Environmental Triggers for Connective Tissue Disease

The Case of COVID-19 Associated With Dermatomyositis-Specific Autoantibodies

Maria De Santis; Natasa Isailovic, Francesca Motta; Caterina Ricordi; Angela Ceribelli; Ezio Lanza; Elena Azzolini; Salvatore Badalamenti; Antonio Voza; Carlo Selmi

Disclosures

Curr Opin Rheumatol. 2021;33(6):514-521.

Abstract and Introduction

Abstract

Purpose of Review: The aim of the present review is to analyze the link between autoimmune diseases and environmental factors, in particular severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) as it shares numerous features with the interstitial lung disease associated with connective tissue diseases positive for rare autoantibodies directed at highly specific autoantigens (i.e., MDA5 and RIG1) among the intracellular sensors of SARS-CoV-2 in the innate response against viruses.

Recent Findings: As shown in recent publications and in our original data, specific autoantibodies may be functionally relevant to COVID-19 infection. We evaluated sera from 35 hospitalized patients with COVID-19 to identify antinuclear antibodies and autoantibodies directed against specific antigenic targets, and we identified anti-nuclear antibodies (ANA) in 20/35 of patients with COVID-19 (57%), in patients with need for supplemental oxygen (90% vs. 20% in ANA-negative cases; P < 0.0001). In 7/35 COVID-19 sera, we detected anti-MJ/NXP2 (n = 3), anti-RIG1 (n = 2), anti-Scl-70/TOPO1 (n = 1), and anti-MDA5 (n = 1), overall associated with a significantly worse pulmonary involvement at lung computerized tomography scans. Eleven (31%) patients were positive for antibodies against the E2/E3 subunits of mitochondrial pyruvate dehydrogenase complex.

Summary: Viral infections such as COVID-19 are associated with ANA and autoantibodies directed toward antiviral signaling antigens in particular in patients with worse pulmonary involvement.

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Abstract and Introduction
Infections and Autoimmunity
Autoantibodies in COVID-19 Viral Infection: Our Experience
The Evolving Scenario of COVID-19 and Autoimmune Diseases
Conclusion
References
Sidebar

Table 1. ANA titers and patterns in hospitalized patients with COVID-19
	n:20		n: 15
ANA pattern		Cytoplasmatic pattern
Speckled	9 (45%)	Speckled	5 (33.3%)
Nucleolar	6 (30%)	Reticular	9 (60%)
Homogeneous	3 (15%)	Polar/Golgi-like	1 (6.6%)
Mitotic spindle	1 (5%)
Nuclear dots	1 (5%)
Titer		Titer
1:80	1 (5%)	1:80	1 (6.6%)
1:160	6 (30%)	1:160	2 (13.3%)
1:320	3 (15%)	1:320	4 (26.6%)
1:640	6 (30%)	1:640	2 (13.3%)
1:1280	4 (20%)	1:1280	6 (40%)

ANA, anti-nuclear antibodies.

