Publications by authors named "Michelle Petri"

424 Publications

Reply to "More steps forward to optimize the dosing of hydroxychloroquine".

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.

First, regarding "triple positivity" (meaning positive for lupus anticoagulant, anticardiolipin and anti-beta 2 glycoprotein). In our cohort we have not found "triple positivity" to be that useful in predicting thrombotic events. For one thing, we have observed that lupus anticoagulant fluctuates over time in SLE, but even when intermittently positive, is still a risk factor for thrombosis (1). Furthermore, we have shown that anticardiolipin does not add to the thrombotic risk in SLE (2) over and above lupus anticoagulant.
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http://dx.doi.org/10.1002/art.41880DOI Listing
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

Anti-beta 2 glycoprotein I IgA in the SLICC classification criteria dataset.

Lupus 2021 May 6:9612033211014248. Epub 2021 May 6.

Amsterdam University Medical Centres, University of Amsterdam, Amsterdam, Netherlands.

Objective: Anti-beta 2 glycoprotein I IgA is a common isotype of anti-beta 2 glycoprotein I in SLE. Anti-beta 2 glycoprotein I was not included in the American College of Rheumatology (ACR) SLE classification criteria, but was included in the Systemic Lupus International Collaborating Clinics (SLICC) criteria. We aimed to evaluate the prevalence of anti-beta 2-glycoprotein I IgA in SLE versus other rheumatic diseases. In addition, we examined the association between anti-beta 2 glycoprotein I IgA and disease manifestations in SLE.

Methods: The dataset consisted of 1384 patients, 657 with a consensus physician diagnosis of SLE and 727 controls with other rheumatic diseases. Anti-beta 2 glycoprotein I isotypes were measured by ELISA. Patients with a consensus diagnosis of SLE were compared to controls with respect to presence of anti-beta 2 glycoprotein I. Among patients with SLE, we assessed the association between anti-beta 2 glycoprotein I IgA and clinical manifestations.

Results: The prevalence of anti-beta 2 glycoprotein I IgA was 14% in SLE patients and 7% in rheumatic disease controls (odds ratio, OR 2.3, 95% CI: 1.6, 3.3). It was more common in SLE patients who were younger patients and of African descent (p = 0.019). Eleven percent of SLE patients had anti-beta 2 glycoprotein I IgA alone (no anti-beta 2 glycoprotein I IgG or IgM). There was a significant association between anti-beta 2 glycoprotein I IgA and anti-dsDNA (p = 0.001) and the other antiphospholipid antibodies (p = 0.0004). There was no significant correlation of anti-beta 2 glycoprotein I IgA with any of the other ACR or SLICC clinical criteria for SLE. Those with anti-beta 2 glycoprotein I IgA tended to have a history of thrombosis (12% vs 6%, p = 0.071), but the difference was not statistically significant.

Conclusion: We found the anti-beta 2 glycoprotein I IgA isotype to be more common in patients with SLE and in particular, with African descent. It could occur alone without other isotypes.
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http://dx.doi.org/10.1177/09612033211014248DOI Listing
May 2021

Risk Factors For Infection And Health Impacts Of The Covid-19 Pandemic In People With Autoimmune Diseases.

Clin Infect Dis 2021 May 6. Epub 2021 May 6.

Department of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: People with autoimmune or inflammatory conditions taking immunomodulatory/suppressive medications may have higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Methods: We included participants with autoimmune or inflammatory conditions followed by specialists at Johns Hopkins. Participants completed periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare. We assessed whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterized pandemic-associated changes to care and mental health.

Results: 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medications) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were associated with higher odds of COVID-19. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions therein, which disproportionately affected individuals experiencing changes to employment or income.

Conclusions: Glucocorticoid exposure may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1093/cid/ciab407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135997PMC
May 2021

Transcription Factor Activity Inference in Systemic Lupus Erythematosus.

Life (Basel) 2021 Apr 1;11(4). Epub 2021 Apr 1.

Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, 18016 Granada, Spain.

Background: Systemic Lupus Erythematosus (SLE) is a systemic autoimmune disease with diverse clinical manifestations. Although most of the SLE-associated loci are located in regulatory regions, there is a lack of global information about transcription factor (TFs) activities, the mode of regulation of the TFs, or the cell or sample-specific regulatory circuits. The aim of this work is to decipher TFs implicated in SLE.

Methods: In order to decipher regulatory mechanisms in SLE, we have inferred TF activities from transcriptomic data for almost all human TFs, defined clusters of SLE patients based on the estimated TF activities and analyzed the differential activity patterns among SLE and healthy samples in two different cohorts. The Transcription Factor activity matrix was used to stratify SLE patients and define sets of TFs with statistically significant differential activity among the disease and control samples.

Results: TF activities were able to identify two main subgroups of patients characterized by distinct neutrophil-to-lymphocyte ratio (NLR), with consistent patterns in two independent datasets-one from pediatric patients and other from adults. Furthermore, after contrasting all subgroups of patients and controls, we obtained a significant and robust list of 14 TFs implicated in the dysregulation of SLE by different mechanisms and pathways. Among them, well-known regulators of SLE, such as STAT or IRF, were found, but others suggest new pathways that might have important roles in SLE.

Conclusions: These results provide a foundation to comprehend the regulatory mechanism underlying SLE and the established regulatory factors behind SLE heterogeneity that could be potential therapeutic targets.
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http://dx.doi.org/10.3390/life11040299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065841PMC
April 2021

Impact of systemic lupus erythematosus disease activity, hydroxychloroquine and NSAID on the risk of subsequent organ system damage and death: analysis in a single US medical centre.

Lupus Sci Med 2021 04;8(1)

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Objective: To assess the impact of mild-moderate systemic lupus erythematosus (SLE) disease activity during a 12-month period on the risk of death or subsequent organ system damage.

Methods: 1168 patients with ≥24 months of follow-up from the Hopkins Lupus Cohort were included. Disease activity in a 12-month observation period was calculated using adjusted mean Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI), defined as the area under the curve divided by the time interval. Damage accrual in the follow-up period was defined as change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score ≥1 among patients without prior damage. Patients visited the clinic quarterly and had SELENA-SLEDAI and SDI assessed at every visit.

