Sex-specific relationships of inflammatory biomarkers with blood pressure in older adults.

Emerging evidence indicates an association between blood pressure and inflammation, yet this relationship remains unclear in older adults, despite the elevated prevalence of hypertension. We investigated the association between blood pressure, high sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and white blood cell (WBC) count in a cohort of 3571 older adults aged 65 and above, and 587 middle-aged participants (55-59 years old). In women aged 65 and above, the relationship between inflammatory markers and blood pressure was consistent, with hs-CRP and WBC emerging as predictors of high blood pressure. For hs-CRP, the adjusted odds ratio (OR) was 1.5 (95% CI, 1.07 to 2.10, P = 0.02), and for WBC, the adjusted OR was 1.41 (95% CI, 1.02 to 1.94, P = 0.04), comparing the highest to the lowest quartiles. In men, only the WBC count was significantly associated with an increased OR for high BP (adjusted OR 1.49, 95% CI, 1.09 to 2.02, P = 0.01) across quartiles. Across the entire study population, in a fully adjusted model, all inflammatory markers were modestly associated with blood pressure levels, while the effect of being over 65 years was the most significant predictor of high blood pressure (OR 1.84, 95% CI, 1.50 to 2.25, P < 0.001). The link between key inflammation markers and blood pressure in older adults varies by sex and biomarker type and may differ from the relationship observed in younger individuals. These relationships are likely to be affected by factors linked to age.

A practical guide to estimating treatment effects in patients with rheumatic diseases using real-world data.

OBJECTIVE: Randomized controlled trials are considered the gold standard in study methodology. However, due to their study design and inclusion criteria, these studies may not capture the heterogeneity of real-world patient populations. In contrast, the lack of randomization and the presence of both measured and unmeasured confounding factors could bias the estimated treatment effect when using observational data. While causal inference methods allow for the estimation of treatment effects, their mathematical complexity may hinder their application in clinical research. METHODS: We present a practical, nontechnical guide using a common statistical package (Stata) and a motivational simulated dataset that mirrors real-world observational data from patients with rheumatic diseases. We demonstrate regression analysis, regression adjustment, inverse-probability weighting, propensity score (PS) matching and two robust estimation methods. RESULTS: Although the methods applied to control for confounding factors produced similar results, the commonly used one-to-one PS matching method could yield biased results if not thoroughly assessed. CONCLUSION: The guide we propose aims to facilitate the use of readily available methods in a common statistical package. It may contribute to robust and transparent epidemiological and statistical methods, thereby enhancing effectiveness research using observational data in rheumatology.

Pain catastrophizing in rheumatic diseases: prevalence, origin, and implications.

Pain is a crucial factor in rheumatic disorders, and reducing it is a primary goal of successful treatment. Adaptive pain-coping strategies can enhance this improvement, but maladaptive approaches such as pain catastrophizing may worsen overall patient well-being. This narrative review aims to provide a concise overview of the existing knowledge on pain catastrophizing in the most prevalent specific rheumatic disorders. The objective of this study was to improve understanding of this phenomenon and its implications, as well as to pinpoint potential directions for future research. We conducted searches in the MEDLINE/PubMed, SCOPUS, and DOAJ bibliography databases to identify articles related to pain catastrophizing in rheumatoid arthritis, psoriatic arthritis, axial spondylarthritis, systemic sclerosis, systemic lupus erythematosus, Sjögren's syndrome, juvenile idiopathic arthritis, and osteoarthritis (non-surgical treatment). Data extraction was performed on November 1, 2023. The investigators screened the identified articles to determine their relevance and whether they met the inclusion criteria. Following a bibliography search, which was further expanded by screening of citations and references, we included 156 records in the current review. The full-text analysis centred on pain catastrophizing, encompassing its prevalence, pathogenesis, and impact. The review established the role of catastrophizing in amplifying pain and diminishing various aspects of general well-being. Also, potential treatment approaches were discussed and summarised across the examined disorders. Pain catastrophizing is as a significant factor in rheumatic disorders. Its impact warrants further exploration through prospective controlled trials to enhance global patient outcomes.

