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The aims of this study were to investigate the prevalence of cryofibrinogenemia in a cohort of patients with systemic sclerosis (SSc) regardless of clinical manifestations, who were admitted to our hospital and determine the associations among CF positivity, disease features and ongoing therapies. This was a monocentric and retrospective study. The inclusion criteria were a diagnosis of SSc (according to the ACR/EULAR 2013 classification criteria), regular administration of i.v. prostanoids, and CF testing between February 2020 and February 2022. Data on demographic, clinical, and immunological features and ongoing treatments were retrospectively collected. Categorical data were compared with the chi-square test or Fisher's exact test, while quantitative variables comparisons were carried out with Student's t test or Mann‒Whitney test. In total, 101 SSc patients were ultimately enrolled. The majority of patients were female (92.1%) and had the limited cutaneous form of SSc (81.2%). CF positivity was observed in 69.3% of the patients, whereas only 9% presented cryoglobulins and CF. CF positivity was negatively associated to RNAP3 antibodies (p = 0.027). No direct associations with specific clinical phenotypes were observed. No associations with immunosuppressive treatments were identified, however a positive association with nifedipine administration (p = 0.040), and a negative association with endothelin receptor antagonists (ERAs) plus phosphodiesterase-5 (PDE5) inhibitors regimen (p = 0.031) were observed. Macitentan administration was also associated to CF cryocrit ≥ 1% (p = 0.045). Among patients who were not treated with ERAs, an estimated pulmonary artery systolic pressure ≥ 30 mmHg was significantly associated with CF positivity (p = 0.025). Moreover, a cryocrit ≥3% was associated with a relative risk of 3.44 (95% CI 1.26-9.39, p = 0.016) for digital amputation and 5.17 (95% CI 1.18-22.6, p = 0.029) for death. Isolated CF is a frequent phenomenon observed in SSc patients and is associated with a higher administration of vasoactive drugs, probably identifying a SSc clinical phenotype with a more severe microvascular involvement. Moreover, a higher cryocrit is associated with an increased risk of death and digital amputations. Screening SSc patients for CF would represent an opportunity to provide better therapeutic approaches by anticipating ERA administration in an earlier phase, thereby preventing the manifestation of severe microvascular involvement. Key Points • Cryofibrinogen is a cryoprotein that can cause microangiopathic damage. • Isolated cryofibrinogenemia is common in patients with systemic sclerosis. • SSc patients should be tested for cryofibrinogen because a high cryocrit (≥ 3%) is associated with death and/or digital amputation due to necrosis. • Cryofibrinogen is associated with indirect markers of pulmonary arterial hypertension in patients not treated with endothelin receptor agonists (ERAs). • ERAs could play a role in preventing cryofibrinogen damage., Competing Interests: Declarations. Open data sharing: The data sets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interest: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2025. The Author(s).)

Gastrointestinal involvement (GI) is a frequent and troublesome complication of systemic sclerosis (SSc), whose etiology is poorly understood, though it is hypothesized that autoimmunity and progressive vasculopathy may play a role. Vasculopathy is considered one of the main pathogenetic pathways responsible for many of the clinical manifestations of SSc, and, therefore, studying the principal splanchnic vessels (i.e., superior mesenteric artery-SMA and inferior mesenteric artery-IMA) with Doppler Ultrasound (DUS) may provide further insights into measuring the progression of vasculopathy, evaluating its possible association with SSc GI symptoms, and determining whether it plays a role in the development or severity of SSc GI disease. A cohort of SSc patients consecutively recruited underwent DUS examination, and associations with GI (UCLA-GIT 2.0 questionnaire) and extraintestinal SSc characteristics were evaluated. Semiquantitative DUS parameters (resistive index-RI and pulsatility index-PI), were applied for splanchnic vessel assessment in SSc patients and healthy subjects (HS). Moreover, a review and meta-analysis of the literature to understand which the values of the main semiquantitative DUS parameters (RI and PI) are both in SSc patients and HS has been conducted. Seventy-eight patients completed DUS examinations and clinical assessments. 30 (39%) were classified as diffuse cutaneous SSc (dcSSC), 35 (45%) as limited cutaneous SSc (lcSSc) and 13 (17%) as sine scleroderma. A significant difference was found both for SMA RI (p for trend = 0.032) and SMA PI (p for trend = 0.004) between patients with sine scleroderma, lcSSc and dcSSc, with lower values observed in the sine scleroderma and lcSSc groups. IMA RI and PI were significantly correlated with GI symptoms such as fecal incontinence (ῥ - 0.33, p = 0.008 and ῥ - 0.30, p = 0.021, respectively). By multivariate analysis, significant associations were confirmed between SMA RI and SMA PI and mRSS (β 0.248, p = 0.030 and β 2.995, p = 0.004, respectively) and with bosentan (β 0.400, p = 0.003 and β 3.508, p = 0.001, respectively), but not with anticentromere antibody (ACA). No significant differences were found between the weighted median values of SMA RI and SMA PI of SSc patients compared to those of HS that were derived from the meta-analysis of the literature (p = 0.72 and p = 0.64, respectively). This cross-sectional study confirms that the splanchnic vasculature of SSc patients can noninvasively been studied with DUS. Vascular splanchnic involvement correlates with the presence and/or severity of specific clinical features in SSc, including GI. Larger and prospective studies are needed to confirm these preliminary observations and to examine the role of DUS in SSc-risk stratification and GI progression and to obtain definitive data regarding both HS and SSc patients splanchnic DUS parameters., (© 2024. The Author(s).)

Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is a systemic small-vessel vasculitis characterized by the proliferation of B-cell clones producing pathogenic immune complexes, called cryoglobulins. It is often secondary to hepatitis C virus (HCV), autoimmune diseases, and hematological malignancies. CV usually has a mild benign clinical course, but severe organ damage and life-threatening manifestations can occur. Recently, evidence in favor of rituximab (RTX), an anti-CD 20 monoclonal antibody, is emerging in CV: nevertheless, questions upon the safety of this therapeutic approach, especially in HCV patients, are still being issued and universally accepted recommendations that can help physicians in MCS treatment are lacking. A Consensus Committee provided a prioritized list of research questions to perform a systematic literature review (SLR). A search was made in Medline, Embase, and Cochrane library, updated to August 2021. Of 1227 article abstracts evaluated, 27 studies were included in the SLR, of which one SLR, 4 RCTs, and 22 observational studies. Seventeen recommendations for the management of mixed cryoglobulinemia with rituximab from the Italian Study Group of Cryoglobulinemia (GISC) were developed to give a valuable tool to the physician approaching RTX treatment in CV., (© 2022. The Author(s).)

Introduction: Covid-19 infection poses a serious challenge for immune-compromised patients with inflammatory autoimmune systemic diseases. We investigated the clinical-epidemiological findings of 1641 autoimmune systemic disease Italian patients during the Covid-19 pandemic., Method: This observational multicenter study included 1641 unselected patients with autoimmune systemic diseases from three Italian geographical areas with different prevalence of Covid-19 [high in north (Emilia Romagna), medium in central (Tuscany), and low in south (Calabria)] by means of telephone 6-week survey. Covid-19 was classified as (1) definite diagnosis of Covid-19 disease: presence of symptomatic Covid-19 infection, confirmed by positive oral/nasopharyngeal swabs; (2) highly suspected Covid-19 disease: presence of highly suggestive symptoms, in absence of a swab test., Results: A significantly higher prevalence of patients with definite diagnosis of Covid-19 disease, or with highly suspected Covid-19 disease, or both the conditions together, was observed in the whole autoimmune systemic disease series, compared to "Italian general population" (p = .030, p = .001, p = .000, respectively); and for definite + highly suspected diagnosis of Covid-19 disease, in patients with autoimmune systemic diseases of the three regions (p = .000, for all comparisons with the respective regional general population). Moreover, significantly higher prevalence of definite + highly suspected diagnosis of Covid-19 disease was found either in patients with various "connective tissue diseases" compared to "inflammatory arthritis group" (p < .000), or in patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs treatments (p = .011)., Conclusions: The finding of a higher prevalence of Covid-19 in patients with autoimmune systemic diseases is particularly important, suggesting the need to develop valuable prevention/management strategies, and stimulates in-depth investigations to verify the possible interactions between Covid-19 infection and impaired immune-system of autoimmune systemic diseases. Key Points • Significantly higher prevalence of Covid-19 is observed in a large series of patients with autoimmune systemic diseases compared to the Italian general population, mainly due to patients' increased susceptibility to infections and favored by the high exposure to the virus at medical facilities before the restriction measures on individual movement. • The actual prevalence of Covid-19 in autoimmune systemic diseases may be underestimated, possibly due to the wide clinical overlapping between the two conditions, the generally mild Covid-19 disease manifestations, and the limited availability of virological testing. • Patients with "connective tissue diseases" show a significantly higher prevalence of Covid-19, possibly due to deeper immune-system impairment, with respect to "inflammatory arthritis group". • Covid-19 is more frequent in the subgroup of autoimmune systemic diseases patients without ongoing conventional synthetic disease-modifying anti-rheumatic drugs, mainly hydroxyl-chloroquine and methotrexate, which might play some protective role against the most harmful manifestations of Covid-19.

