Publications by authors named "Joan T Merrill"

226 Publications

Tissue factor upregulation is associated with SARS-CoV-2 in the lungs of COVID-19 patients.

J Thromb Haemost 2021 Jul 8. Epub 2021 Jul 8.

Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation (OMRF), Oklahoma City, Oklahoma, USA.

Background: A substantial proportion of patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe/critical coronavirus disease 2019 (COVID-19) characterized by acute respiratory distress syndrome (ARDS) with thrombosis.

Objectives: We tested the hypothesis that SARS-CoV-2--induced upregulation of tissue factor (TF) expression may be responsible for thrombus formation in COVID-19.

Methods: We compared autopsy lung tissues from 11 patients with COVID-19--associated ARDS with samples from 6 patients with ARDS from other causes (non-COVID-19 ARDS) and 11 normal control lungs.

Results: Dual RNA in situ hybridization for SARS-CoV-2 and TF identified sporadic clustered SARS-CoV-2 with prominent co-localization of SARS-CoV-2 and TF RNA. TF expression was 2-fold higher in COVID-19 than in non-COVID-19 ARDS lungs (P = .017) and correlated with the intensity of SARS-CoV-2 staining (R  = .36, P = .04). By immunofluorescence, TF protein expression was 2.1-fold higher in COVID-19 versus non-COVID-19 ARDS lungs (P = .0048) and 11-fold (P < .001) higher than control lungs. Fibrin thrombi and thrombi positive for platelet factor 4 (PF4) were found in close proximity to regions expressing TF in COVID-19 ARDS lung, and correlated with TF expression (fibrin, R  = .52, P < .001; PF4, R  = .59, P < .001).

Conclusions: These data suggest that upregulation of TF expression is associated with thrombus formation in COVID-19 lungs and could be a key therapeutic target. Correlation of TF expression with SARS-CoV-2 in lungs of COVID-19 patients also raises the possibility of direct TF induction by the virus.
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http://dx.doi.org/10.1111/jth.15451DOI Listing
July 2021

Immune Response to  in Lupus Patients Is Associated With a Subset of Lupus-Associated Autoantibodies.

Front Immunol 2021 28;12:635072. Epub 2021 May 28.

Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.

Interactions between gut microbes and the immune system influence autoimmune disorders like systemic lupus erythematosus (SLE). Recently, , a gram-positive commensal gut bacterium, was implicated as a candidate pathobiont in SLE. The present study was undertaken to evaluate the influence of exposure on clinical parameters of SLE. Since circulating IgG antibodies to whole bacteria have been established as a surrogate marker for bacterial exposure, anti- IgG antibodies were measured in banked serum samples from SLE patients and healthy controls in the Oklahoma Cohort for Rheumatic Diseases. The associations between anti- antibody titers and clinical indicators of lupus were studied. Antibodies to human RNA were studied in a subset of patients. Our results show that sera from both patients and healthy controls had IgG and IgA antibodies reactive with . The antibody titers between the two groups were not different. However, SLE patients with Ribosomal P autoantibodies had higher anti- IgG titers compared to healthy controls. In addition to anti-Ribosomal P, higher anti- titers were also significantly associated with the presence of anti-dsDNA and anti-Sm autoantibodies. In the subset of patients with anti-Ribosomal P and anti-dsDNA, the anti- titers correlated significantly with antibodies to human RNA. Our data show that both healthy individuals and SLE patients were sero-reactive to In SLE patients, the immune response to was associated with antibody response to a specific subset of lupus autoantigens. These findings provide additional evidence that may be a pathobiont for SLE in susceptible individuals.
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http://dx.doi.org/10.3389/fimmu.2021.635072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193979PMC
May 2021

Neuropsychiatric Events in Systemic Lupus Erythematosus.

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Copenhagen Lupus and Vasculitis Clinic, 4242, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: To determine predictors for change in neuropsychiatric (NP) event status in a large, prospective, international, inception cohort of SLE patients METHODS: Upon enrollment and annually thereafter, NP events attributed to SLE and non-SLE causes and physician determined resolution were documented. Factors potentially associated with onset and resolution of NP events were determined by time-to-event analysis using a multistate modelling structure.

