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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

Objective

Large descriptive studies of pain in systemic sclerosis (SSc) are lacking. The present study estimated prevalence, severity, and associations between SSc clinical variables and pain in all patients with SSc and in limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) subsets.

Methods

Patients enrolled in a multicenter SSc registry (n = 585) completed a standardized clinical assessment and questionnaires about their physical and psychosocial health, including a pain severity numerical rating scale (NRS; range 0–10). Pain prevalence and severity were estimated with descriptive statistics. Crude and adjusted associations between specific SSc clinical variables and pain were estimated with linear regression for the entire group and by SSc subtype.

Results

Of the patients, 484 (83%) reported pain (268 [46%] mild pain [NRS 1–4], 155 [27%] moderate pain [NRS 5–7], and 61 [10%] severe pain [NRS 8–10]). More frequent episodes of Raynaud's phenomenon, active ulcers, worse synovitis, and gastrointestinal (GI) symptoms were associated with pain in multivariate analysis adjusting for demographic variables, depressive symptoms, and comorbid conditions. Patients with dcSSc reported only slightly higher mean ± SD pain than those with lcSSc (dcSSc 3.9 ± 2.8 versus lcSSc 3.4 ± 2.7; Hedges's g = 0.18, P = 0.05). Regression estimates did not differ significantly between SSc subsets.

Conclusion

Pain symptoms were common in the present study of patients with SSc and were independently associated with more frequent episodes of Raynaud's phenomenon, active ulcers, worse synovitis, and GI symptoms. Subsetting by extent of skin involvement was only minimally related to pain severity and did not affect associations with clinical variables. More attention to pain and how to best manage it is needed in SSc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

Systemic sclerosis (SSc) is a multisystem disease characterized by immune system activation, fibrosis, and vasculopathy. SSc is highly heterogeneous, although patients are most commonly classified as having either limited cutaneous SSc (lcSSc; skin involvement limited to the face, neck, and areas distal to the knees and elbows) or diffuse cutaneous SSc (dcSSc; skin involvement proximal and distal to the knees/elbows and/or trunk) (1). Patients with dcSSc typically have more rapidly progressive disease with earlier organ-system involvement and a worse prognosis than patients with lcSSc (2). SSc is far more common in women than in men, with typical disease onset in the childbearing years (3). SSc is associated with high morbidity and mortality (4), disability (5, 6), high health care use and productivity losses (7, 8), and compromised health-related quality of life (9, 10). There is no known cure for SSc; therefore, research aimed at preventing disability and improving patients' quality of life is urgently needed.

Pain is prominent in rheumatic diseases and is associated with more frequent physician consultation, greater disability, and diminished quality of life (11). Moreover, patients with rheumatic disease have been shown to prioritize improvements in pain management above any other treatment area (12). Studies in small numbers of patients with SSc have reported significant associations between pain and physical, social, and emotional health (13–20). An earlier study on 337 patients with SSc (21) from our multicenter Canadian SSc registry showed that pain was a strong and significant independent predictor of worse quality of life after adjusting for demographic, clinical, and psychosocial variables. Despite these findings, pain has received relatively little attention in SSc, and current understandings are based on a small number of studies with relatively small sample sizes.

Only 3 studies have assessed the prevalence of pain in SSc (13, 19, 20), and each reported that pain was common, occurring in 60–75% of patients. Mean pain in SSc samples has been suggested to be in the mild range (15, 17) and has been found to be similar to that in other chronic pain and rheumatic disease groups in studies that used the same pain assessment tools for comparison (9, 13, 22). Several studies have assessed pain in subsets of patients with lcSSc and dcSSc (13, 18, 19, 22–24), and all have reported higher pain scores in dcSSc cases than in lcSSc cases. Most of these studies have reported small and statistically nonsignificant differences, with the exception of a study by Malcarne et al (18) that reported a moderate-to-large and statistically significant effect size. Larger sample sizes are required to obtain robust estimates of the prevalence and the severity of pain in SSc and to determine whether patients with lcSSc and dcSSc experience clinically meaningful differences in pain.

