Publications by authors named "Cristina Arriens"

19 Publications

  • Page 1 of 1

Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial.

Lancet 2021 May 7;397(10289):2070-2080. Epub 2021 May 7.

Research, Aurinia Pharmaceuticals, Victoria, BC, Canada. Electronic address:

Background: Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis.

Methods: This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499.

Findings: Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64-4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments.

Interpretation: Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis.

Funding: Aurinia Pharmaceuticals.
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http://dx.doi.org/10.1016/S0140-6736(21)00578-XDOI Listing
May 2021

A Multianalyte Assay Panel With Cell-Bound Complement Activation Products Predicts Transition of Probable Lupus to American College of Rheumatology-Classified Lupus.

ACR Open Rheumatol 2021 Feb 4;3(2):116-123. Epub 2021 Feb 4.

Exagen, Inc, Vista, California, and Loma Linda University, Loma Linda, California.

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.
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http://dx.doi.org/10.1002/acr2.11219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882535PMC
February 2021

Autoantibody-positive healthy individuals with lower lupus risk display a unique immune endotype.

J Allergy Clin Immunol 2020 12 22;146(6):1419-1433. Epub 2020 May 22.

Department of Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, Okla; Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Okla; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, Okla. Electronic address:

Background: Autoimmune diseases comprise a spectrum of illnesses and are on the rise worldwide. Although antinuclear antibodies (ANAs) are detected in many autoimmune diseases, up to 20% of healthy women are ANA-positive (ANA+) and most will never develop clinical symptoms. Furthermore, disease transition is higher among ANA+ African Americans compared with ANA+ European Americans.

Objective: We sought to determine the immune features that might define and prevent transition to clinical autoimmunity in ANA+ healthy individuals.

Methods: We comprehensively phenotyped immune profiles of African Americans and European Americans who are ANA-negative (ANA-) healthy, ANA+ healthy, or have SLE using single cell mass cytometry, next-generation RNA-sequencing, multiplex cytokine profiling, and phospho-signaling analyses.

Results: We found that, compared with both ANA- and ANA+ healthy individuals, patients with SLE of both races displayed T-cell expansion and elevated expression of type I and II interferon pathways. We discovered a unique immune signature that suggests a suppressive immune phenotype and reduced CD11C autoimmunity-associated B cells in healthy ANA+ European Americans that is absent in their SLE or even healthy ANA- counterparts, or among African American cohorts. In contrast, ANA+ healthy African Americans exhibited elevated expression of T-cell activation markers and higher plasma levels of IL-6 than did healthy ANA+ European Americans.

Conclusions: We propose that this novel immune signature identified in ANA+ healthy European Americans may protect them from T-cell expansion, heightened activation of interferon pathways, and disease transition.
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http://dx.doi.org/10.1016/j.jaci.2020.04.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680268PMC
December 2020

Cell-bound complement activation products associate with lupus severity in SLE.

Lupus Sci Med 2020 04;7(1)

Exagen Inc, Vista, California, USA.

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 R=0.145).

Conclusion: Abnormalities in complement activation as measured by CB-CAPs are associated with increased LSI.
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http://dx.doi.org/10.1136/lupus-2019-000377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228655PMC
April 2020

Lupus patient decisions about clinical trial participation: a qualitative evaluation of perceptions, facilitators and barriers.

Lupus Sci Med 2020 15;7(1):e000360. Epub 2020 Mar 15.

College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

Objective: Although SLE disproportionately affects minority racial groups, they are significantly under-represented in clinical trials in the USA. This may lead to misleading conclusions in race-based subgroup analyses. We conducted focus groups to evaluate the perceptions of diverse patients with lupus about clinical trial participation.

Methods: A qualitative research design employed three 90 min focus groups led by a trained moderator and guided by the Theory of Planned Behaviour. Open-ended questions about trial participation included advantages and disadvantages (behavioural beliefs), approving and disapproving significant others (normative beliefs), and participation enhancers and barriers (control beliefs). Discussions were recorded, transcribed and analysed to identify emerging themes.

