Over the last 10 years, the evaluation of the neutrophil-to-lymphocyte ratio (NLR) as an emerging marker of diseases has become a compelling field of bio-medical research. Although a precise and unique cut-off value has not been yet found, its role as a flag of immune system homeostasis is well established. NLR has a well-known prognostic value and independently correlates with mortality in the general population and in several specific subsets of disease (sepsis, pneumonia, COVID-19, cancer, etc.). Moreover, NLR was recently considered as part of the decision-making processes concerning the admission/recovery of patients with COVID-19 pneumonia. This review aims to provide an overview of the main use of this biomarker, focusing on the pathophysiology and the molecular basis underlying its central role as a reliable mirror of inflammatory status and adaptive immunity.

Objective: Digital ulcerations are one of the most frequent manifestations of microangiopathy in patients with systemic sclerosis (SSc; scleroderma). The early detection of SSc patients who are at high risk to develop digital ulcers could allow a preventive treatment of these complications with reduction of morbidity and social costs. The aim of our study was to develop a capillaroscopic skin ulcer risk index (CSURI) that can predict the onset of new digital ulcers by using nailfold videocapillaroscopy (NVC) in patients with SSc.Methods: We performed NVC in 120 consecutive unselected patients with SSc (13 men, 107 women, mean ± SD age 56.1 ± 13.4 years, mean ± SD SSc duration 44.7 ± 60.7 months) to assess the total number of capillaries in the distal row (N), maximum loop diameter (D), number of megacapillaries (M), and the M:N ratio.Results: Within 3 months since NVC examination, 35 of 120 patients experienced digital ulcers. A significant association between ischemic lesions and the M:N ratio, N, and D was observed; the combination of these parameters allowed us to develop the CSURI, which is characterized by the formula D × M:N². A receiver operating characteristic curve analysis showed an area under the curve of 0.926 for ulcer appearance, with specificity and sensitivity of 85.9% and 94.3%, respectively, at the cutoff value of 2.94. Interestingly, 33 of 35 patients with new skin ulcers had a CSURI >2.94, but only 2 of 35 had a CSURI ≤2.94.Conclusion: The proposed CSURI may represent a novel tool with the ability to predict the development of digital ulcers in patients with scleroderma.

The treatment of systemic sclerosis (SSc) represents a great clinical challenge because of the complex disease pathogenesis including vascular, fibrotic, and immune T- and B-lymphocyte-mediated alterations. Therefore, SSc should be treated by combined or sequential therapies according to prevalent clinico-pathogenetic phenotypes. Some preliminary data suggest that rituximab (RTX) may downregulate the B-cell over expression and correlated immunological abnormalities. Here, we describe a series of 10 SSc patients (4M and 6F, mean age 46±13.5SD years, mean disease duration 6.3±2.7SD years; 5 pts had limited and 5 diffuse SSc cutaneous subset) treated with one or more cycles of RTX (4 weekly infusions of 375mg/m(2)). The main indications to RTX were interstitial lung fibrosis, cutaneous, and/or articular manifestations unresponsive to previous therapies; ongoing treatments remained unchanged in all cases. The effects of RTX were evaluated after 6months of the first cycle and at the end of long-term follow-up period (37±21SD months, range 18-72months). An updated review of the world literature was also done. RTX significantly improved the extent of skin sclerosis in patients with diffuse SSc at 6months evaluation (modified Rodnan skin score from 25±4.3 to 17.2±4.6; p=.022). A clinical improvement of other cutaneous manifestations, namely hypermelanosis (7/7), pruritus (6/8), and calcinosis (3/6) was observed. Moreover, arthritis revealed particularly responsive to RTX showing a clear-cut reduction of swollen and tender joints in 7/8 patients; while lung fibrosis detected in 8/10 remained stable in 6/8 and worsened in 2/8 at the end of follow-up. Pro-inflammatory cytokines, namely IL6, IL15, IL17, and IL23, evaluated in 3 patients with diffuse cutaneous SSc, showed a more or less pronounced reduction after the first RTX cycle. These observations are in keeping with the majority of previous studies including 6 single case reports and 10 SSc series (from 5 to 43 pts), which frequently reported the beneficial effects of RTX on some SSc manifestations, particularly cutaneous sclerosis, along with the improvement/stabilization of lung fibrosis. Possible discrepancies among different clinical studies can be related to the etiopathogenetic complexity of SSc and not secondarily to the patients' selection and disease duration at the time of the study. The present study and previous clinical trials suggest a possible therapeutical role of RTX in SSc, along with its good safety profile. The specific activity of RTX on B-cell-driven autoimmunity might explain its beneficial effects on some particular SSc clinical symptoms, namely the improvement of skin and articular involvement, and possibly the attenuation of lung fibrosis.

