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2.
ACR Open Rheumatol ; 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33605563

RESUMO

OBJECTIVE: The increase in cardiovascular events (CVEs) in systemic lupus erythematosus (SLE) is not fully explained by traditional risk factors. We previously identified four biomarkers (proinflammatory high-density lipoprotein, leptin, soluble TNF-like weak inducer of apoptosis (sTWEAK), and homocysteine) that we combined with age and diabetes to create the predictors of risk for elevated flares, damage progression, and increased cardiovascular diseasein patients with SLE (PREDICTS) risk profile. PREDICTS more accurately identified patients with SLE at risk for progression of subclinical atherosclerosis than any individual variable. We examined whether PREDICTS can also identify patients with SLE at risk for future CVEs. METHODS: A total of 342 patients with SLE and 155 matched control subjects participated in this longitudinal prospective study. A high PREDICTS score was defined as three or more predictors or diabetes + one or more predictor. The biomarkers were measured at baseline using published methods. All major adverse CVEs (MACEs) were confirmed by medical record review. RESULTS: During 116 months of follow-up, 5% of patients with SLE died, 12% had a cerebrovascular event, and 5% had a cardiac event. Overall, 20% of patients with lupus experienced any new MACE compared with 5% of control subjects (P < 0.0001). More patients with SLE with a new MACE had high PREDICTS score at baseline (77%) versus patients with no new events (34%) (P < 0.0001). High baseline PREDICTS score also associated with cerebrovascular (P < 0.0001) and cardiac events (P < 0.0001) in SLE. Using Cox regression, a baseline high PREDICTS score associated with a 3.7-fold increased hazard ratio (HR) for a new MACE (P < 0.0001) in SLE. Hypertension (HR = 2.1; P = 0.006) was also a risk. CONCLUSION: A high PREDICTS score and hypertension confer increased risk for new MACEs in patients with SLE.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33547784

RESUMO

OBJECTIVES: Atacicept reduced SLE disease activity in the Phase IIb ADDRESS II study, particularly in patients with high disease activity (HDA; SLEDAI-2K ≥10) at screening. We assessed long-term safety and efficacy of atacicept in the long-term extension (LTE) of ADDRESS II. METHODS: In the 24-week, randomised, double-blind, placebo-controlled ADDRESS II study, patients received weekly atacicept (75 or 150 mg) or placebo. Atacicept was continued at the same dose in atacicept-treated patients in the LTE; placebo-treated patients switched to atacicept 150 mg. Long-term safety was the primary end point. Secondary endpoints included SLE responder index (SRI)-4 and SRI-6 response rates and flares. RESULTS: 253 patients entered the ADDRESS II LTE; 88 received atacicept 150 mg, 82 atacicept 75 mg and 83 placebo/atacicept 150 mg. Median active treatment duration in the LTE was 83.8 weeks. Frequencies of treatment-emergent adverse events (TEAEs) were similar across groups (90.4-93.2%). 12.5%, 14.6% and 21.7% of patients in the atacicept 150 mg, atacicept 75 mg and placebo/atacicept 150 mg groups reported serious TEAEs during the treatment period. The proportions of patients with TEAEs leading to discontinuation were 5.7%, 4.9% and 10.8%, respectively. SRI-4 and SRI-6 response rates were maintained with atacicept in the modified intent-to-treat and HDA populations and those on continuous 150 mg had a reduced risk of first severe flare and longer time to first severe flare vs those who initially received placebo. CONCLUSION: Long-term treatment with atacicept 150 mg in SLE patients had an acceptable safety profile, with durable efficacy. CLINICAL TRIAL REGISTRATION NUMBER: NCT02070978.

