Biomarker analysis from the phase 2b randomized placebo-controlled trial of riociguat in early diffuse cutaneous systemic sclerosis.

OBJECTIVE: To examine disease and target engagement biomarkers in the RISE-SSc trial of riociguat in early diffuse cutaneous systemic sclerosis and their potential to predict the response to treatment. METHODS: Patients were randomized to riociguat (n = 60) or placebo (n = 61) for 52 weeks. Skin biopsies and plasma/serum samples were obtained at baseline and week 14. Plasma cyclic guanosine monophosphate (cGMP) was assessed using radio-immunoassay. Alpha smooth muscle actin (αSMA) and skin thickness were determined by immunohistochemistry, mRNA markers of fibrosis by qRT-PCR in skin biopsies, and serum CXC motif chemokine ligand 4 (CXCL-4) and soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) by enzyme-linked immunosorbent assay. RESULTS: By week 14, cGMP increased by 94 ± 78% with riociguat and 10 ± 39% with placebo (p < 0.001, riociguat vs placebo). Serum sPECAM-1 and CXCL-4 decreased with riociguat vs placebo (p = 0.004 and p = 0.008, respectively). There were no differences in skin collagen markers between the 2 groups. Higher baseline serum sPECAM-1 or the detection of αSMA-positive cells in baseline skin biopsies were associated with a larger reduction of modified Rodnan skin score from baseline at week 52 with riociguat vs placebo (interaction P-values 0.004 and 0.02, respectively). CONCLUSION: Plasma cGMP increased with riociguat, suggesting engagement with the nitric oxide-soluble guanylate cyclase-cGMP pathway. Riociguat was associated with a significant reduction in sPECAM-1 (an angiogenic biomarker) vs placebo. Elevated sPECAM-1 and the presence of αSMA-positive skin cells may help to identify patients who could benefit from riociguat in terms of skin fibrosis. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02283762.

Progranulin, sICAM-1, and sVCAM-1 May Predict an Increased Risk for Ventricular Arrhythmias in Patients with Systemic Sclerosis.

In systemic sclerosis (SSc), fibrosis of the myocardium along with ongoing autoimmune inflammation can alter the electric function of the cardiac myocytes, which may increase the risk for ventricular arrhythmias and sudden cardiac death. We analyzed the electrocardiographic (ECG) variables describing ventricular repolarization such as QT interval, QT dispersion (QTd), T wave peak-to-end interval (Tpe), and arrhythmogeneity index (AIX) of 26 patients with SSc and 36 healthy controls. Furthermore, echocardiographic and laboratory parameters were examined, with a focus on inflammatory proteins like C-reactive ptotein (CRP), soluble intracellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), and progranulin (PGRN). The CRP, sICAM-1, and sVCAM-1 levels were positively correlated with the length of the QT interval. Although the serum PGRN levels were not increased in the SSc group compared to the controls, in SSc patients, the PGRN levels were positively correlated with the QT interval and the AIX. According to our results, we conclude that there may be a potential association between autoimmune inflammation and the risk for ventricular arrhythmias in patients with SSc. We emphasize that the measurement of laboratory parameters of inflammatory activity including CRP, PGRN, sVCAM-1, and sICAM-1 could be helpful in the prediction of sudden cardiac death in patients with SSc.

Natural Autoantibodies in Biologic-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients: Associations with Vascular Pathophysiology.

Cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAb) are involved in innate immunity, as well as autoimmunity, inflammation, and atherosclerosis. There have not been any studies assessing the effects of biologics on nAAbs in RA and AS, also in relation to vascular pathophysiology. Fifty-three anti-TNF-treated RA and AS patients were included in a 12-month follow-up study. Anti-citrate synthase (CS) and anti-topoisomerase I fragment 4 (TOPO-F4) IgM and IgG levels were determined by ELISA. Ultrasonography was performed to assess brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV). Other variables were also evaluated at baseline and 6 and 12 months after treatment initiation. Anti-TNF therapy improved FMD in RA and PWV in AS and stabilized ccIMT. TNF inhibition increased anti-CS IgM and IgG, and possibly also anti-TOPO-F4 IgG levels. Various correlation analyses revealed that nAAbs might be independently involved in autoimmunity as well as changes in inflammation and vascular pathology over time in biologic-treated patients (p < 0.05). We also found associations between anti-TOPO-F4 IgG and anti-Hsp60 IgG (p < 0.05). Baseline nAAb levels or nAAb level changes might determine changes in CRP, disease activity, FMD, PWV, and ccIMT over time (p < 0.05). The interplay between arthritis and inflammatory atherosclerosis, as well as the effects of anti-TNF biologics on these pathologies, might independently involve nAAbs.

