Systemic sclerosis in the time of COVID-19.

The COVID-19 pandemic represents one of the biggest challenges of the 21st century. In addition to the general effect on society and health-care systems, patients with systemic sclerosis and their physicians face specific challenges related to the chronic nature of their disease, the involvement of multiple organs, and the use of immunosuppressive treatments. Data from registries and single centre cohorts indicate that the risk of contracting SARS-CoV-2 does not seem to increase substantially in people with systemic sclerosis; conversely, severe COVID-19 outcomes are seen more frequently in these patients than in the general population. Vaccination against SARS-CoV-2 is therefore highly recommended for patients with systemic sclerosis; however, no specific recommendations are available regarding the different vaccine platforms. Both patients and physicians should be aware that the effectiveness of vaccines might be reduced in patients taking immunosuppressive therapy, because antibody responses might be blunted, specifically in patients treated with rituximab and mycophenolate mofetil.

Open questions on the management of targeted therapies for the treatment of systemic sclerosis-interstitial lung disease: results of a EUSTAR survey based on a systemic literature review.

Background: The results of randomized controlled (RCT) and retrospective studies have expanded the armamentarium of drugs for systemic sclerosis (SSc) - interstitial lung disease (ILD) treatment. The correct positioning of these drugs is not yet clarified. Objectives: Systemic literature review (SLR) on rituximab (RTX), tocilizumab (TCZ), nintedanib and abatacept (ABT) for the treatment of SSc-ILD. The results of the SLR were used to create a dedicated survey. Design: The study was performed as a systematic review. Data sources and methods: the SLR was performed using the following terms: "(systemic sclerosis OR scleroderma) AND (interstitial lung disease OR lung fibrosis OR pulmonary fibrosis) AND (rituximab OR tocilizumab OR abatacept OR nintedanib)". The results of the SLR were integrated in a survey including 8 domains. These were sent to all EUSTAR members and to the participants of the 2020 Scleroderma World Congress. Results: 41 studies (34 on RTX, 5 on TCZ, 2 on ABT, and 1 on nintedanib) were identified. RCTs supported the use of TCZ and nintedanib, while retrospective studies supported the use of RTX for SSc-ILD. No clear data were obtained about ABT. The survey showed that RTX is the most available option (96%) whereas the most frequent reason for targeted therapy introduction is lung progression while on csDMARDs (86% RTX, 59% TCZ and 63% nintedanib). Combination therapy was the most frequently mentioned therapeutic scheme for nintedanib (75%) and RTX (63%). Physicians' perception of safety was similar for all drugs, while drug efficacy was the same for RTX and nintedanib, followed by TCZ (4.8 ± 2). The most frequently raised concerns pertained to efficacy, safety and combination regimens. Conclusion: Our SLR supports the use of RTX, TCZ and nintedanib for SSc-ILD patients and underlines the need for more data about upfront combination versus monotherapy. It also highlighted the need to identify predictors supporting drug choice according to both pulmonary and extra-pulmonary manifestations.

The Role of the Multidisciplinary Health Care Team in the Management of Patients with Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare connective tissue disease characterised by immune dysfunction, vascular damage and fibrosis affecting the skin and multiple internal organs. The clinical spectrum of SSc is wide and its manifestations may lead to severe morbidity and mortality, in addition to a great impact on patients' quality of life. Due to the multifaceted clinical manifestations of SSc, its management requires a combined expertise of different medical specialists to guarantee an adequate disease control and prevent organ complications. Multi-disciplinary teams (MDT), which are composed by physicians and other specialized health professionals, represent therefore a key element for the comprehensive management of SSc patients. Moreover, MTD can improve communication and patients' empowerment while the presence of dedicated nurses can help patients to ask questions about their condition. The scope of this narrative review is to analyse the available evidences regarding the role of MDT in the management of SSc patients, and how this holistic approach may improve different disease domains and the overall prognosis. MDT regarding the cardiovascular and lung complication are the more represented in literature, given the great impact in prognosis. Nonetheless, MDT have been shown to be fundamental also in other disease domains as they can intercept early manifestations, thus stratifying patients based on the individual risks in order to personalize patients' follow-up. MDTs may also minimize the treatment delay, enabling fast-track specialist referral. On the other hand, there are few trials specifically studying MDT in SSc and several authors have highlight the lack of standardization.

