Association of Race and Risk of Future Scleroderma Renal Crisis at Systemic Sclerosis Diagnosis.

OBJECTIVE: Scleroderma renal crisis (SRC) is a rare and severe manifestation of systemic sclerosis (SSc). Although it is well documented that Black patients with SSc have worse morbidity and mortality than non-Black patients, racial predilection for SRC is underreported. We examine the association of race and future development of SRC in an SSc cohort. METHODS: Using the electronic health record of the US Military Health System, we conducted a comprehensive chart review of each patient with SSc from 2005 to 2016. The final study cohort was comprised of 31 SRC cases and 322 SSc without SRC controls. We conducted logistic regression of SRC as the outcome variable and race (Black versus non-Black) as the primary predictor variable, adjusted for age, estimated glomerular filtration rate, hypertension, and proteinuria at SSc diagnosis. RESULTS: Of 353 patients, 294 had identifiable race (79 Black, 215 non-Black). Thirteen of 79 Black patients (16.5%) versus 16 of 215 (7.4%) non-Black patients developed SRC (P = 0.02). On adjusted analysis, Black patients had a significantly higher risk of developing SRC than non-Black patients (odds ratio 6.4 [95% confidence interval 1.3-31.2], P = 0.02). Anti-Ro antibody was present in a higher proportion of Black SRC patients versus Black patients without SRC (45% versus 14%, P = 0.01). Conversely, older age, thrombocytopenia, and anti-RNA polymerase III antibody at SSc diagnosis were significantly associated with future SRC in the non-Black cohort. CONCLUSION: Black race was independently associated with a higher risk of future SRC. Further studies are needed to elucidate the mechanisms that underlie this important association.

Focal Segmental Glomerulosclerosis, Risk Factors for End Stage Kidney Disease, and Response to Immunosuppression.

Background: FSGS is a heterogeneic glomerular disease. Risk factors for kidney disease ESKD and the effect of immunosuppression treatment (IST) has varied in previously published cohorts. These cohorts were limited by relatively small case numbers, short follow-up, lack of racial/ethnic diversity, a mix of adult and pediatric patients, lack of renin-angiotensin-aldosterone system (RAAS) inhibition, or lack of subgroup analysis of IST. Methods: We compared demographics, clinical characteristics, histopathology, and IST to long-term renal survival in a large, ethnically diverse, adult cohort of 338 patients with biopsy-proven FSGS with long-term follow-up in the era of RAAS inhibition using data from the US Department of Defense health care network. Results: Multivariate analysis showed that nephrotic-range proteinuria (NRP), eGFR <60 ml/min per 1.73 m2, hypoalbuminemia, interstitial fibrosis and tubular atrophy, and interstitial inflammation at diagnosis and the absence of remission were all associated with worse long-term renal survival. IgM, C3, and a combination of IgM/C3 immunofluorescence staining were not associated with reduced renal survival. IST was not associated with improved renal survival in the whole cohort, or in a subgroup with NRP. However, IST was associated with better renal survival in a subgroup of patients with FSGS with both NRP and hypoalbuminemia and hypoalbuminemia alone. Conclusions: Our study suggests that IST should be reserved for patients with FSGS and nephrotic syndrome. It also introduces interstitial inflammation as a potential risk factor for ESKD and does not support the proposed pathogenicity of IgM and complement activation.

Autoantibodies are present before the clinical diagnosis of systemic sclerosis.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disorder associated with vascular dysfunction and fibrotic changes in the skin, vasculature and internal organs. Although serologic abnormalities are an important diagnostic tool for SSc, little is known about whether autoantibodies precede clinical diagnosis. Here we investigated the presence of autoantibodies before SSc diagnosis and assessed whether certain autoantibodies might associate with the future onset of scleroderma renal crisis (SRC), a potentially fatal complication of the disease. Using the Department of Defense Serum Repository, autoantibodies were analyzed from archived, prospectively collected, longitudinal serum samples from sixteen individuals with SRC (SSc/SRC) and thirty cases of SSc without SRC (SSc/no SRC), matched for age, sex, and race. Seventy five percent (12/16) of the SSc/SRC and 40% (12/30) of the SSc/no SRC were seropositive for at least one autoantibody prior to clinical diagnosis (up to 27.1 years earlier, mean = -7.4 years). Although both disease groups demonstrated a heterogeneous immunoreactivity profile against the autoantigen panel, the SSc/SRC subjects showed two enriched clusters with one featuring elevated levels of autoantibodies against Ro52 and/or Ro60 and another with high levels of immunoreactivity against the RNA polymerase complex. Consistent with larger spectrum of immunoreactivity and the elevated levels of autoantibodies in SSc/SRC, the total response against the autoantigen panel from the last time point of the seropositive subjects revealed that the SSc/SRC cohort harbored higher antibody levels (p = 0.02) compared to SSc/no SRC. Overall, our findings demonstrate that relevant seropositive autoantibodies often precede the clinical diagnosis of SSc/no SRC and SSc/SRC.

