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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY
  8. APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY

Objective

To document disease activity and functional status in patients with scleroderma (systemic sclerosis [SSc]) and Raynaud's phenomenon (RP) and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in these patients.

Methods

Patients with SSc and moderate-to-severe RP participating in a multicenter RP treatment trial completed daily diaries documenting the frequency and duration of RP attacks and recorded a daily Raynaud's Condition Score (RCS). Mean scores for the 2-week periods prior to baseline (week 0), end of trial (week 6), and posttrial followup (week 12) were calculated. At weeks 0, 6, and 12, physicians completed 3 global assessment scales and performed clinical assessments of digital ulcers and infarcts; patients completed the Health Assessment Questionnaire (HAQ), the Arthritis Impact Measurement Scales 2 (AIMS2) mood and tension subscales, 5 specific SSc/RP-related visual analog scales (VAS), and 3 other VAS global assessments. We used these measures to document baseline disease activity and to assess their construct validity, sensitivity to change, and reliability in trial data.

Results

Two hundred eighty-one patients (248 women, 33 men; mean age 50.4 years [range 18–82 years]) from 14 centers participated. Forty-eight percent had limited cutaneous SSc; 52% had diffuse cutaneous SSc. Fifty-nine patients (21%) had digital ulcers at baseline. Patients had 3.89 ± 2.33 (mean ± SD) daily RP attacks (range 0.8–14.6), with a duration of 82.1 ± 91.6 minutes/attack. RCS for RP activity (possible range 0–10) was 4.30 ± 1.92. HAQ scores (0–3 scale) indicated substantial disability at baseline (total disability 0.86, pain 1.19), especially among the subscales pertaining to hand function (grip, eating, dressing). AIMS2 mood and tension scores were fairly high, as were many of the VAS scores. Patients with digital ulcers had worse RCS, pain, HAQ disability (overall, grip, eating, and dressing), physician's global assessment, and tension, but no significant difference in the frequency of RP, duration of RP, patient's global assessment, or mood, compared with patients without digital ulcers. VAS scores for digital ulcers as rated by the patients were not consistent with the physician's ratings. Factor analysis of the 18 measures showed strong associations among variables in 4 distinct domains: disease activity, RP measures, digital ulcer measures, and mood/tension. Reliability of the RCS, HAQ pain and disability scales, and AIMS2 mood and tension subscales was high. The RP measures demonstrated good sensitivity to change (effect sizes 0.33–0.76).

Conclusion

Our findings demonstrate that the significant activity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide information beyond the quantitative metrics of RP attacks. We propose a core set of measures for use in clinical trials of RP in SSc patients that includes the RCS, patient and physician VAS ratings of RP activity, a digital ulcer/infarct measure, measures of disability and pain (HAQ), and measures of psychological function (AIMS2).

Raynaud's phenomenon (RP) is present in more than 95% of patients with scleroderma (systemic sclerosis [SSc]) and typically precedes the onset of systemic disease by several years. The effect of RP on quality of life and functioning in patients with SSc is highly variable and depends on multiple factors, including the frequency, duration, and severity of attacks, the presence and activity of digital ulcers, and concomitant scleroderma-related problems, such as skin tightening, arthritis, pain, and dyspnea. In addition to the pain, annoyance, and functional disability of RP attacks, many patients report that they change their daily routine to accommodate their RP and may have significant anxiety associated with their disease, often expressing fears of digital ulceration and autoamputation.

Accurate and precise measures of disease activity and functional status in patients with RP will be critical to future clinical trials of new therapeutic agents for SSc in general, as well as for RP in particular. Previous trials of RP treatments have mostly utilized simple measures of the frequency and duration of RP attacks. More recent therapeutic trials of RP have incorporated composite measures of RP activity (1, 2), although these outcome measures have not been formally validated.

Similarly, although there has been extensive development of instruments to measure health status and physical function in patients with various rheumatic diseases, including osteoarthritis, rheumatoid arthritis, and systemic lupus erythematosus, it is only in the last decade that similar instruments for scleroderma have been tested and developed (3). Comprehensive understanding of the clinical impact of this disease and assessment of new therapies for SSc and RP require validated and reliable methods of measuring functional and clinical status.

The current study was undertaken to document disease activity and functional status in patients with SSc and RP and to determine the sensitivity to change, reliability, ease of use, and validity of various outcome measures in a group of these patients followed longitudinally. Concurrent clinical data on digital ulcers and infarcts also allowed for evaluation of measures of these aspects of SSc and RP. Our purpose was to gain insight into the utility of these instruments for use in future research studies of patients with SSc and RP.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY
  8. APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY

Study subjects.

The study subjects were patients with scleroderma who were participating in a multicenter, double-blind, randomized, placebo-controlled treatment trial of oral iloprost for RP. The study inclusion criteria and results of the trial, which found no benefit from iloprost treatment, have been previously reported (1). Patients were eligible for the study if they fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) preliminary classification criteria for SSc (4), were at least 18 years old, and experienced an average of 6 or more RP attacks per week. All subjects gave their informed consent to participate in the study, and the study was approved by the Institutional Review Board of each participating institution. Data from 14 of the 16 treatment study sites were available for the present analysis.