Results: During follow-up (median 7 years), 39% of patients accrued new damage in any organ system (7% cardiovascular and 3% renal) and 8% died. In adjusted models, an increased SELENA-SLEDAI score increased the risk of death (HR=1.22, 95% CI 1.13 to 1.32, p<0.001), renal damage (HR=1.24, 95% CI 1.08 to 1.42, p=0.003) and cardiovascular damage (HR=1.17, 95% CI 1.07 to 1.29, p<0.001). Hydroxychloroquine use reduced the risk of death (HR=0.46, 95% CI 0.29 to 0.72, p<0.05) and renal damage (HR=0.30, 95% CI 0.13 to 0.68, p<0.05). Non-steroidal anti-inflammatory drug use increased the risk of cardiovascular damage (HR=1.66, 95% CI 1.04 to 2.63, p<0.05). Without prior damage, an increased adjusted mean SELENA-SLEDAI score increased the risk of overall damage accrual (HR=1.09, 95% CI 1.04 to 1.15, p<0.001).

Conclusions: Each one-unit increase in adjusted mean SELENA-SLEDAI during a 12-month observation period was associated with an increased risk of death and developing cardiovascular and renal damage.
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http://dx.doi.org/10.1136/lupus-2020-000446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039259PMC
April 2021

Systemic lupus Erythematosus and geomagnetic disturbances: a time series analysis.

Environ Health 2021 Mar 16;20(1):28. Epub 2021 Mar 16.

Division of Rheumatology, Johns Hopkins University School of Medicine, 1830 East Monument Street Suite 7500, Baltimore, MD, 21205, USA.

Background: To examine the influence of solar cycle and geomagnetic effects on SLE disease activity.

Methods: The data used for the analysis consisted of 327 observations of 27-day Physician Global Assessment (PGA) averages from January 1996 to February 2020. The considered geomagnetic indices were the AP index (a daily average level for geomagnetic activity), sunspot number index R (measure of the area of solar surface covered by spots), the F10.7 index (measure of the noise level generated by the sun at a wavelength of 10.7 cm at the earth's orbit), the AU index (upper auroral electrojet index), and high energy (> 60 Mev) proton flux events. Geomagnetic data were obtained from the Goddard Space Flight Center Space Physics Data Facility. A time series decomposition of the PGA averages was performed as the first step. The linear relationships between the PGA and the geomagnetic indices were examined using parametric statistical methods such as Pearson correlation and linear regression, while the nonlinear relationships were examined using nonparametric statistical methods such as Spearman's rho and Kernel regression.

Results: After time series deconstruction of PGA averages, the seasonality explained a significant fraction of the variance of the time series (R = 38.7%) with one cycle completed every 16 years. The analysis of the short-term (27-day) relationships indicated that increases in geomagnetic activity Ap index (p < 0.1) and high energy proton fluxes (> 60 Mev) (p < 0.05) were associated with decreases in SLE disease activity, while increases in the sunspot number index R anticipated decreases in the SLE disease activity expressed as PGA (p < 0.05). The short-term correlations became statistically insignificant after adjusting for multiple comparisons using Bonferroni correction. The analysis of the long-term (297 day) relationships indicated stronger negative association between changes in the PGA and changes in the sunspot number index R (p < 0.01), AP index (p < 0.01), and the F10.7 index (p < 0.01). The long-term correlations remained statistically significant after adjusting for multiple comparisons using Bonferroni correction.

Conclusion: The seasonality of the PGA averages (one cycle every 16 years) explains a significant fraction of the variance of the time series. Geomagnetic disturbances, including the level of geomagnetic activity, sunspot numbers, and high proton flux events may influence SLE disease activity. Studies of other geographic locales are needed to validate these findings.
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http://dx.doi.org/10.1186/s12940-021-00692-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962208PMC
March 2021

Association of systemic lupus erythematosus autoantibody diversity with breast cancer protection.

Arthritis Res Ther 2021 02 25;23(1):64. Epub 2021 Feb 25.

Division of Rheumatology, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Building Center Tower, Suite 4100, Baltimore, MD, 21224, USA.

Background: Epidemiologic data suggest that patients with systemic lupus erythematosus (SLE) have a lower risk of breast cancer than women in the general population. In light of mechanistic studies suggesting that anti-DNA antibodies have anti-cancer effects, we sought to examine breast cancer risk in autoantibody strata in a well-characterized SLE cohort.

Methods: SLE patients without a cancer diagnosis prior to entry in the Hopkins Lupus Cohort were studied (N = 2431). Overall and site-specific cancer incidence was calculated in racial strata and compared with the US Surveillance, Epidemiology and End Results (SEER) registry. Breast cancer incidence was further examined in autoantibody subsets. Patients were considered positive for an autoantibody if they were ever positive for a specificity during their disease course.

Results: Patients with SLE had a 37% lower risk of breast cancer (SIR 0.63, 95% CI 0.39-0.95). The risk of HPV-associated cancers (SIR 4.39, 95% CI 2.87-6.44) and thyroid cancer (SIR 2.27, 95% CI 1.04-4.30) was increased. Cancer risk varied by race, with breast cancer protection occurring in non-African Americans (SIR 0.29, 95% CI 0.11-0.63) and the increased risk of HPV-associated cancers occurring in African Americans (SIR 7.23, 95% CI 4.35-11.3). Breast cancer risk was decreased in patients ever positive for anti-dsDNA (SIR 0.55, 95% CI 0.29-0.96), anti-La (SIR 0.00, 95% CI 0.00-0.78), and lupus anticoagulant (SIR 0.37, 95% CI 0.10-0.94). Patients who were positive for fewer (0-2) SLE autoantibodies did not have a lower risk of breast cancer (SIR 0.84, 95% CI 0.47-1.39), but patients with 3+ autoantibodies had a 59% decreased risk (SIR 0.41, 95% CI 0.16-0.84).

Conclusions: Positivity for multiple SLE autoantibodies was associated with a lower risk of breast cancer, supporting the hypothesis that a highly diversified immune response may exert an anti-cancer effect against some cancers. Validation of racial differences in cancer risk in SLE is required to determine whether cancer screening strategies should be targeted to racial subgroups.
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http://dx.doi.org/10.1186/s13075-021-02449-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905617PMC
February 2021

Sub-Setting Systemic Lupus Erythematosus by Combined Molecular Phenotypes Defines Divergent Populations in Two Phase III Randomized Trials.