Results: NP events occurred in 955/1,827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. For SLE NP events multivariate analysis revealed positive associations with male sex, concurrent non-SLE NP events excluding headache, active SLE and corticosteroids. There was a negative association with Asian race/ethnicity, post-secondary education, and immunosuppressive or anti-malarial drugs. For non-SLE NP events, excluding headache, there was a positive association with concurrent SLE NP events and negative associations with African and Asian race/ethnicity. NP events attributed to SLE had a higher resolution rate than non-SLE NP events, with the exception of headache that had comparable resolution rates. For SLE NP events, multivariate analysis revealed resolution was more common with Asian race/ethnicity and for central/focal NP events. For non-SLE NP events resolution was more common with African race/ethnicity and less common with older age at SLE diagnosis.

Conclusions: In a large and long-term study of the occurrence and resolution of NP events in SLE we identified subgroups with better and worse prognosis. The course of NP events differs greatly depending on their nature and attribution.
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http://dx.doi.org/10.1002/art.41876DOI Listing
May 2021

What Did Not Work: The Drug or the Trial?

Authors:
Joan T Merrill

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Oklahoma Medical Research Foundation, 825 NE 13th St., Oklahoma City, OK, 73104, USA.

In this issue of Arthritis & Rheumatology, the paper by Isenberg et al, entitled Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor, Fenebrutinib (GDC-0853), in Systemic Lupus Erythematosus reports results of a Phase 2 trial of fenebrutinib, an inhibitor of Bruton's tyrosine kinase (BTK). This treatment met expected pharmacodynamic targets, decreasing phosphorylated BTK, dampening plasmablast signals, and lowering anti-dsDNA and IgG. No concerning safety signal was observed.
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http://dx.doi.org/10.1002/art.41810DOI Listing
May 2021

Anifrolumab reduces flare rates in patients with moderate to severe systemic lupus erythematosus.

Lupus 2021 Jul 12;30(8):1254-1263. Epub 2021 May 12.

BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.

Background: Systemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab's effect on flares, including those arising with glucocorticoid taper.

Methods: TULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). For patients receiving baseline glucocorticoid ≥10 mg/day, attempted taper to ≤7.5 mg/day prednisone or equivalent from Weeks 8-40 was required and defined as sustained reduction when maintained through Week 52. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores versus the previous visit. Flare assessments were compared for patients receiving anifrolumab versus placebo.

Results: Compared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates (rate ratio 0.75, 95% confidence interval [CI] 0.60-0.95), prolonged time to first flare (hazard ratio 0.70, 95% CI 0.55-0.89), and fewer patients with ≥1 flare (difference -9.3%, 95% CI -16.3 to -2.3), as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had ≥1 flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from ≥10 mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185).

Conclusions: Analyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE.TULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912);TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).
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http://dx.doi.org/10.1177/09612033211014267DOI Listing
July 2021

SARS-CoV-2 vaccines in patients with SLE.

Lupus Sci Med 2021 03;8(1)

Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation Arthritis and Clinical Immunology Research Program, Oklahoma City, Oklahoma, USA.

As the Moderna (mRNA-1273) and Pfizer/BioNTech (BNT162b2) vaccines become available to patients with autoimmune diseases and SLE, practitioners will have to inform them about the safety and efficacy of these vaccines. Here we discuss the challenges of applying vaccine data to patients with autoimmune diseases and the evidence available in the literature that may help in the decision process.
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http://dx.doi.org/10.1136/lupus-2021-000479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941677PMC
March 2021

Safety and clinical activity of atacicept in the long-term extension of the Phase IIb ADDRESS II study in systemic lupus erythematosus.

Rheumatology (Oxford) 2021 Feb 6. Epub 2021 Feb 6.

Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Objectives: Atacicept reduced SLE disease activity in the Phase IIb ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II.

Methods: In the 24-week, randomised, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary end point. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares.

Results: 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4-93.2%). 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo.

Conclusion: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy.

Clinical Trial Registration Number: NCT02070978.
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http://dx.doi.org/10.1093/rheumatology/keab115DOI Listing
February 2021

Commentary: Systematic Review of Safety and Efficacy of Atacicept in Treating Immune-Mediated Disorders.