Resilience is defined as "the capacity of individuals to cope successfully with significant change or adversity". The challenge posed by the COVID-19 pandemic may potentially represent an overwhelmingly stressful event for patients with chronic diseases. Aim of our study was to investigate the levels of resilience in individuals with inflammatory arthritis living in Emilia Romagna, the third hardest-hit Italian region during the ongoing COVID-19 pandemic. To this purpose, we developed a survey consisting of four different sections assessing demographic characteristics, the 14-item resilience scale (RS14) and questionnaires evaluating depression and anxiety. Consecutive patients with inflammatory arthritis were recruited over a short time frame immediately after the end of national lockdown and compared with control individuals from the general population. One hundred twenty-two patients and 173 controls were included. Levels of resilience, as measured by RS14 score, were significantly higher in patients with inflammatory arthritis (82.6 ± 14.0 vs 79.0 ± 12.8, p = 0.018). After stratification for gender, the difference in RS14 score was maintained in women (p = 0.045), but not in men (p = 0.252). High resilience, defined as having a RS14 score > 90, was significantly more prevalent in patients than in controls (30% vs 16%, p = 0.009). In arthritis patients, no significant differences in RS14 were observed after stratification for specific diagnosis, age, or disease duration and activity. Our findings suggest that patients with inflammatory arthritis may be more resilient than the general population towards unexpected stressful events such as the ongoing COVID-19 pandemic. Key Points • Living with inflammatory arthritis may foster resilience. • After COVID-19, patients with inflammatory arthritis were more resilient than the general population.

Introduction: Systemic sclerosis (SSc) is an autoimmune disease characterized by endothelial dysfunction, which is also associated with other disorders, such as atherosclerosis. The direct role of SSc in facilitating cardiovascular events should be clarified. We compared the prevalence of established coronary artery disease (CAD) between SSc and type 2 diabetes, a well-known phenotype associated with high cardiovascular risk., Methods: In this cross-sectional study, we evaluated a cohort of 290 unselected female SSc patients, in comparison with 265 aged-matched female type 2 diabetics. "Established CAD" was defined as previous myocardial infarction, unstable angina or ischemia documented by ECG and troponin elevation, necessity/previous treatment with coronary angioplasty or stenting. Age subgroups < 45 (Q1), 45-54 (Q2), 55-64 (Q3), 65-74 (Q4), and ≥ 75 (Q5) years were considered for SSc and diabetes., Results: CAD prevalence resulted lower in SSc patients than in diabetics (10% (95%CI 6.9-14.1) versus 19.2% (95%CI 14.9-24.4); p = 0.0023). In Q2 patients, CAD never occurred in SSc (95%CI 0-8.4), but in 9.4% of diabetics (95%CI 3.7-20.7, p = 0.0567); in Q3 subjects, CAD was reported in 5.6% (95%CI 1.8-13.8) of SSc, but in 20% (95%CI 12.4-30.5) of diabetics (p = 0.0127). Instead, for Q4 and particularly Q5 patients, CAD prevalence was comparable in SSc and diabetes., Conclusions: The prevalence of established CAD in SSc was lower compared with diabetics. However, in older SSc patients the prevalence of CAD was similar to that observed in diabetics.

The term "HCV syndrome" encompasses several organ- and systemic pathophysiological states, which often recognize autoimmunity or neoplastic evolution in their pathophysiology, as well as chronic HCV infection as trigger. The clinical features of HCV patients are heterogenous, and may include endocrine or metabolic disorders, namely autoimmune thyroiditis, type 2 diabetes mellitus, and erectile/sexual dysfunctions. In this review, we summarize current knowledge on the endocrine/metabolic diseases associated with chronic HCV infection, focusing on the main concepts emerged in the recent literature in this field. The application of this knowledge in everyday clinical practice may be relevant, in order to reinforce a holistic vision of the patient with chronic HCV infection, stimulating in turn a multi-disciplinary approach, thus increasing the probability of early diagnosis, more effective treatments, and a better prognostic outcome.

Hypovitaminosis D is increasingly reported in autoimmune diseases. We investigated the 25-OH-vitamin D (25-OH-vitD) levels in systemic sclerosis (SSc) patients, in correlation with disease's features. We measured the 25-OH-vitD serum levels in 140 consecutive patients (F/M 126/15; mean age 61 ± 15.1 years), 91 without (group A) and 49 with (group B) 25-OH-cholecalciferol supplementation. Patients of group A invariably showed low 25-OH-vitD levels (9.8 ± 4.1 ng/ml vs. 26 ± 8.1 ng/ml of group B); in particular, 88/91 (97%) patients showed vitamin D deficiency (<20 ng/ml), with very low vitamin D levels (<10 ng/ml) in 40 (44%) subjects. Only 15/49 (30.6%) patients of group B reached normal levels of 25-OH-vitD (≥30 ng/ml), whereas vitamin D deficiency persisted in 12/49 (24.5%) individuals. Parathormone levels inversely correlated with 25-OH-vitD (r = -0.3, p < 0.0001). Of interest, hypovitaminosis D was statistically associated with autoimmune thyroiditis (p = 0.008), while calcinosis was more frequently observed in patients of group A (p = 0.057). Moreover, we found significantly higher percentage of serum anticentromere antibodies in group B patients with 25-OH-vitD level ≥30 ng/ml (8/15 vs. 6/34; p = 0.017). In literature, hypovitaminosis D is very frequent in SSc patients. An association with disease duration, calcinosis, or severity of pulmonary involvement was occasionally recognized. Hypovitaminosis D is very frequent in SSc and severe in a relevant percentage of patients; furthermore, less than one third of supplemented subjects reached normal levels of 25-OH-vitD. The evaluation of 25-OH-vitD levels should be included in the routine clinical work-up of SSc. The above findings expand previous observations and may stimulate further investigations.