Rheumatology (Oxford) 2021 Feb 12. Epub 2021 Feb 12.

Lilly Biotechnology Center, 10290 Campus Point Drive, San Diego CA, 92121, USA.

Objectives: Heterogeneity of systemic lupus erythematosus (SLE) patients in clinical trials remains a challenge for developing new therapies. This study used a combinatorial analysis of four molecular biomarkers to define key sources of heterogeneity.

Methods: Combinations of IFN(high/low), anti-dsDNA(+/-), C3 and C4(low/normal) were used to subset n = 1747 patients from two randomized phase 3 trials. A dichotomous classification scheme defined SLE(+) as: IFNhigh, anti-dsDNA(+), C3(low) and/or C4(low). SLE(-) required all of the following: IFNlow, anti-dsDNA(-), C3(normal) and C4(normal). Additional analyses subset the data further by IFN, anti-dsDNA and complement.

Results: The trials enrolled n = 2262 patients of which n = 1747 patients had data for IFN, anti-dsDNA, C3 and C4 at baseline. There were n = 247 patients in the SLE(-) population and n = 1500 patients in the SLE(+) population. The SLE(-) population had more mucocutaneous and musculoskeletal disease at baseline, while SLE(+) had more hematologic, renal and vascular involvement. There was lower concomitant medication use in the SLE(-) population for corticosteroids and immunosuppressants, except for methotrexate. Time to severe flare was significantly longer in SLE(-) vs SLE(+) (p < 0.0001) and SRI-4 response rate was significantly lower in SLE(-) vs SLE(+) (p = 0.00016). The United States had more SLE(-) patients (22%) than Mexico/Central America/South America (10%), Europe (7%) and the rest of the world (5%).

Conclusion: Combinatorial analysis of 4 molecular biomarkers revealed subsets of SLE patients that discriminated by disease manifestations, concomitant medication use, geography, time to severe flare and SRI-4 response. These data may be useful for designing clinical trials and identifying subsets of patients for analysis.
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http://dx.doi.org/10.1093/rheumatology/keab144DOI Listing
February 2021

RISK FACTORS FOR INFECTION AND HEALTH IMPACTS OF THE COVID-19 PANDEMIC IN PEOPLE WITH AUTOIMMUNE DISEASES.

medRxiv 2021 Feb 5. Epub 2021 Feb 5.

Department of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: People with autoimmune or inflammatory conditions who take immunomodulatory/suppressive medications may have a higher risk of novel coronavirus disease 2019 (COVID-19). Chronic disease care has also changed for many patients, with uncertain downstream consequences.

Objective: Assess whether COVID-19 risk is higher among those on immunomodulating or suppressive agents and characterize pandemic-associated changes to care.

Design: Longitudinal registry study.

Participants: 4666 individuals with autoimmune or inflammatory conditions followed by specialists in neurology, rheumatology, cardiology, pulmonology or gastroenterology at Johns Hopkins.

Measurements: Periodic surveys querying comorbidities, disease-modifying medications, exposures, COVID-19 testing and outcomes, social behaviors, and disruptions to healthcare.

Results: A total of 265 (5.6%) developed COVID-19 over 9 months of follow-up (April-December 2020). Patient characteristics (age, race, comorbidity, medication exposure) were associated with differences in social distancing behaviors during the pandemic. Glucocorticoid exposure was associated with higher odds of COVID-19 in multivariable models incorporating behavior and other potential confounders (OR: 1.43; 95%CI: 1.08, 1.89). Other medication classes were not associated with COVID-19 risk. Diabetes (OR: 1.72; 95%CI: 1.08, 2.73), cardiovascular disease (OR: 1.68; 95%CI: 1.24, 2.28), and chronic kidney disease (OR: 1.76; 95%CI: 1.04, 2.97) were each associated with higher odds of COVID-19. Pandemic-related disruption to care was common. Of the 2156 reporting pre-pandemic utilization of infusion, mental health or rehabilitative services, 975 (45.2%) reported disruptions. Individuals experiencing changes to employment or income were at highest odds of care disruption.

Limitations: Results may not be generalizable to all patients with autoimmune or inflammatory conditions. Information was self-reported.

Conclusions: Exposure to glucocorticoids may increase risk of COVID-19 in people with autoimmune or inflammatory conditions. Disruption to healthcare and related services was common. Those with pandemic-related reduced income may be most vulnerable to care disruptions.
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http://dx.doi.org/10.1101/2021.02.03.21251069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872366PMC
February 2021

Lower vitamin D is associated with metabolic syndrome and insulin resistance in systemic lupus: data from an international inception cohort.

Rheumatology (Oxford) 2021 Feb 8. Epub 2021 Feb 8.

Department of Rheumatology, Kantonsspital Schaffhausen, Schaffhausen, Schaffhausen, CH.

Objectives: Vitamin D (25(OH)D) deficiency and metabolic syndrome (MetS) may both contribute to increased cardiovascular risk in systemic lupus erythematosus (SLE). We aimed to examine the association of demographic factors, SLE phenotype, therapy and vitamin D levels with MetS and insulin resistance.

Methods: The Systemic Lupus International Collaborating Clinics (SLICC) enrolled patients recently diagnosed with SLE (<15 months) from 33 centres across 11 countries from 2000. Clinical, laboratory and therapeutic data were collected. Vitamin D level was defined according to tertiles based on distribution across this cohort, which were set at T1 (10-36 nmol/l), T2 (37-60 nmol/l) and T3 (61-174 nmol/l). MetS was defined according to the 2009 consensus statement from the International Diabetes Federation. Insulin resistance was determined using the HOMA-IR model. Linear and logistic regressions were used to assess the association of variables with vitamin D levels.

Results: Of the 1847 patients, 1163 (63%) had vitamin D measured and 398 (34.2%) subjects were in the lowest 25(OH)D tertile. MetS was present in 286 of 860 (33%) patients whose status could be determined. Patients with lower 25(OH)D were more likely to have MetS and higher HOMA-IR. The MetS components, hypertension, hypertriglyceridemia and decreased HDL were all significantly associated with lower 25(OH)D. Increased average glucocorticoid exposure was associated with higher insulin resistance.

