Outcome measure
Primary outcome measure (number of trials)
Other outcome measures assessed (number of trials)
Frequency of attacks
Duration of attacks
Severity of attacks
1 [28]
RCS
1 [18]
Attack symptoms
Physician global assessment
1 [7]
Patient global assessment
1 [7]
Variable | All patients (n = 249) | Systemic sclerosis RP (N = 132) | Primary RP (N = 117) |
|---|---|---|---|
Patient assessment of RP on a VAS | 0.47 | 0.49 | 0.46 |
Physician assessment of RP on a VAS | 0.54 | 0.52 | 0.57 |
Attack symptoms: | 0.76 | 0.78 | 0.72 |
Pain during the attack of RP on a VAS | 0.78 | 0.79 | 0.76 |
Numbness during the attack of RP on a VAS | 0.77 | 0.81 | 0.70 |
Tingling during the attack of RP on a VAS | 0.77 | 0.76 | 0.79 |
Average attacks/day | 0.79 | 0.75 | 0.86 |
Duration of the attacks in minutes | 0.61 | 0.63 | 0.61 |
Raynaud’s condition score (RCS) | 0.70 | 0.74 | 0.65 |
Patient-Reported Outcomes
Patient-reported measures are typically captured using daily diary to reduce the day-to-day variability seen in RP. Data is collected daily using electronic diaries or paper and pencil on daily basis for 1 or 2 weeks. Electronic diaries have found to be reliable and valid when compared to paper diaries [4].
Raynaud’s Condition Score (RCS): RCS is a daily self-assessment, graded on a scale of 0–10 based on the patient’s perceived impact of the frequency, duration, and severity of their RP (Fig. 17.1). This measure was developed by investigator consensus on the eve of a large-scale trial and was felt to offer an omnibus measure of patient perception of the impact of environmental cold and its impact on daily activity and quality of life. This score is a subjective measure of the impact of RP and incorporates the daily frequency, duration, and severity and impact of RP attacks on a scale of 0–10. Validation of its utility as a measure of outcome was post facto [5]. The majority of studies using RCS average the daily values over 1–2 weeks. All diary methods are considered to suffer from poor adherence to patient-driven data collection and recall bias. Minimally important difference estimates have been reported for RCS and range from 14 to 15 points (0–100 scale) for improvement [6].
Fig. 17.1
Raynaud’s condition score
Frequency of attacks: The frequency of attacks is the mean number of attacks per day, typically averaged on a weekly or biweekly basis. Patients are typically asked to record the number of attacks they have daily in a diary. The average attack frequency from the first week is usually compared to the average number of attacks during the final week of the study.
Duration of attacks: The average duration of attacks is another patient-recorded outcome where daily averages are generally used to calculate weekly averages. Duration of attacks can often be difficult for patients to record since in some cases, their attacks can persist throughout the day whereas in other cases, attacks can last for only seconds. A severe attack may also be perceived as lasting longer by the patient based on the degree of discomfort.
Symptoms during an attack: These are assessed based on pain, tingling, numbness, and attack symptoms as defined below:
Pain: The degree of pain for each attack is recorded on a visual analog scale (VAS) or on a Likert scale and can be recorded on either a 0–10 or 0–100 scale.
Tingling: The tingling per attack is recorded on a visual analog scale (VAS) or on a Likert scale and can be recorded on either a 0–10 or 0–100 scale.
Numbness: The numbness per attack is recorded on a visual analog scale (VAS) or on a Likert scale and can be recorded on either a 0–10 or 0–100 scale.
Attack symptoms: Gladue et al. recently proposed taking the highest average value of pain, tingling, and numbness over the period of assessment and terming it as a single collective parameter (attack symptoms) as they had high correlation coefficients, 0.77–0.78 [3]. Currently, this awaits prospective validation in a trial of an active agent.
Patient visual analogue score: A patient VAS of global assessment of RP has been used in many trials; however depending on the trial it may include different parameters. In some cases, the patient VAS has been used to assess either RP disease activity and/or assess the severity of the RP, whereas other times the patient VAS has been used to assess the overall burden of RP, which also takes into account not only the severity of RP but also the interference with daily life, similar to the intent of the Raynaud Condition Score. Patient VAS can be recorded on a 0–10 or 0–100 scale. Patient VAS is associated with a high degree of variability both within patients and between patients (Table 17.2) and can be associated with recall bias.
Physician-Reported Outcomes
Physician VAS: The physician VAS of global assessment of RP has been utilized in many trials and can either assess the severity of RP disease severity focusing on the actual Raynaud’s attacks [7] or the overall burden of RP and influence on one’s daily activities [8]. Physician VAS can also be scored on a scale of 0–10 or 0–100. The physician VAS is a subjective assessment that assesses the change in RP for a given patient. It relies on the patient giving an accurate account of the change in their RP that can be reproducibly and consistently assessed by the physician. Data regarding intra- and inter-observer variability are lacking.
Variability of Individual Outcome Measures
Gladue et al. evaluated the placebo data from 249 patients pooled from three clinical trials in RP [3]. All trials used all six outcome measures (patient and physician VAS, attack symptoms, attack frequency, duration of RP attacks, and the RCS) and the percent improvement between the run-in period and the treatment week. Figure 17.2 shows the percent of patients with a given percent improvement in the outcome measure. As can be seen the placebo response rate is consistently high among individual outcome measures. This may relate to outcome measures used or inherent variability associated with RP. As an example, the placebo rate is the improvement in outcomes without any intervention, which can be influenced by lifestyle changes or weather or by the inherent effect of placebo for the syndrome. When the placebo rate is high it is difficult to detect improvement from an active therapeutic agent. In addition, no study to our knowledge excludes outliers in reported attack symptoms, which can dramatically affect the analysis. Use of a defined blinded placebo run-in to exclude “placebo responders” prior to randomization could be employed to assure a more consistent response during the subsequent comparison with active agent.