Results: Patients with SLE (n=23) aged 21-72, with increased proportion of minority groups (65%), participated. Reported advantages of trial participation included altruism and personal benefit. Disadvantages included uncertainties, disappointment, information burden, and life-health balance. Although some patients had discussed research participation with approving or disapproving family or friends, self-approval superseded external approval. Barriers included logistics and time, and facilitators included flexibility in scheduling, advance notice of studies, streamlined forms, and hope for SLE improvement.

Conclusions: Knowledge about potential benefits of clinical trial participation was high. Minority patients demonstrated confidence in making their own informed decisions, but major barriers for all participants included burdensome forms, travel, childcare, and work. These suggest a major impact on minority and all recruitment from behavioural and control aspects, which should be considered in the logistics of trial design. This does not minimise the potential importance of improved access and education about clinical research.
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http://dx.doi.org/10.1136/lupus-2019-000360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073780PMC
May 2021

Adults with systemic lupus exhibit distinct molecular phenotypes in a cross-sectional study.

EClinicalMedicine 2020 Mar 4;20:100291. Epub 2020 Mar 4.

Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, USA.

Background: The clinical and pathologic diversity of systemic lupus erythematosus (SLE) hinders diagnosis, management, and treatment development. This study addresses heterogeneity in SLE through comprehensive molecular phenotyping and machine learning clustering.

Methods: Adult SLE patients ( = 198) provided plasma, serum, and RNA. Disease activity was scored by modified SELENA-SLEDAI. Twenty-nine co-expression module scores were calculated from microarray gene-expression data. Plasma soluble mediators ( = 23) and autoantibodies ( = 13) were assessed by multiplex bead-based assays and ELISAs. Patient clusters were identified by machine learning combining K-means clustering and random forest analysis of co-expression module scores and soluble mediators.

Findings: SLEDAI scores correlated with interferon, plasma cell, and select cell cycle modules, and with circulating IFN-α, IP10, and IL-1α levels. Co-expression modules and soluble mediators differentiated seven clusters of SLE patients with unique molecular phenotypes. Inflammation and interferon modules were elevated in Clusters 1 (moderately) and 4 (strongly), with decreased T cell modules in Cluster 4. Monocyte, neutrophil, plasmablast, B cell, and T cell modules distinguished the remaining clusters. Active clinical features were similar across clusters. Clinical SLEDAI trended highest in Clusters 3 and 4, though Cluster 3 lacked strong interferon and inflammation signatures. Renal activity was more frequent in Cluster 4, and rare in Clusters 2, 5, and 7. Serology findings were lowest in Clusters 2 and 5. Musculoskeletal and mucocutaneous activity were common in all clusters.

Interpretation: Molecular profiles distinguish SLE subsets that are not apparent from clinical information. Prospective longitudinal studies of these profiles may help improve prognostic evaluation, clinical trial design, and precision medicine approaches.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/j.eclinm.2020.100291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058913PMC
March 2020

Scoring systemic lupus erythematosus (SLE) disease activity with simple, rapid outcome measures.

Lupus Sci Med 2019 30;6(1):e000365. Epub 2019 Dec 30.

Department of Rheumatology, Columbia University, New York City, New York, USA.

Objective: Existing methods for grading lupus flares or improvement require definition-based thresholds as increments of change. Visual analogue scales (VAS) allow rapid, continuous scaling of disease severity. We analysed the performance of the SELENA SLEDAI Physician's Global Assessment (SSPGA) and the Lupus Foundation of America-Rapid Evaluation of Activity in Lupus (LFA-REAL) as measures of improvement or worsening in SLE.

Methods: We evaluated the agreement between prospectively collected measures of lupus disease activity [SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index 2004 (BILAG 2004), Cutaneous Lupus Area and Severity Index (CLASI), SSPGA and LFA-REAL] and response [(SLE Responder Index (SRI)-4 and BILAG-Based Combined Lupus Assessment (BICLA)] in a clinical trial.

