Abstract
Objective: To determine if SARS-CoV-2 mRNA vaccination has an impact on the clinical course of systemic lupus erythematosus (SLE).
Methods: Puerto Ricans with SLE who received mRNA COVID-19 vaccines were studied. Demographic parameters, clinical manifestations, disease activity (per Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), disease damage (per Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), emergency room visits, hospitalizations, and pharmacologic therapy were determined. Baseline variables (prior to vaccination) were compared between patients with and without exacerbation after SARS-CoV-2 vaccination. Among those with exacer- bation, clinical outcomes were determined up to 1 year after vaccination.
Results: Of the entire cohort (n = 247), 14 (5.7%) had post-vaccination exacerbations. Photosensitivity, oral ulcers, anti- Ro antibodies, higher SLEDAI score, and corticosteroids exposure were associated with post-vaccination flares. Among those with post-vaccination flares, 10 (71.4%) had major organ involvement. No significant differences were observed for mean SLEDAI scores, emergency room visits, hospitalizations, disease damage, and exposure to immunosuppressive drugs before and after SARS-CoV-2 mRNA vaccination. At 12 months of follow-up, all patients were fully controlled without evidence of active disease.
Conclusion: In our group of SLE patients, 5.7% had a disease flare after SARS-CoV-2 mRNA vaccination. Most had exacerbations involving major organs/systems. Mucocutaneous manifestations, anti-Ro antibodies, disease activity, and corticosteroids were associated with flares. Awareness of these factors and the possibility of a major lupus flare after vaccination with COVD-19 vaccines is critical to provide timely and effective therapy.
Keywords
Systemic lupus erythematosus, renal lupus, musculoskeletal
Introduction
Systemic lupus erythematosus (SLE) is a chronic hetero- geneous autoimmune disease characterized by the forma- tion of autoantibodies and immune complexes that cause inflammation of multiple organs. The pathogenesis of SLE involves a loss of tolerance caused by the imbalance be- tween cell apoptosis and debris clearance, leading to the stimulation of an inflammatory response through the activation of pattern recognition receptors (PRRs) and production of type I interferon (IFN), and the enhancement of B-cell differentiation and sustained autoantibody production.
The role of vaccines in patients with autoimmune con- ditions and the risk of disease activation after vaccination have long been investigated. In SLE, immunization with influenza and human papillomavirus are among the antiviral vaccines most associated with lupus flares. Because of the mechanism of mRNA vaccines for COVID-19, it is not unexpected that these could also induce an exacerbation in SLE patients. These vaccines are based on mRNA coding for the desired antigenic proteins which is delivered en- capsulated in nanoparticles or liposomes to avoid degra- dation. Once inside the cell, the mRNA binds to PRRs including the Toll-like receptors (TLRs) 3, 7, 8, and 9, which recognize chains of double-stranded (ds) RNA or single-stranded (ss) RNA7 These events result in the acti- vation of several pro-inflammatory cascades and surge of cytokines including IFN-gamma in synergy with type I INF signaling pathways and complement activation. Fur- thermore, a strong Th1-type CD4+ and CD8 + T cells re- sponse is elicited by these vaccines. Thus, they could produce a potent immune response that may enhance Tfh response and autoantibodies production in SLE patients.
Given the pro-inflammatory effect of the mRNA COVID-19 vaccine, the lack of inclusion of patients with autoimmune rheumatic diseases in SARS-CoV-2 mRNA vaccines clinical trials raises the concern about the impact of the vaccine on disease activity and outcomes in this group of individuals. Also, mRNA vaccines that translate into im- munogenic proteins can result in viral antigen mimicry leading to aberrant activation of the innate and acquired immune system predisposing individuals to unwanted im- munological side effects. Only a few studies have ex- amined the impact of mRNA COVID-19 vaccines in SLE. Therefore, we sought to determine the factors associated with flares in a cohort of SLE patients, the proportion and severity of flares, and the short- and mid-term outcomes of those that had post-vaccination disease exacerbations.
