Vitamin D Status in Patients with Primary Antiphospholipid Syndrome (PAPS): A Systematic Review and Meta-Analysis.

Primary antiphospholipid syndrome (PAPS) is a systemic autoimmune disorder, characterised by consistently high levels of antiphospholipid antibodies, thrombosis, and/or pregnancy morbidity. Due to various suspected causes, deficient or insufficient levels of vitamin D in the serum have been reported in patients with PAPS; however, the reports have been sporadic and inconclusive. This systematic review and meta-analysis aimed to comprehensively evaluate the serum vitamin D levels in patients with PAPS compared to controls. A protocol was registered in PROSPERO (Registration No. CRD42019132128) and a systematic literature search was conducted through Google Scholar, PubMed, Web of Science, Scopus, and ScienceDirect databases without restricting language and year. Pooled prevalence, mean difference (MD), and odds ratio (OR) along with 95% confidence intervals (CI) were determined by using a random effects model. Study quality was assessed by the Joana Brigg's Institute (JBI) protocol and publication bias was evaluated by a trim and fill funnel plot, Begg's, and Egger's tests. The pooled prevalence of vitamin D deficiency and insufficiency was found to be 32.2% [95% CI: 16.3-48.2] and 61.5% [95% CI: 40.2-82.8], respectively. Serum levels of vitamin D were considerably lower in the PAPS patients compared to controls (MD: -5.75, 95% CI: -9.73 to -1.77; p = 0.005). Multiple sensitivity analyses showed that the results remained statistically significant, demonstrating the robustness of this meta-analysis. No significant publication bias was detected in determining the MD of serum vitamin D levels in PAPS and controls. In conclusion, PAPS patients had greater rates of vitamin D deficiency or insufficiency, higher frequency of thrombosis, and lower serum vitamin D levels than healthy individuals.

Novel Therapeutic Strategies in the Treatment of Systemic Sclerosis.

Systemic sclerosis is a connective tissue disease of unknown origin and with an unpredictable course, with both cutaneous and internal organ manifestations. Despite the enormous progress in rheumatology and clinical immunology, the background of this disease is largely unknown, and no specific therapy exists. The therapeutic approach aims to treat and preserve the function of internal organs, and this approach is commonly referred to as organ-based treatment. However, in modern times, data from other branches of medicine may offer insight into how to treat disease-related complications, making it possible to find new drugs to treat this disease. In this review, we present therapeutic options aiming to stop the progression of fibrotic processes, restore the aberrant immune response, stop improper signalling from proinflammatory cytokines, and halt the production of disease-related autoantibodies.

Immunopathogenesis and Novel Therapeutics Strategies of Systemic Lupus Erythematosus.

Systemic lupus erythematosus is a chronic connective tissue disease of unknown origin and unpredictable course [...].

Psychological Implications to the Therapy of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic and multi-systemic autoimmune disease, which has a deleterious impact on patients' psychological well-being. This paper aims to review the existing literature on empirical research on psychological outcomes of SLE and psychological interventions to improve well-being in SLE patients. A search of significant English language articles was conducted in PubMed, Medline, ScienceDirect, Scopus, and ResearchGate databases. Titles and abstracts were screened for the relevant terms, including "systemic lupus erythematosus", "childhood-onset systemic lupus erythematosus", "juvenile systemic lupus erythematosus", "lupus nephritis", and their respective synonyms along with "depression", "anxiety", "fatigue", "medical adherence", "health-related quality of life", "self-management" or "intervention". The articles were evaluated by independent reviewers and the lists of eligible publications were compared whilst disagreements were settled by discussion. Of the 59 publications sought for retrieval, 35 papers were shortlisted based on predefined inclusion/exclusion criteria. They were classified according to their content and the methodology applied. Research topics including "anxiety and depression in SLE" and "self-management interventions for SLE patients" were identified and are presented in this review. As the prognosis and life expectancy of SLE patients are improving, further research on the psychological outcomes of SLE and the evidence-based psychological interventions to improve patients' well-being are justified.

The Prevalence of Anticitrullinated Protein Antibodies in Older Poles-Results from a Population-Based PolSenior Study.