Conclusions: MetS and insulin resistance are associated with lower vitamin D in patients with SLE. Further studies could determine whether vitamin D repletion confers better control of these cardiovascular risk factors and improve long-term outcomes in SLE.
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http://dx.doi.org/10.1093/rheumatology/keab090DOI Listing
February 2021

Intracellular homocysteine metabolites in SLE: plasma S-adenosylhomocysteine correlates with coronary plaque burden.

Lupus Sci Med 2021 01;8(1)

Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background And Aims: We hypothesised that intracellular homocysteine and homocysteine metabolite levels in patients with SLE are disproportionately elevated compared with the levels seen in healthy subjects and that they are independently associated with coronary plaque in SLE.

Methods: A liquid chromatography-tandem mass spectrometry absolute quantification assay was used for the determination of six analytes in both plasma and peripheral blood mononuclear cells (PBMCs): homocysteine (Hcy), S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), methionine (Met), cystathionine (Cysta) and 5-methyltetrahydrofolate (5m-THF). We then compared intracellular (PBMC) and extracellular (plasma) Hcy and Hcy metabolite (SAM, SAH, Met, Cysta and 5m-THF) concentrations in 10 patients with SLE and in 10 age, sex and ethnicity matched controls. Subjects with a history of diabetes mellitus, cardiovascular disease, hypertension, alcohol consumption in excess of 3 units per day, anaemia, renal insufficiency (serum creatinine >1.5 mg/dL) and pregnancy were excluded. All patients with SLE had two coronary CT angiography studies as screening for occult coronary atherosclerotic disease.

Results: Plasma from patients with SLE had higher levels of Hcy (p<0.0001), SAH (p<0.05), SAM (p<0.001) and lower levels of Met (p<0.05) and Cysta (p<0.001) compared with controls. PBMC intracellular concentrations from patients with SLE had higher levels of Cysta (p<0.05), SAH (p<0.05), SAM (p<0.001) and lower levels of 5m-THF (p<0.001). Plasma SAH showed a positive correlation with total coronary plaque, calcified plaque and non-calcified plaque (p<0.05).

Conclusion: Intracellular concentrations of Hcy metabolites were significantly different between patients with SLE and controls, despite similar intracellular Hcy levels. Plasma SAH was positively correlated with total coronary plaque, calcified plaque and non-calcified plaque.
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http://dx.doi.org/10.1136/lupus-2020-000453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825256PMC
January 2021

Association of Higher Hydroxychloroquine Blood Levels With Reduced Thrombosis Risk in Systemic Lupus Erythematosus.

Arthritis Rheumatol 2021 Jun 2;73(6):997-1004. Epub 2021 May 2.

Johns Hopkins University School of Medicine, Baltimore, Maryland.

Objective: Hydroxychloroquine (HCQ) has a primary role in the prophylaxis and treatment of systemic lupus erythematosus (SLE) and may be protective against thrombosis in SLE. Optimal weight-based dosing of HCQ is unknown. This study was undertaken to examine the usefulness of HCQ blood monitoring in predicting thrombosis risk in a longitudinal SLE cohort.

Methods: HCQ levels were serially quantified from EDTA whole blood by liquid chromatography-tandem mass spectrometry. The mean HCQ blood levels calculated prior to thrombosis or until the last visit were compared using t-tests between patients with and those without thrombosis. Pooled logistic regression was used to analyze the association between rates of thrombosis and HCQ blood level. Rate ratios (RRs) and 95% confidence intervals (95% CIs) were calculated.

Results: In 739 patients with SLE, thrombosis occurred in 38 patients (5.1%). The mean ± SD HCQ blood level was lower in patients who developed thrombosis versus those who did not develop thrombosis (720 ± 489 ng/ml versus 935 ± 580 ng/ml; P = 0.025). Thrombosis rates were reduced by 13% for every 200-ng/ml increase in the most recent HCQ blood level (RR 0.87 [95% CI 0.78-0.98], P = 0.025) and by 13% for mean HCQ blood level (RR 0.87 [95% CI 0.76-1.00], P = 0.056). Thrombotic events were reduced by 69% in patients with mean HCQ blood levels ≥1,068 ng/ml versus those with levels <648 ng/ml (RR 0.31 [95% CI 0.11-0.86], P = 0.024). This remained significant after adjustment for confounders (RR 0.34 [95% CI 0.12-0.94], P = 0.037).

Conclusion: Low HCQ blood levels are associated with thrombotic events in SLE. Longitudinal measurement of HCQ levels may allow for personalized HCQ dosing strategies. Recommendations for empirical dose reduction may reduce or eliminate the benefits of HCQ in this high-risk population.
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http://dx.doi.org/10.1002/art.41621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169526PMC
June 2021

Predictors of osteonecrosis in systemic lupus erythematosus: A prospective cohort study.

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

Division of Rheumatology, Johns Hopkins University School of Medicine, USA.

Objectives: We determined the predictors of osteonecrosis in a longitudinal lupus cohort, emphasizing the role of maximal prednisone dose and duration.

Methods: Data from 2428 patients were included in the analysis based on 224295 person-months of follow-up. We used pooled logistic regression to assess the relationship between risk factors and rates of osteonecrosis. After identifying a set of variables related to osteonecrosis incidence, we fit a final multivariable model to identify the most important risk factors for incident osteonecrosis.

Results: In 18691 person-years of follow up after cohort entry, 122 incident osteonecrosis event were observed. In the multivariable analysis, African-Americans had twice the risk of osteonecrosis compared to Caucasians. Males and smokers had 80% and 50% increased risk of osteonecrosis compared to females and non-smokers, respectively. For every 10 year increase in the age of diagnosis, there was a 20% reduced risk of osteonecrosis. Patients diagnosed after the 1990's had a 50% reduced risk of osteonecrosis compared to those diagnosed before the 1990's. A daily dose of prednisone of 20-39 mg or higher, when administered for more than a month, or a daily prednisone dose of 40 mg or higher, even when administered for one month, significantly increased the risk of osteonecrosis. Use of pulse methylprednisolone or intramuscular triamcinolone was not associated with an increased risk of osteonecrosis.

