Immune-Mediated Disease Flares or New-Onset Disease in 27 Subjects Following mRNA/DNA SARS-CoV-2 Vaccination

Abstract

Background: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs.

Methods: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes.

Findings: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the mRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Other immune-mediated conditions included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare.

Interpretation: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred.

Funding: none.

Keywords: COVID-19; adenoviral vector-based vaccine; immune-mediated diseases; mRNA-based vaccine; vaccine safety.

Figure 1

Causality assessment of “Adverse Events Following Immunization” (AEFIs) after “Coronavirus Disease 2019” (COVID-19) vaccination based on the World Health Organization (WHO) guidelines, which propose a comprehensive four-step analytical and algorithmic diagramming process (namely, evaluation and assessment of (i) the temporal association between vaccine administration and AEFI/immune-mediated disease (IMD); (ii) a plausible time window between vaccine administration and AEFI/IMD; (iii) other causes, such as underlying co-morbidities or drugs taken by the patient, which could explain the insurgence of AEFI/IMD; and, (iv) strength of the causal association, based on what is currently known from the literature).

Figure 2

Panel (A) (Case 2)—Florid clinical arthritis of the proximal interphalangeal joints (dotted red circles). Concomitant, painless rash on two toe tips (orange circles). Panel (B) (Case 23)—Severe articular swelling of the right ankle, left wrist, and the small joints of the fingers (dotted red circles). Panel (C) (Case 9)—dactylitis of the third finger (black arrowheads) associated with chilblain lesion of the second finger (red arrow). Panel (D) (Case 10)—chilblain-like lesions of the fingers and palms, associated with urticarial lesions of the wrists (blue dotted square), thighs and elbows (blue dotted arrows).

Figure 3

Panels (A,B) (Cases 11 and 12)—Oral aphthous lesions and small joints arthritis, Behçet’s disease. Panel (C) (Case 22)—Vasculitic lesions of the skin on lower limbs and forearms. Histology consistent with fibrinoid necrosis of small vessels. Panel (D) (Case 17)—Pustular skin lesions on the forehead and face, Behçet’s disease.

Figure 4

Panel (A) (Case 4)—Parasternal, long axis view from a 2-D echocardiogram showing a small-sized posterior pericardial effusion (white arrow). Panel (B) (Case 27)—Computerized tomography scan demonstrating posterior pericardial effusion (white arrow) and bilateral pleural effusion (white arrowheads). Panel (C) (Case 7)—Magnetic resonance imaging of the brain showing demyelinating lesions in the left mesencephalic (dotted white arrow) and in the right peri-ventricular occipital white matter (white dotted square).