Faculty Bibliography

Background/Purpose: Little is known about the association of healthcare costs with damage accrual in SLE. We describe the costs associated with damage states across the disease course using multi-state modeling. Methods: Patients fulfilling the revised ACR classification criteria for SLE from 32 centres in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, SLE disease activity (SLEDAI-2K), damage (SLICC/ACR Damage Index [SDI] if > 6 months from diagnosis), hospitalizations, medications, dialysis, and utilization of selected medical/surgical procedures were collected. Annual health resource utilization was costed using 2015 Canadian prices. Annual costs associated with SDI states were obtained from multiple regressions adjusting for age, race/ethnicity, and disease duration. As there were relatively few transitions to SDI states 5 - 11, these were merged into a single SDI state. Five and 10-year cumulative costs were estimated by multiplying annual costs associated with each SDI state by the expected duration in each state, which was forecasted using a multi-state Markov model (Bruce IN et al. Ann Rheum Dis 2015;74:1706-13). Results: 1641 patients participated, 89.2% female, 48.9% Caucasian, mean age at diagnosis 35.2 years (SD 13.4), mean disease duration at enrollment 0.5 years (SD 0.3), and mean follow up 6.1 years (range 0.1 - 13.7 years). Health resource utilization and annual costs (after adjustment using regression) were markedly higher in those with higher SDIs Conclusion: Patients with the highest baseline SDIs incur annual costs and 10-year cumulative costs that are approximately 20-fold higher than those with the lowest baseline SDI. By estimating the expected duration in each SDI state and incorporating annual costs, disease severity at presentation can be used to predict future healthcare costs, critical knowledge for cost-effectiveness evaluations of novel therapies. (Table Presented)

OBJECTIVE:Antinuclear antibodies (ANAs) are detected in ∼18% of females, yet autoimmune disease develops in only 5-8%. Immunologic differences between ANA-positive healthy individuals and patients with systemic lupus erythematosus (SLE) may elucidate the regulatory mechanisms by which ANA-positive individuals avoid transition to clinical autoimmune disease. METHODS:Healthy individuals (n = 790) were screened for autoantibodies specific for 11 antigens associated with lupus, systemic sclerosis, and Sjögren's syndrome. From this screening, 31 European American ANA-positive healthy individuals were selected and demographically matched to ANA-negative controls and SLE patients. Serum cytokine profiles, leukocyte subset frequency, and reactivity were analyzed by multiplex assays, immunophenotyping, and phosphospecific flow cytometry. RESULTS:Of 790 individuals screened, 57 (7%) were ANA-positive. The majority of proinflammatory cytokines, including interferon-γ (IFNγ), tumor necrosis factor, interleukin-17 (IL-17), and granulocyte colony-stimulating factor, exhibited a stepwise increase in serum levels from ANA-negative controls to ANA-positive healthy individuals to SLE patients (P < 0.0001). IFNα, IFNβ, IL-12p40, and stem cell factor/c-Kit ligand were increased in SLE patients only (P < 0.05). B lymphocyte stimulator (BlyS) was elevated in SLE patients but decreased in ANA-positive individuals (P < 0.001). Further, IL-1 receptor antagonist (IL-1Ra) was down-regulated in SLE patients only (P < 0.0001). ANA-positive individuals had increased frequencies of monocytes, memory B cells, and plasmablasts and increased levels of pSTAT-1 and pSTAT-3 following IFNα stimulation compared with ANA-negative controls (P < 0.05). CONCLUSION:ANA-positive healthy individuals exhibit dysregulation in multiple immune pathways yet differ from SLE patients by the absence of elevated IFNs, BLyS, IL-12p40, and stem cell factor/c-Kit ligand. Further, severely decreased levels of IL-1Ra in SLE patients compared with ANA-positive individuals may contribute to disease development. These results highlight the importance of IFN-related pathways and regulatory elements in SLE pathogenesis.

