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SLE is marked by immune dysregulation linked to varied clinical disease activity. Using a unique longitudinal cohort of SLE patients, this study seeks to identify optimal immune mediators informing an empirically refined Flare Risk Index (FRI) reflecting altered immunity prior to clinical disease flare.SLE-associated plasma mediators (n=37) were evaluated by microfluidic immunoassay in 46 Pre-Flare and 53 Pre-Nonflare samples selected from a unique longitudinal cohort of 106 patients with classified SLE (meeting ACR and SLICC criteria). Autoantibody specificities, hybrid SLEDAI (hSLEDAI) scores, clinical features, and medication usage were also compared at Pre-Flare (111±47 days prior to Flare) vs. Pre-Nonflare (99±21 days prior to Nonflare) time points. Variable importance was determined by random forest with logistic regression subsequently applied to determine the optimal number and type of analytes informing a refined FRI.Pre-Flare vs. Pre-Nonflare differences were not associated with demographics, autoantibody specificities, hSLEDAI scores, clinical features, nor medication usage. Forward selection and backward elimination of mediators ranked by variable importance drew up to 17 candidates differentiating Pre-Flare from Pre-Nonflare. A final combination of 11 mediators best informed a newly refined FRI, achieving a maximum of 97% sensitivity and 98% specificity after applying decision curve analysis to define low, medium, and high FRI scores.We verified altered immune mediators associated with imminent disease flare; a subset improved the FRI to identify SLE patients at risk of imminent flare. This molecularly-informed proactive management approach could be critical in prospective clinical trials and the clinical management of lupus.

Systemic lupus erythematosus (SLE) is an autoimmune disease that primarily affects women of childbearing age. Pregnancy-related morbidity and mortality are well described in SLE; however, better management of disease activity throughout the disease course have minimized periods of disease activity and damage accrual, making pregnancy more feasible and desirable. A growing body of literature has defined risk factors for adverse pregnancy outcomes in patients with SLE, and coordinated medical and obstetric management has allowed most patients with SLE to safely achieve full-term pregnancies by timing pregnancy to maximal disease quiescence and use of pregnancy-compatible medications from preconception through lactation.

Objective Individuals with systemic lupus erythematosus (SLE) are at high risk for infections and SLE- and medication-related complications. The present study was undertaken to define a set of SLE-specific adverse outcomes that could be prevented, or their complications minimized, if timely, effective ambulatory care had been received. Methods We used a modified Delphi process beginning with a literature review and key informant interviews to select initial SLE-specific potentially preventable conditions. We assembled a panel of 16 nationally recognized US-based experts from 8 subspecialties. Guided by the RAND-UCLA Appropriateness Method, we held 2 survey rounds with controlled feedback and an interactive webinar to reach consensus regarding preventability and importance on a population level for a set of SLE-specific adverse conditions. In a final round, the panelists endorsed the potentially preventable conditions. Results Thirty-five potential conditions were initially proposed; 62 conditions were ultimately considered during the Delphi process. The response rate was 100% for both survey rounds, 88% for the webinar, and 94% for final approval. The 25 SLE-specific conditions meeting consensus as potentially preventable and important on a population level fell into 4 categories: vaccine-preventable illnesses (6 conditions), medication-related complications (8 conditions), reproductive health-related complications (6 conditions), and SLE-related complications (5 conditions). Conclusion We reached consensus on a diverse set of adverse outcomes relevant to SLE patients that may be preventable if patients receive high-quality ambulatory care. This set of outcomes may be studied at the health system level to determine how to best allocate resources and improve quality to reduce avoidable outcomes and disparities among those at highest risk.

Background Women with systemic lupus erythematosus (SLE) are at risk of premature ovarian failure when treated with cyclophosphamide. This risk is increased when autoimmune thyroid disease is present. We undertook this study to determine whether the presence of ovarian autoimmunity also increased the risk of early ovarian failure among women receiving cyclophosphamide. Methods We examined the records of women enrolled in the Lupus Family Registry and Repository, a cross-sectional study of ~3300 SLE subjects, for treatment with cyclophosphamide as well as menopausal status. We defined premature menopause as permanent, spontaneous cessation of menstruation before age 45. We measured anti-ovarian antibodies by enzyme-linked immunosorbent assay using stored sera. Results There were 258 women treated with cyclophosphamide in whom presence of absence or premature menopause could by defined. A total of 169 (65.6%) had premature ovarian failure, while 89 (34.6%) did not. While anti-ovarian antibodies were present in a small percentage of patients, there was no association of premature menopause to either level of these antibodies (16.2 ± 20.3 units vs 17.4 ± 21.7 units, P = NS by Fisher's exact test), or positivity on this testing (11 of 169 [6.5%] positive vs 8 of 89 [8.9%], χ2 = 0.53, P = .46, 95% CI 0.95-1.1). Neither renal disease nor hypothyroidism increased the risk of premature ovarian failure in these women receiving cyclophosphamide. Conclusion Anti-ovarian antibodies among women with SLE are not associated with premature ovarian failure after treatment with cyclophosphamide.

ObjectiveTo address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes.MethodspSS patients met American–European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200.ResultsTranscriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell–attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1α, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters.ConclusionMolecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

Lupus nephritis is the most common organ-threatening manifestation of systemic lupus erythematosus, affecting more than one-third of patients. Induction of remission and maintenance of relapse-free disease have been and continue to be a critical focus of investigation. Because the need for renal replacement therapy in those with an insufficient response to therapy is associated with significantly increased morbidity and mortality, providers and patients are willing to accept moderate to high levels of adverse events associated with treatment. Current standard-of-care regimens for induction and maintenance immunosuppression have led to resumption of adequate renal function and minimization of proteinuria for many patients. Current practice is to maintain maintenance immunosuppression indefinitely for fear of flare upon therapy withdrawal. For those with sustained quiescent disease after several years of maintenance therapy, the risk-to-benefit analysis for ongoing immunosuppression shifts toward an increasing consideration of the adverse effects of immunosuppressive agents. The time has come to begin to study, in a careful and controlled manner, the possibility of withdrawal of immunosuppressant therapy in patients with nephritis who have achieved sustained remission.

ObjectiveAlthough SLE disproportionately affects minority racial groups, they are significantly under-represented in clinical trials in the USA. This may lead to misleading conclusions in race-based subgroup analyses. We conducted focus groups to evaluate the perceptions of diverse patients with lupus about clinical trial participation.MethodsA qualitative research design employed three 90 min focus groups led by a trained moderator and guided by the Theory of Planned Behaviour. Open-ended questions about trial participation included advantages and disadvantages (behavioural beliefs), approving and disapproving significant others (normative beliefs), and participation enhancers and barriers (control beliefs). Discussions were recorded, transcribed and analysed to identify emerging themes.ResultsPatients with SLE (n=23) aged 21–72, with increased proportion of minority groups (65%), participated. Reported advantages of trial participation included altruism and personal benefit. Disadvantages included uncertainties, disappointment, information burden, and life–health balance. Although some patients had discussed research participation with approving or disapproving family or friends, self-approval superseded external approval. Barriers included logistics and time, and facilitators included flexibility in scheduling, advance notice of studies, streamlined forms, and hope for SLE improvement.ConclusionsKnowledge about potential benefits of clinical trial participation was high. Minority patients demonstrated confidence in making their own informed decisions, but major barriers for all participants included burdensome forms, travel, childcare, and work. These suggest a major impact on minority and all recruitment from behavioural and control aspects, which should be considered in the logistics of trial design. This does not minimise the potential importance of improved access and education about clinical research.

