the IBM-FRS hand function items did correlate better to finger flexor strength score than to grip strength, suggesting that the attempt in accentuating IBM-specific symptoms was partially successful.
The discrepancy between patient-perceived function and objective strength testing has been noted in other functional domains of IBM. Prior studies suggest a non-linear correlation between lower extremity function (6-minute walk test) and weakness (knee extension strength) in IBM patients because of the patient’s ability to adapt and maintain function despite weakness isolated to particular regions [9]. Possibly function is independent of strength; function and strength both may need to be assessed.
DeMuro et al. identify a discrepancy between how the patients rate their ability to transition from sit to stand and examiner observation/impression [16]. Their paper suggests re-wording the IBM-FRS to take into consideration the various aids available to patients (including devices or caregiver assistance) in daily activity. Refining the IBM-FRS may more accurately reflect true level of function of IBM patients. The 11-item modified FRS (termed sIBM Physical Functioning Assessment, sIFA) based on patient-reported outcomes is used as a secondary outcome in clinical trials of bimagrumab [16,17]. Some doses showed significant improvement in the sIFA questionnaire but the data was ultimately not published since the trial did not meet their primary outcome. Additionally, a newly modified FRS has been proposed based on a Rasch analysis but has not been validated [18]. Interestingly, the authors also note the presence of item gaps in the current FRS based on the Rasch analysis that may be the decrease in sensitivity to change. This is similar to our observation (Fig. 5). Therefore, a combination of functional patient-reported outcome measures and direct strength measurements may enhance detection of clinical decline or improvement to benefit outcome assessment for time-limited clinical trials.
As finger flexor weakness tends to be unique to IBM, loss of handgrip strength is able to separate IBM patients from controls (Fig. 4). Our data shows that grip strength was quite variable earlier on in the disease, but became less variable and regress towards lower strength over 20 years. Prior studies suggested that grip strength in IBM patients can decrease by 10.7% per year; [9] however, our data shows that this change can be quite variable depending on both the stage of the disease and characteristics unique to individual patients given the heterogeneous nature of IBM. This is similar to the findings in quadricep strength [15]. Conversely, finger flexor assessment did not demonstrate a particular pattern over time. This may be a simple reflection of the heterogeneous quality of IBM, but may also be because of the lack of sophisticated methods for strength measurement. A beneficial future direction would include the development of simple devices to consistently measure force generated by distal finger flexors.
Our study is limited by the cross-sectional nature of assessing 81 patients with reported duration of symptoms ranging anywhere from 2 years to 39 years as opposed to a truly longitudinal study. The diagnosis of IBM and the disease’s duration of symptoms was dependent on patient reporting; the duration of the disease may be subject to recall bias. The strength in our study is the number of IBM patients assessed, which is unprecedented.
Our study is a unique cross-sectional look at the clinical features of IBM, including grip strength, finger flexor strength, and the IBM-FRS. We can clearly see the extent of heterogeneity of IBM when looking at these parameters based on duration of symptoms. The large clinical variation of this slow but steadily progressive disorder makes selection of meaningful end-points for clinical trials challenging. While the IBM-FRS is favored in many clinical trials, it remains to be optimized since the design of the measurement does not incorporate patient-reported outcomes; and hand-function domain items intended to reflect changes in hand function had a lower than anticipated association with grip strength and, more importantly, with finger flexor strength—a hallmark unique to IBM. We suggest the incorporation of patient-reported outcomes to modify the current IBM-FRS, and the development of a finger flexor dynamometer device.
Supplementary Material
Acknowledgments
We would like to thank Susan Dooley for help with the project as well as John J. Jones and Patricia Osborne for help editing the manuscript.
Footnotes
Supplementary materials
Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.nmd.2019.12.002.
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