Organ-specific Disease Activity Research Articles

Anti-LAMP-2 Antibody Seropositivity in Children with Primary Systemic Vasculitis Affecting Medium- and Large-Sized Vessels.

Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.

The Type I Interferon Signature Reflects Multiple Phenotypic and Activity Measures in Dermatomyositis.

The type 1 interferon (IFN) pathway is up-regulated in dermatomyositis (DM). We sought to define how organ-specific disease activity as well as autoantibodies and other clinical factors are independently associated with systemic type I IFN activity in adult patients with DM. RNA sequencing was performed on 355 whole blood samples collected from 202 well-phenotyped DM patients followed up during the course of their clinical care. A previously defined 13-gene type I IFN score was modeled as a function of demographic, serologic, and clinical variables using both cross-sectional and longitudinal data. The pattern of type I IFN-driven transcriptional response was stereotyped across samples with a sequential modular activation pattern strikingly similar to systemic lupus erythematosus. The median type I IFN score was higher or lower in patients with anti-melanoma differentiation-associated protein 5 (anti-MDA-5) or anti-Mi-2 antibodies, respectively, compared to patients without these antibodies. Absolute type I IFN score was independently associated with muscle and skin disease activity, interstitial lung disease, and anti-MDA-5 antibodies. Changes in the type I IFN score over time were significantly associated with changes in skin or muscle disease activity. Stratified analysis accounting for heterogeneity in organ involvement and antibody class revealed high correlation between changes in the type I IFN score and skin disease activity (Spearman's ρ=0.84-0.95). The type I IFN score is independently associated with skin and muscle disease activity as well as certain clinical and serologic features in DM. Accounting for the effect of muscle disease and anti-MDA-5 status revealed that the type I IFN score is strongly correlated with skin disease activity, providing support for type I IFN blockade as a therapeutic strategy for DM.

Measurement of specific organ domains in lupus randomized controlled trials: a scoping review.

Randomized controlled trials (RCTs) in SLE (lupus) typically adopt composite responder definitions as primary efficacy endpoints; however, outcomes within individual organ domains are also important to understand. The aim of this scoping review was to evaluate how organ-specific disease activity and therapeutic responses have been measured and reported in lupus RCTs. We searched MEDLINE, EMBASE, Cochrane registry and clinicaltrials.gov. Eligible studies were RCTs investigating efficacy of an immune-directed drug therapy in active SLE, published January 2000-March 2021, excluding studies limited to lupus nephritis. Data were extracted independently in duplicate into a template and summarized descriptively. Thirty-four RCTs were included, of which 32 (94%) reported activity and/or responses in at least one organ domain. Study populations had a high, although variable, frequency of baseline musculoskeletal and mucocutaneous activity and low, but also variable, representation of other domains. Definitions of organ-specific responses were inconsistent, even within individual instruments. Response in most organ domains were evaluated using BILAG and SLEDAI components but meaningful comparison between treatment arms was limited by small subgroups analysed in a post hoc fashion. Specific mucocutaneous and arthritis instruments were also used, including within pre-specified organ-specific endpoints, which discriminated between treatment arms in some studies. Mucocutaneous and musculoskeletal manifestations predominate in SLE RCTs. Organ-specific outcome measures are commonly reported, but definitions of involvement and response are inconsistent. Research into the development of new outcome measures for key organ domains, and validation and comparison of response definitions using existing instruments, is needed.

Development and Implementation of a Pilot Registry for Monitoring the Efficacy and Safety of Novel Therapies in Patients with Systemic Lupus Erythematosus.

The therapeutic armamentarium in Systemic Lupus Erythematosus (SLE) is expanding with the introduction of novel biologic and small-molecule agents. Complementary to randomized controlled trials, registry-based studies are advantageous due to the inclusion of a wider range of patients from daily practice and the potential for long-term monitoring of the efficacy and safety of therapies. Moreover, data from registries can be used to identify disease phenotypes that best respond to biologic agents, and to correlate clinical response with parameters such as co-administered therapies and comorbidities. In this project, we will use the configuration of the Hellenic Registry of Biologic Therapies for inflammatory arthritides in order to design a dedicated SLE module with variables pertaining to global and organ-specific disease activity, severity, flares, organ damage/outcome, comorbidities and adverse events. The second stage will involve the pilot implementation of this platform for the multicentric registration of SLE patients who are treated with belimumab. The significance lies in the development of a structured registry that enables the assessment of the disease burden and the long-term efficacy and safety of existing and future biological agents in SLE. Piloting the registry can serve as a basis for establishing nationwide collaborative efforts.

A Spatial-Temporal Analysis of Organ-Specific Lupus Flares in Relation to Fine Particulate Matter Pollution and Temperature

Objectives: We performed a spatial-time cluster analysis of the Hopkins Lupus Cohort with the goal of identifying potential clusters of SLE organ specific flares and their relation to temperature changes and fine particulate matter pollution (PM2.5). Methods: 1261 patients who fulfilled the SLICC classification criteria for SLE and who had recorded home addresses were included in the analysis. Disease activity was expressed as the Lupus Activity Index. Assessment of rash, joint involvement, serositis, neurologic, pulmonary, renal, and hematologic activity was quantified on a 0-3 VAS. An organ specific flare was defined as an increase in visual analogue scale (VAS) of 1 point or more compared to the previous visit. Average temperature and PM2.5 exposure over a period of 10 days prior to patient visit were obtained. Spatiotemporal cluster detection was conducted using the SaTScan software. Regression models were used for adjustment and included age, sex, and race, as well as PM2.5 and temperature. Results: Three statistically significant (p<0.05) unadjusted clusters were identified for joint flares, four rash flare clusters, one hematologic flare cluster, four neurologic flare clusters, three serositis flare clusters, four renal flare clusters, and five pulmonary flare clusters. Most of the identified clusters changed in significance, temporal, or spatial extent after adjusting for temperature, PM2.5 concentration, and individual covariates. Conclusions: We describe the first space-time clusters of lupus organ-specific disease activity. Seasonal, as well as multi-year cluster patterns were identified, differing in extent and location for the various organ-specific flare types. Further study focusing on each individual lupus organ-specific activity will be required to better understand the driving forces behind these observed changes. Funding Statement: The Hopkins Lupus Cohort is supported by a grant from the National Institute of Health (NIH AR 43727 and 69572). This publication was also made possible by Grant Number UL1 RR 025005 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Dr. George Stojan is a Jerome L. Greene Foundation Scholar. Dr. Frank Curriero is supported by NIH grant R01AI123931. Declaration of Interests: The authors state: None. Ethics Approval Statement: The Hopkins Lupus Cohort has been approved by the Johns Hopkins University School of Medicine Institutional Review Board and complies with the Health Insurance Portability and Accountability Act.

Analysis of Serum Interleukin (IL)-1β and IL-18 in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease characterized by biological and clinical heterogeneity. The interleukin (IL)-1 superfamily is a group of innate cytokines that contribute to pathogenesis in many autoimmune diseases. IL-1β and IL-18 are two members that have been shown to play a role in murine lupus-like models, but their role in human SLE remains poorly understood. Here, IL-1β and IL-18 were quantified by enzyme-linked immunosorbent assay in the serum of healthy controls (HCs) and SLE patients from a prospectively followed cohort. Disease activity and organ damage were assessed using SLE disease activity index 2000 (SLEDAI-2K) and SLE damage index scores (SDI), respectively. 184 SLE patients (mean age 44.9 years, 91% female, 56% double-stranded deoxyribonucleic acid positive) were compared to 52 HC. SLE patients had median [IQR] SLEDAI-2K of 4 [2,6], and SDI of 1 [0–2]. Serum IL-18 levels were statistically significantly higher in SLE patients compared to HCs. Univariable linear regression analyses showed that patients with active renal disease or irreversible organ damage had statistically significantly elevated serum IL-18 levels. The association between serum IL-18 and active renal disease was confirmed in multivariable analysis after adjusting for ethnicity and organ damage. High baseline serum IL-18 levels were associated with organ damage at the subsequent visit. Serum IL-1β levels were not significantly elevated in SLE patients when compared to HCs and had no association with overall or organ-specific disease activity or organ damage in cross-sectional and longitudinal analyses. Our data suggest that serum IL-18 and IL-1β have different clinical implications in SLE, with IL-18 being potentially associated with active renal disease.