Front Immunol 2020 11;11:592639. Epub 2020 Nov 11.

Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States.

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http://dx.doi.org/10.3389/fimmu.2020.592639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687657PMC
May 2021

Prediction of hospitalizations in systemic lupus erythematosus using the Systemic Lupus International Collaborating Clinics Frailty Index (SLICC-FI).

Arthritis Care Res (Hoboken) 2020 Nov 5. Epub 2020 Nov 5.

Emory University School of Medicine, Division of Rheumatology, Atlanta, Georgia, USA.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) predicts mortality and damage accrual in SLE, but its association with hospitalizations has not been described. We estimated the association of baseline SLICC-FI values with future hospitalizations in the SLICC inception cohort.

Methods: Baseline SLICC-FI scores were calculated. The number and duration of inpatient hospitalizations during follow-up were recorded. Negative binomial regression was used to estimate the association between baseline SLICC-FI values and the rate of hospitalizations per patient-year of follow-up. Linear regression was used to estimate the association of baseline SLICC-FI scores with the proportion of follow-up time spent in hospital. Multivariable models were adjusted for relevant baseline characteristics.

Results: The 1549 SLE patients eligible for this analysis were mostly female (88.7%) with mean (SD) age 35.7 (13.3) years and median (IQR) disease duration 1.2 (0.9-1.5) years at baseline. Mean (SD) baseline SLICC-FI was 0.17 (0.08). During mean (SD) follow-up of 7.2 (3.7) years, 614 patients (39.6%) experienced 1570 hospitalizations. Higher baseline SLICC-FI values (per 0.05 increment) were associated with more frequent hospitalizations during follow-up (Incidence Rate Ratio 1.21; 95%CI 1.13-1.30), adjusting for baseline age, sex, corticosteroid use, immunosuppressive use, ethnicity/location, SLE disease activity index 2000 (SLEDAI-2K), SLICC/ACR damage index (SDI), and disease duration. Among patients with ≥1 hospitalization, higher baseline SLICC-FI values predicted a greater proportion of follow-up time spent hospitalized (Relative Rate 1.09; 95%CI 1.02-1.16).

Conclusion: The SLICC-FI predicts future hospitalizations among incident SLE patients, further supporting the SLICC-FI as a valid health measure in SLE.
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http://dx.doi.org/10.1002/acr.24504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096857PMC
November 2020

Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies.

Arthritis Care Res (Hoboken) 2020 Oct 7. Epub 2020 Oct 7.

Division of Rheumatology, Inflammation and Immunity, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Non-white people are more likely to develop systemic lupus erythematosus (SLE), yet are underrepresented in SLE clinical trials. The efficacy and safety of drugs may be influenced by ancestry, and ancestrally diverse study populations are necessary to optimize treatments across the full spectrum of patients. However, barriers to entry into clinical trials are amplified in non-white populations. To address these issues, a conference was held in Bethesda, Maryland from October 15 -16 , 2019 entitled "Increasing Ancestral Diversity in Systemic Lupus Erythematosus Clinical Studies: Overcoming the Barriers." Participants included people with lupus, lupus physicians, lupus clinical trialists, treatment developers from biotechnology, social scientists, patient advocacy groups, and United States government representatives (the Office of Minority Health, Centers for Disease Control and Prevention, National Institutes of Health, and the Food and Drug Administration). For all of these groups, the organizers purposefully included people of non-white ancestry. Decreased participation of non-white SLE patients in clinical research was evaluated through historical, societal, experiential, and pragmatic perspectives, and several interventional programs to increase non-white patient participation in SLE and non-SLE research were described and discussed. The presentations and discussions highlighted the need for changes at the societal, institutional, research team, referring physician, and patient education levels to achieve equitable ancestral representation in SLE clinical studies.
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http://dx.doi.org/10.1002/acr.24474DOI Listing
October 2020

Cancer risk in a large inception SLE cohort: Effects of demographics, smoking, and medications.

Arthritis Care Res (Hoboken) 2020 Aug 19. Epub 2020 Aug 19.

Department of Rheumatology, Center for Rheumatology Research Fossvogur, Landspitali University Hospital, Reykjavik, Iceland.

Objective: To assess cancer risk factors in incident SLE.

Methods: Clinical variables and cancer outcomes were assessed annually among incident SLE patients. Multivariate hazard regression models (over-all risk, and most common cancers) included demographics and time-dependent medications (corticosteroids, antimalarial drugs, immunosuppressants), smoking, and adjusted mean SLE Disease Activity Index-2K.

Results: Among 1668 patients (average 9 years follow-up), 65 cancers occurred: 15 breast, 10 non-melanoma skin, seven lung, six hematological, six prostate, five melanoma, three cervical, three renal, two each gastric, head and neck, and thyroid, and one each rectal, sarcoma, thymoma, and uterine cancers. Half of cancers (including all lung cancers) occurred in past/current smokers, versus one-third of patients without cancer. Multivariate analyses indicated over-all cancer risk was related primarily to male sex and older age at SLE diagnosis. In addition, smoking was associated with lung cancer. For breast cancer risk, age was positively and anti-malarial drugs were negatively associated. Anti-malarial drugs and higher disease activity were also negatively associated with non-melanoma skin cancer (NMSC) risk, whereas age and cyclophosphamide were positively associated. Disease activity was associated positively with hematologic and negatively with NMSC risk.

Conclusions: Smoking is a key modifiable risk factor, especially for lung cancer, in SLE. Immunosuppressive medications were not clearly associated with higher risk except for cyclophosphamide and NMSC. Antimalarials were negatively associated with breast cancer and NMSC risk. SLE activity was associated positively with hematologic cancer and negatively with NMSC. Since the absolute number of cancers was small, additional follow-up will help consolidate these findings.
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http://dx.doi.org/10.1002/acr.24425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892637PMC
August 2020

Emerging evidence of a COVID-19 thrombotic syndrome has treatment implications.

Nat Rev Rheumatol 2020 10 30;16(10):581-589. Epub 2020 Jul 30.

Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Reports of widespread thromboses and disseminated intravascular coagulation (DIC) in patients with coronavirus disease 19 (COVID-19) have been rapidly increasing in number. Key features of this disorder include a lack of bleeding risk, only mildly low platelet counts, elevated plasma fibrinogen levels, and detection of both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and complement components in regions of thrombotic microangiopathy (TMA). This disorder is not typical DIC. Rather, it might be more similar to complement-mediated TMA syndromes, which are well known to rheumatologists who care for patients with severe systemic lupus erythematosus or catastrophic antiphospholipid syndrome. This perspective has critical implications for treatment. Anticoagulation and antiviral agents are standard treatments for DIC but are gravely insufficient for any of the TMA disorders that involve disorders of complement. Mediators of TMA syndromes overlap with those released in cytokine storm, suggesting close connections between ineffective immune responses to SARS-CoV-2, severe pneumonia and life-threatening microangiopathy.
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http://dx.doi.org/10.1038/s41584-020-0474-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391481PMC
October 2020

Evaluating change in disease activity needed to reflect meaningful improvement in quality of life for clinical trials in cutaneous lupus erythematosus.

J Am Acad Dermatol 2021 Jun 16;84(6):1562-1567. Epub 2020 Jul 16.

Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pennsylvania; Department of Dermatology, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background: Outcome measures of clinical trials in cutaneous lupus erythematosus (CLE) should reflect clinically meaningful improvement in disease activity, as measured by the Cutaneous Lupus Disease Area and Severity Index activity score (CLASI-A).

Objective: We aimed to define the degree of improvement in disease activity meaningful to a patient's quality of life.

Methods: The change in the CLASI-A in 126 patients needed to predict meaningful change in QoL, as defined by the Emotions and Symptoms subscales of the Skindex-29, was evaluated by linear regression models.

Results: In patients with an initial CLASI-A of ≥8, a 42.1% or ≥7-point and a 31.0% or ≥5-point decrease in CLASI-A predicts meaningful improvement in the Emotions and the Symptoms subscales, respectively.

Limitations: This is a retrospective study of prospectively collected data at a single site.