Type I interferons (IFN) causes inflammatory responses to pathogens, and can be elevated in autoimmune diseases such as systemic lupus erythematosus (SLE). We previously reported unexpected associations of increased numbers of B lymphocytes expressing the DNA-binding protein ARID3a with both IFN alpha (IFNα) expression and increased disease activity in SLE. Here, we determined that IFNα producing low density neutrophils (LDNs) and plasmacytoid dendritic cells (pDCs) from SLE patients exhibit strong associations between ARID3a protein expression and IFNα production. Moreover, SLE disease activity indices correlate most strongly with percentages of ARID3a(+) LDNs, but were also associated, less significantly, with IFNα expression in LDNs and pDCs. Hierarchical clustering and transcriptome analyses of LDNs and pDCs revealed SLE patients with low ARID3a expression cluster with healthy controls and identified gene profiles associated with increased proportions of ARID3a- and IFNα-expressing cells of each type. These data identify ARID3a as a potential transcription regulator of IFNα-related inflammatory responses and other pathways important for SLE disease activity.

Administrative databases, registers, and other sources of big data can be interesting sources to address important research questions on reproduction in women with rheumatic diseases. There are many different types of administrative datasets worldwide, and it is important to understand the type of data present and unavailable in each dataset, validity and potential misclassification of data, and the ability to link maternal data with infant data. This article discusses the advantages and methodologic issues associated with administrative database use for the conduct of observational studies on reproductive issues in women with rheumatic diseases.

To identify known teratogenic medications that may be used to treat SLE and discuss alternative therapeutics that can be used throughout pregnancy in order to manage maternal autoimmune diseases. Teratogenic immunosuppressive medications include methotrexate, mycophenolatemofetil, and cyclophosphamide. In anticipation of pregnancy, such medications should be discontinued and replaced with immunosuppressive medications including azathioprine and cyclosporine and assessed for disease stability. Pregnancy is an important aspect to women’s lives, and a diagnosis of SLE should not necessarily preclude the ability to bear children. Pregnancy outcomes among SLE women are favorable when disease is well controlled prior to conception and teratogenic medications are avoided. Several immunosuppressive therapies that are compatible with pregnancy are available to treat flares that may occur during pregnancy. Hydroxychloroquine use throughout pregnancy is associated with improved outcomes for both mother and infant. Risks of medication use need to be balanced with risks of active maternal disease.

Although the female predominance of autoimmune diseases is not completely understood, sex hormones are thought to play a role. Attention to lifelong reproductive health is especially important for women with autoimmune disorders. Many of these women require long-term immunosuppressive therapy that may affect their ability to clear infections, including viruses, and may alter natural tumor surveillance mechanisms. As a result, women with autoimmune diseases may have different risks for common reproductive-related malignancies that may in turn affect screening guidelines and other preventive measures, including vaccination. Women with autoimmune diseases need to adhere diligently to screening recommendations.

Background:Trials and clinical observations have demonstrated the efficacy of mycophenolate mofetil (MMF) for SLE treatment. Long-term use of MMF is associated with adverse events, pregnancy risks, drug monitoring, and increased cost. Current management continues therapy indefinitely. Whether immunosuppression may be safely withdrawn or whether risks of withdrawal outweigh the benefits of continuation is unknown.Objectives:To compare rates of clinically significant disease reactivation (CSDR), major flares, and all flares in patients with quiescent SLE on stable MMF randomized to maintain or withdraw MMF. The goal is to provide guidance for clinicians and patients on the risks of MMF withdrawal.Methods:Adults with quiescent SLE (SELENA-SLEDAI without serologies Results:102 subjects were randomized (50 MA, 52 WA); 1 subject in each arm was ineligible and 10 terminated early (7 MA, 3 WA). Mean disease duration was 13 years; 76% had a history of nephritis; mean baseline SLEDAI was 2.2. 5 MA subjects (10%) had CSDR, compared to 9 WA (17%). Median time to CDSR was 38 weeks in both arms. BILAG A flares occurred in 1MA subject (pancreatitis) vs. 4 WA (cranial neuropathy, panniculitis, 2 nephritis). Kaplan-Meier curves overlapped for CDSR, BILAG A flares, and all SLEDAI flares (Figure). Based on these data, we are 86% confident that the increased risk of CDSR with MMF withdrawal is less than 15% over 60 weeks. AEs were similar between groups; infections occurred more commonly in MA (63 vs. 49).Conclusion:In this cohort of subjects with quiescent SLE on long term MMF serious flares occurred infrequently in subjects continuing or withdrawing MMF without differences in time to flare. MMF withdrawal may be considered in subjects with prolonged quiescent disease.Table 1.Baseline and Demographic CharacteristicsMaintenance armWithdrawal armTotalRandomized5052102Female, n (%)39 (78)47 (90)86 (84)White, n (%)25 (50)19 (37)44 (43)Black, n (%)19 (38)22 (42)41 (40)Hispanic/Latino, n (%)10 (20)12 (23)22 (22)Age, Years, mean (SD)42.4 (12.9)41.6 (12.5)42.0 (12.6)Disease Duration, Years, mean (SD)13.6 (8.2)12.2 (7.9)12.9 (8.0)H/O Lupus Nephritis, n (%)40 (80)38 (73)78 (76.5)On Baseline Steroids, n (%)18 (36)23 (44)41 (40)Prednisone Dose, mg, mean (SD)4.8 (2.7)3.3 (1.7)4.0 (2.3)MMF Duration, Years, mean (SD)6.8 (4.3)6.4 (4.3)6.6 (4.3)Baseline MMF Dose, mg, mean1,6121,6681,640SELENA-SLEDAI*, mean (SD)2.4 (1.76)1.9 (1.76)2.2 (1.77)Positive DsDNA, n (%)35 (70)27 (52)62 (61)Low C31, n (%)14 (28)9 (17)23 (23)Low C41, n (%)6 (12)5 (10)11 (11)Figure.Kaplan-Meier Estimates of Flare EndpointsDisclosure of Interests:Eliza Chakravarty: None declared, Tammy Utset: None declared, Diane L Kamen Consultant of: Consulted on SLE survey development for Lilly and consulted on SLE trial protocol development for EMD Serono in 2019, Gabriel Contreras Grant/research support from: Genentech, Merck, Consultant of: Genentech, Merck, William Joseph McCune: None declared, Kenneth C Kalunian: None declared, Cynthia Aranow: None declared, Megan Clowse Grant/research support from: GSK, Pfizer, Consultant of: UCB, Astra-Zeneca, Speakers bureau: UCB, Ellen Goldmuntz: None declared, Jessica Springer: None declared, Lynette Keyes-Elstein: None declared, Bill Barry: None declared, Ashley Pinckney: None declared, Judith James: None declared

