BackgroundA 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 methodsSSc 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.ResultsAT-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).ConclusionThis RCT strongly confirms that AT-G is effective in inducing IDU healing in SSc patients.Trial registrationClinicalTrials.gov, NCT03406988. Registered retrospectively on 25 January 2018.

BackgroundSome 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.MethodsTwo 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.ResultsThe 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.ConclusionsThis 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.

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.

We retrospectively evaluated the efficacy of autologous hematopoietic stem cell transplantation (AHSCT) in 18 patients with rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc), and compared their disease outcomes with those of 36 demographically-and clinically-matched patients treated with conventional therapies. Cutaneous involvement, by performing modified Rodnan skin score (mRss), lung diffusion capacity, by measuring diffusing capacity of lung for carbon monoxide (DLCO), and disease activity, by applying the European Scleroderma Study Group (ESSG) scoring system, were the outcome variables measured at the baseline time and then every 12 months for the following 60 months in both the AHSCT-treated patients and the control group. In the AHSCT group, treatment-related mortality was 5.6%. In this group, both mRss and ESSG scores showed a significant reduction 1 year after AHSCT (P o 0.002); and these results were maintained until the end of follow-up. Conversely, DLCO values remained stable during the whole period of follow-up. Survival rate of AHSCT group was much higher than that observed in the whole control group (P = 0.0005). The probability that the ESSG score and mRss would remain at a high level, and DLCO could decrease, was significantly higher in the control group as a whole and in the subgroup of control patients treated with cyclophosphamide than in the AHSCT group. This study confirms that the AHSCT is effective in prolonging survival, as well as in inducing a rapid reduction of skin involvement and disease activity, and preserving lung function in patients with rp-dcSSc.

Markers characterizing vascular activation are found to be increased in SSc patients from the earliest stages of disease when clinical and laboratory findings of advanced disease cannot yet be detected. These abnormalities progress with the appraisal of the first sclerodermatous manifestation in defSSc and further increase with the onset of fibrotic manifestations.

Calcium pyrophosphate deposition (CPPD) disease is an arthropathy caused by calcium pyrophosphate dihydrate (CPP) crystal deposits in articular tissues, most commonly fibrocartilage and hyaline cartilage. According to EULAR, four different clinical presentations can be observed: 1) asymptomatic CPPD; 2) osteoarthritis (OA) with CPPD; 3) acute CPP crystal arthritis; 4) chronic CPP inflammatory crystal arthritis. Acute CPP crystal arthritis is characterized by sudden onset of pain, swelling and tenderness with overlying erythema, usually in a large joint, most often the knee, wrist, shoulder, and hip. Occasionally, ligaments, tendons, bursae, bone and the spine can be involved. CPPD of the atlanto-occipital joint (crowned dens syndrome) can cause periodic acute cervico-occipital pain with fever, neck stiffness and laboratory inflammatory syndrome. Chronic inflammatory arthritis is characterized by joint swelling, morning stiffness, pain, and high ESR and CRP. The relationship between OA and CPPD is still unclear. The main problem is whether such crystals are directly involved in the pathogenesis of OA or if they are the result of joint degeneration. Diagnosis is based on evaluation of history and clinical features, conventional radiology, and synovial fluid examination. Non-polarized light microscopy should be used initially to screen for CPPD crystals based upon their characteristic morphology, and compensated polarized light microscopy, showing the crystals to be weakly positive birefringent, is recommended for definitive identification, although this last pattern only occurs in about 20% of samples. The main goals of CPPD therapy are control of the acute or chronic inflammatory reaction and prevention of further episodes.

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REVIEW tation (HSCT) has demonstrated to be an effective treatment to cure some patients with severe autoimmune diseases (3), including scleroderma. After encouraging pilot studies showing beneficial effects of HSCT on immunomodulation, fibrosis and angiogenesis (4), controlled clinical trials definitively established HSCT as a true disease-modifying treatment of SSc (5, 6). Still, the transplant-related mortality that can reach 10%, and the not entirely negligible disease-progression rates after HSCT, indicate that further improvements have still to be researched. Multipotent mesenchymal stromal cells (MSCs) have been used in many animal and human studies as an attractive candidate for cell-based therapies. MSCs comprise a heterogeneous population of cells with multilineage differentiation potential that are preferentially able to home to the sites of damage, and secrete various cytokines and growth factors that can have immunomodulatory, angiogenic, anti-inflammatory and anti-apoptotic effects (7). From the clinical perspective, one of the most attractive properties of MSCs is their low immunogenicity, which allows their safe therapeutic application in allogeneic and even xenogeneic settings (7, 8). In terms of the source of MSCs, those derived from the bone marrow (BM) are the first and the most extensively characterized (9). BM-MSCs are currently used in the graft-versus-host-disease and have been tested in a variety of immune-mediated diseases (10-12). More recently, MSCs have been isolated from various other sources including adipose tissue (AT), umbilical cord