The intersection of COVID-19 and autoimmunity.

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.

Serologic features of cohorts with variable genetic risk for systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease with genetic, hormonal, and environmental influences. In Western Europe and North America, individuals of West African descent have a 3-4 fold greater incidence of SLE than Caucasians. Paradoxically, West Africans in sub-Saharan Africa appear to have a low incidence of SLE, and some studies suggest a milder disease with less nephritis. In this study, we analyzed sera from African American female SLE patients and four other cohorts, one with SLE and others with varying degrees of risk for SLE in order to identify serologic factors that might correlate with risk of or protection against SLE. METHODS: Our cohorts included West African women with previous malaria infection assumed to be protected from development of SLE, clinically unaffected sisters of SLE patients with high risk of developing SLE, healthy African American women with intermediate risk, healthy Caucasian women with low risk of developing SLE, and women with a diagnosis of SLE. We developed a lupus risk index (LRI) based on titers of IgM and IgG anti-double stranded DNA antibodies and levels of C1q. RESULTS: The risk index was highest in SLE patients; second highest in unaffected sisters of SLE patients; third highest in healthy African-American women and lowest in healthy Caucasian women and malaria-exposed West African women. CONCLUSION: This risk index may be useful in early interventions to prevent SLE. In addition, it suggests new therapeutic approaches for the treatment of SLE.

Hydroxychloroquine: balancing the need to maintain therapeutic levels with ocular safety: an update.

PURPOSE OF REVIEW: Antimalarial drugs including chloroquine, its less toxic quinolone-derivative hydroxychloroquine (HCQ), and quinacrine have become cornerstones in the treatment of autoimmune diseases including systemic lupus, rheumatoid arthritis, sarcoidosis, and Sjogren syndrome; cutaneous disorders, antiphospholipid syndrome, and have recently been employed at higher dioses in oncology. Benefits include anti-inflammatory effects, protection against thrombosis, and improved control of hyperglycemia and hyperlipidemia. In general, both the therapeutic advantages and the toxic effects of the drugs correlate with the dose and the duration of therapy. Here we summarize the current literature regarding the administration and the safety profile of HCQ in management of rheumatologic disease and focus on the most recent revised American Academy of Ophthalmology (AAO) guidelines for prevention and detection of hydroxychloroquine retinopathy to help guide therapeutic decision-making for patients. RECENT FINDINGS: The risk of antimalarial-induced retinal toxicity is better predicted by calculating the daily dosage based on 5 mg/kg total body weight rather than 6.5 mg/kg lean body weight and reducing dosage in patients with risk factors such as renal failure. The risk of retinal toxicity after 5 years is substantially increased even when these guidelines are followed; hence dose reduction is appropriate with long-term use. Newer techniques provide improved detection of early signs of retinal damage. These advances are reflected in the revised AAO guidelines 2016, which are in part based on the retrospective study by Melles and Marmor of HCQ toxicity. SUMMARY: The most important changes in practice guidelines include dose calculation based on total body weight, dose reduction after long-term use, and intensified screening with techniques including optical coherence tomography (OCT) after 5 years.

Establishing clinical severity for PROMIS® measures in adult patients with rheumatic diseases.

PURPOSE: Different patient-reported outcome (PRO) measures are used for rheumatic diseases (RD). The aims of this study are-(1) Identify PROMIS® domains most relevant to care of patients with RD, (2) Collect T-Score metrics in patients with RD, and (3) Identify clinically meaningful cut-points for these domains. METHODS: A convenience sample of RD patients was recruited consecutively during clinic visits, and asked to complete computer-adaptive tests on thirteen Patient-Reported Outcomes Measurement Information System (PROMIS®) instruments. Based on discussion with clinical providers, four measures were chosen to be relevant and actionable (from rheumatologists' perspective) in RD patients. Data from RD patients were used to develop clinical vignettes across a range of symptom severity. Vignettes were created based on most likely item responses at different levels on the T-score metric (mean = 50; SD = 10) and anchored at 5-point intervals (0.5 SDs). Patients with RD (N = 9) and clinical providers (N = 10) participated as expert panelists in separate one-day meetings using a modified educational standard setting method. RESULTS: Four domains (physical function, pain interferences, sleep disturbance, depression) that are actionable at the point-of-care were selected. For all domains, patients endorsed cut-points at lower levels of impairment than providers by 0.5 to 1 SD (e.g., severe impairment in physical function was defined as a T-score of 35 by patients and 25 by providers). CONCLUSIONS: We used a modified educational method to estimate clinically relevant cut-points to classify severity for PROMIS measures This allows for meaningful interpretation of PROMIS® measures in a clinical setting of RD population.

Diminished white matter integrity in patients with systemic lupus erythematosus.

PURPOSE: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that can affect the central nervous system. Neuropsychiatric symptoms are found in 25-70% of patients. Using diffusion tensor imaging (DTI) various studies have reported changes in white matter integrity in SLE patients with neuropsychiatric symptoms (NPSLE patients). The purpose of this study was to investigate, if regional changes in white matter integrity can also be detected in SLE patients without neuropsychiatric symptoms (non-NPSLE patients). METHODS: Applying DTI and tract based spatial statistics (TBSS) we investigated 19 NPSLE patients, 19 non-NPSLE and 18 healthy controls. Groups were matched for age and sex. Image pre-processing was performed using FSL, following the TBSS pipeline (eddy current correction, estimation of fractional anisotropy (FA), normalization, skeletonization of the group mean FA image). A general linear model with threshold-free cluster enhancement was used to assess significant differences between the three groups. RESULTS: Statistical analyses revealed several regions of decreased prefrontal white matter integrity (decreased FA) in both groups of SLE patients. The changes found in the non-NPSLE patients (as compared to healthy controls) overlapped with those in the NPSLE patients, but were not as pronounced. CONCLUSIONS: Our data suggest that changes in regional white matter integrity, in terms of a decrease in FA, are present not only in NPSLE patients, but also in non-NPSLE patients, though to a lesser degree. We also demonstrate that the way statistical maps are corrected for multiple comparisons has a profound influence on whether alterations in white matter integrity in non-NPSLE patients are deemed significant.