Measurements.

All study subjects completed a set of outcome measurement instruments at the baseline pretreatment visit, after completing 6 weeks of treatment, and 6 weeks after treatment cessation. The patients also recorded a daily RP attack diary regarding the activity of their RP. Study physicians completed outcome assessments of the patients at the baseline, week 6, and week 12 study visits. These study instruments are described in detail below.

RP attack diary.

Each day for 14 days, patients recorded the number of RP attacks as well as the duration of each RP attack (in minutes). They then completed the Raynaud's Condition Score (RCS). The RCS is a daily self-assessment of RP activity using a 0–10 ordinal scale. The RCS incorporates the cumulative daily frequency, duration, severity, and impact of RP attacks. Details of the diary and a copy of the RCS data form are provided in Appendix A. Data from the RP attack diary were averaged over the 2-week period preceding the baseline visit and over the 2-week period prior to each posttreatment assessment visit.

Assessment of cutaneous digital tip ulcers/infarcts.

The number and position of cutaneous digital tip ulcers or infarcts on any finger were recorded by physicians. New lesions were noted in particular. Data on both ulcers and infarcts were collected.

Health Assessment Questionnaire (HAQ).

The HAQ is a self-administered instrument that measures physical disability in 8 domains of function: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activity (5, 6). A visual analog scale (VAS) for pain is also part of the HAQ. The results for the 8 subscales, the composite disability score, and the pain measurement are each reported on a 0–3 scale. The HAQ has been used extensively in studies of rheumatoid arthritis (5, 6) and has also been validated in patients with scleroderma (7–13).

Scleroderma-specific VAS.

Patients completed 5 VAS scales that were originally developed by Steen and Medsger (13) to measure the impact of SSc on the daily activity of intestinal disease, breathing problems, RP, digital ulcers, and overall disease during the previous week. These 15-cm scales were scored continuously from 0 to 3. In this analysis, the 5 Scleroderma HAQ (SHAQ) measures are referred to as the SHAQ VAS for RP, digital ulcers, overall disease, intestinal disease, and breathing problems.

Physician's and patient's global and symptom-specific assessments of disease activity.

Physicians at 14 centers and patients at 12 centers completed 15-cm VAS scales assessing overall health, RP disease activity, and activity of digital ulcers. Scores were converted to a continuous 0–3 scale. These disease activity measurements differ from the SHAQ VAS measures outlined above, which concentrated on the functional impact of disease. For these instruments, the term “severity” was used to measure the extent of disease activity and associated disability or discomfort the patient experienced during the period indicated. The exact wording of these VAS questions is provided in Appendix B, Table A.

Table A. Patient's and physician's global and symptom-specific activity assessments
Patient's assessmentPhysician's assessment
For the RP VAS
“In the past week how severe was your Raynaud's disease?”“How severe would you rate the patient's Raynaud's disease for the past week?”
For the digital ulcers VAS
“In the past week how severe were your finger ulcers?”“How severe would you rate the patient's finger ulcers for the past week?”
For the global condition VAS
“In the past week how severe was your overall health?”“How severe would you rate the patient's overall health for the past week?”

Arthritis Impact Measurement Scales 2 (AIMS2) for mood and tension.

To explore emotional aspects of RP in SSc, patients completed both the mood (depression) and the tension scales of the AIMS2. The AIMS2 is a self-administered measurement of physical, emotional, and social well-being (14, 15). For this study, only these 2 scales, of a total of 12 available scales, were administered. Each scale is scored continuously from 0 to 10.

Statistical analysis.

We computed group summary statistics for patient characteristics and outcome measures, including means, standard deviations, ranges, and proportions as appropriate. Between-group comparisons were tested using the Wilcoxon rank sum test for continuous variables and Fisher's exact test for categorical variables.

We used principal components factor analysis with varimax rotation (16) to explore the extent to which there was overlap between the measures collected. We also applied this technique to the subscales of the HAQ. Factor analysis is a variable reduction technique that allocates the total variance associated with a set of measures to a smaller number of variables (factors) that are independent linear combinations of the original measures. The stronger the factor, the greater the percentage of total variance it explains. Varimax rotation of the factors retains their independence, while associating each measure more uniquely with a single factor. Factor loadings (range −1.00 to +1.00) of each measure represent Pearson correlations of that measure with each of the hypothesized factors. We considered measures with factor loadings >0.50 to be contributors to a particular factor (17). We also examined residuals from the factor analysis (discrepancies between observed and estimated between-measure correlations) to assess the adequacy of the factor model.

Construct validity of the RCS, HAQ, AIMS2 subscales, and all 12 of the VAS scales was measured by correlation (within the factor analysis) with other variables and by subgroup comparisons.

