Laura Geraldino-Pardilla

Immunologic characteristics of intrarenal T cells: Trafficking of expanded CD8+ T cell β-chain clonotypes in progressive lupus nephritis

OBJECTIVE To better define the immunologic character of the T cell infiltrate in lupus nephritis. METHODS We performed double immunohistochemical staining and clonotypic T cell receptor (TCR) β-chain sequencing in multiple anatomic regions isolated by laser-capture microdissection from renal biopsy samples. RESULTS Systemic lupus erythematosus (SLE) kidneys have a variably patterned and often extensive infiltrate of predominantly clonally expanded T cells of CD4 and CD8 lineages. CD4+ T cells were prominent in nearly two-thirds of SLE biopsy samples and were distributed as broad periglomerular aggregates or intermixed with CD8+ T cells forming periglomerular caps. Sequencing of the TCR from periglomerular regions showed a predominance of clonally expanded T cells. The CD8+ T cells, which were present in all biopsy samples, often adhered to Bowmans capsule and infiltrated the tubular epithelium. They exhibited features that suggest participation in an adaptive immune response: differentiation into CD28(null) memory-effector phenotype, trafficking of the same expanded clonotype to different regions of the kidney and to the peripheral blood, and clonal persistence for years in repeat biopsy samples. CD8+ T cell tubulitis was especially associated with progressive changes. CONCLUSION The immunologic characteristics of the infiltrating CD4+ and CD8+ T cells in the lupus kidney indicate that they have the potential to mediate injury, which may be relevant to development of progressive renal failure. Whereas the oligoclonality of the CD4+ T cell infiltrate is consistent with the paradigm of SLE as a class II major histocompatibility complex-associated autoimmune disease, the finding of CD8+ T cell clonality and trafficking implies participation in a distinct systemic adaptive immune response.

The Incidence and Prevalence of Systemic Lupus Erythematosus in New York County (Manhattan), New York: The Manhattan Lupus Surveillance Program

The Manhattan Lupus Surveillance Program (MLSP) is a population‐based registry designed to determine the prevalence of systemic lupus erythematosus (SLE) in 2007 and the incidence from 2007 to 2009 among residents of New York County (Manhattan), New York, and to characterize cases by race/ethnicity, including Asians and Hispanics, for whom data are lacking.

Methaemoglobinaemia and haemolysis following pegloticase infusion for refractory gout in a patient with a falsely negative glucose-6-phosphate dehydrogenase deficiency result

Objective To quantify James Bond’s consumption of alcohol as detailed in the series of novels by Ian Fleming. Design Retrospective literature review. Setting The study authors’ homes, in a comfy chair. Participants Commander James Bond, 007; Mr Ian Lancaster Fleming. Main outcome measures Weekly alcohol consumption by Commander Bond. Methods All 14 James Bond books were read by two of the authors. Contemporaneous notes were taken detailing every alcoholic drink taken. Predefined alcohol unit levels were used to calculate consumption. Days when Bond was unable to consume alcohol (such as through incarceration) were noted. Results After exclusion of days when Bond was unable to drink, his weekly alcohol consumption was 92 units a week, over four times the recommended amount. His maximum daily consumption was 49.8 units. He had only 12.5 alcohol free days out of 87.5 days on which he was able to drink. Conclusions James Bond’s level of alcohol intake puts him at high risk of multiple alcohol related diseases and an early death. The level of functioning as displayed in the books is inconsistent with the physical, mental, and indeed sexual functioning expected from someone drinking this much alcohol. We advise an immediate referral for further assessment and treatment, a reduction in alcohol consumption to safe levels, and suspect that the famous catchphrase “shaken, not stirred” could be because of alcohol induced tremor affecting his hands. Read @ http://www.bmj.com/content/347/bmj.f7255

Association of Anti‐Citrullinated Peptide Antibodies with Coronary Artery Calcification in Rheumatoid Arthritis

Citrullinated proteins have been found within atherosclerotic plaque. However, studies evaluating the association between anti–citrullinated protein antibodies (ACPAs) and imaging measures of atherosclerosis in patients with rheumatoid arthritis (RA) have been limited to seroreactive citrullinated fibrinogen or citrullinated vimentin and have rendered contradictory results. Therefore, our objective was to evaluate this association using an extended panel of ACPAs in a larger sample of RA patients without clinical cardiovascular disease (CVD).