Because SSc is a complex multisystem disease, pain may have multiple sources. One focus group study (n = 19) (20) reported that participants described joint and musculoskeletal pain, skin pain, pain associated with Raynaud's phenomenon, gastrointestinal (GI) and digestive pain, and pain in the distal extremities (tightness, calcinosis, and ulcers). Two quantitative studies have examined bivariate associations between specific SSc clinical variables and pain. One study of 82 patients with SSc (22) reported crude associations between the presence of ≥11 fibromyalgia tender points, joint involvement, GI disease, and pain. The second study (n = 281) (25) reported significantly higher pain scores in patients with active digital tip ulcers. Only 1 published study in SSc (n = 114) (18) has examined associations between multiple clinical variables and pain using multivariate analysis. That study examined 28 potential clinical predictor variables, but reported significant multivariate associations only between pain and higher skin score, patient-reported leg swelling, and patient-reported joint tenderness. A limitation of that study, however, was that significant results from unadjusted analyses were used to screen in variables for multivariate analysis, and an automated stepwise procedure was used for final variable selection. This is known to lead to model overfitting, as well as variable selection/ exclusion decisions and parameter estimates that often do not generalize to other data sets (26). No studies have examined whether associations between clinical variables and pain differ between patients with lcSSc and dcSSc.

The objectives of the present study were to estimate the prevalence, severity, and associations of specific clinical variables with pain in all patients with SSc as well as in patients with lcSSc and dcSSc separately, using large sample data from a convenience sample of nearly 600 patients enrolled in a multicenter SSc registry.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

Study design.

The present study was a cross-sectional analysis of a convenience sample of patients with SSc enrolled in the Canadian Scleroderma Research Group (CSRG) Registry. The CSRG Registry is an ongoing cohort study of patients with SSc from 15 Canadian centers. Patients are recruited by participating CSRG rheumatologists who confirm the diagnosis of SSc. Participants must be ≥18 years of age, fluent in English or French, likely to be compliant with study procedures, and able to give informed consent. Patients meeting criteria for another rheumatic disease in addition to SSc are also eligible to enroll. Registry patients annually undergo a standardized clinical assessment and complete questionnaires assessing demographic information and physical and psychosocial health outcomes. Only patients with a diagnosis of either lcSSc or dcSSc were included in the present study.

Study measures.

Independent variables.

Information regarding age, sex, race, and postsecondary education was obtained from a patient-reported demographic questionnaire. Patients were classified into SSc subsets according to the criteria for SSc by LeRoy et al (27). SSc disease duration was defined as the number of years from the date of first non–Raynaud's phenomenon manifestation of SSc until the date of first study visit. Skin involvement was assessed with the modified Rodnan skin thickness score (MRSS) (28) ranging from 0 to 51. The severity of Raynaud's phenomenon was assessed with the number of patient-reported episodes in the past week (25, 29). Rheumatologists recorded the presence of active digital tip ulcers, other active ulcers, visible or palpable calcinosis, and tendon friction rubs during the clinical assessment. Severity of finger contractures was assessed by recording the fingertip-to-palm distance from the tip of the third finger to the distal palmar crease of the more severely affected hand (30). Severity of other joint contractures was measured with the sum of the number of sites (wrists, elbows, hips, knees, and/or ankles on both sides of the body) with a total score range of 0–10. The 28–swollen joint count (31) was used as an objective measure of joint swelling. Elevated creatinine kinase level, defined according to laboratory cutoffs (42–396 units/liter for men and 24–240 units/liter for women), was used as an index of muscle involvement.

GI symptoms previously reported to be associated with pain in a focus group study of patients with SSc (20) were assessed by summing the number of positive responses to the following 6 patient-reported questions: “I have (or have had) on most days either now or since the onset of my scleroderma: 1) difficulty in swallowing—food or liquids sometimes get stuck behind my breastbone on the way down; 2) food or acid-tasting liquid that comes back up into my mouth or nose (acid reflux); 3) burning feeling rising from my stomach or lower chest up towards my neck (heartburn); 4) constipation; 5) diarrhea; 6) visible swelling of my abdomen or bloating.” Using patient reports of GI symptoms is noninvasive and has been shown to be a reliable and valid measure of GI disease (32). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D) (33), a 20-item self-report scale for which patients rate the frequency of depressive symptoms in the past week ranging from 0–60. The cutoff for clinically significant depressive symptoms is 16 (33, 34). Comorbid conditions known to be associated with pain were defined as the presence of patient-reported osteoarthritis (OA) or back pain.

