Epigenetic activation and memory at a TGFB2 enhancer in systemic sclerosis.

In systemic sclerosis (SSc), previously healthy adults develop an inflammatory prodrome with subsequent progressive fibrosis of the skin and viscera. SSc has a weak signature for genetic contribution, and there are few pathogenic insights or targeted treatments for this condition. Here, chromatin accessibility and transcriptome profiling coupled with targeted epigenetic editing revealed constitutive activation of a previously unannotated transforming growth factor-ß2 (TGFB2) enhancer maintained through epigenetic memory in SSc. The resulting autocrine TGFß2 signaling enforced a profibrotic synthetic state in ex vivo fibroblasts from patients with SSc. Inhibition of NF-κB or BRD4 achieved sustained inhibition of TGFB2 enhancer activity, mitigated profibrotic gene expression, and reversed dermal fibrosis in patient skin explants. These findings suggest a potential epigenetic mechanism of fibrosis in SSc and inform a regulatory mechanism of TGFB2, a major profibrotic cytokine.

Neuroimaging evidence of white matter inflammation in newly diagnosed systemic lupus erythematosus.

OBJECTIVE: Central nervous system (CNS) involvement occurs frequently in systemic lupus erythematosus (SLE) and frequently results in morbidity. The primary pathophysiology of CNS involvement in SLE is thought to be inflammation secondary to autoantibody-mediated vasculitis. Neuroimaging studies have shown hypometabolism (representing impending cell failure) and atrophy (representing late-stage pathology), but not inflammation. The purpose of this study was to detect the presence and regional distribution of inflammation (hypermetabolism) and tissue failure, apoptosis, or atrophy (hypometabolism). METHODS: Eighty-five patients with newly diagnosed SLE, who had no focal neurologic symptoms, were studied. Disease activity was quantified using the Safety of Estrogens in Lupus Erythematosus: National Assessment version of the SLE Disease Activity Index (SELENA-SLEDAI), a validated index of SLE-related disease activity. 18Fluorodeoxyglucose (FDG) positron emission tomography (PET) images of glucose uptake were analyzed by visual inspection and as group statistical parametric images, using the SELENA-SLEDAI score as the analysis regressor. RESULTS: SELENA-SLEDAI-correlated increases in glucose uptake were found throughout the white matter, most markedly in heavily myelinated tracts. SELENA-SLEDAI-correlated decreases were found in the frontal and parietal cortex, in a pattern similar to that seen during visual inspection and presented in previous reports of hypometabolism. CONCLUSION: The SELENA-SLEDAI-correlated increases in glucose consumption are potential evidence of inflammation, consistent with prior reports of hypermetabolism in inflammatory disorders. To our knowledge, this is the first imaging-based evidence of SLE-induced CNS inflammation in an SLE inception cohort. The dissociation among 18FDG uptake characteristics, spatial distribution, and disease activity correlation is in accordance with the notion that glucose hypermetabolism and hypometabolism reflect fundamentally different aspects of the pathophysiology of SLE with CNS involvement.

Memantine in systemic lupus erythematosus: a randomized, double-blind placebo-controlled trial.

OBJECTIVES: Cognitive impairment affects up to 80% of systemic lupus erythematosus (SLE) patients within 10 years of diagnosis. Memantine, a seronergic receptor and nicotine acetylcholine receptor antagonist, acts on the glutamatergic system through the NMDA receptor and is used to treat dementia. We investigated whether it had benefit for SLE cognitive impairment. METHODS: A randomized double-blind, placebo-controlled single-center 12-week trial of memantine titrated to 20 mg/d was performed, using a 2:1 randomization ratio, in 51 SLE patients. The primary outcome measures were change in the Automated Neuropsychological Assessment Metrics throughput scores at 12 weeks. RESULTS: There were no statistically significant differences between treatment groups or change from baseline in any of the Automated Neuropsychological Assessment Metrics throughput scores at 6 or 12 weeks. For the American College of Rheumatology cognitive battery, the only statistically significant findings were for the Controlled Oral Word Association Test-S words at 6 and 12 weeks. At 12 weeks, the memantine group exhibited greater improvement compared with the placebo group (3.6 ± 1.8 vs 0.5 ± 3.8 words, P = 0.03). In a subset analysis limited to patients that scored ≥1 standard deviation below normal controls at baseline, no significant differences between treatment groups were found. CONCLUSIONS: In this first clinical trial of memantine in SLE, patients treated with memantine did not exhibit significant improvement in cognitive performance compared with the placebo group, regardless of the degree of impairment at baseline, with the exception of controlled oral word association.

Depression and cognitive impairment in newly diagnosed systemic lupus erythematosus.

