Genetic predisposition between coronavirus disease 2019 and rheumatic diseases: A 2-sample Mendelian randomization study.

OBJECTIVE: The causalities between the coronavirus disease 2019 (COVID-19) and the risk of rheumatic diseases remain unclear. The purpose of this study was to investigate the causal effect of COVID-19 on rheumatic disease occurrence. METHODS: Single nucleotide polymorphisms (SNPs), acquired from published genome-wide association studies, were used to perform 2-sample Mendelian randomization (MR) on cases diagnosed with COVID-19 (n = 13 464), rheumatic diseases (n = 444 199), juvenile idiopathic arthritis (JIA, n = 15 872), gout (n = 69  374), systemic lupus erythematosus (SLE, n = 3094), ankylosing spondylitis (n = 75 130), primary biliary cholangitis (PBC, n = 11 375) and primary Sjögren's syndrome (n = 95 046). Three MR methods were used in the analysis based on different heterogeneity and pleiotropy using the Bonferroni correction. RESULTS: The results revealed a causality between COVID-19 and rheumatic diseases with an odds ratio (OR) of 1.010 (95% confidence interval [CI], 1.006-1.013; P = .014). In addition, we observed that COVID-19 was causally associated with an increased risk of JIA (OR 1.517; 95%CI, 1.144-2.011; P = .004), PBC (OR 1.370; 95%CI, 1.149-1.635; P = .005), but a decreased risk of SLE (OR 0.732; 95%CI, 0.590-0.908; P = .004). Using MR, 8 SNPs were identified to associate with COVID-19 and recognized as significant variables. None of them were previously reported in any other diseases. CONCLUSIONS: This is the first study to use MR to explore the impact of COVID-19 on rheumatic diseases. From a genetic perspective, we found that COVID-19 could increase the risk of rheumatic diseases, such as PBC and JIA, but decrease that of SLE, thereby suggesting a potential surge in the disease burden of PBC and JIA following the COVID-19 pandemic.

A case of systemic lupus erythematosus presenting with intestinal lymphangiectasia-associated protein-losing enteropathy accompanying hyperinflammation.

Systemic lupus erythematosus (SLE) has the potential to affect virtually every organ; however, gastrointestinal system manifestations are relatively rare compared to other autoimmune diseases such as systemic sclerosis and inflammatory bowel disease. A 29-year-old female patient attended to the emergency room with abdominal distention, acute onset abdominal pain and constipation. She had watery chronic diarrhea (4-5 times/d) and weight loss (6 kg, 12%) for 4 months. While there was increased intestinal wall thickness, air-liquid levels were shown on abdomen computed tomography scan. The patient underwent abdominal surgery due to diagnosis of ileus. Ileocecal resection was performed and pathologic evaluation revealed intestinal lymphangiectasia. Autoimmune serology was performed with the following resulats: anti-nuclear antibody 1/3200 with homogenous pattern, anti-DNA antibody and anti-Sm/ribonucleoprotein antibodies were positive in addition to low complement levels (C3: 0.28 [0.9-1.8 g/L], C4: 0.06 [0.1-0.4 g/L]) indicating diagnosis of SLE. Development of intestinal involvement in SLE (lupus enteritis) is mainly grouped into 3 headings such as mesenteric vasculitis, pseudo-obstruction, and protein-losing enteropathy. Although the pathogenesis of intestinal lymphangiectasia remains unknown, it has been reported that immune complex-mediated visceral vasculitis may result in bowel wall and mucosal edema. To our knowledge this is the first case report accompanying hyperinflammatory response in addition to intestinal lymphangiectasia in SLE. On the other hand, clinicians should be alert for other reasons for hyperinflammatory syndromes rather than COVID-19, even during the pandemic.

A systematic review of the incidence, management and prognosis of new-onset autoimmune connective tissue diseases after COVID-19.