4.
ACR Open Rheumatol ; 2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33538130

RESUMO

OBJECTIVE: To evaluate the usefulness of biomarkers to predict the evolution of patients suspected of systemic lupus erythematosus (SLE), designated as probable SLE (pSLE), into classifiable SLE according to the American College of Rheumatology (ACR) classification criteria. METHODS: Patients suspected of SLE were enrolled by lupus experts if they fulfilled three ACR criteria for SLE and were followed for approximately 1-3 years to evaluate transition into ACR-classifiable SLE. Individual cell-bound complement activation products (CB-CAPs), serum complement proteins (C3 and C4), and autoantibodies were measured by flow cytometry, turbidimetry, and enzyme-linked immunosorbent assay, respectively. Blood levels of hydroxychloroquine (HCQ) were measured by mass spectrometry. A multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. A MAP of greater than 0.8 reflected the optimal cutoff for transition to SLE. Time to fulfillment of ACR criteria was evaluated by Kaplan-Meier analysis and Cox proportional hazards model. RESULTS: Of the 92 patients with pSLE enrolled, 74 had one or two follow-up visits 9-35 months after enrollment for a total of 128 follow-up visits. Overall, 28 patients with pSLE (30.4%) transitioned to ACR-classifiable SLE, including 16 (57%) in the first year and 12 (43%) afterwards. A MAP score of greater than 0.8 at enrollment predicted transition to classifiable SLE during the follow-up period (hazard ratio = 2.72; P = 0.012), whereas individual biomarkers or fulfillment of Systemic Lupus International Collaborating Clinics criteria did not. HCQ therapy was not associated with the prevention of transition to SLE. CONCLUSION: Approximately one-third of patients with pSLE transitioned within the study period. MAP of greater than 0.8 predicted disease evolution into classifiable SLE.

5.
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.

6.
Front Immunol ; 11: 554725, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33072095

RESUMO

Systemic Lupus Erythematosus (SLE) is a chronic inflammatory autoimmune disease in which type I interferons (IFN) play a key role. The IFN response can be triggered when oxidized DNA engages the cytosolic DNA sensing platform cGAS-STING, but the repair mechanisms that modulate this process and govern disease progression are unclear. To gain insight into this biology, we interrogated the role of oxyguanine glycosylase 1 (OGG1), which repairs oxidized guanine 8-Oxo-2'-deoxyguanosine (8-OH-dG), in the pristane-induced mouse model of SLE. Ogg1 -/- mice showed increased influx of Ly6Chi monocytes into the peritoneal cavity and enhanced IFN-driven gene expression in response to short-term exposure to pristane. Loss of Ogg1 was associated with increased auto-antibodies (anti-dsDNA and anti-RNP), higher total IgG, and expression of interferon stimulated genes (ISG) to longer exposure to pristane, accompanied by aggravated skin pathology such as hair loss, thicker epidermis, and increased deposition of IgG in skin lesions. Supporting a role for type I IFNs in this model, skin lesions of Ogg1 -/- mice had significantly higher expression of type I IFN genes (Isg15, Irf9, and Ifnb). In keeping with loss of Ogg1 resulting in dysregulated IFN responses, enhanced basal and cGAMP-dependent Ifnb expression was observed in BMDMs from Ogg1 -/- mice. Use of the STING inhibitor, H151, reduced both basal and cGAMP-driven increases, indicating that OGG1 regulates Ifnb expression through the cGAS-STING pathway. Finally, in support for a role for OGG1 in the pathology of cutaneous disease, reduced OGG1 expression in monocytes associated with skin involvement in SLE patients and the expression of OGG1 was significantly lower in lesional skin compared with non-lesional skin in patients with Discoid Lupus. Taken together, these data support an important role for OGG1 in protecting against IFN production and SLE skin disease.

7.
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.

8.
J Clin Rheumatol ; 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-33065630

RESUMO

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that may affect every organ. The multiple pathogenic mechanisms and heterogeneous phenotypes of SLE present unique challenges in the management of this complex disease. This article discusses new SLE therapies from the last 10 years. We will address new information in the realms of lifestyle interventions, antimalarials, nonsteroidal anti-inflammatory drugs, glucocorticoids, immunosuppressive disease modifying antirheumatic drugs, biological therapies, and other modalities as they pertain to SLE.

9.
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.

