ArticlePDF Available

New-Onset Systemic Lupus Erythematosus after mRNA SARS-CoV-2 Vaccination

February 2022
2022(1):1-4

DOI:10.1155/2022/6436839

License
CC BY 4.0

Authors:

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease resulting from the interaction of genetic and environmental factors. In addition, some antiviral vaccines have been associated with the onset of SLE. Few cases of SLE occurring after SARS-CoV-2 mRNA have been reported. Herein, we report the case of a 27-year-old woman with type I diabetes mellitus and family history of SLE who presented with symmetric inflammatory polyarthritis of the proximal interphalangeal joints, metacarpophalangeal joints, wrists, knees, and ankles two weeks after receiving the second dose of the SARS-CoV-2 mRNA-1273 vaccine. Laboratory results revealed positive antinuclear, anti-dsDNA, anti-Ro, and anti-La/SSB antibodies and low C4 levels. She was initially treated with low-dose prednisone and hydroxychloroquine. Hydroxychloroquine was discontinued after she developed an urticarial rash. Subsequently, mycophenolate mofetil was added after she developed proteinuria. This case highlights the importance of considering the diagnosis of SLE in patients who present with inflammatory polyarthritis after COVID-19 vaccination.

Access to this full-text is provided by Wiley.

Learn more

Content available from Case Reports in Rheumatology

This content is subject to copyright. Terms and conditions apply.

Case Report

New-Onset Systemic Lupus Erythematosus after mRNA

SARS-CoV-2 Vaccination

Laisha B´

aez-Negr ´

on and Luis M. Vil´

Division of Rheumatology, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico

Correspondence should be addressed to Luis M. Vil´

a; luis.vila2@upr.edu

Received 20 December 2021; Accepted 20 January 2022; Published 11 February 2022

Academic Editor: Gregory J. Tsay

aez-Negr´

on and Luis M. Vil´

a. is is an open access article distributed under the Creative Commons

Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is

properly cited.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease resulting from the interaction of genetic and en-

vironmental factors. In addition, some antiviral vaccines have been associated with the onset of SLE. Few cases of SLE occurring

after SARS-CoV-2 mRNA have been reported. Herein, we report the case of a 27-year-old woman with type I diabetes mellitus and

family history of SLE who presented with symmetric inﬂammatory polyarthritis of the proximal interphalangeal joints, met-

acarpophalangeal joints, wrists, knees, and ankles two weeks after receiving the second dose of the SARS-CoV-2 mRNA-1273

vaccine. Laboratory results revealed positive antinuclear, anti-dsDNA, anti-Ro, and anti-La/SSB antibodies and low C4 levels. She

was initially treated with low-dose prednisone and hydroxychloroquine. Hydroxychloroquine was discontinued after she de-

veloped an urticarial rash. Subsequently, mycophenolate mofetil was added after she developed proteinuria. is case highlights

the importance of considering the diagnosis of SLE in patients who present with inﬂammatory polyarthritis after COVID-

19 vaccination.

1. Introduction

Systemic lupus erythematosus (SLE) is a chronic autoim-

mune disease characterized by dysregulation of the immune

system [1]. Its etiopathogenesis involves the interaction of

genetic and environmental factors such as ultraviolet light

exposure, cigarette smoking, and infections [2]. Also, some

vaccines have been linked with the onset of SLE including

hepatitis B, human papilloma virus, and measles [3–6]. More

recently, it has been reported that mRNA SARS-CoV-2

vaccines could trigger SLE ﬂares and may induce the de-

velopment of new-onset rheumatic diseases [7]. SARS-CoV-

2 mRNA vaccines increase the levels of type I interferon

(INF) which is not only known to play a critical role in the

antiviral response but also an important cytokine in the

pathogenesis of SLE [8–10]. Few cases of new-onset SLE

occurring after SARS-CoV-2 mRNA vaccination have been

reported [11, 12]. Herein, we describe a 27-year-old woman

who developed SLE two weeks after receiving the second

dose of the SARS-CoV-2 mRNA-1273 vaccine.

2. Case Presentation

A 27-year-old-woman with type 1 diabetes mellitus de-

veloped tiredness, weight loss (2 kg), symmetric poly-

arthralgia involving the proximal interphalangeal (PIP)

joints, metacarpophalangeal (MCP) joints, wrists, knees,

and ankles, and prolonged morning stiﬀness (1-2 hours)

two weeks after receiving the second dose of SARS-CoV-2

mRNA-1273 vaccine. ese symptoms were managed with

nonsteroidal anti-inﬂammatory drugs, but she did not

improve. She had no history of fever, anorexia, photo-

sensitivity, malar rash, alopecia, mucosal ulcers, Raynaud’s

phenomenon, chest pain, cough, shortness of breath, or

sicca symptoms. Her mother had SLE treated with

hydroxychloroquine.

On initial visit, temperature was 37.3°C, blood pressure

was 116/80 mmHg, and heart rate was 87 beats per minute.

Physical examination showed symmetric joint tenderness

and swelling of the 2

to 5

PIPs and MCPs associated with

limited range of movement and joint tenderness of the

Hindawi

Case Reports in Rheumatology

Volume 2022, Article ID 6436839, 4 pages

https://doi.org/10.1155/2022/6436839

wrists, knees, and ankles bilaterally. e remainder of the

physical exam was normal.

Laboratory tests revealed a white blood cell count of 7.6/

μL, hemoglobin of 13.9 g/dL, and platelet count of 372,000/

μL of. Serum creatinine was normal at 0.65 mg/dL. Alkaline

phosphatase, aspartate aminotransferase, and alanine ami-

notransferase levels were normal. She had mild hypo-

albuminemia at 3.3 g/dl. Urinalysis showed trace protein

without microscopic hematuria, pyuria, or urinary casts.

