Geographical heterogeneity of clinical and serological phenotypes of systemic sclerosis observed at tertiary referral centres. The experience of the Italian SIR-SPRING registry and review of the world literature

Introduction: Systemic sclerosis (SSc) is characterized by a complex etiopathogenesis encompassing both host genetic and environmental -infectious/toxic- factors responsible for altered fibrogenesis and diffuse microangiopathy. A wide spectrum of clinical phenotypes may be observed in patients' populations from different geographical areas. We investigated the prevalence of specific clinical and serological phenotypes in patients with definite SSc enrolled at tertiary referral centres in different Italian geographical macro-areas. The observed findings were compared with those reported in the world literature. Materials and methods: The clinical features of 1538 patients (161 M, 10.5%; mean age 59.8 ± 26.9 yrs.; mean disease duration 8.9 ± 7.7 yrs) with definite SSc recruited in 38 tertiary referral centres of the SPRING (Systemic sclerosis Progression INvestiGation Group) registry promoted by Italian Society of Rheumatology (SIR) were obtained and clustered according to Italian geographical macroareas. Results: Patients living in Southern Italy were characterized by more severe clinical and/or serological SSc phenotypes compared to those in Northern and Central Italy; namely, they show increased percentages of diffuse cutaneous SSc, digital ulcers, sicca syndrome, muscle involvement, arthritis, cardiopulmonary symptoms, interstitial lung involvement at HRCT, as well increased prevalence of serum anti-Scl70 autoantibodies. In the same SSc population immunusppressive drugs were frequently employed. The review of the literature underlined the geographical heterogeneity of SSc phenotypes, even if the observed findings are scarcely comparable due to the variability of methodological approaches. Conclusion: The phenotypical differences among SSc patients' subgroups from Italian macro-areas might be correlated to genetic/environmental co-factors, and possibly to a not equally distributed national network of information and healthcare facilities

Histopathology of vasculitis

The range of pathologies that are related to primitive vasculitis is broad, complex and not as typical as we would expect. Clinicians should be aware that several forms of primitive and systemic vasculitis, regardless of the size of the affected vessel, may exhibit identical histological alterations. This observation has important clinical implications as it means that cases of vasculitis do not correspond clinically and histologically. Thus, while histology remains the diagnostic gold standard, it can be used only as part of the most complete clinical assessment possible. Another point worth of the clinician’s attention is that vasculitis histology changes over time, as do disease evolution and activity, even without considering the masking effects of treatment and the possibility of sampling error due to the patchy occurrence of vasculitis. The purpose of this review is to identify the most common forms of vasculitis in clinical practice, and to provide guidance to the clinician on the pathology of the vessels

One-year clinical experience on the use of Nintedanib in Systemic Sclerosis

AIM- Systemic Sclerosis (SSc) is a complex autoimmune disease characterized by vascular damage, immune activation and fibrosis of the skin and internal organs. Interstitial lung disease (ILD) is one of the most common causes of death. In 2019 Nintedanib was approved for SSc-related ILD, due to randomized clinical trials (RCTs) demonstrating a reduction in the annual rate of decline in Forced Vital Capacity (FVC). METHODS We reviewed eleven patients with SSc-related ILD from January 2020 to January 2021 and who started Nintedanib 150 mg twice a day. RESULTS- Non-Specific Interstitial Pneumonia (NSIP) was the most frequent HRCT pattern, followed by Usual Interstitial Pneumonia (UIP) and UIP/NSIP pattern. The mean of Modified Rodnan Skin Score (mRSS) at baseline was 9.23 (±10SD) points without any significant improvement during the follow-up. Patients continued their ongoing therapy for lung involvement. Mean FVC was 2233.6 ml [+/- 1066 ml] (61.3% predicted) at beginning and remained stable during the follow-up period. The mean modified British Council Medical Questionnaire (mmRC) decreased from 3 at baseline to 2.5 at the end of follow up and the mean of the Borg scale of dyspnea ameliorated from 7.27 at baseline to 6 at twelve months. Both the differences were not significant. Two patients stop therapy: one for partial intestinal obstruction and one for incoercible diarrhea. CONCLUSION- Nintedanib was generally well tolerated and we did not record any serious adverse even

3ronchial hyperreactivity in systemic sclerosis patients: influence of associated Sjogren's syndrome

Abstract Objective-To determine the frequency and relative risk of bronchial hyperreactivity to methacholine in systemic sclerosis patients with or without associate

Photobiomodulation Therapy: A New Light in the Treatment of Systemic Sclerosis Skin Ulcers

Introduction: Skin ulcers (SU) represent one of the most frequent manifestations of systemic sclerosis (SSc), occurring in almost 50% of scleroderma patients. SSc-SU are often particularly difficult to treat with conventional systemic and local therapies. In this study, a preliminary evaluation of the role and effectiveness of blue light photobiomodulation (PBM) therapy with EmoLED\uae in the treatment of scleroderma skin ulcers (SSc-SU) was performed. Methods: We retrospectively analyzed 12 consecutive SSc patients with a total of 15 SU on finger hands. All patients were treated with adequate systemic therapy and local treatment for SU; after a standard skin ulcer bed preparation with debridement of all lesions, EmoLED\uae was performed. All patients were locally treated every week during 2 months of follow-up; SU data were collected after 4 weeks (T4) and 8 weeks (T8). Eight SSc patients with comparable SU were also evaluated as controls. Results: The application of EmoLED\uae in addition to debridement apparently produced faster healing of SU. Complete healing of SU was recorded in 41.6% cases during EmoLED\uae treatment. Significant improvements in SU area, length, and width, wound bed, and related pain were observed in EmoLED\uae patients from T0 to T8. Control subjects treated with standard systemic/local therapies merely showed an amelioration of SU area and width at the end of the follow-up. No procedural or post-procedural adverse events were reported. Conclusions: The positive clinical results and the absence of side effects suggest that EmoLED\uae could be a promising tool in the management of SSc-SU, with an interesting role to play in the healing process in addition to conventional systemic and local treatments

