COVID-19 and systemic sclerosis: clinicopathological implications from Italian nationwide survey study
Authors: Clodoveo Ferri, Dilia Giuggioli, Vincenzo Raimondo, Lorenzo Dagna, Valeria Riccieri, Elisabetta Zanatta, Serena Guiducci, Antonio Tavoni, Rosario Foti, Giovanna Cuomo, Rossella De Angelis, Franco Cozzi, Giuseppe Murdaca, Ilaria Cavazzana, Nicoletta Romeo, Veronica Codullo, Francesca Ingegnoli, Roberta Pellegrini, Giuseppe Varcasia, Alessandra Della Rossa, Maria De Santis, Giuseppina Abignano, Michele Colaci, Maurizio Caminiti, Massimo L'Andolina, Ennio Lubrano, Amelia Spinella, Federica Lumetti, Giacomo De Luca, Silvia Bellando-Randone, Elisa Visalli, Silvia Bilia, Daiana Giannini, Francesco Masini, Greta Pellegrino, Erika Pigatto, Elena Generali, Francesca Dall'Ara, Giuseppa Pagano Mariano, Simone Barsotti, Giorgio Pettiti, Giovanni Zanframundo, Raffaele Brittelli, Vincenzo Aiello, Daniela Scorpiniti, Tommaso Ferrari, Rodolfo Caminiti, Corrado Campochiaro, Salvatore D'Angelo, Florenzo Iannone, Marco Matucci-Cerinic, Andrea Doria, Mario Miccoli, Poupak Fallahi, Alessandro Antonelli, Clodoveo Ferri, Dilia Giuggioli, Vincenzo Raimondo, Lorenzo Dagna, Valeria Riccieri, Elisabetta Zanatta, Serena Guiducci, Antonio Tavoni, Rosario Foti, Giovanna Cuomo, Rossella De Angelis, Franco Cozzi, Giuseppe Murdaca, Ilaria Cavazzana, Nicoletta Romeo, Veronica Codullo, Francesca Ingegnoli, Roberta Pellegrini, Giuseppe Varcasia, Alessandra Della Rossa, Maria De Santis, Giuseppina Abignano, Michele Colaci, Maurizio Caminiti, Massimo L'Andolina, Ennio Lubrano, Amelia Spinella, Federica Lumetti, Giacomo De Luca, Silvia Bellando-Randone, Elisa Visalli, Silvia Bilia, Daiana Giannini, Francesco Masini, Greta Pellegrino, Erika Pigatto, Elena Generali, Francesca Dall'Ara, Giuseppa Pagano Mariano, Simone Barsotti, Giorgio Pettiti, Giovanni Zanframundo, Raffaele Brittelli, Vincenzo Aiello, Daniela Scorpiniti, Tommaso Ferrari, Rodolfo Caminiti, Corrado Campochiaro, Riccardo Cecchetti, Pietro Gigliotti, Domenico Olivo, Francesco Ursini, Veronica Brusi, Riccardo Meliconi, Raffaele Scarpa, Enrico Fusaro, Anna Linda Zignego, Salvatore D'Angelo, Florenzo Iannone, Marco Matucci-Cerinic, Andrea Doria, Mario Miccoli, Sabrina Rosaria Paparo, Francesca Ragusa, Giusy Elia, Silvia Martina Ferrari, Poupak Fallahi, Alessandro Antonelli
Journal: The Lancet Rheumatology (2021)

The ongoing COVID-19 pandemic caused by the novel β-coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses a serious challenge for the management of patients with different pre-existing comorbidities,1WHOCoronavirus disease 2019 (COVID-19): situation report, 51.https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf?sfvrsn=1ba62e57_10Date: March 11, 2020Date accessed: March 11, 2020Google Scholar, 2Guan WJ Ni ZY Hu Y et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; 382: 1708-1720Crossref PubMed Scopus (20525) Google Scholar including rheumatic autoimmune systemic diseases.3Gianfrancesco MA Hyrich KL Gossec L et al.Rheumatic disease and COVID-19: initial data from the COVID-19 Global Rheumatology Alliance provider registries.Lancet Rheumatol. 2020; 2: e250-e253Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 4Ferri C Giuggioli D Raimondo V et al.COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series.Clin Rheumatol. 2020; 39: 3195-3204Crossref PubMed Scopus (110) Google Scholar, 5Fredi M Cavazzana I Moschetti L Andreoli L Franceschini F Brescia Rheumatology COVID-19 Study GroupCOVID-19 in patients with rheumatic diseases in northern Italy: a single-centre observational and case-control study.Lancet Rheumatol. 2020; 2: e549-e556Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar These diseases affect a non-negligible proportion of individuals worldwide and are characterised by profound immune system alterations and increased susceptibility to infections, frequently aggravated by immune-modulating therapies.3Gianfrancesco MA Hyrich KL Gossec L et al.Rheumatic disease and COVID-19: initial data from the COVID-19 Global Rheumatology Alliance provider registries.Lancet Rheumatol. 2020; 2: e250-e253Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar, 4Ferri C Giuggioli D Raimondo V et al.COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series.Clin Rheumatol. 2020; 39: 3195-3204Crossref PubMed Scopus (110) Google Scholar, 5Fredi M Cavazzana I Moschetti L Andreoli L Franceschini F Brescia Rheumatology COVID-19 Study GroupCOVID-19 in patients with rheumatic diseases in northern Italy: a single-centre observational and case-control study.Lancet Rheumatol. 2020; 2: e549-e556Summary Full Text Full Text PDF PubMed Scopus (110) Google Scholar, 6Lu C Li S Liu Y Role of immunosuppressive therapy in rheumatic diseases concurrent with COVID-19.Ann Rheum Dis. 2020; 79: 737-739PubMed Google Scholar Among autoimmune systemic diseases, patients with connective tissue diseases or systemic vasculitis showed a higher prevalence of symptomatic SARS-CoV-2 infection (ie, COVID-19) than did patients with chronic arthritis.4Ferri C Giuggioli D Raimondo V et al.COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series.Clin Rheumatol. 