autoimmunity, COVID-19, cytokine storm, endotheliitis, Raynaud phenomenon, systemic sclerosis



  1. Giuggioli, Dilia MD, PhD
  2. Spinella, Amelia MD, PhD
  3. de Pinto, Marco MD
  4. Mascia, Maria Teresa MD
  5. Salvarani, Carlo MD


ABSTRACT: In 2019, the novel SARS-CoV-2 infection emerged, causing the disease called COVID-19, which primarily affects the respiratory tract and lung at alveolar and interstitial levels. Systemic sclerosis (SSc) is an autoimmune connective disease characterized by vascular abnormalities and diffuse and progressive fibrosis of the skin and internal organs. Raynaud phenomenon (RP) occurs in virtually all patients affected by SSc and, in most cases, is an onset symptom of the disease; that is, RP may appear several years before overt illness. Although the exact pathophysiologic pathways leading to RP and SSc are still unknown, several infectious agents, especially viruses, have been suggested as possible triggering factors. Here, the authors describe the first case of RP secondary to SSc following SARS-CoV-2 infection.


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Raynaud phenomenon (RP) is a vasospastic disease characterized by digital pallor, cyanosis, and extremity pain. The pathophysiology of RP is poorly understood; in RP related to systemic sclerosis (SSc; a connective tissue disease characterized by skin and visceral organ involvement), abnormalities in vascular structure and function may play major roles. Infectious agents have been proposed as possible triggering factors.1 Among these, SARS-CoV-2 infection may play a part in the pathogenesis of RP because it can infect vascular and endothelial cells.2 Herein, the authors report the case of a 53-year-old woman who developed secondary RP after an episode of acute SARS-CoV-2 infection.



In March 2020, the patient presented to the ED with complaints of malaise, myalgia, high fever, mild cough, headache, and one episode of diarrhea. Her medical history was unremarkable; she worked as a nurse. A nasopharyngeal swab reverse transcription-polymerase chain reaction test was positive for SARS-CoV-2 infection. In the ED, physical examination revealed a mildly impaired general condition without hemodynamic or respiratory instability. Vital signs were within the normal range except for fever (38[degrees] C), and oxygen saturation was 98% on air. Chest radiography showed mild interstitial infiltrates in both lungs, and laboratory results reflected normal lymphocytes, normal procalcitonin (0.04 ng/mL), and elevated C-reactive protein (65 mg/L). She was treated with azithromycin for 5 days and hydroxychloroquine in a dose of 400 mg twice a day for 1 day and then 200 mg every 12 hours for 5 days with gradual improvement.


In April 2020, she presented to the ED with weakness, dysgeusia, and "white and blue hands" during water contact. In May 2020, she was referred to the authors' rheumatology unit for the persistent painful pallor and cyanosis of her fingers, polyarthralgia, myalgia, and fatigue. She also presented with sicca syndrome, occasional palpitations, and dyspnea on exertion (Borg scale 3/10).


Her providers noted the presence of RP (Figure 1), puffy fingers, a positive Schirmer test in both eyes, and circulating antinuclear antibodies with an anticentromere pattern. Nailfold videocapillaroscopy revealed an "early scleroderma pattern" (Figure 2). Virologic investigation confirmed the presence of serum immunoglobulin G anti-SARS-CoV-2 antibodies. Doppler signals of the upper extremities and hands were normal, as were thyroid and clotting functions. The patient decided not to repeat the chest X-ray to limit exposure to radiation. Pulmonary function tests showed only mild impairment in the diffusing capacity of the lung for carbon monoxide (79%).

Figure 1 - Click to enlarge in new windowFigure 1.
Figure 2 - Click to enlarge in new windowFigure 2.

Because of her puffy fingers, telangiectasia, and the scleroderma pattern noted on videocapillaroscopy, the patient was diagnosed with very early SSc, in line with the findings of the VEDOSS (Very Early Diagnosis of Systemic Sclerosis) project.3 The patient was advised to avoid cold and to use gloves and warmers; an oral calcium-channel blocker (nifedipine 10 mg daily) and a topical capsaicin cream, if needed, were prescribed to treat the patient's RP. Skin hydration with hemp oil, germ oil, and ceramide skin care products was suggested to prevent cutaneous xerosis, fissures, and/or digital lesions, and topical medications and hyaluronic acid were recommended to treat xerostomia.4 Follow-up with the patient is ongoing; her clinical status is stable, with some mucocutaneous manifestations.


The patient provided written informed consent to publish this information and the associated images.



The appearance of SSc shortly after an acute episode of viral infection suggests a possible triggering role for SARS-CoV-2. Immune system dysregulation alters fibroblasts and vascular alterations, such as those seen in COVID-19 infections, may contribute to SSc development.1,5-8 The presence of RP and diffuse microangiopathy suggests that endothelial injury is the first step in SSc pathogenesis. SARS-CoV-2 uses the angiotensin-converting enzyme-2 receptor in pneumocytes to infect its host. Because this enzyme is widely expressed in endothelial cells, COVID-19 can cause diffuse endotheliitis.2 An altered inflammatory immune response leading to cytokine storm syndrome could contribute to endothelial and/or fibroblast damage in genetically predisposed individuals who contract COVID-19.3 Finally, SARS-CoV-2 may trigger a host antiviral response that is responsible for specific autoantibodies cross-reacting with endothelial autoantigens.4 This molecular mimicry mechanism has also been suggested for different viruses and in disorders characterized by diffuse vascular disease, including SSc.5



To the authors' knowledge, this is the first observation of RP secondary to SSc following SARS-CoV-2 infection. SARS-CoV-2-driven autoimmunity may be critical in the cascade of events leading to typical SSc alterations. Providers should also consider possible contributions from genetic and/or environmental cofactors. Further studies with larger populations are needed to investigate the possible correlation between SARS-CoV-2 infection and the development of autoimmune diseases, in particular RP and connective tissue diseases such as SSc.




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