Background Autoimmune diseases comprise a spectrum of illnesses and are on the rise worldwide. Although antinuclear antibodies (ANAs) are detected in many autoimmune diseases, up to 20% of healthy women are ANA-positive (ANA+) and most will never develop clinical symptoms. Furthermore, disease transition is higher among ANA+ African Americans compared with ANA+ European Americans. Objective We sought to determine the immune features that might define and prevent transition to clinical autoimmunity in ANA+ healthy individuals. Methods We comprehensively phenotyped immune profiles of African Americans and European Americans who are ANA-negative (ANA−) healthy, ANA+ healthy, or have SLE using single cell mass cytometry, next-generation RNA-sequencing, multiplex cytokine profiling, and phospho-signaling analyses. Results We found that, compared with both ANA− and ANA+ healthy individuals, patients with SLE of both races displayed T-cell expansion and elevated expression of type I and II interferon pathways. We discovered a unique immune signature that suggests a suppressive immune phenotype and reduced CD11C+ autoimmunity-associated B cells in healthy ANA+ European Americans that is absent in their SLE or even healthy ANA− counterparts, or among African American cohorts. In contrast, ANA+ healthy African Americans exhibited elevated expression of T-cell activation markers and higher plasma levels of IL-6 than did healthy ANA+ European Americans. Conclusions We propose that this novel immune signature identified in ANA+ healthy European Americans may protect them from T-cell expansion, heightened activation of interferon pathways, and disease transition.

Background A universal hallmark of systemic lupus erythematosus (SLE) is the presence of antinuclear antibodies (ANAs). While their cognate antigens and ANA levels can associate with SLE subphenotypes, many individuals develop ANAs years prior to autoimmune disease manifestations or never develop any clinical symptoms. At present, the mechanisms governing the transition from autoantibody production to disease onset remain unknown. Methods To ascertain differences in immune cell populations and their transcriptional state, we performed scRNA-seq on peripheral blood mononuclear cells from 30 patients, including African and European American individuals with lupus-associated autoantibodies (n=10), SLE patients (n=10), and ANA- healthy controls (n=10). Transcriptomes were analyzed using canonical correlation analysis, the results of which were used by a smart local moving algorithm to identify cell population clusters and by Uniform Manifold Approximation and Projection for visualization. Differential expression of genes was assessed using Model-based Analysis of Single Cell Transcriptomics. Results Distinct cell populations could be identified for each disease classification. EA ANA +individuals showed a decrease in the number of naive B cells relative to SLE and healthy individuals; in contrast, AA ANA +individuals had higher numbers of centrocytes. Additionally, AA SLE patients demonstrated an enrichment of plasma cells relative to both ANA +and healthy individuals while FCRL5, a marker of dysfunctional B cells, was increased only in SLE memory B cells. Overall, AA ANA +cell populations showed an upregulation in a number of heat shock genes in ANA+ (HSPA6, HSPA1A, DNAJB1). Multipotent progenitor (MPP) cells from SLE patients of both ethnicities were marked by upregulation of interferon stimulated genes; ANA +MPPs, however, differed in that cells from AA individuals had an upregulation of housekeeping genes (GAPDH, PGK1) while anti-inflammatory NFKB1A was increased in EA MPPs. Comparison of a manually curated list of regulatory factors demonstrated dysregulation of several genes, including upregulation of TGFB across all AA ANA +cell clusters and an increase in CD46 in EA ANA +clusters. Similarly, gene set enrichment analysis of differentially regulated genes indicated activation of stress response pathways in AA and EA ANA +individuals. Conclusions These data indicate that substantial transcriptional and cell population differences exist among immune cells from ANA+, SLE, and healthy individuals, including an activated stress response and enhanced immune regulation in the cells from ANA +individuals. Our results suggest that cells from ANA +individuals may be regulating reactions to stimulation, and exhaustion of that response may allow for transition to SLE. Funding Source(s): NIH U54GM104938, U01AI101934, U19AI082714, and P30AR053483.

Background Systemic lupus erythematosus (SLE) is commonly treated with broad immunosuppression, including cyclophosphamide. Use of this agent can result in ovarian toxicity leading to premature menopause. Ovarian failure is associated with concomitant hypothyroidism. We hypothesized that hypothyroidism might be a marker for ovarian autoimmunity because organ-specific autoimmune diseases tend to occur together. We undertook this study to determine whether anti-ovarian antibodies are associated with premature ovarian failure among SLE women who received cyclophosphamide. Methods All SLE women with a history of cyclophosphamide therapy were identified in the Lupus Registry and Repository (LFRR). All subjects were shown to meet the revised ACR classification criteria. Premature menopause was defined as spontaneous lack of menstrual periods prior to age 45. Anti-ovarian antibodies were measured by ELISA (Anti-Ovarian Ab ELISA, IBL, Minneapolis, catalog # IB9184). Data were analyzed by Students T test and chi square testing. The protocol received ethical approval from the University of Oklahoma Health Sciences Center and Oklahoma Medical Research Foundation IRBs. Results Among ~3000 SLE women enrolled in the LFRR who had received cyclophosphamide, we found 169 with menopause before age 45 along with 73 who underwent menopause after age 45 and 16 patients over age 45 who were still having menstrual periods at the time of evaluation. Thus, there were a total of 89 SLE women who did not have premature menopause. Mean anti-ovarian antibodies in the 169 with premature ovarian failure was 16.2 units (SD=20.3), while the mean among those without premature menopause was 17.4 units (SD=21.7). These values were not statistically different between the groups. 11 of 169 (6.5%) prematurely menopausal SLE women had a positive result and 8 of 89 (8.9%) without premature menopausal were positive (2=0.53, p=0.46, OR=1.02 (95% CI 0.95–1.1). Conclusions Anti-ovarian antibodies were present at low levels (~10% positivity) among women with SLE. However, the presence of these antibodies was not related to premature ovarian failure after cyclophosphamide. Funding Source(s): NIH grants AR053483, AI082714, GM104938. VA grant BX0011451

Background Systemic lupus erythematosus (SLE) is an autoimmune disorder with a variable clinical presentation and periods of waxing and waning disease. Heterogeneity in SLE is influenced by genetic and non-genetic susceptibility found in different ethnicities that drive disease expression and severity. The immune pathways that contribute to heightened disease activity in lupus and immune variation by race are critical to understanding SLE disease mechanisms and outcomes. Methods Peripheral whole blood samples of European or African American healthy controls (n=18) and SLE patients with either high (SLEDAI4) (n=20) or low (SLEDAI Results European American SLE patients with high disease activity were differentiated from patients with low disease activity by reduced frequencies of peripheral B cells, specifically naive B cells (CD27-IgD+CD24 lo) (p=0.0101) and double negative B cells (CD27-IgD-) (p=0.0220), while African American patients with high disease activity had elevated frequencies of memory B cells (CD27 +IgD CD38+) (p Conclusions Our results support a model where race influences heightened SLE disease activity mechanisms with alterations in B cell signaling, and greater dysregulation in phospho-signaling and pro-inflammatory soluble mediators observed in African American patients. Funding Source(s): NIH (U19AI082714, U19AI082719, U54GM104938, P30GM103510, U01AI101934)

