ABSTRACT
BACKGROUND: Systemic lupus erythematosus (SLE) is characterised by increased cardiovascular morbidity and mortality risk. We aimed to examine the prevalence of traditional cardiovascular risk factors and their control in an international survey of patients with systemic lupus erythematosus. METHODS: In this multicentre, cross-sectional study, cardiovascular risk factor data from medical files of adult patients (aged ≥18) with SLE followed between Jan 1, 2015, and Jan 1, 2020, were collected from 24 countries, across five continents. We assessed the prevalence and target attainment of cardiovascular risk factors and examined potential differences by country income level and antiphospholipid syndrome coexistence. We used the Systemic Coronary Risk Evaluation algorithm for cardiovascular risk estimation, and the European Society of Cardiology guidelines for assessing cardiovascular risk factor target attainment. People with lived experience were not involved in the research or writing process. FINDINGS: 3401 patients with SLE were included in the study. The median age was 43·0 years (IQR 33-54), 3047 (89·7%) of 3396 patients were women, 349 (10.3%) were men, and 1629 (48·1%) of 3390 were White. 556 (20·7%) of 2681 patients had concomitant antiphospholipid syndrome. We found a high cardiovascular risk factor prevalence (hypertension 1210 [35·6%] of 3398 patients, obesity 751 [23·7%] of 3169 patients, and hyperlipidaemia 650 [19·8%] of 3279 patients), and suboptimal control of modifiable cardiovascular risk factors (blood pressure [target of <130/80 mm Hg], BMI, and lipids) in the entire SLE group. Higher prevalence of cardiovascular risk factors but a better blood pressure (target of <130/80 mm Hg; 54·9% [1170 of 2132 patients] vs 46·8% [519 of 1109 patients]; p<0·0001), and lipid control (75·0% [895 of 1194 patients] vs 51·4% [386 of 751 patients], p<0·0001 for high-density lipoprotein [HDL]; 66·4% [769 of 1158 patients] vs 60·8% [453 of 745 patients], p=0·013 for non-HDL; 80·9% [1017 of 1257 patients] vs 61·4% [486 of 792 patients], p<0·0001 for triglycerides]) was observed in patients from high-income versus those from middle-income countries. Patients with SLE with antiphospholipid syndrome had a higher prevalence of modifiable cardiovascular risk factors, and significantly lower attainment of BMI and lipid targets (for low-density lipoprotein and non-HDL) than patients with SLE without antiphospholipid syndrome. INTERPRETATION: High prevalence and inadequate cardiovascular risk factor control were observed in a large multicentre and multiethnic SLE cohort, especially among patients from middle-income compared with high-income countries and among those with coexistent antiphospholipid syndrome. Increased awareness of cardiovascular disease risk in SLE, especially in the above subgroups, is urgently warranted. FUNDING: None.
Subject(s)
Antiphospholipid Syndrome , Cardiovascular Diseases , Heart Disease Risk Factors , Lupus Erythematosus, Systemic , Humans , Lupus Erythematosus, Systemic/epidemiology , Lupus Erythematosus, Systemic/complications , Cross-Sectional Studies , Male , Female , Adult , Middle Aged , Prevalence , Cardiovascular Diseases/epidemiology , Antiphospholipid Syndrome/epidemiology , Antiphospholipid Syndrome/complications , Risk Factors , Hypertension/epidemiologyABSTRACT
ABSTRACT: Pseudolymphomatous cutaneous angiosarcoma (cAS) is a rare subtype characterized by a prominent lymphocytic infiltrate, posing diagnostic challenges due to its resemblance to lymphoid neoplastic processes. We present a novel case highlighting the clinical and histopathological features, notably its association with persistent firm facial edema in a patient with systemic sclerosis (SSc). A 47-year-old woman with a 21-year history of SSc presented with firm palpebral edema evolving to involve the entire face and cervical region over six months. Diagnostic imaging revealed inflammatory changes in orbital regions, supradiaphragmatic lymphadenopathies, and lytic lesions. Skin biopsy demonstrated a diffuse neoplasm with vascular channels and solid areas, accompanied by dense lymphocytic proliferation. Pseudolymphomatous cutaneous angiosarcoma, a rare malignant neoplasm, exhibits variable clinical presentations and rapid progression. Histologically, it manifests as irregularly shaped vascular channels lined by prominent endothelial cells. Immunohistochemistry, particularly markers such as v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG), aids in diagnosis. Notably, this case marks the first presentation of cAS with persistent facial edema in SSc, highlighting the association between SSc and cancer risk. This case underscores the diagnostic challenges posed by cAS and emphasizes the importance of early detection for optimal patient outcomes. Further understanding of its association with autoimmune disorders such as SSc is crucial for comprehensive management strategies.