Conclusions: Oral prednisone at 20-39 mg for more than one month, or 40 mg daily for even one month remained the most important corticosteroid predictor of osteonecrosis.
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http://dx.doi.org/10.1002/acr.24541DOI Listing
December 2020

Antiphospholipid Patterns Predict Risk of Thrombosis in Systemic Lupus Erythematosus.

Rheumatology (Oxford) 2020 Dec 17. Epub 2020 Dec 17.

Department of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective: We evaluated which antiphospholipid antibody combinations increase the risk of future thrombosis in patients with SLE.

Methods: This prospective cohort study consisted of SLE patients who had been tested for all seven antiphospholipid antibodies [lupus anticoagulant (LAC), anticardiolipin (aCL) isotypes IgM, IgG, IgA, and anti-β2-glycoprotein I isotypes IgM, IgG, IgA]. Pooled logistic regression was used to assess the relationship between antiphospholipid antibodies and thrombosis.

Results: There were 821 SLE patients with a total of 75048 person-months of follow up. During the follow-up we observed 88 incident cases of thrombosis: 48 patients with arterial, 37 with venous and three with both arterial and venous thrombosis. In individual models; LAC was the most predictive of any [3.56 (2.01, 6.30) p < 0.0001], venous [4.89 (2.25, 10.64) p < 0.0001], and arterial [3.14 (1.41, 6.97) p = 0.005] thrombosis. Anti-β2-glycoprotein I IgA positivity was a significant risk factor for any [2.00 (1.22, 3.3) p = 0.0065] and venous [2.8 (1.42, 5.51) p = 0.0029] thrombosis. Only anti-β2-glycoprotein I IgA appeared to add significant risk to any [1.73 (1.04, 2.88) p = 0.0362], and venous [2.27 (1.13, 4.59) p = 0.0218] thrombosis among those with LAC. We created an interaction model with four categories based on combinations of LAC and other antiphospholipid antibodies to look at the relationships between combinations and the risk of thrombosis. In this model LAC remained the best predictor of thrombosis.

Conclusion: 'Our study demonstrated that in SLE, LAC remained the best predictor of thrombosis and adding additional antiphospholipid antibodies did not add to the risk, with the exception anti-β2-glycoprotein I IgA.'
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http://dx.doi.org/10.1093/rheumatology/keaa857DOI Listing
December 2020

Antiphospholipid Antibody Profile Stability Over Time: Prospective Results From the APS ACTION Clinical Database and Repository.

J Rheumatol 2020 Sep 1. Epub 2020 Sep 1.

The APS ACTION registry was created using REDCAP provided by the Clinical and Translational Science Center at Weill Cornell Medical College (CTSC grant UL1 TR000457). For this work, EG was supported by Clinical and Translational Science Center at Weill Cornell Medicine (UL1 TR002384). E. Gkrouzman, MD, MS, Hospital for Special Surgery, New York, New York, USA; E. Sevim, MD, Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York, New York, USA; J. Finik, MPH, Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, New York, USA; D. Andrade, MD, PhD, University of São Paulo, São Paulo, Brazil; V. Pengo, MD, University Hospital Padova, Padova, Italy; S. Sciascia, MD, PhD, Center of Research of Immunopathology and Rare Diseases, University of Turin, Turin, Italy; M.G. Tektonidou, MD, PhD, National and Kapodistrian University of Athens, Athens, Greece; A. Ugarte, MD, Hospital Universitario Cruces, Barakaldo, País Vasco, Spain; C.B. Chighizola, MD, PhD, Clinical Immunology & Rheumatology Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy; H.M. Belmont, MD, Hospital for Joint Diseases, New York University, New York, New York, USA; C. Lopez-Pedrera, PhD, Rheumatology Service, IMIBIC/Reina Sofia Hospital, University of Cordoba, Cordoba, Spain; L. Ji, MD, Rheumatology and Immunology Department, Peking University First Hospital, Beijing, China; P. Fortin, MD, CHU de Québec-Université Laval, Québec City, Québec, Canada; M. Efthymiou, PhD, H. Cohen, MD, Haemostasis Research Unit, Department of Haematology, University College London, London, UK; G. Ramires de Jesus, MD, MSc, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil; D.W. Branch, MD, University of Utah and Intermountain Healthcare, Salt Lake City, Utah, USA; C. Nalli, MD, Rheumatology and Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy; M. Petri, MD, MPH, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; E. Rodriguez, MD, Hospital Universitario 12 de Octubre, Madrid, Spain; R. Cervera, MD, PhD, FRCP, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain; J.S. Knight, MD, PhD, Division of Rheumatology, University of Michigan, Ann Arbor, Michigan, USA; T. Atsumi, MD, PhD, Hokkaido University Hospital, Sapporo, Japan; R. Willis, MD, Antiphospholipid Standardization Laboratory, University of Texas Medical Branch, Galveston, Texas, USA; M.L. Bertolaccini, PhD, Academic Department of Vascular Surgery, King's College London British Heart Foundation Centre of Excellence, School of Cardiovascular Medicine & Sciences, London, UK; J. Rand, MD, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York, USA; D. Erkan, MD, MPH, Barbara Volcker Center for Women and Rheumatic Diseases, Hospital for Special Surgery, Weill Cornell Medicine, New York, New York, USA. MP (Hopkins Lupus Cohort) is supported by a grant from the NIH RO1 AR069572. PF is recipient of a tier 1 Canada Research Chair on Systemic Autoimmune Rheumatic Diseases. MLB is supported by the King's British Heart Foundation Centre for Research Excellence Award RE/18/2/34213. The rest of the authors report no conflicts of interest. Address correspondence to Dr. E. Gkrouzman, 535 East 70th Street, New York, NY 10021, USA. Email: Accepted for publication August 18, 2020.

Objective: The APS ACTION Registry studies long-term outcomes in persistently antiphospholipid antibody (aPL)-positive patients. Our primary objective was to determine whether clinically meaningful aPL profiles at baseline remain stable over time. Our secondary objectives were to determine (1) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and (2) predictors of unstable aPL profiles over time.