Association of anti-citrullinated protein or peptide antibodies with left ventricular structure and function in rheumatoid arthritis

Objective. High levels of ACPAs in RA are associated with more severe arthritis and worse prognosis. However, the role of ACPAs in mediating the increased risk of heart failure in RA remains undefined. We examined whether specific ACPAs were associated with subclinical left ventricular (LV) phenotypes that presage heart failure. Methods. Sera from RA patients without clinical cardiovascular disease were assayed for specific ACPAs using a custom Bio‐Plex bead assay, and their cross‐sectional associations with cardiac magnetic resonance‐derived LV measures were evaluated. High ACPA level was defined as ≥ 75th percentile. Findings were assessed in a second independent RA cohort with an expanded panel of ACPAs and LV measures assessed by 3D‐echocardiography. Results. In cohort 1 (n = 76), higher levels of anti‐citrullinated fibrinogen41‐60 and anti‐citrullinated vimentin antibodies were associated with a 10 and 6% higher adjusted mean LV mass index (LVMI), respectively, compared with lower antibody levels (P < 0.05). In contrast, higher levels of anti‐citrullinated biglycan247‐266 were associated with a 13% lower adjusted mean LVMI compared with lower levels (P < 0.001). In cohort 2 (n = 74), the association between ACPAs targeting citrullinated fibrinogen and citrullinated vimentin peptides or protein and LVMI was confirmed: higher anti‐citrullinated fibrinogen556‐575 and anti‐citrullinated vimentin58‐77 antibody levels were associated with a higher adjusted mean LVMI (19 and 15%, respectively; P < 0.05), but no association with biglycan was found. Conclusion. Higher levels of antibodies targeting citrullinated fibrinogen and vimentin peptides or protein were associated with a higher mean LVMI in both RA cohorts, potentially implicating autoimmune targeting of citrullinated proteins in myocardial remodelling in RA.

Immune modulation of rheumatoid arthritis

The approval - several years ago - of the first tumour necrosis factor-α (TNF-α) inhibitor for the management of rheumatoid arthritis launched a new era in the therapeutics of rheumatology. Since then an almost cataclysmic discovery of new treatment targets and corresponding biologic agents ensued. Nowadays, the rheumatologist and the rheumatologic patient have the luxury of several immune modulators available to successfully treat the majority of patients with RA or other inflammatory arthritides and conditions. In this review we focus on a discussion of the approved immune modulators/biologic agents available for the treatment of rheumatoid arthritis. We also present an overview of agents under development. For the immune modulators discussed, we describe their mechanism of action and summarise initial data and recent updates on efficacy and safety.

Arterial Inflammation Detected with 18F-Fluoro-Deoxyglucose Positron Emission Tomography in Rheumatoid Arthritis

In addition to traditional risk factors, excess cardiovascular disease (CVD) in rheumatoid arthritis (RA) is attributed to enhanced vascular and/or systemic inflammation. In several small studies using 18F‐fluorodeoxyglucose–positron emission tomography/computed tomography (18F‐FDG–PET/CT) to directly assess vascular inflammation, FDG uptake was higher in RA patients than in controls. Using a substantially larger sample of RA patients, we sought to identify RA disease characteristics independently associated with vascular FDG uptake.

Transcriptional Profiling of Synovial Macrophages Using Minimally Invasive Ultrasound-Guided Synovial Biopsies in Rheumatoid Arthritis

Currently, there are no reliable biomarkers for predicting therapeutic response in patients with rheumatoid arthritis (RA). The synovium may unlock critical information for determining efficacy, since a reduction in the numbers of sublining synovial macrophages remains the most reproducible biomarker. Thus, a clinically actionable method for the collection of synovial tissue, which can be analyzed using high‐throughput strategies, must become a reality. This study was undertaken to assess the feasibility of utilizing synovial biopsies as a precision medicine‐based approach for patients with RA.

ECG non-specific ST-T and QTc abnormalities in patients with systemic lupus erythematosus compared with rheumatoid arthritis

Objectives Cardiovascular disease (CVD) is a leading cause of death in systemic lupus erythematosus (SLE) and in rheumatoid arthritis (RA). Although only explored in one study, ECG non-specific ST-T abnormalities, in addition to corrected QT-interval (QTc) prolongation, were recently reported in an SLE inception cohort. Importantly, these ECG abnormalities are known predictors of CVD mortality in the general population, yet their prevalence in patients with established SLE has not been evaluated. Methods We cross-sectionally investigated the presence of non-specific ST-T and QTc abnormalities in 50 patients with SLE, predominantly Hispanic and black, without CVD or SLE-related cardiac involvement and compared them with 139 patients with RA without CVD. Demographics, disease-specific characteristics and CVD risk factors were ascertained and adjusted for. Results Patients with SLE (mean age 36±13 years, 92% women, 6 years median disease duration, 96% Hispanics and blacks) had a 3.3-fold higher adjusted prevalence of non-specific ST-T abnormalities (56% vs 17%; p <0.0001) compared with RA, despite the older age and higher percentage of men in the RA group. The QTc was 26 ms longer in SLE compared with RA (p=0.002) in the setting of a higher percentage of women, blacks, Hispanics and higher C reactive protein levels in the SLE group. Conclusions This study demonstrates a high prevalence of ECG abnormalities in predominantly Hispanic and black patients with SLE. Longitudinal evaluation of the progression to potentially life-threatening arrhythmias and/or cardiovascular events is warranted.

Lack of Association of Oral Calcium Supplementation With Coronary Artery Calcification in Rheumatoid Arthritis

To investigate the association between oral calcium supplementation and coronary artery calcification among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD).