Prevalence of concomitant rheumatologic diseases and autoantibody specificities among racial and ethnic groups in SLE patients.

Objective: Leveraging the Manhattan Lupus Surveillance Program (MLSP), a population-based registry of cases of systemic lupus erythematosus (SLE) and related diseases, we investigated the proportion of SLE with concomitant rheumatic diseases, including Sjögren's disease (SjD), antiphospholipid syndrome (APLS), and fibromyalgia (FM), as well as the prevalence of autoantibodies in SLE by sex and race/ethnicity. Methods: Prevalent SLE cases fulfilled one of three sets of classification criteria. Additional rheumatic diseases were defined using modified criteria based on data available in the MLSP: SjD (anti-SSA/Ro positive and evidence of keratoconjunctivitis sicca and/or xerostomia), APLS (antiphospholipid antibody positive and evidence of a blood clot), and FM (diagnosis in the chart). Results: 1,342 patients fulfilled SLE classification criteria. Of these, SjD was identified in 147 (11.0%, 95% CI 9.2-12.7%) patients with women and non-Latino Asian patients being the most highly represented. APLS was diagnosed in 119 (8.9%, 95% CI 7.3-10.5%) patients with the highest frequency in Latino patients. FM was present in 120 (8.9%, 95% CI 7.3-10.5) patients with non-Latino White and Latino patients having the highest frequency. Anti-dsDNA antibodies were most prevalent in non-Latino Asian, Black, and Latino patients while anti-Sm antibodies showed the highest proportion in non-Latino Black and Asian patients. Anti-SSA/Ro and anti-SSB/La antibodies were most prevalent in non-Latino Asian patients and least prevalent in non-Latino White patients. Men were more likely to be anti-Sm positive. Conclusion: Data from the MLSP revealed differences among patients classified as SLE in the prevalence of concomitant rheumatic diseases and autoantibody profiles by sex and race/ethnicity underscoring comorbidities associated with SLE.

Platelet bound complement split product (PC4d) is a marker of platelet activation and arterial vascular events in Systemic Lupus Erythematosus.

Platelet-bound complement activation products (PC4d) are associated with thrombosis in Systemic Lupus Erythematosus (SLE). This study investigated the effect of PC4d on platelet function, as a mechanistic link to arterial thrombosis. In a cohort of 150 SLE patients, 13 events had occurred within five years of enrollment. Patients with arterial events had higher PC4d levels (13.6 [4.4-24.0] vs. 4.0 [2.5-8.3] net MFI), with PC4d 10 being the optimal cutoff for event detection. The association of arterial events with PC4d remained significant after adjusting for antiphospholipid status, smoking, and prednisone use (p = 0.045). PC4d levels correlated with lower platelet counts (r = -0.26, p = 0.002), larger platelet volumes (r = 0.22, p = 0.009) and increased platelet aggregation: the adenosine diphosphate (ADP) concentration to achieve 50% maximal aggregation (EC50) was lower in patients with PC4d 10 compared with PC4d < 10 (1.6 vs. 3.7, p = 0.038, respectively). These results suggest that PC4d may be a mechanistic marker for vascular disease in SLE.

Prevalence of progressive multifocal leukoencephalopathy (PML) in adults and children with systemic lupus erythematosus.

