Serum IL-17 and TNFα as prognostic biomarkers in systemic sclerosis patients: a prospective study.

Recent reports have demonstrated that endothelial injury is critical in the pathogenesis of systemic sclerosis (SSc) and is associated with increased levels of circulating inflammatory biomarkers. This study aims to analyze the serum concentrations of selected cytokines and evaluate their relationship with SSc clinics and the long-term course of the disease. This study included 43 SSc patients and 24 matched healthy controls. In both groups, we measured serum levels of inflammatory cytokines related to the inflammatory response, such as tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-4, IL-6, IL-10, and IL-17, and fibroblast activation protein (FAP). Additionally, in SSc patients, we evaluated the presence of four single nucleotide polymorphisms (SNPs) located in the promotor region of the TNFA gene, namely rs361525, rs1800629, rs1799964, and rs1799724, which might be related to increased TNFα concentrations. The main aim consisted of associating inflammatory cytokines with (1) clinical disease characteristics and (2) longitudinal observation of survival and cancer prevalence. SSc patients were characterized by a 17% increase in serum TNFα. There was no other difference in serum cytokines between the studied groups and diffuse vs. limited SSc patients. As expected, evaluated serum cytokines correlated with inflammatory biomarkers (e.g., IL-6 and C-reactive protein). Interestingly, patients with higher IL-17 had decreased left ventricle ejection fraction. During the median 5-year follow-up, we recorded four cases of neoplastic diseases (lung cancer in two cases, squamous cell carcinoma of unknown origin, and breast cancer with concomitant multiple myeloma) and nine deaths. The causes of death included lung cancer (n = 2), renal crisis (n = 1), multiple-organ failure (n = 1), and unknown reasons in five cases. Surprisingly, higher TNFα was associated with an increased cancer prevalence, while elevated IL-17 with death risk in the follow-up. Furthermore, the AG rs361525 genotype referred to higher TNFα levels than GG carriers. Both AG rs361525 and CT rs1799964 genotypes were associated with increased cancer risk. Higher serum concentrations of TNFα characterize the SSc patients, with the highest values associated with cancer. On the other hand, increased IL-17 in peripheral blood might predict poor SSc prognosis. Further research is needed to validate these findings.

Association between clinical features and course of systemic sclerosis and serum interleukin-8, vascular endothelial growth factor, basic fibroblast growth factor, and interferon alpha.

BACKGROUND: Certain mediators, such as soluble growth factors and cytokines, among others, are implicated in the immunopathogenesis of systemic sclerosis (SSc). OBJECTIVES: This study aimed to examine the association between serum levels of vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), interferon alpha (IFN-α), and basic fibroblast growth factor (bFGF) and the clinical presentation and course of SSc. MATERIAL AND METHODS: This longitudinal, observational study included 43 patients with SSc and 24 healthy subjects. Serum concentrations of VEGF, IL-8, IFN-α, and bFGF were measured at baseline in patients previously treated for SSc. Medical history of patients was analyzed retrospectively at the time of cytokine measurement to infer clinical correlations, and during follow-up for a median of 5 years, assessing the incidence of death or cancer. RESULTS: The bFGF and IFN-α concentrations differed between SSc patients and controls (p < 0.01). In turn, organ involvement and SSc phenotypes did not impact studied cytokine concentrations, similar to systemic steroid and/or immunosuppressant use at enrollment. However, we have documented a positive correlation between the current oral steroid dose and serum levels of IL-8 and bFGF. Furthermore, patients with a VEGF level ≥95.7 pg/mL and IFN-α level ≥3.6 pg/mL required cyclophosphamide therapy more often, currently or in the past (approx. 3-fold and 4-fold, respectively). Substantially elevated VEGF and IFN-α concentrations at baseline were associated with higher cancer occurrence (n = 4) during follow-up, while elevated circulating IL-8 level was associated with an increased risk of death (n = 9). CONCLUSIONS: The SSc group was characterized by higher serum concentrations of bFGF and IFN-α compared to healthy controls. Patients treated with cyclophosphamide or receiving higher systemic steroid doses, thus suffering from a more severe disease type, had increased cytokine levels. Elevated circulating IFN-α and VEGF levels might be correlated with cancer, whereas raised IL-8 levels may be associated with an increased risk of death. However, further research is needed to verify our findings.