Risk Factors for Future Scleroderma Renal Crisis at Systemic Sclerosis Diagnosis.

OBJECTIVE: Systemic sclerosis (SSc) is a disease of autoimmunity, fibrosis, and vasculopathy. Scleroderma renal crisis (SRC) is one of the most severe complications. Corticosteroid exposure, presence of anti-RNA polymerase III antibodies (ARA), skin thickness, and significant tendon friction rubs are among the known risk factors at SSc diagnosis for developing future SRC. Identification of additional clinical characteristics and laboratory findings could expand and improve the risk profile for future SRC at SSc diagnosis. METHODS: In this retrospective cohort study of the entire military electronic medical record between 2005 and 2016, we compared the demographics, clinical characteristics, and laboratory results at SSc diagnosis for 31 cases who developed SRC after SSc diagnosis to 322 SSc without SRC disease controls. RESULTS: After adjustment for potential confounding variables, at SSc diagnosis these conditions were all associated with future SRC: proteinuria (p < 0.001; OR 183, 95% CI 19.1-1750), anemia (p = 0.001; OR 9.9, 95% CI 2.7-36.2), hypertension (p < 0.001; OR 13.1, 95% CI 4.7-36.6), chronic kidney disease (p = 0.008; OR 20.7, 95% CI 2.2-190.7), elevated erythrocyte sedimentation rate (p < 0.001; OR 14.3, 95% CI 4.8-43.0), thrombocytopenia (p = 0.03; OR 7.0, 95% CI 1.2-42.7), hypothyroidism (p = 0.01; OR 2.8, 95% CI 1.2-6.7), Anti-Ro antibody seropositivity (p = 0.003; OR 3.9, 95% CI 1.6-9.8), and ARA (p = 0.02; OR 4.1, 95% CI 1.2-13.8). Three or more of these risk factors present at SSc diagnosis was sensitive (77%) and highly specific (97%) for future SRC. No SSc without SRC disease controls had ≥ 4 risk factors. CONCLUSION: In this SSc cohort, we present a panel of risk factors for future SRC. These patients may benefit from close observation of blood pressure, proteinuria, and estimated glomerular filtration rate, for earlier SRC identification and intervention. Future prospective therapeutic studies could focus specifically on this high-risk population.

Integrating scientific data for drug discovery and development using the Life Sciences Grid.

BACKGROUND: There are many daunting challenges for companies who wish to bring novel drugs to market. The information complexity around potential drug targets has increased greatly with the introduction of microarrays, high-throughput screening and other technological advances over the past decade, but has not yet fundamentally increased our understanding of how to modify a disease with pharmaceuticals. Further, the bar has been raised in getting a successful drug to market as just being new is no longer enough: the drug must demonstrate improved performance compared with the ever increasing generic pharmacopeia to gain support from payers and government authorities. In addition, partly as a consequence of a climate of concern regarding the safety of drugs, regulatory authorities have approved fewer new molecular entities compared to historical norms over the past few years. OBJECTIVE: To overcome these challenges, the pharmaceutical industry must fully embrace information technology to bring better understood compounds to market. An important first step in addressing an unmet medical need is in understanding the disease and identifying the physiological target(s) to be modulated by the drug. Deciding which targets to pursue for a given disease requires a multidisciplinary effort that integrates heterogeneous data from many sources, including genetic variations of populations, changes in gene expression and biochemical assays. METHOD: The Life Science Grid was developed to provide a flexible framework to integrate such diverse biological, chemical and disease information to help scientists make better-informed decisions. RESULTS/CONCLUSION: The Life Science Grid has been used to rapidly and effectively integrate scientific information in the pharmaceutical industry and has been placed in the open source community to foster collaboration in the life sciences community.