Hypochromic red cells as a prognostic indicator of survival among patients with systemic sclerosis screened for pulmonary hypertension

BACKGROUND: Patients with systemic sclerosis (SSc) are frequently affected by iron deficiency, particularly those with pulmonary hypertension (PH). The first data indicate the prognostic importance of hypochromic red cells (% HRC) > 2% among patients with PH. Hence, the objective of our study was to investigate the prognostic value of % HRC in SSc patients screened for PH. METHODS: In this retrospective, single-center cohort study, SSc patients with a screening for PH were enrolled. Clinical characteristics and laboratory and pulmonary functional parameters associated with the prognosis of SSc were analyzed using uni- and multivariable analysis. RESULTS: From 280 SSc patients screened, 171 could be included in the analysis having available data of iron metabolism (81% female, 60 ± 13 years of age, 77% limited cutaneous SSc, 65 manifest PH, and 73 pulmonary fibrosis). The patients were followed for 2.4 ± 1.8 (median 2.4) years. HRC > 2% at baseline was significantly associated with worse survival in the uni- (p = 0.018) and multivariable (p = 0.031) analysis independent from the presence of PH or pulmonary parenchymal manifestations. The combination of HRC > 2% and low diffusion capacity for carbon monoxide (DLCO) ≤ 65% predicted was significantly associated with survival (p < 0.0001). CONCLUSION: This is the first study reporting that HRC > 2% is an independent prognostic predictor of mortality and can possibly be used as a biomarker among SSc patients. The combination of HRC > 2% and DLCO ≤ 65% predicted could serve in the risk stratification of SSc patients. Larger studies are required to confirm these findings

Right heart size and function significantly correlate in patients with pulmonary arterial hypertension – a cross-sectional study

Background: The objective of this study was to assess, whether right atrial (RA) and ventricular (RV) size is related to RV pump function at rest and during exercise in patients with pulmonary arterial hypertension (PAH). Methods: We included 54 patients with invasively diagnosed PAH that had been stable on targeted medication. All patients underwent clinical assessments including right heart catheterization and echocardiography at rest and during exercise. RV output reserve was defined as increase of cardiac index (CI) from rest to peak exercise (∆CIexercise). Patients were classified according to the median of RA and RV-area. RV pump function and further clinical parameters were compared between groups by student’s t-test. Uni- and multivariate Pearson correlation analyses were performed. Results: Patients with larger RA and/or RV-areas (above a median of 16 and 20cm2, respectively) showed significantly lower ∆CIexercise, higher mean pulmonary arterial pressure, pulmonary vascular resistance at rest and NT-proBNP levels. Furthermore, patients with higher RV-areas presented with a significantly lower RV stroke volume and pulmonary arterial compliance at peak exercise than patients with smaller RV-size. RV area was identified as the only independent predictor of RV output reserve. Conclusion: RV and RA areas represent valuable and easily accessible indicators of RV pump function at rest and during exercise. Cardiac output reserve should be considered as an important clinical parameter. Prospective studies are needed for further evaluation

Treatment of active lupus nephritis with the novel immunosuppressant 15-deoxyspergualin: an open-label dose escalation study

Introduction: As the immunosuppressive potency of 15-deoxyspergualin (DSG) has been shown in the therapy of renal transplant rejection and Wegener's granulomatosis, the intention of this study was to evaluate the safety of DSG in the therapy of lupus nephritis (LN). Methods: Patients with histologically proven active LN after prior treatment with at least one immunosuppressant were treated with 0.5 mg/kg normal body weight/day DSG, injected subcutaneously for 14 days, followed by a break of one week. These cycles were repeated to a maximum of 9 times. Doses of oral corticosteroids were gradually reduced to 7.5 mg/day or lower by cycle 4. Response was measured according to a predefined decision pattern. The dose of DSG was adjusted depending on the efficacy and side effects. Results: 21 patients were included in this phase-I/II study. After the first DSG injection, one patient was excluded from the study due to renal failure. 5 patients dropped out due to adverse events or serious adverse events including fever, leukopenia, oral candidiasis, herpes zoster or pneumonia. 11/20 patients achieved partial (4) or complete responses (7), 8 were judged as treatment failures and one patient was not assessable. 12 patients completed all 9 cycles; in those patients, proteinuria decreased from 5.88g/day to 3.37g/day (P = 0.028), Selena-SLEDAI decreased from 17.6 to 11.7. In 13/20 patients, proteinuria decreased by at least 50%; in 7 patients to less than 1g/day. Conclusions: Although the number of patients was small, we could demonstrate that DSG provides a tolerably safe treatment for LN. The improvement in proteinuria encourages larger controlled trials