Spot urine protein to creatinine ratio was 0.47. yroid

stimulating hormone and free thyroxine levels were normal.

Levels of 25-hydroxyvitamin D were low at 21 ng/ml.

Westergren erythrocyte sedimentation rate (ESR) was ele-

vated at 88 mm/h, but C-reactive protein levels were normal.

She had positive anti-nuclear (ANA, 1 : 160 titer, speckled

pattern), anti-Ro, and anti-La antibodies. Anti-dsDNA

antibodies were elevated at 46 IU/mL (normal range <10 IU/

mL). She had low C4 levels at 12 mg/dL (normal range:

14–53 mg/dL) but had normal C3 levels. Anti-Smith and

anti-RNP antibodies were negative. e lupus anticoagulant

test, anti-cardiolipin (IgA, IgM, and IgG), and anti-B2

glycoprotein I (IgA, IgM, and IgG) antibodies were negative.

Rapid plasma reagin (RPR), human immunodeﬁciency vi-

rus, hepatitis B, and hepatitis C tests were negative. X-rays of

the hands and wrists were unremarkable.

Our patient fulﬁlled both the 2012 Systemic Lupus In-

ternational Collaborating Clinics (total of 5 criteria; at least,

4 criteria are required for classiﬁcation) and the 2019 Eu-

ropean League Against Rheumatism/American College of

Rheumatology (total of 19 points; at least, 10 points are

required for classiﬁcation) criteria for SLE [13, 14]. She was

initially treated with hydroxychloroquine 300 mg daily and

prednisone 5 mg daily. Two weeks after, she developed an

urticarial rash. Hydroxychloroquine was discontinued with

complete resolution of the rash. Over the next eight weeks,

she persisted with inﬂammatory polyarthritis, proteinuria

increased (spot urine protein to creatinine ratio �0.64), ESR

increased at 98 mm/h, and she continued with elevated anti-

dsDNA antibodies (58 IU/mL) and low C4 levels (10 mg/dL).

Prednisone dose was increased to 20 mg daily, and myco-

phenolate mofetil was started at 1 g daily. Four weeks later,

polyarthritis subsided, but she continued with proteinuria

(300 mg/dL) and elevated ESR at 86 mm/h. Mycophenolate

mofetil dose was increased to 2 g daily, resulting in a fa-

vorable clinical response. Two months after this dose

change, proteinuria decreased to 30 mg/dL. Prednisone dose

could be lowered to 10 mg daily without her having a

reactivation of her SLE.

3. Discussion

We describe a 27-year-old woman who developed SLE two

weeks after receiving the second dose of the mRNA SARS-

CoV-2 vaccine. SLE was manifested by constitutional

symptoms, polyarthritis, subnephrotic-range proteinuria,

low C4 levels, and positive ANA, and anti-ds-DNA anti-

bodies, anti-SSA/Ro, and anti-SSB/La antibodies. Because

our patient had a genetic predisposition for lupus, it is not

surprising that she developed SLE after a potential trigger

such as the COVID-19 vaccine. She has a ﬁrst-degree relative

with lupus and also has type I diabetes mellitus, both being

strong risk factors for SLE [15–17]. Individuals who have a

ﬁrst degree relative with SLE have a 10 times increased risk

of developing lupus [15]. Likewise, type 1 diabetes mellitus is

strongly associated with SLE [16, 17]. e latter is not un-

expected as type I diabetes mellitus and SLE share common

pathophysiologic mechanisms including the association

with PTPN22 and STAT4 polymorphisms [18].

To the best of our knowledge, two cases of new-onset SLE

occurring after SARS-CoV-2 mRNA vaccination have been

reported, both of which presented with cutaneous mani-

festations [11, 12]. Kreuter et al. reported a 79-year-old man

who developed fatigue and papulosquamous and annular

skin eruptions ten days after receiving the BNT162b2mRNA

vaccine [11]. Laboratory tests disclosed positive for ANA (1 :

320 titer), rheumatoid factor, and anti-Ro and anti-La

antibodies. Skin biopsy was consistent with subacute cuta-

neous lupus. Treatment with hydroxychloroquine and in-

travenous corticosteroids resulted in complete resolution of

manifestations. Gambicher et al. described a 74-year-old

woman who developed erythematous macules and papules.

Laboratory tests showed positive ANA (1 : 640 titer, speckled

pattern) and anti-Ro and anti-La antibodies. e patient was

diagnosed with Rowell syndrome (erythema multiforme-like

lesions coexisting with lupus) after a skin biopsy [12].

Like the abovementioned case reports, constitutional

symptoms and ANA and anti-Ro and anti-La positivity

occurred as the initial manifestations in our patient.

Moreover, our patient developed subnephrotic-range pro-

teinuria. Although she also had history of type I diabetes

mellitus, she had no evidence of other microvascular organ

damage such as peripheral neuropathy or retinopathy, which

is usually concomitantly seen in patients with kidney in-

volvement related to diabetes mellitus [19]. In addition, the

time association between proteinuria and other SLE clinical

manifestations as well as the presence of anti-dsDNA an-

tibodies favors this manifestation as SLE related [20].

In addition to new-onset SLE after mRNA COVID-19

vaccination, two case reports have linked the SARS-CoV-2

viral vector vaccine with SLE [21, 22]. Zavala et al. reported a

23-year-old woman who developed alopecia, lymphopenia,

nephrotic-range proteinuria, low C3 levels, positive ANA (1:

1280 titer, homogenous pattern), and elevated anti-dsDNA

antibodies one week after the ﬁrst dose of the AZD1222

ChAdOX1 nCoV-19 vaccine. Kidney biopsy showed class V

glomerulonephritis. She was treated with hydroxy-

chloroquine, mycophenolate mofetil, and high-dose corti-

costeroids with improvement after three weeks of follow-up

[21]. Patil et al. described a 22-year-old woman who ex-

perienced right knee pain two weeks after receiving the ﬁrst

dose of the Covishield vaccine. After the second dose, she

developed fever, polyarthralgia, bipedal edema, and pete-

chiae on lower extremities. Laboratories were remarkable for

thrombocytopenia, albuminuria, positive ANA (1 : 320 titer),

and elevated anti-dsDNA antibodies. She was treated with

hydroxychloroquine, mycophenolate mofetil, and prednis-

olone. She had signiﬁcant improvement of symptoms after

one month [22].

