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Background A randomized controlled trial (RCT) was performed to confirm preliminary uncontrolled data indicating that regional adipose tissue (AT) grafting (G) is effective in inducing ischemic digital ulcer (IDU) healing in patients with systemic sclerosis (SSc). Patients and methods SSc patients with IDUs were randomized to be blindly treated with AT-G or a sham procedure (SP). AT-G consisted of injection, at the base of the finger with the IDU, of 0.5–1 ml AT after centrifugation of fat aspirate. The SP consisted of false liposuction and local injection of saline solution. The primary endpoint was to compare the cumulative prevalence of healed IDUs in the two groups within the following 8 weeks. Results AT-G and the SP were carried out in 25 and 13 patients, respectively. The two groups were comparable for age, gender, disease duration, and SSc subtypes. IDU healing was observed in 23/25 and 1/13 patients treated with AT-G and the SP, respectively ( p  < 0.0001). The 12 patients who received the unsuccessful SP underwent a rescue AT-G. In all of them, IDU healing was observed after 8 weeks of observation. It was noticeable that in the AT-G-treated patients a significant reduction of pain intensity (measured by visual analogue scale) was recorded after 4 and 8 weeks ( p  < 0.0001 in all cases). Similarly, a significant increase of capillary numbers in the affected finger was recorded by nailfold videocapillaroscopy after 4 and 8 weeks ( p  < 0.0001 in both cases). Conclusion This RCT strongly confirms that AT-G is effective in inducing IDU healing in SSc patients. Trial registration ClinicalTrials.gov, NCT03406988 . Registered retrospectively on 25 January 2018.

There is a great deal of evidence pointing to interferons (IFNs) as being key cytokines in the pathogenesis of different systemic autoimmune diseases, including primary Sjögren’s syndrome (pSS). In this disease, a large number of studies have shown that an overexpression of type I IFN, the ‘so-called’ type I IFN signature, is present in peripheral blood mononuclear cells, and that this finding is associated with the development of systemic extra-glandular manifestations, and a substantial production of autoantibodies and inflammatory cytokines. In contrast, the absence or a milder expression of type I IFN signature and low level of inflammatory cytokines characterizes patients with a different clinical phenotype, where the disease is limited to glandular involvement and often marked by the presence of widespread pain and depression. The role of type II (IFNγ) in this subset of pSS patients, together with the potentially related activation of completely different immunological and metabolic pathways, are emerging issues. Expression of both types of IFNs has also been shown in target tissues, namely in minor salivary glands where a predominance of type II IFN signature appeared to have a certain association with the development of lymphoma. In view of the role played by IFN overexpression in the development and progression of pSS, inhibition or modulation of IFN signaling has been regarded as a potential target for the therapeutic approach. A number of therapeutic compounds with variable mechanisms of action have been tested or are under consideration for the treatment of patients with pSS.

Systemic Sclerosis (SSc) is a complex autoimmune disease, characterized by high mortality and morbidity. The heterogeneity in terms of extent, severity, and rate of progression of skin and internal organ involvement gives rise to many difficulties in finding the optimal therapeutic interventions for SSc and, to date, no disease-modifying agents are available. In this scenario, it is not surprising that SSc was one of the first autoimmune diseases challenged with high-dose immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (AHSCT). In the last decades, AHSCT has emerged as a treatment option for refractory SSc through a reduction of the aberrant immune cells, followed by re-constitution of a new, self-tolerant immune system. After several case series and pilot studies, more recently three randomized controlled trials have shown a benefit in skin involvement, organ functions and quality of life measures in AHSCT compared to monthly cyclophosphamide. In addition, although AHSCT presents a certain risk of mortality, it has been shown that the overall survival is better, compared to the cyclophosphamide group. Current evidence suggests that SSc patients who are most likely to benefit from AHSCT are early, active, with rapidly progressing diffuse skin disease, and mild involvement of internal organs. As the studies have progressed, it has become evident the need for a more rigorous patient selection, the optimization of transplant and post-transplant procedures, and the intervention of multidisciplinary teams of specialists to increase the safety and efficacy of AHSCT in SSc.

Mesenchymal stromal cells (MSCs) have received attention as an ideal source of regenerative cells because of their multipotent differentiation potential. Adipose tissue is an attractive source of MSCs. Recent studies have shown that autologous fat grafting may be effective in the treatment of systemic sclerosis (SSc), but no specific study exists that aimed at investigating whether adipose tissue-derived stromal cells (ADSCs) from SSc patients maintain normal phenotypic and functional characteristics. The purpose of the current study was to investigate whether ADSCs from patients with SSc (SSc-ADSCs) are phenotypically and functionally identical to those from healthy controls (HC-ADSCs). Adipose tissue samples were obtained from 10 patients with SSc and from 8 HCs. Both MSC populations were evaluated for their capacity to (a) express specific MSC surface antigens by flow cytometry analysis, (b) proliferate, (c) differentiate along the adipogenic and osteogenic lineages, (d) suppress in vitro lymphocyte proliferation induced by a mitogenic stimulus, and (e) support endothelial cell (EC) tube formation. ADSCs from SSc patients and HCs showed similar surface phenotype and multilineage differentiation capabilities. In PBMC proliferation inhibition assays, no significant differences were observed between SSc- and HC-ADSCs. Using ADSC/EC cocultures, both SSc- and HC-ADSCs improved tube formation by both HC- and SSc-ECs. This effect was enhanced under hypoxic conditions in all of the cocultures. SSc-ADSCs exhibited the same phenotypic pattern, proliferation and differentiation potentials, and immunosuppressive properties as those from HCs. The proangiogenic activity shown by SSc-ADSCs, namely, under hypoxic conditions, suggests that autologous ADSC grafting may represent a possible therapeutic option for SSc.