Outcome variable

Pain severity was assessed with an 11-point numerical rating scale (NRS) ranging from 0 to 10 (where 0 = no pain and 10 = very severe pain) in the last week. The NRS was adapted from the pain visual analog scale (VAS) of the Stanford Health Assessment Questionnaire (HAQ), which has been validated for use in SSc clinical trials (35). Compared with VAS measures, NRS are more simple to complete and score and have been shown to be as reliable and responsive as a VAS in patients with ankylosing spondylitis (36), and even more reliable for assessing pain in patients with rheumatoid arthritis (RA) (37). Studies in cancer and musculoskeletal pain groups have recommended NRS cutoffs of ≤4, 5–7, and >7 for mild, moderate, and severe pain, respectively (38, 39).

Statistical analysis.

Standard descriptive statistics were used to describe the prevalence and severity of pain symptoms in all patients and separately in lcSSc and dcSSc subsets. The magnitude of the differences in pain severity between SSc subsets was estimated with their mean difference and 95% confidence interval (95% CI), as well as with Hedges's g, a measure of standardized effect size (40). Effect sizes were interpreted based on Cohen's operational guidelines for small, medium, and large effect sizes (small = 0.2, medium = 0.5, and large = 0.8) (41). Separate bivariate linear regressions of each independent variable with pain as the response were performed to calculate unadjusted regression estimates and 95% CIs. Multivariate linear regression including all independent variables simultaneously was used to calculate adjusted regression estimates and 95% CIs. Descriptive analyses were examined to identify variable ranges that were either inconsistent with background knowledge of SSc, or had too much measurement error or too little variability to contribute usefully to multivariate analysis (42). Separate multivariate linear regressions were then performed in lcSSc and dcSSc subsets using the same prespecified independent variables and were compared by calculating estimated regression coefficient differences and 95% CIs.

The association between pain and depression is temporally ambiguous; therefore, we also performed a separate multivariate analysis adjusting for symptoms of depression. Data on comorbid conditions were not collected for all subjects. Therefore, to include the maximum number of subjects in the present study, multivariate analysis adjusting for comorbid conditions was performed separately in a subgroup with this information. Multivariate imputation by chained equations (MICE) (43) was also performed to examine potential differences in effect estimates of clinical variables due to missing observations. The MICE and mitools packages in R (R Foundation, Vienna, Austria) were used to generate 5 complete copies of the data set, and the MIcombine command was used to generate averaged multivariate regression coefficients and adjusted 95% CIs across the 5 data sets.

All statistical procedures were performed using the Statistical Package for the Social Sciences, version 13 (SPSS, Chicago, IL), and R: A Language and Environment for Statistical Computing, version 2.8.1 (R Foundation).

Ethics committee approval for CSRG Registry procedures was obtained at each site, and each patient provided written informed consent.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

Patient sample.

The present study included patients enrolled in the CSRG Registry between September 2004 and November 2008, which included information from 877 patient records. We excluded 51 patient records (6%) because SSc subset status was not recorded (n = 26) or the patient had a diagnosis of sine SSc (n = 25). Of the 826 eligible patient records, 585 (71%) had complete observations for all variables included in the main analyses.

Demographic and clinical characteristics for all SSc, lcSSc, and dcSSc cases are presented in Table 1. The mean ± SD age for the total sample was 56 ± 12 years, 506 (87%) were female, 523 (89%) were white, and 279 (48%) had ≥1 year of postsecondary education. Of the total sample, 536 patients (92%) met the American College of Rheumatology (ACR; formerly the American Rheumatism Association) criteria for SSc (44), and median (interquartile range [IQR]) disease duration was 9 (4–15) years. Of the patients, 358 (61%) had lcSSc and 227 (39%) had dcSSc. Patients with dcSSc tended to have more skin involvement, digital tip and other ulcers, finger and other joint contractures, tendon rubs, and to score ≥16 on the CES-D than patients with lcSSc. Swollen joints, comorbid OA, and back pain were more common in lcSSc cases than in dcSSc cases. There were no significant differences (P < 0.05) observed between partial observations excluded from the present study (n = 241) and complete observations included in the present study (n = 585) with respect to demographic characteristics, disease duration, the proportion of patients meeting the ACR criteria for SSc, or lcSSc/dcSSc subset status.