Conclusions: A CLASI-A score of ≥8 for trial entry allows for inclusion of patients with milder disease where CLASI-A improvement by ≥50% is clinically significant and meaningful.
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http://dx.doi.org/10.1016/j.jaad.2020.07.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106875PMC
June 2021

Accrual of Atherosclerotic Vascular Events in a Multicenter Inception Systemic Lupus Erythematosus Cohort.

Arthritis Rheumatol 2020 10 25;72(10):1734-1740. Epub 2020 Aug 25.

Hairmyres Hospital, East Kilbride, Scotland, UK.

Objective: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE.

Methods: A large 33-center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient-years, and univariable and multivariable relative risk regression models.

Results: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow-up visit after enrollment, for a total of 13,666 patient-years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32-0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55-10.30]) and a body mass index of >40 kg/m (HR 2.74 [95% CI 1.04-7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17-9.27], P < 0.001).

Conclusion: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.
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http://dx.doi.org/10.1002/art.41392DOI Listing
October 2020

Autoantibody-positive healthy individuals with lower lupus risk display a unique immune endotype.

J Allergy Clin Immunol 2020 12 22;146(6):1419-1433. Epub 2020 May 22.

Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Okla; Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Okla; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Okla. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jaci.2020.04.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680268PMC
December 2020

Comparison of the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology Systemic Lupus Erythematosus Classification Criteria With Two Sets of Earlier Systemic Lupus Erythematosus Classification Criteria.

Arthritis Care Res (Hoboken) 2020 May 20. Epub 2020 May 20.

Kantonsspital, Schaffhausen, Switzerland.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) 2012 systemic lupus erythematosus (SLE) classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria and compared its performance to the revised ACR 1997, the unweighted SLICC 2012, and the newly reported European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria sets.

Methods: The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were reemployed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules.

Results: The weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis.

Conclusion: The 2 new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a data set originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived and whether the goal is to prioritize sensitivity or specificity.
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http://dx.doi.org/10.1002/acr.24263DOI Listing
May 2020

Lupus patient decisions about clinical trial participation: a qualitative evaluation of perceptions, facilitators and barriers.

Lupus Sci Med 2020 15;7(1):e000360. Epub 2020 Mar 15.

College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Objective: Although 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.

Methods: A 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.

Results: Patients 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.

Conclusions: Knowledge 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.
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http://dx.doi.org/10.1136/lupus-2019-000360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073780PMC
May 2021

Low frequency of flares during pregnancy and post-partum in stable lupus patients.

Arthritis Res Ther 2020 03 19;22(1):52. Epub 2020 Mar 19.

Hospital for Special Surgery, 535 E 70th Street, New York, NY, 10021, USA.

Background: Lupus patients are at risk for pregnancy loss, and it has been generally accepted that women with SLE should have low disease activity prior to conception. However, there are conflicting results regarding the effect of pregnancy on SLE flares. This study aims to identify predictors of flares during and after pregnancy in SLE patients with inactive or stable disease activity during the first trimester and to characterize and estimate the frequency of post-partum flares in these patients.

Methods: SLE patients in the multicenter, prospective PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study were evaluated for flares during and after pregnancy using the SELENA-SLEDAI Flare Index. Flares during pregnancy were assessed in all 384 patients and post-partum flares in 234 patients with study visits 2-6 months post-partum. Logistic regression models were fit to the data to identify independent risk factors for flare.

Results: During pregnancy, 20.8% of patients had mild/moderate flares and 6.25% had severe. Post-partum, 27.7% of patients had mild/moderate flares and 1.7% had severe. The mild flares rarely required treatment. Younger age, low C4 and higher PGA at baseline were independently associated with higher risk of having at least one mild/moderate or severe flare during pregnancy. Older patients were at decreased risk of flare, as well as those with quiescent disease at baseline. No variables evaluated at baseline or the visit most proximal to delivery was significantly associated with risk of flare post-partum. Medications were not associated with flare during or after pregnancy.

Conclusion: In patients with inactive or stable mild disease activity at the time of conception, lupus disease flares during and after pregnancy are typically mild and occur at similar rates. Flares during pregnancy are predicted by the patients' age and clinical and serological activity at baseline.
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http://dx.doi.org/10.1186/s13075-020-2139-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081564PMC
March 2020

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study.

