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1.
PLoS One ; 15(1): e0226516, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31929535

RESUMO

OBJECTIVE: Based on US National Health and Nutrition Examination Survey (NHANES) data, we attempted to provide an unbiased, population-based estimate of autoantibody prevalence overall and by age and sex. METHODS: US autoantibody prevalence estimates for detectable rheumatoid factor, anti-thyroglobulin, anti-thyroperoxidase, anti-transglutaminase, anti-endomysial, anti-GAD65, antinuclear autoantibodies, and autoantibodies to extractable nuclear antigens were estimated from the 1960-1962 National Health Examination Survey, NHANES III (1988-1994), and the NHANES 1999-2014 cross-sectional surveys. Survey design variables and sample weights were used to account for differential probabilities of selection within the complex survey design. Data analysis used SASTM and SUDAAN™ software. US Census Bureau data were used to estimate the absolute numbers of persons with autoantibodies. RESULTS: NHANES III data show that the overall US prevalence of having a detectable serum autoantibody is substantial in adults, in both women and men. Thyroid autoantibodies were present in 18% of US adults (31 million persons) including 10% of younger adults and 25% of older persons. Overall autoantibody prevalences increased significantly with age: 32% of US adults 60+ years of age (12.8 million persons) had at least one of the four autoantibodies rheumatoid factor, anti-thyroglobulin, anti-thyroperoxidase, or anti-tissue transglutaminase. Older women had higher levels of autoantibodies, but this was a relative difference. Autoantibody prevalence in both sexes was substantial (women 39%; men 22%). Fourteen percent of adults 60+ years of age have multiple autoantibodies. CONCLUSIONS: Autoantibodies are present in a significant fraction of the general population, especially in older adults and women relative to men. Although all known clinically significant autoantibodies were not analyzed, these data provide an important population perspective on the scope and magnitude of humoral autoimmunity in the US. This is vital for prevention efforts to reduce autoimmune disease and helps clarify the potential impact of autoimmunity on the general population.

2.
J Biopharm Stat ; 30(1): 160-177, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31730441

RESUMO

Evaluating the association between diseases and the longitudinal pattern of pharmacological therapy has become increasingly important. However, in many longitudinal studies, self-reported medication usage data collected at patients' follow-up visits could be missing for various reasons. These pieces of missing or inaccurate/untenable information complicate determining the trajectory of medication use and its complete effects for patients. Although longitudinal models can deal with specific types of missing data, inappropriate handling of this issue can lead to a biased estimation of regression parameters especially when missing data mechanisms are complex and depend upon multiple sources of variation. We propose a latent class-based multiple imputation (MI) approach using a Bayesian quantile regression (BQR) that incorporates cluster of unobserved heterogeneity for medication usage data with intermittent missing values. Findings from our simulation study indicate that the proposed method performs better than traditional MI methods under certain scenarios of data distribution. We also demonstrate applications of the proposed method to data from the Prospective Study of Outcomes in Ankylosing Spondylitis (AS) cohort when assessing an association between longitudinal nonsteroidal anti-inflammatory drugs (NSAIDs) usage and radiographic damage in AS, while the longitudinal NSAID index data are intermittently missing.

3.
Ann Rheum Dis ; 79(2): 193-201, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31604704

RESUMO

OBJECTIVES: The Assessment of SpondyloArthritis International Society (ASAS) aimed to develop a set of quality standards (QS) to help improve the quality of healthcare provided to adult patients affected by axial spondyloarthritis (axSpA) worldwide. METHODS: An ASAS task force developed a set of QS using a stepwise approach. First, key areas for quality improvement were identified, discussed, rated and agreed on. Thereafter, areas were prioritised and statements for the most important key areas were phrased on consensus. Appropriate quality measures were defined to allow quantification of the QS at the community level. RESULTS: The ASAS task force, consisting of 20 rheumatologists, two physiotherapists and two patients, selected and proposed 34 potential key areas for quality improvement which were then commented by 140 ASAS members and patients. Within that process three new key areas came up, which led to a re-evaluation of all 37 key areas by 120 ASAS members and patients. Five key areas were identified as most important to determine quality of care: referral including rapid access, rheumatology assessment, treatment, education/self-management and comorbidities. Finally, nine QS were agreed on and endorsed by the whole ASAS membership. CONCLUSIONS: ASAS successfully developed the first set of QS to help improving healthcare for adult patients with axSpA. Even though it may currently not be realistic to achieve the QS in all healthcare systems, they provide high-quality of care framework for patients with axSpA that should be aimed for.