10.
Arthritis Rheumatol ; 72(10): 1734-1740, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32515554

RESUMO

OBJECTIVE: In previous studies, atherosclerotic vascular events (AVEs) were shown to occur in ~10% of patients with systemic lupus erythematosus (SLE). We undertook this study to investigate the annual occurrence and potential risk factors for AVEs in a multinational, multiethnic inception cohort of patients with SLE. METHODS: A large 33-center cohort of SLE patients was followed up yearly between 1999 and 2017. AVEs were attributed to atherosclerosis based on SLE being inactive at the time of the AVE as well as typical atherosclerotic changes observed on imaging or pathology reports and/or evidence of atherosclerosis elsewhere. Analyses included descriptive statistics, rate of AVEs per 1,000 patient-years, and univariable and multivariable relative risk regression models. RESULTS: Of the 1,848 patients enrolled in the cohort, 1,710 had ≥1 follow-up visit after enrollment, for a total of 13,666 patient-years. Of these 1,710 patients, 3.6% had ≥1 AVEs attributed to atherosclerosis, for an event rate of 4.6 per 1,000 patient-years. In multivariable analyses, lower AVE rates were associated with antimalarial treatment (hazard ratio [HR] 0.54 [95% confidence interval (95% CI) 0.32-0.91]), while higher AVE rates were associated with any prior vascular event (HR 4.00 [95% CI 1.55-10.30]) and a body mass index of >40 kg/m2 (HR 2.74 [95% CI 1.04-7.18]). A prior AVE increased the risk of subsequent AVEs (HR 5.42 [95% CI 3.17-9.27], P < 0.001). CONCLUSION: The prevalence of AVEs and the rate of AVE accrual demonstrated in the present study is much lower than that seen in previously published data. This may be related to better control of both the disease activity and classic risk factors.

11.
Lupus Sci Med ; 7(1)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32371480

RESUMO

OBJECTIVES: To evaluate the association between lupus severity and cell-bound complement activation products (CB-CAPs) or low complement proteins C3 and C4. METHODS: All subjects (n=495) fulfilled the American College of Rheumatology (ACR) classification criteria for SLE. Abnormal CB-CAPs (erythrocyte-bound C4d or B-lymphocyte-bound C4d levels >99th percentile of healthy) and complement proteins C3 and C4 were determined using flow cytometry and turbidimetry, respectively. Lupus severity was estimated using the Lupus Severity Index (LSI). Statistical analysis consisted of multivariable linear regression and groups comparisons. RESULTS: Abnormal CB-CAPs were more prevalent than low complement values irrespective of LSI levels (62% vs 38%, respectively, p<0.0001). LSI was low (median 5.44, IQR: 4.77-6.93) in patients with no complement abnormality, intermediate in patients with abnormal CB-CAPs (median 6.09, IQR: 5.31-8.20) and high in the group presenting with both abnormal CB-CAPs and low C3 and/or C4 (median 7.85, IQR: 5.51-8.37). Odds of immunosuppressant use was higher in subjects with LSI ≥5.95 compared with subjects with LSI <5.95 (1.60 vs 0.53, p<0.0001 for both). Multivariable regression analysis revealed that higher LSI scores associated with abnormal CB-CAPs-but not low C3/C4-after adjusting for younger age, race and longer disease duration (p=0.0001), which were also independent predictors of disease severity (global R2=0.145). CONCLUSION: Abnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.

