The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) led to a pandemic in the late 2019 and affected the worldwide population resulting in almost five million deaths and more than 200 million confirmed cases [1]. Since the pandemic progressed, more studies shed light on the topic and researchers started speculating that comorbidities can increase the risk of adverse outcomes in COVID-19 disease [2]. Autoimmune diseases (ADs) including systemic sclerosis (SSc) were one of the comorbidities that came under scrutiny as researchers hypothesized that extensive use of immunosuppressive and anti-cytokine drugs for the treatment of these conditions may put the patients at higher risk of COVID-19 infection [3]. On the contrary, one study suggested that morbidity and mortality of COVID-19 infection in SSc patients may not be as severe as initially thought [4]. Due to these inconsistencies among the studies and challenges surrounding the management of SSc patients during the pandemic, we reviewed the recently published articles on the topic.

A recent systematic review and meta-analysis by Akiyama et al. with 319 025 patients identified that prevalence of COVID-19 in AD patients was 1.1% [3]. A subgroup analysis in the aforementioned study also showed that 1641 patients with either of systemic lupus erythematous (SLE), Sjögren’s syndrome (SjS), and SSc had 3.4% prevalence of COVID-19 [3]. The prevalence of COVID-19 in SLE, SjS, and SSc patients was the highest among other ADs in this systematic review and the authors attributed it to higher glucocorticoid use (60.3%) in them. Due to complications of glucocorticoids in SSc patients (e.g., scleroderma renal crisis), they are usually treated with lower doses and shorter durations of glucocorticoids [5]. Additionally, the SLE, SjS, and SSc population in Akiyama et al. study mainly consisted of SLE patients and it is unknown whether the findings of this study still hold true in patient populations consisting of only SSc subjects [3].

The subgroup analysis of case-control articles in the Akiyama et al. study also revealed that COVID-19 prevalence was significantly higher among AD patients when compared with the controls (OR: 2.19, 95% CI: 1.05 to 4.58, p = 0.038). A national survey study performed in Italy with 1636 SSc patients (mean age = 59.5 years, 68% with limited form and 17% with systemic Sclerosis) reported 1% cumulative prevalence of confirmed COVID-19 cases over a 6-week period [6]. In the previous letter from Iran, we observed a 6-month cumulative prevalence of 6% [7]. This higher prevalence is expected due to longer period of the study and different prevalence of COVID-19 in general population in that time in the two countries [6,7]. The Italian survey showed that confirmed COVID-19 cases were significantly more common among the SSc patients when compared to the general population (0.85% vs. 0.34%, p value = 0.001). It is important to note that the number of confirmed COVID-19 cases among SSc patients in the Italian population might be an underestimate, since 30% of COVID-19 cases were asymptomatic in that time period [6].

Overall, it appears that SSc patients are more prone to getting infected with COVID-19 and reports from previous studies suggesting COVID-19 prevalence is not higher among SSc patients may not be reliable as they did not include a control group [4]. Even though most of the studies agree about the higher prevalence of COVID-19 in AD and SSc patients, data about severity and mortality of COVID-19 infection in SSc patients is not conclusive as most of the studies are observational studies without appropriate sample size and control groups [4,6,8]. Subgroup analysis in the Akiyama et al. study revealed that hospitalization, intensive unit care (ICU) admission, mechanical ventilation, and mortality were not more common among patients with ADs when compared with the controls [3]. The Italian survey study reported four deceased patients among 61 COVID-19 infected SSc subjects [6]. Another cohort study from Italy reported one deceased patient, whereas in our letter in Iran no SSc patients died because of COVID-19 infection [4,7]. Additional studies comparing the severity outcomes and mortality between confirmed COVID-19 cases with previous history of SSc and COVID-19 patients without SSc are required to reach firm conclusions on the topic.

Several pathobiological characteristics of SSc and COVID-19 are considered to be similar. Vasculopathy, cytokine release syndrome, and fibrosis have all been known to occur in both of the conditions and this has raised the question whether COVID-19 can further exacerbate SSc. This similarity has been so enormous that rheumatologists have been deemed well placed to move into COVID-19 care [9]. It has been proposed that IL-6 levels raise in the COVID-19 associated cytokine storm and represent a lung immune over-reaction. Some reports have even suggested the use of anti-IL6 therapy [10]. Tocilizumab, an IL-6 antagonist, has been recently approved by the US Food and Drug Administration as an alternative agent in the initial therapy of ILD in SSc patients [11]. Tocilizumab may be a viable alternative initial therapy for SSc-ILD patients during the pandemic as there may be no need to discontinue the drug if patients are infected with COVID-19 [11].