Background In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages (MHEs) and microthromboses (MTs), observed in nailfold videocapillaroscopy was a good indicator of the steady state level of disease activity (DA) in patients with systemic sclerosis (SSc) when the European Scleroderma Study Group (EScSG) index was considered the gold standard. Aim of the study To verify whether the NEMO score could be (i) a valid tool to assess DA, even when the modified European Scleroderma Trials and Research (EUSTAR) index was considered to be the comparator, and (ii) a sensitive method to capture the DA overtime changes. Patients and methods The NEMO score and the EScSG and EUSTAR indices were contemporarily assessed at baseline (T0) and after a follow-up of 4–56 months (T1) in 98 patients with SSc. The differences (Δ) between the T1 and T0 values of the NEMO score and the EScSG and EUSTAR indices were calculated and compared to each other. Results NEMO score values were very closely correlated with the corresponding values of the EScSG and EUSTAR indices both at T0 and T1 observations ( p  < 0.0001 in all cases with the exception of the correlation with EScSG values at T1 ( p  < 0.03)). The values of the two composite DA indices were also strictly related to each other in both T0 and T1 observations ( p  < 0.0001). Receiver operating characteristic (ROC) curve analysis showed the NEMO score had a good sensitivity and specificity in classifying patients with a predefined level of DA (scores ≥ 3.0 and ≥ 2.5 for the EScSG and EUSTAR indices, respectively, p  < 0.0001 in both cases). Δ values of the NEMO score were significantly correlated with the corresponding values of both the EScSG and EUSTAR indices. Weighted Cohen’s k level of agreement between Δ values of the NEMO score and those of the EScSG and EUSTAR indices was moderate (0.55 and 0.59, respectively). Conclusions NEMO score proves to be a feasible, non-invasive, and valid tool to assess steady state levels and changes over time of DA in patients with SSc. Thus, it can represent an alternative or complementary method to measure this disease status entity in this disorder.

In view of the new possibilities for the treatment of primary Sjögren's syndrome (pSS) given by the availability of new biotechnological agents targeting the various molecular and cellular actors of the pathological process of the disease, classification criteria aimed at selecting patients to be enrolled in therapeutic trials, and validated outcome measures to be used as response criteria to these new therapies, have been developed and validated in the last decades. Unfortunately, the therapeutic trials so far completed with these new treatments have yielded unsatisfactory or only partially positive results. The main issues that have been evoked to justify the poor results of the new therapeutic attempts are: (i) the extreme variability of the disease phenotypes of the patients enrolled in the trials, which are dependent on different underlying patterns of biological mechanisms, (ii) the fact that the disease has a long indolent course, and that most of the enrolled patients might already have irreversible clinical features. The advances in the research of new disease biomarkers that can better distinguish the different clinical phenotypes of patients and diagnose the disease in an earlier phase are also discussed.

Background Nailfold videocapillaroscopy (NVC) is a feasible method that allows the observation of the microvascular changes that mark the course of systemic sclerosis (SSc). In previous studies, we demonstrated that the NEMO score, i.e. the cumulative number of microhaemorrhages and microthromboses, is a good indicator of the steady-state level and overtime changes of disease activity (DA) in SSc. Objectives To verify whether high NEMO scores, which mirror a very active microvascular derangement in the fingers, may be associated with the subsequent development of ischaemic digital ulcers (IDUs). Methods The NEMO score was assessed at baseline (T0) in 98 patients with SSc, all classified according to the ACR-EULAR criteria. Of them, 90 were females, 48 had the limited and 50 had the diffuse cutaneous variant of SSc. Afterwards, the patients were closely followed up for 2 years, and the appearance of new IDUs recorded at any time of the follow-up. The T0-NEMO score values of patients who developed IDUs were compared to those of patients who did not. A receiver operating curve (ROC) was constructed, and the area under the curve (AUC) calculated by plotting the sensitivity and 1-specificity of the different NEMO score values in predicting the subsequent development of IDUs. Results During the follow-up, 38 out of 98 patients developed one or more IDUs. The NEMO score at T0 was significantly higher in those who developed IDUs with respect to those who did not [median 14.5 (95% CI 11.0–21.5) and 4.5 (95% CI 4.0–6.0), respectively, p  < 0.0001]. The ROC curve derived from different T0-NEMO score values had an AUC of 0.79 (95% CI 0.69–0.86, p  < 0.0001). A NEMO score of ≥ 12 had a sensitivity of 83.3% (95% CI 71.5–91.7) and a specificity of 63.2% (95% CI 46.0–78.2), with positive (P) and negative (N) predictive (PV) values of 58.9% (95% CI 44.7–72.2) and 85.6% (71.8–94.4), respectively. A NEMO score of ≥ 16 had a sensitivity of 95.0% (95% CI 86.1–99.0) and a NPV of 93.4% (77.5–99.2). Conclusions Being a valid tool to measure DA levels in SSc, the NEMO score also appears to be closely related to the subsequent development of IDUs in this disease.