OBJECTIVE: Cognitive impairment is present in 80% of patients with systemic lupus erythematosus (SLE) 10 years after diagnosis. The natural history of cognitive dysfunction in newly diagnosed SLE is unknown. We examined the association of depression and cognitive performance in newly diagnosed SLE. METHODS: A multicenter cohort of 111 patients newly diagnosed (within 9 months) with SLE underwent cognitive function testing using an automated battery [Automated Neuropsychological Assessment Metrics (ANAM)] with 9 subtests. Depression was measured using the Calgary Depression Scale (CDS). RESULTS: The patient cohort was 97.3% female, 55.9% white, 15.3% African American, 20.7% Hispanic, mean age 37.8 years, mean education 15.2 years. CDS score ranged from 0 to 18 (mean 5.0 ± 4.6). CDS score did not differ by age, sex, ethnicity, or prednisone dose. Higher Krupp Fatigue Severity Scale scores and presence of fibromyalgia were significantly associated with higher CDS score (p < 0.001; p = 0.006, respectively). Depressed patients, defined by a CDS score > 6, had significantly poorer performance on 5 ANAM throughput measures: code substitution (p = 0.03), continuous performance (p = 0.02), matching-to-sample (p = 0.04), simple reaction time (p = 0.02), and the Sternberg memory test (p = 0.04). Adjusting for age, sex, ethnicity, education, and prednisone dose, a higher CDS score remained significantly associated with poorer performance on 3 measures, but the association was slightly attenuated for code substitution and matching-to-sample. Depression was not associated with mathematical or spatial processing. CONCLUSION: Depression, a modifiable risk factor, is associated with significantly poorer function in several cognitive domains in patients newly diagnosed with SLE. Treatment of depression when the CDS score is greater than 6 may improve cognitive functioning and should be further studied.

Brain magnetic resonance imaging in newly diagnosed systemic lupus erythematosus.

OBJECTIVE: We wished to determine the prevalence of cerebral atrophy and focal lesions in a cohort of patients with newly diagnosed systemic lupus erythematosus (SLE) and the association of these brain abnormalities with clinical characteristics. METHODS: A total of 97 patients with SLE, within 9 months of diagnosis, with 4 or more American College of Rheumatology classification criteria, were enrolled. Brain magnetic resonance imaging was performed. RESULTS: The patients were 97% female, mean age 38.1 (SD 12.2) years, education 15.1 (2.8) years; 59 Caucasian, 11 African American, 19 Hispanic, 5 Asian, and 3 other ethnicity. Cerebral atrophy was prevalent in 18% (95% CI 11%-27%): mild in 12%, moderate in 5%. Focal lesions were prevalent in 8% (95% CI 4%-16%): mild in 2%, moderate in 5%, severe in 1%. Patients with cerebral atrophy were more likely to have anxiety disorder (p = 0.04). Patients with focal lesions were more likely to be African American (p = 0.045) and had higher Safety of Estrogens in Lupus Erythematosus National Assessment SLEDAI scores (p = 0.02) and anti-dsDNA (p = 0.05). CONCLUSION: In this population with newly diagnosed SLE, brain abnormalities were prevalent in 25% of patients. These findings suggest that the brain may be affected extremely early in the course of SLE, even before the clinical diagnosis of SLE is made. Followup of these patients is planned, to determine the reversibility or progression of these abnormalities and their association with and potential predictive value for subsequent neuropsychiatric SLE manifestations.

Cognitive function in a systemic lupus erythematosus inception cohort.

OBJECTIVE: Measurable cognitive impairment occurs in 30-75% of patients with systemic lupus erythematosus (SLE). We compared cognitive functioning in recently-diagnosed SLE patients and normal controls. METHODS: The Automated Neuropsychological Assessment Metrics (ANAM), a repeatable computerized cognitive battery assessing cognitive processing speed and efficiency, was administered to 111 recently diagnosed SLE patients and 79 normal controls. Throughput scores on ANAM subtests were compared using linear regression. RESULTS: After adjusting for age, gender, ethnicity, and education, SLE patients scored significantly lower than controls on throughput measures of 4 ANAM subtests: code substitution immediate recall (p = 0.02), continuous performance (p = 0.02), matching to sample (p = 0.02), and Sternberg subtest (p = 0.0002). CONCLUSIONS: Recently diagnosed SLE patients performed significantly worse than normal controls on 4 of 9 ANAM subtests. ANAM subtests of cognitive efficiency requiring sustained attention/vigilance, visuospatial span of attention/working memory, and simple reaction time showed the greatest impairment. These cognitive deficits were particularly striking, because the SLE patients in this sample were not selected for the presence of neuropsychiatric manifestations, had mild SLE-related disease/damage, and were recently diagnosed with SLE. This suggests that deficits in cognitive efficiency and sustained attention are present early in the course of SLE and in the absence of other significant neuropsychiatric manifestations.