Pulmonary and extra-pulmonary effects of lung transplantation in an Italian cohort of patients with systemic sclerosis.

OBJECTIVES: Lung transplantation (LuTx) is a life-saving intervention for Systemic Sclerosis (SSc) patients with end-stage lung disease. The aim of this study was to evaluate patients' survival and LuTx outcomes on systemic disease manifestations. METHODS: A retrospective evaluation was conducted on SSc patients who underwent LuTx between 2010 and 2021. Outcomes assessed at baseline, 6, 12, and 24 months post-LuTx included skin involvement by modified Rodnan skin score (mRSS), global disease activity using a modified EUSTAR index (0-9 scale). Lung function rescue was evaluated by forced vital capacity (FVC). Patient survival was assessed by Kaplan-Meier analysis. RESULTS: 13 SSc patients were included, with a male/female ratio 9/4 and a median age of 48.7 years. Nine patients were affected by diffuse cutaneous scleroderma (dcSSc) and four by limited cutaneous scleroderma (lcSSc). FVC significantly increased from 56% of the predicted value at baseline to 78% at 2 years (p= 0.003). mRSS decreased from 7.4 ± 3.8-3.3 ± 2.5 in patients with dcSSc (p= 0.02). The modified EUSTAR index score decreased from 2.54 ± 1.8 at baseline to 0.49 ± 0.5 at 2 years (p= 0.02). Survival rate was 92.3% at 2 years, and 76.9% at 5 years. No unexpected adverse events were observed. CONCLUSIONS: In SSc patients undergoing LuTx, an excellent 2-year survival was observed, without any disease-related adverse events. Our study supports LuTx as a viable option in SSc patients with end-stage lung disease. Apart from expected recovery of lung function, LuTx was associated with improvement of mRSS and global systemic disease activity.

Tumoral calcinosis of the spine in the course of systemic sclerosis: report of a new case and review of the literature.

We report here a case of a 62-year-old Caucasian woman, suffering from diffuse cutaneous systemic sclerosis (SSc), who developed a tumoural calcinosis (TC) localised in the left side of the neck around the cervical spine that caused severe pain and motion impairment, without involvement of regional neurological structures. A review of the literature on this issue (based on PubMed database) allowed us to identify 35 previously described cases of TC in para-vertebral area in the course of SSc. The main characteristics of these patients have been summarised.

Interstitial Lung Disease in Rheumatoid Arthritis: A Practical Review.

Rheumatoid arthritis (RA) is a systemic inflammatory disease, which primarily causes symmetric polyarthritis. An extrarticolar involvement is common, and the commonly involved organ is lungs. Although cardiac disease is responsible for most RA-related deaths, pulmonary disease is also a major contributor, accounting for ~10-20% of all mortality. Pulmonary disease is a common (60-80% of patients with RA) extra-articular complication of RA. Optimal screening, diagnostic, and treatment strategies of pulmonary disease remain uncertain, which have been the focus of an ongoing investigation. Clinicians should regularly assess patients with RA for the signs and symptoms of pulmonary disease and, reciprocally, consider RA and other connective tissue diseases when evaluating a patient with pulmonary disease of an unknown etiology. RA directly affects all anatomic compartments of the thorax, including the lung parenchyma, large and small airways, pleura, and less commonly vessels. In addition, pulmonary infection and drug-induced lung disease associated with immunosuppressive agents used for the treatment of RA may occur.

Anti-IL6 treatment of serious COVID-19 disease: A monocentric retrospective experience.