EClinicalMedicine 2020 Mar 4;20:100291. Epub 2020 Mar 4.

Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.

Background: The clinical and pathologic diversity of systemic lupus erythematosus (SLE) hinders diagnosis, management, and treatment development. This study addresses heterogeneity in SLE through comprehensive molecular phenotyping and machine learning clustering.

Methods: Adult SLE patients ( = 198) provided plasma, serum, and RNA. Disease activity was scored by modified SELENA-SLEDAI. Twenty-nine co-expression module scores were calculated from microarray gene-expression data. Plasma soluble mediators ( = 23) and autoantibodies ( = 13) were assessed by multiplex bead-based assays and ELISAs. Patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators.

Findings: SLEDAI scores correlated with interferon, plasma cell, and select cell cycle modules, and with circulating IFN-α, IP10, and IL-1α levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. Monocyte, neutrophil, plasmablast, B cell, and T cell modules distinguished the remaining clusters. Active clinical features were similar across clusters. Clinical SLEDAI trended highest in Clusters 3 and 4, though Cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in Cluster 4, and rare in Clusters 2, 5, and 7. Serology findings were lowest in Clusters 2 and 5. Musculoskeletal and mucocutaneous activity were common in all clusters.

Interpretation: Molecular profiles distinguish SLE subsets that are not apparent from clinical information. Prospective longitudinal studies of these profiles may help improve prognostic evaluation, clinical trial design, and precision medicine approaches.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/j.eclinm.2020.100291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058913PMC
March 2020

Attainment of treat-to-target endpoints in SLE patients with high disease activity in the atacicept phase 2b ADDRESS II study.

Rheumatology (Oxford) 2020 10;59(10):2930-2938

Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.

Objective: Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients.

Methods: Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician's Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response.

Results: Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095].

Conclusion: At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE.

Trail Registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.
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http://dx.doi.org/10.1093/rheumatology/keaa029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516108PMC
October 2020

Scoring systemic lupus erythematosus (SLE) disease activity with simple, rapid outcome measures.

Lupus Sci Med 2019 30;6(1):e000365. Epub 2019 Dec 30.

Department of Rheumatology, Columbia University, New York City, New York, USA.

Objective: Existing 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.

Methods: We 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.

Results: Fifty 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 p<0.0001). Changes (∆) in SSPGA and LFA-REAL compared with screening correlated with each other (r=0.857) and with changes in SLEDAI and BILAG (∆SSPGA: r=0.678 (∆SLEDAI), r=0.624 (∆BILAG); ∆LFA-REAL: r=0.686 (∆SLEDAI) and 0.700 (∆BILAG); all p<0.0001). Changes in SSPGA and LFA-REAL strongly correlated with SRI-4 and BICLA by receiver operating characteristic analysis (p<0.0001 for all). Additionally, LFA-REAL correlated to individual BILAG organ scores (musculoskeletal: r=0.842, mucocutaneous: r=0.826 (p<0.0001 for both)).

Conclusion: SSPGA 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 Number: NCT02270957.
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http://dx.doi.org/10.1136/lupus-2019-000365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937422PMC
December 2019

Neuropsychiatric events in systemic lupus erythematosus: a longitudinal analysis of outcomes in an international inception cohort using a multistate model approach.

Ann Rheum Dis 2020 03 8;79(3):356-362. Epub 2020 Jan 8.

Copenhagen Lupus and Vasculitis Clinic, 4242, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients.

Methods: Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states.

Results: NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001).

Conclusions: NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.
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http://dx.doi.org/10.1136/annrheumdis-2019-216150DOI Listing
March 2020

Author Correction: Immunologic findings precede rapid lupus flare after transient steroid therapy.

Sci Rep 2019 Nov 20;9(1):17514. Epub 2019 Nov 20.

Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-54275-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863844PMC
November 2019

SLE clinical trials: impact of missing data on estimating treatment effects.

Lupus Sci Med 2019 3;6(1):e000348. Epub 2019 Oct 3.

Medicine, Division of Rheumatology, New York University School of Medicine, New York City, New York, USA.

