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An excessive systemic pro-inflammatory state increases the risk of severe disease and mortality in patients with coronavirus disease 2019 (COVID-19). However, there is uncertainty regarding whether specific biomarkers of inflammation can enhance risk stratification in this group. We conducted a systematic review and meta-analysis to investigate an emerging biomarker of systemic inflammation derived from routine hematological parameters, the systemic inflammation index (SII), in COVID-19 patients with different disease severity and survival status. A systematic literature search was conducted in PubMed, Web of Science, and Scopus, between the 1 of December 2019 and the 15 of March 2023. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and the Grades of Recommendation, Assessment, Development and Evaluation, respectively (PROSPERO registration number: CRD42023420517). In 39 studies, patients with a severe disease or non-survivor status had significantly higher SII values on admission compared to patients with a non-severe disease or survivor status (standard mean difference (SMD)=0.91, 95% CI 0.75 to 1.06, p<0.001; moderate certainty of evidence). The SII was also significantly associated with the risk of severe disease or death in 10 studies reporting odds ratios (1.007, 95% CI 1.001 to 1.014, p=0.032; very low certainty of evidence) and in six studies reporting hazard ratios (1.99, 95% CI 1.01 to 3.92, p=0.047; very low certainty of evidence). Pooled sensitivity, specificity, and area under the curve for severe disease or mortality were 0.71 (95% CI 0.67 to 0.75), 0.71 (95% CI 0.64 to 0.77), and 0.77 (95% CI 0.73 to 0.80), respectively. In meta-regression, significant correlations were observed between the SMD and albumin, lactate dehydrogenase, creatinine, and D-dimer. Our systematic review and meta-analysis has shown that the SII on admission is significantly associated with severe disease and mortality in patients with COVID-19. Therefore, this inflammatory biomarker derived from routine haematological parameters can be helpful for early risk stratification in this group. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023420517.

Activation of the complement system has been observed in coronavirus disease 19 (COVID-19). We conducted a systematic review and meta-analysis with meta-regression to investigate possible differences in the serum concentrations of two routinely measured complement components, C3 and C4, in COVID-19 patients with different severity and survival status. We searched PubMed, Web of Science and Scopus, between January 2020 and February 2021, for studies reporting serum complement C3 and C4, measures of COVID-19 severity, and survival. Eligibility criteria were a) reporting continuous data on serum C3 and C4 concentrations in COVID-19 patients, -b) investigating COVID-19 patients with different disease severity and/or survival status, c) adult patients, d) English language, e) ≥10 patients, and f) full-text available. Using a random-effects model, standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated to evaluate differences in serum C3 and C4 concentrations between COVID-19 patients with low vs. high severity or survivor vs. non-survivor status. Risk of bias was assessed using the Newcastle-Ottawa scale whereas publication bias was assessed with the Begg’s and Egger’s tests. Certainty of evidence was assessed using GRADE. Nineteen studies in 3,764 COVID-19 patients were included in the meta-analysis. Both C3 and C4 concentrations were significantly lower in patients with high disease severity or non-survivor status than patients with low severity or survivor status (C3 SMD=-0.40, 95% CI -0.60 to -0.21, p<0.001; C4 SMD=-0.29, 95% CI -0.49 to -0.09, p=0.005; moderate certainty of evidence). Extreme between-study heterogeneity was observed (C3, I 2 = 82.1%; C4, I 2 = 84.4%). Sensitivity analysis, performed by sequentially removing each study and re-assessing the pooled estimates, showed that the magnitude and direction of the effect size was not modified. There was no publication bias. In meta-regression, the SMD of C3 was significantly associated with white blood cell count, C-reactive protein (CRP), and pro-thrombin time, whereas the SMD of C4 was significantly associated with CRP, pro-thrombin time, D-dimer, and albumin. In conclusion, lower concentrations of C3 and C4, indicating complement activation, were significantly associated with higher COVID-19 severity and mortality. C3 and C4 might be useful to predict adverse clinical consequences in these patients. Systematic Review Registration: PROSPERO, Registration number: CRD42021239634.