Can we define difficult-to-treat systemic sclerosis?

INTRODUCTION: Systemic sclerosis (SSc) is a chronic autoimmune rheumatic disease characterized by microvascular alterations, immunopathology, and widespread fibrosis involving various organs. It is considered difficult to treat due to several reasons: complex pathogenesis, heterogeneity, late diagnosis, limited treatment options for certain organ manifestations, lack of personalized medicine. AREAS COVERED: This review presents the heterogeneity, survival and organ manifestations with their risk factors of systemic sclerosis and their current treatment options, while drawing attention to difficult-to-treat forms of the disease, based on literature indexed in PubMed. EXPERT OPINION: Despite recent advances in the management of SSc over the last decades, the disease presents significant morbidity and mortality. Although available treatment protocols brought significant advancements in terms of survival in SSc-associated interstitial lung disease and pulmonary arterial hypertension, less success has been achieved in the treatment of Raynaud's phenomenon and digital ulcers and the results are modest in case of heart, gastrointestinal, and renal manifestations. There are patients who do not respond to treatment and deteriorate even with adequate therapy. They can be considered difficult-to treat (D2T) cases. We have created a possible score system based on the individual organ manifestations and highlighted treatment options for the D2T SSc category.

Granulomatosis with polyangiitis or its mimic? A case report.

Differentiation between granulomatosis with polyangiitis (GPA) limited to the upper airways and cocaine-induced midline destructive lesion (CIMDL) may be particularly difficult because of their common histopathologic features and antineutrophil cytoplasmic antibody (ANCA) profiles. We herein present a case involving a young woman with an initial diagnosis of GPA based on upper and lower airway manifestations and constitutional symptoms, histopathologic evidence of granulomas, a positive cytoplasmic ANCA indirect immunofluorescent test result, and proteinase 3 positivity by enzyme-linked immunosorbent assay (ELISA). CIMDL was confirmed based on the appearance of a hard palate perforation, positivity for methylecgonine on urine toxicology, a positive perinuclear ANCA indirect immunofluorescent test result, and subsequent human neutrophil elastase (HNE) ANCA positivity by ELISA. Finally, based on the coexistence of CIMDL, constitutional symptoms, and lower airway manifestations, the diagnosis was modified to cocaine-induced GPA mimic. Urine toxicology for cocaine and HNE ELISA are indicated in young patients with GPA who develop limited airway disease to check for the presence of CIMDL and cocaine-/levamisole-induced ANCA-associated vasculitis. Continued abstinence from cocaine is the first-choice therapy for both CIMDL and cocaine-induced GPA mimic.

A novel way to evaluate autoantibody interference in samples with mixed antinuclear antibody patterns in the HEp-2 cell based indirect immunofluorescence assay and comparison of conventional microscopic and computer-aided pattern recognition.

BACKGROUND: A major challenge of the HEp-2 cell-based indirect immunofluorescence (IIF) assays is the correct identification of the individual anti-nuclear antibodies (ANAs) if more than one is present in a sample. We created artificial mixes by pooling two different samples with a single autoantibody in different titers. Comparison of the expected and observed patterns and titers clarifies the interference between the two tested ANAs. METHODS: Serum samples with a single homogeneous or speckled ANA pattern were serially diluted and mixed in 16 combinations, providing end-point titers of 1:5,120 to 1:80 for both patterns. These mixes were tested by a HEp-2 IIF assay and were evaluated by conventional evaluation, the EUROPattern (EPa) system and on-screen analysis. RESULTS: Homogeneous pattern can alter the identification of the speckled pattern much more than vice versa, but both has an interfering effect on the other. The effect of the interfering on the tested pattern was higher if the titer of the former one was higher. The pattern recognition efficacy of conventional and the on-screen evaluation was similar and superior compared to the EPa analysis. CONCLUSIONS: The application of artificial mixed samples can help the evaluation of the efficacy of manual and computer-aided ANA HEp-2 pattern recognition.

Untangling the relationship between smoking and systemic sclerosis: an analysis of the EUSTAR cohort.