2Case Reports in Rheumatology

SARS-CoV-2 mRNA vaccines may also induce exacer-

bations in previously controlled SLE patients. A recent study

in a lupus cohort showed that 11.4% of patients had a disease

exacerbation after vaccination [23]. e most common ﬂare

manifestations were oral ulcers, serositis, arthritis, pericarditis,

thrombocytopenia, and renal involvement. Most patients did

not require additional immunosuppressive treatment. Con-

versely, some case reports have documented SLE ﬂares that

have required immunosuppressive therapy [24, 25]. Niebel

et al. reported a 73-year-old woman with subacute cutaneous

lupus in full remission who experienced disseminated ery-

thematous patches ten days after the ﬁrst dose of the BNT16b2

mRNA vaccine. e symptoms improved with systemic and

topical corticosteroids for three weeks [24]. Also, Tuschen

et al. described a 41-year-old woman with lupus nephritis who

was in clinical remission who developed nephrotic-range

proteinuria seven days after receiving the ﬁrst dose of the BNT

162b2 vaccine. e patient responded well to mycophenolate

mofetil and prednisone therapy [25].

Based on the SARS-CoV-2 mRNA vaccine mechanism, it

is not unforeseen that SARS-CoV-2 mRNA vaccines could

cause new-onset SLE or induce lupus exacerbations. A lipid

nanoparticle protects the mRNA and facilitates its trans-

portation to the lymph nodes where it is engulfed by

dendritic cells [8]. Once inside the cell, the mRNA is rec-

ognized in the endosome by toll-like receptors (TLRs) in

dendritic cells [7, 26]. TLR-7 and TLR-8 bind single-

stranded RNA, and once activated, it leads to the production

of type I INF and proinﬂammatory cytokines [24]. Prior

studies have demonstrated type I INF level elevation within

24 hours returning to normal within fourteen days after

having administered SARS-CoV-2 mRNA vaccine [27]. On

the other hand, SLE is characterized by impaired phagocytic

clearance of apoptotic material and immune tolerance

disruption to self-antigens. e immune complexes com-

posed of autoantibodies and apoptotic debri are endocytosed

and sensed by TLRs [28]. Since SLE complexes are made of

endogenous RNA and DNA nucleic acids, they are detected

by TLR-7 and TLR-9 [28, 29]. ese pattern recognition

receptors create a signal leading to the expression of IL-6,

TNF-alpha, and type I INF comparable to the eﬀect of

COVID-19 mRNA vaccines [28–30].

Antiviral vaccines, other than COVID-19, such as

hepatitis B, human papilloma virus, and measles vaccines

have been linked with SLE [3–6]. In a murine model of

lupus, hepatitis B vaccine and its adjuvants accelerate SLE by

producing glomerulonephritis and elevated levels of anti-

dsDNA antibodies [6]. Adjuvants can stimulate an immune

response by acting as a ligand for TLRs [31]. In contrast to

the SARS-CoV-2 vaccine, HPV vaccine is thought to cause

SLE through molecular mimicry [32]. As noted for our

patient, it is proposed that these antiviral vaccines could

induce lupus in genetically predisposed individuals [31, 32].

Although mRNA SARS-CoV-2 vaccines contain no adju-

vants, it is important to highlight that non-mRNA vaccines may

contain adjuvants that could induce an inﬂammatory response

[33]. e autoimmune/inﬂammatory syndrome disease in-

duced by adjuvants (ASIA) or Shoenfeld’s syndrome is char-

acterized by constitutional symptoms, arthralgias, myalgias,

myositis, neurological manifestations, and the appearance of

autoantibodies [34]. Some adjuvants induce this inﬂammatory

response through the expression of proinﬂammatory cytokines

such as interferon, IL-1, and IL-6 [35]. Furthermore, ASIA

syndrome has been linked with the occurrence of SLE and

antiphospholipid syndrome, among other autoimmune disor-

ders [35]. It appears that this syndrome occurs more frequently

in patients with genetic predisposition to develop

autoimmunity.

In summary, we report a woman who developed SLE

after mRNA SARS-CoV-2 vaccination. Although it is un-

usual, it is important to maintain a high level of awareness of

SLE in patients who present with inﬂammatory polyarthritis

after mRNA SARS-CoV-2 vaccination, particularly in those

with risk factors for autoimmune diseases. Early recognition

is critical to initiate prompt and eﬀective therapy.

Data Availability

Data can be obtained from the corresponding author upon

request.

Consent

Written informed consent was obtained from the patient for

publication of this case.

Disclosure

is work was performed as part of the employment of the

authors at the University of Puerto Rico Medical Sciences

Campus. e employer was not involved in the manuscript

writing, editing, approval, or decision to publish.

Conflicts of Interest

e authors declare that there are no conﬂicts of interest

regarding the publication of this article.

References

[1] G. C. Tsokos, “Autoimmunity and organ damage in systemic

lupus erythematosus,” Nature Immunology, vol. 21, no. 6,

pp. 605–614, 2020.

[2] C. G. Parks, A. de Souza Espindola Santos, M. Barbhaiya, and

K. H. Costenbader, “Understanding the role of environmental

factors in the development of systemic lupus erythematosus,”

Best Practice & Research Clinical Rheumatology, vol. 31, no. 3,

pp. 306–320, 2017.