Objective: A common problem in clinical trials is missing data due to participant dropout and loss to follow-up, an issue which continues to receive considerable attention in the clinical research community. Our objective was to examine and compare current and alternative methods for handling missing data in SLE trials with a particular focus on multiple imputation, a flexible technique that has been applied in different disease settings but not to address missing data in the primary outcome of an SLE trial.

Methods: Data on 279 patients with SLE randomised to standard of care (SoC) and also receiving mycophenolate mofetil (MMF), azathioprine or methotrexate were obtained from the Lupus Foundation of America-Collective Data Analysis Initiative Database. Complete case analysis (CC), last observation carried forward (LOCF), non-responder imputation (NRI) and multiple imputation (MI) were applied to handle missing data in an analysis to assess differences in SLE Responder Index-5 (SRI-5) response rates at 52 weeks between patients on SoC treated with MMF versus other immunosuppressants (non-MMF).

Results: The rates of missing data were 32% in the MMF and 23% in the non-MMF groups. As expected, the NRI missing data approach yielded the lowest estimated response rates. The smallest and least significant estimates of differences between groups were observed with LOCF, and precision was lowest with the CC method. Estimated between-group differences were magnified with the MI approach, and imputing SRI-5 directly versus deriving SRI-5 after separately imputing its individual components yielded similar results.

Conclusion: The potential advantages of applying MI to address missing data in an SLE trial include reduced bias when estimating treatment effects, and measures of precision that properly reflect uncertainty in the imputations. However, results can vary depending on the imputation model used, and the underlying assumptions should be plausible. Sensitivity analysis should be conducted to demonstrate robustness of results, especially when missing data proportions are high.
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http://dx.doi.org/10.1136/lupus-2019-000348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784820PMC
October 2019

Prediction of Damage Accrual in Systemic Lupus Erythematosus Using the Systemic Lupus International Collaborating Clinics Frailty Index.

Arthritis Rheumatol 2020 04 12;72(4):658-666. Epub 2020 Feb 12.

Emory University School of Medicine, Atlanta, Georgia.

Objective: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC FI values with damage accrual in the SLICC inception cohort.

Methods: The baseline visit was defined as the first visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short Form 36) were assessed. Baseline SLICC FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression was used to estimate the association between baseline SLICC FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics.

Results: The 1,549 systemic lupus erythematosus (SLE) patients eligible for this analysis were mostly female (88.7%) with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5 years) at baseline. The mean ± SD baseline SLICC FI was 0.17 ± 0.08. Over a mean ± SD follow-up of 7.2 ± 3.7 years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC FI values (per 0.05 increase) were associated with higher rates of increase in the SDI during follow-up (incidence rate ratio [IRR] 1.19 [95% confidence interval 1.13-1.25]), after adjusting for age, sex, ethnicity/region, education, baseline SLE Disease Activity Index 2000, baseline SDI, and baseline use of glucocorticoids, antimalarials, and immunosuppressive agents.

Conclusion: Our findings indicate that the SLICC FI predicts damage accrual in incident SLE, which further supports the SLICC FI as a valid health measure in SLE.
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http://dx.doi.org/10.1002/art.41144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113092PMC
April 2020

Soluble urokinase plasminogen activator receptor (suPAR) levels predict damage accrual in patients with recent-onset systemic lupus erythematosus.

J Autoimmun 2020 01 17;106:102340. Epub 2019 Oct 17.

Department of Clinical Sciences Lund, Section of Rheumatology, Lund University, Lund, Sweden.

Objective: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE.

Methods: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI).

Results: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007).

Conclusion: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.
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http://dx.doi.org/10.1016/j.jaut.2019.102340DOI Listing
January 2020

Economic Evaluation of Damage Accrual in an International Systemic Lupus Erythematosus Inception Cohort Using a Multistate Model Approach.

Arthritis Care Res (Hoboken) 2020 12;72(12):1800-1808

Hairmyres Hospital, East Kilbride, Scotland, UK.

Objective: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling.

Methods: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model.

Results: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0.

Conclusion: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.
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http://dx.doi.org/10.1002/acr.24092DOI Listing
December 2020

Peripheral Nervous System Disease in Systemic Lupus Erythematosus: Results From an International Inception Cohort Study.

Arthritis Rheumatol 2020 01 28;72(1):67-77. Epub 2019 Nov 28.

