Serum Cytokines as Biomarkers in Heart Failure with Preserved Ejection Fraction and Sleep Apnea: A Prospective Cohort Study.

Heart failure with preserved ejection fraction (HFpEF) and obstructive sleep apnea (OSA) frequently co-occur and this comorbidity represents a separate phenotype of HFpEF. While many research attempts are focused on biomarkers of HFpEF, currently, there is a lack of validated biomarkers of HFpEF and OSA. In this study, we aimed to evaluate prognostic significance of several serum cytokines in patients with HFpEF and OSA. The patients with HFpEF and OSA were recruited from the Sleep Apnea Center of Novosibirsk, Russian Federation and followed up for 12 months. The main analyzed outcomes were five-point major adverse cardiovascular events (MACE) and the 6-min walk test (6MWT). The analyzed cytokines were circulating IL-6, IL-10, and VEGF measured at baseline. We recruited 77 male patients with HFpEF and OSA, the data of 71 patients were available for analyses. Patients who developed MACE had four-fold elevated concentrations of serum IL-10. There was no association between baseline cytokine levels and longitudinal changes in 6MWT. Circulating IL-10 levels are positively associated with MACE in men with HFpEF and OSA and thus may be a potential prognostic biomarker in this subgroup of patients. These results should be confirmed in larger studies encompassing both males and females.

Pleiotropic Effects of Comarum palustre L. in Patients with Osteoarthritis and Diabetes Mellitus with High Comorbidity Burden: An Exploratory Study.

BACKGROUND: Patients with osteoarthritis (OA) and diabetes mellitus (DM) are at increased risk of polypharmacy. A potential approach to this group of patients could be the use of herbal treatments influencing multiple biological pathways and aiming simultaneously at both OA and related comorbid conditions. Comarum palustre L. is widely used in traditional medicine but there is a lack of studies evaluating its pleiotropic effects in OA and DM. PRIMARY STUDY OBJECTIVE: To investigate pleiotropic effects of Comarum palustre L. in patients with OA and diabetes mellitus (DM). METHODS: This was open-label, single-arm exploratory study on patients with knee OA and DM. SETTING: Single-center study. PARTICIPANTS: Fifteen adult patients (mean age 68.6 years, fourteen women, one man) with knee OA and DM. INTERVENTION: The patients received Comarum palustre L.tablets 500 mg twice daily for 28 days. PRIMARY OUTCOME MEASURE: Changes from baseline in Visual Analogue Scale (VAS) for Pain. RESULTS: At the end of treatment there were significant reductions in VAS pain (effect size (ES) 1.45, 95% confidence interval (CI) 0.61 to 2.3), OA symptoms (ES 1.1 95% CI (-1.9 to -0.29), and disability (ES -0.88 95% CI -1.66 to -0.09). Treatment with Comarum palustre L. resulted in decrease in total cholesterol (TC), cholesterol ratio, and an increase in HDL-C. There was decrease of circulating TNF-α concentrations, and increase in circulating IL-10 and adiponectin levels. CONCLUSION: Treatment with Comarum palustre L.is associated with pleiotropic effects in patients with OA and comorbid DM. These results provide a rationale for larger randomized controlled studies.

Tear cytokines as potential biomarkers in non-infectious uveitis: post hoc analysis of a randomised clinical trial.

PURPOSE: The study aimed to evaluate cytokines in tears as potential biomarkers in non-infectious uveitis. METHODS: Tear samples were obtained using Schirmer strips from 50 patients enrolled in a randomised controlled study of simvastatin in non-infectious uveitis and from a control group of 30 healthy participants. The concentrations of IL-6, IL-8, IL-10, and IFN-γ in tears were measured at the study's baseline and again after 8 weeks of treatment using commercial enzyme-linked immunosorbent assay kits. RESULTS: The concentrations of tears IL-6 and IL-10 were increased in patients with non-infectious uveitis in comparison with the healthy participants. Longer disease duration was associated with elevated levels of IL-6. The concentrations of the studied cytokines in tears did not correlate with the extent of eye inflammation at baseline. No link between the changes in cytokine levels and changes in clinical parameters during treatment was observed. Baseline IL-10 concentrations independently predicted the development of the clinical response to treatment at weeks 4 and 8. CONCLUSION: Although elevated in non-infectious uveitis patients, tear cytokine levels do not correlate with eye inflammation and are not sensitive to change after treatment. However, the level of IL-10 may be a predictive biomarker of response to the treatment of uveitis. TRIAL REGISTRATION: NCT04183387.

