key: cord-0721888-i89nc49r
authors: Lemoine, Chantal; Padilla, Cristina; Krampe, Noah; Doerfler, Sean; Morgenlander, Adam; Thiel, Brent; Aggarwal, Rohit
title: Systemic lupus erythematous after Pfizer COVID-19 vaccine: a case report
date: 2022-03-16
journal: Clin Rheumatol
DOI: 10.1007/s10067-022-06126-x
sha: 5c76d734d675aae13fbd28581b1d817b95f9e7f7
doc_id: 721888
cord_uid: i89nc49r

The Pfizer-BioNTech COVID-19 vaccine has been authorized by the U.S. Food and Drug Administration as it demonstrated 95% effectiveness against the SARS-CoV-2 virus. Although the initial vaccine trials showed a favorable side effect profile, there have been concerns regarding activation of aberrant immune responses, triggering autoimmunity. This is a case report of a 68-year-old woman without history of autoimmune conditions, who presented to our emergency department 7 days after receiving the Pfizer-BioNTech COVID-19 vaccine. Her initial symptoms were suggestive of polymyalgia rheumatica, and she had nearly complete response to steroids. Interestingly, she later met criteria for classified systemic lupus erythematous given the development of inflammatory arthritis, positive ANA, and positive dsDNA. The temporal relationship of her symptoms that started 2 days after vaccine administration could suggest a possible association between the Pfizer-BioNTech COVID-19 and the development of systemic lupus erythematous.

Pfizer-BioNTech COVID-19 vaccine is part of a novel class of mRNA vaccines that instructs human cells to create viral spike protein, invoking the immune system to create antibodies against SARS-CoV-2. Although highly effective against the SARS-CoV-2 infection [1] , shared peptides between the spike protein and human proteins propose a mechanism for development of autoimmunity through molecular mimicry [2] that could be similar to the mechanism behind autoimmunity following COVID-19 infection [3] . Systemic lupus erythematous (SLE) is a chronic, systemic autoimmune disease with diverse clinical presentation. Multiple factors, including genetic, environmental, and immunologic, have been linked to its pathogenesis [4] . We present the first reported case of SLE following Pfizer-BioNTech COVID-19 vaccination.

