Faculty Bibliography
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Clinical Features and Select Dysregulated Immune Parameters Distinguish Blood Relatives Who Remain Clinically Stable or Progress to Incomplete Lupus or Classified SLE in the Lupus Autoimmunity in Relatives (LAUREL) Follow-up Cohort [Meeting Abstract]
Background/Purpose: Identifying populations at risk of SLE is essential to curtail inflammatory damage and identify individuals for prevention trials. Unaffected blood relatives (BRs) of lupus patients have increased risk of SLE. Some BRs have autoantibodies (AutoAbs) or SLE clinical features, but do not progress, some progress, but do not meet the required >= 4 ACR classification criteria (incomplete lupus, ILE), while others progress to classified SLE. The goal of this study is to determine factors that distinguish previously healthy BRs who remain stable or subsequently progress to ILE or SLE.
Method(s): This is a nested study of re-enrolled BRs of SLE patients (n=436) who previously enrolled in a genetics study (mean time to follow-up = 6.3 yrs) and did not meet SLE classification at baseline (BL). Of the 177 (41%) and 259 (59%) who did/did not meet additional ACR criteria at follow-up (FU) in this cohort, we compared the 56 BRs who transitioned to SLE (>=4 ACR criteria) to 34 BRs who met 3 ACR criteria (ILE) at FU and 154 race/sex/age (+/- 5 years) matched BRs with < 3 ACR criteria at FU. BRs provided clinical and demographic information, and completed the SLE-specific portion of the CTD Screening Questionnaire (CSQ) at BL and FU. Medical records were reviewed for ACR classification criteria. BL and FU plasma samples were assessed for autoantibody production (ANA, anti-dsDNA, aCL, Ro, La, Sm, nRNP, and ribosomal p antibodies) and for 52 soluble inflammatory and regulatory mediators by xMAP and ELISA assay.
Result(s): 133/244 (55%) of BRs evaluated in this nested cohort did not have any change in ACR criteria between BL and FU (Fig. 1, red circles, Nonprogressors [NP]), while the remaining 111 BRs accrued >=1 classification criteria (Fig. 1, black circles, Progressors). There was no difference in time to FU between NP and Progressor BRs. No significant differences were seen in ACR criteria, either at BL or FU, between BRs with ILE at BL who were NP vs. those who progressed to SLE at FU. Yet, a number of differences were seen at BL in BRs meeting 2 ACR criteria at BL who were NP vs. those who progressed to ILE or SLE at FU. NP BRs with BL ACR Score = 2 were more likely to meet immunologic criteria (p< 0.0001), while those BRs with ACR score <= 2 who progressed to ILE or SLE were more likely to meet clinical criteria at BL, particularly malar rash (p=0.0126) or arthritis (p=0.0054). In addition, these same NP had significantly lower SLE-CSQ scores and features at BL (Fig. 2A), with lower plasma levels of IL-2Ralpha and lower ANA titers. At FU, ACR Score = 2 NP had lower levels of BLyS and accumulated fewer AutoAbs (Fig. 2B). At both BL and FU, levels of the regulatory mediator Native TGF-beta were significantly higher in ACR Score = 2 NP (Fig. 2B). For those BRs with ILE at BL, those who progressed to SLE at FU had higher BL levels of SCF, MCP-3, and more AutoAb specificities than BL ILE NP BRs, with no difference in levels of Native TGF-beta (Fig. 2C).
Conclusion(s): BRs of known SLE patients who progress to ILE or SLE compared to BRs who remain stable are more likely to have elevated inflammatory mediators, reduced regulatory mediators, and meet as few as one clinical ACR classification criterion. This suggests that ANA or serologic positivity alone is not predictive of progression to ILE or SLE in lupus relatives
Method(s): This is a nested study of re-enrolled BRs of SLE patients (n=436) who previously enrolled in a genetics study (mean time to follow-up = 6.3 yrs) and did not meet SLE classification at baseline (BL). Of the 177 (41%) and 259 (59%) who did/did not meet additional ACR criteria at follow-up (FU) in this cohort, we compared the 56 BRs who transitioned to SLE (>=4 ACR criteria) to 34 BRs who met 3 ACR criteria (ILE) at FU and 154 race/sex/age (+/- 5 years) matched BRs with < 3 ACR criteria at FU. BRs provided clinical and demographic information, and completed the SLE-specific portion of the CTD Screening Questionnaire (CSQ) at BL and FU. Medical records were reviewed for ACR classification criteria. BL and FU plasma samples were assessed for autoantibody production (ANA, anti-dsDNA, aCL, Ro, La, Sm, nRNP, and ribosomal p antibodies) and for 52 soluble inflammatory and regulatory mediators by xMAP and ELISA assay.
