The CRISTAL Index: Improving the assessment of new scleroderma treatments in clinical trials

Assessing treatments for limited cutaneous scleroderma

During 2020, SRUK, in partnership with the World Scleroderma Foundation, funded the CRISTAL Project led by Professor Dinesh Khanna of the University of Michigan (USA), and Dr Alain Lescoat of the University of Rennes (France).

This project was funded as part of a grant call on ‘outcome measures’. These are measurable changes in a patient that are monitored during clinical trials to allow clinicians to determine whether the treatment being tested is effective. The CRISTAL project set out to develop a set of outcome measures which could be used to assess the efficacy of treatments for the most common subset of systemic sclerosis - ‘limited cutaneous scleroderma’ (lcSSc). This is an unmet area of need within systemic sclerosis research.

Why are new outcome measures needed for limited SSc?

Limited systemic sclerosis is a debilitating condition affecting the skin on the lower limbs, hands, feet, neck and face along with the internal organs. It is the most common form of systemic sclerosis, accounting for around 70% of all cases. Despite this, there are fewer treatments being tested in patients with limited SSc than in those with diffuse SSc. This is because one of the most common outcome measures used to test the effectiveness of treatments in clinical trials is the modified Rodnan Skin Score (mRSS). Since those with lSSc have a lesser degree of skin involvement, the use of the mRSS is less effective in assessing whether a treatment is of clinical benefit in these patients.

This means that there is a pressing need for outcome measures that can be used to adequately assess the efficacy of treatments for lcSSc. To work in practice, outcome measures can be grouped together to give an ‘index’, which is a collection of multiple relevant measures which can all be assessed to indicate how effective a prospective treatment is. The CRISS index, which has had an impact in testing treatments for the diffuse form of the disease, is an example of this type of index.

The team in Michigan therefore aspire to create a similar index for lcSSc, by identifying and validating outcome measures that can be grouped together to effectively and comprehensively assess potential treatments.

The CRISTAL Project: What did the team identify?

Clinicians and patients can have very different views on an individual’s condition and what constitutes both an improvement or the worsening of symptoms. Because of this, the team wished to work in partnership with those living with lcSSc, as well as the clinical community, to establish a set of outcome measures which include included measures that are important to patients.

As such, Professor Khanna and Dr Lescoat sought to add to the areas they had identified through review of the scientific literature, by identifying measures that are of particular importance to patients. To this end, they carried out focus groups with people based in the United States. From these sessions, 15 symptoms were identified as being particularly troublesome for patients and were highlighted as potential candidate areas for outcome measures. Ten of these areas were systemic sclerosis specific, and included gastrointestinal involvement, calcinosis and Raynaud’s. The remaining five were more general domains, including symptoms such as fatigue and pain. This gave the team 15 initial candidate areas for outcome measures for lcSSc.

They then put the list of outcome measures gathered from patient focus groups, along with the techniques that would be used to measure them, to a team of international experts who were invited to rate these measures in terms of various factors including feasibility, reliability and validity.

Finally, the team held a two-day consensus meeting involving 11 clinical experts on lcSSc and three patient partners. Through this consensus meeting, 18 potential outcome measures were endorsed to be included in a future study into their validity and reliability, based on the real-life longitudinal data collected from lcSSc patients.

Potential outcomes

Dr Khanna and Dr Lescoat are now ready to validate the utility of the candidate outcome measures through an observational study. This will take significant strides towards the development of the CRISTAL index, which could generate considerable benefits for lcSSc patients in the coming years.

Firstly, the selection of patient-informed, consensus-based and data-driven outcome measures has the potential to lead to the design of trials with strong potential of achieving regulatory approval. This means that the development of the index could propel the advancement of effective drug treatments for lcSSc in the not-too-distant future, which might grant lcSSc patients better access to effective therapies that can manage their symptoms, thereby improving their health and quality of life. 

Furthermore, because the proposed candidate outcome measures have been selected through a consensus process which heavily involves patients as well as clinicians, individuals may also be more likely to receive access to treatments targeted at the symptoms of lcSSc that are particularly troublesome from the patient perspective. As a result, symptoms which may not be adequately alleviated by current treatment options might be better dealt with, and means that the experience of the patient is central from the earliest stages of the drug development process.

SRUK hopes that this research will lead to the successful development of the CRISTAL index in the coming years, and we are very excited to see how this might propel the development of effective treatments for people living with lcSSc in the near future.