Subject(s)
Edema , Hemangiosarcoma , Scleroderma, Systemic , Skin Neoplasms , Humans , Female , Hemangiosarcoma/pathology , Hemangiosarcoma/complications , Middle Aged , Skin Neoplasms/pathology , Skin Neoplasms/complications , Scleroderma, Systemic/complications , Scleroderma, Systemic/pathology , Edema/pathology , Pseudolymphoma/pathology , Face/pathologyABSTRACT
Objetivo: Describir la distribución de los reumatólogos de adultos y pediátricos con certificación vigente en México y los factores asociados a esta distribución. Métodos: Se revisaron las bases de datos del Consejo Mexicano de Reumatología y del Colegio Mexicano de Reumatología de 2020. Se calculó la tasa de reumatólogos por cada 100.000 habitantes por estado de la República Mexicana. Para conocer el número de habitantes por estado, se consultaron los resultados del censo de población del Instituto Nacional de Estadística y Geografía de 2020. Se analizó el número de reumatólogos con certificación vigente por estado, edad y sexo. Resultados: En México hay registrados 1.002 reumatólogos de adultos, con una edad promedio de 48,12±13 años. Predominó el género masculino con una relación de 1,18:1. Se identificaron 94 reumatólogos pediatras, con una edad promedio de 42,25±10,4 años, con predominio del género femenino con una relación de 2,2:1. En la Ciudad de México y Jalisco se reportó más de un reumatólogo/100.000 habitantes en la especialidad de adultos y solo en la Ciudad de México en pediátricos. La certificación vigente es de 65 a 70% en promedio y los factores asociados a una mayor prevalencia fueron edad menor, género femenino y ubicación geográfica. Conclusiones: Existe escasez de reumatólogos en México y en el área pediátrica hay regiones desatendidas. Es importante que las políticas de salud apliquen medidas que permitan una regionalización más equilibrada y eficiente de esta especialidad. Aunque la mayoría de los reumatólogos cuentan con certificación vigente, es necesario establecer estrategias esta proporción.(AU)
Objective: Describe the distribution of adult and pediatric rheumatologists with current certification in Mexico and the factors associated with this distribution. Methods: The databases of the Mexican Council of Rheumatology and the Mexican College of Rheumatology for 2020 were reviewed. The rate of rheumatologists per 100,000 inhabitants by state of the Mexican Republic was calculated. To find out the number of inhabitants by state, the results of the 2020 population census of the National Institute of Statistics and Geography were consulted. The number of rheumatologists with current certification by state, age, and sex was analyzed. Results: In Mexico, there are 1002 registered adult rheumatologists with a mean age of 48.12±13 years. The male gender prevailed with a ratio of 1.18:1. Ninety-four pediatric rheumatologists were identified with a mean age of 42.25±10.4 years, with a predominance of the female gender with a ratio of 2.2:1. In Mexico City and Jalisco, more than one rheumatologist/100,000 inhabitants were reported in the specialty of adults and only in Mexico City in pediatrics. The current certification is 65 to 70% on average and the factors associated with a higher prevalence were younger age, female gender and geographic location. Conclusions: There is a shortage of rheumatologists in Mexico and in the pediatric area there are underserved regions. It is important that health policies apply measures that allow a more balanced and efficient regionalization of this specialty. Although most rheumatologists have current certification, it is necessary to establish strategies to increase this proportion.(AU)