Comparative effectiveness and persistence of SB4 and reference etanercept in patients with psoriatic arthritis in Norway.

OBJECTIVE: We aim to compare drug effectiveness and persistence between reference etanercept (ETN) and ETN biosimilar SB4 in psoriatic arthritis (PsA) patients naïve to ETN and to investigate drug effectiveness and persistence in those undergoing mandatory non-medical switch from ETN to SB4. METHODS: Retrospective comparative database study including 1138 PsA patients treated with ETN or SB4 (years 1999-2021) in Norway. Disease activity score in 28 joints (DAS28) and drug persistence were compared between unmatched ETN (n=644) and SB4 (n=252) cohorts and in matched analyses (n=144, both cohorts) at baseline using propensity score (PS) to adjust for confounders. Drug persistence was analyzed with Kaplan-Meier method. RESULTS: In unmatched analyses, difference in change from baseline between ETN (n=140) and SB4 (n=132) for DAS28 at 1 year was mean 0.67 (95% confidence interval [95%CI] 0.38-0.96) in favor of ETN. In PS-matched analyses, difference in change from baseline between ETN (n=54) and SB4 (n=54) was 0.09 (95%CI -0.33-0.50) and mean difference assessed with ANCOVA model 0.01 (95%CI -0.38-0.40), both within predefined equivalence margin (±0.6). Drug persistence at 1 year was 0.75 (95%CI 0.71-0.78) for ETN, 0.58 (95%CI 0.51-0.63) for SB4, HR 2.45 (95%CI 2.02-2.97) in unmatched analysis, and 0.55 (95%CI 0.46-0.63) for ETN, 0.60 (95%CI 0.51-0.67) for SB4, HR 1.29 (95%CI 0.94-1.76) in PS-matched cohorts. CONCLUSION: At 1 year, outcomes for PsA disease activity and drug persistence were comparable for patients treated with either ETN or SB4. In patients undergoing mandatory non-medical switch from ETN to SB4, drug effectiveness was maintained in 2-year period.

Endothelial dysfunction and risk factors for atherosclerosis in psoriatic arthritis: overview and comparison with rheumatoid arthritis.

Endothelial dysfunction (ED) is defined as an impairment in the vasodilatory, anti-thrombotic, and anti-inflammatory properties of the cells that make up the lining of blood vessels. ED is considered a key step in the development of atherosclerotic cardiovascular disease. The association between ED and systemic inflammatory diseases is well established. However, the prevalence and clinical significance of ED in psoriatic arthritis (PsA) have been investigated to a lesser extent. This review aims to explore the link between ED and PsA, including ED in macro- and microcirculation, as well as risk factors for its occurrence in PsA and its relationship with atherosclerosis in PsA. Furthermore, the ED in PsA was compared with that of rheumatoid arthritis (RA). Regarding ED in the microcirculation, the coronary flow reserve was found to be significantly reduced in individuals with PsA. The relationship between PsA and macrovascular ED is more pronounced, along with more advanced atherosclerosis detected in patients with PsA. These results are consistent with those obtained in RA studies. On the other hand, arterial stiffness and signs of vascular remodeling were found more frequently in RA than in PsA, with the potential role of efficient anti-TNF treatment in patients with PsA and psoriasis explaining this finding. The impact of ED on cardiovascular diseases and the burden of this risk caused independently by PsA have not yet been precisely established, however, this group of patients requires special attention with regard to cardiovascular events.

Clinical and laboratory characteristics of early-onset and delayed-onset lupus nephritis patients: A single-center retrospective study.