Immune Checkpoint Inhibitor Related Rheumatological Complications: Cooperation between Rheumatologists and Oncologists.

In cancer, immune checkpoint inhibitors (ICIs) improve patient survival but may lead to severe immune-related adverse events (irAEs). Rheumatic irAEs are a distinct entity that are much more common in a real-life than in clinical trial reports due to their unspecific symptoms and them being a rare cause of hospitalization. This review focuses on an interdisciplinary approach to the management of rheumatic irAEs, including cooperation between oncologists, rheumatologists, and immunologists. We discuss the immunological background of rheumatic irAEs, as well as their unique clinical characteristics, differentiation from other irAEs, and treatment strategies. Importantly, steroids are not the basis of therapy, and nonsteroidal anti-inflammatory drugs should be administered in the front line with other antirheumatic agents. We also address whether patients with pre-existing rheumatic autoimmune diseases can receive ICIs and how antirheumatic agents can interfere with ICIs. Interestingly, there is a preclinical rationale for combining ICIs with immunosuppressants, particularly tumor necrosis factor α and interleukin 6 inhibitors. Regardless of the data, the mainstay in managing irAEs is interdisciplinary cooperation between oncologists and other medical specialties.

Prothrombotic state, endothelial injury, and echocardiographic changes in non-active sarcoidosis patients.

Sarcoidosis is a multisystem inflammatory granulomatous disease of unknown cause that most commonly affects lungs and lymph nodes, with frequent yet asymptomatic cardiac involvement. The epidemiologically associated cardiovascular risk suggests an underlying prothrombotic state and endothelial dysfunction, currently understudied in the available literature. Therefore, we aimed to investigate prothrombotic plasma properties together with selected echocardiographic and laboratory biomarkers of cardiovascular injury in that disease. N = 53 patients with pulmonary sarcoidosis in clinical remission and N = 66 matched controls were assessed for inflammatory and endothelial injury biomarkers, plasma thrombin generation profile, and echocardiographic and lung function parameters. Sarcoidosis cases had impaired systolic and diastolic left ventricular function, higher concentrations of inflammatory markers, D-dimer and factor VIII activity compared to the controls. The coexistence of extrapulmonary disease was associated with elevated circulating vascular cell adhesion molecule 1, while cases with hypercalcemia had higher thrombomodulin concentration. Sarcoidosis was characterized by the unfavorably altered thrombin generation profile, reflected by the 16% higher endogenous thrombin potential (ETP), 24% increased peak thrombin concentration, and 12% shorter time to thrombin peak in comparison to the control group. ETP was higher in cases with proxies of pulmonary restriction, extrapulmonary-extracutaneous manifestation, and need for corticosteroids use. Despite the clinical remission, sarcoidosis is related to prothrombotic plasma properties and signs of endothelial injury, likely contributing to the higher risk of cardiovascular events. In addition, subclinical cardiac involvement may play an additional role, although further clinical and experimental studies are needed to verify these findings.

Genetic Association between TNFA Polymorphisms (rs1799964 and rs361525) and Susceptibility to Cancer in Systemic Sclerosis.

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine that plays an important role in the pathogenesis of autoimmune diseases. The aim of the study was to establish an association between TNF-α promoter variability and systemic sclerosis (SSc). The study included 43 SSc patients and 74 controls. Four single nucleotide polymorphisms (rs361525, rs1800629, rs1799724, and rs1799964) located at the promoter of the TNFA gene were genotyped using commercially available TaqMan allelic discrimination assays with real-time PCR. The rs1799724 allele was associated with an increased SSc susceptibility (p = 0.028). In turn, none of the polymorphisms studied were related to the clinical and laboratory parameters of SSc patients, except for a higher prevalence of anti-Ro52 antibodies in the AG rs1800629 genotype in comparison to GG carriers (p = 0.04). Three of four cancer patients had both CT rs1799964 and AG rs361525 genotypes; thus, both of them were related to the increased risk of cancer, as compared to the TT (p = 0.03) and GG carriers (p = 0.0003), respectively. The TNFA C rs1799724 variant is associated with an increased risk of SSc, while the CT rs1799964 and AG rs361525 genotypes might enhance cancer susceptibility in SSc patients, although large observational and experimental studies are needed to verify the above hypothesis.