Little is known about the occurrence of antibodies in older subjects. We analyzed the prevalence of anticitrullinated protein antibodies (anti-CCP) in a representative cohort of Polish older adults, participants of PolSenior substudy. Randomly selected 1537 serum samples of community-dwelling participants aged 65 and over. Questionnaires were completed by qualified interviewers and laboratory assessments served as a database for this analysis. The frequency of anti-CCP seropositivity (N = 50) was estimated at 3.25% (95% CI: 2.45-4.30%), being higher among women-4.05% (2.83-5.73%) than men-2.41% (1.48-3.86%). The frequency of anti-CCP seropositivity was decreasing with age from 4.29% in aged 65-74 years and 4.07% in 70-84 years to 1.50% in aged 85 years or above (p < 0.05). Hypoalbuminemia, inflammatory status (C-reactive protein >10 mg/dL or interleukin-6 ≥10 pg/mL), and female gender were associated with increased, while age ≥85 years with decreased risk of seropositivity. Multivariable logistic regression revealed that hypoalbuminemia, inflammatory status, and age ≥85 years were independently associated factors of anti-CCP seropositivity. The decreased frequency of anti-CCP seropositivity in the oldest old suggests shorter survival of the seropositive individuals who developed rheumatoid arthritis. It seems that low symptomatic RA remains frequently undiagnosed in older subjects.

Plasma and Urine Levels of Glycosaminoglycans in Patients with Systemic Sclerosis and Their Relationship to Selected Interleukins and Marker of Early Kidney Injury.

Systemic sclerosis (SSc) is a chronic connective tissue disease characterized by immune system dysfunction, vasculopathy, and progressive fibrosis of the skin and internal organs, resulting from excessive accumulation of extracellular matrix (ECM) elements, including collagen and proteoglycans (PGs). An uncontrolled PG proliferation, caused by disturbances in their metabolism in tissues, is most likely reflected in the quantitative changes of their components, i.e., glycosaminoglycans (GAGs), in body fluids. Therefore, the aim of this study was to quantify the different types of GAGs in the blood and urine of systemic sclerosis patients. Chondroitin/dermatan sulfates (CS/DS) and heparan sulfates/heparin (HS/H) were quantified by hexuronic acid assay and electrophoretic fractionation, while hyaluronic acid (HA) and keratan sulfates were evaluated using ELISA tests. In turn, individual urinary GAGs were determined using the Blyscan™ Sulfated Glycosaminoglycan Assay Kit. Our results showed that the plasma concentrations of CS/DS, HS/H, HA, and KS in systemic sclerosis patients were significantly higher compared with those in healthy subjects. In the case of urine measurements, we have found that in SSc patients, CS/DC concentrations were significantly higher, while HA concentrations were significantly lower compared with the values observed in the urine of healthy subjects. Importantly, the found by us correlations between plasma keratan sulfate levels and both the duration of the disease and the severity of skin lesions, as expressed by the Rodnan scale, seems to suggest this GAG as a potential marker in assessing disease progression and activity. In addition, a level of urinary excretion of all types of GAGs due to their high positive correlation with uACR, may be a valuable complementary test in the diagnosis of early renal dysfunction in the course of SSc.

Understanding Ocular Findings and Manifestations of Systemic Lupus Erythematosus: Update Review of the Literature.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease. Up to one-third of patients suffering from SLE have various ocular manifestations. The ocular findings may represent the initial manifestation of the systemic disease and may lead to severe ocular complications, and even loss of vision. Ocular manifestations are often associated with degree of systemic inflammation, but also can precede the occurrence of systemic symptoms. Early diagnosis and adequate management of patients with SLE are crucial and require cooperation between various specialists. Proper preparation of ophthalmologists can help to differentiate between complication of SLE and other ocular disorders. New therapies for SLE are promising for potential benefits, however, ocular side effects are still unknown.

Jak Inhibitors for Treatment of Autoimmune Diseases: Lessons from Systemic Sclerosis and Systemic Lupus Erythematosus.

Systemic sclerosis and systemic lupus erythematosus represent two distinct autoimmune diseases belonging to the group of connective tissue disorders. Despite the great progress in the basic science, this progress has not been translated to the development of novel therapeutic approaches that can radically change the face of these diseases. The discovery of JAK kinases, which are tyrosine kinases coupled with cytokine receptors, may open a new chapter in the treatment of so far untreatable diseases. Small synthetic compounds that can block Janus kinases and interact directly with cytokine signalling may provide therapeutic potential in these diseases. In this review, we discuss the therapeutic potential of Jak kinases in light of the cytokine network that JAK kinases are able to interact with. We also provide the theoretical background for the rationale of blocking cytokines with specific JAK inhibitors.

Adhesion molecules: a way to understand lupus.