Results: Fifty patients (47 females, mean age 45 (±11.6) years) were assessed at 528 consecutive visits (average 10.6 (±4.1) visits/patient). Changes in disease activity compared with baseline were examined in 478 visit pairs. SSPGA and LFA-REAL correlated with each other (r=0.936), and with SLEDAI and BILAG (SSPGA: r=0.742 (SLEDAI), r=0.776 (BILAG); LFA-REAL: r=0.778 (SLEDAI), r=0.813 (BILAG); all p<0.0001). Changes (∆) in SSPGA and LFA-REAL compared with screening correlated with each other (r=0.857) and with changes in SLEDAI and BILAG (∆SSPGA: r=0.678 (∆SLEDAI), r=0.624 (∆BILAG); ∆LFA-REAL: r=0.686 (∆SLEDAI) and 0.700 (∆BILAG); all p<0.0001). Changes in SSPGA and LFA-REAL strongly correlated with SRI-4 and BICLA by receiver operating characteristic analysis (p<0.0001 for all). Additionally, LFA-REAL correlated to individual BILAG organ scores (musculoskeletal: r=0.842, mucocutaneous: r=0.826 (p<0.0001 for both)).

Conclusion: SSPGA and LFA-REAL are reliable surrogates of common SLE trial end points and could be used as continuous or dichotomous response measures. Additionally, LFA-REAL can provide individualised scoring at the symptom or organ level.

Trial Registration Number: NCT02270957.
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http://dx.doi.org/10.1136/lupus-2019-000365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937422PMC
December 2019

Complement Activation in Patients With Probable Systemic Lupus Erythematosus and Ability to Predict Progression to American College of Rheumatology-Classified Systemic Lupus Erythematosus.

Arthritis Rheumatol 2020 01 25;72(1):78-88. Epub 2019 Nov 25.

Exagen, Inc., Vista, California, and Georgetown University, Washington, DC.

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.
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http://dx.doi.org/10.1002/art.41093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972605PMC
January 2020

Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE): study protocol for a randomized controlled trial.

Trials 2018 Dec 20;19(1):694. Epub 2018 Dec 20.

University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.

Background: Onset of systemic lupus erythematosus (SLE) is preceded by a preclinical phase characterized by expression of autoantibodies and nonspecific clinical symptoms. Hydroxychloroquine is a treatment for lupus that is widely used based on longstanding experience and a very good safety profile. Existing data suggest that treatment with hydroxychloroquine may postpone the onset of disease. However, prospective studies that prove and quantify the efficacy of hydroxychloroquine in the preclinical phase of lupus have not been done. This study will test the hypothesis that early hydroxychloroquine use can prevent accumulation of clinical abnormalities and modify immune responses that define SLE.

Methods: A randomized, double-blind, placebo-controlled trial of hydroxychloroquine vs placebo will be conducted. Participants will have incomplete lupus erythematosus as defined by the presence of antinuclear antibody (ANA) positivity at a titer of 1:80 or greater, as well as one or two additional criteria from the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. The age range will be 15-45 years and the treatment phase will be 96 weeks. The primary endpoint will be the increase in the number of features of SLE defined by the 2012 SLICC classification schema. Secondary outcomes will include the proportion of participants who transition to a classification of SLE as defined by SLICC criteria.

Discussion: A major challenge for improving therapies in patients with SLE is early detection of disease. The ANA test that is widely used to screen for SLE has low specificity and interpretation of its significance is challenging. The Study of Anti-Malarials in Incomplete Lupus Erythematosus (SMILE) trial will provide insights into the appropriate target population for intervention, and will assess whether hydroxychloroquine can slow progression as measured by the accumulation of criteria. Ophthalmologic safety in this population will be assessed. The study will investigate candidate biomarkers that will guide treatment decisions and will accumulate a specimen biobank that will be available to the lupus research community for further in-depth mechanistic studies. This trial is a first step toward testing the feasibility of disease prevention strategies in SLE.