The identification of new, easily measurable biomarkers might assist clinicians in diagnosing and managing systemic sclerosis (SSc). Although the full blood count is routinely assessed in the evaluation of SSc, the diagnostic utility of specific cell-derived inflammatory indices, i.e., neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), has not been critically appraised in this patient group. We conducted a systematic review and meta-analysis of studies investigating the NLR, PLR, and MLR, in SSc patients and healthy controls and in SSc patients with and without relevant complications. PubMed, Scopus, and Web of Science were searched from inception to 23 February 2024. Risk of bias and certainty of evidence were assessed using validated tools. In 10 eligible studies, compared to controls, patients with SSc had significantly higher NLR (standard mean difference, SMD=0.68, 95% CI 0.46 to 0.91, p<0.001; I  = 74.5%, p<0.001), and PLR values (SMD=0.52, 95% CI 0.21 to 0.83, p=0.001; I  = 77.0%, p=0.005), and a trend towards higher MLR values (SMD=0.60, 95% CI -0.04 to 1.23, p=0.066; I  = 94.1%, p<0.001). When compared to SSc patients without complications, the NLR was significantly higher in SSc with interstitial lung disease (ILD, SMD=0.31, 95% CI 0.15 to 0.46, p<0.001; I  = 43.9%, p=0.11), pulmonary arterial hypertension (PAH, SMD=1.59, 95% CI 0.04 to 3.1, p=0.045; I  = 87.6%, p<0.001), and digital ulcers (DU, SMD=0.43, 95% CI 0.13 to 0.74, p=0.006; I  = 0.0%, p=0.49). The PLR was significantly higher in SSc patients with ILD (SMD=0.42, 95% CI 0.25 to 0.59, p<0.001; I  = 24.8%, p=0.26). The MLR was significantly higher in SSc patients with PAH (SMD=0.63, 95% CI 0.17 to 1.08, p=0.007; I  = 66.0%, p=0.086), and there was a trend towards a higher MLR in SSc patients with ILD (SMD=0.60, 95% CI -0.04 to 1.23, p=0.066; I  = 94.1%, p<0.001). Pending the results of appropriately designed prospective studies, the results of this systematic review and meta-analysis suggest that blood cell-derived indices of inflammation, particularly the NLR and PLR, may be useful in the diagnosis of SSc and specific complications. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024520040.

Background. The rapid onset of a systemic pro-inflammatory state followed by acute respiratory distress syndrome is the leading cause of mortality in patients with COVID-19. We performed a retrospective observational study to explore the capacity of different complete blood cell count (CBC)-derived inflammation indexes to predict in-hospital mortality in this group. Methods. The neutrophil to lymphocyte ratio (NLR), derived NLR (dNLR), platelet to lymphocyte ratio (PLR), mean platelet volume to platelet ratio (MPR), neutrophil to lymphocyte × platelet ratio (NLPR), monocyte to lymphocyte ratio (MLR), systemic inflammation response index (SIRI), systemic inflammation index (SII), and the aggregate index of systemic inflammation (AISI) were calculated on hospital admission in 119 patients with laboratory confirmed COVID-19. Results. Non-survivors had significantly higher AISI, dNLR, NLPR, NLR, SII, and SIRI values when compared to survivors. Similarly, Kaplan–Meier survival curves showed significantly lower survival in patients with higher AISI, dNLR, MLR, NLPR, NLR, SII, and SIRI. However, after adjusting for confounders, only the SII remained significantly associated with survival (HR = 1.0001; 95% CI, 1.0000–1.0001, p = 0.029) in multivariate Cox regression analysis. Conclusions. The SII on admission independently predicts in-hospital mortality in COVID-19 patients and may assist with early risk stratification in this group.