12.
Rheumatology (Oxford) ; 59(10): 2930-2938, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32107560

RESUMO

OBJECTIVE: Low disease activity (LDA) and remission are emerging treat-to-target (T2T) endpoints in SLE. However, the rates at which these endpoints are met in patients with high disease activity (HDA) are unknown. Atacicept, which targets B lymphocyte stimulator and a proliferation-inducing ligand, improved disease outcomes in SLE patients with HDA (SLEDAI-2K ≥10) at baseline in the phase 2b ADDRESS II study. This is a post hoc analysis of T2T endpoints in these patients. METHODS: Patients received weekly atacicept (75 or 150 mg s.c.) or placebo for 24 weeks (1:1:1 randomization). Attainment of three T2T endpoints, LDA (SLEDAI-2K ≤ 2), Lupus Low Disease Activity State (LLDAS) and remission (clinical SLEDAI-2K = 0, prednisone-equivalent ≤5mg/day and Physician's Global Assessment <0.5), was assessed and compared with SLE Responder Index (SRI)-4 and SRI-6 response. RESULTS: Of 306 randomized patients, 158 (51.6%) had baseline HDA. At week 24, 37 (23.4%) HDA patients attained LDA, 25 (15.8%) LLDAS and 17 (10.8%) remission. Each of these endpoints was more stringent than SRI-4 (n = 87; 55.1%) and SRI-6 (n = 67; 42.4%). Compared with placebo (n = 52), at week 24, patients treated with atacicept 150 mg (n = 51) were more likely to attain LDA [odds ratio (OR) 3.82 (95% CI: 1.44, 10.15), P = 0.007], LLDAS [OR 5.03 (95% CI: 1.32, 19.06), P = 0.018] or remission [OR 3.98 (95% CI: 0.78, 20.15), P = 0.095]. CONCLUSION: At week 24, LDA, LLDAS and remission were more stringent than SRI-4 and SRI-6 response, were attainable in the HDA population and discriminated between treatment with atacicept 150 mg and placebo. These results suggest that T2T endpoints are robust outcome measures in SLE clinical trials and support further evaluation of atacicept in SLE. TRAIL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01972568.

13.
Ann Rheum Dis ; 79(3): 356-362, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31915121

RESUMO

OBJECTIVES: Using a reversible multistate model, we prospectively examined neuropsychiatric (NP) events for attribution, outcome and association with health-related quality of life (HRQoL), in an international, inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Annual assessments for 19 NP events attributed to SLE and non-SLE causes, physician determination of outcome and patient HRQoL (short-form (SF)-36 scores) were measured. Time-to-event analysis and multistate modelling examined the onset, recurrence and transition between NP states. RESULTS: NP events occurred in 955/1827 (52.3%) patients and 592/1910 (31.0%) unique events were attributed to SLE. In the first 2 years of follow-up the relative risk (95% CI) for SLE NP events was 6.16 (4.96, 7.66) and non-SLE events was 4.66 (4.01, 5.43) compared with thereafter. Patients without SLE NP events at initial assessment had a 74% probability of being event free at 10 years. For non-SLE NP events the estimate was 48%. The majority of NP events resolved over 10 years but mortality was higher in patients with NP events attributed to SLE (16%) versus patients with no NPSLE events (6%) while the rate was comparable in patients with non-SLE NP events (7%) compared with patients with no non-SLE events (6%). Patients with NP events had lower SF-36 summary scores compared with those without NP events and resolved NP states (p<0.001). CONCLUSIONS: NP events occur most frequently around the diagnosis of SLE. Although the majority of events resolve they are associated with reduced HRQoL and excess mortality. Multistate modelling is well suited for the assessment of NP events in SLE.


Assuntos
Lúpus Eritematoso Sistêmico/psicologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/psicologia , Adulto , Feminino , Humanos , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/mortalidade , Vasculite Associada ao Lúpus do Sistema Nervoso Central/mortalidade , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Análise Multinível , Estudos Prospectivos , Qualidade de Vida
14.
Arthritis Rheumatol ; 72(1): 67-77, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31390162