Trial Registration: ClinicalTrials.gov, NCT 03030118 . Registered on 24 January 2017.
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http://dx.doi.org/10.1186/s13063-018-3076-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302430PMC
December 2018

Mock Recruitment for the Study of Antimalarials in an Incomplete Lupus Erythematosus Trial.

Arthritis Care Res (Hoboken) 2019 11;71(11):1425-1429

Penn State College of Medicine, Hershey, Pennsylvania.

Objective: Recruitment to randomized clinical trials is expensive and often falls short of goals, limiting achievement of measurable outcomes. To prepare for a trial in patients with incomplete forms of lupus, a mock recruitment protocol was carried out at 4 proposed study sites. The objective was to determine levels of interest in patients and to uncover potential barriers to enrollment.

Methods: After obtaining institutional review board approval, study coordinators approached individuals who generally fit proposed criteria for the trial. A standardized script was followed in a structured interview. Levels of interest were determined and any reasons for concerns were collected with an open-ended format.

Results: A total of 45 subjects were interviewed, of which 73% expressed an interest in the trial, and 64% said they were likely to enroll. Concerns of those who were not interested included risk of hydroxychloroquine, desire not to receive placebo, and lack of time for participation.

Conclusion: The mock recruitment suggests that the trial will be attractive to suitable patients. The concerns raised support other data indicating that provision of information is crucial to achieving enrollment goals. Mock recruitment of potential investigators should be considered also to address referral concerns.
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http://dx.doi.org/10.1002/acr.23802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487234PMC
November 2019

Establishing Surrogate Kidney End Points for Lupus Nephritis Clinical Trials: Development and Validation of a Novel Approach to Predict Future Kidney Outcomes.

Arthritis Rheumatol 2019 03 1;71(3):411-419. Epub 2019 Feb 1.

Ohio State University Wexner Medical Center, Columbus.

Objective: End points currently used in lupus nephritis (LN) clinical trials lack uniformity and questionably reflect long-term kidney survival. This study was undertaken to identify short-term end points that predict long-term kidney outcomes for use in clinical trials.

Methods: A database of 944 patients with LN was assembled from 3 clinical trials and 12 longitudinal cohorts. Variables from the first 12 months of treatment after diagnosis of active LN (prediction period) were assessed as potential predictors of long-term outcomes in a 36-month follow-up period. The long-term outcomes examined were new or progressive chronic kidney disease (CKD), severe kidney injury (SKI), and the need for permanent renal replacement therapy (RRT). To predict the risk for each outcome, hazard index tools (HITs) were derived using multivariable analysis with Cox proportional hazards regression.

Results: Among 550 eligible subjects, 54 CKD, 55 SKI, and 22 RRT events occurred. Variables in the final CKD HIT were prediction-period CKD status, 12-month proteinuria, and 12-month serum creatinine level. The SKI HIT variables included prediction-period CKD status, International Society of Nephrology (ISN)/Renal Pathology Society (RPS) class, 12-month proteinuria, 12-month serum creatinine level, race, and an interaction between ISN/RPS class and 12-month proteinuria. The RRT HIT included age at diagnosis, 12-month proteinuria, and 12-month serum creatinine level. Each HIT validated well internally (c-indices 0.84-0.92) and in an independent LN cohort (c-indices 0.89-0.92).

Conclusion: HITs, derived from short-term kidney responses to treatment, correlate with long-term kidney outcomes, and now must be validated as surrogate end points for LN clinical trials.
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http://dx.doi.org/10.1002/art.40724DOI Listing
March 2019

Systemic lupus erythematosus biomarkers: the challenging quest.

Rheumatology (Oxford) 2017 04;56(suppl_1):i32-i45

Department of Biomedical Engineering, University of Houston, Houston, TX, USA.