The resemblance of pathophysiology between the two diseases has led to clinical similarities as well. One challenge has been to differentiate the chest CT imaging characteristics of the two conditions. It has been suggested that CT imaging of some hospitalized patients with Nonspecific interstitial pneumonia due to SSc can be mistaken with COVID-19 lung involvement [12]. This confusion can result in SSc patients receiving high dose immunosuppressive therapies (e.g., pulse methylprednisolone). These therapies can expose SSc patients to hospital acquired infections or scleroderma renal crisis and further complicate their disease course [12]. A study by Martina Orlandi et al. has suggested some methods to differentiate COVID-19 lung involvement from SSc related interstitial lung disease (ILD) [12]. Fibrosis inside focal ground glass opacities (GGO) in upper or lower lobes and reticulation in lower lobes (especially if it was bilateral/symmetrical or with signs of fibrosis) were more specific for SSc related ILD, whereas consolidations in the lower lobes, consolidations with peripheral distributions, and rounded-shaped GGOs in the lower lobes were more specific for COVID-19 pneumonia [12]. Although the aforementioned study compared CT characteristics of the two conditions, differentiating CT scans of patients with superimposed COVID-19 pneumonia on SSc-ILD from CT scans of subjects with only SSc related lung involvement still remains a challenge.  This finding further complicates the results of previous studies as some of the patients who were reported to be highly suspected of COVID-19 without positive RT-PCR result may have been SSc patients with ILD and no COVID-19 pneumonia. Additionally, some SSc patients with positive RT-PCR and CT evidence of COVID-19 lung involvement may simply have COVID-19 infection without the associated pneumonia and the CT characteristics may be because of their previous ILD.

Another challenge in managing SSc patients in COVID-19 pandemic has been to either continue or stop their immunosuppressive treatment. Currently world scleroderma foundation recommends that rheumatologists should decide on a case-specific basis [13]. A subgroup analysis of the Akiyama et al. study showed that treatment of AD patients with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) e.g., hydroxychloroquine, cyclophosphamide, cyclosporine, methotrexate, and mycophenolate mofetil/mycophenolic acid was associated with more severe COVID-19 outcomes, however, monotherapy with biologic or targeted synthetic DMARDs (b/tsDMARDs) e.g., abatacept, belimumab, rituximab (anti-CD20 monoclonal antibody), tocilizumab (IL-6 receptor antagonist), and particularly anti-TNF was associated reduced risk of hospitalization and mortality due to COVID-19 [3]. Mycophenolate mofetil and cyclophosphamide are currently the preferred first line treatment options for SSc-ILD [14]. The Italian national survey also revealed that SSc patients with ILD were more prone to getting infected with COVID-19 than SSc patients without prior ILD (1.9% vs. 0.4%, p value = 0.001) [6]. This finding may be due to higher usage of mycophenolate mofetil and cyclophosphamide among SSc-ILD patients [14]. Reports on the use of rituximab have been conflicting. Contrary to the Akiyama et al. study, one report has suggested severe COVID-19 pneumonia in three SSc patients taking rituximab [15]. These findings indicate that SSc-ILD patients may be more prone to getting infected with severe forms of COVID-19 infection due to previous lower lung capacity and taking csDMARDs [16]. In our previous study 40% of the patients with COVID-19 were taking mycophenolate mofetil [7], however, due to low statistical power we did not compare the differences between the therapies of the infected and not infected patients. Future studies with larger sample sizes and control groups can help in this regard.

SSc patients also faced several problems in continuing their routine follow-up during the pandemic. Due to rapid progression of COVID-19 cases, all hospitals had to allocate all of their beds to COVID-19 patients and most of the outpatient clinics closed [16]. Cardiopulmonary screening and routine follow ups of SSc patients were postponed [4]. Rheumatologists also became reluctant to hospitalize SSc subjects to reduce COVID-19 infection risk [17]. This put the patients at an increased risk of disease progression and comorbidities. Close medical follow up is required for these patients as screening their heart, lungs, and kidneys is a vital step in their management. Furthermore, they require several hospitalizations for active peptic ulcers, Scleroderma Renal Crisis, myositis or cardiomyopathy, and receiving intravenous therapies (e.g., iloprost, cyclophosphamide, etc.). Home visits by the physicians, allocation of specific non-Covid wards for hospitalization of immunocompromised patients, utilization of telemedicine methods, reducing contact during the clinic visits, separating the clinic days of immunocompromised patients from others, and performing rapid COVID-19 tests are all effective ways to improve the quality of care that SSc patients receive during the pandemic [7].

In conclusion, the prevalence of COVID-19 infection appears to be higher among SSc subjects but the data about the severity and mortality of the condition remains inconclusive. Most of the studies are preliminary investigations with low statistical power and weak assumptions without firm evidence. Management of the SSc patients during the pandemic still remains a challenge and more studies are required on the topic to further clarify the ambiguities currently present in the literature.

Authors declare no conflicts of interest.