We evaluated the sensitivity to change of the RCS, HAQ, AIMS2 scales, and all 12 of the VAS scales in terms of both effect size and standardized response mean. The effect size is the mean change in a measure over time divided by the initial standard deviation of the measure, and it is expressed in standard deviation units (18, 19). Effect sizes have been proposed and utilized as a method of assessing the amount of change over time of different outcome measurement instruments and comparing these measurements with each other and with more traditional clinical measures of disease activity. The standardized response mean has as its divisor the change in standard deviation, rather than the baseline standard deviation, and it measures the ease of detecting change or responsiveness of a measure (20).

We also examined the variability of the measures during the relatively stable posttrial period, obtaining the standard deviation of the difference between week 6 and week 12 (week 6 and week 8 for RCS, attack frequency, and attack duration). We used this standard deviation, divided by the observed range of the variable at baseline to approximate repeated-measure reliability (21), for the purpose of estimating the relative reliability of the study measures.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY
  8. APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY

We studied 281 patients with SSc and RP at 14 academic centers between November 1995 and May 1996. Baseline clinical characteristics of the study subjects are summarized in Table 1. Patients had a mean age of 50.4 years (range 18–82 years) and were predominantly white (86.5%) and female (88.3%). They had experienced RP for a mean ± SD of 13.5 ± 10.2 years and been diagnosed as having SSc for a mean ± SD 8.5 ± 7.3 years. Limited cutaneous SSc was present in 48.0%, and diffuse cutaneous SSc was present in 52.0%. Fifty-nine patients (21.0%) had digital ulcers at baseline.

Table 1. Baseline characteristics of the 281 patients with systemic sclerosis (SSc)
CharacteristicResult
Age, mean ± SD years50.4 ± 11.6
Sex, % female88.3
Race/ethnicity, % 
 Caucasian86.5
 African American7.8
 Hispanic3.2
 Asian2.1
RP duration, mean ± SD years13.5 ± 10.2
SSc duration since diagnosis, mean ± SD years8.5 ± 7.3
Diffuse cutaneous SSc, %52.0
Limited cutaneous SSc, %48.0
Current smoker, %18.2
Digital ulcers, %21.0

The results of measurements of RP activity, functional status, and psychological well-being at baseline are summarized in Table 2. At baseline, study subjects experienced an average of 3.89 RP attacks per day (range 0.8–14.6), with a mean duration of 82.1 minutes per attack (range 1.6–667.2). The mean daily RCS was 4.30. Patients had appreciable functional disability and pain, with a mean overall HAQ disability score of 0.86 (range 0.0–2.6) and mean HAQ pain score of 1.19 (range 0.0–3.0).

Table 2. Outcome measures at baseline for all study patients and by digital ulcer status
MeasurementRangeMean ± SDDigital ulcers
PossibleObservedPresent (n = 59)Absent (n = 222)P
  • * RP = Raynaud's phenomenon; VAS = visual analog scale; AIMS2 = Arthritis Impact Measurement Scales 2; HAQ = health assessment questionnaire.

  • One of the 5 scales of the Scleroderma HAQ (SHAQ) developed by Steen and Medsger (13).

RP variables      
 Raynaud's Condition Score0–100.2–104.30 ± 1.925.034.100.0005
 RP attack frequency, no. per day0.8–14.63.89 ± 2.333.923.880.7087
 RP attack duration, minutes1.6–667.282.1 ± 91.684.481.50.8911
 SHAQ VAS for RP0.0–30.0–31.15 ± 0.871.531.050.0003
 Physician's assessment of RP (by VAS)0.0–30.0–31.36 ± 0.581.591.300.0015
 Patient's assessment of RP (by VAS)0.0–30.0–31.37 ± 0.621.611.310.0031
Digital ulcer variables      
 SHAQ VAS for digital ulcers0.0–30.0–30.75 ± 0.931.730.490.0001
 Physician's assessment of digital ulcers (by VAS)0.0–30.0–30.50 ± 0.711.290.290.0001
 Patient's assessment of digital ulcers (by VAS)0.0–30.0–30.79 ± 0.881.710.520.0001
Psychological scales      
 AIMS2 mood scale0.0–100.0–92.87 ± 1.693.172.800.1395
 AIMS2 tension scale0.0–100.0–94.30 ± 1.714.674.210.0712
Disability and global measures      
 HAQ disability scale0.0–30.0–2.60.86 ± 0.631.030.810.0183
 SHAQ VAS for overall disease0.0–30.0–31.17 ± 0.771.521.080.0002
 Physician's global assessment (by VAS)0.0–30.0–30.87 ± 0.571.040.820.0002
 Patient's global assessment (by VAS)0.0–30.0–30.96 ± 0.691.030.940.3963
Pain      
 HAQ pain scale0.0–30.0–31.19 ± 0.751.501.110.0009
Other areas      
 SHAQ VAS for intestinal disease0.0–30.0–2.80.53 ± 0.710.610.510.1185
 SHAQ VAS for breathing problems0.0–30.0–30.43 ± 0.650.390.440.2552
HAQ subscales      
 Grip0.0–30.0–31.38 ± 0.911.671.300.0051
 Activity0.0–30.0–30.97 ± 0.941.160.920.0730
 Eating0.0–30.0–30.97 ± 0.921.260.900.0268
 Dressing/grooming0.0–30.0–30.94 ± 0.801.310.850.0002
 Reach0.0–30.0–30.93 ± 0.951.110.880.1109
 Hygiene0.0–30.0–30.76 ± 1.020.890.730.2448
 Walking0.0–30.0–30.46 ± 0.710.440.460.7436
 Arising0.0–30.0–30.44 ± 0.630.390.460.3050