Table 1. Demographic and clinical characteristics of CSRG sample of patients with SSc*
VariablesAll SSclcSScdcSSc
  • *

    Values are the number (percentage) unless otherwise indicated. CSRG = Canadian Scleroderma Research Group; SSc = systemic sclerosis; lcSSc = limited cutaneous SSc; dcSSc = diffuse cutaneous SSc; IQR = interquartile range; MRSS = modified Rodnan skin thickness score; GI = gastrointestinal; CES-D = Center for Epidemiologic Studies Depression Scale.

Cases585 (100)358 (61)227 (39)
Age, mean ± SD years56 ± 1257 ± 1253 ± 11
Female506 (87)321 (90)185 (82)
Race, white523 (89)326 (91)197 (87)
Postsecondary education279 (48)171 (48)108 (48)
Disease duration, median (IQR) years9 (4–15)10 (4–17)7 (3–14)
Skin score, median (IQR) MRSS (0–51)7 (4–15)4 (2–8)17 (11–25)
Episodes of Raynaud's phenomenon, median (IQR)4 (1–7)4 (1–7)3 (1–7)
Active digital tip ulcers52 (9)23 (6)29 (13)
Active other ulcers (not digital tips)105 (18)40 (11)65 (29)
Calcinosis175 (30)109 (30)66 (29)
Finger contractures201 (34)81 (23)120 (53)
Other joint contractures108 (19)27 (8)81 (36)
Swollen joint count98 (17)68 (19)30 (13)
Tendon friction rubs99 (17)31 (9)68 (30)
Abnormal creatinine kinase level (n = 491)16 (3)8 (2)8 (4)
Total GI symptoms, median (IQR)2 (1–4)2 (1–4)2 (1–4)
 Problems swallowing325 (56)197 (55)128 (56)
 Acid reflux386 (66)226 (63)160 (71)
 Heartburn258 (44)152 (43)106 (47)
 Stomach bloating224 (38)138 (39)86 (38)
 Constipation164 (28)95 (27)69 (30)
 Diarrhea134 (23)77 (22)57 (25)
Depressive symptoms, mean ± SD CES-D score (0–60)14 ± 1013 ± 1015 ± 10
Depression screen positive (CES-D score ≥16)211 (36)113 (32)98 (43)
Painful comorbidities (n = 509)218 (43)149 (48)69 (35)
Osteoarthritis103 (20)81 (26)22 (11)
Back pain174 (34)117 (38)57 (29)

Prevalence and severity of pain in patients with SSc.

Of the patients, 484 (83%) experienced pain symptoms, with more than one-third reporting pain symptoms in the moderate or severe range (mild: 268 [46%], moderate: 155 [27%], and severe: 61 [10%]) (Table 2). The mean ± SD pain score for the total sample was 3.6 ± 2.8, for the dcSSc subset was 3.9 ± 2.8, and for the lcSSc subset was 3.4 ± 2.7. The mean difference in pain severity between subsets was statistically significant (mean difference 0.51; 95% CI 0.06, 0.97). However, the effect size for this difference (Hedges's g = 0.18; 95% CI 0.01, 0.35) was small, and distributions of patients reporting mild, moderate, and severe pain were similar in both subsets (Table 2).

Table 2. Prevalence of pain in patients with SSc*
VariablesAll SSc (n = 585)lcSSc (n = 358)dcSSc (n = 227)
  • *

    Values are the number (percentage). SSc = systemic sclerosis; lcSSc = limited cutaneous SSc; dcSSc = diffuse cutaneous SSc; NRS = numerical rating scale.