The protective effect of tumor necrosis factor-alpha inhibitors in COVID-19 in patients with inflammatory rheumatic diseases compared to the general population: a comparison of two German registries

Objectives: To investigate, whether inflammatory rheumatic diseases (IRD) inpatients are at higher risk to develop a severe course of SARS-CoV-2 infections compared to the general population, data from the German COVID-19 registry for IRD patients and data from the Lean European Survey on SARS-CoV-2 (LEOSS) infected patients covering inpatients from the general population with SARS-CoV-2 infections were compared. Methods: 4310 (LEOSS registry) and 1139 cases (IRD registry) were collected in general. Data were matched for age and gender. From both registries, 732 matched inpatients (LEOSS registry: n = 366 and IRD registry: n = 366) were included for analyses in total. Results: Regarding the COVID-19 associated lethality, no significant difference between both registries was observed. Age > 65°years, chronic obstructive pulmonary disease, diabetes mellitus, rheumatoid arthritis, spondyloarthritis and the use of rituximab were associated with more severe courses of COVID-19. Female gender and the use of tumor necrosis factor-alpha inhibitors (TNF-I) were associated with a better outcome of COVID-19. Conclusion: Inflammatory rheumatic diseases (IRD) patients have the same risk factors for severe COVID-19 regarding comorbidities compared to the general population without any immune-mediated disease or immunomodulation. The use of rituximab was associated with an increased risk for severe COVID-19. On the other hand, the use of TNF-I was associated with less severe COVID-19 compared to the general population, which might indicate a protective effect of TNF-I against severe COVID-19 disease

Current Therapeutic Options in the Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of the joints. Untreated RA leads to a destruction of joints through the erosion of cartilage and bone. The loss of physical function is the consequence. Early treatment is important to control disease activity and to prevent joint destruction. Nowadays, different classes of drugs with different modes of action are available to control the inflammation and to achieve remission. In this review, we want to discuss differences and similarities of these different drugs

Reduction of Proinflammatory Effector Functions Through Remodeling of Fatty Acid Metabolism in CD8+ T Cells From Rheumatoid Arthritis Patients

Objective. Rheumatoid arthritis (RA) CD8+ T cells maintain their effector proinflammatory phenotype by changing their metabolism toward aerobic glycolysis. However, their massive energy and biosynthesis needs may require additional substrates other than glucose. Since systemic alterations in lipid metabolism have been reported in RA patients, we explored the role of fatty acid (FA) metabolism in CD8+ T cells to identify potential targets to curb their proinflammatory potential. Methods. The expression of FA metabolism–related genes was analyzed for total CD8+ T cells and CD8+ T cell subsets in the data of RA patients and healthy controls retrieved from the GEO database. Functional assays were performed using peripheral blood CD8+ T cells isolated from RA (n = 31), psoriatic arthritis (n = 26), and spondyloarthritis (n = 21) patients receiving different therapies (disease-modifying antirheumatic drugs, biologics, and JAK inhibitors) and from healthy controls (n = 14). We quantified the expression of FA transporters, lipid uptake, intracellular FA content, cytokine production, activation, proliferation, and capacity to inhibit tumor cell growth, either with or without FA metabolism inhibitors. Results. The CD8+ T cell gene expression profile of FA metabolism–related genes was significantly different between untreated RA patients and healthy controls. RA patients who had a good clinical response after 6 months of methotrexate therapy had significantly increased expression of FA metabolism–related genes. Cell surface expression of the FA transporters FA binding protein 4 (FABP4) and G protein–coupled receptor 84 (GPR84) and FA uptake were higher in effector and memory CD8+ T cells from RA patients compared to those from healthy controls. In vitro blockade of FA metabolism significantly impaired CD8+ T cell effector functions. Conclusion. RA CD8+ T cells present an altered FA metabolism, which could provide potential therapeutic targets to control their proinflammatory profile, particularly therapies directed against the transport and oxidation of free FA.Dr. Kraus’s work was supported by an Add-On Fellowship from the Joachim Herz Foundation. Dr. Lorenz’s work was supported by the Heidelberg Medical School. Dr. Souto-Carneiro’s work was supported by the German Research Foundation (grant SO 1402/1-1