Systemic lupus erythematosus is a connective disease in which all vitally important organs may be affected. The etiology of the disease is largely unknown and almost all immunological mechanisms have been proposed as the pathophysiological background of the disease. Among them, endothelial damage and dysfunction seem to play a pivotal role. Endothelial damage can be accurately measured using adhesion molecules such asintercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), platelet endothelial cell adhesion molecule (PECAM) and selectins. In this review we discuss the role of well-known cellular adhesion molecules as pathogenic factors in disease development as well as disease activity biomarkers.

Differential Impact of Biologic Therapy on Heart Function Biomarkers in Rheumatoid Arthritis Patients: Observational Study on Etanercept, Adalimumab, and Tocilizumab.

BACKGROUND: Rheumatoid arthritis (RA) represents the most frequent form of inflammatory arthritis, affecting approximately 1% of the population worldwide. The introduction of novel therapeutic strategies targeting proinflammatory cytokines (TNF-α and interleukin-6) revolutionized the treatment of RA. This kind of treatment, although effective in a substantial portion of patients, may potentially cause many side effects. Among them, cardiovascular safety is one of the main concerns. OBJECTIVES: In the present study, we investigated the impact of treatment with anti-TNF-α and anti-IL-6 agents on heart function and levels of heart function biomarkers. METHODS: To measure this, we used cardiac function biomarkers, such as NT-pro Brain Natriuretic Peptide, mid regional pro-Atrial Natriuretic Peptide, Galectin-3, and Heart-Type Fatty Acid-Binding Protein and compared them to patients treated with methotrexate as well as healthy controls. RESULTS: Patients treated with biologics were characterized by low disease activity or were in remission. The disease activity in these groups was significantly lower than in the methotrexate group. All patients recruited for the study were characterized by normal heart function measured using echocardiography (EF>50%). With the exception of MR-proANP between tocilizumab and adalimumab (median: 1.01 vs. 0.49 nmol/L, p<0.05), we failed to observe any significant differences in biomarkers levels between groups treated with biologics. Contrary to this, patients on MTX showed higher NT-proBNP levels compared to adalimumab and healthy controls (p<0.05 for both). Striking differences have been shown in regard to H-FABP. The levels of these biomarkers were elevated in all biologics and the methotrexate group compared to healthy controls. CONCLUSION: As this biomarker reflects potential heart injury, we suggest that heart damage proceeds in a continuous manner in RA patients despite effective treatment and attainment of remission/low disease activity. This finding, however, should be verified in a larger cohort of RA patients to ascertain if the routine assessment of H-FABP may be useful for the detection of patients with RA who are at risk of development of heart damage.

CHLD score, a new score based on traditional risk factor evaluation and long-term cardiovascular outcomes in patients with systemic sclerosis.

The aim of the study was to assess the predictors of major adverse cardiovascular events (MACE) in patients with systemic sclerosis (SSc) without pulmonary arterial hypertension. The study comprised 68 patients with SSc who were followed up for the median time of 99 (96; 107) months. The main exclusion criteria involved tricuspid regurgitation maximal velocity > 2.8 m/s and structural heart disease. At baseline the patients underwent clinical assessment of cardiovascular risk factors, 6-min walk test, transthoracic echocardiography and biomarker testing, including growth differentiation factor 15 (GDF-15). The primary composite endpoint was onset of MACE defined as death, myocardial infarction, myocardial revascularization and hospitalization for heart failure. The follow-up consisted of outpatient visits at 1 year intervals and telephone interview every 6 months. The baseline analysis revealed that chronic kidney disease (HR 28.13, 95%CI 4.84-163.38), lung fibrosis on high resolution computed tomography (HR 4.36, 95%CI 1.04-18.26) and GDF-15 concentration (unit HR 1.0006, 95%CI 1.0002-1.0010) were independent predictors of MACE occurrence. CHLD (Chronic kidney disease, Hypertension, hyperLipidaemia, Diabetes mellitus) score was formulated which assigned 1 point for the presence of arterial hypertension, hyperlipidaemia, diabetes mellitus and chronic kidney disease. After inclusion of CHLD score in Cox proportional model, it remained the only independent predictor of MACE onset (unit HR per 1 point 3.46; 95%CI 2.06-5.82, p < 0.0001). Joint assessment of traditional risk factors in the form of CHLD score may serve as a reliable predictor of long-term outcome in patients with SSc without pulmonary arterial hypertension.

