Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma.

ObjectiveAutoimmune responses to DNA topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (ILD) and mortality. Anti-topo I antibodies (ATAs) are associated with specific HLA-DRB1 alleles, and the frequency of HLA-DR-restricted topo I-specific CD4+ T cells is associated with the presence, severity, and progression of ILD. Although this strongly implicates the presentation of topo I peptides by HLA-DR in scleroderma pathogenesis, the processing and presentation of topo I has not been studied.MethodsWe developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of topo I presented by monocyte-derived dendritic cells (mo-DCs) from 6 ATA-positive patients with scleroderma. Mo-DCs were pulsed with topo I protein, HLA-DR-peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce CD4+ T cell activation in 11 ATA-positive and 11 ATA-negative scleroderma patients.ResultsWe found that a common set of 10 topo I epitopes was presented by Mo-DCs from scleroderma patients with diverse HLA-DR variants. Sequence analysis revealed shared peptide-binding motifs within the HLA-DRβ chains of ATA-positive patients and a subset of topo I epitopes with distinct sets of anchor residues capable of binding to multiple different HLA-DR variants. The NAPA-derived epitopes elicited robust CD4+ T cell responses in 73% of ATA-positive patients (8 of 11), and the number of epitopes recognized correlated with ILD severity (P = 0.025).ConclusionThese findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma

Cerebral Venous Thrombosis Mimicking a Discrete Brain Mass: A Case Report and Literature Review

The differential diagnosis for a focal brain lesion in a patient with systemic lupus erythematosus (SLE) is broad and includes infection, malignancy, and vascular and inflammatory etiologies. One rarely considered vascular pathology is cerebral venous thrombosis (CVT), which is often associated with a delay in diagnosis because of variable presentation and rare incidence. We present the case of a young woman with a new discrete brain lesion that appeared in the context of highly active SLE and was ultimately diagnosed with a CVT. We provide a literature review for diagnosis and management of cerebral venous thrombosis, a potentially serious complication of untreated systemic lupus erythematosus

Longitudinal assessment of patient-reported outcome measures in systemic sclerosis patients with gastroesophageal reflux disease : Scleroderma Clinical Trials Consortium

Objective: Validated gastrointestinal (GI) symptoms scales are used in clinical practice to assess patient-reported GI involvement. We sought to determine whether University of California, Los Angeles (UCLA) GI Tract Questionnaire (GIT) 2.0 Reflux scale, Patient-Reported Outcomes Measurement Information System (PROMIS) Reflux scale, and the Quality of Life in Reflux and Dyspepsia questionnaire (QOLRAD) are sensitive to identifying changes in GI symptoms following therapeutic intervention in participants with systemic sclerosis (SSc) and gastroesophageal reflux disease (GERD). Methods: Participants with active GERD were recruited during clinical visits at 6 international SSc centers. Patient-reported outcome surveys and the GI self-reported questionnaire were completed at baseline and again at 4 weeks following a single intervention, and patients were classified as " improved" or " not improved." Effect size (ES) was calculated to assess the sensitivity to change. ES was interpreted as 0.50-0.79 as moderate effect and = 0.80 as large effect. Results: There were 116 participants with SSc and active GERD who enrolled. The average age was 53.8 years and mean disease duration was 12.0 years. The UCLA GIT 2.0 Reflux scale and PROMIS Reflux scale had a significant correlation at baseline (0.61, p < 0.0001), and both instruments correlated with the QOLRAD domains (-0.56 to -0.71). In participants who had the UCLA GIT 2.0, PROMIS Reflux scale, and QOLRAD administered over 2 timepoints (n = 57) and were classified as improved, the ES was large for the UCLA GIT 2.0 and PROMIS Reflux scale, and moderate to large across all QOLRAD domains. Conclusion: The UCLA GIT 2.0 Reflux scale, PROMIS Reflux scale, and QOLRAD are sensitive to change and can be included in future clinical trials