Systemic sclerosis (SSc), a chronic autoimmune condition, is characterized by microvascular dysfunction, ineffective angiogenesis, and fibrosis. The identification of robust biomarkers reflecting these processes may assist in clinical management and lead to the discovery of new therapies. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating one such biomarker, vascular endothelial growth factor (VEGF), in SSc patients and healthy controls and in SSc patients with localized or diffuse disease, different video capillaroscopy patterns (early, active, or late), and presence or absence of complications. We searched PubMed, Scopus, and Web of Science from inception to 15 May 2024. We assessed the risk of bias and the certainty of evidence using the JBI checklist for analytical studies and GRADE, respectively. In 42 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum VEGF concentrations (standard mean difference, SMD=0.93, 95% CI 0.71 to 1.15, p<0.001; moderate certainty). In further analyses, VEGF concentrations were significantly higher in SSc patients with diffused disease than those with localized disease (SMD=0.30, 95% CI 0.01 to 0.59, p=0.046; very low certainty), in patients with late vs. active video capillaroscopy pattern (SMD=0.35, 95% CI 0.09 to 0.61, p=0.008; very low certainty), and in patients with pulmonary hypertension than those without (SMD=0.93, 95% CI 0.34 to 1.53, p=0.002; very low certainty). By contrast, no significant differences were observed between SSc patients with and without digital ulcers, interstitial lung disease, and telangiectasias, whereas limited evidence was available for alveolitis. Meta-regression and subgroup analysis of studies investigating VEGF in SSc patients and controls showed no significant associations between the effects size and various patient and study characteristics, including SSc duration and use of corticosteroids, immunosuppressors and vasodilators. By contrast, significant associations were observed with the geographical location where the study was conducted. The results of this systematic review and meta-analysis suggest that VEGF can be useful in the assessment and management of SSc and in the identification of novel therapeutic strategies in this patient group. https://www.crd.york.ac.uk/prospero, identifier CRD42024552925.

Patients with systemic sclerosis (SSc) have an increased risk of endothelial dysfunction, atherosclerosis, and cardiovascular events compared to the general population. Therefore, the availability of robust circulating biomarkers of endothelial dysfunction and atherogenesis may facilitate early recognition and management of cardiovascular risk in SSc. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating various types of circulating cell adhesion molecules involved in endothelial dysfunction and atherogenesis (i.e., immunoglobulin-like vascular cell, VCAM-1, intercellular, ICAM-1, platelet endothelial cell, PECAM-1, neural cell, NCAM, Down syndrome cell, DSCAM, and endothelial cell-selective, ESAM, adhesion molecules, E-, L-, and P-selectin, integrins, and cadherins) in SSc patients and healthy controls. We searched PubMed, Scopus, and Web of Science from inception to 1 May 2024. Risk of bias and certainty of evidence were assessed using validated tools. In 43 eligible studies, compared to controls, patients with SSc had significantly higher plasma or serum concentrations of ICAM-1 (standard mean difference, SMD=1.16, 95% CI 0.88 to 1.44, p<0.001; moderate certainty), VCAM-1 (SMD=1.09, 95% CI 0.72 to 1.46, p<0.001; moderate certainty), PECAM-1 (SMD=1.65, 95% CI 0.33 to 2.98, p=0.014; very low certainty), E-selectin (SMD=1.17, 95% CI 0.72 to 1.62, p<0.001; moderate certainty), and P-selectin (SMD=1.10, 95% CI 0.31 to 1.90, p=0.007; low certainty). There were no significant between-group differences in L-selectin concentrations (SMD=-0.35, 95% CI -1.03 to 0.32, p=0.31; very low certainty), whereas minimal/no evidence was available for cadherins, NCAM, DSCAM, ESAM, or integrins. Overall, no significant associations were observed between the effect size and various patient and study characteristics in meta-regression and subgroup analyses. The results of this systematic review and meta-analysis suggest that specific circulating cell adhesion molecules, i.e., ICAM-1, VCAM-1, PECAM-1, E-selectin, and P-selectin, can be helpful as biomarkers of endothelial dysfunction and atherogenesis in the assessment of cardiovascular risk in SSc patients. https://www.crd.york.ac.uk/prospero/, identifier CRD42024549710.