Immune dysfunction in COVID-19 and judicious use of antirheumatic drugs for the treatment of hyperinflammation

In the Wuhan province of China, almost two years ago, in December 2019, the novel Coronavirus 2019 has caused a severe involvement of the lower respiratory tract leading to an acute life-threatening respiratory syndrome, coronavirus disease-19 (COVID-19). Subsequently, coronavirus 2 (SARS-CoV-2) rapidly spread to the entire world causing a pandemic and affected every single person on earth either directly or indirectly with destroying all facets of social life and economy. Since the announcement of COVID-19 as a global pandemic, we have witnessed tremendous scientific work on all aspects of COVID-19 across the globe, which has never been witnessed before. The most remarkable achievement would be the introduction of vaccines, which provide protection from the severe infection and is the only premise for the control of disease. However, despite the tremendous work, the number of treatments either antiviral or immunomodulatory for infected patients are considerably limited, yet disease is causing substantial morbidity and mortality. COVID-19 follows heterogenous disease course among infected individuals, and dysregulated immune system is primarily responsible for the worse outcomes. Immune deficiency, being on corticosteroids for inflammatory diseases, delayed interferon response and advanced age adversely influence prognosis with impairing viral clearance. On the other hand, exuberant immune response with features of cytokine storm is the leading cause of death, which can be alleviated by use of either general immunosuppression with corticosteroids or selective neutralization of potent pro-inflammatory cytokines such as interleukin (IL)-1 and IL-6. Herein, we summarized the potential effective immunomodulatory treatments emphasizing in which patient population it is the most suitable, which dose should be administered, and which is the most appropriate timepoint to administer the drug during the course of the disease.

The positive side of the coin: Sars-Cov-2 pandemic has taught us how much Telemedicine is useful as standard of care procedure in real life.

Patients and health workers were at high risk of infection during the Sars-Cov-2 pandemic lockdown. For this reason, other medical and clinical approaches such as Telemedicine were necessary. Despite Telemedicine was born before COVID-19, the pandemic was the opportunity to accelerate a process already underway for at least a decade and to blow all the barriers away. Our aim is to describe the experience of Telemedicine during and immediately after the first lockdown to assure the follow-up in a 'virtual' outpatient clinic dedicated to Rheumatic and Musculoskeletal Diseases (RMDs) and to give an overview of Telemedicine in the rheumatology field. We retrospectively evaluated the patient flow to our rheumatology division from March to September 2020 and, in accordance with local restrictions, three periods were selected. In the 1st period, 96.96% of the outpatient clinic cases were shifted to Telemedicine; these decreased to 52.45% in the 2nd period, while the 3rd period was characterized by the return of the patients at the clinic (97.6%). Diagnostic procedures were postponed during the 1st period, reduced drastically during the 2nd and performed regularly during the third period. Intravenous infusions were maintained as much as possible during the three periods, to assure therapeutic continuity. Shifting stable patients to Telemedicine has the potential to allow continuity of care, while reducing the risk of contagion during a pandemic. In the next future, the integration of Telemedicine as standard of care for specific clinical applications might assure assistance for RMDs patients also in non-pandemic conditions.

The role of chest CT in deciphering interstitial lung involvement: systemic sclerosis versus COVID-19.

OBJECTIVE: The aim of this study was to identify the main CT features that may help in distinguishing a progression of interstitial lung disease (ILD) secondary to SSc from COVID-19 pneumonia. METHODS: This multicentric study included 22 international readers grouped into a radiologist group (RADs) and a non-radiologist group (nRADs). A total of 99 patients, 52 with COVID-19 and 47 with SSc-ILD, were included in the study. RESULTS: Fibrosis inside focal ground-glass opacities (GGOs) in the upper lobes; fibrosis in the lower lobe GGOs; reticulations in lower lobes (especially if bilateral and symmetrical or associated with signs of fibrosis) were the CT features most frequently associated with SSc-ILD. The CT features most frequently associated with COVID- 19 pneumonia were: consolidation (CONS) in the lower lobes, CONS with peripheral (both central/peripheral or patchy distributions), anterior and posterior CONS and rounded-shaped GGOs in the lower lobes. After multivariate analysis, the presence of CONs in the lower lobes (P < 0.0001) and signs of fibrosis in GGOs in the lower lobes (P < 0.0001) remained independently associated with COVID-19 pneumonia and SSc-ILD, respectively. A predictive score was created that was positively associated with COVID-19 diagnosis (96.1% sensitivity and 83.3% specificity). CONCLUSION: CT diagnosis differentiating between COVID-19 pneumonia and SSc-ILD is possible through a combination of the proposed score and radiologic expertise. The presence of consolidation in the lower lobes may suggest COVID-19 pneumonia, while the presence of fibrosis inside GGOs may indicate SSc-ILD.

Similarities between COVID-19 and systemic sclerosis early vasculopathy: A "viral" challenge for future research in scleroderma.