In this group of scleroderma patients who were selected specifically for RP activity and for whom severe pulmonary or gastrointestinal disease was an exclusion criterion, the scores on the SHAQ VAS scales measuring self-reported impact of disease manifestations demonstrated greater scores for RP and digital ulcer activity than for breathing or intestinal problems. More than one-third of the subjects scored zero at baseline on the impact of breathing (36%) and intestinal problems (34%). Study subjects demonstrated fairly high levels of depressed mood and tension on the AIMS2, with mean scores on both subscales similar to those reported for patients with rheumatoid arthritis or osteoarthritis (15).

The scores for HAQ subscales that pertain to activities that involve a substantial amount of hand function (grip, eating, dressing) were generally higher than the scores for subscales that involve less hand function (activity, hygiene, walking, reach, and arising). Grip scores were especially higher. Despite these higher scores for hand function–related subscales of the HAQ, there was no evidence that these subscales form a separate factor for these patients with SSc and RP. All 8 subscales loaded strongly on a first principal components factor that explained 54% of the variance (data not shown).

Many of the clinical outcome measures differed between patients with and patients without digital ulcers at baseline (Table 2). Although there was no significant difference in RP attack frequency or duration between these subgroups, the RCS for patients with digital ulcers was significantly higher than that for patients without digital ulcers (5.03 versus 4.10; P = 0.0005). The patient's and physician's assessments of disease activity for RP and digital ulcers were higher in subjects with digital ulcers. However, the activity of and limitation due to digital ulcers were noted even among the patients who had been classified by physicians as having no digital ulcers at baseline. While physicians rated the overall scleroderma disease activity in patients with digital ulcers significantly higher than that in patients without digital ulcers, the patient's global self-assessments in these two groups did not differ significantly. Scores for tension and mood as measured by AIMS2 scales were slightly, but not significantly, higher among patients with digital ulcers.

Rates of disability and pain as measured by the HAQ were significantly higher among patients with digital ulcers compared with those without digital ulcers (Table 2). Compared with patients without digital ulcers, patients with digital ulcers had significantly higher disability for those domains that involve direct hand use (grip, eating, and dressing) than for those domains that do not involve direct hand use (activity, reach, hygiene, walking, and arising).

Table 3 presents factor loadings from our factor analysis of the 18 measures at baseline. The first 4 factors together explained 67% of the variance. Varimax rotation identified a strong first factor that included the RCS and the patient's other overall measures of RP impact and activity. This factor also included the HAQ disability and pain scales, all global measures, and SHAQ VAS for breathing problems. This result indicates that each of these measures has strong intercorrelations and are measuring similar aspects of disease activity in patients with SSc and RP. All 3 variables relating to digital ulcer activity loaded together on a separate, second factor, while the RP attack frequency and duration, together with the physician's assessment of RP activity, were in a third factor, which also had some partial loading (0.45) of the RCS. The fourth factor had high loadings only for the two AIMS2 psychological measures.

Table 3. Factor structure of outcome measures at baseline*
MeasurementFactor 1Factor 2Factor 3Factor 4
  • *

    RP = Raynaud's phenomenon; VAS = visual analog scale; AIMS2 = Arthritis Impact Measurement Scales 2; HAQ = health assessment questionnaire.

  • Factor loadings >0.50 following varimax rotation.

  • One of the 5 scales of the Scleroderma HAQ (SHAQ) developed by Steen and Medsger (13).

