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Background The clinical outcomes of diabetes can be influenced by primary care providers’ (PCP) treatment approaches. This study explores the association between PCP approaches to management and performance measured by established diabetes metrics and related costs. Methods In phase one, Electronic Medical Records were used to extract diabetes related metrics using Healthcare Effectiveness Data and Information Set (HEDIS), for patients with diabetes who had office visits to 44 PCP practices from April 2019 to March 2020. Using those metrics and scoring system, PCP practices were ranked and then categorized into high- and low-performing groups (top and bottom 25%, n  = 11 each), with a total of 19,059 clinic visits by patients with a diagnosis of diabetes. Then extensive analysis was performed to evaluate a correlation between treatment approaches and diabetes outcomes across the top and bottom performing practices. In phase 2, patients with diabetes who were attributed to the aforementioned PCP practices were identified in a local health plan claims data base (a total of 3,221 patients), and the allowed amounts from their claims were used to evaluate differences in total and diabetes-related healthcare costs by providers’ performance. Results Comparing 10,834 visits in high-performing practices to 8,235 visits in low-performing practices, referrals to certified diabetes care and education specialists and provider-to-provider electronic consults (e-consults) were higher in high-performing practices (Z = 6.06, p  < .0001), while traditional referrals were higher in low-performing practices (Z = -6.94, p  < .0001). The patient-to-provider ratio was higher in the low-performing group (M = 235.23) than in the high-performing group (M = 153.26) (Z = -2.82, p  = .0048). Claims data analysis included 1,825 and 1,396 patients from high- and low-performing providers, respectively. The patient-to-provider ratio was again higher in the low-performing group ( p  = .009, V = 0.62). Patients receiving care from lower-performing practices were more likely to have had a diabetes-related hospital observation (5.7% vs. 3.9%, p  = .02; V = 0.04) and higher diabetes-related care costs ( p  = .002; d = − 0.07); these differences by performance status persisted when controlling for differences in patient and physician characteristics. Patients seeing low-performing providers had higher Charlson Comorbidity Index scores (Mdn = 3) than those seeing high-performing providers (Mdn = 2). Conclusions Referrals to the CDCES and e-Consult were associated with better measured diabetes outcomes, as were certain aspects of cost and types of hospital utilization. Higher patients to providers ratio and patients with more comorbidities were observed in low performing group.

Background Nephrolithiasis as a feature of rheumatologic diseases is under recognized. Understanding presenting features, diagnostic testing is crucial to proper management. Case presentation A 32 year old woman with a history of recurrent complicated nephrolithiasis presented to a rheumatologist for a several month history of fatigue, dry eyes, dry mouth, arthralgias. She had a positive double-stranded DNA, positive SSA and SSB antibodies. She was diagnosed with Systemic Lupus erythematosus (SLE) and Sjogren's syndrome and was started on mycophenalate mofetil. Of relevance was a visit to her local emergency room 4 years earlier with profound weakness with unexplained marked hypokalemia and a non-anion gap metabolic acidosis. Approximately one year after that episode she developed flank pain and nephrocalcinosis. She had multiple issues over the ensuing years with stones and infections on both sides. Interventions included extracorporeal shockwave lithotripsy as well as open lithotomy and eventual auto-transplantation of left kidney for recurrent ureteric stenosis. 24 h stone profile revealed marked hypocitraturia, normal urine calcium, normal urine oxalate and uric acid. She was treated with potassium citrate. Mycophenolate was eventually stopped due to recurrent urinary tract infections and she was started on Belimumab. Because of recurrent SLE flares, treatment was changed to Rituximab (every 6 months) with clinical and serologic improvement. Her kidney stone frequency gradually improved and no further interventions needed although she continued to require citrate repletion for hypocitraturia. Conclusions Nephrolithiasis can be a prominent and even presenting feature in Sjogrens syndrome as well as other rheumatologic diseases. Prompt recognition and understanding disease mechanisms is important for best therapeutic interventions for kidney stone prevention as well as treatment of underlying bone mineral disease.

