Lupus Biomarkers Research Articles

Novel biomarker discovery through comprehensive proteomic analysis of lupus mouse serum

ObjectivesThe difficulty of monitoring organ-specific pathology in systemic lupus erythematosus (SLE) often complicates disease prognostication and treatment. Improved non-invasive biomarkers of active organ pathology, particularly lupus nephritis, would improve patient care. We sought to validate and apply a novel strategy to generate the first comprehensive serum proteome of a lupus mouse model and identify mechanism-linked lupus biomarker candidates for subsequent clinical investigation. MethodsSerum levels of 1308 diverse proteins were measured in eight adult female MRL/lpr lupus mice and eight control MRL/mpj mice. ELISA validation confirmed fold increases. Protein enrichment analysis provided biological relevance to findings. Individual protein levels were correlated with measures of lymphoproliferative, humoral, and renal disease. ResultsFour hundred and six proteins were increased in MRL/lpr serum, including proteins increased in human SLE such as VCAM-1, L-selectin, TNFRI/II, TWEAK, CXCL13, MCP-1, IP-10, IL-10, and TARC. Newly validated proteins included IL-6, IL-17, and MDC. Results of pathway enrichment analysis, which revealed enhancement of cytokine signaling and immune cell migration, reinforced the similarity of the MRL/lpr disease to human pathology. Fifty-two proteins positively correlated with at least one measure of lupus-like disease. TECK, TSLP, PDGFR-alpha, and MDC were identified as novel candidate biomarkers of renal disease. ConclusionsWe successfully validated a novel serum proteomic screening strategy in a spontaneous murine lupus model that highlighted potential new biomarkers. Importantly, we generated a comprehensive snapshot of the serum proteome which will enable identification of other candidates and serve as a reference for future mechanistic and therapeutic studies in lupus.

Variations in clinical presentation and biomarkers among biopsy-proven lupus nephritis patients: a Top End retrospective cohort study.

Lupus nephritis (LN) is a common feature of systemic lupus erythematosus (SLE) and affects 50% of patients with SLE. Racial differences in incidence and prevalence have been well documented worldwide. In Australia, higher incidence and prevalence of SLE had been previously reported in Aboriginal and Torres Strait Australians compared with non-Indigenous Australians. To describe the differences in clinical features and lupus biomarkers between Aboriginal and Torres Strait Islander Australian and non-Indigenous Australian patients with LN. We retrospectively identified all consecutive biopsy-proven LN patients in our institution and compared the clinical features and lupus biomarkers between Aboriginal and Torres Strait Islander Australians and non-Indigenous Australians. Of the 33 consecutive biopsy-proven LN patients, 26 self-identified as of Aboriginal and Torres Strait Islander descent. The estimated incidence of LN in Aboriginal and Torres Strait Islander Australian and non-Indigenous Australians were 5.08 and 0.47 per 100 000 patient-years respectively. Neurological manifestations (23.08% vs 0%), haematological manifestations (46.50% vs 16.67) and right-heart catheter proven pulmonary arterial hypertension (23.08% vs 0%) were more frequently observed among Indigenous Australian patients compared with non-Indigenous Australian patients. The incidence of positive extractable nuclear antigen was also higher among Indigenous Australian patients (84.62% vs 57.14%). The present study further supports the observation that lupus in Aboriginal and Torres Strait Islander Australians were of a 'distinct phenotype' compared with non-Indigenous Australians. Future research should be aimed at delineating the reason for this observed difference.