Methods
Study population
A retrospective study was performed in a cohort of adult SLE patients followed at the Rheumatology clinic of the Uni- versity of Puerto Rico School of Medicine, San Juan, Puerto Rico, and one private rheumatology practice located in San Juan. Patients included in this study were adults ≥21 years of age, had Puerto Rican ethnicity (self and four grandparents), fulfilled the 1997 revised American College of Rheumatology classification criteria, received at least one dose of the SARS-CoV-2 mRNA approved vaccines between December 2020 and June 2021, and had at least 12 months of follow-up after vaccination. SLE exacerbation was defined as an increase in disease activity requiring an adjustment of the immunosuppressive therapy. All patients were immediately evaluated at our clinics when they developed the post- vaccination flare. The day of the exacerbation was defined as the day on which the patient developed clinical manifestations attributed to a lupus reactivation.
Variables
Demographic parameters (gender, age, and SLE disease duration), SLE manifestations, comorbidities, pharmaco- logic therapy, disease activity, and damage accrual were ascertained. Comorbidities included cigarette smoking, overweight/obesity (body mass index >25), dyslipidemia, arterial hypertension, diabetes mellitus, coronary artery disease, and chronic kidney disease. Disease activity was determined using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and disease damage by the Systemic Lupus International Collaborating Clinics/ ACR Damage Index (SDI). Exposure to the following drugs was gathered: corticosteroids, hydroxychloroquine, mycophenolate mofetil, azathioprine, belimumab, cyclo- phosphamide, tacrolimus, methotrexate, rituximab, non- steroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and as- pirin. Type of SARS-CoV-2 mRNA vaccine received was also ascertained.
Clinical outcomes
For those who had post-vaccination lupus flares, disease activity, hospitalizations (any cause and those attributed to SLE), emergency room visits (any cause and those attributed to SLE), damage accrual, prednisone dose (or equivalent) exposure, and treatment with other immunosuppressive drugs were evaluated before and after baseline visits. Finally, mortality was assessed, including major causes of death, if any.
Statistical analysis
For the analysis, the cohort was divided in two groups based on the occurrence of a lupus flare after COVID-19 vaccination. Baseline (prior to vaccination) demographic parameters, clinical manifestations, disease activity, comorbidities, and pharmacotherapy were compared be- tween patients with and without lupus flares using chi- square test or Mann–Whitney test. For SLE patients that experienced post-vaccination flares, exacerbations, emer- gency room visits, hospitalizations, SLEDAI scores, SDI scores, and changes to immunosuppressive drug regimens were compared before and after SARS-CoV-2 mRNA vaccination. The mean number of emergency room visits, hospitalizations, and exacerbations for each 3-month study period, before and after the baseline visit, was calculated. Visits before (12, 6, and 3 months prior to baseline) and after (3, 6, and 12 months post vaccination) a lupus flare were grouped to make comparisons. Statistical analyses were performed using Wilcoxon signed-rank test and exact McNemar’s test, as appropriate. Statistical significance was set at p < 0.05. The statistical software STATA version 15 (STATA Corp.; College Station, TX, USA) was used to perform the analyses.
Results
A total of 247 patients with SLE underwent vaccination with SARS-CoV-2 mRNA vaccines. The mean (standard deviation [SD]) age of the study population at the study visit was 49.5 (13.5), and the mean (SD) disease duration was 16.0 (8.7).
Fourteen patients (5.7%) had an exacerbation post- vaccination. Patients who developed a lupus flare after COVID-19 vaccine had a higher baseline SLEDAI mean score (2.9 vs 1.2, p = 0.003), and a higher proportion of photosensitivity (78.6% vs 50.0%, p = 0.039), oral ulcers (35.7% vs 17.2%, p = 0.021), anti-Ro antibodies (50.0% vs 23.3%, p = 0.024), past exposure to intravenous (IV) methylprednisolone pulse (21.4% vs 3.0%, p < 0.001), and current use of corticosteroids (78.6 vs 50.9, p = 0.045) than those that did not have an exacerbation (Table 1). No significant differences were found for age, sex, disease duration, type of vaccine, comorbidities, damage accrual, or other immunosuppressive drugs.