[3] H. Soldevilla, S. Briones, and S. Navarra, “Systemic lupus

erythematosus following HPV immunization or infection?”

Lupus, vol. 21, no. 2, pp. 158–161, 2012.

[4] A. B. N. de Mattos, L. Garbo Baroni, and L. d. L. Zanotto,

“Subacute cutaneous lupus erythematosus triggered after

measles vaccination,” Lupus, vol. 30, no. 5, pp. 833–835, 2021.

[5] N. Agmon-Levin, Y. Zafrir, Z. Paz, T. Shilton, G. Zandman-

Goddard, and Y. Shoenfeld, “Ten cases of systemic lupus

erythematosus related to hepatitis B vaccine,” Lupus, vol. 18,

no. 13, pp. 1192–1197, 2009.

[6] N. Agmon-Levin, M. T. Arango, S. Kivity et al., “Immuni-

zation with hepatitis B vaccine accelerates SLE-like disease in

Case Reports in Rheumatology 3

a murine model,” Journal of Autoimmunity, vol. 54, pp. 21–32,

2014.

[7] A. Watad, G. De Marco, H. Mahajna et al., “Immune-me-

diated disease ﬂares or new-onset disease in 27 subjects

following mRNA/DNA SARS-CoV-2 vaccination,” Vaccines,

vol. 9, no. 5, p. 435, 2021.

[8] J. R. Teijaro and D. L. Farber, “COVID-19 vaccines: modes of

immune activation and future challenges,” Nature Reviews

Immunology, vol. 21, no. 4, pp. 195–197, 2021.

[9] A. A. Stegelmeier, M. Darzianiazizi, K. Hanada et al., “Type I

interferon-mediated regulation of antiviral capabilities of

neutrophils,” International Journal of Molecular Sciences,

vol. 22, no. 9, p. 4726, 2021.

[10] W. Tang, A. D. Askanase, L. Khalili, and J. T. Merrill, “SARS-

CoV-2 vaccines in patients with SLE,” Lupus Science &

Medicine, vol. 8, no. 1, Article ID e000479, 2021.

[11] A. Kreuter, M. J. Licciardi-Fernandez, S. N. Burmann,

B. Burkert, F. Oellig, and A.-L. Michalowitz, “Induction and

exacerbation of subacute cutaneous lupus erythematosus

following mRNA-based or adenoviral vector-based SARS-

CoV-2 vaccination,” Clinical and Experimental Dermatology,

vol. 47, no. 1, pp. 161–163, 2022.

[12] T. Gambichler, L. Scholl, H. Dickel, L. Ocker, and

R. Stranzenbach, “Prompt onset of Rowell’s syndrome fol-

lowing the ﬁrst BNT162b2 SARS-CoV-2 vaccination,” Journal

of the European Academy of Dermatology and Venereology,

vol. 35, no. 7, pp. e415–e416, 2021.

[13] M. Petri, A. M. Orbai, and G. S. Alarc´

on, “Derivation and

validation of the Systemic Lupus International Collaborating

Clinics classiﬁcation criteria for systemic lupus eryth-

ematosus,” Arthritis & Rheumatism, vol. 64, no. 8,

pp. 2677–2686, 2012.

[14] M. Aringer, K. Costenbader, and D. Daikh, “2019 European

League against rheumatism/American College of Rheuma-

tology classiﬁcation criteria for systemic lupus eryth-

ematosus,” Arthritis & Rheumatology, vol. 71, no. 9,

pp. 1400–1412, 2019.

[15] C. J. Ulﬀ-Møller, J. Simonsen, K. O. Kyvik, S. Jacobsen, and

M. Frisch, “Family history of systemic lupus erythematosus

and risk of autoimmune disease: nationwide Cohort Study in

Denmark 1977–2013,” Rheumatology, vol. 56, no. 6,

pp. 957–964, 2017.

[16] K. Hemminki, X. Li, J. Sundquist, and K. Sundquist, “Familial

association between type 1 diabetes and other autoimmune

and related diseases,” Diabetologia, vol. 52, no. 9,

pp. 1820–1828, 2009.

[17] Y. K. Bao, L. G. Weide, V. C. Ganesan et al., “High prevalence

of comorbid autoimmune diseases in adults with type 1 di-

abetes from the HealthFacts database,” Journal of Diabetes,

vol. 11, no. 4, pp. 273–279, 2019.

[18] M. I. Zervou, D. Mamoulakis, C. Panierakis, D. T. Boumpas,

and G. N. Goulielmos, “STAT4: a risk factor for type 1 di-

abetes?” Human Immunology, vol. 69, no. 10, pp. 647–650,

2008.

[19] A. Avogaro and G. P. Fadini, “Microvascular complications in

diabetes: a growing concern for cardiologists,” International

Journal of Cardiology, vol. 291, pp. 29–35, 2019.

[20] B. Goilav and C. Putterman, “e role of anti-DNA antibodies

in the development of lupus nephritis: a complementary, or

alternative, viewpoint?” Seminars in Nephrology, vol. 35, no. 5,

pp. 439–443, 2015.

[21] M. F. Zavala-Miranda, S. G. Gonz´alez-Ibarra, A. A. P´erez-

Arias, N. O. Uribe-Uribe, and J. M. Mejia-Vilet, “New-onset

systemic lupus erythematosus beginning as class V lupus

nephritis after COVID-19 vaccination,” Kidney International,

vol. 100, no. 6, pp. 1340-1341, 2021.

[22] S. Patil and A. Patil, “Systemic lupus erythematosus after

COVID-19 vaccination: a case report,” Journal of Cosmetic

Dermatology, vol. 20, no. 10, pp. 3103-3104, 2021.