The neutrophil-to-lymphocyte ratio (NLR) is an inflammatory marker predicting the prognosis of several diseases. We aimed to assess its role as a predictor of mortality or admission to the intensive care unit in COVID-19 patients. We retrospectively evaluated a cohort of 411 patients with COVID-19 infection. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) of patients with COVID-19 were compared. The median age of our sample was 72 years (interquartile range: 70–75); 237 were males. Hypertension, diabetes and ischemic heart disease were the most common comorbidities. The study population was subdivided into three groups according to NLR tertiles. Third-tertile patients were older, showing significantly higher levels of inflammatory markers; 133 patients (32%) died during hospitalization, 81 of whom belonged to the third tertile; 79 patients (19%) were admitted to ICU. NLR showed the largest area under the curve (0.772), with the highest specificity (71.9%) and sensitivity (72.9%), whereas CRP showed lower sensitivity (60.2%) but slightly higher specificity (72.3%). Comparisons between NLR and CRP ROC curves were significantly different (p = 0.0173). Cox regression models showed that the association between NLR and death was not weakened after adjustment for confounders. Comparisons of ROC curves showed no significant differences between NLR, PLR, and CRP. Cox regression analysis showed that NLR predicted the risk of admission to ICU independently of demographic characteristics and comorbidities (HR: 3.9597, p < 0.0001). These findings provide evidence that NLR is an independent predictor of mortality and a worse outcome in COVID-19 patients and may help identify high-risk individuals with COVID-19 infection at admission.

Introduction The early detection of systemic sclerosis (SSc) patients at high risk of developing digital ulcers could allow preventive treatment, with a reduction of morbidity and social costs. In 2009, a quantitative score, the capillaroscopic skin ulcer risk index (CSURI), calculated according to the formula ‘D×M/N^2’, was proposed, which was highly predictive of the appearance of scleroderma digital ulcers within 3 months of capillaroscopic evaluation. Objectives This multicentre study aims to validate the predictive value and reproducibility of CSURI in a large population of SSc patients. Methods CSURI was analysed in 229 unselected SSc patients by nailfold videocapillaroscopy (NVC). All patients were re-evaluated 3 months later with regard to the persistence and/or appearance of new digital ulcers. Results 57 of 229 patients presented with digital ulcers after 3 months. The receiver operating characteristic curve analysis showed an area under the curve of 0.884 (95% CI 0.835 to 0.922), with specificity and sensitivity of 81.4% (95% CI 74.8 to 86.89) and 92.98% (95% CI 83.0 to 98.0), respectively, at the cut-off value of 2.96. The reproducibility of CSURI was validated on a random sample of 81 patients, with a κ-statistic measure of interrater agreement of 0.8514. Conclusions The role of CSURI was confirmed in detecting scleroderma patients with a significantly high risk of developing digital ulcers within the first 3 months from NVC evaluation. CSURI is the only method validated to predict the appearance of digital ulcers and its introduction into routine clinical practice might help optimise the therapeutic strategy of these harmful SSc complications.

Objectives. To measure serum levels of CXCL10 and CCL2 chemokines in patients with SSc, and relate the findings to clinical phenotype and disease progression. Methods. Serum CXCL10 and CCL2 were assayed in 72 consecutive newly diagnosed SSc patients and in 72 sex- and age-matched controls. In 37 SSc and 37 controls, serum CXCL10 and CCL2 were re-evaluated 5 yrs later. Results. SSc at onset showed significantly higher CXCL10 serum levels than controls (216 ± 126 vs 92 ± 53 pg/ml; P < 0.0001), as well as CCL2 (388 ± 172 vs 318 ± 120 pg/ml; P = 0.01). CXCL10 was significantly increased in SSc with interstitial lung involvement or with kidney involvement (P = 0.01 and P = 0.02, respectively). A significant decrease of CXCL10 was observed from the baseline after 5 yrs in SSc (137 ± 112 vs 270 ± 122 pg/ml, respectively; P < 0.0001), while no significant change was observed for CCL2 (418 ± 176 vs 405 ± 164 pg/ml; P = NS); the CCL2/CXCL10 ratio significantly increased at the fifth year (1.7 ± 0.8 vs 3.5 ± 2.5; P < 0.0001). No significant variations were observed in controls from the basal to the 5-yr evaluation with regards to CXCL10, CCL2 or CCL2/CXCL10 ratio. Conclusions. Our study demonstrates high serum levels of CXCL10 (Th1) and CCL2 (Th2) chemokines in newly diagnosed SSc. High values of CXCL10 are associated with a more severe clinical phenotype (lung and kidney involvement). CXCL10 declined during the follow-up, while CCL2 remained unmodified, suggesting that the disease progresses from the early Th1 inflammatory condition to the advanced Th2-like stage.