The mean age (SD) of patients who had a lupus flare after vaccination was 43.7 (12.5) years, of which 12 (85.7%) were females (Table 1). The mean (SD) SLE duration was 16.9 (11.9) years. Most patients received the BioNTech/ Pfizer vaccine (57.1%). SLE exacerbations were more common after the second SARS-CoV-2 mRNA dose ad- ministration (64.3%) with a mean (SD) flare onset of 24 days (23.7) and median of 13 days post-vaccination (Table 2). Of the 14 patients who experienced an exacer- bation, ten (71.4%) had major organ involvement including renal (n = 7), central nervous system (n = 1), lung (n = 1), and liver (n = 1). In the group of patients with renal in- volvement, one had new-onset proteinuria, while the others had past history of proteinuria. Among the latter, proteinuria increased from <0.5 g/24 hours to a range between 1 and 3.5 g/24 hours. Three patients with preexisting renal in- volvement had kidney biopsies at lupus nephritis onset, two had diffuse proliferative glomerulonephritis and one had membranous glomerulonephritis. None of the seven pa- tients with new-onset or worsening proteinuria had dete- rioration of serum creatinine. The patient with central nervous system involvement had a severe lupus headache after vaccination that was not responsive to analgesics. The patient with lung involvement had preexisting pleuro- parenchymal fibroelastosis and had worsening of cough and dyspnea post-vaccination. The patient with liver involve- ment had prior biopsy-proven autoimmune hepatitis and after vaccination had a 9-fold increase in liver enzymes. The predominant flare manifestations were arthritis (57.1%), followed by proteinuria (42.9%), photosensitivity (21.4%), and malar rash (14.3%). All patients were treated with oral corticosteroids, either by starting the medication or in- creasing the established dose. None required IV cortico- steroids. Two patients required initiation of mycophenolate mofetil and one patient was started on tacrolimus. The mean (SD) time to resolution of SLE flare was 41.5 (34.3) days.
Among patients who had post-vaccination flares, no significant differences were observed for SLEDAI scores, SDI scores, emergency room visits, and hospitalization before and after COVID-19 vaccination (Table 3). There was a trend toward an increased use of mycophenolate mofetil (54.6% vs 81.8%, p = 0.08). After a follow-up of 12 months, all patients were controlled with no evidence of active disease. No deaths occurred during the study period.
Discussion
We assessed the associated factors and clinical outcomes in a group of patients with SLE from Puerto Rico who ex- perienced a lupus flare after vaccination with SARS-CoV-2 mRNA vaccines. Mucocutaneous manifestations, anti-Ro antibodies, higher disease activity and corticosteroids were associated with lupus exacerbations. Fourteen (5.7%) vaccinated SLE patients had an exacerbation post- vaccination. Ten of these patients experienced major organ/system involvement including renal, central nervous system, lung, and liver requiring changes in immunosup- pressive therapy to control disease activity. However, we did not observe significant differences in emergency room visits, hospitalizations, damage accrual, and exposure to corticosteroids or other immunosuppressive therapies be- fore and after lupus flares. After 12 months of follow-up, all SLE exacerbations had completely resolved.
We found that patients who had lupus exacerbation after COVID-19 vaccination had a higher baseline SLEDAI score and a higher proportion of photosensitivity, mouth ulcers, anti-Ro antibodies, past exposure to pulse methyl- prednisolone therapy, and current corticosteroid use. To the best of our knowledge, the differences between patients with and without post-vaccination exacerbations have not been previously explored. We do not have a clear explanation for some of our findings, but interestingly, most of the case reports of post-vaccination lupus flares describe cutaneous manifestations and anti-Ro antibodies as main manifestations. On the other hand, we are not surprised about the association with higher disease activity and corticosteroids exposure as immunosuppressor treatment for severe SLE is a clinical predictor of subsequent lupus flares.
