Patient-Reported Outcomes in Scleroderma: Why it Matters

PROS AND PROMS

Patient-reported outcomes (PROs) are defined as “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else”. (1) PROs is an umbrella term that covers not only symptoms but also function, health-related quality of life (HRQL), satisfaction and so on. They capture patient experiences of disease that clinical assessments, blood tests, imaging (eg. CT scans and cardiac echocardiograms) and biopsies cannot. PROs have in fact become a central part of drug approvals as regulatory agencies including Health Canada, the US Food and Drugs Administration and the European Medicines Agency now require data not only on survival (and other measures of biological effectiveness) but on how patients “feel and function” when considering applications for new drug approvals.

Patient-reported outcomes measures (PROMs) are the questionnaires that measure PROs in a standardized way. PROMs are either generic, in that they can be used across various health conditions, or specific, in that they aim to capture aspects of disease that are particular to a certain condition.

GENERIC PROMS

The three most commonly used generic PROMs in scleroderma are patient global assessments, the Health Assessment Questionnaire (HAQ) and the Medical Trust Short-Form 36 (SF-36). The Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) is emerging as a novel generic PROM for scleroderma.

Patient Global Assessments of disease generally ask patients to rate their overall health over a given period of time (eg. past week, past month), for example using a 10 cm visual analogue scale or numerical rating scale ranging from 0 to 10 (Figure 1). Studies have shown that scleroderma patients often rate disease severity as worse compared to physician ratings, suggesting that patient ratings capture different, possibly more complex psychosocial factors that physicians do not take into account. (2) On the other hand, in a disease as heterogeneous as scleroderma, with some patients having predominantly skin, others gastrointestinal and others still respiratory symptoms, Patient Global Assessments lack granularity.

PROMS SPECIFIC FOR SCLERODERMA

As mentioned above, the HAQ is a generic measure of musculoskeletal function. To supplement the HAQ with scleroderma- specific content, Steen and Medsger proposed in 1997 to add 5 symptom scales asking patients to rate how much overall disease, Raynaud’s phenomenon, finger ulcers, breathing and gastrointestinal problems interfere with daily activities (Figure 2).(6) Higher scores represent worse symptoms. The addition of these symptom scales to the HAQ, which is commonly referred to as the Scleroderma-HAQ or S-HAQ, was an important first step towards developing scleroderma-specific PROs and capturing important information from the patient’s perspective. The extent of skin disease has traditionally been measured by the modified Rodnan skin score (mRSS), which is an assessment of skin thickness ranging from 0-3 in 17 areas of the body performed by a physician (range 0-51, with higher scores representing worse skin thickening). The mRSS is commonly used as a primary endpoint in clinical trials as it has been shown to predict internal organ involvement and mortality in scleroderma. However, it does not

capture the subjective experience of skin changes in scleroderma. The Scleroderma skin patient-reported outcome (SSPRO) was recently developed with the input of patients to capture the patients’ experiences of skin-related health changes in scleroderma.(7) It is an 18-item patient questionnaire that assesses 4 domains: physical effects, physical limitations imposed by skin tightness, emotional effects and social effects, with each item being graded from 0 to 6 (range 0-108, with higher scores representing worse assessments). The SSPRO has been shown to capture how a patient feels and functions (by correlating it with traditional PROMs). Interestingly, in one clinical trial, the SSPRO correlated only moderately with the mRSS, (8) indicating that there are likely additional factors beyond assessments of skin severity by physicians that shape the experience of SSc patients regarding their skin condition.

Raynaud’s phenomenon is highly variable and episodic. By its nature, it is one of the symptoms of scleroderma that is best measured by patient reports. In the past, many studies of treatments for Raynaud’s phenomenon used Raynaud’s Condition Score (Figure 3). Patients are asked to rate their Raynaud’s phenomenon from 0–10, taking into account the frequency, duration, pain, numbness, and impact of RP attacks on that day. An average can be taken when the questionnaire is rated on multiple days using a diary. However, several clinical trials of potent vasodilators such as tadalafil, selexipag and bosentan have not shown the expected beneficial results when using Raynaud’s Condition Score, while other PROs such as the HAQ showed improvement. This suggests that the single item Raynaud’s Condition Score does not capture the multifaceted experience of Raynaud’s phenomenon.

In recent years, there has been remarkable progress in better measuring Raynaud’s phenomenon. Extensive patient input was collected to develop a conceptual framework for capturing the lived experience of how scleroderma patients “feel and function” concerning their Raynaud’s (Figure 4).(9) From this, a novel scleroderma-specific measure of Raynaud’s phenomenon, the Assessment of Systemic sclerosis-associated RAynaud’s Phenomenon (ASRAP) questionnaire, was developed and recently published.(10) It consists of 10 items covering not only frequency and duration of attacks but also facets such as ‘emotional distress’, ‘exacerbating factors’, ‘self-management’ and ‘adaptation’. The ASRAP should provide a more nuanced measure of Raynaud’s phenomenon in scleroderma and provide a useful tool to test new treatments for this often debilitating problem.

Visible disfigurement especially of the face and hands is common in scleroderma and has been associated with body image dissatisfaction and social discomfort. Body image is inherently personal and PROs have been developed and tested in scleroderma. In particular, the Body Concealment Scale for Scleroderma (BCSS) was developed to capture the unique body image concerns of scleroderma patients (Table 1). (11)

Many other PROMs cover a broad range of scleroderma patient experiences including breathlessness, gastrointestinal symptoms and hand function (Table 2). Most of the measures are limited to a single organ and are not specific to scleroderma. The EULAR ScleroID is a novel, disease-specific, composite PROM that was designed to capture the global burden of disease (Figure 5). (12) It consists of 10 items including pain and fatigue. Each of the items is weighted and the final score ranges from 0 to 10, with higher scores indicating worse disease. It is a promising new tool to capture patient experience in future studies of scleroderma.

Although there has been tremendous progress in measuring PROs in scleroderma in the last 2 decades, the disease-specific instruments developed with extensive patient input, in particular the ASRAP and EUSTAR ScleroID, have yet to be used in clinical trials. Those studies are highly anticipated.

IMPORTANCE OF MEASURING PROS

PROs provide a unique opportunity to capture the personal experiences of scleroderma patients and add tremendous depth to our understanding of how they “feel and function”, above and beyond standard biomedical measures of disease. PROs are used to identify research priorities of relevance to patients, to advocate for health care resources and for regulatory drug approvals. Although more work on PROs in scleroderma remains, the advances of the last two decades have given a voice to scleroderma patients that can only get stronger with time.