Methods: A clinically meaningful aPL profile was defined as positive lupus anticoagulant (LAC) test and/or anticardiolipin (aCL)/anti-β glycoprotein-I (anti-β-GPI) IgG/M ≥ 40 U. Stable aPL profile was defined as a clinically meaningful aPL profile in at least two-thirds of follow-up measurements. Generalized linear mixed models with logit link were used for primary objective analysis.

Results: Of 472 patients with clinically meaningful aPL profile at baseline (median follow-up 5.1 yrs), 366/472 (78%) patients had stable aPL profiles over time, 54 (11%) unstable, and 52 (11%) inconclusive. Time did not significantly affect odds of maintaining a clinically meaningful aPL profile at follow-up in univariate ( = 0.906) and multivariable analysis ( = 0.790). Baseline triple aPL positivity decreased (OR 0.25, 95% CI 0.10-0.64, = 0.004) and isolated LAC test positivity increased (OR 3.3, 95% CI 1.53-7.13, = 0.002) the odds of an unstable aPL profile over time.

Conclusion: Approximately 80% of our international cohort patients with clinically meaningful aPL profiles at baseline remain stable at a median follow-up of 5 years; triple aPL-positivity increase the odds of a stable aPL profile. These results will guide future validation studies of stored blood samples through APS ACTION Core Laboratories.
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http://dx.doi.org/10.3899/jrheum.200513DOI Listing
September 2020

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

Evaluation of different ways to identify persistent positivity of lupus anticoagulant in systemic lupus erythematosus.

Lupus Sci Med 2020 11;7(1)

School of Medicine, Department of Epidemiology and Preventive Medicine, University of Maryland, Baltimore, Maryland, USA.

Objective: Persistent positivity for lupus anticoagulant has been associated with an increased risk of thrombosis among patients with SLE. Persistent positivity is often defined as having two positive assessments separated by more than 90 days. Our objective was to determine whether frequent repeated lupus anticoagulant testing would identify more patients with persistent positivity, and whether the additional patients identified were still at increased risk of thrombosis.

Methods: Using a large longitudinal cohort with frequent lupus anticoagulant testing, we compared three different hypothetical clinical strategies for identifying persistent positivity: (1) assessment of lupus anticoagulant twice more than 90 days apart; (2) assessment of lupus anticoagulant annually, with repeat testing if an annual assessment was positive; and (3) assessment of lupus anticoagulant 16 times (approximately quarterly for 4 years). The prevalence of persistent positivity was compared between the approaches and by demographic subgroups. Subgroups based on these definitions were compared with respect to the risk of thrombosis in subsequent follow-up using discrete survival analysis.

Results: Among the 785 patients included in our analysis, the prevalence of persistent lupus anticoagulant as defined by the first two patient assessments was 4.3%. Annual assessment resulted in a prevalence of 6.6%, and using all 16 assessments resulted in a prevalence of 10.5%. The prevalence was substantially higher in men than in women, and in Caucasians than in African-Americans (p<0.01 for all comparisons). The rate of thrombosis was significantly elevated among those with persistently positive lupus anticoagulant by definition (HR ranging from 2.75 to 3.42) relative to those without persistently positive lupus anticoagulant.

Conclusion: While there are other risk factors for thrombosis (including other antiphospholipid subtypes), more frequent testing (not limited to twice over 3 months) for lupus anticoagulant would be useful for identifying more patients with SLE at elevated risk for thrombosis.
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http://dx.doi.org/10.1136/lupus-2020-000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607609PMC
November 2020

Predictors of the start of declining eGFR in patients with systemic lupus erythematosus.

Lupus 2021 Jan 28;30(1):15-24. Epub 2020 Oct 28.

Department of Epidemiology & Public Health, School of Medicine, University of Maryland, Baltimore, MD, USA.

Objective: To characterize the longitudinal trajectory of estimated glomerular filtration rate (eGFR) in patients with systemic lupus erythematosus (SLE) and identify predictors of the change in eGFR trajectory.

Methods: The longitudinal eGFR levels of patients in the Hopkins Lupus Cohort were modelled by piecewise linear regression to evaluate the slope of different line segments. The slopes were classified into declining (≤-4 mL/min/1.73 m per year), stable (-4 to 4 mL/min/1.73 m per year), and increasing (≥4 mL/min/1.73 m per year) states. The transition rate between states and the impact of clinical parameters were estimated by a Markov model.

Results: The analysis was based on 494 SLE patients. At a mean follow-up of 8.8 years, 347 (70.2%), 107 (21.7%), 33 (6.7%), and 7 (1.4%) patients had zero, one, two, and three state transitions, respectively. In patients with no transition, 37 (10.7%), 308 (88.8%), and 2 (0.6%) were in declining, stable, and increasing state, respectively. In patients with one transition, 43 (40.2%) changed from declining to stable state while 29 (27.1%) changed from stable to declining state. When patients were in a non-declining GFR state, those who were younger and African Americans were more likely to transition to a declining GFR state. In adjusted analyses, high blood pressure, C4 and low hematocrit were associated with change from non-declining to declining state. High urine protein-to-creatinine ratio also tended to be associated with change from non-declining to declining state. African American patients were less likely to move from declining to non-declining state. Use of prednisone was associated with change from declining to non-declining state.

Conclusions: Patients with high blood pressure, low complement C4, low haematocrit, and high urine protein-to-creatinine ratio are more likely to have a declining eGFR trajectory, while the use of prednisone stabilizes the declining eGFR trajectory.
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http://dx.doi.org/10.1177/0961203320966393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770013PMC
January 2021

Measures of Fatigue in Patients With Rheumatic Diseases: A Critical Review.

Arthritis Care Res (Hoboken) 2020 10;72 Suppl 10:369-409

University of Alabama at Birmingham, and Universidad Peruana Cayetano Heredia, Lima, Peru.

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http://dx.doi.org/10.1002/acr.24246DOI Listing
October 2020

Baricitinib-associated changes in global gene expression during a 24-week phase II clinical systemic lupus erythematosus trial implicates a mechanism of action through multiple immune-related pathways.

Lupus Sci Med 2020 10;7(1)

Eli Lilly and Company, Indianapolis, Indiana, USA.