[23] P. M. Izmirly, M. Y. Kim, and M. Samanovic, “Evaluation of

immune response and disease status in SLE patients following

SARS-CoV-2 vaccination,” Arthritis & Rheumatology, vol. 74,

no. 2, pp. 284–294, 2022.

[24] D. Niebel, V. Ralser-Isselstein, K. Jaschke, C. Braegelmann,

T. Bieber, and J. Wenzel, “Exacerbation of subacute cutaneous

lupus erythematosus following vaccination with BNT162b2

mRNA vaccine,” Dermatologic erapy, vol. 34, no. 4, Article

ID e15017, 2021.

[25] K. Tuschen, J. H. Br¨

asen, J. Schmitz, M. Vischedyk, and

A. Weidemann, “Relapse of class V lupus nephritis after

vaccination with COVID-19 mRNA vaccine,” Kidney Inter-

national, vol. 100, no. 4, pp. 941–944, 2021.

[26] S. Linares-Fern´

andez, C. Lacroix, J. Y. Exposito, and

B. Verrier, “Tailoring mRNA vaccine to balance innate/

adaptive immune response,” Trends in Molecular Medicine,

vol. 26, no. 3, pp. 311–323, 2020.

[27] P. A. Ntouros, N. I. Vlachogiannis, M. Pappa et al., “Eﬀective

DNA damage response after acute but not chronic immune

challenge: SARS-CoV-2 vaccine versus Systemic Lupus

Erythematosus,” Clinical Immunology, vol. 229, Article ID

108765, 2021.

[28] J. M. Kim, S. H. Park, H. Y. Kim, and S.-K. Kwok, “A

plasmacytoid dendritic cells-type I interferon Axis is critically

implicated in the pathogenesis of systemic lupus eryth-

ematosus,” International Journal of Molecular Sciences, vol. 16,

no. 6, pp. 14158–14170, 2015.

[29] R. G. Bonegio, J. D. Lin, B. Beaudette-Zlatanova, M. R. York,

H. Menn-Josephy, and K. Yasuda, “Lupus-associated immune

complexes activate human neutrophils in an FccRIIA-de-

pendent but TLR-independent response,” e Journal of

Immunology, vol. 202, no. 3, pp. 675–683, 2019.

[30] G. Lorenz and H. J. Anders, “Neutrophils, dendritic cells, toll-

like receptors, and interferon-αin lupus nephritis,” Seminars

in Nephrology, vol. 35, no. 5, pp. 410–426, 2015.

[31] N. L. Bragazzi, A. Watad, K. Sharif et al., “Advances in our

understanding of immunization and vaccines for patients

with systemic lupus erythematosus,” Expert Review of Clinical

Immunology, vol. 13, no. 10, pp. 939–949, 2017.

[32] Y. Segal and Y. Shoenfeld, “Vaccine-induced autoimmunity:

the role of molecular mimicry and immune crossreaction,”

Cellular and Molecular Immunology, vol. 15, no. 6, pp. 586–

594, 2018.

[33] K. S. Park, X. Sun, M. E. Aikins, and J. J. Moon, “Non-viral

COVID-19 vaccine delivery systems,” Advanced Drug De-

livery Reviews, vol. 169, pp. 137–151, 2021.

[34] A. Watad, M. Quaresma, N. L. Bragazzi et al., “e auto-

immune/inﬂammatory syndrome induced by adjuvants

(ASIA)/Shoenfeld’s syndrome: descriptive analysis of 300

patients from the international ASIA syndrome registry,”

Clinical Rheumatology, vol. 37, no. 2, pp. 483–493, 2018.

[35] A. Watad, M. Quaresma, S. Brown et al., “Autoimmune/in-

ﬂammatory syndrome induced by adjuvants (Shoenfeld’s

syndrome)-an update,” Lupus, vol. 26, no. 7, pp. 675–681,

2017.

4Case Reports in Rheumatology

A Comprehensive Review on the Intricate Interplay between COVID-19 Immunization and the New Onset of Pemphigus Foliaceus

Article

Full-text available

Jul 2024

Autoimmune bullous diseases (AIBDs) are characterized by the formation of vesicles, bullous lesions, and mucosal erosions. The autoantibodies target the cellular anchoring structures from the surface of epidermal keratinocyte named desmosomes, leading to a loss of cellular cohesion named acantholysis. AIBDs are classified into intraepidermal or subepidermal types based on clinical features, histological characteristics, and immunofluorescence patterns. Pemphigus foliaceus (PF) is an acquired, rare, autoimmune skin condition associated with autoantibodies that specifically target desmoglein-1, leading to a clinical presentation characterized by delicate cutaneous blisters, typically sparing the mucous membranes. Several factors, including genetic predisposition, environmental triggers, malignancies, medication use, and vaccination (for influenza, hepatitis B, rabies, tetanus, and more recently, severe acute respiratory syndrome Coronavirus 2 known as SARS-CoV-2), can potentially trigger the onset of pemphigus. With the advent of vaccines playing a pivotal role in combatting the 2019 coronavirus disease (COVID-19), extensive research has been conducted globally to ascertain their efficacy and potential cutaneous adverse effects. While reports of AIBDs post-COVID-19 vaccination exist in the medical literature, instances of PF following vaccination have been less commonly reported worldwide. The disease’s pathophysiology is likely attributed to the resemblance between the ribonucleic acid (RNA) antigen present in these vaccines and cellular nuclear matter. The protein produced by the BNT-162b2 messenger ribonucleic acid (mRNA) vaccine includes immunogenic epitopes that could potentially trigger autoimmune phenomena in predisposed individuals through several mechanisms, including molecular mimicry, the activation of pattern recognition receptors, the polyclonal stimulation of B cells, type I interferon production, and autoinflammation. In this review, we present a comprehensive examination of the existing literature regarding the relationship between COVID-19 and PF, delving into their intricate interactions. This exploration improves the understanding of both pemphigus and mRNA vaccine mechanisms, highlighting the importance of close monitoring for PF post-immunization.