The Role Of IL-6 In TMPD-Treated Lupus Arthritis Mice

Lupus or systemic lupus erythematosus is a chronic autoimmune disease with systemic inflammation manifestations mainly in targeted organs. The appropriate animal model for lupus is necessary. The induction method by using 2,6,10,14 tetramethylpentadecane (TMPD) reveals more complex manifestations than other hydrocarbons. However, the autophagy of macrophages as an effect of TMPD makes differences to make the decision in lupus biomarker as a targeted therapy in lupus arthritis. Thus, this research focused on the role of CD68+IL-6 produced by macrophages and total IL-6 in lupus in correlation to the arthritis severity. The naïve and TMPD-treated groups (n=3) were induced by means of 0.5 ml TMPD i.p. After 6 months, the mice were sacrificed then the fresh spleens were prepared as isolated cells to be measured by using flow cytometry method. The knee joints were prepared for histology observation. The statistical analysis was performed by using T-test SPSS 22 version. The results showed the relative percentage of CD68+IL-6+ in the TMPD-treated group increased significantly (P<0.05) with the value of 62.38±9.97 %, compared to naïve group 49.70±2.34 %. Moreover, the total IL-6 did not increase significantly (P>0.05). Meanwhile, the arthritis severity score of the TMPD-treated group revealed severe erosion with the grade of 3.7±1.06, higher significantly (P<0.05) than the naïve group (0.5±0.71). The joint spaces in both groups were not significantly different. Finally, the observations gave the clear information that despite the autophagy potency, the CD68+IL-6 and the arthritis severity score were good markers in lupus preclinical study. Keywords: CD68+IL-6; inflammation; lupus arthritis; TMPD

Protein arrays for biomarker discovery in lupus.

Lupus is one of the most common autoimmune diseases, yet many mechanisms of its pathogenesis are not fully known. Over the last few years, advances in protein array technology have accelerated rapidly, resulting in many promising insights toward the discovery of novel lupus biomarkers that may become useful in disease diagnosis and management. Still, only two types of analytical protein arrays thus far, being antibody and antigen arrays, have found notable usage toward lupus biomarker discovery. In this review, we summarize current protein array technologies being used for biomarker discoveries in lupus and associated biomarker findings, as well as protein arrays that are likely to be used for lupus biomarker discovery in the near future.

Lupus Biomarker Discovery, Validation, Approval, and Impact on Clinical Trials

Current estimates suggest that bringing a new therapeutic from the laboratory to the patient requires 16–17 years and US$4–5 billion. One of the challenges in lupus clinical trials is the dearth of available biomarkers to identify those most likely to respond, to demonstrate response, and to predict adverse events. The lupus biomarker discovery pipeline, much like the lupus pharmaceutical discovery pipeline, has seen many potential advances but enjoyed all too few ultimate successes. New lupus biomarkers are essential and certain to accelerate lupus drug discovery and to move “lupology” from being less of an art to being more of a science. There is no precise path to lupus biomarker validation, FDA approval is generally not required, a multidisciplinary team is essential to optimize success, and a commercial partner is almost required to move advances in academia through the translational process. Despite the relatively few successes to date, the trajectory for lupus biomarker discovery and validation is steep and more promising than ever. Tandem and synergic advances in lupus biomarker validation and approval of new lupus therapeutics are hopefully on the horizon.

Promising biomarkers for systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with heterogeneous manifestations. Of particular importance for clinicians are the precise assessment of disease activity and the ability to make appropriate therapeutic decisions. Therefore, interest has increased in biomarkers that can be measured as indicators of pathogenic processes, disease activity and response to management. This article introduces well-studied, as well as newly discovered, biomarkers related to SLE, divided into categories for diagnosis, disease activity and organ involvement. The lack of reliable biomarkers for lupus hampers the assessment of disease activity and impedes the evaluation of treatment response. Although many reports of lupus biomarkers have been published, few longitudinal and interventional studies have validated the utility of any biomarker for monitoring disease activity. Consortiums of investigators will certainly help in recruiting sufficient number of patients and facilitating the development of standardized assays. Moreover, owing to the multifactorial nature of lupus, a multiplexed approach will clearly be essential. Another promising approach is the use of high-throughput technology, including DNA and antibody microarrays, flow cytometry and proteomic techniques.

Biomarkers in systemic lupus erythematosus: challenges and prospects for the future

The search for lupus biomarkers to diagnose, monitor, stratify, and predict individual response to therapy is currently more intense than ever before. This effort is essential for several reasons. First, epidemic overdiagnosis and underdiagnosis of lupus, even by certified rheumatologists, leads to errors in therapy with concomitant side effects which may be more serious than the disease itself. Second, identification of lupus flares remains as much an art as it is a science. Third, the capacity to stratify patients so as to predict those who will develop specific patterns of organ involvement is not currently possible but would potentially lead to preventive therapeutic strategies. Fourth, only one new drug for the treatment of lupus has been approved by the US Food and Drug Administration in over 50 years. A major obstacle in this pipeline is the dearth of biomarkers available to prove a patient has responded to an experimental therapeutic intervention. This review will summarize the challenges faced in the discovery and validation of lupus biomarkers, the most promising lupus biomarkers identified to date, and the promise of future directions.