OBJECTIVE: To review similarities between COVID-19 and systemic sclerosis (SSc) early vasculopathy to provide novel insights into both diseases. METHODS: A narrative review of the literature supplemented with expert opinion. RESULTS: There is clear evidence that the endothelium is at the centre stage in SSc and COVID-19, with endothelial cell activation/injury and dysfunction creating the crucial evolving step in the pathogenesis of both diseases. The angiotensin system has also been implicated in the early stages of both COVID-19 and SSc. Autoptic studies provide novel insights into the effects of SARS-CoV-2 on the endothelium. Normal endothelium and endothelial dysfunction in COVID-19 and SSc are discussed. It is debated whether SARS-CoV-2 infection triggers autoimmunity with production of autoantibodies which is of mechanistic interest because other viral illnesses are potentially involved in endothelial dysfunction and in SSc pathogenesis. CONCLUSION: COVID-19 is due to a direct assault of SARS-CoV-2 on the vascular system as an acute infection, whereas SSc remains a chronic/sub-acute autoimmune disease of largely unknown etiology Further study and exploration of the SARS-CoV-2 pathogenic mechanisms might provide further useful milestones in the understanding of the early SSc pathogenesis.

Combined lung and cardiac ultrasound in COVID-related acute respiratory distress syndrome.

BACKGROUND: Lung ultrasound (LU) is a useful tool for monitoring lung involvement in novel coronavirus (COVID) disease, while information on echocardiographic findings in COVID disease is to date scarce and heterogeneous. We hypothesized that lung and cardiac ultrasound examinations, serially and simultaneously performed, could monitor disease severity in COVID-related ARDS. METHODS: We enrolled 47 consecutive patients with COVID-related ARDS (1st March-31st May 2020). Lung and cardiac ultrasounds were performed on admission, at discharged and when clinically needed. RESULTS: Most patients were mechanically ventilated (75%) and veno-venous extracorporeal membrane oxygenation was needed in ten patients (21.2%). The in-ICU mortality rate was 27%%. On admission, not survivors showed a higher LUS score (p = 0.006) and a higher incidence of consolidations (p = 0.003), lower values of LVEF (p = 0.027) and a higher RV/LV ratio (0.008). At discharge, a significant reduction in the incidence of subpleural consolidations (p < 0.001) and, thus, in LUS score (p < 0.001) and an increase in patter A findings (p < 0.001) together with reduced systolic pulmonary arterial pressures were detectable. In not survivors at final examination, an increased in LUS score (p < 0.001), and in RV/LV ratio (p < 0.001) associated with a reduction in TAPSE (p = 0.013) were observed. A significant correlation was observed between LUS and systolic pulmonary arterial pressure (p = 0.04). LUS and RV/LV resulted independent predictors of in-ICU death. CONCLUSIONS: In COVID-related ARDS, the combined lung and cardiac ultrasound proved to be an useful clinical tool in monitoring disease progression and in identifying parameters (LU score and RV/LV ratio) able to risk stratifying these patients.

The impact of COVID-19 on rare and complex connective tissue diseases: the experience of ERN ReCONNET.

During the COVID-19 pandemic, the need to provide high-level care for a large number of patients with COVID-19 has affected resourcing for, and limited the routine care of, all other conditions. The impact of this health emergency is particularly relevant in the rare connective tissue diseases (rCTDs) communities, as discussed in this Perspective article by the multi-stakeholder European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN ReCONNET). The clinical, organizational and health economic challenges faced by health-care providers, institutions, patients and their families during the SARS-CoV-2 outbreak have demonstrated the importance of ensuring continuity of care in the management of rCTDs, including adequate diagnostics and monitoring protocols, and highlighted the need for a structured emergency strategy. The vulnerability of patients with rCTDs needs to be taken into account when planning future health policies, in preparation for not only the post-COVID era, but also any possible new health emergencies.

COVID-19 and systemic sclerosis: Rising to the challenge of a pandemic.

COVID-19, caused by infection of the novel coronavirus SARS-CoV-2, has caused a pandemic of enormous impact that has challenged healthcare and political system throughout the world. This new health emergency has occurred on top of the usual burden of diseases, including systemic sclerosis, and has led to many unanticipated consequences. An early consequence of the pandemic was postponement of the Sixth Systemic Sclerosis World Congress that was recently completed as a successful virtual congress with more than 1000 delegates. In this article, we summarise the relevance and impact of COVID-19 from the perspective of systemic sclerosis. Shared concepts of pathogenesis are considered, and the relevant literature emerging about COVID-19 and systemic sclerosis summarised. The specific impact of this pandemic on delivery of optimal scleroderma care is considered, together with the broader effect on rheumatic and musculoskeletal diseases and the activities of European League Against Rheumatism. As the World continues to struggle against this new infectious disease, it is notable that expertise and growing understanding of systemic sclerosis has been able to help tackle COVID-19. Moreover, the essential adjustments to deliver clinical care and establishment of new ways of working due to the pandemic have offered potential avenues for future improvement in systemic sclerosis care.