Fibrates as drugs with senolytic and autophagic activity for osteoarthritis therapy.

BACKGROUND: Ageing-related failure of homeostasis mechanisms contributes to articular cartilage degeneration and osteoarthritis (OA), for which disease-modifying treatments are not available. Our objective was to identify molecules to prevent OA by regulating chondrocyte senescence and autophagy. METHODS: Human chondrocytes with IL-6 induced senescence and autophagy suppression and SA-ß-gal as a reporter of senescence and LC3 as reporter of autophagic flux were used to screen the Prestwick Chemical Library of approved drugs. Preclinical cellular, tissue and blood from OA and blood from OA and ageing models were used to test the efficacy and relevance of activating PPARα related to cartilage degeneration. FINDINGS: Senotherapeutic molecules with pro-autophagic activity were identified. Fenofibrate (FN), a PPARα agonist used for dyslipidaemias in humans, reduced the number of senescent cells via apoptosis, increased autophagic flux, and protected against cartilage degradation. FN reduced both senescence and inflammation and increased autophagy in both ageing human and OA chondrocytes whereas PPARα knockdown conferred the opposite effect. Moreover, PPARα expression was reduced through both ageing and OA in mice and also in blood and cartilage from knees of OA patients. Remarkably, in a retrospective study, fibrate treatment improved OA clinical conditions in human patients from the Osteoarthritis Initiative (OAI) Cohort. INTERPRETATION: These results demonstrate that FDA-approved fibrate drugs targeting lipid metabolism protect against cartilage degeneration seen with ageing and OA. Thus, these drugs could have immediate clinically utility for age-related cartilage degeneration and OA treatment. FUND: This study was supported by Instituto de Salud Carlos III- Ministerio de Ciencia, Innovación y Universidades, Spain, Plan Estatal 2013-2016 and Fondo Europeo de Desarrollo Regional (FEDER), "Una manera de hacer Europa", PI14/01324 and PI17/02059, by Innopharma Pharmacogenomics platform applied to the validation of targets and discovery of drugs candidates to preclinical phases, Ministerio de Economía y Competitividad, by grants of the National Instiutes of Health to PDR (P01 AG043376 and U19 AG056278). We thank FOREUM Foundation for Research in Rheumatology for their support.

H1-antihistamines are associated with lower prevalence of radiographic knee osteoarthritis: a cross-sectional analysis of the Osteoarthritis Initiative data.

BACKGROUND: There is growing evidence that mast cells (MCs) play a role in knee osteoarthritis (OA). H1-antihistamines block H1-receptors of histamine, which is an important mediator of MCs. There is a lack of data on whether H1-antihistamines can influence OA. We hypothesized that the use of H1-antihistamines may be linked to the reduced prevalence of knee OA. METHODS: Baseline data from the Osteoarthritis Initiative cohort were analysed cross-sectionally. Unadjusted and adjusted logistic regression models were performed to compare the prevalence of knee OA in H1-antihistamine users and non-users. Generalized estimating equations were used to adjust for the correlation between knees. Knee OA was defined as (1) Kellgren-Lawrence (KL) grade ≥ 2 or total joint replacement or (2) KL grade ≥ 2 and joint space narrowing or total joint replacement. RESULTS: The analysed sample consisted of 8545 knees (664 knees of H1-antihistamine users and 7881 knees of H1-antihistamine non-users). The use of H1-antihistamines was associated with reduced prevalence of knee OA in unadjusted and adjusted models using both the first (adjusted OR, 0.77; 95% CI, 0.62, 0.96; P < 0.02) and second (adjusted OR, 0.75; 95% CI, 0.62, 0.93; P < 0.008) definitions of knee OA. CONCLUSIONS: H1-antihistamines are associated with a reduced prevalence of knee OA. The findings indicate that this class of drugs should be further evaluated for possible structure-modifying properties in knee OA.