4.
Rheum Dis Clin North Am ; 46(1): xiii-xiv, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757290
5.
Artigo em Inglês | MEDLINE | ID: mdl-31866044

RESUMO

About half of patients with systemic lupus erythematosus (SLE) are diagnosed with lupus nephritis (LN). Patients with SLE are also at increased risk for diabetes, hypertension and obesity, which together account for >70% of end-stage renal disease in the general population. The frequencies of non-LN related causes of kidney disease, and their contribution to kidney disease development and progression among patients with SLE have been inadequately studied. We hypothesize that a substantial, and increasing proportion of kidney pathology in patients with SLE might not directly relate to LN but instead might be explained by non-immune mediated factors such as diabetes, hypertension, and obesity. The goal of the manuscript is to draw attention to hypertension, diabetes and obesity as potential alternative causes of kidney damage in patients with SLE. Further, we suggest that misclassification of kidney disease etiology in patients with SLE might have important ramifications for clinical trial recruitment, epidemiologic investigation, and clinical care. Future studies aiming to elucidate and distinguish discrete causes of kidney disease - both clinically and histologically - among patients with SLE are desperately needed as improved understanding of disease mechanisms is paramount to advancing therapeutic discovery. Collaboration among rheumatologists, pathologists, nephrologists, and endocrinologists, and the availability of dedicated research funding, will be critical to the success of such efforts.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31600025

RESUMO

OBJECTIVE: The aim of this study was to determine the association of perceived stress with incident inflammatory arthritis (IA) defined as having at least 1 joint consistent with rheumatoid arthritis (RA)-like synovitis based on exam. METHODS: We conducted a prospective cohort study in the Studies of the Etiologies of Rheumatoid Arthritis (SERA). Participants without IA were recruited if they were a first degree relative of a RA proband or screened positive for anti-cyclic citrullinated peptide autoantibody (ACPA). Perceived stress was measured using the Perceived Stress Scale-14 (PSS) in which scores can range from 0 to 56 and a higher score indicates greater perceived stress. The total PSS score as well as two sub-scores indicative of perceived distress and self-efficacy were averaged across all study visits until development of IA or last follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) of IA associated with average PSS scores were obtained using Cox proportional hazards models. RESULTS: The mean total PSS score was 20.4. We found that a one-point increase in the perceived distress score was significantly associated with a 10 percent increase in the risk of IA (adjusted HR: 1.10; 95%CI: 1.02, 1.19). Total PSS and self-efficacy were not associated with IA risk (adjusted HR: 1.05 (95%CI: 0.99, 1.10) and 1.04 (95%CI: 0.91, 1.18), respectively. CONCLUSIONS: An association between perceived distress and incident IA was observed in this at-risk cohort. Replication of this finding in other preclinical and at-risk RA populations is needed.

7.
Rheum Dis Clin North Am ; 45(4): ix-x, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31564300
8.
Artigo em Inglês | MEDLINE | ID: mdl-31529687

RESUMO

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) increase blood pressure and potentially cardiovascular burden, which may limit their use in ankylosing spondylitis (AS). Our objective was to determine the association of NSAID use with incident hypertension in a longitudinal AS cohort. METHODS: Adults with AS were enrolled in a prospective cohort study of patient outcomes and examined every 4-6 months. Hypertension was defined by patient-reported hypertension; anti-hypertensive medication use; or, on two consecutive visits, systolic blood pressure ≥140 mm Hg or diastolic ≥90 mm Hg. Continuous NSAID use was dichotomized based on the validated NSAID index. We assessed the association of NSAID use as a time-varying exposure with the incidence of hypertension using Cox proportional hazards models. RESULTS: Of the 1282 patients in the cohort, 628 patients without baseline hypertension had at least one year of follow up, and were included in the analysis. Of these, 72% were male, the mean age at baseline was 39 ± 13 years, and 200 used NSAIDs continuously. On follow-up, 129 developed incident hypertension. After controlling for other variables, continuous NSAID use was associated with a hazard ratio (HR) of 1.12 for incident hypertension (95% CI, 1.04-1.20), compared to non-continuous or no use. The association did not differ in subgroups defined by age, body mass index, biologic use, or disease activity. CONCLUSION: In our prospective, longitudinal AS cohort, continuous NSAID use was associated with a 12% increased risk for the development of incident hypertension, as compared to non-continuous or no NSAID use.