BACKGROUND:Decreased heart rate variability (HRV) is associated with adverse outcomes in cardiovascular diseases and has been observed in patients with systemic lupus erythematosus (SLE). We examined the relationship of HRV with SLE disease activity and selected cytokine pathways. METHODS:Fifty-three patients from the Oklahoma Lupus Cohort were evaluated at two visits each. Clinical assessments included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group (BILAG) index, physician global assessment (PGA), and Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI Flare Index. HRV was assessed with a 5-minute electrocardiogram, and the following HRV parameters were calculated: square root of the mean of the squares of differences between adjacent NN intervals (RMSSD), percentage of pairs of adjacent NN intervals differing by more than 50 milliseconds (pNN50), high-frequency power (HF power), and low frequency to high frequency (LF/HF) ratio, which reflects sympathetic/vagal balance. Plasma cytokine levels were measured with a multiplex, bead-based immunoassay. Serum B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL) were measured with an enzyme-linked immunosorbent assay. Linear regression analysis was applied. RESULTS:Baseline HRV (pNN50, HF power, LF/HF ratio) was inversely related to disease activity (BILAG, PGA) and flare. Changes in RMSSD between visits were inversely related to changes in SLEDAI (p = 0.007). Age, caffeine, tobacco and medication use had no impact on HRV. Plasma soluble tumor necrosis factor receptor II (sTNFRII) and monokine induced by interferon gamma (MIG) were inversely related with all baseline measures of HRV (p = 0.039 to <0.001). Plasma stem cell factor (SCF), interleukin (IL)-1 receptor antagonist (IL-1RA), and IL-15 showed similar inverse relationships with baseline HRV, and weaker trends were observed for interferon (IFN)-α, interferon gamma-induced protein (IP)-10, and serum BLyS. Changes in the LF/HF ratio between visits were also associated with changes in sTNFRII (p = 0.021), MIG (p = 0.003), IFN-α (p = 0.012), SCF (p = 0.001), IL-1RA (p = 0.023), and IL-15 (p = 0.010). On the basis of multivariate linear regression, MIG was an independent predictor of baseline HRV after adjusting for plasma IL-1RA, SCF, IFN-α, IP-10, and serum BLyS. In a similar model, the sTNFRII impact remained significant after adjusting for the same variables. CONCLUSIONS:Impaired HRV, particularly the LF/HF ratio, is associated with lupus disease activity and several cytokines related to IFN type II and TNF pathways. The strongest association was with MIG and sTNFRII, expanding previous immune connections of vagal signaling.

OBJECTIVE:Systemic lupus erythematosus (SLE) is a relapsing autoimmune disease that affects multiple organ systems. T cells play an important role in the pathogenesis of lupus; however, early T cell events triggering disease flares are incompletely understood. This study was undertaken to examine DNA methylation in naive CD4+ T cells from lupus patients to determine if epigenetic remodeling in CD4+ T cells is an early event in lupus flares. METHODS:A total of 74 lupus patients with an SLE Disease Activity Index score of 0-18 were included. Naive CD4+ T cells were isolated from peripheral blood samples, and DNA was extracted for genome-wide methylation assessment. RNA was also extracted from a subset of patients to determine the relationship between epigenetic changes and transcription activity using RNA sequencing and microRNA arrays. RESULTS:We demonstrated that naive CD4+ T cells in lupus undergo an epigenetic proinflammatory shift, implicating effector T cell responses in lupus flare. This epigenetic landscape change occurs without changes in expression of the corresponding genes, poises naive CD4+ T cells for Th2, Th17, and follicular helper T cell immune responses, and opposes inhibitory transforming growth factor β signaling. Bioinformatics analyses indicate that the epigenetic modulator EZH2 might play an important role in shifting the epigenetic landscape, with increased disease activity in lupus naive CD4+ T cells. Further, the expression of microRNA-26a, which is sensitive to glucose availability and targets EZH2, was negatively correlated with disease activity in lupus patients. CONCLUSION:An epigenetic landscape shift in naive CD4+ T cells that favors T cell activation and non-Th1 immune responses predates transcription activity and correlates with lupus activity. A role for EZH2 dysregulation in triggering lupus flares warrants further investigation.

Background To describe cancer incidence in the largest inceptionSLE cohort in the world.Materials and methods Patients meeting ACR criteria for newonset SLE were enrolled across 32 centres. At enrolment and annual assessments, new cancer diagnoses (in the interveningyear) were recorded by the examining physician. Confirmation ofcancers was done by reviewing medical files including pathologyreports. Of 1848 patients enrolled (across 1999-2011), 1676 hadat least one follow-up. Patients were followed until death, lastvisit, or end of study interval for this analysis (August 2015).Results Of 1676 patients followed, the majority (88.7%) werefemale and 828 (49.4%) were Caucasian (16.5% black, 15.2%Asian, 15.2% Hispanic, 3.7% other). Average age at SLE diagnosis was 34.6 (standard deviation, SD 13.3) years. At baseline,1085 (64.7%) patients were never-smokers; the remainder werecurrent (n = 248) or ex-smokers (n = 342). Average follow-upfrom cohort entry was 6.9 (SD 3.6) years. Two patients had cancer (one squamous cell skin and one breast cancer) prior to theirSLE diagnosis; these cancers were not included in our analyses.We observed 46 cancers in 46 subjects (with three other subjects reported to have cervical intraepithelial neoplasia, a premalignant condition). At cancer diagnosis, the average age was 51.7(SD 15.3) years and the average SLE duration was 4.8 (SD 3.1)years. The most common cancer type was breast (n = 9), followed by non-melanoma skin cancer (n = 8, six of which werebasal cell), lung (n = 6), prostate (n = 5), four head and neck(tonsillar, tongue, and two oral), cervical (n = 2), thyroid(n = 2), melanoma (n = 2) and one each of Non-Hodgkin lymphoma, leukaemia, multiple myeloma, meduloblastoma braincancer, renal carcinoma, gastric carcinoid, thymoma, and cutaneous dermatofibrosarcoma. Most of the cancer cases were female(34 cases, 73.9%) and Caucasian (34 cases, 73.9%). Four cancercases were Hispanic, 4 were black, and 4 were Asian. Twenty ofthe 46 patients (43.5%) who developed cancers were current(n = 4) or ex-smokers (n = 16); five of the six lung cancers werecurrent (n = 1) or ex-smokers (n = 4).Conclusions Just under 3% of the incident SLE cohort developed a cancer over an average follow-up of 6.9 years. The mostcommon cancers were breast, non-melanoma skin, and lung cancers. The vast majority of lung cancers were smokers, supportingthe belief that lung cancer risk in SLE (as in the general population) is largely driven by smoking. Further analyses will determine the standardised incidence rates for these cancers in SLE,versus the general population