SLE, a multisystem heterogeneous disease, is characterized by production of antibodies to cellular components, with activation of both the innate and the adaptive immune system. Decades of investigation of blood biomarkers has resulted in incremental improvements in the understanding of SLE. Owing to the heterogeneity of immune dysregulation, no single biomarker has emerged as a surrogate for disease activity or prediction of disease. Beyond identification of surrogate biomarkers, a multitude of clinical trials have sought to inhibit elevated SLE biomarkers for therapeutic benefit. Armed with new -omics technologies, the necessary yet daunting quest to identify better surrogate biomarkers and successful therapeutics for SLE continues with tenacity.
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http://dx.doi.org/10.1093/rheumatology/kew407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850341PMC
April 2017

Prognostic significance of repeat biopsy in lupus nephritis: Histopathologic worsening and a short time between biopsies is associated with significantly increased risk for end stage renal disease and death.

Clin Immunol 2017 12 3;185:3-9. Epub 2016 Dec 3.

Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, OK 73104, United States. Electronic address:

Background/purpose: Approximately half of patients with systemic lupus erythematosus (SLE) develop lupus nephritis (LN), a major cause of morbidity and early mortality in that disease. Prolonged renal inflammation is associated with irreversible kidney damage which confers a 30% risk of end stage renal disease (ESRD), making early, aggressive treatment mandatory. Failure to achieve therapeutic response or recurrence of renal flare often prompts repeat biopsy. However, the role of repeat biopsy in determining long-term renal prognosis remains controversial. For this reason repeat biopsies are usually not utilized unless clinical evidence of refractory or recurrent disease is already present, despite known mismatches between clinical and biopsy findings. The current study quantifies the degree to which histopathologic worsening between first and second biopsies and duration between them predicts ESRD and death.

Methods: Medical records of 141 LN patients with more than one biopsy were obtained from a single large urban medical center. Cases were attained using billing codes for diagnosis and procedures from 1/1999-1/2015. Biopsy worsening was defined as unfavorable histopathologic classification transitions and/or increased chronicity; if neither were present, the patient was defined as non-worsening. We used Cox proportional hazard models to study the relationship between ESRD and survival adjusting for covariates which included age at first biopsy, gender, race, initial biopsy class, and initial induction therapy.

Results: Of 630 patients screened, 141 had more than one biopsy. Advancing chronicity was detected in 48 (34.0%) and a renal class switch to worse grade of pathology was found in 54 (38.3%). At least one of these adverse second biopsy features was reported in 79 (56.0%) patients. Five years following initial biopsy, 28 (35.4%) of those with worsening histopathology on second biopsy developed ESRD, compared to 6 (9.7%) of non-worsening patients and 10 (12.7%) of patients with worsening histopathology had died compared to 2 (3.2%) of non-worsening patients. Biopsy worsening was associated with a significantly greater 15-year risk of ESRD (Hazard Ratio 4.2, p=0.0001) and death (Hazard Ratio 4.3, p=0.022), adjusting for age, gender, race, biopsy class, and treatment. Time between first and second biopsies was <1year in 32 patients, 1-5years in 81, and >5years in 28. Over a 15-year period, those with <1year between first and second biopsies (presumably enriched for patients with early clinical signs of progression) had a significantly greater risk of ESRD (Hazard Ratio 13.7, p<0.0001) and death (Hazard Ratio 16.9, p=0.0022) after adjusting for age, gender, race, biopsy class, and treatment.

Conclusion: A repeat renal biopsy demonstrating worsening pathology increases the risk of ESRD and death more than four-fold compared to non-worsening patients. Given known potential mismatch between biopsy and clinical data, repeat biopsies may add important information and justify changes in treatment not considered on clinical grounds. Earlier detection of poor prognostic signs in those without early clinical deterioration might improve outcomes in enough patients to reconsider cost effectiveness of routine repeat biopsy.
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http://dx.doi.org/10.1016/j.clim.2016.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457715PMC
December 2017

Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.

Clin Immunol 2016 08 27;169:58-68. Epub 2016 May 27.