Kyriakopoulos Seneff 2024 beta thalassemia

Article

Full-text available

Sep 2024

Background: β-thalassemia heterozygotes produce sensitive levels of fetal hemoglobin and hemoglobin A2 to remain asymptomatic for life compared to β-thalassemia intermedia and β-thalassemia major patients. The asymptomatic β0 thalassemia minor individuals rarely deteriorate to the point of requiring a blood transfusion. Case report: An asymptomatic individual with a pure β0-thalassemia trait, after his first and only Pfizer modified mRNA COVID-19 injection, immediately developed cardiological, neurological, and other clinically important symptoms. The patient’s severe physical impairments resembled a presyncope (about to feint) syndrome. Multiple hematological tests prior to and after the Pfizer injection revealed that the patient sustained a medically important rise in fetal hemoglobin and concurrently a remarkable drop of his hemoglobin A2 levels, compared to prior to mRNA injection. Moreover, the alterations in his life sustaining fetal hemoglobin and hemoglobin A2 levels was accompanied by a clinically significant lowering of blood hemoglobin concentration that required blood transfusion. The patient’s antibody response to the spike protein remains very high (> 10,000 AU/ml) even almost three years after the Pfizer injection. Furthermore, the elevated levels of C-reactive protein — through May 2024 — after the mRNA injection, apart from pointing to multi-organ systemic inflammation, are consistent with his elevated levels of anti-p53 autoantibodies. Conclusions: The simultaneous decrease of patient blood hemoglobin levels was consistent with the hematological readings of mean corpuscular volume, hematocrit, ferritin, folate, and zinc level deteriorations soon after the mRNA injection, which, apart from his double digit rise in C-reactive protein, resemble overall the pathological manifestations of a β-thalassemia worsening condition. By performing an investigative literature review we conclude that an autoimmune hematological disorder contributed to the patient’s severe hematological stress.

Pathology Deterioration in a Pure β-zero Thalassemia Heterozygote After mRNA COVID-19 Vaccination: A Case Report and Literature Review

Article

Full-text available

Aug 2024

06092024 Kyriakopoulos Seneff Final 21072024

Article

Full-text available

Sep 2024

An asymptomatic individual with a pure β0-thalassemia trait, after his first and only Pfizer modified mRNA COVID-19 injection, immediately developed cardiological, neurological, and other clinically important symptoms. The patient’s severe physical impairments resembled a presyncope (about to feint) syndrome. Multiple hematological tests prior to and after the Pfizer injection revealed that the patient sustained a medically important rise in fetal hemoglobin and concurrently a remarkable drop of his hemoglobin A2 levels, compared to prior to mRNA injection. Moreover, the alterations in his life sustaining fetal hemoglobin and hemoglobin A2 levels was accompanied by a clinically significant lowering of blood hemoglobin concentration that required blood transfusion. The patient’s antibody response to the spike protein remains very high (> 10,000 AU/ml) even almost three years after the Pfizer injection. Furthermore, the elevated levels of C-reactive protein — through May 2024 — after the mRNA injection, apart from pointing to multi-organ systemic inflammation, are consistent with his elevated levels of anti-p53 autoantibodies.

Interferon gene expression declines over time post-COVID infection and in long COVID patients

Article

Aug 2024

Background: Interferons (IFNs) represent a first-line defense against viruses and other pathogens. It has been shown that an impaired and uncontrolled release of these glycoproteins can result in tissue damage and explain severe progression of coronavirus disease 2019 (COVID-19). However, their potential role in Long-COVID syndrome (LC) remains debateable. Objectives: The objective of the present study is to shed further light on the possible role of IFNs (and related genes) gene expression patterns in the progression of COVID-19 and LC patients. Methods: We carried out a multi-cohort study by analyzing the IFN gene expression patterns (using different IFN gene signatures) in five cohorts of acute COVID-19 (n = 541 samples) and LC patients (n = 188), and compared them to patterns observed in three autoimmune diseases (systemic lupus erythematous [n = 242], systemic sclerosis [n = 91], and Sjögren's syndrome [n = 282]). Results: The data show that, while the interferon signatures are strongly upregulated in severe COVID-19 patients and autoimmune diseases, it decays with the time from symptoms onset and in LC patients. Differential pathway analysis of IFN-related terms indicates an over activation in autoimmune diseases (IFN-I/II) and severe COVID-19 (IFN-I/II/III), while these pathways are mostly inactivated or downregulated in LC (IFN-I/III). By analyzing six proteomic LC datasets, we did not find evidence of a role of IFNs in this condition. Conclusion: Our findings suggest a potential role of cytokine exhaustion mediated by IFN gene expression inactivation as a possible driver of LC.

Characteristics of emerging new autoimmune diseases after COVID ‐19 vaccination: A sub‐study by the COVAD group