IntroductionT Cell autoantibodies, TIgG and TIgM, as well as the T Cell-bound complement protein fragment C4d (TC4d) are novel diagnostic biomarkers that have demonstrated high specificity and sensitivity for SLE. The present study aims to characterize the clinical performance characteristics of the emergent T Cell biomarkers in a multi-center clinical validation cohort.MethodsA cohort of 400 adult patients enrolled across 3 academic and 2 community-based autoimmune rheumatic centers, comprised of 105 SLE patients, 173 patients with autoimmune rheumatic diseases (ARD), 83 apparently healthy volunteers (AHV) and 39 other (non-autoimmune) disease (OD) controls were tested for TC4d, TIgG, TIgM and an extensive autoantibody profile. Diagnostic specificity was assessed against the ARD, AHV and OD groups, individually. Semi-quantitative flow cytometry analysis included TIgG and TIgM autoantibodies, cell-bound complement activation products (CB-CAPs), TC4d, erythrocyte-bound C4d (EC4d) and B lymphocyte-bound C4d (BC4d). Conventional autoantibodies and soluble complement proteins, C3 and C4, were assessed by ELISA and immunoturbidimetry, respectively.ResultsROC analysis distinguishing ANA-positive (ANA+) SLE (N = 91) from ARD, TIgG, BC4d and TC4d demonstrated AUC values 0.81, 0.80 and 0.79, respectively, outperforming anti-dsDNA (0.72), C3 (0.69), TIgM (0.67), C4 (0.66) and anti-Smith (0.61). A similar ranking of discriminatory power was observed in ROC analysis distinguishing ANA+ SLE vs. OD as well as ANA+ SLE vs. AHV. At 95% diagnostic specificity for SLE vs. AHV, the sensitivity (95% CI) of TC4d, TIgG and TIgM for SLE was 58.1% (48.1 – 67.7%), 31.4% (22.7 – 41.2%) and 29.5% (21.0 – 39.2%), respectively. The T Cell SLE biomarkers uniquely identified 19% (20/105) of SLE patients who were otherwise negative (serologically inactive) for conventional SLE autoantibodies and had normal serum complement levels. Among the serologically inactive SLE subset, the T Cell SLE biomarkers collectively identified 53% of subjects.ConclusionsThe novel SLE biomarkers TC4d, TIgG and TIgM consistently outperform conventional markers across multiple cohorts. Their integration enhances diagnostic sensitivity, especially in SLE-specific autoantibody negative patients with normal complement levels. When coupled with conventional biomarkers, these novel tests may enable earlier and more accurate SLE detection, leading to more timely diagnosis and treatment.

Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.

There is concern that exogenous female hormones may worsen disease activity in women with systemic lupus erythematosus (SLE). To evaluate the effect of hormone replacement therapy (HRT) on disease activity in postmenopausal women with SLE. Randomized, double-blind, placebo-controlled noninferiority trial conducted from March 1996 to June 2002. 16 university-affiliated rheumatology clinics or practices in 11 U.S. states. 351 menopausal patients (mean age, 50 years) with inactive (81.5%) or stable-active (18.5%) SLE. 12 months of treatment with active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up rate was 82% for the HRT group and 87% for the placebo group. The primary end point was occurrence of a severe flare as defined by Safety of Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus Erythematosus Disease Activity Index composite. Severe flare was rare in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT group and 0.049 for the placebo group, yielding an estimated difference of 0.033 (P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference was 0.078, within the prespecified margin of 9% for noninferiority. Mild to moderate flares were significantly increased in the HRT group: 1.14 flares/person-year for HRT and 0.86 flare/person-year for placebo (relative risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was 0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1 case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient developed deep venous thrombosis. Findings are not generalizable to women with high-titer anticardiolipin antibodies, lupus anticoagulant, or previous thrombosis. Adding a short course of HRT is associated with a small risk for increasing the natural flare rate of lupus. Most of these flares are mild to moderate. The benefits of HRT can be balanced against the risk for flare because HRT did not significantly increase the risk for severe flare compared with placebo.

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. Recent studies have greatly expanded the number of established SLE risk alleles, but the distribution of multiple risk alleles in cases versus controls and their relationship to subphenotypes have not been studied. We studied 22 SLE susceptibility polymorphisms with previous genome-wide evidence of association (p < 5 x 10⁻¹²⁸) in 1919 SLE cases from 9 independent Caucasian SLE case series and 4813 independent controls. The mean number of risk alleles in cases was 15.1 (SD 3.1) while the mean in controls was 13.1 (SD 2.8), with trend p = 4 x 10⁻⁸. We defined a genetic risk score (GRS) for SLE as the number of risk alleles with each weighted by the SLE risk odds ratio (OR). The OR for high-low GRS tertiles, adjusted for intra-European ancestry, sex, and parent study, was 4.4 (95% CI 3.8-5.1). We studied associations of individual SNPs and the GRS with clinical manifestations for the cases: age at diagnosis, the 11 American College of Rheumatology classification criteria, and double-stranded DNA antibody (anti-dsDNA) production. Six subphenotypes were significantly associated with the GRS, most notably anti-dsDNA (OR(high-low) = 2.36, p = 9e-9), the immunologic criterion (OR(high-low) = 2.23, p = 3e-7), and age at diagnosis (OR(high-low) = 1.45, p = 0.0060). Finally, we developed a subphenotype-specific GRS (sub-GRS) for each phenotype with more power to detect cumulative genetic associations. The sub-GRS was more strongly associated than any single SNP effect for 5 subphenotypes (the above plus hematologic disorder and oral ulcers), while single loci are more significantly associated with renal disease (HLA-DRB1, OR = 1.37, 95% CI 1.14-1.64) and arthritis (ITGAM, OR = 0.72, 95% CI 0.59-0.88). We did not observe significant associations for other subphenotypes, for individual loci or the sub-GRS. Thus our analysis categorizes SLE subphenotypes into three groups: those having cumulative, single, and no known genetic association with respect to the currently established SLE risk loci.