Objective: To characterise the molecular pathways impacted by the pharmacologic effects of the Janus kinase (JAK) 1 and JAK2 inhibitor baricitinib in SLE.

Methods: In a phase II, 24-week, randomised, placebo-controlled, double-blind study (JAHH), RNA was isolated from whole blood in 274 patients and analysed using Affymetrix HTA2.0 array. Serum cytokines were measured using ultrasensitive quantitative assays.

Results: Gene expression profiling demonstrated an elevation of , and multiple interferon (IFN) responsive genes at baseline in patients with SLE. Statistical and gene network analyses demonstrated that baricitinib treatment reduced the mRNA expression of functionally interconnected genes involved in SLE including -target, -target and target genes and multiple IFN responsive genes. At baseline, serum cytokines IFN-α, IFN-γ, interleukin (IL)-12p40 and IL-6 were measurable and elevated above healthy controls. Treatment with baricitinib significantly decreased serum IL-12p40 and IL-6 cytokine levels at week 12, which persisted through week 24.

Conclusion: Baricitinib treatment induced significant reduction in the RNA expression of a network of genes associated with the JAK/STAT pathway, cytokine signalling and SLE pathogenesis. Baricitinib consistently reduced serum levels of two key cytokines implicated in SLE pathogenesis, IL-12p40 and IL-6.
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http://dx.doi.org/10.1136/lupus-2020-000424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549481PMC
October 2020

Loss of antiphospholipid antibody positivity post-thrombosis in SLE.

Lupus Sci Med 2020 10;7(1)

Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

Background/purpose: Loss of positivity of antiphospholipid antibodies has been observed in clinical practice post-thrombosis in patients with SLE with secondary antiphospholipid syndrome (APS). Our study defined the frequency of this loss and the duration before positivity recurred.

Methods: In this prospective study, patients with SLE having at least two positive antiphospholipid markers prior to thrombosis and at least 1 year of follow-up after thrombosis were included. Antiphospholipid markers included lupus anticoagulant (dilute Russell viper venom test >45 s followed by mixing and confirmatory tests) and/or anticardiolipin titre (aCL IgG ≥20, aCL IgM ≥20 and/or aCL IgA ≥20). The percentage of visits with positive antiphospholipid markers after thrombosis was calculated. For patients with a negative antiphospholipid marker any time after thrombosis, survival estimates were performed to calculate the time to return of antiphospholipid positivity.

Results: In APS due to SLE, complete loss of antiphospholipid positivity post-thrombosis was up to 41% for aCL IgG, 51% for IgM and 50% for IgA, but only 20% for those with lupus anticoagulant. Of those who at some point lost aCL IgG or became negative for lupus anticoagulant, the majority (60% and 76%, respectively) reacquired the antibody within 5 years. In contrast, of those who lost aCL IgM or IgA, fewer reacquired it within 5 years (37% and 17%, respectively).

Conclusion: Intermittent positivity of antiphospholipid antibodies is present in APS due to SLE. These fluctuations make it difficult to decide on length of anticoagulation. Lupus anticoagulant is more likely to persist post-thrombosis.
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http://dx.doi.org/10.1136/lupus-2020-000423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539588PMC
October 2020

Characteristics of Antiphospholipid Antibody Positive Patients in AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking.

Arthritis Care Res (Hoboken) 2020 Sep 28. Epub 2020 Sep 28.

Barbara Volcker Center for Women and Rheumatic Disease, Hospital For Special Surgery, Weill Cornell Medicine, New York, NY, USA.

Objective: To describe baseline characteristics of antiphospholipid antibody (aPL)-positive patients, overall and by clinical and laboratory subtypes, enrolled in an international registry.

Methods: AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking Registry includes persistently aPL-positive adults. We evaluated baseline sociodemographic and aPL-related (APS classification criteria and "non-criteria") characteristics of patients overall and in subgroups (aPL-positive without APS, APS overall, thrombotic APS [TAPS] only, obstetric APS [OAPS] only, and both TAPS/OAPS). We assessed baseline characteristics of patients tested for three aPL (lupus anticoagulant test [LA], anticardiolipin antibody [aCL], and anti-β -Glycoprotein-I [aβ GPI]) by aPL profiles (LA only, single, double, and triple aPL positivity).

Results: Of 804 aPL-positive patients (mean age: 45 ± 13y; female: 74%; white 68%; other systemic autoimmune diseases: 36%), 80% were classified as APS (55% TAPS, 9% OAPS, and 15% TAPS/OAPS). In the overall cohort, 71% had vascular thrombosis, 50% with pregnancy history had obstetric morbidity, and 56% had at least one non-criteria manifestation. Among those with three aPL tested (n: 660), 42% were triple aPL positive. While single, double and triple aPL positive subgroups had similar frequencies of vascular, obstetric, and non-criteria events, these events were lowest in the single aPL subgroup consisting of aCL or aβ GPI only.

Conclusion: Our study demonstrates the heterogeneity of aPL-related clinical manifestations and laboratory profiles in a multicenter, international cohort. Within single aPL-positivity, LA may be a major contributor to clinical events. Future prospective analyses, using standardized core laboratory aPL tests, will help clarify aPL risk profiles and improve risk stratification.
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http://dx.doi.org/10.1002/acr.24468DOI Listing
September 2020

Cutaneous vasculitis in SLE.

Lupus Sci Med 2020 09;7(1)

Division of Rheumatology, Johns Hopkins Medicine, Baltimore, Maryland, USA.

Objectives: We determined the temporal association between clinical and serological disease manifestations and development of cutaneous small vessel vasculitis in a large prospective multiethnic cohort.

Methods: Patients with SLE diagnosed according to the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria or the revised classification criteria as defined by the American College of Rheumatology (ACR) were enrolled in the Hopkins Lupus Cohort. Cutaneous small vessel vasculitis was determined as a component of the Systemic Lupus Erythematosus Disease Activity Index. SLE-associated cutaneous small vessel vasculitis lesions were reported clinically. They presented as punctate lesions, palpable purpura, tender erythematous plaques or macules with or without necrosis. No histopathological diagnosis was pursued to confirm the diagnosis of vasculitis or to differentiate it from other causes of digital lesions in patients with SLE. Disease manifestations that preceded the first occurrence of cutaneous small vessel vasculitis lesions were analysed using Kaplan-Meier. Cox regression analysis was used to assess the relationship between baseline clinical and immunological manifestations and the development of cutaneous small vessel vasculitis. We adjusted for gender, race and age at SLE diagnosis.