ABSTRACT: COVID-19 is causing a high influx of patients suffering from serious respiratory complications leading the necessity to find effective therapies. These patients seem to present with cytokine perturbation and high levels of IL6. Tocilizumab and sarilumab could be effective in this condition.We retrospectively collected data about 112 consecutive hospitalized in a single center.Fifty (IL6 group) treated with tocilizumab (8 mg/kg intravenously [IV], 2 infusions 12 hours apart) or sarilumab 400 mg IV once and 62 treated with the standard of care but not anti-cytokine drugs (CONTROL group).To determine whether anti-IL6 drugs are effective in improving prognosis and reducing hospitalization times and mortality in COVID-19 pneumonia.To date 84% (42/50) of IL6 group patients have already been discharged and only 2/50 are still recovered and intubated in intensive care. Six/fifty patients (12%) died: 5/6 due to severe respiratory failure within a framework of severe acute respiratory distress syndrome (ARDS), 1 suffered an acute myocardial infarction, and 1 died of massive pulmonary thromboembolism. There were no adverse treatment events or infectious complications. Compared to the CONTROL group they showed a lower mortality rate (12% versus 43%), for the same number of complications and days of hospitalization.Anti-IL6 drugs seem to be effective in the treatment of medium to severe forms of COVID-19 pneumonia reducing the risk of mortality due to multi-organ failure, acting at the systemic level and reducing inflammation levels and therefore microvascular complications. However, it is essential to identify the best time for treatment, which, if delayed, is rendered useless as well as counterproductive. Further studies and ongoing clinical trials will help us to better define patients eligible as candidates for more aggressive intervention.

Regional grafting of autologous adipose tissue is effective in inducing prompt healing of indolent digital ulcers in patients with systemic sclerosis: results of a monocentric randomized controlled study.

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.

Autologous Hematopoietic Stem Cell Transplantation for Treatment of Systemic Sclerosis.

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.

The cumulative number of micro-haemorrhages and micro-thromboses in nailfold videocapillaroscopy is a good indicator of disease activity in systemic sclerosis: a validation study of the NEMO score.

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.

Phenotypical and Functional Characteristics of In Vitro-Expanded Adipose-Derived Mesenchymal Stromal Cells From Patients With Systematic Sclerosis.

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.

From mechanisms of action to therapeutic application: A review on current therapeutic approaches and future directions in systemic sclerosis.

Systemic sclerosis (SSc) is one of the most complex connective tissue diseases. Although the pathogenesis of SSc still remains elusive, it is generally accepted that initial vascular injury due to autoimmunity might result in the constitutive activation of fibroblasts and fibrosis. All of these three processes interact and affect one another resulting in a polymorphous spectrum of clinical and pathologic manifestations of SSc. The disease pleomorphism poses numerous difficulties in defining the ideal outcomes to be used in clinical trials. Despite significant progress over the past decades, the clinical management of patients with SSc remains a challenge. Novel therapies are currently being tested in the treatment of SSc and have the potential for modifying the disease process and improving the clinical outcomes. However, the evaluation of the studies is still difficult, due to either the small size of included patients or the different types and phases of the scleroderma disease under scrutiny.

Autologous fat grafting in the treatment of fibrotic perioral changes in patients with systemic sclerosis.

Autologous fat tissue grafting (AFTG) has been successfully used in the treatment of different sclerotic conditions, including localized scleroderma. Patients with advanced systemic sclerosis (SSc)-related perioral thickening and mouth opening limitation are candidates for this therapeutic approach. AFTG of the lips was performed to improve mouth opening in patients with SSc. We enrolled in the study 20 female patients with diffuse SSc (median age 35 ± 15 years and 11 ± 10 years of disease duration). Two-milliliter fractions of autologous fat drawn from trochanteric or periumbilical areas were injected in eight different sites around the mouth. Baseline and after-treatment mouth opening changes were assessed by measuring interincisal distance and oral perimeter, while skin hardness was tested by digital durometer. Pre- and posttreatment modifications of microvascular architecture were assessed by counting capillaries in the inferior lip videocapillaroscopy (VC) images and by scoring the microvascular density (MVD) in anti-CD34/CD31 immunohistochemical (IH) stained perioral skin biopsy sections. Similarly, histological sections were examined to evaluate dermoepidermic junction (DEJ) modifications. Three months after treatment, both the interincisal distance and oral perimeter significantly increased (p < 0.001). At the same time, a significant skin neovascularization became evident, both considering the VC images (p < 0.001) and MVD scores in IH sections (p < 0.0001). Finally, some skin histological aspects also improved, as shown by the significant changes in DEJ flattening scores (p < 0.0001). The present study suggests that, in patients with SSc, AFTG can improve mouth opening and function, induce a neovascularization, and partially restore the skin structure.

Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis.