Amsterdam University Medical Centers, Amsterdam, The Netherlands.

Objective: To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients.

Methods: Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate.

Results: Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow-up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF-36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy.

Conclusion: PNS disease is an important component of total NPSLE and has a significant negative impact on health-related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution.
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http://dx.doi.org/10.1002/art.41070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935421PMC
January 2020

Immunologic findings precede rapid lupus flare after transient steroid therapy.

Sci Rep 2019 06 13;9(1):8590. Epub 2019 Jun 13.

Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 73104, USA.

Systemic lupus erythematosus (SLE) flares elicit progressive organ damage, leading to disability and early mortality. This study evaluated clinical and immunologic factors associated with impending flare in the Biomarkers of Lupus Disease study. Autoantibodies and 32 soluble mediators were measured by multiplex assays, immune pathway activation by gene expression module scores, and immune cell subset frequencies and activation states by flow cytometry. After providing baseline samples, participants received transient steroids to suppress disease and were followed until flare. Flare occurred early (within 60 days of baseline) in 21 participants and late (90-165 days) in 13. At baseline, compared to the late flare group, the early flare group had differential gene expression in monocyte, T cell, interferon, and inflammation modules, as well as significantly higher frequencies of activated (aCD11b) neutrophils and monocytes, and activated (CD86) naïve B cells. Random forest models showed three subgroups of early flare patients, distinguished by greater baseline frequencies of aCD11b monocytes, or CD86 naïve B cells, or both. Increases in these cell populations were the most accurate biomarkers for early flare in this study. These results suggest that SLE flares may arise from an overlapping spectrum of lymphoid and myeloid mechanisms in different patients.
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http://dx.doi.org/10.1038/s41598-019-45135-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6565690PMC
June 2019

Development and content validity of the Lupus Foundation of America rapid evaluation of activity in lupus (LFA-REAL™): a patient-reported outcome measure for lupus disease activity.

Health Qual Life Outcomes 2019 Jun 7;17(1):99. Epub 2019 Jun 7.

Department of Clinical Pharmacology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK, 73104, USA.

Background/purpose: The LFA REAL™ is a measurement system for evaluating lupus disease activity from both clinician and patient perspectives. Patients' viewpoints are captured using a patient-reported outcome (PRO) questionnaire. A series of visual analog scales are designed to rate disease severity and progress over the past 4 weeks. Brief instructions guide the patient to distinguish between active, potentially reversible symptoms and chronic pain or discomfort that are more likely due to damage. Beyond its simplicity and efficiency, the PRO can provide versatile assessments from a global, organ-based, and symptom-specific level. This paper describes the patient-centered approach used to evaluate the content validity of the LFA-REAL PRO.

Methods: The PRO was developed in accordance with FDA guidance. A two-phase qualitative study was performed with 25 lupus patients, 10 who participated in concept elicitation (Phase 1) and 15 in cognitive debriefing interviews (Phase 2). Qualitative data were analyzed using ATLAS.ti software v7.5. Upon completion of the interviews, participants completed the draft PRO and additional measures to characterize the sample.

Results: The mean age of participants was 45.6 and 88% were female, as expected in a lupus population. The mean SF-36 physical component score was 29.8 and the mean mental component score was 46.4. Phase 1 elicited symptom saturation and mapping of the draft PRO. Fatigue was reported by 100% of patients, highlighting its importance as a measurable domain. Additionally, 100% of patients spontaneously mentioned arthritis, which may be more important to this group than previously estimated, substantiating the approach of this PRO to break down components of arthritis into joint pain, stiffness, and swelling. Shortness of breath and fever were reported more frequently than expected. Phase 2 data demonstrated that participants found the instrument easy to use and offered recommendations to improve clarity, leading to adjustments in wording and formatting.

Conclusions: Results suggest that the LFA-REAL PRO has content validity and, with some modifications suggested by participants, is ready for quantitative validation, including tests of reliability, validity, responsiveness to change, and performance relative to other PROs used in lupus trials. After validation, the LFA-REAL system is intended for use in clinical practice and research.
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http://dx.doi.org/10.1186/s12955-019-1151-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555910PMC
June 2019