RP variables    
 Raynaud's Condition Score0.620.310.450.12
 RP attack frequency0.120.070.800.17
 RP attack duration−0.04−0.010.790.04
 SHAQ VAS for RP0.740.350.150.20
 Physician's assessment of RP (by VAS)0.380.310.610.00
 Patient's assessment of RP (by VAS)0.670.360.370.01
Digital ulcer variables    
 SHAQ VAS for digital ulcers0.290.870.050.17
 Physician's assessment of digital ulcers (by VAS)0.120.860.140.05
 Patient's assessment of digital ulcers (by VAS)0.190.900.070.10
Psychological scales    
 AIMS mood scale0.240.060.100.83
 AIMS tension scale0.180.090.090.85
Disability and global measures    
 HAQ disability scale0.68−0.02−0.080.21
 SHAQ VAS for overall disease0.790.300.120.20
 Physician's global assessment (by VAS)0.520.190.170.16
 Patient's global assessment (by VAS)0.720.190.150.18
Pain    
 HAQ pain scale0.740.320.230.15
Other areas    
 SHAQ VAS for intestinal disease0.330.180.050.49
 SHAQ VAS for breathing problems0.67−0.14−0.150.22

These findings indicate that in these patients with SSc and RP, the RP, digital ulcer, and psychological measures are separable in terms of correlation, as well as conceptually. However, the patient's summary assessments of the frequency, duration, severity, and impact of RP attacks are strongly associated with measures of disability and overall impact and activity of the disease.

When only those patients with some indication of digital ulcer problems (163 patients with physician rating of digital ulcer severity >0) were included in the factor analysis, the same factor structure was obtained (data not shown), indicating that RP and digital ulcer activity are separable factors among individuals with SSc who experience both of these problems. We found that 35% of the residuals from the factor analysis shown in Table 3 exceeded 0.05 in absolute value. When a fifth factor was allowed, this percentage dropped to 28%. The sole effect of retaining and rotating this additional factor would have been to locate the physician's global assessment measure in a separate factor. We chose to keep the analysis limited to 4 factors.

Two hundred sixty-one patients (93%) remained in the study at 6 weeks and completed the followup assessments. One hundred forty-five of these patients (52%) received iloprost and 136 (48%) received placebo. There were no differences in RP measures between the iloprost and placebo groups (1). RP improved during the study period, with significant reductions in the mean frequency (−1.16 attacks per day, a 29.8% reduction) and duration (−29.8 minutes per attack, a 36.3% reduction) of RP attacks as well as in the RCS (−1.16 daily score, a 27.0% reduction). This improvement in RP was reflected in many of the other outcome measures as well (Table 4). These improvements occurred to a similar extent in both the placebo group and the treatment group (data not shown), and we present the results for the combined study cohort.

Table 4. Change in outcome measures between baseline and end of treatment
MeasurementMean ± SD change from baselineSRMES
  • * SRM = standardized response mean; ES = effect size; RP = Raynaud's phenomenon; VAS = visual analog scale; AIMS2 = Arthritis Impact Measurement Scales 2; HAQ = health assessment questionnaire.

  • One of the 5 scales of the Scleroderma HAQ (SHAQ) developed by Steen and Medsger (13).

RP variables   
 Raynaud's Condition Score1.16 ± 1.810.640.60
 RP attack frequency0.87 ± 1.680.520.37
 RP attack duration29.84 ± 74.160.400.33
 SHAQ VAS for RP0.40 ± 0.760.530.46
 Physician's assessment of RP (by VAS)0.44 ± 0.690.640.76
 Patient's assessment of RP (by VAS)0.40 ± 0.690.580.65
Digital ulcer variables   
 SHAQ VAS for digital ulcers0.14 ± 0.710.200.15
 Physician's assessment of digital ulcers (by VAS)0.13 ± 0.590.220.18
 Patient's assessment of digital ulcers (by VAS)0.17 ± 0.720.240.19
Psychological scales   
 AIMS2 mood scale0.33 ± 1.080.310.20
 AIMS2 tension scale0.34 ± 1.260.270.20
Disability and global measures   
 HAQ disability scale0.09 ± 0.350.260.14
 SHAQ VAS for overall disease0.23 ± 0.640.360.30
 Physician's global assessment (by VAS)0.11 ± 0.550.200.19
 Patient's global assessment (by VAS)0.09 ± 0.730.120.13
Pain   
 HAQ pain scale0.24 ± 0.680.350.32
Other areas   
 SHAQ VAS for intestinal disease0.04 ± 0.640.060.06
 SHAQ VAS for breathing problems0.00 ± 0.450.000.00
HAQ subscales   
 Grip0.10 ± 0.810.120.11
 Activity0.07 ± 0.640.100.07
 Eating0.18 ± 0.700.260.20
 Dressing/grooming0.16 ± 0.620.260.16
 Reach0.06 ± 0.700.090.06
 Hygiene0.01 ± 0.700.020.01
 Walking0.07 ± 0.550.130.10
 Arising0.07 ± 0.590.110.10

Table 4 also shows the effect sizes (standardized changes) and standardized response means (measuring relative sensitivity to change) for each measure. Moderate effect sizes (0.33–0.76) were seen for each of the RP-related variables: RCS, RP frequency, RP duration, patient's self-assessment of the impact of RP on daily activity, and both the physician's and the patient's assessments of overall RP activity. Pain (effect size 0.32) and overall VAS (effect size 0.30) had slightly smaller effect sizes, while the psychological scales both had a small effect size of 0.20, similar to the effect sizes for these measures in patients with rheumatoid arthritis (18). All other measures had smaller standardized changes. The improvement in the 3 hand function–related aspects of the HAQ tended to be slightly greater than for the other HAQ subscales. Negligible effect sizes (0.00 and 0.06, respectively) were seen for the patient's assessment of the impact of pulmonary and intestinal disease.