There is an increasing interest in the pathophysiological role of the kynurenine pathway of tryptophan metabolism in the regulation of immune function and inflammation. We sought to address the link between this pathway and the presence rheumatic diseases (RD) by conducting a systematic review and meta-analysis of studies reporting the plasma or serum concentrations of tryptophan, kynurenine, and other relevant metabolites in RD patients and healthy controls. We searched electronic databases for relevant articles published between inception and the 30 th of June 2023. Risk of bias and certainty of evidence were assessed using the Joanna Briggs Institute Critical Appraisal Checklist and the Grades of Recommendation, Assessment, Development and Evaluation Working Group system. In 24 studies selected for analysis, compared to controls, RD patients had significantly lower tryptophan (standard mean difference, SMD= -0.71, 95% CI -1.03 to -0.39, p<0.001; I 2  = 93.6%, p<0.001; low certainty of evidence), and higher kynurenine (SMD=0.69, 95% CI 0.35 to 1.02, p<0.001; I 2  = 93.2%, p<0.001; low certainty), kynurenine to tryptophan ratios (SMD=0.88, 95% CI 0.55 to 1.21, p<0.001; I 2  = 92.9%, p<0.001; moderate certainty), 3-hydroxykynurenine (SMD=0.74, 95% CI 0.30 to 1.18, p=0.001; I 2  = 87.7%, p<0.001; extremely low certainty), and quinolinic acid concentrations (SMD=0.71, 95% CI 0.31 to 1.11, p<0.001; I 2  = 88.1%, p<0.001; extremely low certainty). By contrast, there were non-significant between-group differences in kynurenic acid, 3-hydroxyanthranilic acid, kynurenic acid to kynurenine ratio, or quinolinic acid to kynurenine acid ratio. In meta-regression, the SMD of tryptophan, kynurenine, and kynurenine to tryptophan ratio were not associated with age, publication year, sample size, RD duration, C-reactive protein, or use of anti-rheumatic drugs and corticosteroids. In subgroup analysis, the SMD of tryptophan, kynurenine, and kynurenine to tryptophan ratio was significant across different types of RD, barring rheumatoid arthritis. Therefore, we have observed significant alterations in tryptophan, kynurenine, 3-hydroxykynurenine, and quinolinic acid concentrations in RD patients. Further research is warranted to determine whether these biomarkers can be useful for diagnosis and management in this patient group. (PROSPERO registration number: CRD CRD42023443718).

There is an ongoing search for novel biomarkers to enhance diagnosing and monitoring patients with rheumatic diseases (RDs). We conducted a systematic review and meta-analysis to investigate the potential role of the soluble cluster of differentiation 40 (sCD40) and sCD40 ligand (sCD40L), involved in humoral and cellular immune response, as candidate biomarkers of RDs. We searched PubMed, Web of Science, and Scopus from inception to 30 June 2024 for studies investigating circulating sCD40 and sCD40L concentrations in RD patients and healthy controls. We assessed the risk of bias using the Joanna Briggs Institute Critical Appraisal Checklist for analytical studies and the certainty of evidence using the Grades of Recommendation, Assessment, Development and Evaluation Working Group system. Compared to controls, RD patients had significantly higher sCD40L (31 studies; standard mean difference, SMD=0.87, 95% CI 0.60 to 1.13, p<0.001; low certainty of evidence) and sCD40 (five studies; SMD=1.32, 95% CI 0.45 to 2.18, p=0.003; very low certainty of evidence) concentrations. In meta-regression and subgroup analysis, the effect size of the between-group differences in sCD40L was significantly associated with sample size, mean RD duration, specific RD, biological matrix assessed, and analytical method used. By contrast, there were no associations with age, sex, C-reactive protein, erythrocyte sedimentation rate, use of disease-modifying antirheumatic drugs or glucocorticoids, or geographical location. There were no significant differences in sCD40L concentrations between RD patients with and without active disease (eight studies; SMD=0.12, 95% CI -0.09 to 0.33, p=0.26; very low certainty). By contrast, sCD40 concentrations were significantly higher in RD patients with active disease (three studies; SMD=0.36, 95% CI 0.08 to 0.84, p=0.013; very low certainty). Our systematic review and meta-analysis suggests the potential role of sCD40 and sCD40L as candidate biomarkers to detect the presence of RDs (sCD40 and sCD40L) and monitor disease activity (sCD40). Large, appropriately designed prospective studies in a wide range of RDs are warranted to investigate whether measuring sCD40 and sCD40L can significantly improve the performance of currently available diagnostic criteria and serological biomarkers. (PROSPERO registration number: CRD42024577430).

