Cristina Pamfil

Diagnostic criteria for systemic lupus erythematosus: has the time come?

Systemic lupus erythematosus (SLE) is a multiorgan disease with protean manifestations. Because SLE is uncommon and heterogeneous, its diagnosis can pose a considerable challenge, especially for clinicians with limited expertise of the disease. This is particularly true at the early stages of SLE, when an inadequate number of features to secure the diagnosis might be present, and for patients presenting with uncommon features, which can nonetheless be severe and require prompt treatment. Furthermore, the suboptimal performance of immunological testing in patients referred for possible SLE has been highlighted. As a result, SLE remains largely a clinical diagnosis that is made after excluding alternative diagnoses. Diagnostic criteria can expedite diagnosis and treatment, but are not available for SLE. Thus, SLE classification criteria are often used, but strict adherence to these criteria could delay diagnosis. Therefore, while eagerly awaiting diagnostic criteria for this disease, we propose interim potential solutions to facilitate its diagnosis.

EULAR recommendations for neuropsychiatric systemic lupus erythematosus vs usual care: results from two European centres

OBJECTIVE To compare the European League Against Rheumatism (EULAR) recommendations for the management of NPSLE with usual care in two tertiary centres and to detect potential pitfalls in their use for diagnosis and treatment. METHODS A chart-based review of NPSLE manifestations was conducted in two European centres. Diagnostic and treatment decisions were compared against the EULAR recommendations for general NPSLE and specific manifestations. RESULTS We studied a total of 94 patients who experienced 123 lupus-related neuropsychiatric events over 10 years. In 80% of the events, at least one EULAR-defined risk factor (previous NPSLE, generalized disease activity or aPL positivity) was present. Overall, there was good concordance between clinical care and recommendations for diagnosis and treatment (68.7% and 62.7% of events, respectively). Brain MRI was performed in the absence of a clear EULAR recommendation in 42.9% of events; therein, it was more frequently normal compared with imaging performed according to the recommendations (52.4% vs 18.5%, P = 0.008), and it did not influence management. Among patients reporting cognitive dysfunction, only 27.8% underwent the recommended neuropsychological assessment. In line with the recommendations, immunosuppressants were more frequently given in events suggestive of an inflammatory process (80.5% vs 47.6% in non-inflammatory events, P < 0.001). Notably, 52% of cerebrovascular events were managed with combined immunosuppressive/antithrombotic therapy due to either coexisting generalized lupus activity or recurrence despite prior antithrombotic treatment. CONCLUSION Despite good concordance between EULAR recommendations for NPSLE and usual clinical practice, we identified a number of issues (such as overutilization of brain MRI, suboptimal evaluation of cognitive dysfunction, and frequent use of immunosuppressives in cerebrovascular disease) that need to be investigated further.

Coexistence of systemic lupus erythematosus and multiple sclerosis: prevalence, clinical characteristics, and natural history.

OBJECTIVES The coexistence of systemic lupus erythematosus (SLE) and multiple sclerosis (MS) in the same individual has rarely been described. Our objective was to report on the prevalence, clinical characteristics, and prognosis of cases fulfilling the criteria for both SLE and MS. METHODS We utilized existing patient cohorts from the Departments of Rheumatology and Neurology, University of Crete, and screened patients diagnosed with either SLE (n = 728) or MS (n = 819) for features of both diseases. The clinical, laboratory, and neuroimaging findings were assessed. RESULTS We identified nine patients who fulfilled the diagnostic criteria for both SLE and MS, corresponding to a prevalence rate of 1.0-1.2% in each cohort. All patients were women, with an average age at SLE diagnosis of 42.1 years (range: 34-56 years). The diagnosis of SLE preceded the development of MS in five patients, with a time lag ≤ 5 years in four of them. Initial presentation of MS included spinal symptoms in seven patients. All patients had features of mild SLE with predominantly cutaneous, mucosal, and musculoskeletal manifestations. Accordingly, therapeutic decisions were mainly guided by the severity of the neurological syndrome. During the median follow-up of 4 years (range: 1-10 years), three patients remained stable and the remaining experienced gradual deterioration in their neurological status. SLE remained quiescent in all patients while on standard immunomodulatory MS therapy. CONCLUSIONS Occurrence of both diseases in the same individual is rare, corroborating data that suggest distinct molecular signatures. SLE and MS coexistence was not associated with a severe phenotype for either entity.

Subclinical myocardial impairment in SLE: insights from novel ultrasound techniques and clinical determinants.