Digital ulcers (DUs) are a rather frequent and invalidating complication in systemic sclerosis (SSc), often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. In the present study, we have tentatively treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. Fifteen patients with SSc having a long-lasting DU in only one fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection, at the basis of the corresponding finger, of 0.5-1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end point. Furthermore, the posttherapy variation of the number of capillaries, observed in the nailfold video capillaroscopy (NVC) exam and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A rather fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range 2-7 weeks). A significant reduction of pain intensity was observed after a few weeks (p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment (p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded (p < 0.0001). Even with the limitations related to the small number of patients included and to the open-label design of the study, the observed strongly favorable outcome suggests that local grafting with ATDCs could represent a promising option for the treatment of SSc-related DUs unresponsive to more consolidated therapies.

Nailfold videocapillaroscopy micro-haemorrhage and giant capillary counting as an accurate approach for a steady state definition of disease activity in systemic sclerosis.

INTRODUCTION: Nailfold videocapillaroscopy (NVC) in systemic sclerosis (SSc) is a procedure commonly used for patient classification and subsetting, but not to define disease activity (DA). This study aimed to evaluate whether the number of micro-haemorrhages (MHE), micro-thrombosis (MT), giant capillaries (GC), and normal/dilated capillaries (Cs) in NVC could predict DA in SSc. METHODS: Eight-finger NVC was performed in 107 patients with SSc, and the total number of MHE/MT, GC, and the mean number of Cs were counted and defined as number of micro-haemorrhages (NEMO), GC and Cs scores, respectively. The European Scleroderma Study Group (ESSG) index constituted the gold standard for DA assessment, and scores ≥ 3.5 and = 3 were considered indicative of high and moderate activity, respectively. RESULTS: NEMO and GC scores were positively correlated with ESSG index (R = 0.65, P < 0.0001, and R = 0.47, P <0.0001, respectively), whilst Cs score showed a negative correlation with that DA index (R = -0.30, P <0.001). The area under the curve (AUC) of receiver operating characteristic plots, obtained by NEMO score sensitivity and specificity values in classifying patients with ESSG index ≥ 3.5, was significantly higher than the corresponding AUC derived from either GC or Cs scores (P <0.03 and P <0.0006, respectively). A modified score, defined by the presence of a given number of MHE/MT and GC, had a good performance in classifying active patients (ESSG index ≥ 3, sensitivity 95.1%, specificity 84.8%, accuracy 88.7%). CONCLUSIONS: MHE/MT and GC appear to be good indicators of DA in SSc, and enhances the role of NVC as an easy technique to identify active patients.

TNF-alpha antagonist survival rate in a cohort of rheumatoid arthritis patients observed under conditions of standard clinical practice.

A cohort of rheumatoid arthritis (RA) patients in the Lombardy Rheumatology Network (LOHREN) registry and receiving anti-TNF therapy was evaluated after 6, 12, 24, and 36 months. Of the 1114 patients in the registry 1064 met the clinical criteria for inclusion with 519 receiving infliximab, 303 adalimumab, and 242 etanercept. The therapeutic survival curve of these patients showed that the likelihood of continuing anti-TNF therapy was 78.8% after 12 months, 65.2% after 24 months, and 52.9% after 36 months, with a risk of dropout similar for inefficacy and adverse events. There were 405 anti-TNF therapy discontinuations (38.1%): 180 (16.9%) due to inefficacy, 194 (18.2%) adverse events, and 31 (2.9%) other reasons. Four deaths (2 septicemia, 1 postinfective cerebritis, 1 heart failure) were considered to be related to anti-TNF therapy. Of the discontinuations, 219 (54.1%) occurred within the first 12 months: 110 due to adverse events, 89 inefficacy, and 20 due to other reasons. After 36 months, the likelihood of survival on etanercept (62.5%) was significantly greater than the likelihood of survival on infliximab (49.1%) or adalimumab (53.6%). A higher risk of therapy discontinuations due to adverse events was associated with increasing age, a corticosteroid > 5 mg/day, a high erythrocyte sedimentation rate (ESR), a higher risk of therapy discontinuations due to inefficacy was associated with the previous use of > or = 4 disease-modifying antirheumatic drugs (DMARDs) and a high ESR. Comorbidities, increasing DAS28 values and co-therapy with methotrexate were associated with a lower risk of discontinuation.