OBJECTIVES: To untangle the association between smoking and systemic sclerosis (SSc). METHODS: In the European Scleroderma Trials and Research cohort, the autoantibody status was compared between ever-smokers and never-smokers. Time until disease progression was assessed using Kaplan-Meier curves. Cox models were built to investigate the influence of smoking over 15 years of follow-up. All analyses were performed for the total cohort and stratified for sex and for positivity of anti-centromere (ACA) and anti-topoisomerase antibodies (ATA). RESULTS: Overall, 12 314 patients were included in the study. Of these, 10 393 were women (84%), 4637 were ACA-positive (38%), 3919 were ATA-positive (32%) and 4271 (35%) were ever-smokers. In men, but not in women, smoking was associated with mortality (HR 1.63, 95% CI 1.23 to 2.16, p=0.001). Ever-smoking women were at higher risk for skin progression (HR 1.10, 95% CI 1.00 to 1.22, p=0.046) and for 'any organ progression' (HR 1.07, 95% CI 1.00 to 1.13, p=0.036). In women, 34% of never-smokers were ATA-positive compared with 21% of ever-smokers (p<0.001). In the group of ever-smokers, higher exposure rates, reflected by the number of pack-years (OR 0.98, 95% CI 0.97 to 0.99, p<0.001) and by smoking duration (OR 0.96, 95% CI 0.95 to 0.97, p<0.001), were associated with lower frequency of ATA. In ACA-positive patients, the risk of mortality (HR 1.29, 95% CI 1.02 to 1.63, p=0.033), cardiac involvement (HR 1.25, 95% CI 1.03 to 1.43, p=0.001), skin progression (HR 1.21, 95% CI 1.03 to 1.42, p=0.018) and 'any organ progression' (HR 1.14, 95% CI 1.05 to 1.24, p=0.002) was increased among smokers. In ATA-positive smoking patients, mortality (HR 1.40, 95% CI 1.10 to 1.78, p=0.006), skin progression (HR 1.19, 95% CI 1.03 to 1.37, p=0.020) digital ulcers (HR 1.17, 95% CI 1.02 to 1.34, p=0.029) and 'any organ progression' (HR 1.11, 95% CI 1.00 to 1.22, p=0.048) occurred more frequently. CONCLUSIONS: Our stratified analysis demonstrates that smoking is associated with an increased risk for mortality in male SSc patients but not in women. Strikingly, smoking is associated with lower prevalence of ATA positivity, in particular in women. In both ATA-positive and ACA-positive patients, smoking is a risk factor for mortality, skin progression and 'any organ progression'.

Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): open-label, long-term extension of a phase 2b, randomised, placebo-controlled trial.

BACKGROUND: The phase 2b Riociguat Safety and Efficacy in Patients with Diffuse Cutaneous Systemic Sclerosis (RISE-SSc) trial investigated riociguat versus placebo in early diffuse cutaneous systemic sclerosis. The long-term extension evaluated safety and exploratory treatment effects for an additional year. METHODS: Patients were enrolled to RISE-SSc between Jan 15, 2015, and Dec 8, 2016. Those who completed the 52-week, randomised, parallel-group, placebo-controlled, double-blind phase were eligible for the long-term extension. Patients originally assigned to riociguat continued therapy (riociguat-riociguat group). Those originally assigned to placebo were switched to riociguat (placebo-riociguat group), adjusted up to 2·5 mg three times daily in a 10-week, double-blind dose-adjustment phase, followed by an open-label phase. Statistical analyses were descriptive. Safety including adverse events and serious adverse events was assessed in the long-term safety analysis set (all patients randomly assigned and treated with study medication in the double-blind phase who continued study medication in the long-term extension). The RISE-SSc trial is registered with ClinicalTrials.gov, NCT02283762. FINDINGS: In total, 87 (72%) of 121 patients in the main RISE-SSc study entered the long-term extension (riociguat-riociguat, n=42; placebo-riociguat, n=45). 65 (75%) of 87 patients were women, 22 (25%) were men, and 62 (71%) were White. Overall, 82 (94%) of 87 patients in the long-term extension had an adverse event; most (66 [76%] of 87) were of mild to moderate severity, with no increase in pulmonary-related serious adverse events in patients with interstitial lung disease. INTERPRETATION: No new safety signals were observed with long-term riociguat in patients with early diffuse cutaneous systemic sclerosis. Study limitations include the absence of a comparator group in this open-label extension study. FUNDING: Bayer and Merck Sharp & Dohme.