The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; The Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States. Electronic address:

Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE.
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http://dx.doi.org/10.1016/j.clim.2016.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193537PMC
August 2016

Antibody-Array-Based Proteomic Screening of Serum Markers in Systemic Lupus Erythematosus: A Discovery Study.

J Proteome Res 2016 07 7;15(7):2102-14. Epub 2016 Jun 7.

Department Biomedical Engineering, University of Houston , Houston, Texas 77204, United States.

A discovery study was carried out where serum samples from 22 systemic lupus erythematosus (SLE) patients and matched healthy controls were hybridized to antibody-coated glass slide arrays that interrogated the level of 274 human proteins. On the basis of these screens, 48 proteins were selected for ELISA-based validation in an independent cohort of 28 SLE patients. Whereas AXL, ferritin, and sTNFRII were significantly elevated in patients with active lupus nephritis (LN) relative to SLE patients who were quiescent, other molecules such as OPN, sTNFRI, sTNFRII, IGFBP2, SIGLEC5, FAS, and MMP10 exhibited the capacity to distinguish SLE from healthy controls with ROC AUC exceeding 90%, all with p < 0.001 significance. These serum markers were next tested in a cohort of 45 LN patients, where serum was obtained at the time of renal biopsy. In these patients, sTNFRII exhibited the strongest correlation with eGFR (r = -0.50, p = 0.0014) and serum creatinine (r = 0.57, p = 0.0001), although AXL, FAS, and IGFBP2 also correlated with these clinical measures of renal function. When concurrent renal biopsies from these patients were examined, serum FAS, IGFBP2, and TNFRII showed significant positive correlations with renal pathology activity index, while sTNFRII displayed the highest correlation with concurrently scored renal pathology chronicity index (r = 0.57, p = 0.001). Finally, in a longitudinal cohort of seven SLE patients examined at ∼3 month intervals, AXL, ICAM-1, IGFBP2, SIGLEC5, sTNFRII, and VCAM-1 demonstrated the ability to track with concurrent disease flare, with significant subject to subject variation. In summary, serum proteins have the capacity to identify patients with active nephritis, flares, and renal pathology activity or chronicity changes, although larger longitudinal cohort studies are warranted.
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http://dx.doi.org/10.1021/acs.jproteome.5b00905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193538PMC
July 2016

Placebo-controlled randomized clinical trial of fish oil's impact on fatigue, quality of life, and disease activity in Systemic Lupus Erythematosus.

Nutr J 2015 Aug 18;14:82. Epub 2015 Aug 18.

Department of Biomedical Engineering, University of Houston, Houston, TX, USA.

Introduction: A recent metabolomic screen of sera from patients with Systemic Lupus Erythematosus (SLE) found reduction of antioxidants and substrates for energy generation. These metabolic alterations may underlie one of the most common features of SLE--fatigue. The metabolomic studies also noted reduced omega-3 fatty acids, which are powerful anti- oxidants. This deficiency may be causally related to oxidative stress, inflammation, disease activity, and fatigue in SLE. Supplementation of omega-3 fatty acids using fish oil in SLE has been shown to reduce oxidative stress in other studies. The objective of this study is to evaluate the effect of fish oil supplementation on clinical measures of fatigue, quality of life, and disease activity as part of a randomized clinical trial.

Methods: Fifty SLE patients recruited in outpatient clinics were randomized 1:1 to fish oil supplementation or olive oil placebo, and blinded to their treatment group. At baseline and after 6 months of treatment, RAND Short Form-36 (RAND SF-36), Fatigue Severity Scale (FSS), SLE Disease Activity Index (SLEDAI), and Physician Global Assessment (PGA) were completed; serum was also collected for soluble mediator analysis.