In most cases, standardized response means for the different measures in Table 4 were comparable to the corresponding effect sizes, indicating that changes were not notably easy or difficult to detect in relation to the size of the effect. An exception is the HAQ disability scale, in which changes, though small in this population, are relatively easy to detect, compared with changes in overall disease impact and activity measures obtained using a VAS.

We examined the associations between changes in digital ulcers and infarcts during the trial and the other measures (data not shown). There was a negative association between the number of new ulcers developing during the trial and the physician's assessment of improvement in digital ulcer activity (r = −0.187, P = 0.003), but no association with the patient's assessment of digital ulcer activity improvement over the same time period (r = 0.007, P = 0.929) or with the patient's assessment of improvement in activity limitation due to digital ulcers (r = −0.084, P = 0.191). However, the count of all new infarcts between baseline and end of trial was negatively associated with improvement over the same time period in the patient's assessment of limitation of activity due to digital ulcers (r = −0.129, P = 0.045).

We found clear differences between the 18 study measures with respect to relative consistency (reliability) during the stable posttrial period (Table 5). The 12 VAS measures, including the pain VAS from the HAQ, were the least reliable, with standard deviations of the difference falling between 15.0% and 25.3% of the baseline range. The RCS, RP attack frequency, and RP duration had values between 4.6% and 10.3% of the baseline range. The two psychological scales of the AIMS2 and the disability score of the HAQ had intermediate values, ranging between 11.7% and 14.7% of their baseline ranges.

Table 5. Relative reliability of the studied measures at the posttrial period*
MeasurementRange at baselineSD of differenceSD of difference/range, %
  • *

    SD of difference represents the standard deviation of the difference between week 2 and week 12 scores. RP = Raynaud's phenomenon; VAS = visual analog scale; AIMS2 = Arthritis Impact Measurement Scales 2; HAQ = health assessment questionnaire.

  • One of the 5 scales of the Scleroderma HAQ (SHAQ) developed by Steen and Medsger (13).

RP variables   
 Raynaud's Condition Score9.81.0110.3
 RP attack frequency13.80.977.0
 RP attack duration665.630.574.6
 SHAQ VAS for RP30.6321.0
 Physician's assessment of RP (by VAS)30.5919.7
 Patient's assessment of RP (by VAS)30.7023.3
Digital ulcer variables   
 SHAQ VAS for digital ulcers30.6120.3
 Physician's assessment of digital ulcers (by VAS)30.4816.0
 Patient's assessment of digital ulcers (by VAS)30.6321.0
Psychological scales   
 AIMS2 mood scale91.0511.7
 AIMS2 tension scale91.3214.7
Disability and global measures   
 HAQ disability scale2.60.3111.9
 SHAQ VAS for overall disease30.6120.3
 Physician's global assessment (by VAS)30.5618.7
 Patient's global assessment (by VAS)30.7625.3
Pain   
 HAQ pain scale30.6421.3
Other areas   
 SHAQ VAS for intestinal disease2.80.5620.0
 SHAQ VAS for breathing problems30.4515.0

The investigators' subjective opinions were that the RCS, HAQ, VAS (all 12), and AIMS2 subscales were all well-accepted by patients and physicians and were quite easy to administer and complete. The small size and portability of the RP diary contributed to its high acceptance and completion rate.

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY
  8. APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY

This study demonstrates that the Raynaud's Condition Score, the HAQ, and the mood and tension scales of the AIMS2 are reliable measures among patients with SSc and RP. It also shows that the RCS and other RP measures are quite sensitive to change, and that patients' assessments of pain and of the overall impact of disease also change, but slightly less so in the context of this short-term clinical trial. No gold standard for measuring RP disease activity currently exists. However, the construct, content, criterion, and discriminant validities of the RCS, HAQ, and the 12 VAS scales for RP in scleroderma are each supported by this study (22). Specifically, the substantial associations between these outcome measures and both the patient's and physician's assessments of RP disease activity, the sensitivity to change of these measures, their reliability, and their ability to discriminate between subjects with and without digital ulcers have all been demonstrated.

Our data support the concept that RP in SSc is a multidimensional construct and that a variety of outcome measures covering several domains of illness are necessary to study this complex clinical condition. These domains include the following: 1) RP activity, 2) digital ulcer activity, 3) functional disability and pain, and 4) psychological states, such as mood and tension. Valid and precise instruments assessing each of these domains are needed for the proper study of RP in SSc. We propose a core set of outcome measures for use in clinical trials of RP in SSc and when studying RP and SSc both cross-sectionally and longitudinally (Table 6). This core set includes the RCS, the patient's and physician's RP activity VAS measures, a digital ulcer/infarct measure, a measure of disability and pain (HAQ), and measures of psychological function (AIMS2). Measures of RP attack frequency and duration, while inherent in the collection of data for the RCS, are not proposed as primary outcome measures, but rather, as supplementary data. Similarly, a measure of overall SSc disease activity may be useful to investigators but is not of primary importance in a study of RP or digital ulcers.