Background Anti-nuclear antibody (ANA) positivity is a principal feature of individuals with an autoimmune disease, yet up to one in five healthy individuals are ANA-positive (ANA+) and will never develop overt disease. Understanding differences in immune cell physiology between ANA+healthy individuals and individuals with clinical SLE remains a critical goal in the understanding of SLE pathogenesis across ethnicities. Methods Blood specimens and information on disease activity were collected from European (EA) and African American (AA) individuals classified and matched in groups as ANA- healthy controls (n=24), ANA +healthy (n=24) or SLE patients (n=24). Single-cell analysis of cell surface markers was completed by mass cytometry on PBMCs and cellular heterogeneity was visualized using tSNE (figure 1A–B) and manual gating. Further, phospho-specific flow cytometry was used to measure basal levels of pERK, pPLCg2 and p38 and expression following CD3/CD28 (TCR) and anti-IgG and IgM (BCR) stimulation. Whole genome RNA-sequencing was performed on flow cytometry sorted T cells, B cells and monocytes from 35 matched ANA-, ANA +and SLE patients followed by weighted correlation network analysis (WGCNA) and pathway enrichment analyses. Results Both European and African American SLE patients were distinguished from healthy individuals by T cell proliferation (p=0.002) (figure 1C), plasmacytoid dendritic cell activation (p=0.021) and elevated stem cell factor (p=0.0003). EA ANA+healthy individuals exhibited greater immune regulation with reduced T cell numbers (p=0.002) (figure 1C), decreased activation of dendritic cells (p=0.039) and transitional B cells (0.033), and elevated expression of the inhibitory receptor CD85j (p=0.042) on specific immune cell subsets compared to ANA- healthy subjects. Further, a module associated with hematopoiesis, T cell activation and intrinsic apoptosis signaling pathways is expressed at a higher level in T cells of EA ANA+individuals. In contrast, AA ANA+healthy individuals had elevated plasma levels of IL-6 (p=0.018) and reduced inhibitory receptor expression (p=0.0089) compared to ANA- healthy controls. Gene expression modules associated with viral responses and type I IFN pathway activation were identified in AA SLE patient B cells, while similar expression modules were only found in the monocytes of European American SLE patients. Conclusions These results highlight the importance of stem cell factor and T cell expansion in SLE pathogenesis, and suggest that mechanisms of SLE pathogenesis differ by ethnicity. ANA +European Americans may have more effective regulatory mechanisms in place to prevent transition to classified autoimmune disease. Funding Source(s): This work was supported by the NIH under award numbers U54GM104938, U01AI101934, U19AI082714, and P30AR053483.

Herpes zoster is the reactivation of latent varicella zoster virus usually occurring decades after initial exposure, and manifesting as a painful vesicular rash occurring along one or more dermatomes. Zoster incidence increases with age as cell mediated immunity against latent virus wanes. Epidemiological evidence suggests that individuals with underlying rheumatic diseases are at increased risk for zoster. It remains unclear whether this is due to immunosuppressive medications or from immune dysregulation of the underlying disease. A vaccine against zoster is available for individuals 50 years and older. Theoretical risks remain about using this live-attenuated virus vaccine in immunosuppressed individuals.

Systemic lupus erythematosus (SLE) is a highly variable autoimmune disease that can involve severe organ-threatening symptoms, such as lupus nephritis. Certain drugs, such as mycophenolate mofetil (MMF), are effective at reducing morbidity associated with nephritis; however, the immune pathways associated with disease suppression are poorly defined. Here, we provide evidence that MMF inhibits phosphorylation of STAT3 and other associated immune pathways. Using mass cytometry and bead-based or ELISA assays, the systemic phenotype of SLE patients not taking (MMF–) or taking (MMF+) MMF were studied. MMF+ SLE patients had significant reductions in total numbers of transitional B cells, plasmablasts, and T cells, specifically CD4(+) Th17-type and CD4(+) Treg-type cells, compared with MMF– patients. Plasma soluble mediators were decreased in MMF+ patients including chemokines (MIG/CXCL9 and SDF-1α/CXCL12) and growth factors (VEGF-A and PDGF-BB). Soluble mediators and cell subsets grouped by functional properties revealed significant modifications associated with STAT3 and B cell pathways. Further, healthy PBMCs treated with IL-6 revealed a reduction in p-STAT3 following the addition of mycophenolic acid (the active metabolite of MMF). In conclusion, the inhibition of STAT3 phosphorylation by MMF may explain the effectiveness of this treatment in SLE patients, since increased levels of p-STAT3 are associated with disease pathology.

Infections remain a significant source of morbidity and mortality in systemic lupus erythematosus (SLE). Both the underlying disease process and therapeutic immunosuppression can increase susceptibility to a wide variety of pathogens while influencing the clinical course of infections. Because of the atypical presentation of many infections and the varied array of baseline symptoms, distinguishing an acute infection from a lupus flare is a common clinical challenge in treating SLE patients. This challenge is compounded by the need to suppress the immune system enough to prevent autoimmune complications without making patients overly vulnerable to infection. This chapter reviews the impact of infections on lupus morbidity and mortality, risk factors for infection, the clinical spectrum of infections in lupus, proposed mechanisms of infection susceptibility, and biomarkers or other factors that may assist the clinician when differentiating active infection from an SLE disease flare.

Systemic lupus erythematosus (SLE) preferentially affects women during the childbearing years, making issues of contraception, fertility, and pregnancy of the utmost importance to women diagnosed with this chronic disease. It is clear that female sex hormones can affect the immune system and may impact the activity and trajectory of underlying SLE. With improvements in the monitoring and management of SLE, women with the disease have less functional impairments, end-organ damage, or reduced life expectancy; therefore, they increasingly feel healthy enough to bear and raise children. Pregnancy in women with SLE can carry higher risks of adverse maternal and fetal outcomes. Increased disease activity at the time of conception is among the most impactful and modifiable risk factors for adverse pregnancy outcomes. Additionally, a small subset of medications used for SLE are known teratogens and must be avoided during pregnancy. Therefore safe and effective contraception is critical to limit pregnancies to times of relative disease quiescence and while women are not taking teratogenic medications. Many commonly used medications to treat SLE have been shown to be compatible with pregnancy and can help to control underlying disease allowing for reduced risk of preeclampsia, prematurity, and small-for-gestational-age neonates. Similarly, menopause is a time of endogenous changes in female sex steroids that can affect SLE disease activity. Attention to uncomfortable menopausal symptoms as well as bone health and risk of hormonal malignancies are important aspects of managing women with SLE throughout their life spans.