The prevalence and role of functional autoantibodies to angiotensin-converting-enzyme-2 in patients with systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is an autoimmune disease caused by the imbalance between the activity of angiotensin II and angiotensin-(1-7). Their balance should be controlled by angiotensin-converting enzyme 2 (ACE2), which degrades angiotensin II into angiotensin-(1-7). Previously, autoantibodies to ACE2 (anti-ACE2) were identified in patients with vasculopathy due to different connective tissue diseases, including SSc, but their frequency in SSc was not further analyzed. The aim of the research was to investigate the prevalence and potential role of those anti-ACE2 antibodies in SSc patients. MATERIALS AND METHODS: There were enrolled 27 patients with SSc and 23 healthy donors. ELISA assay determined the presence of anti-ACE2 autoantibodies in serum samples. The results were compared to plasma measurements of angiotensin-(1-7) level via commercial ELISA. RESULTS: The presence of anti-ACE2 autoantibodies was confirmed in five patients with SSc and two healthy controls. Two of those SSc subjects were anti-Scl70+, another two were double anti-Scl70+ and anti-Ro/SSA+, and anti-PM/Scl antibodies were detected in one patient. Median plasma level of Ang-(1-7) in anti-ACE2 negative patients was 47.4 pg/ml and stayed below the detection level in anti-ACE2 positive subjects. The plasma level of Ang-(1-7) was undetectable in four SSc patients, and three of them were anti-ACE2 positive. CONCLUSIONS: Anti-ACE2 antibodies appear to be other functional autoantibodies with the potential to dysregulate the balance between Ang II and Ang-(1-7). They are non-specific for SSc and probably result from polyautoimmunity which affect some of SSc patients. Their occurrence in SSc settings may be associated with a severe depletion of plasma Ang-(1-7).

Thromboembolic Adverse Drug Reactions in Janus Kinase (JAK) Inhibitors: Does the Inhibitor Specificity Play a Role?

Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components of receptor activation systems. The discovery of JAK kinases enabled the synthesis of JAK kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious in the treatment of hematologic malignancies and several rheumatological disorders and continue to be investigated in many clinical indications. Blocking multiple cytokines belonging to several cytokine families with a single small molecule may, however, create a potential risk for the patients. Recently, a higher risk of thromboembolic complications, namely, deep vein thrombosis and pulmonary embolism, has been recognized as the main concern during treatment with Jakinibs. At present, it is not entirely clear whether this increased risk is related to direct cytokine blockade, the presence of concomitant diseases in treated patients or other unknown circumstances that work together to increase the risk of this side effect. In this review, we discuss data on the risk of thromboembolic side effects, with special emphasis on the mechanism that may be responsible for this increased risk. Many indirect data indicate that higher thromboembolic risk may be related to the specificity of JAK inhibitor action, such that preferentially blocking one signaling pathway upsets the balance between pro and anti-thrombotic activities.

Clinical Aspects of Janus Kinase (JAK) Inhibitors in the Cardiovascular System in Patients with Rheumatoid Arthritis.

Janus kinase (JAK) inhibitors, a novel class of targeted synthetic disease-modifying antirheumatic drugs (DMARDs), have shown their safety and efficacy in rheumatoid arthritis (RA) and are being intensively tested in other autoimmune and inflammatory disorders. Targeting several cytokines with a single small compound leads to blocking the physiological response of hundreds of genes, thereby providing the background to stabilize the immune response. Unfortunately, blocking many cytokines with a single drug may also bring some negative consequences. In this review, we focused on the activity of JAK inhibitors in the cardiovascular system of patients with RA. Special emphasis was put on the modification of heart performance, progression of atherosclerosis, lipid profile disturbance, and risk of thromboembolic complications. We also discussed potential pathophysiological mechanisms that may be responsible for such JAK inhibitor-associated side effects.

Immunomodulatory Effects of Diet and Nutrients in Systemic Lupus Erythematosus (SLE): A Systematic Review.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ involvement, including the skin, joints, kidneys, lungs, central nervous system and the haematopoietic system, with a large number of complications. Despite years of study, the etiology of SLE remains unclear; thus, safe and specifically targeted therapies are lacking. In the last 20 years, researchers have explored the potential of nutritional factors on SLE and have suggested complementary treatment options through diet. This study systematically reviews and evaluates the clinical and preclinical scientific evidence of diet and dietary supplementation that either alleviate or exacerbate the symptoms of SLE. For this review, a systematic literature search was conducted using PubMed, Scopus and Google Scholar databases only for articles written in the English language. Based on the currently published literature, it was observed that a low-calorie and low-protein diet with high contents of fiber, polyunsaturated fatty acids, vitamins, minerals and polyphenols contain sufficient potential macronutrients and micronutrients to regulate the activity of the overall disease by modulating the inflammation and immune functions of SLE.