Immunization with SARS-CoV-2 mRNA vaccines appears to be effective and safe for patients with autoimmune rheumatic diseases. However, there are some case reports in the literature describing lupus exacerbations after SARS- CoV-2 mRNA vaccination. For example, Kreteur et al. reported a 62-year-old woman with a 6-month history of subacute cutaneous lupus with erythematous squamous papules and plaques over sun-exposed areas with positive antinuclear antibodies (1:320 liter) and positive anti-Ro/La antibodies. Ten days after the first dose of SARS-CoV-2 mRNA vaccine she developed worsening of cutaneous lupus erythematosus as well as fatigue, increased anti- double-stranded DNA antibody levels, leukopenia and C3/C4 hypocomplementemia. She received prednisolone 250 mg/day with improvement of symptoms within 7 days. In addition, Adrienne et al. described a 54-year-old woman with SLE who developed worsening of subacute cutaneous lupus lesions over her face, neck, chest, back, and arms 4 days after her first dose of the SARS-CoV-2 mRNA vaccine. She developed a second flare two weeks after her second vaccine dose. She required an increased dosage of her baseline mycophenolate mofetil therapy. In another case report, Sugiomto et al. reported a 41-year-old woman with a 12-year history of SLE who developed facial erythema, digital ulcers and gangrene, pleural effusions, leukopenia, lymphopenia, myositis, hypocomplementemia and marked elevation of ferritin levels after receiving the mRNA vac- cine. She was diagnosed with a severe SLE exacerbation complicated with hemophagocytic syndrome. She was treated with IV methylprednisolone pulse (1000 g/daily for 3 days) with subsequent tapering with improvement of symptoms in a 3-month period.
Not only cases of lupus flare post COVID-19 vaccination have been reported, but also exacerbations after COVID-19 infection and new-onset SLE after COVID-19 vaccination have been described. For example, a 67-year-old woman developed an erythematous scaly rash over sun- exposed areas two weeks after COVID-19 infection. Lab- oratories tests revealed elevated anti-SS-A antibodies, low complement levels, and a skin biopsy showing epidermal atrophy and vacuolar dermatitis with a positive lupus band test (IgA, IgM, and complement C3). She was treated with systemic corticosteroids and hydroxychloroquine with resolution of symptoms. On the other hand, Baez et.al. described a 27-year-old woman who developed lupus after presenting with symmetric inflammatory polyarthritis, renal manifestations, positive antinuclear, anti-dsDNA, anti-Ro, and anti-La antibodies 2 weeks after receiving the second dose of the SARS-CoV-2 mRNA vaccine. The patient required therapy with prednisone and mycophenolate mo- fetil for disease control.
In our study, 5.7% of lupus patients experienced an exacerbation after the SARS-CoV-2 mRNA vaccines. These results contrast with data from other studies that show a higher proportion of flares. In a lupus cohort of 101 patients, 8.1% had post-vaccination exacerbations that were classified as mild after the first vaccine dose and moderate after the second dose. An even higher prevalence was reported by Connolly et al. with 11.0% flares in lupus patients after vaccination. In another multinational SLE cohort, of patients who received full regimens of SARS-CoV-2 mRNA vaccines, 11.4% had flares of which 1.3% were considered severe. In a study from Latin America, Zavala- Flores et al. reported 27 episodes of flares in a group of 100 patients with SLE. The differences observed between our study and those described here could be attributed to methodological differences. Lupus flares in our population were determined by medical evaluations by rheumatologists whereas in these other studies exacerbations were reported by the patients.