Reduced Insular Glutamine and N-acetylaspartate in systemic lupus erythematosus: a single-voxel (1)H-MR spectroscopy study.

RATIONALE AND OBJECTIVES: To investigate for differences in metabolic concentrations and ratios between patients with systemic lupus erythematosus (SLE) without (group SLE) and those with neurological symptoms (group NPSLE) compared to a healthy control (group HC) in three normal-appearing brain regions: the frontal white matter, right insula (RI), and occipital gray matter and whether changes in any of the metabolites or metabolic ratios are correlated to disease activity and other clinical parameters. MATERIALS AND METHODS: Twenty patients with SLE (18 women and 2 men, age range 23.4-64.6 years, mean age 43.9 years), 23 NPSLE patients (23 women, age range 23.7-69.8 years, mean age 42.4 years), and 21 HC (19 women and 2 men, age range 21.0-65.7 years, mean age 43.4 years) were included. All subjects had conventional brain magnetic resonance imaging and (1)H single-voxel spectroscopy, clinical assessment, and laboratory testing. RESULTS: NPSLE patients had significantly reduced N-acetylaspartate (NAA)/creatine compared to HC (P = .02) and SLE patients (P = .01) in the RI. Lower glutamine/creatine levels were also detected in RI in both patient groups and in frontal white matter in NPSLE patients compared to HC (P = .01, P = .02). NAA/Cr ratio in the RI was significantly negatively correlated with the Systemic Lupus Erythematosus Disease Activity Index (r = -0.41; P = .008), and patients with active SLE symptoms also had a trend toward lower NAA/creatine ratios (1.02 vs 1.12; P = .07). CONCLUSIONS: The present data support previous findings of abnormal metabolic changes in normal-appearing regions in the brain of both SLE and NPSLE patients and raise the possibility that especially NAA, glutamine, and glutamate may be additional biomarkers for cerebral disease activity in SLE patients as these early metabolic changes occur in the brain of SLE patients before neurologic and imaging manifestations become apparent.

A 50-year old woman with nasal congestion, cough, and dyspnea.

We present a 50-year-old woman with progressive dyspnea, cough, and nasal congestion. Evaluation revealed positive skin tests (IgE) to trees and dust mites, early glottic closure on spirometry, and sinus opacities on CT. Diagnostic considerations included allergic and nonallergic rhinitis, asthma, aspirin-exacerbated respiratory disease, vocal cord dysfunction, chronic sinusitis secondary to gastroesophageal reflux disease, and systemic inflammatory and immunologic diseases, including vasculitis. Progresson of her symptoms prompted further investigation, and a biopsy yielded an unexpected diagnosis.

Perfusion-weighted MR imaging in cerebral lupus erythematosus.

RATIONALE AND OBJECTIVE: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a diagnostically challenging, severe, and life-threatening condition, which is currently lacking a "gold standard." Our aim with this study is to look for magnetic resonance (MR) perfusion differences in NPSLE, SLE, and healthy control (HC) patients and correlate our findings with clinical parameters. MATERIALS AND METHODS: Twenty-four NPSLE patients, 21 SLE patients, and 21 HC underwent dynamic susceptibility contrast enhanced MR perfusion using a 3-T scanner. Nine prospectively selected intracranial regions of interest were placed in white and gray matter and the cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT) values were calculated. Subjects underwent clinical evaluation with SLEDAI and serum antibodies. RESULTS: The SLE patients had higher CBF and CBV compared to the HC overall (P = .01) and in specific areas (P = .03-.048). SLE patients with signs of active disease (elevated SLEDAI and anti-double-stranded DNA) had significantly elevated CBV, CBF, and MTT in the posterior cingulate gyrus (P = .01-.02). No significant difference was seen in the magnetic resonance perfusion measurements of NPSLE patients compared to SLE and HC, although the NPSLE patients also showed higher CBV variability compared to the SLE (P = .0004) and HC cohort (P < .0001). CONCLUSION: SLE patients have increased CBV and CBF compared to healthy controls. The SLE patients with clinical markers for active disease have elevated CBV, CBF, and MTT in the posterior cingulate gyrus. NPSLE patients show increased variability in perfusion measurements, which may explain why susceptibility contrast enhanced MRI has not yet provided a specific target for NPSLE.

The apoptotic ligands TRAIL, TWEAK, and Fas ligand mediate monocyte death induced by autologous lupus T cells.

Individuals with systemic lupus erythematosus show evidence of a significant increase in monocyte apoptosis. This process is mediated, at least in part, by an autoreactive T cell subset that kills autologous monocytes in the absence of nominal Ag. We have investigated the apoptotic pathways involved in this T cell-mediated process. Expression of the apoptotic ligands TRAIL, TNF-like weak inducer of apoptosis (TWEAK), and Fas ligand on lupus T cells was determined, and the role of these molecules in the monocyte apoptotic response was examined. We report that these apoptotic ligands mediate the autologous monocyte death induced by lupus T cells and that this cytotoxicity is associated with increased expression of these molecules on activated T cells, rather than with an increased susceptibility of lupus monocytes to apoptosis induced by these ligands. These results define novel mechanisms that contribute to increased monocyte apoptosis characterizing patients with lupus. We propose that this mechanism could provide a source of potentially antigenic material for the autoimmune response and interfere with normal clearing mechanisms.