BACKGROUND: Lupus nephritis (LN) manifests systemic lupus erythematosus (SLE) and is characterized by various clinical and laboratory features. This study aimed to comprehensively evaluate the characteristics of LN patients according to the time of LN diagnosis: early-onset (LN diagnosed within one year from SLE diagnosis) vs. delayed-onset (LN diagnosed more than one year after SLE diagnosis). METHODS: We conducted a retrospective analysis of medical records from all SLE patients treated at the University Hospital in Kraków, Poland, from 2012 to 2022. We collected data on demographic, clinical, and laboratory characteristics, including histological findings, treatment modalities, and disease outcomes. Statistical analyses were performed to identify factors impacting LN development and prognosis. RESULTS: Among 331 LN patients, early-onset was diagnosed in 207 (62.54%) and delayed-onset was documented in 122 cases (36.86%). In 2 (0.6%) LN cases, the time of first kidney manifestation in the SLE course was unknown. Delayed-onset LN had a higher female-to-male ratio and younger age at SLE diagnosis. This group was associated with more severe clinical manifestations. In turn, studied subgroups did not differ in internist comorbidities, kidney histopathology, and family history regarding autoimmune diseases. Delayed-onset LN exhibited a higher frequency of anti-dsDNA, anti-Smith, anti-Ro, anti-RNP, and anti-cardiolipin IgG autoantibodies. During a 14-year follow-up period, 16 patients died. Mortality rate and causes of death were comparable in both analyzed subgroups. CONCLUSIONS: More severe clinical manifestations in delayed-onset LN prompt strict monitoring of non-LN SLE patients to diagnose and treat kidney involvement early. Also, recognizing the higher frequency of autoantibodies such as anti-dsDNA or anti-Smith in delayed-onset LN underscores the potential value of autoantibody profiling as a diagnostic and prognostic tool.

Exploring 5-year changes in general and skin health-related quality of life in psoriatic arthritis patients.

Psoriatic arthritis (PsA) carries a severe disease burden, often leading to deterioration of health-related quality of life (HRQoL). Different comorbidities that are relatively prevalent in PsA are also responsible for compromised HRQoL. To assess real-world data of a 5-year follow-up cohort of PsA patients, focusing on changes in general HRQoL, skin HRQoL, and comorbidities. In this prospective observational study, 114 outpatients diagnosed with PsA were examined at baseline and after 5 years. Data collection included demographics, clinical disease activity measures, and patient-reported outcome measures (PROMs). General HRQoL was assessed with a 15D instrument, and skin HRQoL was assessed with the Dermatology Life Quality Index (DLQI). During the 5-year follow-up, no significant deterioration in HRQoL assessed by 15D (23.53 vs. 23.08, p = 0.85) and DLQI (3.48 vs. 2.68, p = 0.07) was observed. There was no observed decline in other PROMs. The mean total number of comorbidities increased (1.13 vs. 1.39, p < 0.01). A significant improvement in disease activity measures, including 66/68 swollen/tender joint count, Disease Activity Index for Psoriatic Arthritis (all p < 0.01), and Psoriatic Arthritis Severity Index (p = 0.04) was seen. A higher proportion of patients at 5 years were treated with b/tsDMARDs (37.7% vs. 46.5%, p = 0.03). Despite an increased number of comorbidities over 5 years, our PsA cohort showed no decline in HRQoL. This can be attributed to the widespread adoption of modern treatments, leading to improved disease control and the preservation of baseline HRQoL.

Psychopathological symptoms in fibromyalgia and their associations with resistance to pharmacotherapy with SNRI. / Objawy psychopatologiczne w fibromialgii i ich zwiazki z opornoscia na farmakoterapie z zastosowaniem SNRI.