No pain (NRS 0)101 (17)67 (19)34 (15)
Mild pain (NRS 1–4)268 (46)171 (48)97 (43)
Moderate pain (NRS 5–7)155 (27)87 (24)68 (30)
Severe pain (NRS 8–10)61 (10)33 (9)28 (12)

SSc clinical variables and pain in patients with SSc.

Results of bivariate and multivariate linear regression in all patients with SSc are summarized in Table 3. Crude associations between all clinical variables examined and pain were significant. However, only more frequent episodes of Raynaud's phenomenon, presence of other active ulcers, higher swollen joint count, and more GI symptoms were associated with pain in multivariate analyses. Because few patients (9%) had active digital tip ulcers, its 95% CI was wide and did not reach statistical significance.

Table 3. Crude and adjusted linear regression coefficients of clinical variables with pain in all patients with SSc (n = 585)*
VariablesCrudeAdjusted
  • *

    Values are the unstandardized regression coefficient (95% confidence interval). Multivariate regression estimates are adjusted for demographic variables (age, sex, race, level of education) and disease duration. SSc = systemic sclerosis; MRSS = modified Rodnan skin thickness score; FTP = fingertip-to-palm.

  • P < 0.05.

Skin score (MRSS, 0–51)0.04 (0.01, 0.06)0.00 (−0.03, 0.03)
Episodes of Raynaud's phenomenon0.04 (0.01, 0.06)0.03 (0.01, 0.05)
Active digital tip ulcers0.90 (0.12, 1.69)0.40 (−0.36, 1.16)
Active other ulcers1.21 (0.63, 1.78)1.01 (0.42, 1.59)
Finger contractures (FTP)0.19 (0.08, 0.31)0.06 (−0.06, 0.18)
Other joint contractures0.25 (0.10, 0.41)0.12 (−0.06, 0.29)
Swollen joint count (0–28)0.12 (0.04, 0.21)0.12 (0.04, 0.20)
Tendon friction rubs0.81 (0.22, 1.41)0.34 (−0.25, 0.95)
Total gastrointestinal symptoms0.50 (0.38, 0.62)0.46 (0.34, 0.58)

Descriptive statistics showed that only 3% of the present sample had an elevated creatinine kinase level indicative of possible muscle involvement, which was not enough variability to enter in regression analyses and obtain interpretable regression estimates. Therefore, an index of muscle involvement was not included in regression analyses. The point estimates for calcinosis in crude (unstandardized regression coefficient −0.139; 95% CI −0.629, 0.351) and multivariate linear regression analyses (unstandardized regression coefficient −0.426; 95% CI −0.909, 0.570) were not significant and in the wrong direction. Therefore, calcinosis was not retained in regression models.

SSc clinical variables and pain in lcSSc and dcSSc subsets.

Results of bivariate and multivariate linear regression in lcSSc and dcSSc subsets are summarized in Table 4. More GI symptoms were significantly associated with pain in lcSSc and dcSSc subsets. Higher swollen joint count was significantly associated with pain among patients with lcSSc, whereas the presence of other active ulcers was significantly associated with pain among patients with dcSSc. Overall, however, differences in regression effect estimates between patients with lcSSc and dcSSc were small, and none were statistically significant (data not shown).

Table 4. Multivariate linear regression coefficients of clinical variables with pain in lcSSc and dcSSc subsets*
VariableslcSSc (n = 358)dcSSc (n = 227)
  • *

    Values are the unstandardized regression coefficient (95% confidence interval). Multivariate regression estimates are adjusted for demographic variables (age, sex, race, level of education) and disease duration. lcSSc = limited cutaneous systemic sclerosis; dcSSc = diffuse cutaneous SSc; MRSS = modified Rodnan skin thickness score; FTP = fingertip-to-palm.

  • P < 0.05.

Skin score (MRSS, 0–51)0.03 (−0.03, 0.10)0.01 (−0.05, 0.09)
Episodes of Raynaud's phenomenon0.03 (0.00, 0.05)0.04 (0.00, 0.08)
Active digital tip ulcers0.04 (−1.06, 1.15)0.82 (−0.29, 1.92)
Active other ulcers0.85 (−0.02, 1.71)1.16 (0.32, 1.99)
Finger contractures (FTP)0.07 (−0.10, 0.24)0.01 (−0.18, 0.19)
Other joint contractures0.09 (−0.40, 0.58)0.16 (−0.04, 0.35)
Swollen joint count (0–28)0.15 (0.04, 0.26)0.09 (−0.04, 0.21)
Tendon friction rubs0.21 (−0.75, 1.16)0.38 (−0.42, 1.17)
Gastrointestinal symptoms0.56 (0.41, 0.71)0.30 (0.08, 0.52)

Sensitivity analysis.