9.
ACR Open Rheumatol ; 1(5): 292-302, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31453437

RESUMO

Objective: The objective of this study was to assess the performance and reproducibility of the two currently used ocular surface staining scores in the assessment of keratoconjunctivitis sicca in Sjögren syndrome (SS) research classification. Methods: In a multidisciplinary clinic for the evaluation of sicca, we performed all tests for the American European Consensus Group (AECG) and the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria, including the van Bijsterveld score (vBS) and the Ocular Staining Score (OSS), in 994 participants with SS or with non-SS sicca. We analyzed the concordance between the scores, the diagnostic accuracy and correlation with clinical variables, and interrater and intrasubject reproducibility. Results: A total of 308 (31.1%) participants had a discordant vBS and OSS that was due to extra corneal staining points in the OSS. The presence of one or more of the additional points was highly predictive of SS classification (odds ratio = 3.66; P = 1.65 × 10e-20) and was associated with abnormal results of all measures of autoimmunity and glandular dysfunction. Receiver operating characteristic curves showed optimal cutoff values of four for the vBS (sensitivity = 0.62; specificity = 0.71; Youden's J = 0.33) and five for the OSS (sensitivity = 0.56; specificity = 0.75; Youden's J = 0.31). Notably, there was very poor consistency in interobserver mean scores and distributions (P < 0.0001) and in intrasubject scores after a median of 5.5 years (35% changed status of the ocular criterion). Conclusion: Ocular surface staining scores are useful for SS research classification; however, they are subject to significant interrater and intrasubject variability, which could result in changes in classification in 5%-10% of all subjects. These results highlight the need for objective and reproducible markers of disease that have thus far remained elusive for SS.

10.
Rheum Dis Clin North Am ; 45(3): xiii-xiv, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31277757
11.
Artigo em Inglês | MEDLINE | ID: mdl-31199565

RESUMO

OBJECTIVE: To describe the clinical and serological manifestations of Sjögren's syndrome (SS) in ethnic groups of the United States. METHODS: Cross-sectional study of 648 patients with primary SS: 20 African-American (AA), 164 American Indian (AI), 426 European-American (EA) and 38 of other races evaluated in a multi-disciplinary sicca 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=3.01xE-05), the United States (p=2.24E-13) or a lupus cohort at the same institution (p=4.26x10E-27). In contrast, the percentage of AI in the SS cohort (25.3%) was much higher than expected (p=3.17E-09 vs. SLE; p=6.36-26 vs. Oklahoma and p=8.14E-96 vs. USA 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 ESSDAI 3.77±4.78) in comparison to whites (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 (OR 1.39, 95%CI 1.39-8.65, p=0.01), elevated 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). CONCLUSIONS: American Indians 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 amongst AA, but the triad of hypergammaglobulinemia, increased ESR and parotid enlargement warrants extra vigilance for lymphomagenesis. This article is protected by copyright. All rights reserved.