COVID-19 outbreak has quickly spread worldwide, causing a high pressure on the health-care system. In Italy, from March 8, 2020, all the deferrable clinical activities have been suspended to increase the health care offer for COVID-19 patients. The hospital organization has been modified also in order to assure non-COVID-19 patients assistance. The Scleroderma Unit of ASST Pini-CTO Hospital, in Milan, in the region mostly hit by SARS-CoV-2 in Italy, follows more than 600 patients affected by systemic sclerosis (SSc). Patients with SSc need a close follow-up with a regular screening of organ involvement and frequent intravenous treatments. All SSc patients have been educated about ministerial directives to limit COVID-19 spread. The organization of our Scleroderma Unit has been quickly rethought to assure SSc patients assistance in safety for them and for health-care workers during urgent visits or infusion therapies. Using electronic way of communication with frequent virtual contact and guarantying home deliveries of some therapies, we allowed a continuity of care also outside the Hospital.

Background: Mortality rate in patients infected by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) can be related to the presence of comorbidities like diabetes, cardiovascular and pulmonary diseases. On the contrary, few data exist on the impact of CoronaVirus Disease 2019 (COVID-19) on patients with rheumatic disorders, namely in those having pulmonary involvement and treated with immunosuppressive agents. The present survey is aimed at knowing the impact of COVID-19 in a cohort of patients with systemic sclerosis (SSc). Methods: Telephone interviews were carried out during the COVID-19 outbreak in patients with SSc followed in a Rheumatic Disease Unit in Italy. Patients were asked for confirmed SARS-CoV-2 infection, symptoms suggestive of COVID-19, and modification of their therapy. Results: A total number of 526 patients with SSc were contacted and interviewed. Of them, 270 and 256 had limited cutaneous and diffuse cutaneous SSc, respectively. Interstitial lung disease (ILD) was present in 45% of patients and most of them (68.2%) were treated with immunosuppressive therapy. Only two patients were hospitalized for COVID-19-related pneumonia, and one of them died despite invasive ventilator support. An additional 11 patients reported flu-like symptoms compatible with a mild form of COVID-19. Nobody modified the therapy during the COVID-19 outbreak. Conclusion: Despite the large prevalence of ILD and immunosuppressive therapies, which can be considered risk factors for the occurrence and severity of incidental viral infections, the impact of COVID-19, in terms of mortality rate and morbidity, does not appear particularly severe in this large cohort of patients with SSc. Possible mechanisms influencing this figure are discussed.

Background Some abnormalities in nailfold videocapillaroscopy (NVC), such as the presence of micro-haemorrhages (MHEs), micro-thromboses (MTs), giant capillaries (GCs) and reduction in the number of capillaries (nCs), suggest a disease activity (DA) phase in systemic sclerosis (SSc). In a previous paper, we showed that the number of micro-haemorrhages and micro-thromboses (the so-called NEMO score) was the NVC feature more closely associated with DA. The present study was aimed at validating the NEMO score as a measure of DA in patients with SSc. Methods Two cohorts of 122 and 97 patients with SSc who were referred to two different rheumatology units, one in Milan and one in Naples, respectively, constituted the validation cohorts. The NEMO score, the total number of GCs and the mean nCs per digit were the parameters defined in each patient by eight-finger NVC. An expert operator analysed the NVCs in each of the participating units. The European Scleroderma Study Group (ESSG) index was used to define the DA level in each patient at the time of NVC examination. Results The NEMO score was the NVC parameter more strictly correlated with the ESSG score in both the Milan and Naples cohorts ( p  < 0.0001), and it was the only one among the NVC variables that gave a significant contribution in a logistic model where the ESSG score represented the dependent variable. ROC curve analysis confirmed that the NEMO score had the best performance in measuring DA. The AUC of the NEMO score was significantly greater than the AUCs obtained by plotting the sensitivity and specificity of the number of GCs and the mean nCs ( p  < 0.0001 in all cases). The NEMO score values that showed the best sensitivity-specificity balance in capturing patients with a relevant DA level were slightly higher in the Naples cohort than in the Milan cohort. Conclusions This study confirms that the presence of a certain number of MHEs and MTs in NVC may be considered a strong warning signal of a current phase of DA in patients with SSc.