AIMS Myocardial damage is frequent and often silent in systemic lupus erythematosus (SLE). The aim of the study was to determine the prevalence of myocardial damage by novel ultrasound techniques and to systematically assess the relationship between subclinical cardiac dysfunction and SLE-related clinical parameters. MATERIAL AND METHODS Seventy-five consecutive SLE patients without evidence of cardiac disease and seventy-three controls underwent standard transthoracic echocardiography using classical and novel ultrasound techniques: tissue Doppler imaging and speckle tracking echocardiography. Patient characteristics, cumulative organ damage and laboratory data were retrieved by medical chart review. RESULTS Within the cohort, 89.3% of the patients were female; mean+/-SD age and median (IQR) disease duration were 43.2+/-12.5 years and 8.03(6.3) years, respectively. SLE patients exhibited a significant decrement in endocardial longitudinal strain (-18.4% vs 19.3%, p=0.001) compared with controls. Diastolic dysfunction was detected in 34 (45.3%) of SLE patients. Major determinants of systolic and diastolic dysfunction were hypertension (p=0.023 and p<0.001, respectively), associated antiphospholipid syndrome (APS) (p<0.001 and p<0.001, respectively), cumulative damage accrual (p<0.001 and p=0.003, respectively), and disease duration (p=0.03 and p<0.001, respectively). Notably, anti-Ro antibodies were present in 37% of the SLE patients who had better systolic longitudinal performance. Neither disease activity, nor specific organ involvement, were associated with myocardial impairment. CONCLUSION Systolic longitudinal and diastolic performance impairments are frequent findings in SLE patients without overt cardiovascular disease. Cumulative organ damage, disease duration, APS, and hypertension are major determinants for early heart involvement in SLE patients.

Genomic dissection of Systemic Lupus Erythematosus: Distinct Susceptibility, Activity and Severity Signatures

Recent genetic and genomics approaches have yielded novel insights in the pathogenesis of Systemic Lupus Erythematosus (SLE) but the diagnosis, monitoring and treatment still remain largely empirical1,2. We reasoned that molecular characterization of SLE by whole blood transcriptomics may facilitate early diagnosis and personalized therapy. To this end, we analyzed genotypes and RNA-seq in 142 patients and 58 matched healthy individuals to define the global transcriptional signature of SLE. By controlling for the estimated proportions of circulating immune cell types, we show that the Interferon (IFN) and p53 pathways are robustly expressed. We also report cell-specific, disease-dependent regulation of gene expression and define a core/susceptibility and a flare/activity disease expression signature, with oxidative phosphorylation, ribosome regulation and cell cycle pathways being enriched in lupus flares. Using these data, we define a novel index of disease activity/severity by combining the validated Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)1 with a new variable derived from principal component analysis (PCA) of RNA-seq data. We also delineate unique signatures across disease endo-phenotypes whereby active nephritis exhibits the most extensive changes in transcriptome, including prominent drugable signatures such as granulocyte and plasmablast/plasma cell activation. The substantial differences in gene expression between SLE and healthy individuals enables the classification of disease versus healthy status with median sensitivity and specificity of 83% and 100%, respectively. We explored the genetic regulation of blood transcriptome in SLE and found 3142 cis-expression quantitative trait loci (eQTLs). By integration of SLE genome-wide association study (GWAS) signals and eQTLs from 44 tissues from the Genotype-Tissue Expression (GTEx) consortium, we demonstrate that the genetic causality of SLE arises from multiple tissues with the top causal tissue being the liver, followed by brain basal ganglia, adrenal gland and whole blood. Collectively, our study defines distinct susceptibility and activity/severity signatures in SLE that may facilitate diagnosis, monitoring, and personalized therapy.

Response to: “Relationship Between Ventricular Arrhythmias, Conduction Disorders, and Myocardial Fibrosis in Patients With Systemic Sclerosis

Background Delayed-enhancement magnetic resonance imaging (DE-MRI) is a noninvasive diagnostic tool able to identify myocardial fibrosis. In patients with scleroderma, its relationship with arrhythmias and conduction disorders has not been fully explored. Objectives The aim of this study was to evaluate the possible correlations between ventricular arrhythmias, conduction disorders, and myocardial fibrosis in patients with systemic sclerosis. Methods Thirty-six patients with diffuse or limited cutaneous scleroderma underwent 12-lead electrocardiogram (ECG), 24-hour Holter ECG monitoring, transthoracic echocardiography, and cardiac DE-MRI, with gadolinium administration in 33 patients. Results High-quality DE-MRI scans were obtained in 30 patients. Myocardial fibrosis was detected in 25 patients (83.3%). Eighteen patients (60%) had ventricular arrhythmias or conduction disorders. There was no significant difference in ventricular arrhythmia burden (the total number of premature ventricular contractions [PVCs]/24 hours) (48 ± 304 vs. 69 ± 236, P = 0.97), ventricular arrhythmia severity (couplets, triplets, runs) on Holter ECG, or in the presence of conduction disorders (36% vs. 40%, P = 0.86) between patients with and without myocardial fibrosis. In univariate analysis, diffuse fibrosis was weakly associated with the number of PVCs/24 hours (R2 = 0.157, P = 0.03). A number of at least 597 PVCs/24 hours had a sensitivity of 60% and a specificity of 92% in predicting the presence of diffuse fibrosis on DE-MRI (area under the curve = 0.640). Conclusions Delayed-enhancement magnetic resonance imaging can identify myocardial fibrosis in a high percentage of scleroderma patients. Its presence does not seem to influence the ventricular arrhythmia burden and severity or the presence of conduction disorders, with the exception of diffuse myocardial fibrosis, which modestly influences the total number of PVCs/24 hours.