Plasma Glycosaminoglycan Profiles in Systemic Sclerosis: Associations with MMP-3, MMP-10, TIMP-1, TIMP-2, and TGF-Beta.

The aim of the study was to determine whether plasma levels of total glycosaminoglycans (GAGs), matrix metalloproteinases (MMPs) (MMP-3, MMP-10), and their tissue inhibitors (TIMPs) (TIMP-1, TIMP-2) as well as transforming growth factor ß (TGF-ß) differ in the patients with systemic sclerosis (SSc) in relation to the healthy subjects. Plasma samples were obtained from 106 people (64 patients with SSc and 42 healthy individuals) and measured for MMP-3, MMP-10, TIMP-1, TIMP-2, and TGF-ß levels using ELISA methods. GAGs isolated from plasma samples were quantified using a hexuronic acid assay. The plasma levels of total GAGs, TIMP-1, TIMP-2, and TGF-ß were significantly higher, while MMP-3 was significantly decreased in SSc patients compared to the controls. We have revealed a significant correlation between plasma GAGs and TGF-ß (r = -0.47) and TIMP-2 (r = 0.38), respectively. The results of this study revealed that remodeling of the extracellular matrix, reflected by quantitative changes in plasma glycosaminoglycans, occurs during systemic sclerosis. Thus, the alterations in GAG metabolism connected with SSc may lead to systemic changes in the properties of the connective tissue extracellular matrix.

MicroRNA (miRNA): A New Dimension in the Pathogenesis of Antiphospholipid Syndrome (APS).

MicroRNAs (miRNAs) are single-stranded, endogenous RNA molecules that play a significant role in the regulation of gene expression as well as cell development, differentiation, and function. Recent data suggest that these small molecules are responsible for the regulation of immune responses. Therefore, they may act as potent modulators of the immune system and play an important role in the development of several autoimmune diseases. Antiphospholipid syndrome (APS) is an autoimmune systemic disease characterized by venous and/or arterial thromboses and/or recurrent fetal losses in the presence of antiphospholipid antibodies (aPLs). Several lines of evidence suggest that like other autoimmune disorders, miRNAs are deeply involved in the pathogenesis of APS, interacting with the function of innate and adaptive immune responses. In this review, we characterize miRNAs in the light of having a functional role in the immune system and autoimmune responses focusing on APS. In addition, we also discuss miRNAs as potential biomarkers and target molecules in treating APS.

Prevalence of antiphospholipid antibodies in Behçet's disease: A systematic review and meta-analysis.

Behçet's disease (BD) is a multifactorial systemic inflammatory disease of unknown aetiology characterised by several clinical manifestations including vascular involvements (i.e., both arterial and venous thrombosis). Antiphospholipid antibodies (aPLs)-including anticardiolipin (aCL), anti-ß2-glycoprotein I (ß2-GPI) antibodies and lupus anticoagulant (LA) are detected in systemic autoimmune diseases which contribute to thrombosis. The aim of this systematic review and meta-analysis was to evaluate the prevalence of aPLs in patients with BD as compared to controls. A protocol was registered in PROSPERO (Registration No. CRD42018088125) and a systematic literature search was conducted through PubMed, Web of Science, Embase, Scopus and ScienceDirect databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using random-effects model. Quality assessment was carried out by using the modified 9-star Newcastle-Ottawa Scale (NOS). Publication bias was evaluated via visualisation of contour- enhanced and trim and fill funnel plots along with Begg's and Egger's tests. We included ten case-control studies (a total of 999 participants from 380 BD patients and 619 controls) based on the inclusion criteria. The prevalence of aCL (OR: 12.10, 95% CI: 5.15-28.41, p<0.00001) and anti-ß2-GPI antibodies (OR: 23.57, 95% CI: 1.31-423.63, p = 0.03) were statistically significant, however, the prevalence of LA was not significant (OR: 13.77, 95% CI: 0.65-293.59, p = 0.09). The results remained statistically significant from different sensitivity analyses which represented the robustness of this meta-analysis. According to the NOS, 50.0% of the studies were considered as of high methodological quality (low risk of bias). No significant publication bias was detected from contour-enhanced and trim and fill funnel plots or Begg's and Egger's tests. This meta-analysis established that there is a significantly high prevalence of aPLs (i.e., aCL and anti-ß2-GPI antibodies) in patients with BD when compared to controls.