Table 6. Proposed core set of outcome measures for studying RP in scleroderma*
Core areaSpecific measure
  • *

    RP = Raynaud's phenomenon; VAS = visual analog scale; HAQ = Health Assessment Questionnaire; AIMS2 = Arthritis Impact Measurement Scales 2.

  • Part of the Scleroderma HAQ (SHAQ) developed by Steen and Medsger (13).

Primary outcome measures 
 Patient's assessment of RP activityRaynaud's Condition Score
 Physician's assessment of RP activityPhysician's assessment of RP activity (by VAS)
 Patient's assessment of digital ulcer activitySHAQ Digital ulcer VAS
 PainHAQ pain VAS
 DisabilityHAQ disability VAS
 Psychological measuresAIMS mood and tension scales
Supplementary outcome measures 
 RP attack frequencyInherent in Raynaud's Condition Score
 RP attack durationInherent in Raynaud's Condition Score
 Overall scleroderma disease assessmentSHAQ Scleroderma disease VAS

The RCS is an integration of the impact and activity of RP and appears to be an excellent summary measure. The frequency and duration of RP attacks are conventional disease measurements, have obvious face validity, and correlate well with the RCS and global RP assessments. However, while the RCS correlates well with HAQ disability and pain, the frequency and duration of RP do not. The RCS has the advantage over the closed 0–10 scale of frequency and duration measures and good measurement properties that are not available to the open-ended, and often extremely skewed, duration and activity measures. That the RCS values, but not those of the RP frequency or RP duration, differ between patients with and without digital ulcers, exemplifies the additional dimension of disease captured by the RCS.

Our data indicate that problems due to digital ulcers constitute a separate area of concern that should be measured. Digital ulcers had a consistently negative impact on disability and pain in this study population. Furthermore, digital ulcers seemed to increase the patient's self-assessment of RP activity in a manner separate from the frequency and severity of RP attacks. However, the lack of consistency between the patient's and physician's assessments of change in digital ulcer symptoms and possible confusion between ulcers and infarcts on the part of patients or physicians suggests that measures in this area could be made more explicit and result in improved validity.

We also demonstrated that RP in SSc is associated with significant functional disability and discomfort, especially when digital ulcers are present. The HAQ scores for disability and pain in the study subjects were in the range reported for patients with rheumatoid arthritis (23) or systemic lupus erythematosus (24). These measures were even more severe among the subset of patients with SSc and RP who also had digital ulcers. The results from the HAQ subsections support conceptually (face validity) the use of the HAQ to evaluate SSc with RP. Subsections that focus on activities requiring substantial hand function, such as grip or eating, measured higher levels of disability among study subjects than subsections less involved with hand function, such as walking or arising. These results are consistent with findings in a trial of patients with diffuse cutaneous SSc in which hand dysfunction was the major contributor to overall HAQ disability (25).

The impact of RP on patients with scleroderma may be complicated by the degree of sclerodactyly and skin disease that is present. Previous studies have reported a significant correlation between disability, as measured by the HAQ, and both skin score and muscle strength in the hand (7, 13, 25). While HAQ scores partly reflect the impact of skin disease in scleroderma, the strong association between HAQ disability and RCS values suggests that some degree of disability among patients with scleroderma is secondary to their RP. Similarly, the significant differences in HAQ scores between patients with and patients without digital ulcers confirms that RP and digital ulcer activity contribute to disability in SSc.

Several of the VAS measures used in this study, including the HAQ pain VAS, are quite sensitive to change and have the great advantage of being simple to administer. However, they are clearly not as reliable as more detailed, multi-item measures. In addition, careful attention should be given to the exact wording of instructions when VAS measures are set up, so that they can be well-understood by patients, have the same meaning across studies, and hence, achieve greater reliability and transportability.

Psychological state is another domain of illness affected by RP and SSc. The patients' high scores on the AIMS2 mood (depression) and tension scales and the even higher scores among those with digital ulcers offer further support that psychological status should be measured when studying patients with RP and SSc regardless of the presence of digital ulcers.

Our study has some limitations. There were no physical examination or laboratory measurements of non-RP aspects of SSc to compare with the global assessments. Specifically, no modified Rodnan skin scoring, pulmonary function testing, or gastrointestinal function measurements were utilized in this study. However, the treatment trial in which the study subjects were enrolled was designed specifically to detect change in RP disease activity. The 6-week study period was too short for substantial improvement in skin, pulmonary, or gastrointestinal disease in SSc to be likely to occur, as demonstrated by our finding of little or no change in the SHAQ VAS scores for the patient's assessment of pulmonary and gastrointestinal symptoms.