OBJECTIVES: Fibromyalgia (FM) is often comorbid with psychiatric disorders. Moreover, several studies show that psychiatric disorders may be linked to the severity and impact of FM. Therefore, the study described in the article had two main goals: (1) to explore various psychopathological symptom dimensions in patients with fibromyalgia and secondly, (2) to examine the links between psychopathology and response to treatment with serotonin and norepinephrine reuptake inhibitors (SNRI). METHODS: This cross-sectional study was performed between December 2020 and November 2022. The definition of resistance to SNRI was <30% reduction of pain after ≥8 weeks of treatment. 30 FM subjects responsive to SNRI (FM T[+]), 32 patients non-responsive to SNRI (FM T[-]) and 30 healthy controls were enrolled. Participants were examined by physicians and completed self-report tools to evaluate levels of depression (Quick Inventory of Depressive Symptomatology, Hospital Anxiety and Depression Scale), anxiety (State and Trait Anxiety Inventory), anhedonia (Snaith-Hamilton Pleasure Scale), bipolar symptoms (Mood Disorder Questionnaire, Hypomania Checklist), and dissociation (Dissociative Experiences Scale - Revised). ANOVA analysis and a series of simple logistic regressions were used to examine the associations between psychopathological variables and response to SNRI. RESULTS: FM T[-] vs. FM T[+] showed higher levels of: depression, state and trait anxiety and anhedonia as well as higher proportion of scores indicating the presence of anxiety disorder. Increased severity of depression, anxiety and anhedonia were predictors of resistance to SNRI. CONCLUSIONS: Modifiable psychopathological symptoms vary in FM T[+] vs. FM T[-] and are predictors of resistance to SNRI. Psychological assessment should be integrated into standard care for FM patients.

A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

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.

A challenging diagnosis of idiopathic multicentric Castleman disease with complex systemic presentation: A case report.

Key Clinical Message: Idiopathic multicentric Castleman disease (iMCD) is challenging to diagnose due to clinical similarities with other conditions, such as Still's disease. Once diagnosed, iMCD may be effectively managed with the anti-interleukin-6 antibody siltuximab. Abstract: Here, we present the case of a 19-year-old Polish woman with persistent fever and enlarged lymph nodes and whose diagnosis remained inconclusive following initial clinical assessments and extensive laboratory analyses. The patient had subsequent complaints of joint pain and erythema which were suspicious of Still's disease and resolved with treatment with tocilizumab. Later, the progression of symptoms, such as lymphadenopathy, and elevated interleukin-6 levels were consistent with Castleman disease, leading to the diagnosis of idiopathic multicentric Castleman disease seven years after the patient first reported symptoms. Treatment with the anti-interleukin-6 antibody siltuximab resulted in complete symptom resolution and normalization of inflammatory parameters. No adverse events were reported due to treatment with siltuximab.

Systemic and local vascular inflammation and arterial reactive oxygen species generation in patients with advanced cardiovascular diseases.

Background: Systemic inflammation may cause endothelial activation, mediate local inflammation, and accelerate progression of atherosclerosis. We examined whether the levels of circulating inflammatory cytokines reflect local vascular inflammation and oxidative stress in two types of human arteries. Methods: Human internal mammary artery (IMA) was obtained in 69 patients undergoing coronary artery bypass graft (CABG) surgery and left anterior descending (LAD) artery was obtained in 17 patients undergoing heart transplantation (HTx). Plasma levels of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1ß (IL-1ß) were measured using ELISA, high-sensitivity C-reactive protein (hs-CRP) was measured using Luminex, and mRNA expression of proinflammatory cytokines in the vascular tissues was assessed. Furthermore, formation of superoxide anion was measured in segments of IMA using 5 uM lucigenin-dependent chemiluminescence. Vascular reactivity was measured using tissue organ bath system. Results: TNF-α, IL-6 and IL-1ß mRNAs were expressed in all studied IMA and LAD segments. Plasma levels of inflammatory cytokines did not correlate with vascular cytokine mRNA expression neither in IMA nor in LAD. Plasma TNF-α and IL-6 correlated with hs-CRP level in CABG group. Hs-CRP also correlated with TNF-α in HTx group. Neither vascular TNF-α, IL-6 and IL-1ß mRNA expression, nor systemic levels of either TNF-α, IL-6 and IL-1ß were correlated with superoxide generation in IMAs. Interestingly, circulating IL-1ß negatively correlated with maximal relaxation of the internal mammary artery (r = -0.37, p = 0.004). At the same time the mRNA expression of studied inflammatory cytokines were positively associated with each other in both IMA and LAD. The positive correlations were observed between circulating levels of IL-6 and TNF-α in CABG cohort and IL-6 and IL-1ß in HTx cohort. Conclusions: This study shows that peripheral inflammatory cytokine measurements may not reflect local vascular inflammation or oxidative stress in patients with advanced cardiovascular disease (CVD). Circulating pro-inflammatory cytokines generally correlated positively with each other, similarly their mRNA correlated in the arterial wall, however, these levels were not correlated between the studied compartments.

