Pain in individuals with idiopathic inflammatory myopathies, other systemic autoimmune rheumatic diseases, and without rheumatic diseases: A report from the COVAD study

To compare pain intensity among individuals with idiopathic inflammatory myopathies (IIMs), other systemic autoimmune rheumatic diseases (AIRDs), and without rheumatic disease (wAIDs).


| INTRODUC TI ON
Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare systemic autoimmune diseases characterized by a predilection for skeletal muscle inflammation and a variety of extra-muscular manifestations. Muscle symptoms along with extramuscular involvement may limit activities of daily living and negatively affect health-related quality of life (HRQoL). [1][2][3] HRQoL is a multidimensional and complex concept which involves physical and psychological domains as well as social functioning and relationship with the environment. 4,5 Patients with systemic autoimmune rheumatic diseases (AIRDs) have impaired HRQoL compared to the general population. [1][2][3] Importantly, pain is commonly reported by patients and is a major contributor to poor QoL in chronic rheumatic conditions. A large European multicenter study showed that pain was frequent among patients with systemic lupus erythematosus, despite apparent clinical remission. 6,7 Similarly, while previously underplayed as a key clinical feature of IIM, recent qualitative data indicate pain as one of the most important aspects of their disease experience. 8 Increasing recognition of the importance of pain in AIRDs and its negative effect on HRQoL has galvanized efforts to develop tools to reliably assess these symptoms and advance knowledge in the field. The Patient-Reported Outcomes Measurement Information System (PROMIS) set measures, funded by the National Institutes of Health (NIH), provides accurate and valid item banks related to various health domains, calibrated by the item response theory. 9 This flexible and reliable instrument can be used to capture the domains of physical and mental health and social well-being in a variety of conditions, facilitating patient status monitoring and the decisionmaking process. [9][10][11] Although the importance of patient-reported outcomes has become increasingly recognized in AIRDs, studies on pain perceptions in patients with IIMs are scarce. 12 This study aims to compare pain intensity using PROMIS core set measures among a large sample of individuals with IIMs, other AIRDs, and those without rheumatic disease (wAIDs) as well as to understand the association of pain with disease activity, demographics, and functional status.

| Study design
This is an international cross-sectional online patient survey, which is part of the COVID-19 Vaccination in Autoimmune Diseases (COVAD) protocol. 13 While COVAD focused on COVID-19 vaccination, a breadth of supporting data was collected. Here we report an analysis of data related to pain. Ethics approval was obtained from the Institutional Ethics Committee of Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, India. It was obtained as per local guidelines and all participants electronically consented. There was no monetary or other compensation to the patient for participation in the study.

| Study population
Survey participants (patients and wAIDs) were recruited in 94 countries as described elsewhere. 13

| Data collection
All data were collected from the COVAD protocol survey which consisted originally of 37 items. 13 This included questions on COVID vaccination experience of patients (in retrospect, based on recall memory), although the e-survey also assessed pain, fatigue and PROMIS physical function using validated tools in a cross-section at the time of responding to the survey. This status of perceived physician health had nothing to do with COVID vaccine adverse events, and hence were explored in light of this as an independent data set from a cross-section of our study population. The survey was implemented using the web-based survey platform and followed the Checklist for Reporting Results of Internet E-Surveys (CHERRIES) to report the data. 14

| Study variables
The dependent variable was the level of pain in the last 7 days, measured using a numeral rating scale (NRS). Participants were asked to place a mark on a straight line anchored at the values from 0 to 10, in which 0 meant no pain and 10 meant very severe or maximum pain.
Independent variables considered in this study were: demographic data, including age, gender, ethnicity, and country of residence; specific subtype of autoimmune disease, and categories of physical function (general physical health status and ability to carry out routine activities).

| Functional status
General physical health was assessed using 5-category response scales extracted from the PROMIS 10 -a short form for physical function of the PROMIS Global Health instrument. 11,15 In summary, participants were asked, "In general, how would you rate your physical health?", categorized as excellent, very good, good, fair, or poor . The ability to carry out everyday activities was assessed by the   question "To what extent are you able to carry out your everyday   physical activities such as walking, climbing stairs, carrying groceries,   or moving a chair?", defined as completely, mostly, moderately, a little or not at all.

| Disease activity
Participants characterized their disease status in the last 4 weeks as active or inactive based on: (a) patient's own perception; (b) as per patients' self-reported physician's assessment of their disease activity status as informed to them by their physician; and (c) patients on a daily dose equivalent to ≥10 mg prednisone with either muscle weakness, active rash, or arthritis were also considered to have active disease.