Background When found in the absence of antibodies toextractable nuclear antigens (ENA) or anti-double-stranded DNA(dsDNA) (i.e., monospecific), autoantibodies to the nuclear autoantigen dense fine speckles 70 (DFS70) are purported to ruleout SLE. The reported frequency of anti-DFS70 by chemiluminescence (CIA) in SLE is low compared to healthy individuals(0-5.7% vs. 1.3-23.2%), while the frequency of monospecificanti-DFS70 in SLE is even lower at 0-0.4%. There are no studies examining the frequency of anti-DFS70 in an early inceptionSLE cohort. This study determined the prevalence of antiDFS70 in a multi-national, multi-ethnic early inception SLEcohort and examined demographic, clinical, and autoantibodyassociations.Materials and methods Patients fulfilling ACR Classification Criteria for SLE were enrolled in the Systemic Lupus InternationalCollaborating Clinics (SLICC) inception cohort within 15months of diagnosis. Demographic and clinical data were collected at enrollment. ANAs were detected by indirect immunofluorescence on HEp-2 cells (ImmunoConcepts, Sacramento)and ENAs and dsDNA by an addressable laser bead immunoassay (FIDIS Connective13, TheraDiag, Paris). Anti-DFS70 antibodies were measured by CIA (Inova Diagnostics, San Diego).The association between anti-DFS70 and baseline demographic,clinical, and autoantibody profiles was assessed using univariateand multivariate logistic regression. For the most informativemodel, only the remaining statistically significant predictors atthe 95% CI: were included, after eliminating other potentialpredictors individually, starting with the least likely to be associated with the outcome.Results 1137 patients were included; 89.9% were female and93.8% were ANA positive (Table 1). The frequency of antiDFS70 was 7.1% [95% CI: 5.7-8.8%]. 13 of 1137 (1.1%)[95% CI: 0.6-1.9%] were positive for anti-DFS70 only (monospecific). In univariate analysis, patients with musculoskeletalactivity (based on SLEDAI items) or anti-b-2 glycoprotein-1(anti-b2GP1) were more likely to have anti-DFS70, whereasthose with anti-dsDNA, anti-SSA/Ro60, anti-SSB/La, or antiU1RNP were less likely to have anti-DFS70. In multivariateanalysis, patients with musculoskeletal activity (Odd Ratio (OR)1.25 [95% CI: 1.10, 1.41]) or anti-b2GP1 (OR 2.15, 95% CI:1.21, 3.84) were more likely to have anti-DFS70, while thosewith anti-dsDNA (OR 0.53, 95% CI: 0.31, 0.92) or anti-SSB/La(OR 0.25, 95% CI:0.08, 0.82) were less likely to have antiDFS70.Conclusions The prevalence of anti-DFS70 in newly diagnosedSLE patients was at the high end of the range previouslypublished for SLE (7.1% vs. 0-5.7%) and was associated withmusculoskeletal activity and anti-b2GP1. However, 'monospecific' anti-DFS70 was rare (1.1%) and is potentially useful to discriminate between ANA positive healthy individuals and SLE

