A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

Lung Ultrasound in the Screening of Pulmonary Interstitial Involvement Secondary to Systemic Connective Tissue Disease: A Prospective Pilot Study Involving 180 Patients.

OBJECTIVES: The aim of the study was the assessment of lung ultrasound (LUS) as a screening of pulmonary interstitial involvement secondary to systemic connective tissue diseases. METHODS: A prospective study was conducted on the study group comprising 180 patients diagnosed with different systemic connective tissue diseases. Each patient underwent lung ultrasound (LUS), high-resolution chest computed tomography (HRCT), and echocardiography (ECHO). Each imaging examination was blinded and performed by an independent operator. LUS was conducted with convex and linear transducers. RESULTS: The sensitivity and specificity of LUS as compared to HRCT in detecting pulmonary interstitial involvement in the study group were 99.3% and 96.4%, respectively; positive predictive value (PPV) 0.7, negative predictive value (NPV) 3.6. Abnormalities indicating interstitial lung disease (ILD) with fibrosis were most frequently localized bilaterally in the lower fields of the lungs, assessed in the dorsal view. CONCLUSIONS: LUS is an efficient imaging modality that can detect pulmonary interstitial involvement in patients with systemic connective tissue disease with a high sensitivity and specificity. Further prospective studies conducted on a larger population are deemed necessary.

Clinical Impact of Vertical Artifacts Changing with Frequency in Lung Ultrasound.

BACKGROUND: This study concerns the application of lung ultrasound (LUS) for the evaluation of the significance of vertical artifact changes with frequency and pleural line abnormalities in differentiating pulmonary edema from pulmonary fibrosis. STUDY DESIGN AND METHODS: The study was designed as a diagnostic test. Having qualified patients for the study, an ultrasound examination was performed, consistent with a predetermined protocol, and employing convex and linear transducers. We investigated the possibility of B-line artifact conversion depending on the set frequency (2 MHz and 6 MHz), and examined pleural line abnormalities. RESULTS: The study group comprised 32 patients with interstitial lung disease (ILD) (and fibrosis) and 30 patients with pulmonary edema. In total, 1941 cineloops were obtained from both groups and analyzed. The employment of both types of transducers (linear and convex) was most effective (specificity 91%, specificity 97%, positive predictive value (PPV) 97%, negative predictive value (NPV) 91%, LR(+) 27,19, LR(-) 0.097, area under curve (AUC) = 0.936, p = 7 × 10-6). INTERPRETATION: The best accuracy in differentiating the etiology of B-line artifacts was obtained with the use of both types of transducers (linear and convex), complemented with the observation of the conversion of B-line artifacts to Z-line.

Metabolic Pattern of Systemic Sclerosis: Association of Changes in Plasma Concentrations of Amino Acid-Related Compounds With Disease Presentation.

OBJECTIVE: Amino acids (AA) and their derivatives play an integral role in the synthesis of structural and regulatory elements in human organisms and therefore pathologies such as systemic sclerosis that may alter the blood pattern of these compounds. This study aimed to evaluate changes in plasma concentrations of amino acid-related metabolites in systemic sclerosis in a search for potential biomarkers and mechanisms of the disease. METHODS: Plasma samples from 42 patients diagnosed with systemic sclerosis (SSc) according to the 2013 American College of Rheumatology and European League Against Rheumatism ACR/EULAR classification criteria were compared to 27 matched healthy controls. Liquid chromatography/mass spectrometry was applied for the analysis of 36 amino acid-related metabolites. RESULTS: The analysis of plasma AA metabolite patterns revealed the number of changes including an increase (20%) in concentrations of NO synthase (NOS) inhibitor asymmetric dimethylarginine (ADMA) in SSc vs. healthy subjects. Furthermore, SSc patients had higher glutamine, proline, betaine, 1-methylhistidine, and methylnicotinamide levels, while the concentration of tryptophan was lower. The specific metabolic pattern was identified for several aspects of disease presentation. Most interestingly NOS inhibitor L-NAME was elevated in patients with diffuse systemic sclerosis or telangiectasia. CONCLUSIONS: These results provide further evidence for the involvement of endothelium-dependent pathways in the mechanisms and presentation of SSc. Endothelial dysfunction biomarkers may be useful in the assessment of presentation and prognosis in SSc.

Prevalence of malnutrition in systemic sclerosis patients assessed by different diagnostic tools.

Gastrointestinal complaints of scleroderma (SS) patients are risk factors for impaired nutritional status, so insightful assessment is necessary. The aim was comparison of malnutrition rates in SS patients using different tools. Nutritional status was assessed using 7-SGA and SNAQ in 56 patients (47F, 9M) with SS. Anthropometric measurements and analysis of body composition were done. Serum levels of CRP, albumin, and hemoglobin were determined. Retrospectively, in 2018, diagnosis of malnutrition was verified using ESPEN 2015 and GLIM 2018 criteria. Gastrointestinal complaints were present in 76.8% of respondents. BMI < 18.5 was found in only 5.4% subjects. However, the percentage of patients with impaired nutritional status was higher and varied, depending on the tools used: 16.1% in SNAQ, 17.9% according to ESPEN 2015, 23.2% in 7-SGA, and as high as 62.5% when GLIM criteria were used. A significant part of patients with SS is malnourished. Screening for malnutrition should be focused on the percentage of unintentional weight loss, presence of gastrointestinal symptoms, and analysis of body composition. The choice of diagnostic tool appropriate for patients with SS will enable starting on-time nutritional intervention.Key Points:• Gastrointestinal involvement causes a significant proportion of patients to be malnourished.• It is important to look for early signs of malnutrition in patients with SS.• Assessment of nutritional status by adequate tools enables starting on-time nutritional intervention and improving prognosis in SS patients.

[Macrophage activation syndrome: report on three cases]. / Zespól aktywacji makrofagów--opis trzech przypadków.

The macrophage activation syndrome (MAS) is a rare and potentially fatal disease. This syndrome is founded on congenital or acquired dysfunction of NK cells resulting in secondary activation and proliferation of macrophages with excessive cytokine production and organ infiltration. Causes of acquired MAS include viral infections (chiefly EBV and CMV), malignancies, and autoimmune diseases. The macrophage activation syndrome is usually associated with juvenile idiopathic arthritis and adult-onset Still's disease and rarely with rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, and systemic sclerosis. Fever, hepatosplenomegaly, lymphadenopathy, and bi- or pancytopenia in peripheral blood represent typical symptoms of MAS. Hyperferritinemia, hypertriglyceridemia, hypertransaminasemia, and hypofibrinogenemia are among the common laboratory findings. The macrophage activation syndrome is a life-threatening condition requiring aggressive therapy due to multiple organ dysfunction. Treatment also includes elimination of the triggering infection and high-dose glucocorticosteroids. Second-line therapy is based on cyclosporin, intravenous immunoglobulins, and etoposide. The present work focuses on diagnostic and therapeutic difficulties in three patients with the macrophage activation syndrome.