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1.
Arthritis Rheumatol ; 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33403833

RESUMO

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 examined 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. Mean HCQ blood levels calculated prior to thrombosis or until the last visit were compared between patients with and without thrombosis using t-test. Pooled logistic regression was used to analyze the association between rates of thrombosis and HCQ blood level. RESULTS: In 739 patients with SLE, thrombosis occurred in 38 patients (5.1%). Mean HCQ blood level was lower in patients who developed thrombosis vs without thrombosis (720±489 vs 935±580, p=0.025). Thrombosis rates were reduced by 12% for every 200 ng/mL increase in the most recent HCQ blood level (0.87 [0.78, 0.98], p=0.025) and by 13% for mean HCQ blood level (rate ratio 0.87 [0.76,1.00], p=0.056). Thrombotic events were reduced by 69% in patients with mean HCQ blood levels >1068 ng/mL vs <648 ng/mL (0.31 [0.11, 0.86], p=0.024). This remained significant after adjustment for confounders (0.34 [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.

2.
Lupus Sci Med ; 8(1)2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33479047

RESUMO

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.

3.
J Rheumatol ; 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-33259328

RESUMO

OBJECTIVE: 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 a) whether baseline characteristics differ between patients with stable and unstable aPL profiles, and b) predictors of unstable aPL profiles over time. METHODS: Clinically meaningful aPL profile was defined as positive lupus anticoagulant (LA) test and/or anticardiolipin (aCL)/anti-ß2 glycoprotein-I (aß2GPI) 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 years), 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 (p=0.906) and multivariable analysis (p=0.790). Baseline triple aPL positivity decreased (Odds Ratio [OR] 0.25, 95% Confidence Interval [CI] 0.10-0.64, p=0.004) and isolated LA test positivity increased (OR 3.3, 95% CI 1.53-7.13, p=0.002) the odds of an unstable aPL profile over time. CONCLUSION: Approximately 80% of our international cohort patients with clinically meaningful aPL profile at baseline maintain such at a median follow-up of five 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.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33331921

RESUMO

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-ß2-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-ß2-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-ß2-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-ß2-glycoprotein I IgA.'

5.
Artigo em Inglês | MEDLINE | ID: mdl-33342072

RESUMO

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.

6.
Lupus Sci Med ; 7(1)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33139453

RESUMO

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 any 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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33152181

RESUMO

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.

8.
Lupus Sci Med ; 7(1)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33023978

RESUMO

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.

9.
Lupus Sci Med ; 7(1)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33037080

RESUMO

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 STAT1, STAT2 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 STAT1-target, STAT2-target and STAT4-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.

11.
Lupus ; : 961203320966393, 2020 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-33115373

RESUMO

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 m2 per year), stable (-4 to 4 mL/min/1.73 m2 per year), and increasing (≥4 mL/min/1.73 m2 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.

12.
Curr Opin Rheumatol ; 32(6): 590-596, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925250

RESUMO

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.

13.
Lupus Sci Med ; 7(1)2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32963114

RESUMO

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.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32986935

RESUMO

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-ß2 -Glycoprotein-I [aß2 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 aß2 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.

15.
Arthritis Rheumatol ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32936524

RESUMO

We agree with the authors that the lack of findings of a relationship between blood concentration and retinopathy in the Lenfant et al. study may well have been due to the fact that they selected an adherent control group which likely inflated the average hydroxychloroquine levels in their controls relative to typical patients.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32741060

RESUMO

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.

17.
Arthritis Rheumatol ; 72(12): 2166, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32741151
18.
JCI Insight ; 5(15)2020 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-32759501

RESUMO

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.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32813314

RESUMO

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.

20.
Ann Rheum Dis ; 79(10): 1349-1361, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651195

RESUMO

OBJECTIVE: The goal of these studies is to discover novel urinary biomarkers of lupus nephritis (LN). METHODS: Urine from systemic lupus erythematosus (SLE) patients was interrogated for 1000 proteins using a novel, quantitative planar protein microarray. Hits were validated in an independent SLE cohort with inactive, active non-renal (ANR) and active renal (AR) patients, in a cohort with concurrent renal biopsies, and in a longitudinal cohort. Single-cell renal RNA sequencing data from LN kidneys were examined to deduce the cellular origin of each biomarker. RESULTS: Screening of 1000 proteins revealed 64 proteins to be significantly elevated in SLE urine, of which 17 were ELISA validated in independent cohorts. Urine Angptl4 (area under the curve (AUC)=0.96), L-selectin (AUC=0.86), TPP1 (AUC=0.84), transforming growth factor-ß1 (TGFß1) (AUC=0.78), thrombospondin-1 (AUC=0.73), FOLR2 (AUC=0.72), platelet-derived growth factor receptor-ß (AUC=0.67) and PRX2 (AUC=0.65) distinguished AR from ANR SLE, outperforming anti-dsDNA, C3 and C4, in terms of specificity, sensitivity and positive predictive value. In multivariate regression analysis, urine Angptl4, L-selectin, TPP1 and TGFß1 were highly associated with disease activity, even after correction for demographic variables. In SLE patients with serial follow-up, urine L-selectin (followed by urine Angptl4 and TGFß1) were best at tracking concurrent or pending disease flares. Importantly, several proteins elevated in LN urine were also expressed within the kidneys in LN, either within resident renal cells or infiltrating immune cells, based on single-cell RNA sequencing analysis. CONCLUSION: Unbiased planar array screening of 1000 proteins has led to the discovery of urine Angptl4, L-selectin and TGFß1 as potential biomarker candidates for tracking disease activity in LN.


Assuntos
Proteína 4 Semelhante a Angiopoietina/urina , Biomarcadores/urina , Nefrite Lúpica/diagnóstico , Análise Serial de Proteínas , Fator de Crescimento Transformador beta1/urina , Humanos , Nefrite Lúpica/urina
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