12.
Ann Rheum Dis ; 78(9): 1235-1241, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31217170

RESUMO

OBJECTIVE: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with unknown aetiology. Epstein-Barr virus (EBV) is an environmental factor associated with SLE. EBV maintains latency in B cells with frequent reactivation measured by antibodies against viral capsid antigen (VCA) and early antigen (EA). In this study, we determined whether EBV reactivation and single nucleotide polymorphisms (SNPs) in EBV-associated host genes are associated with SLE transition. METHODS: SLE patient relatives (n=436) who did not have SLE at baseline were recontacted after 6.3 (±3.9) years and evaluated for interim transitioning to SLE (≥4 cumulative American College of Rheumatology criteria); 56 (13%) transitioned to SLE prior to the follow-up visit. At both visits, detailed demographic, environmental, clinical information and blood samples were obtained. Antibodies against viral antigens were measured by ELISA. SNPs in IL10, CR2, TNFAIP3 and CD40 genes were typed by ImmunoChip. Generalised estimating equations were used to test associations between viral antibody levels and transitioning to SLE. RESULTS: Mean baseline VCA IgG (4.879±1.797 vs 3.866±1.795, p=0.0003) and EA IgG (1.192±1.113 vs 0.7774±0.8484, p=0.0236) levels were higher in transitioned compared with autoantibody negative non-transitioned relatives. Increased VCA IgG and EA IgG were associated with transitioning to SLE (OR 1.28 95% CI 1.07 to 1.53, p=0.007, OR 1.43 95% CI 1.06 to 1.93, p=0.02, respectively). Significant interactions were observed between CD40 variant rs48100485 and VCA IgG levels and IL10 variant rs3024493 and VCA IgA levels in transitioning to SLE. CONCLUSION: Heightened serologic reactivation of EBV increases the probability of transitioning to SLE in unaffected SLE relatives.

13.
Artigo em Inglês | MEDLINE | ID: mdl-31058466

RESUMO

OBJECTIVE: We investigated prospective change in the prevalence of coronary microvascular dysfunction (CMD) and obstructive coronary artery disease (CAD) in a cohort of systemic lupus erythematosus (SLE) subjects initially evaluated for anginal chest pain (CP). BACKGROUND: Prior work documented a relatively high prevalence of CMD in the absence of obstructive CAD in subjects with SLE. METHODS: Twenty female SLE subjects with CP who underwent stress cardiac magnetic resonance imaging (CMRI) and coronary computed tomography angiography (CCTA) at baseline were re-evaluated at 5 years. RESULTS: Seventeen subjects (85%) were available and re-enrolled, of which eleven (65%) had persistent chest pain on follow up. Fourteen subjects had complete follow up CMRI, of which 36% (5/14) demonstrated CMD on follow up. Further, 25% (1/4) of the originally abnormal MPRI at baseline were lower at follow up, while 2 additionally abnormal MPRI values on follow up were noted in previously normal MPRIs. Both prevalence of CMD and non-obstructive/obstructive CAD were unchanged between baseline and follow up, respectively (both p=ns). During follow up, 33% (5/15) had adverse cardiac outcomes including pericarditis, unstable angina or intracranial aneurysm clipping procedure. CONCLUSIONS: At 5-year follow up of SLE subjects with CP evaluated at baseline and follow up, a majority had persistent CP and nearly half had similar or worse myocardial perfusion consistent with CMD without obstructive CAD. These findings propose an alternative explanation for CP in SLE subjects compared to the more common SLE-related accelerated obstructive CAD accounting for CP and adverse outcomes. These findings support further studies of CMD as an etiology for cardiac morbidity and mortality in SLE. This article is protected by copyright. All rights reserved.

14.
J Rheumatol ; 46(12): 1556-1559, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30988128

RESUMO

OBJECTIVE: We investigated the association of age and anticyclic citrullinated peptide antibodies (anti-CCP) in subjects without rheumatoid arthritis (RA). METHODS: Serum was tested for anti-CCP3.1 (IgG/IgA) in 678 first-degree relatives (FDR) of patients with RA and 330 patients with osteoarthritis (OA). Individual isotypes (anti-CCP-IgA and anti-CCP-IgG) were also tested in all FDR. RESULTS: In FDR, increasing age was significantly associated with positivity for anti-CCP3.1 (per year, OR 1.03) and anti-CCP-IgA (per year, OR 1.05) but not anti-CCP-IgG. In FDR and OA subjects, anti-CCP3.1 prevalence was significantly increased after age 50 years. CONCLUSION: Increasing age in individuals without RA should be considered in the interpretation of anti-CCP3.1 positivity.