A literature review on new-onset autoimmune connective tissue diseases (ACTDs) following COVID-19 is lacking. We evaluated potential associations between COVID-19 and the development of new-onset ACTDs. The "population" was adults with disease terms for ACTDs, including systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), anti-synthetase syndrome, mixed CTD and undifferentiated CTD, and "intervention" as COVID-19 and related terms. Databases were searched for English-language articles published until September 2022. We identified 2236 articles with 28 ultimately included. Of the 28 included patients, 64.3% were female, with a mean age was 51.1 years. The USA reported the most cases (9/28). ACTD diagnoses comprised: 11 (39.3%) IIM (including four dermatomyositis); 7 (25%) SLE; four (14.3%) anti-synthetase syndrome; four (14.3%) SSc; two (7.1%) other ACTD (one lupus/MCTD overlap). Of eight, four (14.3%) patients (including that with lupus/MCTD) had lupus nephritis. The average time from COVID-19 to ACTD diagnosis was 23.7 days. A third of patients were admitted to critical care, one for treatment of haemophagocytic lymphohistiocytosis in SLE (14 sessions of plasmapheresis, rituximab and intravenous corticosteroids) and nine due to COVID-19. 80% of patients went into remission of ACTD following treatment, while three (10%) patients died-one due to macrophage activation syndrome with anti-synthetase syndrome and two from unreported causes. Our results suggest a potential association between COVID-19 and new-onset ACTDs, notably in young females, reflecting more comprehensive CTD epidemiology. The most common diagnosis in our cohort was IIM. The aetiology and mechanisms by which ACTDs emerge following COVID-19 remain unknown and require further research.

Risks of mortality and severe coronavirus disease 19 (COVID-19) outcomes in patients with or without systemic lupus erythematosus.

OBJECTIVES: We compared the outcomes of patients with or without systemic lupus erythematosus (SLE) who were diagnosed with coronavirus disease 19 (COVID-19) and evaluated factors within patients with SLE associated with severe outcomes. METHODS: This retrospective cohort study used the deidentified Optum COVID-19 electronic health record dataset to identify patients with COVID-19 from 1/1/2020 to 31/12/2020. Cases with SLE were matched with general controls at a ratio of 1:10 by age, sex, race and ethnicity and COVID-19 diagnosis date. Outcomes included 30-day mortality, mechanical ventilation, hospitalisation and intensive care unit admission. We evaluated the relationship between COVID-19-related outcomes and SLE using multivariable logistic regression. In addition, within SLE cases, we examined factors associated with COVID-19 related outcomes, including disease activity and SLE therapy. RESULTS: We included 687 patients matched with 6870 controls. Unadjusted rates of outcomes for patients with SLE were significantly worse than for matched controls including mortality (3.6% vs 1.8%), mechanical ventilation (6% vs 2.5%) and hospitalisation (31% vs 17.7%) (all p<0.001). After multivariable adjustment, patients with SLE had increased risks of mechanical ventilation (OR 1.81, 95% CI 1.16 to 2.82) and hospitalisation (OR 1.32, 95% CI 1.05 to 1.65). Among patients with SLE, severe disease activity was associated with increased risks of mechanical ventilation (OR 5.83, 95% CI 2.60 to 13.07) and hospitalisation (OR 3.97, 95% CI 2.37 to 6.65). Use of glucocorticoids, mycophenolate and tacrolimus before COVID-19 was associated with worse outcomes. CONCLUSION: Patients with SLE had increased risk of severe COVID-19-related outcomes compared with matched controls. Patients with severe SLE disease activity or prior use of corticosteroids experienced worse outcomes.

Systemic lupus erythematosus myocarditis after COVID-19 vaccination.

INTRODUCTION: Cases of acute myocarditis have been after administration of the BNT162b2 and Ad26.COV2.S vaccine. OBJECTIVE: Describe another possible mechanism of myocarditis after COVID-19 vaccination. CASE PRESENTATION: We describe the clinical case of a 72-year-old female with pleuritic chest pain one week after the third of the BNT162b2 mRNA vaccine. Serological tests for cardiotropic pathogens were negative, and autoimmunity screening was positive with anti-nuclear antibody (ANA) in 1:160 dilution, Anti-double-stranded DNA (anti-dsDNA), and anti-histone antibodies. 18F-fluoro-deoxy-glucose (FDG) positron emission tomography/computed tomography (PET/CT) showed a focal myocardial and pericardial inflammatory process in the cardiac apex. RESULTS AND DISCUSSION: Systemic lupus erythematosus (SLE) diagnosis was made with myocardial affection. As far as we know, this is the first report of a case of lupus myocarditis after the COVID-19 vaccine. CONCLUSION: Given the pathogenic rationales, the association between SLE and myocarditis should be considered.