Simvastatin as an Adjunct to Conventional Therapy of Non-infectious Uveitis: A Randomized, Open-Label Pilot Study.

PURPOSE: Statins have been shown to reduce ocular inflammation in animal models of uveitis and to prevent development of uveitis in observational studies. There have been no experimental human studies evaluating statins' efficacy and safety in uveitis. In this study, we aimed to investigate efficacy and safety of simvastatin in patients with uveitis. METHODS: For this single-center, open-label, randomized study, we enrolled patients with acute non-infectious uveitis. The patients were randomized to receive 40 mg simvastatin per day for 2 months in addition to conventional treatment or conventional treatment alone. The studied outcomes were the rate of steroid-sparing control of ocular inflammation, measures of ocular inflammation, intraocular pressure, and visual acuity. RESULTS: Fifty patients were enrolled in the study. Twenty-five patients were randomly assigned to receive simvastatin with conventional treatment and 25 to conventional treatment alone. Simvastatin was associated with significantly higher rates of steroid-sparing ocular inflammation control, decrease in anterior chamber inflammation, and improvement in visual acuity. The treatment was well tolerated, no serious adverse effects were observed. CONCLUSIONS: Our findings suggest that statins may have therapeutic potential in uveitis. These results need to be confirmed in double-blind, randomized, controlled studies.

Effects of medication-treated diabetes on incidence and progression of knee osteoarthritis: a longitudinal analysis of the Osteoarthritis Initiative data.

Diabetes has been proposed as a factor involved in the pathogenesis of osteoarthritis (OA). Currently, there is a lack of research evaluating the prospective impact of diabetes on OA structural outcomes. In this study, we assessed the effects of medication-treated diabetes on incidence and progression of knee OA. We analysed longitudinal data from the multi-center, longitudinal, prospective observational Osteoarthritis Initiative (OAI) study. The main outcomes were radiographic OA incidence (development of Kellgren-Lawrence grade 2 with joint space narrowing, JSN) and progression (increase in semiquantitative JSN or a new knee replacement). For the study of incidence, we selected participants with KL <2 or /KL = 2 without JSN at baseline (incidence sample). To evaluate progression, we selected participants with baseline JSN <3 (progression sample). We used generalized estimating equations (GEE) logistic regression with adjustment for potential confounders to evaluate the effects of medication-treated diabetes on knee OA incidence and progression. We studied 3725 knees (3498 non-diabetic and 228 diabetic) in the incidence sample and 3594 knees (3335 non-diabetic and 259 diabetic) in the progression sample. Medication-treated diabetes did not have an effect on knee OA incidence (odds ratio, OR 0.53, 95% confidence interval, CI 0.23-1.5). There was an independent association between medication-treated diabetes and reduced progression of knee OA [OR 0.66, 95% CI (0.44-0.98)]. Medication-treated diabetes has no effect on knee OA incidence but reduces knee OA progression. The role of diabetes and anti-diabetic drugs in knee OA progression needs further exploration.

Treatment of erosive osteoarthritis with peroxisome proliferator-activated receptor alpha agonist fenofibrate: a pilot study.

