Silver, Richard M.

Objective Mycophenolate mofetil (MMF) can stabilize or improve lung function in systemic sclerosis–related interstitial lung disease (SSc‐ILD). We hypothesized that combining MMF with pirfenidone (PFD) would produce a significantly more rapid and/or greater improvement in lung function. Methods A randomized (1:1), double‐blind, placebo (PLA)‐controlled phase 2 trial was conducted in SSc‐ILD in which patients received PFD or PLA (801 mg three times daily) along with MMF (1,500 mg twice daily) for 18 months. The primary outcome was change in percent predicted forced vital capacity (FVC‐%). Linear mixed‐effects models assessed treatment differences in a modified intention‐to‐treat population. Results Only fifty‐one of 150 intended subjects (34%) were randomized (MMF+PLA, n = 24; MMF+PFD, n = 27). The FVC‐% improved from baseline to 18 months by 2.24 ± 1.35 (least‐squares mean [LSM] ± SEM) in the MMF+PLA group and 2.09 ± 1.28 in the MMF+PFD group (LSM treatment difference −0.14; P = 0.93). Median time to achieve a ≥3% improvement in FVC‐% was numerically faster in the MMF+PFD versus MMF+PLA group (12.3 vs 17.8 months, respectively), but the difference was not significant ( P = 0.33). For secondary outcomes, only the change over 18 months in the Patient‐Reported Outcomes Measurement Information System 29‐item physical function score, favoring MMF+PFD, reached statistical significance ( P = 0.04). Although other related patient‐reported outcomes (PROs) numerically favored the MMF+PFD group, as did quantitative high‐resolution computed tomography measures of ILD, the differences between groups did not reach statistical significance. Early withdrawals from study medication and adverse events of special interest were numerically greater with MMF+PFD (n = 8 vs 2 and n = 20 vs 7, respectively). Conclusion In this underpowered study, there was no statistically significant treatment difference in overall change in FVC‐% between groups. MMF+PFD was not as well tolerated as MMF+PLA.

Abstract Objectives To determine the efficacy, safety and pharmacodynamics of belumosudil in patients with diffuse cutaneous systemic sclerosis (dcSSc) treated with background immunosuppressive therapies. Methods Eligible patients were randomised 1:1:1 to receive belumosudil 200 mg once daily (QD) or twice daily (BID), or placebo for 28 weeks (double-blind period). After unblinding, the patients who received belumosudil continued the same dose, whereas the patients who received placebo were re-randomised for one of the belumosudil doses for 24 weeks (open-label extension). Results Thirty-five and 31 patients were treated in the double-blind and open-label periods, respectively. The study was terminated prematurely, and target enrolment was not met. The primary end point, of CRISS score ≥0.60 at week 24, did not exhibit an efficacy signal in the belumosudil vs placebo groups [odds ratio: 1.06 (0.19–5.82; P = 0.9472) for the QD, and 0.39 (0.07–2.35; P = 0.3078) for the BID group]. Belumosudil was well tolerated and exhibited similar safety profiles in both double-blind and open-label periods. Tissue-based RNA sequencing analysis revealed FOXP3 upregulation and STAT3, IL23A and TGF-β downregulation in patients with CRISS score ≥0.60, which supported the mechanism of action of belumosudil. In blood and tissue samples, trends of decreased fibrosis biomarker levels were seen in the belumosudil-treated group vs placebo. Conclusion Efficacy signal for belumosudil could not be detected. Signalling pathway modulation analysis supported the mechanism of action of belumosudil. A trend for decreased fibrosis-related biomarkers was observed in the belumosudil-treated group. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT03919799.

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R 2 for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.