Improvement of Severe Fatigue Following Nuclease Therapy in Patients With Primary Sjögren’s Syndrome: A Randomized Clinical Trial

Abstract

Objective. To assess the safety and efficacy of RSLV-132, an RNase Fc fusion protein, in a phase II randomized, double-blind, placebo-controlled clinical trial in patients with primary Sjögren's syndrome (SS). Methods. Thirty patients with primary SS were randomized to receive treatment with RSLV-132 or placebo intravenously once per week for 2 weeks, and then every 2 weeks for 12 weeks. Eight patients received placebo and 20 patients received RSLV-132 at a dose of 10 mg/kg. Clinical efficacy measures included the European League Against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Profile of Fatigue (ProF), and the Digit Symbol Substitution Test (DSST). Results. Patients randomized to receive RSLV-132 experienced clinically meaningful improvements in the ESSPRI score (P = 0.27), FACIT-F score (P = 0.05), ProF score (P = 0.07), and DSST (P = 0.02) from baseline to day 99, whereas patients who received placebo showed no changes in any of these clinical efficacy measures. This improvement was significantly correlated with increased expression of selected interferon-inducible genes (Pearson's correlations, each P < 0.05). Conclusion. Administration of RSLV-132 improved severe fatigue, as determined by 4 independent patientreported measures of fatigue, in patients with primary SS. Clinicaltrials.gov identifier: NCT03247686.

Revisiting the JOQUER trial: stratification of primary Sjögren’s syndrome and the clinical and interferon response to hydroxychloroquine

“…Our data is consistent with the recent reports that increased fatigue scores are associated with lower serum levels of proinflammatory cytokines [ 7 , 12 , 13 ], and that improvement in fatigue in response to a nuclease therapy was associated with an increase in IFN modular activity in pSS patients [ 14 ]. Taken together, our findings challenge the presumed mechanisms of action of HCQ [ 15 ] and prompt further investigations into the role of IFN activity in pSS pathobiology.…”

Understanding Fatigue in Sjögren’s Syndrome: Outcome Measures, Biomarkers and Possible Interventions

“…Hydroxychloroquine, DHEA, and rituximab failed to improve fatigue in controlled studies (35,37,38). The RSLV-132, an RNase Fc fusion protein, in a phase II study showed improvement of severe fatigue as determined by four independent patient-reported measures of fatigue (33). Ongoing clinical trials are testing new targets on fatigue in pSS, such as, Lanraplenib (GS-9876), Filgotinib (GS-6034), Tirabrutinib (GS-4059), CDZ173, and VIB4920 (Table 2).…”

“…There are many noncoding RNAs in human circulation that have inflammatory gene regulatory functions. It was hypothesized that a reduction of these circulating RNAs in patients with pSS might have a positive effect on symptoms such as fatigue and indeed, the study showed improvement of severe fatigue by four independent patientreported measures (33).…”

“…In a recent phase II double-blind placebo-controlled clinical trial pSS patients were randomized to treatment with RSLV-132 (n=20) or placebo (n=8) (33). RSLV-132 is a biologic drug containing active human RNase with an increased serum halflife compared to wild-type human RNase.…”

Development and Application of the Placebo Response Model in Clinical Trials for Primary Sjögren’s Syndrome

“…A total of 12 articles (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39) published between 2014 and 2020 that met the inclusion criteria were included in the analysis, containing a total of 450 subjects from 13 trials. The detailed literature screening process is shown in Figure 1.…”