Result(s): 133/244 (55%) of BRs evaluated in this nested cohort did not have any change in ACR criteria between BL and FU (Fig. 1, red circles, Nonprogressors [NP]), while the remaining 111 BRs accrued >=1 classification criteria (Fig. 1, black circles, Progressors). There was no difference in time to FU between NP and Progressor BRs. No significant differences were seen in ACR criteria, either at BL or FU, between BRs with ILE at BL who were NP vs. those who progressed to SLE at FU. Yet, a number of differences were seen at BL in BRs meeting 2 ACR criteria at BL who were NP vs. those who progressed to ILE or SLE at FU. NP BRs with BL ACR Score = 2 were more likely to meet immunologic criteria (p< 0.0001), while those BRs with ACR score <= 2 who progressed to ILE or SLE were more likely to meet clinical criteria at BL, particularly malar rash (p=0.0126) or arthritis (p=0.0054). In addition, these same NP had significantly lower SLE-CSQ scores and features at BL (Fig. 2A), with lower plasma levels of IL-2Ralpha and lower ANA titers. At FU, ACR Score = 2 NP had lower levels of BLyS and accumulated fewer AutoAbs (Fig. 2B). At both BL and FU, levels of the regulatory mediator Native TGF-beta were significantly higher in ACR Score = 2 NP (Fig. 2B). For those BRs with ILE at BL, those who progressed to SLE at FU had higher BL levels of SCF, MCP-3, and more AutoAb specificities than BL ILE NP BRs, with no difference in levels of Native TGF-beta (Fig. 2C).
Conclusion(s): BRs of known SLE patients who progress to ILE or SLE compared to BRs who remain stable are more likely to have elevated inflammatory mediators, reduced regulatory mediators, and meet as few as one clinical ACR classification criterion. This suggests that ANA or serologic positivity alone is not predictive of progression to ILE or SLE in lupus relatives
EMBASE:634233200
ISSN: 2326-5205
CID: 4804842
Safety of Obtaining Research Tissue during Clinically Indicated Kidney Biopsies: Data from the Lupus Accelerating Medicines Partnership [Meeting Abstract]
Background/Purpose: Lupus nephritis (LN) is a major complication of systemic lupus erythematous (SLE) and affects ~60% of patients during the course of their disease, leading to significant morbidity and mortality. Previous studies examining the safety of percutaneous kidney biopsy to diagnose LN have found variable complication rates depending on disease type studied, ranging from 4-11% in autoimmune/SLE patients to 15-17% in safety studies of any kidney disease. The purpose of our study was to define the safety of obtaining additional tissue for research during clinically indicated renal biopsies in a SLE cohort.
Method(s): Patients were enrolled across 15 clinical US sites in the SLE Accelerating Medicines Partnership (AMP). Kidney biopsies were clinically indicated to evaluate proteinuria (urine protein creatinine ratio [uPCR] > 0.5). Patients with a history of renal transplant, use of rituximab within 6 months of biopsy, and current pregnancy were excluded. Ultrasound/CT-guided kidney biopsies were performed by interventional radiologists/nephrologists generally using an 18-gauge needle although technique, number of routine passes and core lengths varied. An additional core taken solely for research purposes, or a piece of core with sufficient glomeruli remaining from the routine passes and not required for clinical diagnosis, was collected. All adverse events (AEs) occurring within 30 days of biopsy were reported, including duration, severity, type, and resolution.
Result(s): 482 patients underwent a renal biopsy between 2014 and 2020. All patients met criteria for SLE (ACR or SLICC) and the majority were female (85%). Pathologic assessment of clinical biopsies revealed ISN/RPS Class I-VI for most biopsies, although 45 biopsies (9%) yielded a non-LN diagnosis (Table 1). Overall, 37 patients (8%) experienced an AE with several more than one, with a total of 41 AEs reported. Of these AEs, 8 (20%) were considered by the site investigator to be unrelated or unlikely to be related (included pain, shortness of breath, cardiac arrest, fall, and hemoglobin decrease due to sepsis) and 33 (80%) were deemed possibly, probably, or definitely related to the study procedure. Of these events, 9/33 (28%) were mild, 10 (30%) were moderate, and 12 (36%) were deemed severe. In 18 patients (4%) the AEs were considered serious as defined by inpatient or prolonged hospitalization, significant incapacity, or requiring intervention to prevent permanent impairment. The most common related AEs were bleed-related complications, including hematoma, hemorrhage, and hemoglobin decrease (N= 29). Of these, 18 required hospitalization, with 4 of these patients receiving a blood transfusion. All 29 bleed-related complications resolved. The length of the research biopsy did not associate with an AE.
Conclusion(s): Procurement of an additional kidney biopsy core for research purposes in SLE patients undergoing a clinically-indicated kidney biopsy did not result in an increase in adverse events compared to the adverse event rate in prior studies of the safety of percutaneous kidney biopsy. Accordingly, inclusion of a research core should be considered feasible for future studies to advance discovery of new therapeutic targets and prognostic indicators in LN
Method(s): Patients were enrolled across 15 clinical US sites in the SLE Accelerating Medicines Partnership (AMP). Kidney biopsies were clinically indicated to evaluate proteinuria (urine protein creatinine ratio [uPCR] > 0.5). Patients with a history of renal transplant, use of rituximab within 6 months of biopsy, and current pregnancy were excluded. Ultrasound/CT-guided kidney biopsies were performed by interventional radiologists/nephrologists generally using an 18-gauge needle although technique, number of routine passes and core lengths varied. An additional core taken solely for research purposes, or a piece of core with sufficient glomeruli remaining from the routine passes and not required for clinical diagnosis, was collected. All adverse events (AEs) occurring within 30 days of biopsy were reported, including duration, severity, type, and resolution.