Subject(s)
Humans , Rheumatology , Rheumatic Diseases , Certification , Rheumatologists , Health Workforce , Mexico , Geographic MappingABSTRACT
OBJECTIVE: Describe the distribution of adult and pediatric rheumatologists with current certification in Mexico and the factors associated with this distribution. METHODS: The databases of the Mexican Council of Rheumatology and the Mexican College of Rheumatology for 2020 were reviewed. The rate of rheumatologists per 100,000 inhabitants by state of the Mexican Republic was calculated. To find out the number of inhabitants by state, the results of the 2020 population census of the National Institute of Statistics and Geography were consulted. The number of rheumatologists with current certification by state, age, and sex was analyzed. RESULTS: In Mexico, there are 1002 registered adult rheumatologists with a mean age of 48.12⯱â¯13 years. The male gender prevailed with a ratio of 1.18:1. Ninety-four pediatric rheumatologists were identified with a mean age of 42.25⯱â¯10.4 years, with a predominance of the female gender with a ratio of 2.2:1. In Mexico City and Jalisco, more than one rheumatologist/100,000 inhabitants were reported in the specialty of adults and only in Mexico City in pediatrics. The current certification is 65%-70% on average and the factors associated with a higher prevalence were younger age, female gender and geographic location. CONCLUSIONS: There is a shortage of rheumatologists in Mexico and in the pediatric area there are underserved regions. It is important that health policies apply measures that allow a more balanced and efficient regionalization of this specialty. Although most rheumatologists have current certification, it is necessary to establish strategies to increase this proportion.
Subject(s)
Rheumatologists , Rheumatology , Adult , Humans , Male , Female , Child , Middle Aged , Mexico , Certification , Databases, FactualABSTRACT
OBJECTIVE: Randomised trials of type I anti-CD20 antibodies rituximab and ocrelizumab failed to show benefit in proliferative lupus nephritis (LN). We compared obinutuzumab, a humanised type II anti-CD20 monoclonal antibody that induces potent B-cell depletion, with placebo for the treatment of LN in combination with standard therapies. METHODS: Patients with LN receiving mycophenolate and corticosteroids were randomised to obinutuzumab 1000 mg or placebo on day 1 and weeks 2, 24 and 26, and followed through week 104. The primary endpoint was complete renal response (CRR) at week 52. Exploratory analyses through week 104 were conducted. The prespecified alpha level was 0.2. RESULTS: A total of 125 patients were randomised and received blinded infusions. Achievement of CRR was greater with obinutuzumab at week 52 (primary endpoint, 22 (35%) vs 14 (23%) with placebo; percentage difference, 12% (95% CI -3.4% to 28%), p=0.115) and at week 104 (26 (41%) vs 14 (23%); percentage difference, 19% (95% CI 2.7% to 35%), p=0.026). Improvements in other renal response measures, serologies, estimated glomerular filtration rate and proteinuria were greater with obinutuzumab. Obinutuzumab was not associated with increases in serious adverse events, serious infections or deaths. Non-serious infusion-related reactions occurred more frequently with obinutuzumab. CONCLUSIONS: Improved renal responses through week 104 were observed in patients with LN who received obinutuzumab plus standard therapies compared with standard therapies alone. Obinutuzumab was well tolerated and no new safety signals were identified. TRIAL REGISTRATION NUMBER: NCT02550652.