COVID-19 vaccine safety during pregnancy in women with systemic lupus erythematosus.

COVID-19 vaccination has been shown to be safe in patients with systemic lupus erythematosus (SLE), but data on vaccine-associated adverse events (AEs) during the antenatal and lactation period are scarce or lacking. We investigated COVID-19 vaccination-related AEs in pregnant SLE patients from the COVAD study, a global esurvey involving 157 collaborators from 106 countries. A total of 9201 complete responses were extracted. Among 6787 (73.8%) women, we identified 70 (1.1%) who were exposed to at least one COVID-19 vaccine dose during pregnancy, 11 with SLE. Delayed onset (>7 days) vaccine-related AEs were triangulated with disease activity, treatment changes due to flare after vaccination, and COVID-19 infections in vaccinated pregnant women. Health-related quality of life and physical function was recorded using PROMIS. Age of patients ranged from 28 to 39 years; 5/11 women were of Asian origin. None of these patients reported major vaccine AEs or change in the status of their autoimmune disease. Although minor AEs were common, they did not impair daily functioning, and the symptoms resolved after a median of 3 (IQR: 2.5-5.0) days. All patients reported good to excellent health status. No adverse pregnancy outcomes were reported. Importantly, none of the patients reported thrombotic events post-vaccination, which provides reassurance in a patient population with a high risk for cardiovascular comorbidity and thrombosis, especially in the presence of antiphospholipid antibodies or the antiphospholipid syndrome, a considerable portion of SLE patients. Our findings provide reassurance and can contribute to informed decisions regarding vaccination in patients with SLE and high-risk pregnancies due to their background autoimmune disease. The risk/benefit ratio of COVID-19 vaccination appears favourable, with vaccines both providing passive immunisation to the fetus and active immunisation to the mother with no signals of exacerbation of the mother's autoimmune disease.

Two cases of systemic lupus erythematosus after administration of severe acute respiratory syndrome coronavirus 2 vaccine.

Although there is a great demand for increased coronavirus disease 2019vaccination worldwide, rare side effects of the vaccines in susceptible individuals are attracting attention. We recently treated two patients who developed systemic lupus erythematosus after administration of a severe acute respiratory syndrome coronavirus 2 vaccine from Pfizer-BioNTech or Moderna. While causal relationships between vaccination and adverse events are difficult to discern due to both confounding and masking factors, our findings suggest that attention to possible adjuvant-related autoimmune diseases in certain individuals receiving severe acute respiratory syndrome coronavirus 2 vaccines is appropriate.

SARS-CoV-2 vaccine-triggered conversion from systemic lupus erythematosus (SLE) to bullous SLE and dipeptidyl peptidase 4 inhibitors-associated bullous pemphigoid.

Bullous systemic lupus erythematosus (BSLE) is a rare blistering disease in patients with SLE. BSLE is a heterogenous disease caused by autoantibodies to the basement membrane, mainly type VII collagen. The pathogenesis of the development of autoantibodies in BSLE remains unknown. We report a case of SLE taking dipeptidyl peptidase 4 inhibitors (DPP4i) who developed tense blister lesions after administration of SARS-CoV-2 vaccine. Initial erythematous lesion before administration of SARS-CoV-2 vaccine had not shown IgG deposition at basement membrane both direct and indirect immunofluorescence (IIF). However, the result of those examinations became positive after the administration of SARS-CoV-2 vaccine. Furthermore, IIF test results using NaCl split skin had shown positive against epidermal side. These observations suggest that SARS-CoV-2 vaccination triggered production of autoantibodies that cause bullous SLE. The present case fulfills the diagnostic criteria for both BSLE and DPP4i-associated bullous pemphigoid. Skin lesions were cleared after withdrawal of DPP4i. Therefore, physicians should ask patients who develop blisters after the vaccination whether they are taking DPP4i.