Epstein Barr virus (EBV) is a gamma herpes virus associated with certain malignancies and autoimmune diseases. EBV maintains latency in B cells with occasional reactivation, in part by overcoming the host immune response with viral homologs of several human proteins. EBV interleukin 10 (vIL-10), a lytic phase protein, is a homolog of human IL-10 (hIL-10). The effect of vIL-10 on human monocytes, which are one of the first immune cells to respond to infection, is not known. To understand the role of vIL-10, monocytes from peripheral blood mononuclear cells were stimulated with hIL-10 or vIL-10. Human IL-10 stimulated STAT3 phosphorylation, which is required for suppression of inflammatory responses. However, vIL-10 induced significantly lower phosphorylation of STAT3 compared to hIL-10, and was less efficient in downregulating inflammatory genes. vIL-10 significantly reduced the expression of scavenger receptor CD163 on monocytes, suggesting inhibition of M2 polarization. Furthermore, uptake of apoptotic cells was reduced in vIL-10-stimulated monocytes compared to hIL-10-stimulated monocytes. A neutralizing antibody to IL-10R1 inhibited STAT3 phosphorylation induced by either hIL-10 or vIL-10, suggesting that vIL-10 signals through IL-10R1. Interestingly, vIL-10 suppressed hIL-10-induced STAT3 phosphorylation and inhibited upregulation of suppressors of inflammatory response by hIL-10. We further show that vIL-10 levels were significantly higher in plasma samples from systemic lupus erythematosus (SLE) patients compared to matched unaffected controls. vIL-10 levels did not correlate with hIL-10 levels, but were associated with levels of IgA antibodies to EBV viral capsid antigen, which is an indirect measure of viral reactivation. We propose that the suppression of hIL-10- induced anti-inflammatory genes by vIL-10, together with an increase in inflammatory gene expression, may overcome the anti-inflammatory effects of hIL-10 and exacerbate autoimmune responses in systemic autoimmune diseases.

Background Existing methods for grading lupus flares or improvement in disease activity require definition-based thresholds as increments of change. Visual analogue scales (VAS) allow rapid, continuous scaling of disease severity. We analyzed the performance of two scales, the SELENA SLEDAI Physician’s Global Assessment (SSPGA) and the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REALTM) as measures of progress in SLE. Methods Prospectively, we evaluated the agreement between collected disease activity (SLEDAI, BILAG-2004, CLASI, SSPGA and LFA-REALTM) and response (SRI-4 and BICLA) measures in an ongoing clinical trial. Results 50 patients (47 females, mean age 45±11.6 years) were assessed at 528 consecutive visits (average 10.6±4.1 visits per patient). Changes in disease activity compared to baseline were examined in 478 visit pairs. SSPGA and LFA-REALTM correlated with each other (r=0.936), and with SLEDAI and BILAG [SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); LFA-REALTM: r=0.778 (SLEDAI), r=0.813 (BILAG); all p Conclusions SSPGA and LFA-REALTM are reliable surrogates of common SLE trial endpoints and could be used as continuous or dichotomous response measures. Additionally, LFA-REALTM can provide individualized scoring at the symptom or organ level. Acknowledgements We thank the patients for their participation in the study. Clarification of Abatacept Effects in SLE with Integrated Biologic and Clinical Approaches (The ABC Study) is an ongoing, investigator-initiated, clinical trial, conducted at the Oklahoma Medical Research Foundation (OMRF), with funding from Bristol Myers Squibb (NCT02270957).

Objective To survey an international sample of providers to determine their current practices for the prevention, screening, and treatment of congenital heart block (CHB) due to maternal Ro/SSA antibodies. Methods A survey was designed by the organizing committee of the 9th International Conference of Reproduction, Pregnancy and Rheumatic Diseases. It was sent to attendants of the conference and authors of recent publications or abstracts at ACR 2012, 2013 or 2014 on rheumatic diseases and pregnancy. Results In anti-Ro/SSA positive women, 80% of 49 respondents recommended screening by serial fetal echocardiogram (ECHO), with most starting at week 16 (59%) and stopping at week 28 (25%), although the time to stop varied widely. For women without a prior infant with neonatal lupus, respondents recommend every other week (44%) or weekly (28%) fetal ECHOs. For women with a prior infant with neonatal lupus, 80% recommend weekly fetal ECHOs. To prevent CHB, HCQ was recommended by 67% of respondents and most would start pre-pregnancy (62%). Respondents were asked about medications to treat varying degrees of CHB in a 20-week pregnant, anti-Ro and La positive SLE patient. For first degree, respondents recommended starting dexamethasone (53%) or HCQ (43%). For second degree, respondents recommended starting dexamethasone (88%). For third degree, respondents recommended starting dexamethasone (55%) or IVIg (33%), although 27% would not start treatment. Conclusion Despite the absence of official guidelines, many physicians with a focus on pregnancy and rheumatic disease have developed similar patterns in the screening, prevention and treatment of CHB.

After several decades of deliberation, the US Food and Drug Administration updated the Pregnancy and Lactation Labeling Rule in 2015, eliminating the prior A, B, C, D, X grading system for medication use in pregnancy. Although physicians and patients liked the relative ease of use of this system, it was often misconstrued and not updated to include new data suggesting greater compatibility of medications with pregnancy. The new label is designed to include more clinically relevant data, including data from human studies and registries, and fewer animal data. A key goal of the new label is to assist physicians and patients as they weigh the risks and benefits of medications vs the risks of pregnancy in a woman with a chronic, untreated illness. As such, each label now includes a section outlining the pregnancy risks of the diseases that the medication treats. This review includes a historical perspective on the label change and a guide to the interpretation of the new label. It also includes an assessment of the baseline risk of pregnancy in women with SLE and RA, to help balance the consideration of medication risks and benefits in pregnancy.

Background Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease oftentimes characterised by a waxing and waning disease course. However, mechanisms of disease flare remain elusive. Objectives This study examined relationships between SLE disease activity, immune pathways, and serologic evidence of viral exposures and reactivation within molecular subsets of SLE patients. Methods Serial or single samples of plasma, serum and RNA (n=290) were collected from 184 adult SLE patients who met ACR classification and cohort-matched controls (n=49). Disease activity was assessed by modified SELENA-SLEDAI. Immune pathways were evaluated by modular transcriptional analysis of Illumina Beadchip Microarray gene expression data, as well as by plasma soluble mediators (n=32) by multiplex, bead-based assay and ELISAs. This information was used to subset patients into seven molecular-defined categories by random forest modelling. Viral seropositivity and antibody concentrations were detected by ELISA for antibodies against EBV-Viral Capsid Antigen (VCA) (IgG and IgA), EBV-Early Antigen (EA) (IgG), Cytomegalovirus (CMV) (IgG), and Herpes Simplex Virus (HSV-1) (IgG). Results Serologic evidence of EBV reactivation was more common in SLE patients compared to controls, as measured by antibodies against EBV-EA [IgG] (40% vs 13%; OR=4.57, p=0.0006) or EBV-VCA [IgA] (36% vs 17%; OR=2.70, p=0.019). No differences were noted in CMV or HSV1 seropositivity rates between patients and controls. IgG responses against EBV-VCA were nearly universal among these adult patients and controls; however, concentrations of EBV-VCA IgG were higher in SLE patients compared to controls (ISR=4.44 vs 3.52; p=0.0021), as were EBV-VCA IgA and EBV-EA IgG antibody responses. In cross sectional analysis, SLE patients with higher disease activity (SLEDAI ≥6; n=126) had higher concentrations of EBV-EA IgG than patients with lower (n=166) disease activity (ISR=0.822 vs 0.540; p=0.033). SLE patients with serologic evidence of EBV reactivation by EA IgG responses had higher levels of interferon associated molecules, IP10 (p=3.4×10–14), BLyS (5.5×10–5), and IL-10 (p=0.00013). HSV1 IgG positive SLE patients also showed higher levels of IP10 (2.2×10–7). Antibody responses toward EBV-EA were enriched in molecularly defined patient clusters with higher expression levels of interferon and inflammatory modules, as well as with interferon and inflammatory soluble mediators. Patients within these clusters were also more likely to have major organ involvement, such as renal or neurologic disease. Conclusions Serologic evidence of EBV reactivation is more common in SLE patients compared to healthy controls. EBV-EA IgG responses are elevated in SLE patients with active disease and correspond with increases in interferon-associated mediators. This study provides serologic evidence suggesting a possible role for viral reactivation in SLE disease activity. Acknowledgements This work was supported in part by grants from the National Institutes of Health: U19AI082714, U01AI101934, U54GM104938, P30AR053483, R01AR072401. Disclosure of Interest None declared