The same clinical variables (more frequent episodes of Raynaud's phenomenon, other active ulcers, higher swollen joint count, and more GI symptoms) remained significant after adjusting for depressive symptoms and comorbid conditions (Table 5). Results were also similar after multiple imputation, with the exception that the effect estimate for active digital tip ulcers nearly doubled and reached statistical significance (unstandardized regression coefficient = 0.753; 95% CI 0.110, 1.396) (Table 6).

Table 5. Multivariate regression models of clinical variables with pain adjusting for depressive symptoms and comorbid conditions in all patients with SSc*
VariablesDepressive symptoms (n = 585)Comorbid conditions (n = 508)
  • *

    Values are the unstandardized regression coefficient (95% confidence interval). Multivariate regression estimates are adjusted for demographic variables (age, sex, race, level of education) and disease duration. SSc = systemic sclerosis; MRSS = modified Rodnan skin thickness score; FTP = fingertip-to-palm; CES-D = Center for Epidemiologic Studies Depression Scale; OA = osteoarthritis.

  • P < 0.05.

Skin score (MRSS, 0–51)0.00 (−0.03, 0.03)0.01 (−0.02, 0.04)
Episodes of Raynaud's phenomenon0.03 (0.00, 0.05)0.03 (0.00, 0.05)
Active digital tip ulcers0.48 (−0.24, 1.21)0.43 (−0.35, 1.22)
Active other ulcers0.81 (0.25, 1.37)1.16 (0.54, 1.78)
Finger contractures (FTP)0.03 (−0.08, 0.15)0.02 (−0.10, 0.15)
Other joint contractures0.07 (−0.09, 0.24)0.11 (−0.07, 0.29)
Swollen joint count (0–28)0.11 (0.03, 0.19)0.12 (0.04, 0.20)
Tendon friction rubs0.30 (−0.27, 0.87)0.20 (−0.43, 0.82)
Total gastrointestinal symptoms0.34 (0.22, 0.46)0.44 (0.31, 0.58)
Depressive symptoms (CES-D, 0–60)0.08 (0.06, 0.10) 
Pain condition (OA/back pain) 0.69 (0.23, 1.15)
Table 6. Multivariate linear regression coefficients of clinical variables with pain after multiple imputation of missing observations in all patients with SSc (n = 826)*
Variablesbav (95% CI)
  • *

    Values are the averaged unstandardized regression coefficients across 5 multiple imputed data sets (bav [95% CI]). Multivariate regression estimates are adjusted for demographic variables (age, sex, race, level of education) and disease duration. SSc = systemic sclerosis; 95% CI = 95% confidence interval; MRSS = modified Rodnan skin thickness score; FTP = fingertip-to-palm.

  • P < 0.05.

Skin score (MRSS, 0–51)0.01 (−0.02, 0.03)
Episodes of Raynaud's phenomenon0.03 (0.01, 0.05)
Active digital tip ulcers0.75 (0.11, 1.40)
Active other ulcers0.61 (0.10, 1.11)
Finger contractures (FTP)0.07 (−0.04, 0.18)
Other joint contractures0.11 (−0.06, 0.27)
Swollen joint count (0–28)0.11 (0.04, 0.17)
Tendon friction rubs0.21 (−0.33, 0.76)
Total gastrointestinal symptoms0.42 (0.31, 0.52)

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

Pain was common (83%) in the present study, and more than one-third of patients with SSc reported pain symptoms in the moderate or severe range. After adjusting for demographic variables, depressive symptoms, and comorbidities, specific SSc clinical variables associated with pain included more frequent episodes of Raynaud's phenomenon, other active ulcers, worse synovitis, and GI symptoms. Digital tip ulcers were significant after multiple imputation. Depressive symptoms and painful comorbidities were also significantly associated with pain symptoms in SSc, but their inclusion in models did not alter the observed relationships with SSc variables. Patients with dcSSc reported only minimally higher pain levels compared with patients with lcSSc, and multivariate regression coefficient differences between subsets were small and were not significant.