The aim was to investigate circulating levels of interelukin (IL)-1β, IL-6 and tumor necrosis factor (TNF)-α, chemokine (C-X-C motif) ligand (CXCL)10, CXCL11 and chemokine (C-C motif) ligand (CCL)2 in "mixed cryoglobulinemia and hepatitis C" (MC + HCV). Serum levels of CXCL11, IL-1β, TNF-α, IL-6, and CCL2 were evaluated in 52 MC + HCV vs 52 sex- and age-matched controls to correlate them to the clinical features of mixed cryoglobulinemia. CXCL11 was significantly higher in MC + HCV than in controls (264 ± 279 vs 70 ± 16 pg/mL, respectively; P = 0.0002; univariate analysis of variance (ANOVA)), in particular in 23 MC + HCV with active vasculitis vs those without (293 ± 221 vs 168 ± 57 pg/mL, respectively; P < 0.001; ANOVA). Significantly high IL-1β, IL-6, TNF-α, CXCL10, and CCL2 in MC + HCV vs healthy controls were confirmed. In a multiple linear regression model (CXCL11 or CCL2, vs age, alanine aminotransferase, IL-1β, IL-6, TNF-α, and CXCL10), CXCL11 was significantly associated with high CXCL10 (P < 0.001), while CCL2 with high IL-6 (P < 0.001). This study demonstrates in MC + HCV high serum levels of (a) T-helper 1 chemokines, CXCL11 and CXCL10 (related to each other) and (b) proinflammatory cytokines IL-6 and CCL2 (related to each other).

Skin ulcers are very frequent in scleroderma (SSc), often complicated by local infection; the latter may be responsible for osteomyelitis (OM) of underlying bone. We retrospectively investigate the prevalence of OM in our SSc patients. The study included 248 SSc patients (M/F 21/227, mean age 61 ± 13.5 SD years) followed at our Rheumatology Unit for a mean time period of 60.8 ± 20.9 SD months. Patients with infected skin ulcers were carefully evaluated for complicating OM, which was diagnosed on the basis of typical clinical symptoms, laboratory, and radiological alterations. Skin ulcers were observed in 119/248 (48 %) SSc patients, more frequently digital ulcers (110/119, 92 %). These patients presented a significantly lower mean age (59 ± 14.5 SD vs. 64 ± 12.2 SD years; p = 0.005) and a lower percentage of anticentromere antibodies (40/119, 33.6 %, vs. 66/129, 51.2 %; p = 0.007) compared with those without ulcers. The prevalence of OM in the entire SSc patients' series was 7.7 % (19/248); it was invariably found in the setting of patients with infected digital ulcers, showing a surprisingly high percentage of underlying bone involvement (19/45, 42 %). The OM was localized at the hands in 14 patients and feet in 5; moreover, the most frequently isolated pathogens from infected digital ulcers were Staphylococcus aureus and Escherichia coli. Finally, patients with OM presented a significantly lower mean age (p < 0.016) and higher percentage of anti-Scl70 autoantibodies (p < 0.0128) compared to those without. We firstly demonstrated, in a large cohort of SSc patients, high prevalence of OM, invariably associated to infected digital ulcers, which represent the main predisposing condition for the development of such a harmful complication.

Systemic sclerosis (SSc) pregnant women show a high frequency of premature births and occurrence of renal crisis. Some evidences showed the role of L-arginine in the prevention and treatment of preeclampsia. Here, we report our experience on the effect of L-arginine treatment in four consecutive SSc pregnant women. Two patients, who have planned the pregnancy, were treated with oral L-arginine; both delivered healthy babies without any prenatal complications. The other two, with high risk of pregnancy complications because of severe lung involvement and type 1 diabetes, respectively, underwent i.v. L-arginine: patient 3 had a premature delivery of a 2-kg healthy baby, while patient 4 developed preeclampsia and, at the 28th week, delivered a 1,050-g girl. The neonate had severe respiratory distress syndrome complicated by severe infection and died at day 28. Although limited, our pilot study suggests that L-arginine may be a useful therapeutic agent in pregnant SSc women.