The Role of Immunosuppression in the Development of COVID-19 in Systemic Lupus Erythematosus Patients: A Brief Report.

Recently, due to the coronavirus disease 2019 (COVID-19) pandemic, much concern has been raised about patients with chronic diseases who may become more susceptible to the disease. The present cross-sectional study aimed to characterize the clinical course of COVID-19 in patients with systemic lupus erythematosus (SLE). In addition, a possible correlation between the immunosuppression state and the incidence of COVID-19 is investigated. In May 2020, 500 SLE patients registered in the database of Golestan Rheumatology Research Center (Golestan province, Iran) were selected for this cross-sectional study. Using a questionnaire, patients were contacted by telephone to collect data including demographic characteristics, disease status, drug use, and new clinical symptoms. Data were analyzed using SPSS software version 24.0. Of the 500 selected patients, 355 responded to the phone calls and subsequently enrolled in the study. Among the enrolled patients, 25 were classified as COVID-19 positive, including eight hospitalized patients, of which two required intensive care and subsequently died. COVID-19 incidence was significantly lower in the immunosuppressed patients (2.2% vs. 10%, P=0.01). There was no significant correlation between hydroxychloroquine consumption and the incidence of COVID-19 in SLE patients. Fever, fatigue, dyspnea, and dry cough were the most common clinical symptoms. Our results showed that COVID-19 incidence was lower in immunosuppressed than the non-immunosuppressed SLE patients. Further studies are required to substantiate the role of immunosuppression in the development of COVID-19. A preprint version of this study was published at https://www.researchsquare.com/article/rs-78704/v1 with doi: https://doi.org/10.21203/rs.3.rs-78704/v1.

Peripheral Ulcerative Keratitis in a Young Lady with Systemic Lupus Erythematosus Post Rituximab Infusion-A Case Report.

AIM: We report a new ocular finding of episcleritis (OD) and peripheral ulcerative keratitis (OS) in a 40-year-old lady with a 13-year history of systemic lupus erythematosus (SLE), 3 weeks post-rituximab infusion. MATERIALS & METHODS: Retrospective case report. RESULTS: A 40-year-old lady with a history of SLE and 3 weeks post rituximab infusion developed a new onset episcleritis (OD) and peripheral ulcerative keratitis (OS). As the PUK continued to advance with a leading edge, intravenous methyl prednisolone 1 gm/day was given for 3 days followed by a slow tapering course of oral prednisolone 50 mg/day. Though her ocular inflammation resolved, she developed pneumonia 6 weeks later. At 10 months follow-up, there were no ocular recurrences. She is currently on mycophenolate mofetil 2 gm/day along with oral prednisolone of 10 mg/day. CONCLUSION: This case highlights the new occurrence of episcleritis and PUK in SLE post-rituximab infusion.

COVID-19 diversity: A case of multisystem inflammatory syndrome in children masquerading as juvenile systemic lupus erythematosus.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may present with some systemic lupus erythematosus (SLE) manifestations intermingled with Kawasaki disease features. These emerging presentations were dubbed under the umbrella term 'multisystem inflammatory syndrome in children (MIS-C)'. A one and half-year-old girl, admitted to Mansoura University Children's Hospital (MUCH) with fever, bad general condition, vomiting, widespread maculopapular, vasculitic rash, hands and feet oedema, oral ulceration, arthralgia and lymphadenopathy. Moreover, bicytopenia, positive antinuclear, anti-double-stranded DNA antibodies and low C3 qualified her as a case of juvenile SLE. Despite the child received the initial therapy of immunosuppressive medication, her general condition deteriorated with fever persistence and rash exacerbation. At that time, the skin of her hands and feet started to peel. Thus, an expanded study for other alternatives was obligatory; SARS-CoV-2 infection testing revealed positive IgG serology, and retesting for lupus autoantibodies turned negative. HRCT chest showed bilateral basal consolidation with ground-glass appearance. Furthermore, Echo exhibited coronary artery dilation with thrombus inside. This evolution raised the concern for COVID-related MIS-C syndrome. This report provides a model of COVID-19 heterogeneity with protean immune-related manifestations. This case has a unique presentation that necessities its description, in order to provide a nidus for future studies in this new entity.