Characteristics of idiopathic inflammatory myopathies with novel myositis-specific autoantibodies.

BACKGROUND: In recent years, many novel myositis-specific autoantibodies (MSAs) have been identified. However, their links with the pathogenesis and clinical manifestations of inflammatory myopathies remain uncertain. OBJECTIVES: To characterize the population of adult dermatomyositis (DM) and polymyositis (PM) patients treated at our center for autoimmune diseases using clinical and laboratory measures. MATERIAL AND METHODS: According to the Bohan and Peter criteria, we retrospectively analyzed patients who fulfilled diagnostic criteria for DM or PM. Myositis-specific autoantibodies and myositis-associated autoantibodies (MAAs) were identified using immunoblot assays. RESULTS: Fifty-one PM (71% women) and 36 DM (67% women) Caucasian patients with a median age of 58 (range: 21-88) years who met the definite or probable diagnostic criteria for myositis were included in the study. Myositis-specific autoantibodies were identified in 63 (72%) patients, whereas MAAs were observed in 43 (49%) of them. Interstitial lung disease (ILD) was characteristic of PM patients (67%, χ2 with Yates's correction (χc2) = 13.8078, df = 1, p = 0.0002), being associated with anti-Jo-1 or anti-PL-12 antibodies (fraction comparison test (FCT) 6.4878, p < 0.0001, 6.8354, p = 0.0003, respectively). Interestingly, among patients with anti-MDA5 antibodies (n = 8, 9.2%), all but one had an amyopathic form, with more frequent ILD, skin changes and arthralgias than observed in other patients (FCT 4.7029, p = 0.0228 and p = 7.7986, p = 0.0357, p = 4.7029 and p = 0.0228, respectively). Anti-signal recognition particle (SRP) was strongly associated with the Raynaud's phenomenon (FCT 4.1144, p = 0.0289) and the highest muscle injury markers (Mann-Whitney U test, z = 2.5293, p = 0.0114). Malignancy was recorded in 14 (16%) patients and was equally common in those with PM and DM. The anti-TIF-1γ was the most frequently related to cancer χ2 = 14.7691, df = 1, p < 0.0001). The anti-Mi-2α, similarly prevalent in DM and PM, was typically accompanied by skin changes (FCT 7.7986, p = 0.0357) but not ILD (FCT 8.7339, p = 0.0026). CONCLUSIONS: Identification of MSAs might help to predict the clinical course of the autoimmune myopathy and malignancy risk. However, these antibodies were absent in about 30% of patients with typical PM or DM manifestations, which encourages further research in this area.

Endothelial dysfunction in patients with systemic sclerosis.

INTRODUCTION: Patients with systemic sclerosis experience endothelial dysfunction and damage even in the absence of clinical manifestations. AIM: To evaluate various methods for assessing the endothelial function for their applicability to clinical practice. MATERIAL AND METHODS: Forty-two patients (7 men and 35 women) with systemic sclerosis and 36 controls (11 men and 25 women) matched for age, sex, body mass index, smoking habit, and comorbidities were enrolled in the study. We assessed each participant for typical risk factors for cardiovascular diseases and measured serum levels of vascular cell adhesion molecule-1 (VCAM-1) and thrombomodulin together with flow-mediated dilatation (FMD) of the brachial artery and intima-media thickness (IMT) of the common carotid artery using ultrasonography. RESULTS: Patients with systemic sclerosis did not differ from controls in serum levels of VCAM-1 and thrombomodulin, however, the statistical analysis with adjustment for potential confounders revealed increased levels of thrombomodulin in the patients (p = 0.03). They also had a 45% lower relative increase of FMD (FMD%), and 13% higher IMT (p < 0.01, both, also after adjustment for potential confounders). In a simple regression model, lower FMD% was determined by age (ß = -0.57, 95% confidence interval (CI): -0.72 to -0.43) and C-reactive protein levels (ß = -0.38, 95% CI: -0.55 to -0.22). Thicker IMT was related to age (ß = 0.64, 95% CI: 0.52-0.67), glomerular filtration rate (ß = -0.34, 95% CI: -0.5 to -0.18), and blood thrombomodulin levels (ß = 0.45, 95% CI: 0.13-0.76). CONCLUSIONS: Patients with systemic sclerosis present with endothelial dysfunction which may be detected using ultrasonographic methods. The exact mechanism of observed abnormalities is unknown, but it is possibly related to the chronic inflammation and ischemia-reperfusion injury.

Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages.

Depression is associated with an altered immune response, which could be normalized by antidepressant drugs. However, little is known about the influence of antidepressants on the peripheral immune response and function of macrophages in individuals not suffering from depression. Our studies were aimed at determining the influence of antidepressant drugs on the humoral and cellular immune response in mice. Mice were treated intraperitoneally with imipramine, fluoxetine, venlafaxine, or moclobemide and contact immunized with trinitrophenyl hapten followed by elicitation and measurement of contact sensitivity by ear swelling response. Peritoneal macrophages from drug-treated mice were either pulsed with sheep erythrocytes or conjugated with trinitrophenyl and transferred into naive recipients to induce humoral or contact sensitivity response, respectively. Secretion of reactive oxygen intermediates, nitric oxide, and cytokines by macrophages from drug-treated mice was assessed, respectively, in chemiluminometry, Griess-based colorimetry and enzyme-linked immunosorbent assay, and the expression of macrophage surface markers was analyzed cytometrically. Treatment of mice with fluoxetine, venlafaxine, and moclobemide results in suppression of humoral and cell-mediated immunity with a reduction of the release of macrophage proinflammatory mediators and the expression of antigen-presentation markers. In contrast, treatment with imipramine enhanced the humoral immune response and macrophage secretory activity but slightly suppressed active contact sensitivity. Our studies demonstrated that systemically delivered antidepressant drugs modulate the peripheral humoral and cell-mediated immune responses, mostly through their action on macrophages. Imipramine was rather proinflammatory, whereas other tested drugs expressed immunosuppressive potential. Current observations may be applied to new therapeutic strategies dedicated to various disorders associated with excessive inflammation.

Associations of anthropometric measures on breast cancer risk in pre- and postmenopausal women--a case-control study.

BACKGROUND: The type of silhouette and quantity of fat tissue are correlated with hormonal imbalance which plays a substantial role in breast carcinogenesis. The goal of the study was to investigate the association between various anthropometric characteristics and breast cancer risk. METHODS: Detailed anthropometric assessment was conducted on 487 women of whom 193 had diagnosed breast cancer and were consecutive patients in the Oncology Center, Cracow, Poland between 2002 and 2004. Measurements were divided into four categories: overall body size (body mass index [BMI], waist circumference [WC], waist-hip ratio [WHR]), regional body sizes (skinfold thicknesses, circumferences), thickness of the skeleton (widths, chest diameters), and body proportions. Additionally, results were analyzed in regard to menopausal status. Differences between groups were assessed using Student's t test and Mann-Whitney's test. Models of logistic regression for selected data were built to estimate the odds ratio. Results were considered statistically significant when the P value was less than 0.05. RESULTS: The BMI in both groups was negatively associated with the risk of cancer. Among premenopausal women, WHR increased the risk of breast cancer (WHR > 0.83, OR, 2.72; 95% CI, 1.01-7.27). Anthropometric indices of hip-to-shoulder ratio in postmenopausal (≥84.2 mm, OR, 0.02; 95% CI, 0.01-0.11) and trunk-to-height ratio in both premenopausal women (≥32.76, OR, 0.09; 95% CI, 0.03-0.28) and postmenopausal women (≥32.76, OR, 0.13; 95% CI, 0.05-0.33) were strongly related to a decreased risk of breast cancer. Thicknesses of the triceps and subscapular skinfolds increased the risk of breast cancer. CONCLUSIONS: Women with breast cancer present with an obese type of silhouette with a specific concentration of fat tissue in the central and upper parts of the body.