Results: A total of 2580 patients were studied: 52.4% were Caucasian and 39.4% were African-American. The mean age of the cohort was 45.5±14.5 years. The mean years of cohort follow-up was 7.9±7.6. Cutaneous small vessel vasculitis was observed in 449 (17.3%). The mean time to cutaneous vasculitis after SLE diagnosis was 4.78 years (95% CI 3.96 to 5.60). At least 159 (35%) patients had recurrences of cutaneous vasculitis lesions. Discoid rash, Raynaud's phenomenon, myositis, anaemia, Coombs' positivity, leucopenia, anti-Smith and anti-RNP (Ribonucleoprotein) were significantly associated with the development of cutaneous vasculitis. The SLICC/ACR Damage Index score was higher in patients with cutaneous vasculitis compared with those without cutaneous vasculitis.

Conclusions: Cutaneous vasculitis is frequent (17.3%) and often recurrent (35%). African-Americans are at higher risk of developing cutaneous small vessel vasculitis than Caucasians. Clinical presentations such as myositis and haematological manifestations are predictors of cutaneous vasculitis development. The presence of cutaneous vasculitis is associated with increased organ damage.
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http://dx.doi.org/10.1136/lupus-2020-000411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509964PMC
September 2020

Reply.

Arthritis Rheumatol 2021 02 24;73(2):359. Epub 2020 Dec 24.

Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1002/art.41521DOI Listing
February 2021

New classification criteria for systemic lupus erythematosus.

Curr Opin Rheumatol 2020 11;32(6):590-596

Department of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Purpose Of Review: To compare the recently published European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE with the Systemic Lupus International Collaborating Centers (SLICC) criteria and the earlier ACR criteria, focusing on their key concepts.

Recent Findings: Although the SLICC criteria introduced numbers of new criteria items, the new EULAR/ACR criteria added only noninfectious fever, based on an early SLE cohort study and an SLE patient survey, and condensed hematological, mucocutaneous and neurological items. Whereas the SLICC criteria maintained the overall structure familiar from the ACR criteria, the EULAR /ACR criteria use antinuclear antibodies (ANA) as an obligatory entry criterion, have weighted criteria and group these in domains. Where the SLICC criteria greatly increased sensitivity, losing some specificity, the EULAR/ACR criteria increased specificity again, for excellent classification criteria performance.

Summary: Despite differences in structure and statistical performance, the EULAR/ACR and SLICC criteria agree on the importance of both immunological and clinical findings, on the high impact of lupus nephritis by histology, and on most clinical items.
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http://dx.doi.org/10.1097/BOR.0000000000000740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020886PMC
November 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

Patient ancestry significantly contributes to molecular heterogeneity of systemic lupus erythematosus.

JCI Insight 2020 08 6;5(15). Epub 2020 Aug 6.

AMPEL BioSolutions LLC & RILITE Research Institute, Charlottesville, Virginia, USA.

Gene expression signatures can stratify patients with heterogeneous diseases, such as systemic lupus erythematosus (SLE), yet understanding the contributions of ancestral background to this heterogeneity is not well understood. We hypothesized that ancestry would significantly influence gene expression signatures and measured 34 gene modules in 1566 SLE patients of African ancestry (AA), European ancestry (EA), or Native American ancestry (NAA). Healthy subject ancestry-specific gene expression provided the transcriptomic background upon which the SLE patient signatures were built. Although standard therapy affected every gene signature and significantly increased myeloid cell signatures, logistic regression analysis determined that ancestral background significantly changed 23 of 34 gene signatures. Additionally, the strongest association to gene expression changes was found with autoantibodies, and this also had etiology in ancestry: the AA predisposition to have both RNP and dsDNA autoantibodies compared with EA predisposition to have only anti-dsDNA. A machine learning approach was used to determine a gene signature characteristic to distinguish AA SLE and was most influenced by genes characteristic of the perturbed B cell axis in AA SLE patients.
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http://dx.doi.org/10.1172/jci.insight.140380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455079PMC
August 2020

Reply.

Arthritis Rheumatol 2020 12 7;72(12):2166. Epub 2020 Oct 7.

Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1002/art.41462DOI Listing
December 2020

Cachexia in Systemic Lupus Erythematosus: Risk Factors and Relation to Disease Activity and Damage.

Arthritis Care Res (Hoboken) 2020 Aug 2. Epub 2020 Aug 2.

Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Objective: Cachexia is a disorder characterized by involuntary weight loss in addition to loss of homeostatic control of both energy and protein balance. Despite an abundance of data from other inflammatory diseases, cachexia in SLE remains a largely undescribed syndrome.

Methods: 2406 patients in a prospective SLE cohort had their weight assessed at each visit. Patients were categorized into five predetermined groups based on weight. Cachexia was defined based on modified Fearon criteria (5% stable weight loss in 6 months without starvation relative to the average weight in all prior visits AND/OR weight loss >2% without starvation relative to the average weight in all prior cohort visits and a BMI <20). Risk of cachexia within 5 years of cohort entry was based on Kaplan Meier estimates. The association of prior disease manifestations with risk of cachexia adjusted by current steroid use was determined using Cox regression. An analysis of variance test was used to determine whether SLICC/ACR Damage Index scores varied based on cachexia status.

Results: Within five years of cohort entry, 56% of patients developed cachexia, 18% of which never recovered their weight during follow up. The risk factors for cachexia development were BMI<20, current steroid use, vasculitis, lupus nephritis, serositis, hematologic, positive anti-dsDNA, anti-Sm, and anti-RNP. Patients with intermittent cachexia had significantly higher SLICC/ACR Damage Index compared to those with continuous cachexia or without cachexia.

Conclusion: Cachexia is an underrecognized syndrome in patients with SLE. SLE patients with intermittent cachexia have the highest risk of future organ damage.
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http://dx.doi.org/10.1002/acr.24395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855238PMC
August 2020