2020; 39: 3195-3204Crossref PubMed Scopus (110) Google Scholar Systemic sclerosis represents one of the most severe connective tissue diseases with multi-organ involvement due to concomitancy of fibrosing and microvascular alterations.7Denton CP Khanna D Systemic sclerosis.Lancet. 2017; 390: 1685-1699Summary Full Text Full Text PDF PubMed Scopus (1379) Google Scholar However, the literature on the impact of COVID-19 in patients with systemic sclerosis is limited to anecdotal reports or single-centre survey studies focusing on a miscellanea of rheumatic autoimmune disorders.4Ferri C Giuggioli D Raimondo V et al.COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series.Clin Rheumatol. 2020; 39: 3195-3204Crossref PubMed Scopus (110) Google Scholar, 8Avouac J Airó P Carlier N Matucci-Cerinic M Allanore Y Severe COVID-19-associated pneumonia in 3 patients with systemic sclerosis treated with rituximab.Ann Rheum Dis. 2020; (published online June 5.)http://dx.doi.org/10.1136/annrheumdis-2020-217864Crossref Scopus (67) Google Scholar, 9Bellan M Parisi S Stobbione P et al.Impact of the Covid-19 outbreak on an Italian cohort of systemic sclerosis patients.Scand J Rheumatol. 2020; 49: 505-506Crossref PubMed Scopus (7) Google Scholar Following the rapid spread of COVID-19 in Italy, the restrictions on individual movement have compromised the regular face-to-face activities of outpatient clinics; therefore, telemedicine has represented an effective alternative for the close monitoring of immunocompromised patients. Between March 15 and April 25, 2020, we carried out a nationwide survey study to investigate the cumulative prevalence of COVID-19 in Italian patients with systemic sclerosis resident in geographical macro-areas with different pandemic spread (high in north, medium in central, and low in south Italy). 1636 unselected patients with systemic sclerosis were consecutively investigated by means of a telephone survey done at 27 tertiary referral centres of 14 Italian regions (five northern, three central, and six southern) over a 6-week period. Clinical and serological assessment of patients with systemic sclerosis and telephone interview procedures, including a standardised symptom assessment questionnaire, were carried out as previously described.4Ferri C Giuggioli D Raimondo V et al.COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series.Clin Rheumatol. 2020; 39: 3195-3204Crossref PubMed Scopus (110) Google Scholar COVID-19 was classified according to currently used criteria as definite COVID-19 (signs or symptoms of COVID-19 confirmed by positive oral or nasopharyngeal swabs at PCR testing) or highly suspected COVID-19 (signs or symptoms highly suggestive of COVID-19, but not confirmed by PCR testing due to limited availability of virological tests in that period).4Ferri C Giuggioli D Raimondo V et al.COVID-19 and rheumatic autoimmune systemic diseases: report of a large Italian patients series.Clin Rheumatol. 2020; 39: 3195-3204Crossref PubMed Scopus (110) Google Scholar The results of our nationwide survey are reported in the appendix (pp 1–2). Among 1636 patients with systemic sclerosis, mean age was 59·5 years (SD 12·8), mean disease duration was 11·2 years (8·7), female to male ratio was 8:1, 1112 (68%) patients had limited cutaneous systemic sclerosis, 278 (17%) had systemic sclerosis, 245 (15%) had sine scleroderma systemic sclerosis, 510 (31%) had symptomatic systemic sclerosis-related interstitial lung involvement, 425 (26%) had cardiomyopathy, 507 (31%) had serum anti-Scl70, and 736 (45%) had anticentromere antibodies. Moreover, 1559 (95%) patients were taking at least one of the following drugs: low-dose steroids, conventional synthetic disease-modifying antirheumatic drugs, vasoactive drugs (often iloprost or other prostanoids, bosentan, or calcium channel blockers), or low-dose aspirin; biological disease-modifying antirheumatic drugs were administered in only 72 (4%) of 1636 individuals. After the telephone survey, definite COVID-19 was reported in 14 (1%) patients and highly suspected COVID-19 in 47 (3%) patients (appendix p 1). These prevalences were invariably higher (p=0·0010) than the prevalence reported in the general Italian population of individuals with COVID-19 (349 per 100 000 population; data from the Italian Superior Institute of Health, updated report on April 28, 2020). Compared with the prevalence of COVID-19 in the Italian general population, the proportion of definite COVID-19 among patients with systemic sclerosis might be an underestimate, since 30% of COVID-19 cases in the Italian population in that period were asymptomatic; conversely, the prevalence of highly suspected COVID-19 