Erythrocyte sedimentation rate is a predictor of renal and overall SLE disease activity

Our aim was to assess whether erythrocyte sedimentation rate (ESR) levels correlate with the level of disease activity at each visit and whether a change in ESR could be useful in predicting changes in disease activity. Thousands of visits in a prospective systemic lupus erythematosus (SLE) cohort were analyzed to assess the association of ESR and level of disease activity. We explored whether ESR was cross-sectionally associated with disease activity, whether changes in ESR were associated with changes in disease activity, and whether changes in ESR predicted future changes in disease activity. Visits when patients had cancer, infection, pregnancy or were in renal failure were excluded. After adjusting for confounding factors, mild (25-50 mm/h), moderate (51-75 mm/h), and marked (>75 mm/h) elevations in ESR levels at a given visit correlated with the SELENA-SLEDAI, the Physician Global Assessment (PGA), fatigue, renal, joint, rash, serositis, hematological visual analogue scale (VAS), hematuria and proteinuria (p<0.0001) levels at that visit. A change in ESR between two visits was highly correlated with a concurrent change in PGA, renal, fatigue and joint VAS (p<0.0001). There was no statistically significant correlation between change in ESR between two visits and change in disease activity at a future visit. The subgroup analysis of patients who do not have anti-dsDNA and low complement levels as a feature of their disease showed ESR to be positively associated with SLEDAI, PGA, renal and joint VAS at that visit (p<0.0001), but there were few significant associations between changes in ESR and changes in disease activity. ESR is associated with disease activity in SLE measured by the SELENA-SLEDAI, the PGA, and with organ-specific activity including serositis, rash, joint, renal and hematological VAS. Grouping baseline ESR into four levels does associate with both global and organ-specific disease activity. A change in ESR between two visits was highly correlated with a change in PGA, renal, fatigue and joint VAS. In patients without anti-dsDNA and low complement levels, ESR was positively associated with SLEDAI, PGA, renal and joint VAS at the same visit. Until more specific biomarkers are validated, serial ESR does have some utility in following disease activity in SLE.

Anti–Jo‐1 antibody levels correlate with disease activity in idiopathic inflammatory myopathy

Previous case series have examined the relationship between anti-Jo-1 antibody levels and myositis disease activity, demonstrating equivocal results. Using enzyme-linked immunosorbent assays (ELISAs) and novel measures of myositis disease activity, the current study was undertaken to systematically reexamine the association between anti-Jo-1 antibody levels and various disease manifestations of myositis. Serum anti-Jo-1 antibody levels were quantified using 2 independent ELISA methods, while disease activity was retrospectively graded using the Myositis Disease Activity Assessment Tool, which measures disease activity in 7 different organ systems via the Myositis Disease Activity Assessment Visual Analog Scale (VAS) and the Myositis Intention-to-Treat Index (MITAX) components. Spearman's rank correlation coefficients and mixed linear regression analysis were used to identify associations between anti-Jo-1 antibody levels and organ-specific disease activity in cross-sectional and longitudinal analyses, respectively. Cross-sectional assessment of 81 patients with anti-Jo-1 antibody revealed a modest correlation between the anti-Jo-1 antibody level and the serum creatine kinase (CK) level, as well as muscle and joint disease activity. Correlation coefficients were similar for CK levels (r(s) = 0.38, P = 0.002), myositis VAS (r(s) = 0.36, P = 0.002), and arthritis VAS (r(s) = 0.40, P = 0.001). In multiple regression analyses of 11 patients with serial samples, anti-Jo-1 antibody levels correlated significantly with CK levels (R(2) = 0.65, P = 0.0002), myositis VAS (R(2) = 0.53, P = 0.0008), arthritis VAS (R(2) = 0.53, P = 0.006), pulmonary VAS (R(2) = 0.69, P = 0.005), global VAS (R(2) = 0.63, P = 0.002), and global MITAX (R(2) = 0.64, P = 0.0003). In this large series of patients with idiopathic inflammatory myopathy, anti-Jo-1 antibody levels correlated modestly with muscle and joint disease, an association confirmed by a custom ELISA using recombinant human Jo-1. More striking associations emerged in a smaller longitudinal subset of patients that link anti-Jo-1 antibody levels to muscle, joint, lung, and global disease activity.

Anti-DNA antibodies--overview of assays and clinical correlations.

Many authors have studied the links between levels of anti-dsDNA antibodies and disease activity in patients with SLE. Interpretation of these studies must take into account the facts that there are a range of possible assays for anti-dsDNA and a number of indices available for assessing disease activity. A recent study compared levels of various autoantibodies with organ specific disease activity assessed during the British Isles Lupus Assessment Group (BILAG) index. Anti-dsDNA and anti-heparan sulphate levels were more likely to be raised in patients with renal than non-renal disease. Some anti-DNA antibodies are actually anti-nucleosome antibodies, which lose DNA reactivity when purified under dissociating conditions. Patients with SLE have significantly increased levels of nucleosomes in their sera compared with healthy controls. In patients with SLE, reduced clearance of nucleosomes released from apoptotic cells may induce the formation of anti-nucleosome antibodies.