Erythrocyte C3d and C4d for monitoring disease activity in systemic lupus erythematosus

Disease activity in systemic lupus erythematosus (SLE) is typically monitored by measuring serum C3 and C4. However, these proteins have limited utility as lupus biomarkers, because they are substrates rather than products of complement activation. The aim of this study was to evaluate the utility of measuring the erythrocyte-bound complement activation products, erythrocyte-bound C3d (E-C3d) and E-C4d, compared with that of serum C3 and C4 for monitoring disease activity in patients with SLE. The levels of E-C3d and E-C4d were measured by flow cytometry in 157 patients with SLE, 290 patients with other diseases, and 256 healthy individuals. The patients with SLE were followed up longitudinally. Disease activity was measured at each visit, using the validated Systemic Lupus Activity Measure (SLAM) and the Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). At baseline, patients with SLE had higher median levels of E-C3d and E-C4d (P < 0.0001) in addition to higher within-patient and between-patient variability in both E-C3d and E-C4d when compared with the 2 non-SLE groups. In a longitudinal analysis of patients with SLE, E-C3d, E-C4d, serum C3, and anti-double-stranded DNA (anti-dsDNA) antibodies were each significantly associated with the SLAM and SELENA-SLEDAI. In a multivariable analysis, E-C4d remained significantly associated with these SLE activity measures after adjusting for serum C3, C4, and anti-dsDNA antibodies; however, E-C3d was associated with the SLAM but not with the SELENA-SLEDAI. Determining the levels of the erythrocyte-bound complement activation products, especially E-C4d, is an informative measure of SLE disease activity as compared with assessing serum C4 levels and should be considered for monitoring disease activity in patients with SLE.

The search for lupus biomarkers

Few biomarkers for systemic lupus erythematosus (SLE) have been validated and employed for making clinical decisions. The lack of reliable, specific biomarkers for SLE hampers the proper clinical management of patients with SLE and impedes the development of new lupus therapeutics. This void has led to renewed enthusiasm for identifying biomarkers that precisely and specifically reflect the pathophysiological and clinical changes of SLE. Several laboratory markers have shown early promise as biomarkers for lupus susceptibility, diagnosis and monitoring. These include polymorphisms and copy-number variations of complement C4 and Fcgamma receptor genes (disease susceptibility), cell-bound complement C4d (diagnosis and/or disease activity), CD27(high) plasma cells (disease activity), 'interferon signature' (disease activity) and anti-C1q and anti-NMDA (disease activity and organ involvement). Although these and other promising candidate biomarkers have been identified, they still need to be validated through rigorous, large-scale multicentre studies. This article briefly reviews the historical aspects of lupus biomarkers and summarises current efforts to advance the field.

Biomarkers for systemic lupus erythematosus: a review and perspective

Despite decades of extensive work in the understanding of the etiopathogenesis of systemic lupus erythematosus, few biomarkers have been validated and widely accepted for this disease. The lack of reliable, specific biomarkers not only hampers clinical management of systemic lupus erythematosus but also impedes development of new therapeutic agents. This paper reviews briefly the historical aspects of systemic lupus erythematosus biomarkers and summarizes recent studies on candidate biomarkers. Recognizing the urgent need for lupus biomarkers, a Lupus Biomarker Working Group has recently been initiated to facilitate collaborative efforts aimed at identifying and validating biomarkers for systemic lupus erythematosus. Based on available data, several laboratory markers have shown promise as biomarkers for susceptibility, diagnosis, and disease activity. These include Fc receptor genes (disease susceptibility), complement C4d-bound erythrocytes (diagnosis or disease activity), CD27 plasma cells (disease activity), 'interferon signature' (disease activity), and anti-C1q antibodies (disease activity and organ involvement). There is a longstanding and recently rejuvenated enthusiasm for biomarkers that precisely and specifically reflect the pathophysiologic and clinical changes in systemic lupus erythematosus. Promising candidate biomarkers have been identified but must still be validated through rigorous, large-scale multicenter studies.