Article

May 2024

Background Despite the overall safety and efficacy of COVID‐19 vaccinations, rare cases of systemic autoimmune diseases (SAIDs) have been reported post‐vaccination. This study used a global survey to analyze SAIDs in susceptible individuals' post‐vaccination. Methods A cross‐sectional study was conducted among participants with self‐reported new‐onset SAIDs using the COVID‐19 Vaccination in Autoimmune Diseases (COVAD) 2 study dataset—a validated, patient‐reported e‐survey—to analyze the long‐term safety of COVID‐19 vaccines. Baseline characteristics of patients with new‐onset SAIDs and vaccinated healthy controls (HCs) were compared after propensity score matching based on age and sex in a 1:4 ratio. Results Of 16 750 individuals, 74 (median age 52 years, 79.9% females, and 76.7% Caucasians) had new‐onset SAID post‐vaccination, mainly idiopathic inflammatory myopathies (IIMs) ( n = 23, 31.51%), arthritis ( n = 15; 20.53%), and polymyalgia rheumatica (PMR) ( n = 12, 16.40%). Higher odds of new‐onset SAIDs were noted among Caucasians (OR = 5.3; 95% CI = 2.9–9.7; p < .001) and Moderna vaccine recipients (OR = 2.7; 95% CI = 1.3–5.3; p = .004). New‐onset SAIDs were associated with AID multimorbidity (OR = 1.4; 95% CI = 1.1–1.7; p < .001), mental health disorders (OR = 1.6; 95% CI = 1.3–1.9; p < .001), and mixed race (OR = 2.2; 95% CI = 1.2–4.2; p = .010), where those aged >60 years (OR = 0.6; 95% CI = 0.4–0.8; p = .007) and from high/medium human development index (HDI) countries (compared to very high HDI) reported fewer events than HCs. Conclusion This study reports a low occurrence of new‐onset SAIDs following COVID‐19 vaccination, primarily IIMs, PMR, and inflammatory arthritis. Identified risk factors included pre‐existing AID multimorbidity, mental health diseases, and mixed race. Revaccination was well tolerated by most patients; therefore, we recommend continuing COVID‐19 vaccination in the general population. However, long‐term studies are needed to understand the autoimmune phenomena arising post‐vaccination.

New-onset of rheumatic diseases following COVID-19 vaccination: the report of three cases and a literature review

Article

Apr 2024

Vaccines against coronavirus disease 2019 (COVID-19) have been distributed in most countries for the prevention of onset and aggravation of COVID-19. Recently, there have been increasing numbers of reports on new-onset autoimmune and autoinflammatory diseases following COVID-19 vaccination, however, only little information is available on the long-term safety of these vaccines. Here, we experienced three cases of new-onset rheumatic diseases following COVID-19 vaccination, one case each of rheumatoid arthritis (RA), anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and systemic lupus erythematosus (SLE). The symptom onset ranged from one day to a few days following vaccination. The patients of AAV and SLE were treated successfully with glucocorticoid therapy, and the patient of RA died due to COVID-19. In the literature review of new-onset rheumatic diseases following COVID-19 vaccination, which including seven cases of RA, 37 cases of AAV and 18 cases of SLE, the mean time from vaccination to onset was approximately 11 to 12 days. Most cases improved with glucocorticoid, immunosuppressive drugs and biologic agents. Although such adverse effects are rare, and vaccines are useful in prevent onset and severity of infections, continued accumulation of similar cases is important in terms of examining the long-term safety and understanding pathogenic mechanism of rheumatic diseases.

New approaches to vaccines for autoimmunity

Chapter

Jan 2024

New‐onset systemic lupus erythematosus after BBIBP‐CorV vaccination

Article

Full-text available

Feb 2024

Key Clinical Message While reports of new‐onset systemic lupus erythematosus (SLE) after mRNA‐based COVID‐19 vaccines exist, no such reports have been documented following inactivated vaccines. We describe a case of SLE after receiving the BBIBP‐CorV vaccine. The patient exhibited characteristic SLE criteria, indicating a possible association between the inactivated vaccine and new‐onset SLE.

Self-DNA driven inflammation in COVID-19 and after mRNA-based vaccination: lessons for non-COVID-19 pathologies

Article

Full-text available

Feb 2024

Martin Heil

The coronavirus disease 2019 (COVID-19) pandemic triggered an unprecedented concentration of economic and research efforts to generate knowledge at unequalled speed on deregulated interferon type I signalling and nuclear factor kappa light chain enhancer in B-cells (NF-κB)-driven interleukin (IL)-1β, IL-6, IL-18 secretion causing cytokine storms. The translation of the knowledge on how the resulting systemic inflammation can lead to life-threatening complications into novel treatments and vaccine technologies is underway. Nevertheless, previously existing knowledge on the role of cytoplasmatic or circulating self-DNA as a pro-inflammatory damage-associated molecular pattern (DAMP) was largely ignored. Pathologies reported ‘de novo’ for patients infected with Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 to be outcomes of self-DNA-driven inflammation in fact had been linked earlier to self-DNA in different contexts, e.g., the infection with Human Immunodeficiency Virus (HIV)-1, sterile inflammation, and autoimmune diseases. I highlight particularly how synergies with other DAMPs can render immunogenic properties to normally non-immunogenic extracellular self-DNA, and I discuss the shared features of the gp41 unit of the HIV-1 envelope protein and the SARS-CoV 2 Spike protein that enable HIV-1 and SARS-CoV-2 to interact with cell or nuclear membranes, trigger syncytia formation, inflict damage to their host’s DNA, and trigger inflammation – likely for their own benefit. These similarities motivate speculations that similar mechanisms to those driven by gp41 can explain how inflammatory self-DNA contributes to some of most frequent adverse events after vaccination with the BNT162b2 mRNA (Pfizer/BioNTech) or the mRNA-1273 (Moderna) vaccine, i.e., myocarditis, herpes zoster, rheumatoid arthritis, autoimmune nephritis or hepatitis, new-onset systemic lupus erythematosus, and flare-ups of psoriasis or lupus. The hope is to motivate a wider application of the lessons learned from the experiences with COVID-19 and the new mRNA vaccines to combat future non-COVID-19 diseases.