Few studies in SSc include assessments of pain. This may, in part, be related to the fact that pain appears to be assessed and treated less often in SSc compared with other rheumatic diseases (45). The current study, however, confirms that pain is common in SSc. Pain severity in the present sample of patients with SSc was comparable with that reported in a recent study of patients with RA (46) seeking specialty care for pain symptoms (mean ± SD 3.6 ± 2.8 for SSc and 4.3 ± 2.7 for RA). Two smaller studies that compared measures of quality of life in SSc with those in other rheumatic diseases reported consistent findings with the present study. Danieli et al (9) reported similar Short Form 36 health survey bodily pain scores (range 0–100) in 76 patients with SSc (median 61, IQR 41–77) and 118 patients with RA (median 51, IQR 41–74). Moreover, Johnson et al (22) reported similar HAQ pain VAS scores (range 0–3) in 43 patients with SSc (mean 1.4; 95% CI 1.1, 1.6), 82 patients with psoriatic arthritis (mean 1.2; 95% CI 1.0, 1.4), and 42 patients with RA (mean 1.0; 95% CI 0.8, 1.7).

Studies describing minimum clinically important differences (MCIDs) in SSc and other rheumatic diseases suggest that a 10–20% change in pain measures would correspond to a clinically meaningful difference (47, 48). Based on regression estimates from multivariate analysis (Tables 3 and 6), active ulcers and ≥3 GI symptoms would likely be considered to have independent clinically meaningful effects on pain. Effects estimates for more Raynaud's phenomenon episodes and swollen joint count were also statistically significant; however, patients would need to experience ≥30 Raynaud's phenomenon episodes per week or have ≥8 swollen joints to be associated with a 10% increase in pain symptoms. This suggests that only severe Raynaud's phenomenon symptoms and moderate to severe synovitis would be associated with significant pain symptoms in SSc. Based on the model estimates reported in Table 5, in addition to the SSc symptoms discussed above, painful comorbidities and screening positive for depression (a CES-D score ≥16) would both be associated with a clinically meaningful change in pain symptoms.

Two studies (18, 20) reported a significant association between skin score and pain that was not observed in the present study after adjusting for all other covariates. These conflicting results may be due to the fact that the other studies did not adjust for the full range of covariates included here. If, however, one were to base their judgment on the statistically significant crude point estimate for skin score obtained in the present study (unstandardized regression coefficient = 0.037; 95% CI 0.014, 0.061), only patients with an MRSS score ≥25 would potentially be associated with clinically meaningful pain symptoms.

Patients with dcSSc reported slightly higher pain than patients with lcSSc. However, the effect size for this difference was small (<0.2), and the raw mean difference in pain of 0.51 (95% CI 0.06, 0.97) would not meet the MCID threshold as clinically meaningful. Moreover, there were no significant differences in multivariate regression coefficient estimates between SSc subsets.

Future studies should examine associations between specific measures of tender calcinosis, muscle involvement, sicca symptoms, fibromyalgia and dependent edema, and pain that were unavailable in the present study. Longitudinal studies of pain in SSc will also be necessary for examining the time-varying effects of these clinical covariates in order to begin to identify causal associations. More research clarifying the pathophysiologic mechanisms of pain in SSc as well as the psychosocial risk/protective factors for pain will be needed to develop and implement optimal interventions (49). The role of inflammation in sensitizing pain pathways is an emerging area (50). However, research in pathogenetic processes specific to SSc-related pain is lacking. Multiple psychosocial interventions for pain have been developed and tested primarily in arthritis, including cognitive–behavioral therapy, relaxation, biofeedback, and meditation (51), but the efficacy of such interventions in patients with SSc remains unknown. Research in patient and physician facilitators/barriers to pain treatment in SSc will improve health service delivery.