Hand osteoarthritis (HOA) is a common condition associated with high disease burden and frequently accompanied by comorbidities including dyslipidemia, atherosclerosis and obesity. The most debilitating HOA phenotype is erosive HOA (EHOA), characterized by synovial inflammation, formation of erosions, and substantial decline in hand function. Currently, there is no proven symptomatic treatment for the EHOA. Due to their broad spectrum effects directed on lipid metabolism, inflammation and pain, the agonists of peroxisome proliferator-activated receptor alpha or fibrates are a candidate class of drugs for the treatment of EHOA. In this study, we assessed the influence of fenofibrate treatment on clinical efficacy parameters, in vivo cytokine and adipokine production and concentrations of endothelial progenitor cells (EPC) in patients with EHOA. Fourteen patients received treatment with 145 mg of fenofibrate/day for 12 weeks. Fenofibrate treatment was associated with significant decreases in pain score, tender joint count, duration of morning stiffness, disease activity score, Cochin index, and ESR. Eight (57.14 %) patients developed Outcome Measures in Rheumatology Clinical Trials-Osteoarthritis Research Society response at the end of treatment. Paracetamol consumption did not change during the treatment course. There was a significant reduction in triglyceride levels. No changes were detected in serum pro-inflammatory cytokine and adipokine concentrations while circulating IL-10 levels significantly decreased. There were no differences in circulating EPC numbers before and after the treatment. Fenofibrate was well tolerated, no patient experienced disease flare during the treatment. In conclusion, in EHOA patients, fenofibrate is associated with pleiotropic effects on pain, inflammation, and lipid profile. Larger, controlled studies are needed to confirm these results.

The effects of fenofibrate on inflammation and cardiovascular markers in patients with active rheumatoid arthritis: a pilot study.

Peroxisome proliferator-activated receptors α (PPARα) agonists, or fibrates, are used in the treatment for dyslipidemia. Experimental data suggest that fibrates have anti-inflammatory properties, and PPARα is essential for the differentiation of endothelial progenitor cells (EPC) which diminished pool in rheumatoid arthritis (RA) contributes to accelerated atherosclerosis. The data on fibrates' effects in patients with RA are limited. The aim of this study was to investigate changes in disease activity, inflammatory markers, lipid profile, and circulating EPC in active RA patients treated with fenofibrate. Twenty-seven patients with active RA taking traditional disease-modifying antirheumatic drugs (DMARDs) were prescribed fenofibrate (145 mg/day) for 3 months. All patients received background traditional DMARDs in stable doses. The outcomes measured were clinical disease activity variables, circulating cytokines, adipokines, lipids, and EPC. Twenty-five patients completed the study. At the end of treatment, there was a significant reduction in DAS28, all individual DAS28 components except tender joint count, the duration of morning stiffness, and in the patient's assessment of disease activity. Fifteen (60 %) patients achieved good/moderate EULAR response, while 10 (40 %) patients satisfied ACR20 response criteria. Treatment with fenofibrate resulted in significant decrease in CRP and IL-6 concentrations and improvement in lipid profile. There was no change in the concentrations of circulating EPC. In conclusion, fenofibrate treatment is associated with reduced inflammation and improved lipid profile in RA patients. Large randomized controlled studies are needed to confirm these results and to define the role of fibrates in the treatment for RA.

Efficacy and safety of CH-1504, a metabolically stable antifolate, in patients with active rheumatoid arthritis: results of a phase II multicenter randomized study.

OBJECTIVE: To investigate the potential efficacy, safety, and tolerability of daily use of CH-1504 in patients with active rheumatoid arthritis (RA). US National Institutes of Health database no. NCT00658047. METHODS: In our phase II randomized double-blind double-dummy study, patients naive to methotrexate (MTX; n = 201) and having moderate to severe RA received either CH-1504 (0.25 mg, 0.5 mg, or 1.0 mg once-daily oral doses) or MTX (titrated to 20.0 mg once-weekly oral doses). All received weekly 10-mg folate supplementation. Efficacy and safety were assessed at 2, 4, 8, and 12 weeks, with a treatment-free followup at 16 weeks. Safety and tolerability were assessed. Primary efficacy endpoint was proportion of patients achieving ACR20 response at Week 12. Secondary endpoints included difference from baseline in the 28-joint Disease Activity Score (DAS28) and individual components of the American College of Rheumatology (ACR) composite index. RESULTS: Demographic characteristics were similar in all treatment groups: mean age 54.3 ± 11.4 years, female sex 87%, mean baseline DAS28 6.6 ± 0.9. At Week 12, CH-1504 demonstrated comparable efficacy compared to MTX as measured by ACR20, DAS28, and ACR composite core-set measures, including tender and swollen joints. No dose-response relationship was observed. Adverse events across treatment groups were mild. Liver enzyme levels increased from baseline to Week 16 in the MTX group, with qualitatively lesser increases in the CH-1504 groups. Two patients in the MTX group withdrew because of gastrointestinal-related adverse events. CH-1504 appeared safe and well tolerated at all dose levels. CONCLUSION: CH-1504 has comparable efficacy to MTX and is safe and well tolerated. Metabolically stable antifolates are a promising therapeutic option that warrants further study.