New onset systemic lupus erythematosus opening as class V lupus nephritis after COVID-19 vaccination

Article

Full-text available

Sep 2021

Evaluation of Immune Response and Disease Status in Systemic Lupus Erythematosus Patients Following SARS–CoV‐2 Vaccination

Article

Full-text available

Dec 2021

Objective To evaluate seroreactivity and disease flares after COVID‐19 vaccination in a multiethnic/multiracial cohort of patients with systemic lupus erythematosus (SLE). Methods Ninety SLE patients and 20 healthy controls receiving a complete COVID‐19 vaccine regimen were included. IgG seroreactivity to the SARS–CoV‐2 spike receptor‐binding domain (RBD) and SARS–CoV‐2 microneutralization were used to evaluate B cell responses; interferon‐γ (IFNγ) production was measured by enzyme‐linked immunospot (ELISpot) assay in order to assess T cell responses. Disease activity was measured by the hybrid SLE Disease Activity Index (SLEDAI), and flares were identified according to the Safety of Estrogens in Lupus Erythematosus National Assessment–SLEDAI flare index. Results Overall, fully vaccinated SLE patients produced significantly lower IgG antibodies against SARS–CoV‐2 spike RBD compared to fully vaccinated controls. Twenty‐six SLE patients (28.8%) generated an IgG response below that of the lowest control (<100 units/ml). In logistic regression analyses, the use of any immunosuppressant or prednisone and a normal anti–double‐stranded DNA antibody level prior to vaccination were associated with decreased vaccine responses. IgG seroreactivity to the SARS–CoV‐2 spike RBD strongly correlated with the SARS–CoV‐2 microneutralization titers and correlated with antigen‐specific IFNγ production determined by ELISpot. In a subset of patients with poor antibody responses, IFNγ production was similarly diminished. Pre‐ and postvaccination SLEDAI scores were similar in both groups. Postvaccination flares occurred in 11.4% of patients; 1.3% of these were severe. Conclusion In a multiethnic/multiracial study of SLE patients, 29% had a low response to the COVID‐19 vaccine which was associated with receiving immunosuppressive therapy. Reassuringly, severe disease flares were rare. While minimal protective levels remain unknown, these data suggest that protocol development is needed to assess the efficacy of booster vaccination.

Exacerbation of subacute cutaneous lupus erythematosus following vaccination with BNT162b2 mRNA vaccine

Article

Full-text available

Jun 2021
DERMATOL THER

Type I Interferon-Mediated Regulation of Antiviral Capabilities of Neutrophils

Article

Full-text available

Apr 2021
INT J MOL SCI

Interferons (IFNs) are induced by viruses and are the main regulators of the host antiviral response. They balance tissue tolerance and immune resistance against viral challenges. Like all cells in the human body, neutrophils possess the receptors for IFNs and contribute to antiviral host defense. To combat viruses, neutrophils utilize various mechanisms, such as viral sensing, neutrophil extracellular trap formation, and antigen presentation. These mechanisms have also been linked to tissue damage during viral infection and inflammation. In this review, we presented evidence that a complex cross-regulatory talk between IFNs and neutrophils initiates appropriate antiviral immune responses and regulates them to minimize tissue damage. We also explored recent exciting research elucidating the interactions between IFNs, neutrophils, and severe acute respiratory syndrome-coronavirus-2, as an example of neutrophil and IFN cross-regulatory talk. Dissecting the IFN-neutrophil paradigm is needed for well-balanced antiviral therapeutics and development of novel treatments against many major epidemic or pandemic viral infections, including the ongoing pandemic of the coronavirus disease that emerged in 2019.

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

Article

Full-text available

Apr 2021

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.

Systemic lupus erythematosus after COVID‐19 vaccination: A case report

Article

Aug 2021

Relapse of class V lupus nephritis after vaccination with COVID-19 mRNA vaccine

Article

Aug 2021

Induction and exacerbation of subacute cutaneous lupus erythematosus following messenger‐RNA or adenoviral‐vector based SARS‐CoV‐2 vaccination

Article

Jul 2021

Accumulating evidence exists that COVID‐19 vaccines might induce or exacerbate autoimmune rheumatic diseases. Currently available COVID‐19 vaccines include messenger‐RNA (mRNA) and recombinant adenoviral (AdV) vector vaccines, both encoding SARS‐CoV‐2 spike protein production as the primary target for neutralizing antibodies. We herein report a case of subacute cutaneous lupus erythematosus (SCLE) following mRNA vaccination with BNT162b2, and summarize the current literature on cutaneous lupus erythematosus occurring after COVID‐19 vaccination.

Effective DNA damage response after acute but not chronic immune challenge: SARS-CoV-2 vaccine versus Systemic Lupus Erythematosus

Article

Jun 2021
CLIN IMMUNOL

Whether and how an acute immune challenge may affect DNA Damage Response (DDR) is unknown. By studying vaccinations against Influenza and SARS-CoV-2 (mRNA-based) we found acute increases of type-I interferon-inducible gene expression, oxidative stress and DNA damage accumulation in blood mononuclear cells of 9 healthy controls, coupled with effective anti-SARS-CoV-2 neutralizing antibody production in all. Increased DNA damage after SARS-CoV-2 vaccine, partly due to increased oxidative stress, was transient, whereas the inherent DNA repair capacity was found intact. In contrast, in 26 patients with Systemic Lupus Erythematosus, who served as controls in the context of chronic immune activation, we validated increased DNA damage accumulation, increased type-I interferon-inducible gene expression and induction of oxidative stress, however aberrant DDR was associated with deficiencies in nucleotide excision repair pathways. These results indicate that acute immune challenge can indeed activate DDR pathways, whereas, contrary to chronic immune challenge, successful repair of DNA lesions occurs.

Prompt onset of erythema multiforme following the first BNT162b2 SARS‐CoV‐2 vaccination

Article

Mar 2021

In December 2020, the SARS‐CoV‐2 vaccine (BNT162b2, Comirnaty®, BioNTech/Pfizer) was approved by the European Medicines Agency. Recently, BNT162b2 was started to be administered to high‐risk populations for COVID‐19 in Germany.¹ We here report the first case of an elderly patient who developed erythema multiforme after the first day of vaccination with BNT162b2.