RESUMO

OBJECTIVE: To determine the frequency, clinical characteristics, associations, and outcomes of different types of peripheral nervous system (PNS) disease in a multiethnic/multiracial, prospective inception cohort of systemic lupus erythematosus (SLE) patients. METHODS: Patients were evaluated annually for 19 neuropsychiatric (NP) events including 7 types of PNS disease. SLE disease activity, organ damage, autoantibodies, and patient and physician assessment of outcome were measured. Time to event and linear regressions were used as appropriate. RESULTS: Of 1,827 SLE patients, 88.8% were female, and 48.8% were white. The mean ± SD age was 35.1 ± 13.3 years, disease duration at enrollment was 5.6 ± 4.2 months, and follow-up was 7.6 ± 4.6 years. There were 161 PNS events in 139 (7.6%) of 1,827 patients. The predominant events were peripheral neuropathy (66 of 161 [41.0%]), mononeuropathy (44 of 161 [27.3%]), and cranial neuropathy (39 of 161 [24.2%]), and the majority were attributed to SLE. Multivariate Cox regressions suggested longer time to resolution in patients with a history of neuropathy, older age at SLE diagnosis, higher SLE Disease Activity Index 2000 scores, and for peripheral neuropathy versus other neuropathies. Neuropathy was associated with significantly lower Short Form 36 (SF-36) physical and mental component summary scores versus no NP events. According to physician assessment, the majority of neuropathies resolved or improved over time, which was associated with improvements in SF-36 summary scores for peripheral neuropathy and mononeuropathy. CONCLUSION: PNS disease is an important component of total NPSLE and has a significant negative impact on health-related quality of life. The outcome is favorable for most patients, but our findings indicate that several factors are associated with longer time to resolution.


Assuntos
Doenças dos Nervos Cranianos/fisiopatologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Adulto , Fatores Etários , Estudos de Coortes , Doenças dos Nervos Cranianos/etiologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Mononeuropatias/etiologia , Mononeuropatias/fisiopatologia , Análise Multivariada , Doenças do Sistema Nervoso Periférico/etiologia , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Adulto Jovem
15.
Arthritis Rheumatol ; 72(1): 78-88, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469249

RESUMO

OBJECTIVE: To evaluate the frequency of cell-bound complement activation products (CB-CAPs) as a marker of complement activation in patients with suspected systemic lupus erythematosus (SLE) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology (ACR) criteria. METHODS: Patients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria, patients with primary Sjögren's syndrome (SS), and patients with other rheumatic diseases. Individual CB-CAPs were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. Probable SLE cases were followed up prospectively. RESULTS: The 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE, and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB-CAPs (28%) or MAP (40%) than had low complement levels (9%) (P = 0.0001 for each). In probable SLE, MAP scores of >0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P < 0.01). CONCLUSION: Complement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB-CAPs and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria.


Assuntos
Ativação do Complemento/imunologia , Complemento C3/imunologia , Complemento C4b/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fragmentos de Peptídeos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Complemento C4/imunologia , Complemento C4b/metabolismo , Progressão da Doença , Eritrócitos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Estudos Prospectivos , Doenças Reumáticas/imunologia , Fator Reumatoide/imunologia , Síndrome de Sjogren/imunologia , Adulto Jovem
16.
Arthritis Rheumatol ; 72(4): 658-666, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31631584

RESUMO

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) frailty index (FI) has been shown to predict mortality, but its association with other important outcomes is unknown. We examined the association of baseline SLICC FI values with damage accrual in the SLICC inception cohort. METHODS: The baseline visit was defined as the first visit at which both organ damage (SLICC/American College of Rheumatology Damage Index [SDI]) and health-related quality of life (Short Form 36) were assessed. Baseline SLICC FI scores were calculated. Damage accrual was measured by the increase in SDI between the baseline assessment and the last study visit. Multivariable negative binomial regression was used to estimate the association between baseline SLICC FI values and the rate of increase in the SDI during follow-up, adjusting for relevant demographic and clinical characteristics. RESULTS: The 1,549 systemic lupus erythematosus (SLE) patients eligible for this analysis were mostly female (88.7%) with a mean ± SD age of 35.7 ± 13.3 years and a median disease duration of 1.2 years (interquartile range 0.9-1.5 years) at baseline. The mean ± SD baseline SLICC FI was 0.17 ± 0.08. Over a mean ± SD follow-up of 7.2 ± 3.7 years, 653 patients (42.2%) had an increase in SDI. Higher baseline SLICC FI values (per 0.05 increase) were associated with higher rates of increase in the SDI during follow-up (incidence rate ratio [IRR] 1.19 [95% confidence interval 1.13-1.25]), after adjusting for age, sex, ethnicity/region, education, baseline SLE Disease Activity Index 2000, baseline SDI, and baseline use of glucocorticoids, antimalarials, and immunosuppressive agents. CONCLUSION: Our findings indicate that the SLICC FI predicts damage accrual in incident SLE, which further supports the SLICC FI as a valid health measure in SLE.