Table 2. Comparison of ANA (+) and (–) hospitalized patients with COVID-19
	20 ANA (+)	15 ANA (–)	P value
Female	12 (60%)	5 (33.3%)	0.22
Age	74 (58–61)	76 (73–80)	0.44
Comorbidities
Hypertension	8 (40%)	11 (73.3%)	0.11
Coronary heart disease	3 (15%)	5 (33.3%)	0.98
Diabetes mellitus	1 (5%)	3 (20%)	0.72
Cancer	3 (15%)	5 (33.3%)	0.76
Symptom duration days	5 (2–7)	3 (2–7)	0.7
Days of hospital stay	17.5 (9–24)	11 (8–18)	0.4
Medical therapy
Glucocorticoids	17 (85%)	12 (80%)	0.15
Remdesivir	7 (35%)	4 (26.6%)	0.025
O2 requirement	18 (90%)	3 (20%)	<0.0001
PaO2/FiO2 at admission	299 (242–325)	309 (276–380)	0.2
Pulmonary thromboembolism	1 (5%)	4 (6.6%)	0.18
NIPPV	2	0	0.59
Lung segmentation
Abnormal	14% (9–18)	9% (8–19)	0.4
Hyperinflated	2.5% (1–13)	7% (2–12)	0.3
Poorly aerated	11% (6.5–13)	7% (6–15)	0.6
Nonaerated	3% (1–5)	2% (2–3)	0.8
Compromised ≥ 20%	4 (20%)	2 (13.3%)	0.94
Blood tests
Hemoglobin (g/dL)	14.2 (12.5–15.6)	13.3 (11.4–14)	0.2
Platelet count (10^3/mm^3)	173.5 (148.25–214.25)	200 (160–277)	0.2
Neutrophil count (10^3/mm^3)	4.05 (3.175–6.425)	4.5 (3.3–6.6)	0.6
Lymphocyte count (10^3/mm^3)	0.9 (0.725–1.4)	0.75 (0.375–0.925)	0.03
Eosinophil count (10^3/mm^3)	0 (0–0)	0 (0–0)	0.4
Creatinine (mg/dL)	0.9 (0.8–1.1)	0.9 (0.6–1.3)	0.9
GPT (IU/L)	26 (15–60)	20 (16–42)	0.4
ALP (U/L)	82 (67.75–106.25)	82 (68.25–105.25)	0.45
Gamma-GT (UI/L)	40 (24.75–59.25)	39 (23.75–56.75)	0.08
Troponin (ng/L)	8.25 (4.8–10.8)	12.1 (6.3–34.3)	0.03
CK (U/L)	81 (38–170)	134 (92–203)	0.07
BNP (pg/mL)	41 (22–59)	148 (77–456)	< 0.0001
Inflammatory markers
C-reactive protein (mg/dL)	4.9 (1.9–8.1)	9.1 (4.8–12.5)	0.09
D-dimer (ng/dL)	292 (209–699)	312 (282–1330)	0.3
Ferritin (ng/mL)	314 (214–640)	294 (162–642)	0.6
LDH (IU/L)	299 (249–385)	263 (243–380)	0.6
IL-6 (pg/mL)	37 (24–68)	51 (23–63)	0.9
Procalcitonin (mg/dL)	0.1 (0.06–0.35)	0.09 (0.05–0.16)	0.3
C3 (mg/dL)	140 (138–149)	136 (129–147)	0.3
C4 (mg/dL)	51 (40–63)	39 (30–54)	0.2
COVID-19 serology
Anti-SARS-CoV-2 (S1/S2) IgG	6 (30%)	5 (33.3%)	0.98
Anti-SARS-CoV-2 (S1/S2) IgG titer	5.6 (3.8–18.7)	6.2 (3.8–27.1)	0.9
Anti-SARS-CoV-2 (RBD) IgM	4 (20%)	5 (33.3%)	0.51
Anti-SARS-CoV-2 (S1- RBD) IgM titer	1.37 (0.5–12.2)	0.4 (0.1–10.5)	0.2