We did not study any patients with primary RP, and our results are not generalizable to patients with RP that is not associated with SSc. While the RCS and the RP attack diary method of disease assessment may well be useful in measuring disease activity and impact among patients with primary RP, validation of these outcome measures in primary RP requires additional studies. Furthermore, this study specifically recruited patients with at least moderately active RP, and these results are not generalizable to all patients with SSc.

Our study has several strengths, including its prospective focus on multiple aspects of functional status in patients with RP and SSc, which allows both a fuller characterization of the health status of these patients and the elucidation of its multicomponent nature. The value of our findings is further increased by the large number of patients studied and the good quality of the data, both cross-sectional and longitudinal, gathered from 14 centers with specific expertise in the treatment of scleroderma.

This study demonstrates that the significant severity, disability, pain, and psychological impact of RP and digital ulcers in SSc can be measured by a small set of valid and reliable outcome measures. These outcome measures provide additional information beyond the quantitative metrics of RP attacks. The ability to detect clinically meaningful change in disease activity makes these measures particularly useful for inclusion in trials of new therapeutic agents for RP in SSc. Additionally, as treatments for RP and SSc become more efficacious, these outcome measures may be important tools for clinicians and patients alike. We propose that the core measures of RCS, the patient's and physician's VAS measure of RP activity, the patient's assessment of digital ulcers, the HAQ pain and disability scales, and the AIMS2 mood and tension scales should all be incorporated into future clinical studies of RP in scleroderma.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY
  8. APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY
  • 1
    Wigley FM, Korn JH, Csuka ME, Medsger TA Jr, Rothfield NF, Ellman M, et al. Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum 1998; 41: 6707.
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    Dziadzio M, Denton CP, Smith R, Howell K, Blann A, Bowers E, et al. Losartan therapy for Raynaud's phenomenon and scleroderma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial. Arthritis Rheum 1999; 42: 264655.
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    Merkel PA. Measurement of functional status, self-assessment, and psychological well-being in scleroderma. Curr Opin Rheumatol 1998; 10: 58994.
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    Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 1980; 23: 58190.
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    Steen VD, Medsger TA Jr. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum 1997; 40: 198491.
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    Meenan RF, Gertman PM, Mason JH. Measuring health status in arthritis: the Arthritis Impact Measurement Scales. Arthritis Rheum 1980; 23: 14652.
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    Meenan RF, Mason JH, Anderson JJ, Guccione AA, Kazis LE. AIMS2: the content and properties of a revised and expanded Arthritis Impact Measurement Scales health status questionnaire. Arthritis Rheum 1992; 35: 110.
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    Kazis LE, Anderson JJ, Meenan RF. Effect sizes for interpreting changes in health status. Med Care 1989; 27: S17889.
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    Hawley DJ, Wolfe F. Sensitivity to change of the health assessment questionnaire (HAQ) and other clinical and health status measures in rheumatoid arthritis: results of short-term clinical trials and observational studies versus long-term observational studies. Arthritis Care Res 1992; 5: 1306.
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    Tugwell P, Bombardier C. A methodologic framework for developing and selecting endpoints in clinical trials. J Rheumatol 1982; 9: 75862.
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APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY
  8. APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY

The Raynaud's phenomenon (RP) attack diary consisted of 14 pages (measuring 11 × 15 cm) on which patients recorded the duration (in minutes) of each RP attack, the number of times they were exposed to outdoor temperatures, and the Raynaud's Condition Score (RCS) each day for 14 days (Figure A). If more than 15 attacks of RP occurred in a given day, extra pages were used to record them.

thumbnail image

Figure A. Sample page of the Raynaud's phenomenon attack diary.

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Specific instructions for completing the RCS were printed on the facing page of the diary for each day. The instructions were as follows:“The Raynaud's Condition Score is your rating of how much difficulty you had with your Raynaud's TODAY. Consider how many attacks you had and how long they lasted. Consider how much pain, numbness, or other symptoms the Raynaud's caused in your fingers (including painful sores) and how much the Raynaud's ALONE affected the use of your hands today.”

APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. APPENDIX A: THE RAYNAUD'S PHENOMENON ATTACK DIARY
  8. APPENDIX B: OUTCOME MEASURES USED IN THIS STUDY

Patients completed the Health Assessment Questionnaire pain and disability scales (5, 6), the 5 scleroderma–specific visual analog scales (VAS) previously described by Steen and Medsger (13), and the mood and tension subscales of the Arthritis Impact Measurement Scales 2 (14, 15).

Both the patients and the physicians used 15–cm VAS scales (anchored at 0 = no disease activity and at 100 = very severe disease activity) to rate the severity of 3 disease features during the previous week: Raynaud's phenomenon (RP), digital ulcers, and global condition (Table A). Patients and physicians were instructed to place a mark on the scale to indicate the severity of the feature being assessed. The term “severity” was used to measure the extent of disease activity and associated disability or discomfort the patient experienced during the indicated time period.