We found that SLE exacerbations were more common after the second SARS-CoV-2 mRNA dose administration (64.3%) with a mean and median post-vaccination flare onset of 24 and 13 days, respectively. The predominant flare manifestations were arthritis (57.1%), followed by pro- teinuria (42.9%) and photosensitivity (21.4%), with ten patients experiencing major organ involvement. Similarly, musculoskeletal (arthralgias, arthritis, myalgias) and dermatologic manifestations are the most common flare manifestations reported by other investigators. In most cases, musculoskeletal and dermatologic manifestations were treated with a short course of glucocorticoid therapy.
Major organ involvement after SARS-CoV-2 mRNA vaccine administration has also been reported in the literature. Tuschen et al. described a 42-year-old woman diagnosed with lupus nephritis class V in 2016 on maintenance therapy with hydroxychloroquine who developed worsening proteinuria (0.07 g/day to 6 g/day) 7 days after COVID-19 mRNA BNT162b2 vaccination. She required mycophenolate mofetil (1 g bid) and high dose prednisone (60 mg/daily). In this case, a second dose was not recommended as full re- mission of her proteinuria was not achieved. Other studies have suggested that a history of SLE flares 1 year prior to vaccination and a history of lupus nephritis are associated with an increased risk of lupus flares after SARS-CoV-2 mRNA vaccination.
Given the SARS-CoV-2 mRNA vaccine mechanism of action, there is a possibility that lupus patients could develop a disease flare after immunization. This vaccine may induce a higher titer of autoantibodies by the en- hancement of the T- and B-cell responses when compared to traditional vaccines. After the first dose of the SARS- CoV-2 mRNA vaccine there is a rapid induction of antigen-specific CD4+ T cells, particularly Th1, cTfh cells, and several inflammatory cytokines (IFN-γ, TNF, IL-2). In SLE, enhancement of the IFN pathways is associated with increased autoantibodies and subsequent elevation in IFN activity.30 Also, the imbalance of Th1/ Th2 subsets that are triggered by SARS-CoV-2 mRNA vaccines has been deemed important in the pathogenesis of SLE which certainly raises concerns for vaccine- induced complications.
This study is not without limitations. First, in general, it is challenging to infer or establish causality in post-vaccination adverse events. However, given the absence of significant SLE activity prior to SARS-CoV-2 mRNA vaccination, the temporal relationship with the vaccine exposure, and the potential pro-inflammatory effect of the vaccine, it is very likely that the disease flares observed in our patients were associated with the vaccine. Second, many adverse events reported immediately after the COVID-19 vaccination such as fatigue, fever, arthralgias, and myalgias may overlap with manifestations reported during a lupus flare. Third, the number of patients having post-vaccination lupus flares was relatively small limiting our ability to conduct robust analyses and to have sufficient power to detect significant differences. Fourth, this study was conducted in a group of Puerto Ricans patients that may not be representative of other ethnic populations as disparities in genetic and epigenetic factors may impact clinical outcomes among different ethnic groups. Finally, medication adherence was not examined; thus, we cannot firmly determine whether the exacerbations were caused by the vaccine or by poor adherence. However, we examined disease activity for a year prior to lupus flares and did not observe active disease in any of the patients sug- gesting that poor medication adherence was unlikely. Despite these limitations, this is one of few studies evaluating the short- and intermediate-term clinical outcomes of SLE patients that had SARS-CoV-2 mRNA post-vaccination flares.
In summary, in our group of Puerto Ricans with SLE, a small proportion of patients presented with disease flare after SARS-CoV-2 mRNA vaccination. Although most had exacerbations involving major organ/system involvement, remission was achieved for all patients and clinical mani- festations resolved within 12 months of follow-up. This study suggests that SARS-CoV-2 mRNA immunization does not have a significant impact on the outcomes of lupus patients. Nonetheless, patients undergoing vaccination should be followed closely to assess disease activity and minimize any arising complications.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with re-
spect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, au- thorship, and/or publication of this article.
ORCID iD
Ariana Gonzalez-Melendez: https://orcid.org/0000-0001-6968- 8024
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Original article: https://pubmed.ncbi.nlm.nih.gov/36639887/