Serum concentration of dickkopf-related protein 1 (DKK1) in psoriatic arthritis in the context of bone remodelling.

Psoriatic arthritis (PsA) is a chronic inflammatory disease, characterised by the pathological occurrence of two opposite phenomena-osteoresorption and osteogenesis. Dickkopf-related protein 1 (DKK1) which inhibits the Wingless protein (Wnt) signalling pathway has been shown to be a master regulator of bone remodeling in inflammatory rheumatic diseases. However, the exact relationship between DKK1 serum level and bone remodelling is not clear. The goal of this study is to review state-of-the-art knowledge on the association of serum DKK1 with a bone remodelling in PsA. The MEDLINE-PubMed, EMBASE, Scopus, Web of Science and DOAJ databases were searched for appropriate papers. The English terms: 'DKK1', 'Dickkopf-1' 'Dickkopf related protein 1', 'psoriatic arthritis' and 'PsA' were used for search purposes. Eight original articles and two reviews were identified up to August 2023. In four out of 8 discussed studies DKK1 serum level was higher in PsA patients than in healthy controls [Dalbeth, p < 0.01; Diani, p < 0.001; Chung, p < 0.01; Abd el Hamid, p < 0.001)], it was comparable in another (Daousiss, p = 0.430) and was lower in two (Fassio2017, p < 0.05; Fassio2019, p < 0.05). In one study, the comparative groups included patients with axial spondyloarthritis, where DKK1 serum levels were lower in PsA groups [Jadon, peripheral PsA, p = 0.01]. The true relative serum concentration of DKK1 in PsA, as well as its influence on osteogenesis and osteoresorption, is still equivocal. Further studies on this matter with consistent and stringent methodology are warranted.

Psychological variables associated with resistance to treatment with serotonin and noradrenaline reuptake inhibitors in fibromyalgia.

OBJECTIVE: The treatment of fibromyalgia (FM) often offers only partial pain relief. Among the most effective drugs for FM pain are serotonin and noradrenalin reuptake inhibitors (SNRI). Few studies investigated the affective temperaments and personality features in FM. Our objective was to explore the associations between the affective temperaments, personality traits, schizotypy and response to SNRI treatment in FM. METHODS: 60 FM patients: 30 responsive to SNRI (FM T[+]), 30 non-responsive to SNRI (FM T[-] and 30 healthy controls were recruited. Resistance to SNRI was defined as <30% pain reduction during at least 8-week treatment. Subjects were assessed by physician and filled self-report questionnaires: Temperament Scale of Memphis, Pisa and San Diego- autoquestionnaire, Ten Item Personality Inventory, Oxford-Liverpool Inventory of Feelings and Experiences and Fibromyalgia Impact Questionnaire (FIQ). ANOVA analysis and simple logistic regressions were used to examine the links between psychological variables and lack of response to SNRI. RESULTS: FM T[-] presented higher scores in total FIQ and in physical, work, well-being, pain, fatigue/sleep, stiffness domains than FM T[+]. FM T[-] showed higher levels of: irritable and anxious temperaments, neuroticism, schizotypy than FM T[+]. The levels of depressive, irritable and anxious temperaments, introversion, neuroticism and schizotypy were linked to lack of response to SNRI. CONCLUSIONS: FM T[+] and FM T[-] differ in clinical presentation and psychological features. The levels of affective temperaments, personality and schizotypal traits are associated with lack response to SNRI in FM.