ANA, anti-nuclear antibodies; BNP, brain natriuretic peptide; CK, creatine kinase; IQR, interquartile range; LDH, lactate dehydrogenase; NIPPV, noninvasive positive pressure ventilation; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Table 3. Comparison of SAA (specific autoantibodies) (+) and (–) groups among hospitalized patients with COVID-19
	7 SAA (+)	8 SAA (–)	P value
Female	5 (71.4%)	8 (28.57%)	0.025
Age	80 (72.5–81.5)	74 (65–77.25)	0.18
Comorbidities
Hypertension	2 (28.57%)	17 (60.7%)	0.12
Coronary heart disease	2 (28.57%)	6 (21.4%)	0.68
Diabetes mellitus	1 (14.2%)	3 (10.7%)	0.79
Cancer	2 (28.57%)	6 (21.4%)	0.68
Days of symptom onset before admission	5 (3–7)	3.5 (2–7)	0.7
Days of hospital stay	19 (9–24)	15 (8.75–18.75)	0.42
Medical therapy
Glucocorticoids	6 (85.7%)	23 (82.14%)	0.82
Remdesivir	1 (14.2%)	10 (35.7%)	0.27
O2 requirement	6 (85.7%)	22 (78.57%)	0.49
PaO2/FiO2 at admission	276 (233–324)	311.5 (273.5–364.75)	0.23
Pulmonary thromboembolism	1 (14.2%)	4 (14.2%)	0.99
NIPPV	1 (14.2%)	1 (3.57%)	0.27
Lung segmentation
Abnormal	19% (14–23.5)	12% (8–16)	0.04
Hyperinflated	1% (1–2)	6% (2–14)	0.01
Poorly aerated	13% (11–16.5)	8% (6–13)	0.02
Nonaerated	3% (3–6)	2% (2–3)	0.02
Compromised ≥ 20%	3 (42.85%)	3 (10.7%)	0.043
Blood tests
Hemoglobin (g/dL)	14 (12.9–14.35)	13.8 (12.4–14.85)	0.68
Platelet count (10^3/mm^3)	163 (152.5–253.5)	185 (159–226.75)	0.59
Neutrophil count (10^3/mm^3)	3.5 (3–3.9)	4.2 (3.7–6.75)	0.13
Lymphocyte count (10^3/mm^3)	0.8 (0.75–1.25)	0.9 (0.7–1.1)	0.66
Eosinophil count (10^3/mm^3)	0 (0–0)	0 (0–0)	0.82
Creatinine (mg/dL)	0.94 (0.89–0.99)	0.9 (0.74–1.18)	0.59
GPT (IU/L)	15 (14.5–43–5)	26 (18.5–47)	0.47
ALP (U/L)	72 (59–88.5)	85 (70.5–108)	0.37
Gamma-GT (UI/L)	32.5 (21–58.25)	40.5 (25.2–52.2)	0.79
Troponin (ng/L)	8.7 (5.45–12.02)	9.3 (5.6–17.17)	0.76
CK (U/L)	81 (57.5–152)	113 (60–188)	0.99
BNP (pg/mL)	51 (18.5–67.5)	77 (37–189.55)	0.39
Inflammatory markers (median – IQR)
C-reactive protein (mg/dL)	4.92 (3.72–6.73)	7.69 (2.27–12.45)	0.79
D-dimer (ng/dL)	634 (303.5–1447)	302 (226.5–508.5)	0.52
Ferritin (ng/mL)	256.2 (211.3–288.35)	332.1 (206.25–641.2)	0.47
LDH (IU/L)	334 (260.5–388.5)	279 (243.24–324.25)	0.14
IL-6 (pg/mL)	47 (39.5–65)	36 (23–63)	0.22
Procalcitonin (mg/dL)	0.1 (0.05–0.11)	0.14 (0.05–0.2)	0.42
C3 (mg/dL)	139 (138–148)	139.5 (131.5–147)	0.48
C4 (mg/dL)	47 (35–48)	46 (35.75–57.75)	0.68
COVID-19 serology
Anti-SARS-CoV-2 (anti-S1, S2) IgG positivity	3 (42.85%)	8 (28.57%)	0.33
Anti-SARS-CoV-2 (anti-S1, S2) IgG [AU/mL]	9.15 (4.25–16.2)	5.44 (3.8–20)	0.66
Anti-SARS-CoV-2 (S1- RBD) IgM positivity	3 (42.85%)	6 (21.4%)	0.21
Anti-SARS-CoV-2 (S1- RBD) IgM [Index]	8.35 (3.55–16.35)	0.49 (0.17–3.95)	0.99

BNP, brain natriuretic peptide; CK, creatine kinase; IQR, interquartile range; LDH, lactate dehydrogenase; NIPPV, noninvasive positive pressure ventilation; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.