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , B-Lymphocytes/drug effects , Lupus Nephritis/drug therapy , Adrenal Cortex Hormones/therapeutic use , Adult , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents, Immunological/pharmacology , Double-Blind Method , Drug Therapy, Combination , Enzyme Inhibitors/therapeutic use , Female , Glomerular Filtration Rate , Humans , Lupus Nephritis/physiopathology , Male , Mycophenolic Acid/therapeutic use , Placebos/therapeutic use , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION: Factors related to presentation of neuropsychiatric (NP) SLE manifestations, early in the course of the disease, and during follow up have not been clearly established. PURPOSE: To identify disease and non-disease related factors associated with NP manifestations in early SLE. METHODS: We included 1193 patients from the GLADEL inception cohort free of NP involvement at cohort entry. We evaluated the association of demographic, clinical and laboratory data with NP involvement during follow-up. STATISTICAL METHODS: Independent factors associated with NP involvement were identified using a multivariable Cox regression model. RESULTS: Factors independently associated with NP manifestations were: mestizo ethnicity (HR 1.701, 95% CI 1.282-2.258, p = 0.0002), myalgias/myositis (HR 1.832, 95% CI 1.335-2.515, p = 0.0002), pneumonitis (HR 2.476, 95% CI 1.085-5.648, p = 0.0312), shrinking lung (HR 2.428, 95% CI 1.074-5.493, p = 0.0331) and hemolytic anemia (HR 1.629, 95% CI 1.130-2.347, p = 0.0089). Longer disease duration at cohort entry (13 to 24 months) was associated with a lower risk of developing NP manifestations (HR 0.642, 95% CI 0.441-0.934, p = 0.0206). CONCLUSIONS: Patients with myalgias/myositis, pneumonitis, shrinking lung and hemolytic anemia are at higher risk of NP involvement, whereas longer disease duration at cohort entry is associated with a lower risk of developing NP involvement.
Subject(s)
Lupus Vasculitis, Central Nervous System/epidemiology , Anemia, Hemolytic/epidemiology , Anemia, Hemolytic/etiology , Female , Humans , Latin America/epidemiology , Lung Diseases/epidemiology , Lung Diseases/etiology , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/epidemiology , Lupus Vasculitis, Central Nervous System/etiology , Male , Muscular Diseases/epidemiology , Muscular Diseases/etiology , Prevalence , Time FactorsABSTRACT
Introduction: After more than 20 years of sustained work, the Latin American Group for the Study of Lupus (GLADEL) has made a significant number of contributions to the field of lupus, not only in the differential role that race/ethnicity plays in its course and outcome but also in several other studies including the beneficial effects of using antimalarials in lupus patients and the development of consensus guidelines for the treatment of lupus in our region. Methods: A new generation of "Lupus Investigators" in more than 40 centers throughout Latin America has been constituted in order to continue the legacy of the investigators of the original cohort and to launch a novel study of serum and urinary biomarkers in patients with systemic lupus erythematosus. Results: So far, we have recruited 807 patients and 631 controls from 42 Latin-American centers including 339 patients with SLE without renal involvement, 202 patients with SLE with prevalent but inactive renal disease, 176 patients with prevalent and active renal disease and 90 patients with incident lupus nephritis. Conclusions: The different methodological aspects of the GLADEL 2.0 cohort are discussed in this manuscript, including the challenges and difficulties of conducting such an ambitious project.