| Statistical analysis
Qualitative variables were described using frequencies, and quantitative variables were described using mean and standard deviation if data were normally distributed or median and interquartile range (IQR) if the tested distribution was not assumable to a Gaussian normal curve. Kolmogorov-Smirnov test was used when testing for normality. Continuous variables were compared among ages by groups using analysis of variance or Kruskal-Wallis depending on data distribution. In the case of statistically significant results, Dunn's post hoc test was performed for multiple comparisons between groups. For categorical variables, groups were compared using the Chi-square test. To analyze the predicted pain NRS in multiple scenarios, we performed a negative binomial regression multivariate analysis clustering country of origin and adjusted for age, gender, and ethnicity. P < 0.05 was considered statistically significant and statistical analysis was conducted using STATA version 16.
Among IIMs, patients with overlap myositis and anti-synthetase syndrome had the highest predicted pain NRS in a negative binomial regression analysis clustered by country of origin and adjusted for age, gender, and ethnicity ( Table 2, Table S2). Using patients with dermatomyositis as reference (mean of predicted pain NRS = 3.1), patients with overlap myositis had a statistically higher NRS score (difference of predicted pain NRS = 0.9, 95% CI = 0.3-1.6, P = 0.007), followed by antisynthetase syndrome (difference of predicted pain: NRS = 0.5, 95% CI = −0.2 to 1.2, P = 0.170), and patients with inclusion body myositis had a statistically lower NRS score (difference of predicted pain: NRS = −0.6, 95% CI = −0.8 to −0.4, P < 0.001) ( Table 2).

| Association of pain NRS by disease activity, gender, age, and ethnicity
Predicted pain NRS score of patients with IIMs was higher than  Table 3).
Regardless of disease activity, female patients with IIMs reported more pain than their male counterparts. In general, increasing age was associated with more pain in active as well as inactive disease in IIMs. Hispanic patients reported less pain in some active disease categories in IIMs. Table 4 shows the coefficients of all covariates included in the multivariate binomial regression analysis.

| Association of pain with general health status
The predicted pain NRS score of patients with IIMs was higher than wAIDs but lower than patients with other AIRDs in case of good or fair general health status. However, there was no difference in pain if the subject reported very good or excellent health status. AIRDs had significantly higher pain than IIMs in subjects with poor health status, whereas IIMs were similar to wAIDs ( Table 3).
The female gender was associated with higher pain in all scenarios of general health, except for patients with poor health status, where there was no difference between males and females. Being Asian was associated with lower pain in patients with fair general health, and being Hispanic was associated with lower pain in cases of fair and very good general health. Age had no impact on NRS scores concerning different health statuses (Table 4).

| Association of pain with the ability to carry out routine activities
Patients with IIMs who had an impaired ability to carry out routine activities experienced more intense pain than wAIDs, but less pain than patients with other AIRDs in most scenarios ( Table 3).
The female gender was associated with higher pain, except for patients with extreme disability, where females and males had similar pain levels. Asian ethnicity was associated with lower pain NRS, except for patients with no disability (Table 4).

| DISCUSS ION
In the present study, we showed that patients with IIMs had a higher pain NRS score than wAIDs, but a lower NRS score than patients with other AIRDs. This difference was observed across different levels of disease activity and functional status. An association between pain and poor functional status was seen in all groups, as well as an association between active disease and pain in patients with IIMs and AIRDs. Among IIMs, patients with overlap myositis and antisynthetase syndrome had the highest NRS scores. We hypothesized that this may be explained, at least in part, by the frequent association of antisynthetase syndrome and overlap myositis with arthritis.
An analysis of the covariates included in the multivariable models to predict NRS scores revealed that both male gender and being an wAID had a protective effect on pain scores in almost all scenarios while being female or having an AIRDs was associated with higher pain scores. Age was associated with higher pain NRS scores IIMs, and is one of the strongest predictors of poor QoL in these patients. 25 Pain may be linked to physical activity, even when the activity is of low intensity. 26 Likewise, in fatigue, patients with pain report difficulty carrying out their activities of daily living and, therefore, impairment in QoL. 25 Nonetheless, the contribution of physical activity to pain perception in IIM remains incompletely understood.
In a recent systematic review, Misse et al 27 pointed out studies in which physical exercise was effective and safe in maintaining or improving IIM-related muscle strength and other parameters, pain, and perceived fatigue. 21,28,29 According to a systematic review by Graham

<0.001
Based on patient assessment

CO N FLI C T O F I NTE R E S T S TATE M E NT
ALT has received honoraria for advisory boards and speaking

D I SCL A I M ER
No part of this manuscript is copied or published elsewhere in whole or in part.

E TH I C S A PPROVA L
Ethics approval was obtained from the Institutional Ethics