Utilization of preventive services in a systemic lupus erythematosus population-based cohort: a Lupus Midwest Network (LUMEN) study.

BACKGROUND: Systemic lupus erythematosus (SLE) is a disease that can lead to damage of multiple organs and, along with certain treatments, increase the risk of developing cancer, cardiovascular disease, diabetes, osteoporosis, and infections. Preventive services are particularly important in patients with SLE to mitigate the aforementioned risks. We aimed to evaluate the trends of preventive services utilization in patients with systemic lupus erythematosus, compared with non-SLE population. METHODS: All ≥19-year-old patients in the Lupus Midwest Network (LUMEN) registry, a population-based cohort, with SLE on January 1, 2015, were included and matched (1:1) by sex, age, race, and county to non-SLE comparators. Among both groups, we compared the rates of screenings for breast and cervical cancer, hypertension, hyperlipidemia, diabetes mellitus, and osteoporosis as well as immunizations. RESULTS: We included 440 SLE patients and 430 non-SLE comparators. The probability of breast cancer screening among women with SLE was similar to comparators (hazard ratio [HR] 1.09, 95% CI 0.85-1.39), while cervical cancer screening was lower (HR 0.75, 95% CI 0.58-0.96). Hypertension screening was higher among patients with SLE (HR 1.35, 95% CI 1.13-1.62); however, hyperlipidemia screening was similar to comparators (HR 1.16, 95% CI 0.96-1.41). Diabetes and osteoporosis screenings were more likely to be performed for SLE patients than for comparators (HR 2.46, 95% CI 2.11-2.87; and HR 3.19, 95% CI 2.31-4.41; respectively). Influenza and pneumococcal immunizations were higher among SLE patients (HR 1.31, 95% CI 1.12-1.54; and HR 2.06, 95% CI 1.38-3.09; respectively), while zoster vaccination was similar (HR 1.17, 95% CI 0.81-1.69). CONCLUSIONS: The trends of utilization of preventive services by SLE patients vary according to screening or vaccine compared with the general population. Considering these differences, we demonstrate an opportunity for improvement, particularly in cervical cancer, hyperlipidemia, and osteoporosis screenings and vaccinations.

New-onset systemic lupus erythematosus following BNT162b2 mRNA COVID-19 vaccine: a case series and literature review.

Emerging data evaluated the possible link between the Coronavirus 19 (COVID-19) vaccine and acute flares of rheumatic autoimmune diseases. However, the association between the COVID-19 vaccine and the development of de-novo rheumatic autoimmune diseases remained unclear. We report the first case series of three male patients who developed new-onset systemic lupus erythematosus following receiving Pfizer BNT162b2 mRNA vaccination. The clinical characteristics share some similarities with drug-induced lupus. More patients with SLE following COVID-19 may be diagnosed in the future. Additional studies will provide more significant insights into the possible immunogenic influence of the COVID-19 vaccine.

Urine Soluble CD163 Is a Promising Biomarker for the Diagnosis and Evaluation of Lupus Nephritis.

Introduction: Urine-soluble CD163 (usCD163) is released from alternatively activated macrophages involved in the resolution of inflammation in glomeruli and plays an important role in glomerulonephritis. This study explored the role of usCD163 in patients with systemic lupus erythematosus (SLE). Materials and Methods: usCD163 concentrations were measured cross-sectionally in 261 SLE patients in Taiwan. Clinical and laboratory data were collected, and SLE disease activity scores were calculated to assess the correlation with usCD163. Results: SLE patients with high usCD163 levels tended to be younger, with a higher hospital admission rate, higher prednisolone dose, lower estimated glomerular filtration rate, higher urine protein creatinine ratio (UPCR), more pyuria and hematuria, higher levels of inflammatory markers, higher rates of anemia, neutropenia, and lymphopenia, lower complement 3 (C3) levels, higher anti-double-stranded DNA antibody (anti-dsDNA Ab) levels, and higher disease activity scores (p < 0.05). usCD163 levels were significantly higher in patients with active lupus nephritis (LN) than in those with extrarenal or inactive SLE and correlated with UPCR, disease activity, and anti-dsDNA Ab levels. SLE patients with high usCD163 levels tended to have a higher chronic kidney disease stage. Discussion and conclusion: The usCD163 level correlates with the severity of LN and disease activity in renal SLE.