ABSTRACT
BACKGROUND: Acute transverse myelitis (ATM) is an infrequent but severe complication of systemic lupus erythematosus (SLE). The purpose of study was to describe clinical features and prognostic factors of patients with SLE-related ATM. METHODS: In this medical records review study, data were collected from 60 patients from 16 centers seen between 1996 and 2017 who met diagnostic criteria for SLE and myelitis as defined by the American College of Rheumatology/Systemic International Collaborating Clinics and the Working Group of the Transverse Myelitis Consortium, respectively. Objective neurological impairment was measured with American Spinal Injury Association Impairment Scale (AIS) and European Database for Multiple Sclerosis Grade Scale (EGS). RESULTS: Among patients included, 95% (n = 57) were female, and the average age was 31.6 ± 9.6 years. Myelitis developed after diagnosis of SLE in 60% (n = 36). Symmetrical paraparesis with hypoesthesia, flaccidity, sphincter dysfunction, AIS = A/B, and EGS ≥ 8 was the most common presentation. Intravenous methylprednisolone was used in 95% (n = 57), and 78.3% (n = 47) received intravenous cyclophosphamide. Sensory/motor recovery at 6 months was observed in 75% (42 of 56), but only in 16.1% (9 of 56) was complete. Hypoglycorrhachia and EGS ≥ 7 in the nadir were associated with an unfavorable neurological outcome at 6 months (p < 0.05). A relapse rate during follow-up was observed in 30.4% (17 of 56). Hypoglycorrhachia and hypocomplementemia seem to be protective factors for relapse. Intravenous cyclophosphamide was associated with time delay to relapse. CONCLUSIONS: Systemic lupus erythematosus-related ATM may occur at any time of SLE course, leading to significant disability despite treatment. Relapses are infrequent and intravenous cyclophosphamide seems to delay it. Hypoglycorrhachia, hypocomplementemia, and EGS at nadir are the most important prognostic factors.
Subject(s)
Lupus Erythematosus, Systemic , Myelitis, Transverse , Adult , Female , Humans , Latin America , Lupus Erythematosus, Systemic/complications , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/drug therapy , Myelitis, Transverse/diagnosis , Myelitis, Transverse/drug therapy , Myelitis, Transverse/epidemiology , Neoplasm Recurrence, Local , Prognosis , Young AdultABSTRACT
INTRODUCTION: Rheumatologists are the primary healthcare professionals responsible for patients with rheumatic diseases and should acquire medical ethical competencies, such as the informed consent process (ICP). The objective clinical structured examination is a valuable tool for assessing clinical competencies. We report the performance of 90 rheumatologist trainees participating in a station designed to evaluate the ICP during the 2018 and 2019 national accreditations. METHODS: The station was validated and represented a medical encounter in which the rheumatologist informed a patient with systemic lupus erythematosus with clinically active nephritis about renal biopsy. A trained patient-actor and an evaluator were instructed to assess ICP skills (with a focus on kidney biopsy benefits, how the biopsy is done and potential complications) in obtaining formal informed consent, delivering bad news and overall communication with patients. The evaluator used a tailored checklist and form. RESULTS: Candidate performance varied with ICP content and was superior for potential benefit information (achieved by 98.9% of the candidates) but significantly reduced for potential complications (37.8%) and biopsy description (42.2%). Only 17.8% of the candidates mentioned the legal perspective of ICP. Death (as a potential complication) was omitted by the majority of the candidates (93.3%); after the patient-actor challenged candidates, only 57.1% of them gave a clear and positive answer. Evaluators frequently rated candidate communications skills as superior (≥80%), but ≥1 negative aspect was identified in 69% of the candidates. CONCLUSIONS: Ethical competencies are mandatory for professional rheumatologists. It seems necessary to include an ethics competency framework in the curriculum throughout the rheumatology residency.
