ACR CRISS: A way forward for scleroderma treatment trials?



The phase 2b RISE-SSc study of riociguat

As in the focuSSced and ASSET studies, the primary efficacy endpoint of mean change from baseline in mRSS was not met in the randomized, double-blind, placebo-controlled RISE-SSc study evaluating the safety and efficacy of the soluble guanylate cyclase stimulator riociguat (Adempas) vs. placebo in 121 patients with early dcSSc, reported Oliver Distler, MD, a professor at University Hospital Zurich.

Dr. Oliver Distler of University Hospital Zurich

Dr. Oliver Distler

The mean change in mRSS at 52 weeks was 2.25 vs. 0.97 with riociguat vs. placebo, respectively (P = .08), although the difference in mRSS progression rate showed significant effects favoring riociguat (P = .02), he noted.

In this study, however, the proportion of patients with ACR CRISS probability of improvement (score of 0.60 or higher) at week 52 – a secondary study outcome – was the same at 18% in both arms, Dr. Distler said.

In a way, it’s helpful that the CRISS findings as well as the mRSS outcome in the RISE-SSc study were negative because it shows that “not everything comes up positive using the CRISS,” Dr. Spiera said.

An open-label extension trial of lenabasum

In the open-label extension of a phase 2 trial of lenabasum, Dr. Spiera and his colleagues also found the CRISS useful for assessing response in 36 patients. Lenabasum is a synthetic, nonimunosuppressive, selective cannabinoid receptor type 2 agonist that activates resolution of innate immune responses.

The agent continued to demonstrate acceptable safety and tolerability in dcSSc with no severe or serious adverse events or study discontinuations related to treatment during 12 months of open-label extension dosing, both from baseline and from the start of the extension, they reported in a poster at the ACR meeting. These assessments were based on ACR CRISS score, mRSS, physician global assessment, and multiple patient-reported outcomes.

The median CRISS score was 92% at week 52, and mRSS declined by a mean of 9.4 points (41.3% from baseline). More than a third of patients (35%) achieved a low mRSS of 10 or less.

The investigators noted, however, that definitive attribution of the findings to lenabasum is limited by the use of background therapy, the potential for spontaneous improvement in patients, and open-label dosing.

Evaluating immunosuppressive therapy in SSc

In another study presented at the ACR meeting, Boyang Zheng, MD, a second-year rheumatology fellow at McGill University in Montreal and his colleagues evaluated the effect of current immunosuppressive therapy on the ACR CRISS in 301 adult dcSSc patients without prior immunosuppression who were part of the Canadian Scleroderma Research Group (CSRG) registry.

Patients newly treated with methotrexate, azathioprine, mycophenolate and/or cyclophosphamide for at least 2 years (47 patients) were considered “exposed patients,” and untreated patients with at least the same follow-up duration were considered control subjects (254 patients).

Inverse probability of treatment weighting (IPTW) was performed to balance potential confounders in the two groups, including age, sex, disease duration, and CRISS variables, in an effort “to create a statistical cohort that would resemble a randomized, controlled trial,” Dr Zheng explained.

Prior to IPTW, treated patients trended towards more improvement after 1 year, but with “unimpressive absolute values.”

“But [after IPTW], when you look at overall CRISS at 1 year, more of the treated patients had actually improved – 23% vs. 11.8% in the untreated patients. After adjusting for age, sex, and disease duration, immunosuppression was associated with an almost twofold higher likelihood of improvement, although this was not statistically significant,” he said.

“Most importantly, after our balancing in the statistical cohort – so after balancing and adjusting for covariates ... immunosuppression use was still associated with a higher likelihood of improving [with an] odds ratio of 1.85 and P-value of 0.018,” he said.

The treated patients were sicker, and the CRISS was still able to capture individual patient improvement, he added.

Though limited by the observational design and the fact that “IPTW balancing cannot correct for all possible confounders,” the findings “provide novel evidence to support the use of immunosuppression in diffuse systemic sclerosis, and this reassures us in our current practice; it provides evidence that the CRISS seems to have better sensitivity to change than the mean of individual disease measures,” he said.

However, it also shows that “we have a long way to go to have better treatment for our patients,” he added, noting that only a minority (23%) of the patients in this study improved on the CRISS.


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