Targeting Nuclear Hormone Receptors: PPARα Agonists as Potential Disease-Modifying Drugs for Rheumatoid Arthritis.

In recent years, peroxisome proliferator-activated receptors (PPARs) have received growing interest due to the broad spectrum of their biological activities. PPARα, an isoform of PPAR, plays an important role in lipid homeostasis and inflammation, which makes it a potential target for the treatment of chronic inflammatory disorders, including RA. This paper reviews studies on the properties of PPARα agonists which may be pertinent to the treatment of RA. These properties include effects on lipid metabolism, inflammation, and angiogenesis, as well as interference with glucocorticoid effects, and a potential role in gender dimorphism of autoimmune disorders. However, current clinical experience with this class of drugs in RA is limited. New studies are needed to elucidate whether PPARα agonism may be an effective treatment strategy for RA patients.

High-Dose Immunosupression and Stem Cell Transplantation in Severe Autoimmune Diseases.

High-dose chemotherapy followed by hematopoietic stem cell (SC) transplantation has been recently proposed as a new strategy for the treatment of severe autoimmune diseases. The rationale for using stem cell transplantation to treat autoimmune disease is based on the principle of complete ablation of an aberrant immune system followed by reconstitution of a new immune system deriving from graft. Three different approaches are being currently used: 1) allogeneic SC transplantation, 2) autologous SC rescue following "immunoablation", and 3) intensive immunosuppression alone. By October 2000, a total of 310 patients who received SC transplantation for autoimmune diseases were registered in the European Group for Blood and Marrow Transplantation/European League Against Rheumatism. Five patients with primary severe autoimmune diseases (4 female and 1 male) were enrolled in our Institute from 1998 to 2000. Transplantations were made for systemic lupus erythematosus (SLE, n = 4) and idiopathic thrombocytopenic purpura (ITP, n = 1). Three SLE patients had lupus nephritis, lung vasculitis with pulmonary hypertension, secondary antiphospholipide syndrome, 1 SLE patient had central nervous system involvement with paraplegia, patient with ITP had a relapse after splenectomy and had unresponsive severe thrombocytopenia. Follow up is now 24 months for 1 SLE patient (she is in complete remission), 12 months for the 2nd SLE patient (partial response), ITP patient is well at present, platelets >100 x 10(9), dose of prednisolone is 10 mg/day. 2 SLE patients died on day +11 and +19 due to transplant-associated complications (sepsis). The study is still ongoing and longer follow-up is necessary to assess long-term efficacy of this treatment approach.

Social Stress Disorders and Immunity.

This article reviews recent developments in psychoneuroimmunology concerning the relationships between social-stress disorders and the immune system as well as their clinical consequences. In addition, studies exploring the impact of stress-reducing interventions on clinical course of some immunopathological conditions are presented. The analysis suggests that social stress disorders in different situations have the influence on the quantity and activity of immune cells and may lead to the shift of balance between proinflammatory and immunoregulatory cytokine secretion. However, the type and the size of these effects, their clinical implications in diseases with impaired immunity and the therapeutic benefit of interventions reducing stress remain uncertain and need further research.