Lupus is a complex disease that is often difficult to diagnose. Risks of diagnostic delays include non-specific signs and symptoms that mimic other diseases and a lack of diagnostic criteria and referral pathways for non-specialists. To address these issues, we convened a series of virtual meetings with members of our Addressing Lupus Pillars for Health Advancement clinical care team. Meeting participants included lupus physicians, treatment developers from biotechnology, patient advocacy group representatives from the Lupus Foundation of America and advocacy/government consultants. Causes and consequences of ambiguity in diagnosis and diagnostic delays were evaluated through historical, experiential and evidence-based accounts (survey data, literature reviews and patient testimonials). Discussions highlighted the need for a clearer understanding of the definition of lupus, the natural history of the disease and the need for advancements in biotechnology to support an accurate and timely diagnosis with the potential development of a lupus spectrum.

BackgroundNeuropsychiatric (NP) disease is more common in patients with systemic lupus erythematosus (SLE) than in the general population.1 Increased incidence of NP events (depression and suicidality) has been reported with biologic therapies, including SLE therapies.2 Depression and suicidality were evaluated in patients with SLE treated with anifrolumab, a type I interferon receptor antibody, in the TULIP-1 and TULIP-2 trials.3,4 This analysis aims to understand the impact of anifrolumab treatment on NP manifestations (depression and suicidality) in patients with SLE relative to standard therapy using pooled data from the TULIP trials.MethodsTULIP-1/-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab every 4 weeks in patients with moderate to severe SLE despite standard therapy.3,4Patients with active severe or unstable NP SLE were excluded. Patients who received ≥1 dose of anifrolumab 300 mg or placebo were analyzed for depression and suicidality .3,4 The Personal Health Questionnaire Depression Scale-8 (PHQ-8) and Columbia Suicide Severity Rating Scale (C-SSRS) were used to assess clinical depression and suicidal ideation and behavior, respectively. Incidence of adverse events (AEs) within the standardized Medical Dictionary for Regulatory Activities query of depression (excluding suicide and self-injury) and antidepressant use at baseline and during the study were also assessed.ResultsIn the TULIP pooled analysis, 360 patients received anifrolumab and 365 received placebo. Mean PHQ-8 scores were in the mild range (≥5 to <10); 9.7 in both groups at baseline (table 1). Excluding patients taking antidepressants, mean PHQ-8 scores were 9.5 in the anifrolumab group and 9.7 in the placebo group at baseline. No clinically meaningful worsening in mean PHQ-8 scores was observed from baseline to Week 52 in the anifrolumab (–2.0) or placebo (–1.3) groups; excluding patients taking antidepressants, mean changes in PHQ-8 were –2.0 and –1.2, respectively. Depression AEs during the study were reported in 11 anifrolumab-treated patients (3.1%) and 9 patients who received placebo (2.5%). At baseline, antidepressant use was comparable between groups (anifrolumab group, 7 patients [1.9%]; placebo group, 9 patients [2.5%]). During the study, 8 anifrolumab-treated patients (2.2%) and 12 patients who received placebo (3.3%) used antidepressants; 1 (0.3%) and 4 (1.1%) patients, respectively, initiated antidepressant therapy during the study (1 in the placebo group stopped therapy). Suicidal ideation or behavior, as assessed by C-SSRS, during the study was reported in 5 anifrolumab- treated patients (1.4%) and 11 patients who received placebo (3.0%). Excluding patients taking antidepressants, suicidal ideation or behavior during the study was reported in 4 anifrolumab-treated patients (1.1%) and 9 patients who received placebo (2.5%) (figure 1).ConclusionsPatients with SLE treated with anifrolumab did not experience increased depression, suicidality, or need for antidepressants when compared with standard therapy, irrespective of baseline antidepressant use.ReferencesZhang L, et al. BMC Psychiatry. 2017;17:70.Benlysta (belimumab) [prescribing information]. Philadelphia, PA: GlaxoSmithKline; 2021.Furie RA, et al. Lancet Rheumatol. 2019;1:e208–19.Morand EF, et al. N Engl J Med. 2020;382:211–21.Abstract 607 Table 1PHQ-8 summary All patients Excluding patients taking antidepressants Anifrolumab 300 mg N=360 Placebo N=365 Anifrolumab 300 mg N=360 Placebo N=365 n Meana SD Changeb n Meana SD Changeb n Meana SD Changeb n Meana SD Changeb Baseline 341 9.7 6.26 – 348 9.7 6.11 – 335 9.5 6.21 – 338 9.7 6.09 – Week 24 295 7.6 5.89 –2.1 303 8.0 6.00 –1.5 289 7.5 5.84 –2.1 293 8.1 6.00 –1.5 Week 52 266 7.8 5.99 –2.0 261 7.9 6.03 –1.3 262 7.7 6.00 –2.0 252 7.9 5.96 –1.2 SD, standard deviation. aPHQ-8 classifications: 0–4 = none, 5–9 = mild, 10–14 = moderate, 15–19 = moderately severe, and 20–24 = severe. bMean change from baseline.Abstract 607 Figure 1C-SSRS summary, excluding patients taking antidepressants. aPercentages are based upon all patients included in the analysis within the respective pool and treatment group.AcknowledgementsWriting assistance by Andrea Y. Angstadt, PhD (Fishawack Health). This study was sponsored by AstraZeneca.Submission deadlineAugust 1, 2022 at 11:59 PM ESTDisclosures SM has received speaker fees from AstraZeneca; received consulting fees from AstraZeneca, Exagen Diagnostics, Inc, Cugene, GSK, Lilly, Lupus Foundation of America, and UCB Advisory Board; received grant support from HGS/GSK, AstraZeneca, and AbbVie. CL, IH, MS, and GA are employees of AstraZeneca. LZ, SW and RT are employees and shareholders of AstraZeneca.

Inflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG). Furthermore, we compared complement activation product deposition patterns in rare aorta adventitial and medial biopsies from SLE, RA and non-IRD patients. We examined plasma C3 (p-C3) and terminal complement complexes (p-TCC) in 28 IRDCAD (SLE = 3; RA = 25), 52 non-IRDCAD patients, and 32 IRDNo CAD (RA = 32) from the Feiring Heart Biopsy Study. Aortic biopsies taken from the CAD only patients during CABG were previously evaluated for adventitial MCIs. The rare aortic biopsies from 3 SLE, 3 RA and 3 non-IRDCAD were assessed for the presence of C3 and C3d using immunohistochemistry. IRDCAD patients had higher p-TCC than non-IRDCAD or IRDNo CAD patients (p<0.0001), but a similar p-C3 level (p = 0.42). Circulating C3 was associated with IRD duration (ρ, p-value: 0.46, 0.03). In multiple logistic regression analysis, IRD remained significantly related to the presence and size of MCI (p<0.05). C3 was present in all tissue samples. C3d was detected in the media of all patients and only in the adventitia of IRD patients (diffuse in all SLE and focal in one RA). The independent association of IRD status with MCI and the observed C3d deposition supports the unique relationship between rheumatic disease, and, in particular, SLE with the complement system. Exaggerated systemic and vascular complement activation may accelerate CVD, serve as a CVD biomarker, and represent a target for new therapies.

Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region genotyped in 4 independent SLE case series (total n = 1398) and 2560 healthy controls, along with clinical data for the cases. Using conditional testing, we confirmed the most significant STAT4 haplotype for SLE risk. We then studied a SNP marking this haplotype for association with specific SLE subphenotypes, including autoantibody production, nephritis, arthritis, mucocutaneous manifestations, and age at diagnosis. To prevent possible type-I errors from population stratification, we reanalyzed the data using a subset of subjects determined to be most homogeneous based on principal components analysis of genome-wide data. We confirmed that four SNPs in very high LD (r(2) = 0.94 to 0.99) were most strongly associated with SLE, and there was no compelling evidence for additional SLE risk loci in the STAT4 region. SNP rs7574865 marking this haplotype had a minor allele frequency (MAF) = 31.1% in SLE cases compared with 22.5% in controls (OR = 1.56, p = 10(-16)). This SNP was more strongly associated with SLE characterized by double-stranded DNA autoantibodies (MAF = 35.1%, OR = 1.86, p<10(-19)), nephritis (MAF = 34.3%, OR = 1.80, p<10(-11)), and age at diagnosis<30 years (MAF = 33.8%, OR = 1.77, p<10(-13)). An association with severe nephritis was even more striking (MAF = 39.2%, OR = 2.35, p<10(-4) in the homogeneous subset of subjects). In contrast, STAT4 was less strongly associated with oral ulcers, a manifestation associated with milder disease. We conclude that this common polymorphism of STAT4 contributes to the phenotypic heterogeneity of SLE, predisposing specifically to more severe disease.