Results: Thirty-two patients completed the study. PGA improved significantly in the fish oil group compared with the placebo group (p = 0.015). The RAND SF-36 Energy/fatigue and Emotional well-being scores demonstrated improvement trends (p = 0.092 and 0.070). No clear difference was seen in FSS and SLEDAI (p = 0.350 and p = 0.417). Erythrocyte sedimentation rate and serum IL-12 were reduced (p = 0.008 and p = 0.058); while serum IL-13 was increased by fish oil supplementation (p = 0.033).

Conclusions: In this randomized, placebo-controlled 6-month trial, SLE patients randomized to fish oil supplementation demonstrated improvement in their PGA, RAND SF-36, and some circulating inflammatory markers.

Trial Registration: ClinicalTrials.gov Identifier: NCT02021513 (registered 13 December 2013).
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http://dx.doi.org/10.1186/s12937-015-0068-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538741PMC
August 2015

Nonalcoholic fatty liver disease: a potential consequence of tumor necrosis factor-inhibitor therapy.

Eur J Gastroenterol Hepatol 2015 Oct;27(10):1154-60

aDivision of Gastroenterology and Hepatology bDivision of Rheumatology cDepartment of Pathology, VA North Texas Healthcare System dDivision of Digestive and Liver Diseases eDivision of Rheumatology fDepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Introduction: Although tumor necrosis factor inhibitors (TNFi) might be expected to protect against nonalcoholic fatty liver disease (NAFLD), we have seen patients who appeared to develop NAFLD during TNFi treatment. We aimed to explore risk factors for this TNFi complication in a case-control study.

Methods: We reviewed clinic records at our VA hospital to identify patients with inflammatory diseases who developed aminotransferase elevations during TNFi therapy and who had liver biopsies showing NAFLD. These patients were matched with patients in each of three control groups: (i) inflammatory disease controls: patients on TNFi treatment with normal aminotransferase levels, (ii) nonalcoholic steatohepatitis (NASH) controls: patients with biopsy-proven NASH with no other inflammatory disease, and (iii) healthy controls. Genotyping was performed for PNPLA3, a gene predisposing to NASH.

Results: We identified eight cases (five steatohepatitis, three steatosis); elevated aminotransferase levels were first observed 1-63 months into TNFi therapy (average 12 months). TNFi therapy was stopped in five patients, whose aminotransferase levels then normalized within 2-8 months. There were no significant differences between cases and inflammatory disease controls in the frequency of features of metabolic syndrome. Cases had more methotrexate exposure than inflammatory controls (50 vs. 12.5%, P=0.28). PNPLA3 genotyping revealed mutations in 75% of cases, 38% of inflammatory controls, 88% of NASH controls, and 63% of healthy controls (P=NS).

Conclusion: Our findings suggest that NAFLD can be a side effect of TNFi therapy, and that methotrexate exposure and PNPLA3 gene mutations might be risk factors. Further studies are needed to determine how TNFi causes NAFLD and to confirm these risk factors.
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http://dx.doi.org/10.1097/MEG.0000000000000421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157831PMC
October 2015

Systemic lupus erythematosus diagnostics in the 'omics' era.

Int J Clin Rheumtol 2013 Dec;8(6):671-687

Department of Biomedical Engineering, University of Houston, 3605 Cullen Blvd, Room 2018, Houston, TX 77204, USA.

Systemic lupus erythematosus is a complex autoimmune disease affecting multiple organ systems. Currently, diagnosis relies upon meeting at least four out of eleven criteria outlined by the ACR. The scientific community actively pursues discovery of novel diagnostics in the hope of better identifying susceptible individuals in early stages of disease. Comprehensive studies have been conducted at multiple biological levels including: DNA (or genomics), mRNA (or transcriptomics), protein (or proteomics) and metabolites (or metabolomics). The 'omics' platforms allow us to re-examine systemic lupus erythematosus at a greater degree of molecular resolution. More importantly, one is hopeful that these 'omics' platforms may yield newer biomarkers for systemic lupus erythematosus that can help clinicians track the disease course with greater sensitivity and specificity.
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http://dx.doi.org/10.2217/ijr.13.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4029501PMC
December 2013