Subject(s)
Accreditation , Clinical Competence , Ethics, Medical , Rheumatology/ethics , Accreditation/methods , Accreditation/standards , Biopsy/ethics , Clinical Competence/standards , Humans , Informed Consent/ethics , Informed Consent/standards , Kidney/pathology , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/pathology , Mexico , Physician-Patient Relations/ethics , Rheumatology/standardsABSTRACT
Systemic lupus erythematosus (SLE), a complex and heterogeneous autoimmune disease, represents a significant challenge for both diagnosis and treatment. Patients with SLE in Latin America face special problems that should be considered when therapeutic guidelines are developed. The objective of the study is to develop clinical practice guidelines for Latin American patients with lupus. Two independent teams (rheumatologists with experience in lupus management and methodologists) had an initial meeting in Panama City, Panama, in April 2016. They selected a list of questions for the clinical problems most commonly seen in Latin American patients with SLE. These were addressed with the best available evidence and summarised in a standardised format following the Grading of Recommendations Assessment, Development and Evaluation approach. All preliminary findings were discussed in a second face-to-face meeting in Washington, DC, in November 2016. As a result, nine organ/system sections are presented with the main findings; an 'overarching' treatment approach was added. Special emphasis was made on regional implementation issues. Best pharmacologic options were examined for musculoskeletal, mucocutaneous, kidney, cardiac, pulmonary, neuropsychiatric, haematological manifestations and the antiphospholipid syndrome. The roles of main therapeutic options (ie, glucocorticoids, antimalarials, immunosuppressant agents, therapeutic plasma exchange, belimumab, rituximab, abatacept, low-dose aspirin and anticoagulants) were summarised in each section. In all cases, benefits and harms, certainty of the evidence, values and preferences, feasibility, acceptability and equity issues were considered to produce a recommendation with special focus on ethnic and socioeconomic aspects. Guidelines for Latin American patients with lupus have been developed and could be used in similar settings.
Subject(s)
Antiphospholipid Syndrome/drug therapy , Hematologic Diseases/drug therapy , Kidney Diseases/drug therapy , Lupus Erythematosus, Systemic/drug therapy , Antiphospholipid Syndrome/etiology , Heart Diseases/drug therapy , Heart Diseases/etiology , Hematologic Diseases/etiology , Humans , Kidney Diseases/etiology , Latin America , Lung Diseases/drug therapy , Lung Diseases/etiology , Lupus Erythematosus, Systemic/complications , Lupus Nephritis/drug therapy , Lupus Nephritis/etiology , Mental Disorders/drug therapy , Mental Disorders/etiology , Musculoskeletal Diseases/drug therapy , Musculoskeletal Diseases/etiology , Skin Diseases/drug therapy , Skin Diseases/etiology , Standard of CareABSTRACT
OBJECTIVE: To determine if cognitive dysfunction in patients with systemic lupus erythematosus (SLE) derives from an inflammatory process with continuing disease activity, and increased levels of autoantibodies and inflammatory molecules in serum and cerebrospinal fluid (CSF). METHODS: 100 randomly selected patients participating in an inception SLE cohort were studied. At entry into the cohort, a standardized medical history and extensive laboratory tests profile, including autoantibodies were completed. Follow-up occurred every 3-6 months with assessment of lupus characteristics, comorbidities, and treatment. After a mean follow-up of six-years, cross-sectional evaluation of cognitive function was done with standardized tests, and in a subset of patients an extended profile of autoantibodies, cytokines and chemokines was measured in serum and CSF. RESULTS: At enrollment into the cohort, patients were 26.4±8.2 years of age and lupus duration 5.3±3.7 months. Moderate/severe cognitive dysfunction was diagnosed in 16 patients; in comparison to patients with normal cognitive function, they had lower education 9 vs. 12 years (P = 0.006), higher body mass index 26.7 vs. 24.3 (P = 0.03), positive IgG anticardiolipin antibodies 50% vs 18% (P = 0.009), and a higher median number of concomitant NPSLE syndromes 3 vs. 1, (P = 0.04). The prevalence of cardiovascular-risk factors, other auto-antibodies, lupus activity, treatment, and incidence of critical events did not differ. In serum and CSF, the levels of autoantibodies, cytokines and chemokine were similar, only CCL2 was elevated in CSF [886.1 (374.9-1439.7) vs. 515.8 (3.2-1958.2) pg/mL, P = 0.04]. CONCLUSION: Scant evidence of inflammation in SLE patients with cognitive dysfunction was observed. Only a higher prevalence of IgG anticardiolipin antibodies in serum and increased levels of CCL2 in CSF were detected.