Background Systemic lupus erythematosus (SLE) is characterised by remarkable clinical and pathophysiological diversity, hindering diagnosis, treatment and treatment development. Subsetting of patients based upon clinical presentations alone has not identified homogeneous groups of patients best treated with a directed therapeutic. Objectives To cluster SLE patients into more homogeneous subsets with common molecular pathway signatures, and to assess the clinical, therapeutic, and demographic features enriched in each cluster. Methods Serial or single plasma, serum and RNA samples (n=290) were collected from 198 SLE patients who met ACR classification. Disease activity was assessed by modified SELENA-SLEDAI at an average of 17 visits per patient. Transcriptional co-expression signature module scores were calculated from Illumina Beadchip Microarray gene expression data for 29 immune pathway related modules. Plasma soluble mediators (n=23) and 12 antinuclear autoantibodies (anti-dsDNA, chromatin, ribosomal P, Sm, Sm, SmRNP, RNP, Ro/SSA, La/SSB, centromere B, Scl-70 and Jo-1) were assessed by multiplex bead-based assay and ELISA. Spearman correlations were used for univariate and multivariate analysis using R. Patients were clustered on module signature scores and soluble mediators using random forest and tSNE. Results SLEDAI scores strongly correlated with interferon modules and were modestly correlated with plasmablast and select cell cycle signatures in this adult lupus collection. SLEDAI scores also correlated with soluble levels of IFNa, IL21, IL1a, IL17A, IP10 and MIG. Random forest defined seven clusters of SLE patients with unique molecular phenotypes based upon gene co-expression module signatures and soluble mediators. Inflammation and interferon (IFN) signatures were elevated in Clusters 1 (moderately) and 4, with decreased T cell signatures in Cluster 4. The other clusters had lower IFN and inflammation signatures, but differed in their monocyte, plasmablast and T cell signatures. Clusters 1 and 4 had the highest SLEDAI scores, with high rates of anti-dsDNA, low complement, proteinuria and hematuria; these features were also prominent in Cluster 3, which lacked the IFN and inflammation signatures. Cluster 6 had the highest plasmablast module score, highest IL1a levels, and SLEDAI scored rashes, but only moderate IFN and inflammation module scores. Cluster 2 had higher rates of SLEDAI scored alopecia, a slightly elevated inflammation signature, but lower interferon signature and lower soluble mediator levels. Conclusions SLE subsets can be distinguished by a range of molecular profiles encompassing IFN, T cell, neutrophil, plasmablast, and inflammation co-expression signatures, as well as soluble mediators that vary with disease activity. Prospective longitudinal studies of these molecular profiles may inform clinical trial design and personalised disease management. Acknowledgements This work was supported in part by grants from the National Institutes of Health: U19AI082714, U01AI101934, U54GM104938, and P30AR053483. Disclosure of Interest None declared

Aim To determine whether exposure to tumour necrosis factor (TNF)-α inhibitors increases the risk of herpes zoster (HZ) among people with rheumatoid arthritis (RA). Methods We performed a cohort study of people with RA participating in the Australian Rheumatology Association Database. We identified self-reported cases of HZ and verified using medical records. For the primary analysis, we only included doctor-verified cases. For TNF-α inhibitor exposed groups, we excluded HZ episodes that occurred before TNF-α inhibitor initiation, and for the control group we excluded HZ episodes that occurred prior to 2000 or RA diagnosis. The risk of HZ among participants exposed versus not exposed to TNF-α inhibitors was compared using Cox proportional hazards models including significant covariates affecting the risk. Adjusted hazard ratios (HR) were calculated for TNF inhibitors as a class and for individual agents. Results Among 2157 active RA participants, there were 442 self-reported cases of HZ. From 346 responses from doctors, 249 cases were verified and four were false positives (false positive rate 1.6%). Crude incidence of verified HZ in the entire RA cohort was 15.9/1000 person-years (95% confidence interval (CI): 13.5–18.8). An increased risk of HZ was found for all TNF-α inhibitors combined (fully adjusted HR 1.71; 95% CI: 1.00–2.92) and adalimumab (fully adjusted HR 2.33; 95% CI: 1.22–4.45), but in the fully adjusted model was not increased with etanercept (fully adjusted HR 1.65; 95% CI: 0.90–3.03). No increased risk was found with infliximab (HR 1.29; 95% CI: 0.37–4.47). Conclusions TNF-α inhibitors are associated with an increased risk of HZ in people with RA compared with those who have not been exposed.

Formidable impediments stand in the way of treatment development for lupus. These include the unwieldy size of current trials, international competition for scarce patients, complex outcome measures and a poor understanding of these outcomes in the world at large. The heterogeneity of the disease itself coupled to superimposition of variegated background polypharmacy has created enough immunological noise to virtually ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results in testing failed drugs over the years may not have been negative, but merely uninterpretable. The authors have consulted with many clinical trial investigators, biopharmaceutical developers and stakeholders from government and voluntary sectors. This paper examines the available evidence that supports workable trial designs and proposes approaches to improve the odds of completing interpretable treatment development programs for lupus.

Antigen-specific CD4(+) T cells are implicated in the autoimmune disease systemic lupus erythematosus (SLE), but little is known about the peptide antigens that they recognize and their precise function in disease. We generated a series of MHC class II tetramers of I-E(k)-containing peptides from the spliceosomal protein U1-70 that specifically stain distinct CD4(+) T-cell populations in MRL/lpr mice. The T-cell populations recognize an epitope differing only by the presence or absence of a single phosphate residue at position serine(140). The frequency of CD4(+) T cells specific for U1-70(131-150):I-E(k) (without phosphorylation) correlates with disease severity and anti-U1-70 autoantibody production. These T cells also express RORγt and produce IL-17A. Furthermore, the U1-70-specific CD4(+) T cells that produce IL-17A are detected in a subset of patients with SLE and are significantly increased in patients with mixed connective tissue disease. These studies provide tools for studying antigen-specific CD4(+) T cells in lupus, and demonstrate an antigen-specific source of IL-17A in autoimmune disease.

