Systemic Lupus Erythematosus (SLE) is characterized by B cells lacking IgD and CD27 (double negative; DN). We show that DN cell expansions reflected a subset of CXCR5- CD11c+ cells (DN2) representing ...pre-plasma cells (PC). DN2 cells predominated in African-American patients with active disease and nephritis, anti-Smith and anti-RNA autoantibodies. They expressed a T-bet transcriptional network; increased Toll-like receptor-7 (TLR7); lacked the negative TLR regulator TRAF5; and were hyper-responsive to TLR7. DN2 cells shared with activated naive cells (aNAV), phenotypic and functional features, and similar transcriptomes. Their PC differentiation and autoantibody production was driven by TLR7 in an interleukin-21 (IL-21)-mediated fashion. An in vivo developmental link between aNAV, DN2 cells, and PC was demonstrated by clonal sharing. This study defines a distinct differentiation fate of autoreactive naive B cells into PC precursors with hyper-responsiveness to innate stimuli, as well as establishes prominence of extra-follicular B cell activation in SLE, and identifies therapeutic targets.
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•Autoreactive CD27- IgD- CXCR5- CD11c+ (DN2) B cells expand in lupus patients•DN2 cells derive from naive cells and are poised to generate plasmablasts•DN2 B cells are hyper-responsive to Toll-like receptor-7 signaling•The properties of SLE DN2 B cells stem from distinct transcriptional networks
The role of extrafollicular B cells in human systemic lupus is unknown. Jenks et al. define the main components of this pathway and its prominence in severe disease. Its activation is mediated by hyper-responsiveness to Toll-like receptor-7 and leads to the generation of autoreactive antibody-secreting plasmablasts.
Abstract
Disparities in SLE rates and outcomes have been attributed to genetic and hormonal factors, cigarette smoking and environmental pollutants. However, a growing body of research indicates that ...social determinants of health (SDH) also have substantial impact on the disparities that characterize SLE. According to the World Health Organization, SDH are defined as ‘the conditions in which people are born, grow, work, live, and age’, account for 30–55% of health outcomes, and adversely impact health outcomes among those of low socioeconomic status and stigmatized racial/ethnic groups. We reviewed the impact of key SDH on SLE presentation, management and outcomes, including income, education, neighbourhood factors, healthcare access, discrimination and social support. We found that adverse SDH conditions may lead to more severe SLE with increased morbidity and mortality, and that SDH affect SLE management by dictating the most feasible monitoring and treatment plan for each individual patient based on his or her specific life circumstances (for example, based on health insurance status, distance to nearest provider and/or drug affordability). SDH also have a significant impact on SLE outcomes, with worse disease and psychosocial outcomes associated with lower income level, lower educational attainment, disadvantaged neighbourhoods, lack of health insurance or public health insurance in the USA, travel burden to nearest provider, anti-Black racism and lower social support. Future efforts to improve the management and outcomes of patients with SLE must combat the societal, economic and political forces that perpetuate these inequities.
Objective
Epidemiologic data on systemic lupus erythematosus (SLE) are limited, particularly for racial/ethnic subpopulations in the US. This meta‐analysis leveraged data from the Centers for Disease ...Control and Prevention (CDC) National Lupus Registry network of population‐based SLE registries to estimate the overall prevalence of SLE in the US.
Methods
The CDC National Lupus Registry network includes 4 registries from unique states and a fifth registry from the Indian Health Service. All registries defined cases of SLE according to the American College of Rheumatology (ACR) 1997 revised classification criteria for SLE. Case findings spanned either 2002–2004 or 2007–2009. Given the heterogeneity across sites, a random‐effects model was used to calculate the pooled prevalence of SLE. An estimate of the number of SLE cases in the US was generated by applying sex/race‐stratified estimates to the 2018 US Census population.
Results
In total, 5,417 cases were identified as fulfilling the ACR SLE classification criteria. The pooled prevalence of SLE from the 4 state‐specific registries was 72.8 per 100,000 person‐years (95% confidence interval 95% CI 65.3–81.0). The prevalence estimate was 9 times higher among females than among males (128.7 versus 14.6 per 100,000), and highest among Black females (230.9 per 100,000), followed by Hispanic females (120.7 per 100,000), White females (84.7 per 100,000), and Asian/Pacific Islander females (84.4 per 100,000). Among males, the prevalence of SLE was highest in Black males (26.7 per 100,000), followed by Hispanic males (18.0 per 100,000), Asian/Pacific Islander males (11.2 per 100,000), and White males (8.9 per 100,000). The American Indian/Alaska Native population had the highest race‐specific SLE estimates, both among females (270.6 per 100,000) and among males (53.8 per 100,000). In 2018, an estimated 204,295 individuals (95% CI 160,902–261,725) in the US fulfilled the ACR classification criteria for SLE.