among patients with systemic sclerosis might overestimate the prevalence of COVID-19 compared with the Italian general population. The prevalence of COVID-19 in the macro-areas (Lombardy, Piemonte, Veneto, Emilia Romagna, and Liguria) of northern Italy was higher than that observed in the southern macro-areas (Campania, Molise, Puglia, Calabria, and Sicily; p=0·0030); moreover, significantly increased prevalence of COVID-19 was also found in patients with systemic sclerosis resident in Lombardy, the Italian region with the highest number of cases of COVID-19 in the general population (appendix p 1). Clinically mild-to-moderate COVID-19 manifestations were observed in the majority of systemic sclerosis patients, whereas nine (15%) of 61 symptomatic individuals required hospital admission due to respiratory symptoms. Unfortunately, four of the nine patients who were admitted to hospital died: two men aged 81 years and 85 years, because of COVID-19-related severe pneumonia, and two women, a 42-year-old patient because of rapid worsening of pre-existing systemic sclerosis cardiopulmonary involvement, and 65-year-old individual with systemic sclerosis-related lung fibrosis complicated by acute respiratory distress syndrome, pulmonary venous and arterial thrombotic disease, and embolic stroke. Definite COVID-19 was statistically more frequent in patients with pre-existing systemic sclerosis-related symptomatic interstitial lung involvement than in those without (p<0·0001; appendix p 2). Moreover, the presence or absence of COVID-19 did not correlate with other systemic sclerosis clinical or serological features; no associations were observed between ongoing treatments and the appearance of COVID-19 symptoms, with the exception of significantly lower prevalence of COVID-19 in patients treated with chronic low-dose aspirin than in those who were not (p=0·0060; appendix p 2). Taken together, these findings are particularly noteworthy due to their pathological and clinical implications. Systemic sclerosis is the result of a multifactorial and multistep aetiopathogenetic process whereby numerous genetic, epigenetic, and environmental factors can affect the appearance of different clinical phenotypes and overall outcome.7Denton CP Khanna D Systemic sclerosis.Lancet. 2017; 390: 1685-1699Summary Full Text Full Text PDF PubMed Scopus (1379) Google Scholar Notably, COVID-19 and systemic sclerosis share pathological alterations: interstitial lung involvement that might evolve to fibrosis and endothelial injury responsible for diffuse microangiopathy.7Denton CP Khanna D Systemic sclerosis.Lancet. 2017; 390: 1685-1699Summary Full Text Full Text PDF PubMed Scopus (1379) Google Scholar, 10Varga Z Flammer AJ Steiger P et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Summary Full Text Full Text PDF PubMed Scopus (4570) Google Scholar The fact that definite COVID-19 was more prevalent in patients with pre-existing systemic sclerosis-related symptomatic interstitial lung involvement (than in those without), together with the high prevalence of death among patients with systemic sclerosis admitted to hospital with COVID-19, suggests that the risk of severe COVID-19 is high in patients with systemic sclerosis. These results, as well the low prevalence of COVID-19 in individuals undergoing chronic low-dose aspirin treatment, are in keeping with the pathogenic features described previously.7Denton CP Khanna D Systemic sclerosis.Lancet. 2017; 390: 1685-1699Summary Full Text Full Text PDF PubMed Scopus (1379) Google Scholar, 10Varga Z Flammer AJ Steiger P et al.Endothelial cell infection and endotheliitis in COVID-19.Lancet. 2020; 395: 1417-1418Summary Full Text Full Text PDF PubMed Scopus (4570) Google Scholar Besides the direct virus-related tissue damage, we hypothesise that SARS-CoV-2 might amplify the ongoing systemic sclerosis manifestations during the acute phase of viral infection; later, it might also contribute to advanced scleroderma organ damage. Long-term follow-up studies on large series of patients with systemic sclerosis and SARS-CoV-2 infection might clarify this issue. In-depth investigations on the possible interactions between SARS-CoV-2 infection and a compromised host immune system might provide useful pathogenic and therapeutic insights for both COVID-19 and systemic sclerosis. Given the unpredictable, threatening course of the pandemic, valuable prevention and management strategies for particularly vulnerable individuals, such as patients with scleroderma, are highly advisable. We declare no competing interests. We could not obtain written informed consent from our patients because of the telephone survey was done during the strict lockdown; therefore, all contacted patients who freely agreed to participate in the survey gave oral consent, according to the policy of our institutions. Download .pdf (.21 MB) Help with pdf files Supplementary appendix