Retargeted adenoviruses for radiation-guided gene delivery

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment

Recombinant Human Adenovirus with Rat MIP-2 Gene Insertion Causes Prolonged PMN Recruitment to the Murine Brain

Single injections of recombinant cytokines/chemokines into tissue have provided insights into their possible roles during the inflammatory response. Adenoviral technology may allow us to mimic the in vivo situation more closely, with protein generated in a continuous but transient fashion. Replication-deficient human type 5 adenovirus containing a rat macrophage inflammatory protein-2 ( MIP-2 ) gene insertion and cytomegalovirus promoter was injected into the mouse brain to investigate the inflammatory response to continuous overproduction of MIP-2. Adenovirus with a LacZ gene insertion expressing Β-galactosidase was used as a control. At doses of 10 4 to 10 7 plaque-forming units, a minimal inflammatory response was detected to the LacZ virus, with leukocyte recruitment that was restricted to the injection site. A dose of 10 7 plaque-forming units of both the LacZ and the MIP-2 vector produced extensive transgene product expression that persisted for at least 7 days. Astrocytes, recognized by their morphology, were the predominant cell type expressing MIP-2 and Β-galactosidase. A dose of 10 7 plaque-forming units of MIP-2 vector caused dramatic polymorphonuclear leukocyte (PMN) recruitment to the brain parenchyma after 2 days. PMN recruitment was still observed after 4 and 7 days, but had become more localized to the injection site and was associated with numerous foam-like macrophages. At both 2 and 7 days the blood-brain barrier was breached in the region of leukocyte recruitment. Despite the extent of leukocyte recruitment there were no overt signs of neuronal degeneration or demyelination. Our findings demonstrate that continuous production of MIP-2 in the CNS results in persistent PMN recruitment to the brain parenchyma with no evidence of tachyphylaxis. The lack of PMN recruitment to the brain parenchyma following CNS injury may be a result of deficient production of PMN chemoattractants.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75633/1/j.1460-9568.1996.tb01324.x.pd

[Disease activity assessment in large vessel vasculitis]

Disease activity assessment in large vessel vasculitis (LVV) is often challenging for physicians. In this study, we compared the assessment of disease activity based on inflammatory markers, clinical indices (Indian Takayasu Activity Score [ITAS] and the Kerr/National Institute of Health indices [Kerr/NIH]), and 18F-Fluorodesossiglucose (FGD) vascular uptake at positron emission tomography (Pet). We found that Pet results did not statistically correlate with the clinical indices ITAS and Kerr/NIH, because FDG uptake was increased (grade>2 on a 0-3 scale in at least one evaluated vascular segment) in many patients with inactive disease according to clinical and laboratory parameters (i.e., negative ITAS and Kerr/NIH indices as well as normal erythrocyte sedimentation rate (ESR) and C-reactive protein (PCR)). Similarly, interleukin- 6 and its soluble receptor did not statistically correlate with disease activity. In contrast, clinical indices showed a significant correlation between each other and with inflammatory markers (VES and PCR). These data suggest that while clinical indices and inflammatory markers may be useful to assess disease activity, Pet may be more sensitive

Real life use of prostacyclin analog (Iloprost), a multi-centric survey data from the scleroderma study group Emilia Romagna (Sclero-RER) and review of the literature

Background and aim: Iloprost is recommend worldwide for the treatment of RP and the healing of DUs. The aim of this study is to report the regimens of Iloprost administered in different rheumatological centers within the same regional Health System Methods: A questionnaire exploring different items related to the use of Iloprost was developed and reviewed by three expert rheumatologists. The questionnaire was distributed as an online survey to all local SSc referral centers in Emilia-Romagna (Italy). Data are reported as percentage or median with interquartile range (IQR), as appropriate. An updated review of world literature on this topic was also carried out. Results: All the invited centers completed the survey. There were both local (8) and university hospitals (4). The majority (58%) had a rheumatologist as head physician. All centers used Iloprost: a single monthly administration was the most common treatment (75%). The cycle lasted 1 [IQR 1-2] days with a 0.5-2.0 ng/Kg/min dose according to the drug tolerance of the patients. There were overall 68 spots (beds, reclining armchair, or simple armchair); 2.0 [1.5-4.0] patients were able to receive Iloprost at the same time. University Hospitals had more physicians at their disposal than local hospitals but less paramedic personnel (respectively: 1.8 vs 1.2 physicians, 1.5 vs 2.1 nurses). Conclusions: These observations were in line with the majority of previous studies reporting different regimens, comparing similar (but not identical) dose and schedule administration, however, despite differences being at times substantial, no standard infusion method is yet available. (www.actabiomedica.it)