Sex and anti-inflammatory treatment affect outcome of melanoma and non-small cell lung cancer patients with rheumatic immune-related adverse events

Background Rheumatic immune-related adverse events (R-irAEs) occur in 5–15% of patients receiving immune checkpoint inhibitors (ICI) and, unlike other irAEs, tend to be chronic. Herein, we investigate the factors influencing cancer and R-irAEs outcomes with particular focus on adverse effects of anti-inflammatory treatment.Methods In this prospective, multicenter, long-term, observational study, R-irAEs were comprehensively analyzed in patients with malignant melanoma (MM, n=50) and non-small cell lung cancer (NSCLC, n=41) receiving ICI therapy who were enrolled in the study between August 1, 2018, and December 11, 2022.Results After a median follow-up of 33 months, progressive disease or death occurred in 66.0% and 30.0% of MM and 63.4% and 39.0% of patients with NSCLC. Male sex (progression-free survival (PFS): p=0.013, and overall survival (OS): p=0.009), flare of a pre-existing condition (vs de novo R-irAE, PFS: p=0.010) and in trend maximum glucocorticoid (GC) doses &gt;10 mg and particularly ≥1 mg/kg prednisolone equivalent (sex-adjusted PFS: p=0.056, OS: p=0.051) were associated with worse cancer outcomes. Patients receiving disease-modifying antirheumatic drugs (DMARDs) showed significantly longer PFS (n=14, p=0.011) and OS (n=20, p=0.018). Effects of these variables on PFS and/or OS persisted in adjusted Cox regression models. Additionally, GC treatment negatively correlated with the time from diagnosis of malignancy and the latency from ICI start until R-irAE onset (all p&lt;0.05). R-irAE features and outcomes were independent of other baseline patient characteristics in both studied cancer entities.Conclusion Male sex, flare of pre-existing rheumatologic conditions and extensive GC treatment appeared to be linked with unfavorable cancer outcomes, while DMARD use had a favorable impact. These findings challenge the current dogma of restrictive DMARD use for R-irAE and thus may pave the way to better strategies and randomized controlled trials for the growing number of patients with R-irAE

Oxygenated hemoglobin as prognostic marker among patients with systemic sclerosis screened for pulmonary hypertension

Abstract Oxygenated hemoglobin (OxyHem) in arterial blood may reflect disease severity in patients with systemic sclerosis (SSc). The aim of this study was to analyze the predictive value of OxyHem in SSc patients screened for pulmonary hypertension (PH). OxyHem (g/dl) was measured by multiplying the concentration of hemoglobin with fractional oxygen saturation in arterialized capillary blood. Prognostic power was compared with known prognostic parameters in SSc using uni- and multivariable analysis. A total of 280 SSc patients were screened, 267 were included in the analysis. No signs of pulmonary vascular disease were found in 126 patients, while 141 patients presented with mean pulmonary arterial pressure ≥ 21 mmHg. Interstitial lung disease (ILD) was identified in 70 patients. Low OxyHem ≤ 12.5 g/dl at baseline was significantly associated with worse survival (P = 0.046). In the multivariable analysis presence of ILD, age ≥ 60 years and diffusion capacity for carbon monoxide (DLCO) ≤ 65% were negatively associated with survival. The combination of low DLCO and low OxyHem at baseline could predict PH at baseline (sensitivity 76.1%). This study detected for the first time OxyHem ≤ 12.5 g/dl as a prognostic predictor in SSc patients. Further studies are needed to confirm these results