Result(s): 482 patients underwent a renal biopsy between 2014 and 2020. All patients met criteria for SLE (ACR or SLICC) and the majority were female (85%). Pathologic assessment of clinical biopsies revealed ISN/RPS Class I-VI for most biopsies, although 45 biopsies (9%) yielded a non-LN diagnosis (Table 1). Overall, 37 patients (8%) experienced an AE with several more than one, with a total of 41 AEs reported. Of these AEs, 8 (20%) were considered by the site investigator to be unrelated or unlikely to be related (included pain, shortness of breath, cardiac arrest, fall, and hemoglobin decrease due to sepsis) and 33 (80%) were deemed possibly, probably, or definitely related to the study procedure. Of these events, 9/33 (28%) were mild, 10 (30%) were moderate, and 12 (36%) were deemed severe. In 18 patients (4%) the AEs were considered serious as defined by inpatient or prolonged hospitalization, significant incapacity, or requiring intervention to prevent permanent impairment. The most common related AEs were bleed-related complications, including hematoma, hemorrhage, and hemoglobin decrease (N= 29). Of these, 18 required hospitalization, with 4 of these patients receiving a blood transfusion. All 29 bleed-related complications resolved. The length of the research biopsy did not associate with an AE.
Conclusion(s): Procurement of an additional kidney biopsy core for research purposes in SLE patients undergoing a clinically-indicated kidney biopsy did not result in an increase in adverse events compared to the adverse event rate in prior studies of the safety of percutaneous kidney biopsy. Accordingly, inclusion of a research core should be considered feasible for future studies to advance discovery of new therapeutic targets and prognostic indicators in LN
EMBASE:634233060
ISSN: 2326-5205
CID: 4810622
Glucocorticosteroid usage and major organ damage in patients with systemic lupus erythematosus-meta-analyses of observational studies published between 1979 and 2018 [Meeting Abstract]
Background/Purpose : The impact of glucocorticoid (GC) use on major organ damage in SLE patients has not been formally studied by amalgamating the relevant data published in the literature over the past 40 years. We aimed to study the association between GC use and the occurrence of major organ damage in SLE patients by performing meta-analyses of observational studies published between 1970 and December 2018. Methods : Literature search on PubMed (from 1966 to December 2018) for prevalence and longitudinal studies which reported GC exposure (proportion of GC users in the cohort [%GC use] and/or GC use in defined doses) and the occurrence (prevalence/incidence) of major organ damage in SLE patients using the keywords cataract, cerebrovascular (CVA), stroke, cardiovascular (CVS), angina, myocardial infarction (MI), coronary artery bypass, osteoporosis, avascular necrosis (AVN) and osteonecrosis in respective combinations with lupus was conducted. Studies with sample size < 50 and observation duration < 12 months were excluded. The logit of the proportion of patients with disease damage was modelled as a random effect in the meta-analysis, which was employed to study the association between the proportion of patients with organ damage and variables of GC use (mean daily [mg/day] and cumulative [gm] prednisone [PDN] doses and %GC use). A 2-stage estimation of the random-effects logistic regression models was used with restricted maximum likelihood estimation. Univariate associations between organ damage and moderators were examined for statistical significance, and variables related to GC use were adjusted for SLE disease duration in multivariate models if their univariate P values were < 0.2. Results : Out of 8,882 publications screened, 212 articles involving 205,619 SLE patients were eligible for the metaanalyses (Figure 1), of which 97 were prevalence and 115 were longitudinal studies. Univariate analyses of prevalence studies revealed that mean daily PDN dose (odds ratio [OR]=1.10, p=0.007) and lower proportion of female in the cohort (OR=0.002, p=0.002) were associated with the prevalence of overall CVS events. Mean daily PDN dose (OR=1.52, p< 0.001) and %GC use (OR=2,255.2, p< 0.001) were associated with the prevalence of AVN. A significant association between cumulative PDN dose and prevalence of CVA was found after multivariate adjustment for SLE disease duration (OR=1.07, p=0.017). In longitudinal studies, a significant association was identified between cumulative PDN dose and incidence of cataracts after adjustment for SLE disease duration (OR=1.04, p=0.013). While the incidence of MI in SLE patients has dropped over the past 40 years (OR=0.94, p=0.002), it was associated with % GC use after adjustment for SLE disease duration (OR=8.18, p=0.012). Interestingly, significant univariate associations were found between antimalarial use and lower prevalence of MI (OR=0.05, p=0.002) and lower incidence of CVA (OR=0.20, p=0.032). Conclusion : Independent of SLE disease duration, cumulative PDN dose was associated with higher prevalence of CVA and incidence of cataracts, and higher incidence of MI was associated with overall GC use
EMBASE:633059985
ISSN: 2326-5205
CID: 4633432