Subject(s)
Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Cognitive Dysfunction/etiology , Inflammation Mediators/blood , Inflammation Mediators/cerebrospinal fluid , Lupus Erythematosus, Systemic/complications , Adolescent , Adult , Antibodies, Anticardiolipin/blood , Chemokine CCL2/cerebrospinal fluid , Chemokines/blood , Chemokines/cerebrospinal fluid , Cognitive Dysfunction/immunology , Cohort Studies , Cross-Sectional Studies , Cytokines/blood , Cytokines/cerebrospinal fluid , Female , Humans , Lupus Erythematosus, Systemic/immunology , Male , Middle Aged , Prospective Studies , Young AdultABSTRACT
BACKGROUND: P-gp and BCRP1 are transporter proteins that may confer drug resistance. OBJECTIVE: To compare P-gp and BCRP1 function in rheumatoid arthritis patients with active and inactive disease and to define their relation with disease activity. METHODS: We included 17 active patients paired (age, gender, disease duration) to 17 inactive patients. All had baseline evaluations and 27 had additional six-month follow-up. P-gp and BCRP1 functional activity was measured in peripheral mononuclear cells by flow cytometry. Percentage of lymphocytes able to extrude substrates for P-gp and BCRP1 were recorded in the presence/absence of selective inhibitors. Informed consent was obtained. Descriptive statistics and linear regression model were applied. RESULTS: Active patients had higher efflux function of both transporters than inactive patients: median (25-75 IQR) P-gp of 7.1% (1.4-29.3) vs. 1.6% (0.7-3.5), p = 0.02 and BCRP1 of 6.2% (1.3-22.4) vs. 1.3% (0.7-2), p = 0.007. At baseline, disease activity was the only predictor of both transporter functions. At follow-up, changes in disease activity correlated with shift in P-gp (r = 0.35, p = 0.07) and BCRP1 (r = 0.33, p=0.09) function. CONCLUSIONS: Patients with active rheumatoid arthritis had a higher efflux function of P-gp and BCRP1 compared to inactive patients. The behavior of P-gp and BCRP1 appeared to be conditioned by disease activity.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Adrenal Cortex Hormones/administration & dosage , Antirheumatic Agents/administration & dosage , Arthritis, Rheumatoid/metabolism , Neoplasm Proteins/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , Adrenal Cortex Hormones/metabolism , Adult , Antirheumatic Agents/metabolism , Arthritis, Rheumatoid/drug therapy , Case-Control Studies , Daunorubicin/administration & dosage , Daunorubicin/metabolism , Drug Resistance, Multiple , Female , Humans , Lymphocytes/metabolism , Male , Middle AgedABSTRACT
OBJECTIVE: To compare drug efflux function of ABCB1 and ABCG2 transporters in rheumatoid arthritis (RA) patients with active disease and in remission. METHODS: Twenty two active RA patients (DAS28 ≥3.2) and 22 patients in remission (DAS28<2.6) were selected from an early RA clinic. All patients were evaluated at study inclusion and six months later. ABCB1 and ABCG2 functional activity was measured in peripheral lymphocytes by flow cytometry. The percentage of cells able to extrude substrates for ABCB1 and ABCG2 was recorded. RESULTS: Active patients had higher ABCB1 and ABCG2 activity compared with patients in remission (median [interquartile range]): 3.9% (1.4-22.2) vs (1.3% (0.6-3.2), p = 0.003 and 3.9% (1.1-13.3) vs 0.9% (0.5-1.9) p = 0.006 respectively. Both transporters correlated with disease activity assessed by DAS28, rho = 0.45, p = 0.002 and rho = 0.47, p = 0.001 respectively. Correlation was observed between the time from the beginning of treatment and transporter activity: rho = 0.34, p = 0.025 for ABCB1 and rho = 0.35, p = 0.018 for ABCG2. The linear regression model showed that DAS28 and the time from the onset of treatment are predictors of ABCB1 and ABCG2 functional activity, even after adjustment for treatment. After six months we calculated the correlation between change in DAS28 and change in the functional activity in both transporters and found a moderate and significant correlation for ABCG2 (rho = 0.28, p = 0.04) and a non-significant correlation for ABCB1 (rho = 0.22, p = 0.11). CONCLUSIONS: Patients with active RA have an increased function of ABCB1 and ABCG2, and disease activity is the main determinant of this phenomena.