OBJECTIVE: To define the risk of progressive multifocal leukoencephalopathy (PML) in SLE. METHODS: This is a retrospective observational study to evaluate PML cases in patients with SLE admitted to two large academic hospitals. Using electronic medical record (EMR) data, International Classification of Diseases (ICD) codes identified PML cases among patients with SLE, rheumatoid arthritis (RA) (controls), had renal transplant and with HIV. Medication exposure was reviewed. RESULTS: A total of 5409 Columbia University Medical Center (CUMC) patients and 2046 Northwell Health patients were identified using one ICD code for SLE. Of 7455 patients, three had an ICD code for PML. On EMR review, however, PML was substantiated in only one fatal SLE case with significant immunosuppressant use and severe lymphopenia (<0.5 cells x 109/L); one patient was evaluated for PML but cerebrospinal fluid (CSF) was negative for JC virus and improved with treatment of central nervous system (CNS) lupus. EMR data were very limited for the third patient and diagnosis could not be confirmed. None of the 13 342 patients with RA ICD codes had PML. Of the 5409 patients with an SLE ICD code at CUMC, 212 also had a renal transplant ICD code, and 83 had concomitant HIV/AIDS. Based on inpatient pharmacy records of 5409 hospitalised patients at CUMC, 59.2% were treated with steroids, and 16.09% with immunosuppressants (7.76% mycophenolate, 3.42% cyclophosphamide, 2.88% azathioprine and 2.03% rituximab). No patients with paediatric SLE (pSLE) (n=538) had PML. The combined prevalence of PML in hospitalised patients with SLE at the two hospitals was 13-27/100 000 patients. CONCLUSION: Among 7455 adult patients with SLE ICD codes, there were two PML cases, with only one confirmed case associated with severe lymphopenia and immunosuppressants, corresponding to a prevalence of 13-27 per 100 000 patients. No PML cases in pSLE were found. A high index of suspicion in patients with SLE and CNS manifestations is required for the prompt diagnosis of PML.

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

OBJECTIVE: 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. METHODS: Rheumatologists at 6 US academic sites were trained in minimally invasive ultrasound-guided synovial tissue biopsy. Biopsy specimens obtained from patients with RA and synovial tissue from patients with osteoarthritis (OA) were subjected to histologic analysis, fluorescence-activated cell sorting, and RNA sequencing (RNA-seq). An optimized protocol for digesting synovial tissue was developed to generate high-quality RNA-seq libraries from isolated macrophage populations. Associations were determined between macrophage transcriptional profiles and clinical parameters in RA patients. RESULTS: Patients with RA reported minimal adverse effects in response to synovial biopsy. Comparable RNA quality was observed from synovial tissue and isolated macrophages between patients with RA and patients with OA. Whole tissue samples from patients with RA demonstrated a high degree of transcriptional heterogeneity. In contrast, the transcriptional profile of isolated RA synovial macrophages highlighted different subpopulations of patients and identified 6 novel transcriptional modules that were associated with disease activity and therapy. CONCLUSION: Performance of synovial tissue biopsies by rheumatologists in the US is feasible and generates high-quality samples for research. Through the use of cutting-edge technologies to analyze synovial biopsy specimens in conjunction with corresponding clinical information, a precision medicine-based approach for patients with RA is attainable.

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 fibrinogen 41-60 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 biglycan 247-266 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 fibrinogen 556-575 and anti-citrullinated vimentin 58-77 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.

Primary sclerosing cholangitis and its relationship to the colon in a black cohort of inflammatory bowel disease patients.

BACKGROUND: Recent studies have identified subgroups of inflammatory bowel disease (IBD) patients at increased likelihood for developing primary sclerosing cholangitis (PSC). Most studies look at predominantly white populations. GOALS: The aim of our study was to determine the characteristics of PSC in a black cohort of patients and its relationship to disease location in IBD. STUDY: A retrospective analysis was performed on IBD patients over the age of 18 years. RESULTS: Of the 209 black patients identified as having IBD, 7 (3.5%) had a concomitant diagnosis of PSC; 5/138 (3.6%) ulcerative colitis (UC) patients, and 2/71 (2.8%) Crohn's disease patients (CD). Numerically, more males developed PSC in both the UC and CD subgroups. Age at diagnosis of IBD tended to be younger among PSC cohorts. All PSC-UC patients had pancolitis (P<0.0001), and all PSC-CD patients had a colonic component to their disease. In the UC cohort, PSC patients were statistically more likely to be on immunosuppressive therapy (P<0.0001). CONCLUSIONS: With greater research, physicians will better recognize IBD phenotypes at highest risk of PSC and hopefully identify complications of PSC, including cholangiocarcinoma.

Immunologic characteristics of intrarenal T cells: trafficking of expanded CD8+ T cell ß-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) ß-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 Bowman's 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.

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.