Rheumatoid arthritis (RA) is known to increase the risk of cardiovascular (CV) disease. However, the individual impact of traditional CV risk factors in RA is unknown. To assess the strength of the association between individual CV risk factors and rate of either myocardial infarction (MI), combined CV morbidity (MI, angina pectoris, heart failure, stroke, and peripheral arterial disease (PAD)) or CV mortality in RA patients. RA studies reporting traditional CV risk factors [hypertension, type 2 diabetes (T2D), smoking, hypercholesterolaemia, obesity, and physical inactivity] as exposures and MI, CV morbidity (MI, angina, heart failure, stroke, and PAD combined) or CV mortality alone as outcomes were searched until March 2013 using MEDLINE, Scopus and Cochrane. Meta-analyses combined relative risk (RR) estimates from each study where either the RR and 95% confidence intervals or where raw counts were available. Ten studies reporting sufficient data for inclusion into meta-analyses were identified. Relevant data was available for each risk factor and MI and CV morbidity but no studies reported on CV mortality. Risk of MI increased in RA patients with hypertension (RR 1.84, 95% CI 1.38, 2.46) and T2D (RR 1.89, 95% CI 1.36, 2.63). CV morbidity increased with hypertension (RR 2.24, 95% CI 1.42, 3.06), T2D (RR 1.94, 95% CI 1.58, 2.30), smoking (RR 1.50, 95% CI 1.15, 1.84), hypercholesterolaemia (RR 1.73, 95% CI 1.03, 2.44) and obesity (RR 1.16, 95% CI 1.03, 1.29) but not with physical inactivity (RR 1.00, 95% CI 0.71, 1.29). Hypertension, T2D, smoking, hypercholesterolaemia and obesity increased CV risk in patients with RA. These results highlight the importance of managing CV risk factors in RA, similarly to non-RA patients.

IntroductionThe critical role played by vascular dysfunction and ineffective angiogenesis in the pathophysiology of systemic sclerosis (SSc) suggests that circulating biomarkers reflecting these alterations may be useful in the clinical evaluation of this patient group. We sought to address this issue by conducting a systematic review and meta-analysis of studies investigating a such candidate biomarker, endostatin, an endogenous glycoprotein exerting anti-angiogenic effects, in SSc patients and healthy controls.MethodsA literature search was conducted in the electronic databases Web of Science, PubMed, and Scopus from inception to 27 May 2024. Risk of bias and certainty of evidence were assessed using the JBI checklist for analytical studies and GRADE, respectively.ResultsIn 19 eligible studies, circulating endostatin concentrations were significantly higher in SSc patients than controls (standard mean difference, SMD=0.90, 95% CI 0.56 to 1.23, p<0.001; low certainty of evidence). Endostatin concentrations were also significantly higher in SSc patients with digital ulcers than those without (SMD=0.43, 95% CI 0.24 to 0.62, p<0.001; very low certainty of evidence) and in patients with pulmonary arterial hypertension than those without (SMD=1.21, 95% CI 0.67 to 1.76, p<0.001; very low certainty of evidence). By contrast, no significant differences were observed between SSc patients with limited vs. diffuse disease and those with different video capillaroscopy patterns. There was limited evidence regarding endostatin concentrations in SSc patients with interstitial lung disease, telangiectasias, and gastrointestinal manifestations. There were no significant associations in meta-regression and subgroup analysis of studies investigating endostatin in SSc patients and controls between the effect size and various patient and study characteristics.DiscussionTherefore, the results of this systematic review and meta-analysis suggest that measuring endostatin can be useful in assessing the presence of SSc and specific complications, i.e., digital ulcers and pulmonary arterial hypertension, in these patients.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024558174.