Assuntos
Fragilidade/diagnóstico , Lúpus Eritematoso Sistêmico/diagnóstico , Qualidade de Vida , Adulto , Progressão da Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
17.
J Autoimmun ; 106: 102340, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629628

RESUMO

OBJECTIVE: The soluble urokinase plasminogen activator receptor (suPAR) has potential as a prognosis and severity biomarker in several inflammatory and infectious diseases. In a previous cross-sectional study, suPAR levels were shown to reflect damage accrual in cases of systemic lupus erythematosus (SLE). Herein, we evaluated suPAR as a predictor of future organ damage in recent-onset SLE. METHODS: Included were 344 patients from the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort who met the 1997 American College of Rheumatology classification criteria with 5-years of follow-up data available. Baseline sera from patients and age- and sex-matched controls were assayed for suPAR. Organ damage was assessed annually using the SLICC/ACR damage index (SDI). RESULTS: The levels of suPAR were higher in patients who accrued damage, particularly those with SDI≥2 at 5 years (N = 32, 46.8% increase, p = 0.004), as compared to patients without damage. Logistic regression analysis revealed a significant impact of suPAR on SDI outcome (SDI≥2; OR = 1.14; 95% CI 1.03-1.26), also after adjustment for confounding factors. In an optimized logistic regression to predict damage, suPAR persisted as a predictor, together with baseline disease activity (SLEDAI-2K), age, and non-Caucasian ethnicity (model AUC = 0.77). Dissecting SDI into organ systems revealed higher suPAR levels in patients who developed musculoskeletal damage (SDI≥1; p = 0.007). CONCLUSION: Prognostic biomarkers identify patients who are at risk of acquiring early damage and therefore need careful observation and targeted treatment strategies. Overall, suPAR constitutes an interesting biomarker for patient stratification and for identifying SLE patients who are at risk of acquiring organ damage during the first 5 years of disease.

18.
Arthritis Care Res (Hoboken) ; 72(12): 1800-1808, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31609532

RESUMO

OBJECTIVE: There is a paucity of data regarding health care costs associated with damage accrual in systemic lupus erythematosus. The present study was undertaken to describe costs associated with damage states across the disease course using multistate modeling. METHODS: Patients from 33 centers in 11 countries were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. Annual data on demographics, disease activity, damage (SLICC/American College of Rheumatology Damage Index [SDI]), hospitalizations, medications, dialysis, and selected procedures were collected. Ten-year cumulative costs (Canadian dollars) were estimated by multiplying annual costs associated with each SDI state by the expected state duration using a multistate model. RESULTS: A total of 1,687 patients participated; 88.7% were female, 49.0% were white, mean ± SD age at diagnosis was 34.6 ± 13.3 years, and mean time to follow-up was 8.9 years (range 0.6-18.5 years). Mean annual costs were higher for those with higher SDI scores as follows: $22,006 (Canadian) (95% confidence interval [95% CI] $16,662, $27,350) for SDI scores ≥5 versus $1,833 (95% CI $1,134, $2,532) for SDI scores of 0. Similarly, 10-year cumulative costs were higher for those with higher SDI scores at the beginning of the 10-year interval as follows: $189,073 (Canadian) (95% CI $142,318, $235,827) for SDI scores ≥5 versus $21,713 (95% CI $13,639, $29,788) for SDI scores of 0. CONCLUSION: Patients with the highest SDI scores incur 10-year cumulative costs that are ~9-fold higher than those with the lowest SDI scores. By estimating the damage trajectory and incorporating annual costs, data on damage can be used to estimate future costs, which is critical knowledge for evaluating the cost-effectiveness of novel therapies.