This is a 68-year-old Caucasian woman without history of autoimmune conditions that presented to our emergency department with bilateral proximal upper and lower extremity muscle weakness, stiffness, and pain. She received the first dose of the Pfizer-BioNTech COVID-19 vaccine 2 days prior to symptom onset and 7 days prior to hospital presentation. Initially, she developed a mild headache and experienced soreness at the injection site that resolved the day after vaccination. Two days after receiving the vaccine, she developed acute onset of bilateral shoulder pain, morning stiffness that lasted at least 30 min, and weakness that started in her right shoulder and then progressed to her left shoulder. She also developed bilateral antero-lateral hip pain radiating into her thighs, stiffness and weakness. Over the course of a week, the muscle weakness and pain became so profound, that she was unable to ambulate. During her hospitalization, she did not experience fever, headache, jaw claudication, scalp tenderness, chest pain, rash, other muscle involvement, or respiratory symptoms. Patient reported intentional 47-pound weight loss over the last couple of months. On examination, she had tenderness and 3/5 proximal muscle strength at the hip and shoulder girdles. She had tenderness with active and passive range of motion. She could not get out of bed without assistance. Laboratory studies showed reactive ANA with positive titer 1:640 and presence of cytoplasmic pattern, ESR greater than 130 mm/h, CRP 15.9 mg/dl, and total CPK 23 IU/L ( Table 1 ). The patient tested negative for Covid-19 but Covid-19 antibodies were positive. Further serological work up was negative for RF, anti-CCP, anti-SSA, and anti-SSB antibodies. Complement levels, vitamin D, TSH, and morning cortisol were normal. She had a positive p-ANCA with anti-MPO specificity; however, CT of the chest/sinuses, and urinalysis were unremarkable. She had no features suggestive of vasculitis. CT of the chest, abdomen and pelvis were performed to rule out malignancy, which were all negative. She underwent MRI of the cervical, thoracic, and lumbar spine that showed disc disease with mild impingement at C3-C4 with moderate central canal stenosis, these findings did not explain patient's symptoms. By the time she was admitted to our hospital, lumbar puncture was performed at outside facility due to concern of possible Guillain-Barré. Our neurology team did not consider Guillain-Barré as a possible working diagnosis given her physical examination was not consistent with it. Her lumbar puncture was normal: . For this reason, she received prednisone 20 mg daily and described a "90% improvement" in her muscle weakness and pain on the following day. Muscle strength and tenderness on range of motion in shoulders and hips girdles almost normalized after 2 days of prednisone. Her repeat inflammatory markers after a short interval of 3 days on prednisone were ESR 112 mm/h and CRP 7.7 mg/dl. She was discharged home on a prednisone taper of 20 mg daily for 2 weeks, with instructions to taper by 5 mg every 2 weeks. Three weeks after discharge, patient's muscle weakness, pain and stiffness had continued to improve. Follow-up blood work was noted for decreased inflammatory markers with ESR 55 mm/h, CRP 52.6 mg/dl (Table 1) . However, 2 months later, she experienced recurrent symptoms, developing significant joint pain in shoulders, wrists, hips, knees, and ankles along with morning stiffness lasting all day. She endorsed swelling in her ankles and metacarpophalangeal joints as well as a rash on her forearm and palm of hands. More extensive work-up showed positive ds-DNA (titer 221) and rising inflammatory markers with ESR 68 mm/h and CRP 149.3 mg/dl (Table 1 ). According to the EULAR/ACR-2019 classification criteria, positive ANA with scores more or equal to 10 are indicative of classified SLE. Our patient met this criteria with a total score of 12 points, based on positive ANA, plus joint involvement (+ 6 points) for the clinical domains, as well as the presence of positive ds-DNA (+ 6 points) in the immunological domains [5] . The presence of immune mediated rash did not provide any points as it was not clear if it was consistent with acute cutaneous lupus erythematous given rash was reported but not evidenced on physical exam. Further, the patient had active disease given SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score more than 4 points. Her SLEDAI was 10 points. Points were given for: arthritis (+ 4 points), pyuria (+ 4 points), dsDNA (+ 2 points). There were no other organs affected besides the joints and skin, she did not have lupus nephropathy given no evidence of proteinuria, hematuria, and normal creatinine. She was started on a steroid-sparing agent with azathioprine 50 mg daily for 2 weeks with instructions to increase to 100 mg daily thereafter. Unfortunately, she developed generalized hives when increasing the azathioprine dose for which the medication was stopped. Therefore, the patient was started on methotrexate 20 mg weekly and maintained on prednisone 5 mg daily with improvement of symptoms. Our patient elected to forgo the second dose of COVID-19 vaccine.

Pfizer-BioNTech COVID-19 vaccine has been approved by the U.S. Food and Drug Administration (FDA) in response to the SARS-CoV-2 pandemic. In the phase 3 trial, the vaccine demonstrated 95% efficacy in preventing the SARS-CoV-2 infection [1] with relatively common side effects that included fatigue, headache, chills, muscle pain, and injection site pain [6] . Systemic adverse effects began a median of 1-2 days after vaccination and resolved 1 day later [6] . The FDA briefing of the Moderna vaccine reported three serious adverse events, in which one was the development of rheumatoid arthritis but vaccine contribution could not be excluded [7] . Similarly, some cases of possible Pfizer-BioNTech vaccine association with the development de novo immune thrombocytopenia [8] , acquired hemophilia A [9] , anterior uveitis [10] , and recurrent Bell's palsy [11] have been published in the literature. Multiple cases of cutaneous lupus erythematosus (CLE) have been observed following Pfizer-BioNTech vaccine administration [12] , as well as one case of pre-vaccination CLE developing into SLE following the AstraZeneca adenovirus vector vaccine [13] . Current evidence suggests cases of SLE following hepatitis B [14] and meningococcal [15] vaccines, but conclusive evidence of causation remains unestablished [16] . Likewise, apart from the above presumptive associations, to date, there is no definitive data indicating that SARS-CoV-2 mRNA vaccines cause autoimmunity.