Collecting useful data on a sufficiently large cohort of pregnancies in women with rheumatic disease is a challenge. The original manuscripts that demonstrated the dangers of pregnancy in women with lupus were relatively small case series. As larger prospective cohorts were collected by university-based experts, however, greater safety was demonstrated and the current norms of treatment were determined. In recent years, larger administrative databases have been tapped to study pregnancies not managed within university clinics and to study the long-term impact of maternal rheumatic disease on the offspring. Each of these methods of study has both strengths and weaknesses, adding a unique piece of data to our overall knowledge. We will discuss a range of approaches to the study of rheumatic disease in pregnancy, covering the potential benefits that each brings as well as the biases that can impact study results. When the results of studies are viewed through these lenses, each can contribute to our larger understanding of the rheumatic diseases in pregnancy.

Objective The aim of this study was to investigate the association of menopause with functional status outcomes in women with RA. Methods Participants were women in a US-wide observational cohort who developed RA before menopause. The HAQ measured functional status. We controlled for confounding variables and used univariate and multivariable generalized estimating equation methods with the sandwich estimator of variance. Best models were selected using the quasi-likelihood under the independence model criterion. A sensitivity analysis was performed using linear mixed effects regression models. Results A total of 8189 women were eligible. Of these, 2005 (24.5%) were pre-menopausal, 611 (7.5%) transitioned through menopause during the study, and 5573 (68.1%) were post-menopausal. Within each respective group, the mean (s.d.) ages were 39.7 (7.8), 50.7 (3.4) and 62.3 (9.3) years. Our results showed that women who were pre-menopausal had less functional decline as measured by the HAQ compared with women who were post-menopausal; these results were robust and strong even after adjustment for other significant factors. The ever-use of hormonal replacement therapy, ever having a pregnancy, and longer length of reproductive life were associated with less functional decline. After menopause, the trajectory of functional decline worsened and accelerated in women with RA. Conclusion The results suggest that menopausal status is associated with functional decline in women with RA. Furthermore, menopause is associated with a worsening progression of functional decline. These data indicate that menopause has a significant impact on the level and rate of functional decline in women with RA.

The idiopathic inflammatory myopathies dermatomyositis (DM) and polymyositis (PM) are autoimmune diseases that can affect females of childbearing potential. We assessed pregnancy outcomes in DM and PM patients compared with the general obstetric population.The Nationwide Inpatient Sample (NIS) (1993-2007) was used to identify delivery-associated hospitalizations in women with DM or PM (DM/PM, n = 853). Controls were from the general obstetric population delivery-associated hospitalizations matched to each case by year of delivery. Pregnancy outcomes included hospital length of stay (LOS), hypertensive disorders (HTN), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and cesarean delivery. Multivariate regression analyses were performed using maternal age, race/ethnicity, and diabetes mellitus as covariates.On multivariate analysis, patients with DM/PM had longer LOS compared to controls (p0.001). DM/PM was associated with an increased risk of hypertensive disorders compared to controls (OR = 2.90, 95% CI: 2.00-4.22). There were no differences in rates of PROM, IUGR, or cesarean section in patients with DM/PM compared with controls. Independent of a DM/PM diagnosis, African-American race, older age, and diagnosis of diabetes increased the hospital LOS (p0.001). African-American race and diabetes increased the risk of hypertensive disorders (OR = 1.38, 95% CI: 1.19-1.60; OR = 2.94, 95% CI: 2.04-4.23, respectively) compared to controls.These data suggest that patients with inflammatory myopathies are at increased risk of hypertensive disorders of pregnancy and longer length of hospitalization. Vigilant monitoring of blood pressure is advisable in pregnant patients with DM or PM.

IgG autoantibodies, including antibodies to double-stranded DNA (dsDNA), are pathogenic in systemic lupus erythematosus (SLE), but the mechanisms controlling their production are not understood. To assess the role of invariant natural killer T (iNKT) cells in this process, we studied 44 lupus patients. We took advantage of the propensity of PBMCs from patients with active disease to spontaneously secrete IgG in vitro. Despite the rarity of iNKT cells in lupus blood (0.002-0.05% of CD3-positive T cells), antibody blockade of the conserved iNKT TCR or its ligand, CD1d, or selective depletion of iNKT cells, inhibited spontaneous secretion of total IgG and anti-dsDNA IgG by lupus PBMCs. Addition of anti-iNKT or anti-CD1d antibody to PBMC cultures also reduced the frequency of plasma cells, suggesting that lupus iNKT cells induce B-cell maturation. Like fresh iNKT cells, expanded iNKT-cell lines from lupus patients, but not healthy subjects, induced autologous B cells to secrete antibodies, including IgG anti-dsDNA. This activity was inhibited by anti-CD40L antibody, as well as anti-CD1d antibody, confirming a role for CD40L-CD40 and TCR-CD1d interactions in lupus iNKT-cell-mediated help. These results reveal a critical role for iNKT cells in B-cell maturation and autoantibody production in patients with lupus.

PURPOSE OF REVIEW Tumour necrosis factor inhibitors (TNFi) and other biologic response modifiers are being increasingly used for the treatment of rheumatoid arthritis (RA) among women of childbearing age, raising concerns regarding the potential safety of inadvertent or intentional exposure of these agents to the developing fetus. RECENT FINDINGS TNFi and other biologics whose constructs contain a functional IgGFc piece are actively transported across the placenta during the second and third trimesters of pregnancy. Very little drug passively diffuses to the fetal circulation during the first trimester, when organogenesis occurs. Cumulative data from both the rheumatology and gastroenterology literature suggest that the rate of birth defects following antenatal TNFi exposure does not appear to be higher than that seen in the general population. There are very little data available on pregnancy outcomes following antenatal exposure to other biologic medications for RA. SUMMARY Cumulative evidence suggests that TNFi use during pregnancy carries low risk for teratogenicity. A single case of fatal BCG infection in an exposed neonate following live virus vaccination highlights the potential need to defer live virus vaccines for at least 6 months in exposed neonates until more data of risk factors for infection susceptibility are available.

ObjectiveExisting methods for grading lupus flares or improvement require definition-based thresholds as increments of change. Visual analogue scales (VAS) allow rapid, continuous scaling of disease severity. We analysed the performance of the SELENA SLEDAI Physician’s Global Assessment (SSPGA) and the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) as measures of improvement or worsening in SLE.MethodsWe evaluated the agreement between prospectively collected measures of lupus disease activity [SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index 2004 (BILAG 2004), Cutaneous Lupus Area and Severity Index (CLASI), SSPGA and LFA-REAL] and response [(SLE Responder Index (SRI)-4 and BILAG-Based Combined Lupus Assessment (BICLA)] in a clinical trial.ResultsFifty patients (47 females, mean age 45 (±11.6) years) were assessed at 528 consecutive visits (average 10.6 (±4.1) visits/patient). Changes in disease activity compared with baseline were examined in 478 visit pairs. SSPGA and LFA-REAL correlated with each other (r=0.936), and with SLEDAI and BILAG (SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); LFA-REAL: r=0.778 (SLEDAI), r=0.813 (BILAG); all pConclusionSSPGA and LFA-REAL are reliable surrogates of common SLE trial end points and could be used as continuous or dichotomous response measures. Additionally, LFA-REAL can provide individualised scoring at the symptom or organ level.Trial registration numberNCT02270957.