The systemic sclerosis patient in the COVID-19 era: the challenging crossroad between immunosuppression, differential diagnosis and long-term psychological distress.

COVID-19 is a world health emergency which may inevitably affect the management of a complex autoimmune disease such as systemic sclerosis (SSc). Several SSc patients are frail and, in this pandemic, need a careful protection. The COVID-19 infection might complicate the clinical scenario of interstitial lung disease (ILD) in SSc because it determines a severe pneumonia characterized by radiological features similar to SSc-ILD. The striking CT similarities between the 2 diseases make it difficult to distinguish a worsening of SSc-ILD from COVID-19-ILD superinfection. Moreover, other aspects, like isolation during lock down, may cause a significant psychological stress which will pile up on the already difficult contact with the patients for a routine check-up. Moreover, the drug shortage is a real problem in these times. For these reasons, the rheumatologist in daily clinical practice should carefully differentiate the possible COVID-19 infection in order to optimize the patient management. Therefore, the challenge in everyday life will be to achieve in due time the differential diagnosis as well as the long-term psychological impact.Key Points• SSc patients should be encouraged to continue their chronic therapy; in case of immunosuppressive therapy it must be discontinued for safety in case of COVID-19 infection.• Psychological support must be guaranteed to every SSc patients.• COVID-19 pneuminia is hard to distinguish from an interstitial lung disease due to SSc lung involvment.• Data sharing is fundamental for an optimal managment of SSc patients during COVID-19 pandemia.

The emerging role of lung ultrasound in COVID-19 pneumonia.

In the last decades lung ultrasound (LUS) has become of crucial importance in the evaluation and monitoring of a widely range of pulmonary diseases. One of the major benefits which favours this examination, is that this is a non-invasive, low-cost and radiation-free imaging modality which allows repeated imaging. LUS plays an important role in a wide range of pathologies, including cardiogenic oedema, acute respiratory distress syndrome and fibrosis. Specific LUS findings have proved useful and predictive of acute respiratory distress syndrome which is of particular relevance in the suspicion and monitoring of patients with lung disease. Furthermore, several studies have confirmed the role of LUS in the screening of interstitial lung diseases in connective tissue diseases. Given these data, LUS will likely play an important role in the management of COVID-19 patients from identification of specific abnormalities corresponding to definite pneumonia phases and CT scans findings. In addition, LUS could allow reduction in the exposure of health-care workers to potential infection. Herein, we provide a summary on emerging role of lung ultrasound in COVID-19 pneumonia.

Systemic sclerosis and the COVID-19 pandemic: World Scleroderma Foundation preliminary advice for patient management.

Due to the frequent presence of interstitial lung disease and widespread use of immunosuppressive treatment, systemic sclerosis (SSc) patients may be considered at risk for a more severe disease course and higher mortality when they develop Severe Acute Respiratory Syndrome - Coronavirus - 2 (SARS-CoV-2) virus infection. Therefore, with World Scleroderma Foundation endorsement, experts from different specialties including rheumatology, virology and clinical immunology gathered virtually to answer to the main practical clinical questions regarding SARS-CoV-2 infection coming from both patients and physicians. This preliminary advice is aligned with other national and international recommendations, adapted for SSc patients.

COVID-19, immune system response, hyperinflammation and repurposing antirheumatic drugs

In the Wuhan Province of China, in December 2019, the novel coronavirus 2019 (COVID-19) has caused a severe involvement of the lower respiratory tract leading to an acute respiratory syndrome. Subsequently, coronavirus 2 (SARS-CoV-2) provoked a pandemic which is considered a life-threatening disease. The SARS-CoV-2, a family member of betacoronaviruses, possesses single-stranded positive-sense RNA with typical structural proteins, involving the envelope, membrane, nucleocapsid and spike proteins that are responsible for the viral infectivity, and nonstructural proteins. The effectual host immune response including innate and adaptive immunity against SARS-Cov-2 seems crucial to control and resolve the viral infection. However, the severity and outcome of the COVID-19 might be associated with the excessive production of proinflammatory cytokines "cytokine storm" leading to an acute respiratory distress syndrome. Regretfully, the exact pathophysiology and treatment, especially for the severe COVID-19, is still uncertain. The results of preliminary studies have shown that immune-modulatory or immune-suppressive treatments such as hydroxychloroquine, interleukin (IL)-6 and IL-1 antagonists, commonly used in rheumatology, might be considered as treatment choices for COVID-19, particularly in severe disease. In this review, to gain better information about appropriate anti-inflammatory treatments, mostly used in rheumatology for COVID-19, we have focused the attention on the structural features of SARS-CoV-2, the host immune response against SARS-CoV-2 and its association with the cytokine storm.