A case report of pediatric systemic lupus erythematosus with diffuse alveolar hemorrhage following COVID-19 infection: Causation, association, or chance?

RATIONALE: Diffuse alveolar hemorrhage (DAH) is a rare manifestation of childhood systemic lupus erythematosus (SLE) that can be life-threatening. Several reports have linked previous or concurrent coronavirus disease (COVID-19) infections with a high prevalence of autoimmune and autoinflammatory disorders. PATIENT CONCERNS: We report a case of a 13-year-old female who presented with DAH due to SLE 2 months after a laboratory-confirmed severe COVID-19 infection. DIAGNOSES: The patient was diagnosed with DAH due to SLE 2 months after a laboratory-confirmed severe COVID-19 infection. INTERVENTIONS AND OUTCOMES: The patient was treated with intravenous methylprednisolone pulse, broad-spectrum antibiotics, and supportive measures. In addition, she received 6 sessions of plasma exchange and maintenance methylprednisolone therapy (2 mg/kg/day). The patient then improved and was discharged on prednisolone, hydroxychloroquine, and azathioprine. LESSONS: We suggest plasmapheresis be considered a treatment for SLE-associated DAH in the context of active disease when conventional treatment has failed to induce a rapid response. In addition, further studies are needed to assess the role of COVID-19 as an autoimmune disease trigger, particularly for SLE.

Medium-term impact of the SARS-CoV-2 mRNA vaccine against disease activity in patients with systemic lupus erythematosus.

OBJECTIVES: Numerous case reports have referred to new onset or flare of SLE after SARS-CoV-2 messenger RNA (mRNA) vaccines. Several observational studies showed that the short-term flare rate of SLE after SARS-CoV-2 vaccination is low. However, well-controlled clinical surveys are unavailable and the medium-term impact of the SARS-CoV-2 mRNA vaccines against the flare of SLE is uncertain. Therefore, we aimed to analyse the association between vaccination and medium-term subjective and objective disease activities of SLE and flares using matched pair methods. METHODS: Altogether, 150 patients with SLE from the Kyoto Lupus Cohort were included. Patients who received two doses of the SARS-CoV-2 mRNA vaccines were 1:1 matched with unvaccinated patients based on the first vaccination date. The outcome measures were the SLE Disease Activity Index-2000 (SLEDAI-2K), the Japanese version of the SLE Symptom Checklist Questionnaire (SSC-J) and the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index at 30, 60 and 90 days after vaccination. RESULTS: SLEDAI-2K levels were not significantly different in vaccinated and unvaccinated patients with SLE at 30, 60 and 90 days after the second vaccination (adjusted estimate (95% CI): 30 days: -0.46 (-1.48 to 0.56), p=0.39; 60 days: 0.38 (-0.64 to 1.40), p=0.47; 90 days: 0.40 (-0.54 to 1.34), p=0.41). Similar results were observed in the SSC-J score (adjusted estimate (95% CI), 30 days: 0.05 (-1.46 to 1.56), p=0.95; 60 days: -0.63 (-2.08 to 0.82), p=0.40; 90 days: 0.27 (-1.04 to 1.58), p=0.69) and flare index (adjusted OR (95% CI), 30 days: 0.81 (0.36 to 1.85), p=0.62; 60 days: 1.13 (0.50 to 2.54), p=0.77; 90 days: 0.85 (0.32 to 2.26), p=0.74). CONCLUSION: SARS-CoV-2 vaccination did not significantly influence the medium-term subjective and objective disease activities or flares of SLE until 90 days after the second vaccination.