Objective To analyze the distribution of rheumatology practices in the US and factors associated with that distribution, in order to better understand the supply of the rheumatology workforce. Methods Using the American College of Rheumatology membership database, all practicing adult rheumatologist office addresses were mapped with ArcView software. The number of rheumatologists per Core Based Statistical Area (CBSA) was calculated. To investigate whether sociodemographic factors correlated with clustering of rheumatologists, covariates from the 2010 US Census for each CBSA, including age, sex, race/ethnicity, and median household income, were modeled. Results Many CBSAs, predominantly smaller micropolitan areas, did not have a practicing rheumatologist. For some of these smaller micropolitan areas (with populations of at least 40,000), the closest practicing rheumatologist was more than 200 miles away. However, we also identified several more-populous areas (populations of 200,000 or more) without a practicing rheumatologist. Greater numbers of rheumatologists were more likely to practice in areas with higher population densities and higher median incomes. More rheumatologists were also found in CBSAs in which there were rheumatology training programs. Conclusion These findings demonstrate that many smaller regions of the country have no or few practicing adult rheumatologists. Patients with chronic rheumatic conditions in these areas likely have limited access to rheumatology care. Policy changes could address potential regional rheumatology workforce shortages, but limitations of the current data would need to be addressed prior to implementation of such changes.

Objective.Patients with systemic lupus erythematosus (SLE) are at increased risk of herpes zoster (HZ). Although a vaccine for HZ has been approved by the US Food and Drug Administration, its use in immunocompromised individuals remains controversial because it is a live-attenuated virus vaccine. We performed a pilot study of the immunogenicity of the HZ vaccine (Zostavax) in patients with SLE.Methods.Ten patients with SLE and 10 control subjects ≥ age 50 years participated in this open-label vaccination study. All were seropositive for varicella zoster virus (VZV). Patients with SLE were excluded for SLE Disease Activity Index (SLEDAI) > 4, or use of mycophenolate mofetil, cyclophosphamide, biologics, or > 10 mg prednisone daily. Followup visits occurred at 2, 6, and 12 weeks. Clinical outcomes included the development of adverse events, particularly HZ or vesicular lesions, and SLE flare. Immunogenicity was assessed with VZV-specific interferon-γ-producing enzyme-linked immunospot (ELISPOT) assays and with antibody concentrations.Results.All subjects were women. Patients with SLE were slightly older than controls (60.5 vs 55.3 yrs, p < 0.05). Median baseline SLEDAI was 0 (range 0–2) for patients with SLE. No episodes of HZ, vesicular rash, serious adverse events, or SLE flares occurred. Three injection site reactions occurred in each group: mild erythema or tenderness. The proportion of subjects with a > 50% increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls. Antibody titers increased only among controls following vaccination (p < 0.05).Conclusion.The HZ vaccination yielded a measurable immune response in this cohort of patients with mild SLE taking mild-moderate immunosuppressive medications. No herpetiform lesions or SLE flares were seen in this small cohort of patients.ClinicalTrials.govID:NCT01474720.

Approximately half of patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN), a major cause of morbidity and early mortality in that disease. Prolonged renal inflammation is associated with irreversible kidney damage which confers a 30% risk of end stage renal disease (ESRD), making early, aggressive treatment mandatory. Failure to achieve therapeutic response or recurrence of renal flare often prompts repeat biopsy. However, the role of repeat biopsy in determining long-term renal prognosis remains controversial. For this reason repeat biopsies are usually not utilized unless clinical evidence of refractory or recurrent disease is already present, despite known mismatches between clinical and biopsy findings. The current study quantifies the degree to which histopathologic worsening between first and second biopsies and duration between them predicts ESRD and death.Medical records of 141 LN patients with more than one biopsy were obtained from a single large urban medical center. Cases were attained using billing codes for diagnosis and procedures from 1/1999-1/2015. Biopsy worsening was defined as unfavorable histopathologic classification transitions and/or increased chronicity; if neither were present, the patient was defined as non-worsening. We used Cox proportional hazard models to study the relationship between ESRD and survival adjusting for covariates which included age at first biopsy, gender, race, initial biopsy class, and initial induction therapy.Of 630 patients screened, 141 had more than one biopsy. Advancing chronicity was detected in 48 (34.0%) and a renal class switch to worse grade of pathology was found in 54 (38.3%). At least one of these adverse second biopsy features was reported in 79 (56.0%) patients. Five years following initial biopsy, 28 (35.4%) of those with worsening histopathology on second biopsy developed ESRD, compared to 6 (9.7%) of non-worsening patients and 10 (12.7%) of patients with worsening histopathology had died compared to 2 (3.2%) of non-worsening patients. Biopsy worsening was associated with a significantly greater 15-year risk of ESRD (Hazard Ratio 4.2, p=0.0001) and death (Hazard Ratio 4.3, p=0.022), adjusting for age, gender, race, biopsy class, and treatment. Time between first and second biopsies was1year in 32 patients, 1-5years in 81, and5years in 28. Over a 15-year period, those with1year between first and second biopsies (presumably enriched for patients with early clinical signs of progression) had a significantly greater risk of ESRD (Hazard Ratio 13.7, p0.0001) and death (Hazard Ratio 16.9, p=0.0022) after adjusting for age, gender, race, biopsy class, and treatment.A repeat renal biopsy demonstrating worsening pathology increases the risk of ESRD and death more than four-fold compared to non-worsening patients. Given known potential mismatch between biopsy and clinical data, repeat biopsies may add important information and justify changes in treatment not considered on clinical grounds. Earlier detection of poor prognostic signs in those without early clinical deterioration might improve outcomes in enough patients to reconsider cost effectiveness of routine repeat biopsy.

Objective Women with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) have fewer children on average than other women. We sought to determine the roles of infertility, pregnancy loss, and personal choice on family size in women with these diseases. Methods A reproductive history questionnaire was completed by women with RA and SLE participating in a longitudinal observational study. Within each disease cohort, participants were divided into 3 groups: those interested in having children at symptom onset who had either fewer children than planned (group A) or the same number as planned (group B), and those no longer interested in having children at diagnosis (group C). Results Of the 578 RA and 114 SLE women surveyed, >60% were in group C. Of those interested in having children, 55% with RA and 64% with SLE had fewer children than originally planned. Among women with RA, group A had 1 less pregnancy, 1 less live birth, and an infertility rate 1.5 times higher than group B; the miscarriage rate was similar in both groups. Compared to SLE group B, SLE group A had a similar number of pregnancies, but a 3-fold higher rate of miscarriage and 1 less live birth. Concerns about child health and personal welfare were associated with a lower pregnancy rate. Conclusion In this population, more than one-half of young women with RA or SLE had fewer biologic children than desired. While patient choice plays a role, infertility in RA patients and miscarriage in SLE patients are also important.