16.
J Rheumatol ; 46(12): 1582-1588, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30936280

RESUMO

OBJECTIVE: Cauda equina syndrome (CES) is a rare neurologic complication of longstanding ankylosing spondylitis (AS). It is unclear what causes CES, and no proven or effective therapy has been reported to date. We have encountered 6 patients with longstanding AS diagnosed with CES. We set about to study their features, review the literature, and generate hypotheses regarding pathophysiology, as well as to speculate on the possibilities of early recognition and prevention. METHODS: We obtained permission from 6 patients with longstanding AS and CES to access their medical records and imaging studies for research purposes related to this paper. We collected and reviewed each patient's medical history, imaging studies, disease duration, past therapies especially those that relate to AS, laboratory data, as well as any treatment they received for CES and followup results of each case to the present time. RESULTS: The 6 cases of CES with AS have remarkable similarity to each other in that several decades of the disease had passed before neurologic symptoms and later signs appeared. All cases have fused spines and facet joints without spinal fractures, spinal stenosis, or disc herniation. CONCLUSION: CES is a rare yet debilitating neurologic complication of longstanding AS. The pathophysiology and treatments are far from clear. We postulate that chronic enthesitis of the vertebral column initiates the process that results in dural stiffening and formation of ectasias, causing downstream nerve root damage.

18.
EBioMedicine ; 42: 76-85, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952617

RESUMO

BACKGROUND: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. METHODS: Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb-) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. FINDINGS: Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. INTERPRETATION: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. FUND: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.


Assuntos
Artrite Reumatoide/etiologia , Autoimunidade/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/etiologia , Núcleo Familiar , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico , Autoanticorpos/imunologia , Meio Ambiente , Feminino , Frequência do Gene , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
19.
Arthritis Res Ther ; 21(1): 48, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30728079

RESUMO

OBJECTIVE: The objective was to estimate the incidence of lung disease among patients with systemic lupus erythematosus (SLE). METHODS: Using Swedish register data, we identified patients with SLE and pulmonary diagnoses from the National Patient Register through ICD codes. We matched patients with SLE with individuals from the general population. Patients with SLE with a history of pulmonary disease were excluded. Incidence rates (IR) and 95% confidence intervals (CI) were calculated overall and by type of pulmonary disease for incident (2003-2013) and prevalent SLE separately. Hazard ratios (HR) and 95% CI of the association between SLE and pulmonary disease were estimated using adjusted Cox regression models. Sensitivity analyses using a semi-automated approach to quantitative probabilistic bias analysis accounted for potential bias due to unmeasured confounding by smoking. RESULTS: There were 3209 incident and 6908 prevalent cases of SLE identified. The IRs for pulmonary disease were similar in prevalent and incident SLE (∼14 cases per 1000 person-years). Patients with incident SLE had a nearly sixfold higher rate of pulmonary disease compared to the non-SLE population (HR 5.8 (95% CI 4.8-7.0)). Incident and prevalent SLE was associated with an increased rate of interstitial lung disease (HR 19.0 (95% CI 10.7-34.0) and 14.3 (95% CI 10.8-18.8), respectively). Bias due to unmeasured confounding by smoking was unlikely to explain our findings. CONCLUSION: Lung disease is relatively common in patients with SLE compared to the general population. Clinicians caring for patients with SLE should have heightened suspicion of lung disease, including interstitial lung disease, even early within the disease course or at the time of diagnosis of SLE.

20.
J Clin Invest ; 129(3): 958-961, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776023

RESUMO

Despite advances in understanding systemic lupus erythematosus (SLE) pathogenesis, most clinical trials of new targeted therapies have been met with disappointment. The type I IFN pathway is believed to play an important role in SLE, and the proposed involvement of this pathway helps explain the frustration behind the failure at targeting either IFN-α or the type 1 IFN receptor itself. In this issue of the JCI, Furie et al. report on an intriguing phase 1b study that demonstrates an approach for inhibiting this pathway in the skin using an mAB (BIIB059) that targets the blood DC antigen 2 (BDCA-2) receptor on plasmacytoid DCs (pDCs). BIIB059 decreased IFN expression and improved cutaneous lupus disease activity, with a favorable safety profile. Whether or not this strategy will be effective in managing SLE in other organs remains unanswered. However, these results suggest that closing the door on targeting the type 1 IFN pathway in SLE may be premature and highlight the emerging question of whether an organ-specific approach toward lupus trials and treatment should be the wave of the future.

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