Several limitations should be considered in interpreting results from the present study. This study was based on a convenience sample of patients with SSc. Therefore, limitations associated with this sampling strategy should be considered. The present sample of patients with SSc generally had stable disease (median disease duration 9 years). Patients who are not being cared for by a rheumatologist and patients with very severe SSc who were too sick to participate or who died earlier in their disease course were not included in the present study. This may have resulted in an over-representation of healthier patients in our SSc sample (survival cohort), and the results may therefore not be generalizable to the full spectrum of SSc. Nonetheless, even in this potentially healthier sample, the prevalence and severity of pain were high. Approximately 29% of the present sample had incomplete observations. Partial respondents could possibly have differed systematically from the full respondents included in the present study. Partial respondents, however, were similar to full respondents with respect to demographic variables, disease duration, the proportion of patients meeting the ACR criteria for SSc, and the proportion classified as having lcSSc or dcSSc. Moreover, regression estimates from sensitivity analysis that used multiple imputation to fill in missing observations did not differ substantively from regression estimates that deleted missing observations, other than by improving the precision of model estimates so that effects for digital tip ulcers reached statistical significance. Therefore, although a certain degree of bias in reported model estimates due to missingness cannot be ruled out from the present study, the rigorous sensitivity analyses performed suggest that this bias, if present, was likely minimal. Only a small proportion of patients were male, nonwhite, and had active ulcers; therefore, confidence limits for these variables were wide. This, however, is consistent with the typical presentation of SSc observed in other research studies. Lastly, measures of GI symptoms, episodes of Raynaud's phenomenon, depressive symptoms, and comorbidities were patient reported, so it is possible that there was some misclassification within these measures.

This study also had important strengths. Results from the present study were based on large multicenter data collected using standardized procedures with rigorous data analysis. Therefore, study estimates are likely robust. This study draws attention to the high prevalence of pain symptoms in patients with SSc and associations between multiple clinical variables and pain, including episodes of Raynaud's phenomenon, active ulcers, swollen joints, and GI symptoms. This was the first study to compare associations between SSc clinical variables and pain in patients with lcSSc and dcSSc, and results of no significant differences in regression estimates suggest that subsetting is not important insofar as pain is concerned.

In summary, current understandings of pain in SSc are based on very few descriptive studies with small samples. Therefore, clinicians do not have strong evidence on which to base their understanding of the prevalence, severity, and potential sources of pain in these patients. Results from the present large convenience sample of patients with SSc demonstrate that pain is highly prevalent in these patients and is as severe as in other rheumatic diseases. This suggests that more attention to pain and how to best manage it is needed in SSc. Severe Raynaud's phenomenon, active ulcers, moderate to severe synovitis, and GI symptoms were associated with pain in the present study and may represent clinical targets for interventions. In addition to SSc symptoms, presence of other painful comorbidities as well as depressive symptoms were associated with pain and may add to the severity of pain symptoms in patients with SSc.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Thombs had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Schieir, Thombs, Hanley, Baron.

Acquisition of data. Schieir, Thombs, Hudson, Baron.

Analysis and interpretation of data. Schieir, Thombs, Hudson, Boivin, Steele, Bernatsky, Hanley.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

APPENDIX A

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. AUTHOR CONTRIBUTIONS
  8. REFERENCES
  9. APPENDIX A

MEMBERS OF THE CANADIAN SCLERODERMA RESEARCH GROUP

Additional members of the Canadian Scleroderma Research Group not listed as coauthors include J. Pope: London, Ontario; J. Markland: Saskatoon, Saskatchewan; N. Khalidi: Hamilton, Ontario; D. Robinson: Winnipeg, Manitoba; N. Jones: Edmonton, Alberta; A. Masetto: Sherbrooke, Quebec; E. Sutton: Halifax, Nova Scotia; E. Kaminska: Hamilton, Ontario; P. Docherty: Moncton, New Brunswick; J. P. Mathieu: Montreal, Quebec; M. Abu-Hakima: Calgary, Alberta; D. Smith: Ottawa, Ontario; S. LeClercq: Calgary, Alberta; S. Ligier: Montreal, Quebec; and S. Mittoo: Winnipeg, Manitoba, Canada.