Autoimmunogenicity incited by mRNA vaccines is currently an avenue of intense research. It has been proposed that the response to SARS-Cov-2 infection may trigger autoimmunity through molecular mimicry between the virus and human proteins [3] . Kanduc et al. analyzed peptide sharing between the SARS-CoV-2 spike protein and human proteins and noted significant sharing at the heptapeptide level [2] , hence, it is plausible that the antibodies produced against SARS-CoV-2 spike protein, in response to the vaccine, can cross-react with the host and cause autoimmune diseases in predisposed individuals. Following mRNA vaccination, multiple proinflammatory pathways are activated as a result of the mRNA itself, liposomes or lipid-nanoparticles used to encapsulate mRNA, as well as the binding of receptors required for the spike protein translation; which could explain the reactogenicity associated with mRNA vaccines and the development of immune-mediated diseases [17] . Because mRNA is a single-stranded RNA, it is a ligand for toll-like-receptor (TLR-7) [18] . TLR-7 has increased expression in SLE humans and mice [19, 20] . In addition, the mRNA and adenovirus vaccines both stimulate the production of type 1 interferons, which are integral to the development of SARS-CoV-2 immunity [21] but also have been implicated in the pathogenesis of SLE and other autoimmune conditions [22, 23] . We speculate that individuals who are pre-disposed to SLE may show an exacerbated innate inflammatory response and elevated inflammatory cytokine profile that may contribute to the onset of profound systemic inflammation post-vaccination.

SARS-CoV-2 is known to hyper-stimulate the immune system, which could cause formation of autoantibodies and trigger autoimmune disease. More severe disease correlates with higher level of pro-inflammatory cytokines such as IL-6, TNF, and interferon gamma (IFN-gamma), the latter had been described as an independent risk factor of mortality in moderate to severe COVID-19 infection [24] . These cytokines are also elevated SLE and correlate with disease activity [25] . Interestingly, p-ANCA and c-ANCA positivity has been frequently reported in severely ill patients who have autoimmune vasculitis [3] . While our patient did not get infected with COVID-19, a similar pathway is likely elicited by the vaccine, and these cytokines also are elevated in the pathogenesis of SLE.

Our elderly patient that debuted with clinical manifestations suggestive of PMR and had initial marked improvement with moderate dose steroids, was later confirmed to have classified SLE according to the EULAR/ACR-2019 classification criteria. Interestingly, she also was found to have positive p-ANCA/MPO without evidence of vasculitis further supporting her unusual presentation and autoantibody profile. Given that the constellation of symptoms presented within days after receiving the Pfizer-BioNTech COVID-19 vaccine, this could suggest but not prove a possible etiologic association between the vaccine administration and the development of SLE.

It is worth mentioning that SLE in the elderly is rare, with an incidence of 12-18% and a prevalence of 15-124/100,000 of population worldwide. Diagnosis is often delayed given the low prevalence in this age group as well as nonspecific and sometimes atypical presenting symptoms. These factors usually contribute to diagnosis uncertainty, delay in diagnosis, or misdiagnoses. The disease course is considered to be more benign; and the most common symptoms in this population include fever, weakness, fatigue, arthritis/arthralgias, weight loss, serositis, neuropsychiatric manifestations, lung disease, Raynaud's, and sicca. Other typical lupus symptoms such as rash, glomerulonephritis, photosensitivity, or discoid lupus are uncommon in the elderly population. ANA remains the usual test to screen for disease, although, positive anti-dsDNA and hypocomplentaemia is of lower prevalence. SLE management remains the same in this age group except considering comorbidities and side effect profile of medications in the elderly [26, 27] .

By the time our patient was vaccinated, a total of 26,413 patients were partially vaccinated with mRNA vaccines in Pennsylvania [28] . Notably, this was the only case of possible mRNA-induced SLE known in the University of Pittsburgh Medical Center system, suggesting a very low incidence of disease. Therefore, we hope this report does not discourage against vaccination but raise awareness about the possible association of SLE development after mRNA vaccination in the susceptible population (Table 1) .

Autoantibody formation and autoimmune disease have been observed following SARS-CoV-2 infection as a result of a robust immune response and molecular mimicry. Likewise, the SARS-CoV-2 spike protein shares a significant portion of peptides with human proteins and could incite autoimmune disease or trigger pre-existing autoimmune conditions. Given the strong temporal association between COVID-19 vaccine administration and the development of SLE in our patient, we hypothesize that the mRNA vaccine could have caused hyperstimulation of the patient's immune system. Her aberrant immune response required that she be closely monitored for evolution of her autoimmune disease. We report this case to increase awareness for the possibility of autoimmunity, specifically SLE, following mRNA vaccination against SARS-CoV-2 virus.

Author contribution All authors contributed to the care of the patient and gathering of data. Dr Lemoine and Dr Padilla drafted the initial version. All authors offered corrections, read and approved the final version.

Other disclosure This case report has not been submitted elsewhere and is not under consideration by another journal. The case report information will not be submitted or published elsewhere while it is under review by this journal unless rejected by journal or withdrawn by the authors.

Dr. Aggarwal has received research grant and consulting fee from Pfizer. The other authors have disclosed no conflict of interest.

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