Conclusion
A coordinated network of population‐based SLE registries provides more accurate estimates of the prevalence of SLE and the numbers of individuals affected with SLE in the US in 2018.
Objective
To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN).
Methods
In a multicenter, ...randomized, open‐label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients’ peripheral blood were analyzed by flow cytometry.
Results
Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells.
Conclusion
The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.
Objective
The Georgia Lupus Registry is a population‐based registry designed to improve our ability to estimate the incidence and prevalence of systemic lupus erythematosus (SLE) in a large ...population.
Methods
Potential cases of SLE were identified from multiple sources during the years 2002 through 2004. Cases were defined according to the American College of Rheumatology (ACR) criteria for SLE or a combined definition. Age‐standardized rates were determined and stratified by race and sex. With capture–recapture analyses, we estimated the underascertainment of cases.
Results
Using the ACR case definition, the overall crude and age‐adjusted incidence rate was 5.6 per 100,000, with capture–recapture and combined definition rates being slightly higher. The age‐adjusted incidence rate in women was >5 times higher than that for men (9.2 versus 1.8). Black women had an incidence rate nearly 3 times higher than that in white women, with a significantly higher rate in the group ages 30–59 years. The overall crude and age‐adjusted prevalence rates were 74.4 and 73 per 100,000, respectively. The age‐adjusted prevalence rate in women was nearly 9 times higher than that for men (127.6 versus 14.7). Black women had very high rates (196.2). A striking difference was seen in the proportion of prevalent cases with end‐stage renal disease, with 7‐fold greater involvement among black patients.
Conclusion
With the more complete case‐finding methods we used, the incidence and prevalence rates of SLE are among the highest reported in the US. The results continue to underscore striking sex, age, and racial disparities between black patients and white patients with SLE.
To define biopsychosocial mechanisms of pain that go above and beyond disease activity and organ damage in systemic lupus erythematosus (SLE).
We conducted a cross-sectional analysis of ...patient-reported data in a population-based registry of 766 people with SLE. Predictors of pain intensity and interference were examined using hierarchical linear regression. We built 2 main hierarchical regression models with pain intensity and interference as outcomes, both regressed on disease activity and organ damage. For each model, we sought to establish the relationship between pain outcomes and the primary exposures using sequential steps comprising the inclusion of each construct in 6 stages: demographic, socioeconomic, physical, psychological, behavioral, and social factors. We also conducted sensitivity analyses eliminating all overt aspects of pain in the disease activity measure and reestimated the models.
Disease activity and organ damage explained 32-33% of the variance in pain intensity and interference. Sociodemographic factors accounted for an additional 4-9% of variance in pain outcomes, whereas psychosocial/behavioral factors accounted for the final 4% of variance. In the sensitivity analyses, we found that disease activity and organ damage explained 25% of the variance in pain outcomes.
Disease activity only explained 33% of the variance in pain outcomes. However, there was an attenuation in these associations after accounting for psychosocial/behavioral factors, highlighting their roles in modifying the relationship between disease activity and pain. These findings suggest that multilevel interventions may be needed to tackle the negative effect of pain in SLE.
Objective
The Chronic Disease Self‐Management Program (CDSMP) is designed to enhance patients' self‐efficacy and skills to manage their chronic illness. There is compelling evidence for the benefits ...of the CDSMP among patients with systemic lupus erythematosus (SLE); however, little is known about predictors of participation among Black women with SLE. We examined factors associated with CDSMP initiation and completion in this population.
Methods
We studied 228 Black women with SLE who consented to attend a CDSMP workshop. We used logistic regression to calculate unadjusted and adjusted odds ratios (ORs) for being a CDSMP initiator (a participant registered into the CDSMP who attended at least 1 of the first 2 weekly classes) and a CDSMP completer (a participant who completed at least 4 of 6 weekly classes).
Results
The majority of participants were CDSMP initiators (74% n = 168). Of those, 126 (75%) were CDSMP completers. Older age (adjusted OR ORadj 1.03 95% confidence interval (95% CI) 1.00–1.06) and unemployment/disability (ORadj 2.05 95% CI 1.05–4.14) increased the odds of being a CDSMP initiator. The odds of initiating the CDSMP decreased by 22% for each additional child in the household (OR 0.78 95% CI 0.62–0.98), but this association became nonsignificant in the adjusted model (ORadj 0.89 95% CI 0.68–1.18). The only factor that differed significantly between CDSMP completers and noncompleters was age, with 4% higher odds of being a completer for each additional year of age (ORadj 1.04 95% CI 1.00–1.07).
Conclusion
Our findings suggest that young Black women with SLE face barriers to attend and complete in‐person CDSMP workshops, possibly in relation to work and child care demands.
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