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.

SARS-CoV-2 infection impairs NK cell functions via activation of the LLT1-CD161 axis.

Introduction: Natural killer (NK) cells plays a pivotal role in the control of viral infections, and their function depend on the balance between their activating and inhibitory receptors. The immune dysregulation observed in COVID-19 patients was previously associated with downregulation of NK cell numbers and function, yet the mechanism of inhibition of NK cell functions and the interplay between infected cells and NK cells remain largely unknown. Methods: In this study we show that SARS-CoV-2 infection of airway epithelial cells can directly influence NK cell phenotype and functions in the infection microenvironment. NK cells were co-cultured with SARS-CoV-2 infected epithelial cells, in a direct contact with A549ACE2/TMPRSS2 cell line or in a microenvironment of the infection in a 3D ex vivo human airway epithelium (HAE) model and NK cell surface expression of a set of most important receptors (CD16, NKG2D, NKp46, DNAM-1, NKG2C, CD161, NKG2A, TIM-3, TIGIT, and PD-1) was analyzed. Results: We observed a selective, in both utilized experimental models, significant downregulation the proportion of CD161 (NKR-P1A or KLRB1) expressing NK cells, and its expression level, which was followed by a significant impairment of NK cells cytotoxicity level against K562 cells. What is more, we confirmed that SARS-CoV-2 infection upregulates the expression of the ligand for CD161 receptor, lectin-like transcript 1 (LLT1, CLEC2D or OCIL), on infected epithelial cells. LLT1 protein can be also detected not only in supernatants of SARS-CoV-2 infected A549ACE2/TMPRSS2 cells and HAE basolateral medium, but also in serum of COVID-19 patients. Finally, we proved that soluble LLT1 protein treatment of NK cells significantly reduces i) the proportion of CD161+ NK cells, ii) the ability of NK cells to control SARS-CoV-2 infection in A549ACE2/TMPRSS2 cells and iii) the production of granzyme B by NK cells and their cytotoxicity capacity, yet not degranulation level. Conclusion: We propose a novel mechanism of SARS-CoV-2 inhibition of NK cell functions via activation of the LLT1-CD161 axis.

Monocyte subpopulations display disease-specific miRNA signatures depending on the subform of Spondyloarthropathy.

Spondyloarthropathies (SpA) are a family of rheumatic disorders that could be divided into axial (axSpA) and peripheral (perSpA) sub-forms depending on the disease clinical presentation. The chronic inflammation is believed to be driven by innate immune cells such as monocytes, rather than self-reactive cells of adaptive immune system. The aim of the study was to investigate the micro-RNA (miRNA) profiles in monocyte subpopulations (classical, intermediate and non-classical subpopulations) acquired from SpA patients or healthy individuals in search for prospective disease specific and/or disease subtype differentiating miRNA markers. Several SpA-specific and axSpA/perSpA differentiating miRNAs have been identified that appear to be characteristic for specific monocyte subpopulation. For classical monocytes, upregulation of miR-567 and miR-943 was found to be SpA-specific, whereas downregulation of miR-1262 could serve as axSpA-differentiating, and the expression pattern of miR-23a, miR-34c, mi-591 and miR-630 as perSpA-differentiating markers. For intermediate monocytes, expression levels of miR-103, miR-125b, miR-140, miR-374, miR-376c and miR-1249 could be used to distinguish SpA patients from healthy donors, whereas the expression pattern of miR-155 was identified as characteristic for perSpA. For non-classical monocytes, differential expression of miR-195 was recognized as general SpA indicator, while upregulation of miR-454 and miR-487b could serve as axSpA-differentiating, and miR-1291 as perSpA-differentiating markers. Our data indicate for the first time that in different SpA subtypes, monocyte subpopulations bear disease-specific miRNA signatures that could be relevant for SpA diagnosis/differentiation process and may help to understand SpA etiopathology in the context of already known functions of monocyte subpopulations.