19.
Arthritis Care Res (Hoboken) ; 72(8): 1049-1056, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-31199565

RESUMO

OBJECTIVE: To describe the clinical and serologic manifestations of Sjögren's syndrome (SS) in ethnic groups of the US. METHODS: This was a cross-sectional study of 648 patients with primary SS: 20 African American (AA), 164 American Indian (AI), 426 European American (EA), and 38 patients of other races evaluated in a multidisciplinary Sjögren's International Collaborative Clinical Alliance research clinic. RESULTS: AA subjects comprised 3.1% of the SS cohort, much lower than the percentage of AA in the state of Oklahoma (P = 3.01 × E - 05), the US (P = 2.24E - 13), or a systemic lupus erythematosus (SLE) cohort at the same institution (P = 4.26 × 10E - 27). In contrast, the percentage of AI in the SS cohort (25.3%) was much higher than expected (P = 3.17E - 09 versus SLE cohort, P = 6.36 - 26 versus Oklahoma, and P = 8.14E - 96 versus US population). The SS classification criteria were similar between AA and EA, but subjects of AI ancestry had lower rates of abnormal tear and salivary flow, as well as anti-Ro/SSA and anti-La/SSB antibodies. Paradoxically, AI had higher levels of disease activity (mean ± SD European League Against Rheumatism Sjögren's Syndrome Disease Activity Index score 3.77 ± 4.78) in comparison to EA (2.90 ± 4.12; P = 0.011) and more extraglandular manifestations affecting mainly the articular and glandular domains. Meanwhile, AA patients were characterized by higher rates of hypergammaglobulinemia (odds ratio [OR] 1.39 [95% confidence interval (95% CI) 1.39-8.65]; P = 0.01), elevated erythrocyte sedimentation rate (ESR) (OR 3.95 [95% CI 1.46-9.95]; P = 0.009), and parotid enlargement (OR 4.40 [95% CI 1.49-13.07]; P = 0.02). CONCLUSION: AI are affected at high rates with SS but present with few classical features, potentially preventing timely diagnosis. In contrast to SLE, SS is infrequent and not more severe among AA, but the triad of hypergammaglobulinemia, increased ESR, and parotid enlargement warrants extra vigilance for lymphomagenesis.


Assuntos
Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Índios Norte-Americanos/estatística & dados numéricos , Síndrome de Sjogren/etnologia , Síndrome de Sjogren/epidemiologia , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oklahoma/epidemiologia , Fatores de Risco
20.
J Rheumatol ; 47(1): 72-81, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30988130

RESUMO

OBJECTIVE: To construct a Frailty Index (FI) as a measure of vulnerability to adverse outcomes among patients with systemic lupus erythematosus (SLE), using data from the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort. METHODS: The SLICC inception cohort consists of recently diagnosed patients with SLE followed annually with clinical and laboratory assessments. For this analysis, the baseline visit was defined as the first study visit at which sufficient information was available for construction of an FI. Following a standard procedure, variables from the SLICC database were evaluated as potential health deficits. Selected health deficits were then used to generate a SLICC-FI. The prevalence of frailty in the baseline dataset was evaluated using established cutpoints for FI values. RESULTS: The 1683 patients with SLE (92.1% of the overall cohort) eligible for inclusion in the baseline dataset were mostly female (89%) with mean (SD) age 35.7 (13.4) years and mean (SD) disease duration 18.8 (15.7) months at baseline. Of 222 variables, 48 met criteria for inclusion in the SLICC-FI. Mean (SD) SLICC-FI was 0.17 (0.08) with a range from 0 to 0.51. At baseline, 27.1% (95% CI 25.0-29.2) of patients were classified as frail, based on SLICC-FI values > 0.21. CONCLUSION: The SLICC inception cohort permits feasible construction of an FI for use in patients with SLE. Even in a relatively young cohort of patients with SLE, frailty was common. The SLICC-FI may be a useful tool for identifying patients with SLE who are most vulnerable to adverse outcomes, but validation of this index is required prior to its use.

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