Background Anifrolumab was evaluated in a Phase IIb study ofadults with moderate to severe systemic lupus erythematosus(SLE), in which 305 patients received intravenous infusions ofanifrolumab (300 mg, 1000 mg) or placebo for 48 weeks. Globaldisease activity was reduced in both dose groups compared withplacebo, although a more favourable risk-benefit profile wasobserved with the 300-mg dose. This analysis of the Phase IIbstudy compared the impact of anifrolumab on individual organdomains in patients.Materials and methods Changes from baseline in organ domainactivity were assessed at Week 52 using the SLE Disease ActivityIndex 2000 (SLEDAI-2K) and British Isles Lupus AssessmentGroup (BILAG). SLEDAI domain improvement required a lowerscore compared with baseline in at least one of its components.BILAG organ domain improvement was defined as the transitioning from A or B to a lower score.Results The majority of patients had baseline involvement of themucocutaneous and/or musculoskeletal domains of SLEDAI-2Kand BILAG. A greater percentage of anifrolumab-treated patientsdemonstrated improvement in these frequently involved domainscompared with placebo (Table 1). Potential benefits were observedin most of the other less frequently active domains, including SLEDAI-2K cardiorespiratory, vascular, haematological, and constitutional; and BILAG cardiorespiratory and constitutional domains.In patients with baseline involvement in the SLEDAI-2K immunological domain (positive anti-double-stranded DNA [anti-dsDNA]and/or low complement level), normalisation of anti-dsDNA and/or hypocomplementemia were seen more frequently at Day 365 inpatients receiving anifrolumab compared with placebo (Table 1).However, among patients who had a normal anti-dsDNA and/ornormal complements at baseline, a slightly greater number ofpatients in the 300-mg anifrolumab group had an increase in thescore representing the development of a new anti-dsDNA or hypocomplementemia compared with baseline (Table 1).Conclusions Treatment with anifrolumab resulted in greaterrates of improvement in multiple organ domains compared withplacebo. The greatest impact was seen with 300-mg anifrolumab

OBJECTIVE: To measure antiphospholipid antibody (aPL) variance during pregnancy; to determine if variation affects outcomes. METHODS: We used data from PROMISSE, a multicenter prospective study of pregnant women with aPL and/or SLE. APL was present if any of the following was positive: anticardiolipin (aCL), anti-beta2glycoprotein I (abeta2GPI) titers >/=40 GPL or MPL units, and/or lupus anticoagulant (LAC). APL were measured every trimester and post-partum. Adverse pregnancy outcomes (APOs) were defined as: fetal/neonatal death, preterm delivery <36 weeks due to preeclampsia or placental insufficiency; or growth restriction. RESULTS: One hundred and fifty-two aPL-positive patients were studied: 57% with clinical APS and 36% with SLE. aPL IgG levels were significantly lower during 2nd and 3rd trimesters compared to screening, but IgG aCL and abeta2GPI remained high-positive through pregnancy in 93% and 85% of patients, respectively. APL IgM titers were negative in the majority of patients and fell modestly during pregnancy. LAC frequency also decreased, but 75% remained positive through the 2nd trimester. Only 4% of patients with aPL at baseline did not have aPL at either 2nd or 3rd trimester. Changes in aPL levels or aPL status were not associated with APOs. LAC was the only aPL associated with APOs. CONCLUSION: APL levels decreased marginally during pregnancy, and changes were not associated with pregnancy outcome. Our findings suggest that measurement of aPL early is sufficient to assess risk . Repeat aPL testing through pregnancy is unnecessary

OBJECTIVE: To study bidirectional change and predictors of change in estimated glomerular filtration rate (eGFR) and proteinuria (ePrU) in lupus nephritis (LN) using a multistate modelling approach. METHODS: In the SLICC inception cohort we determined annual eGFR state 1 (eGFR: >60 ml/min), 2 (eGFR: 30-60 mL/min), and 3 (eGFR: <30 ml/min); ePrU state 1 (ePrU: <0.25 gr/day), 2 (ePrU: 0.25-3.0 gr/day), and 3 (ePrU: >3.0 gr/day); End stage renal disease (ESRD) and death. Using multistate modelling, relative transition rates between states indicated improvement and deterioration. RESULTS: In 700/1,826 (38.3%) patients with LN, and mean (SD followup 5.2(3.5) years the likelihood of improvement in eGFR and ePrU was greater than deterioration. After 5 years, estimated transition to ESRD was 62% of patients initially in eGFR state 3 and 11% from ePrU state 3. The probability of remaining in initial eGFR states 1, 2 and 3 was 85%, 11%, 3% and for ePrU was 62%, 29%, 4%. Male sex predicted improvement in eGFR states; older age, race/ethnicity, higher ePrU state and higher renal biopsy chronicity scores predicted deterioration. For ePrU, race/ethnicity, earlier calendar years, damage scores without renal variables and higher renal biopsy chronicity scores predicted deterioration; male sex, positive lupus anticoagulant, class V nephritis and mycophenolic acid use predicted less improvement. CONCLUSION: In LN, the expected improvement and deterioration in renal outcomes can be estimated by multistate modelling and is predicated by identifiable risk factors. New therapeutic interventions for LN should meet or exceed these expectations

OBJECTIVE: More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in approximately 1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjogren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS: All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS: We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P = 0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P = 0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was approximately 2.5 and approximately 2.9 times higher, respectively, than that in women with 46,XX and approximately 25 and approximately 41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.