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.
Introduction Hypereosinophilic syndrome (HES) is a group of a rare diseases characterized by marked eosinophilia in blood or tissue and eosinophil-related clinical manifestations. Benralizumab is a ...humanized, monoclonal antibody against interleukin 5 (IL-5) receptor a, which is expressed on human eosinophils. Case study Here, we present the case of a patient with severe HES in whom treatment with benralizumab, an anti-IL-5 receptor monoclonal antibody, was initiated 6 months ago. Prior to benralizumab administration, the patient was treated with glucocorticoids (GS) and mepolizumab. However, instead of the applied treatment and normal level of peripheral eosinophils the patient presented with fluctuating lower respiratory tract symptoms and recurrent exacerbations of HES. Results Treatment with benralizumab (30 mg s.c. every 4-6 weeks) was started, resulting in significant improvement of respiratory signs and symptoms, normalization of eosinophil count and significant reduction of the methylprednisolone dose (after 5 doses of benralizumab administration). No substantial side effects have been noted during treatment and 6-month follow-up. Conclusions We argue that in the severe and relapsing course of HES, rescue treatment with benralizumab should be taken into account, particularly in cases of relative inefficacy of GS and mepolizumab.
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 (
= 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 (
= 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 (
= 0.03) and GG carriers (
= 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.
Certain mediators, such as soluble growth factors and cytokines, among others, are implicated in the immunopathogenesis of systemic sclerosis (SSc).
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.
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.
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).
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.
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.
Patients with granulomatosis with polyangiitis (GPA) show increased tendency toward thromboembolic phenomena in exacerbation of their disease.
The aim of the study was to evaluate thrombin generation ...potential and fibrinolytic plasma activity in patients with GPA, both in exacerbation and in remission.
We included 38 patients with GPA: 18 with exacerbated GPA and 20 in remission. The control group included 39 healthy participants matched for age and sex. Plasma thrombogenic potential was assessed using calibrated automated thrombography. Plasma fibrinolytic potential was assessed using clot lysis time (CLT). We also measured levels of inflammatory markers, thrombomodulin, and fibrinolysis proteins in all participants.
In the whole group of patients with GPA, endogenous thrombin potential was higher by about 25% (P <0.001), while CLT was lower by about 20% (P = 0.02) when compared with controls. The endogenous thrombin potential was higher, the CLT lower, and the levels of thrombomodulin and inflammation markers (C‑reactive protein, fibrinogen, factor VIII) higher both in patients with exacerbation and in remission than in the control group; no such differences were noted when comparing those with exacerbation and those in remission, however. The only parameter that differentiated patients with GPA exacerbation from those in remission was the D‑dimer level (median interquartile range, 1151 597.2-2468.7 ng/ml vs 340.4 255.1-500.7 ng/ml; P <0.001), a marker of lysis of intravascularly formed fibrin.
Patients with GPA show an increased prothrombotic state, regardless of the disease phase. This is probably related to ongoing low-grade inflammation and endothelial injury. Large clinical studies are required to address the need for, and appropriate type of, antithrombotic prophylaxis during the course of GPA.
Dermatomyositis and polymyositis (DM/PM) are rare autoimmune inflammatory myopathies, characterized by an increased risk of cardiovascular and thromboembolic events, likely related to the ...prothrombotic plasma properties. The aim of this study was to assess the in vitro thrombin generation profile as a biomarker of plasma procoagulant properties in DM/PM patients.
In 58 clinically stable DM/PM patients and 67 controls matched for sex, age, body mass index, we measured plasma thrombin generation potential using the Calibrated Automated Thrombinography (CAT) and analyzed its relationship with clinical disease characteristics, including autoantibodies profile.
Patients with DM/PM had a 21% increase in endogenous thrombin potential (ETP), 36% higher peak thrombin concentration, and 11% faster thrombin generation, compared to controls (p < 0.001, all, also after adjustment for potential confounders). Interestingly, although both diseases did not differ in thrombin generation potential, heterogenous variables predicted elevated ETPs in both of them. In DM, that was higher fibrinogen, C-reactive protein, and total cholesterol, whereas in PM, presence of arthritis and increased blood platelet count. Surprisingly, thrombin formation capacity remained in a robust inverse relationship with serum troponin (r = −0.67, p < 0.001) in the patient group.
DM/PM patients are characterized by an increased thrombin generation potential, suggesting prothrombotic plasma properties in both diseases. However, more studies are needed to verify its rationale and role in DM/PM clinical course and unfavorable clinical outcomes.
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