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Arthritis, Rheumatoid/metabolism , Neoplasm Proteins/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , Adult , Arthritis, Rheumatoid/diagnosis , Biological Transport , Daunorubicin/metabolism , Demography , Female , Flow Cytometry , Follow-Up Studies , Humans , Linear Models , Male , Mitoxantrone/metabolism , Remission Induction , Young AdultABSTRACT
OBJECTIVE: The objective of this study was to define the cytokine and chemokine profiles in cerebrospinal fluid (CSF) from patients with headache as neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: In a post hoc analysis, seven patients hospitalized because of headache were included. Patients were evaluated at hospitalization and 6 months later and a CSF sample was obtained. As controls, CSF from 27 patients with other NPSLE syndromes, 16 SLE patients without a history of NP manifestations (non-NPSLE) and 25 patients with non-autoimmune diseases were studied. Soluble molecules including cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-α and IFN-γ) and chemokines [monocyte chemotactic protein-1, RANTES (regulated on activation normal T cell expressed and secreted), IL-8, monokine induced by IFN-γ (MIG), and IFN-γ-induced protein 10 (IP-10)] were measured with the use of cytometric bead array kits or luminometry. RESULTS: Patients with headache had increased CSF values in the following molecules compared with non-NPSLE and non-autoimmune diseases patients, respectively: IL-6 (208.5, 3.0, 3.0 pg/ml, P < 0.004 and P < 0.001), IL-8 (406.6, 30.0, 19.7 pg/ml, P < 0.05 and P < 0.004), IP-10 (4673, 329.7, 113.6 pg/ml, P = 0.02 and P < 0.002), RANTES (7.5, 2.5, 2.2 pg/ml, P < 0.003 for both) and MIG (944.7, 11.4, 3.5 pg/ml, P = 0.02 and P = 0.001). No clear difference was observed between patients with headache and other NPSLE. Higher levels of inflammatory molecules were found in patients with headache from intracranial hypertension and intractable non-specific headache than patients with migraine. Six months later, when the headache had resolved, all the elevated molecule levels had decreased significantly. CONCLUSION: Headache from intracranial hypertension and intractable non-specific headache, but not migraine, share the inflammatory profile in CSF observed in other NPSLE syndromes.
Subject(s)
Cytokines/cerebrospinal fluid , Headache Disorders/cerebrospinal fluid , Lupus Vasculitis, Central Nervous System/cerebrospinal fluid , Adult , Case-Control Studies , Chemokines/cerebrospinal fluid , Chronic Disease , Female , Follow-Up Studies , Headache Disorders/etiology , Hospitalization , Humans , Lupus Vasculitis, Central Nervous System/complications , MaleABSTRACT
OBJECTIVE: To assess the utility of interferon-α (IFN-α) in serum and cerebrospinal fluid (CSF) as a biomarker of disease activity in central neuropsychiatric systemic lupus erythematosus (cNPSLE). METHODS: Serum and CSF samples were drawn at hospitalization in 34 patients with cNPSLE, 16 surgical SLE, 4 primary neuropsychiatric conditions, and 25 with nonautoimmune conditions, except in 44 non-NPSLE patients in whom only serum was studied. Six months later, serum/CSF and serum samples were taken in 20 cNPSLE and 35 non-NPSLE patients, respectively. SLE activity was assessed at hospitalization, and 6 months later in cNPSLE and non-NPSLE patients. IFN-α was detected by Luminex technology. RESULTS: The mean ± SD age of patients with cNPSLE was 31.4 ± 12.2 years, which was similar across the study groups (p = 0.46). Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores among cNPSLE, non-NPSLE, and SLE-surgical patients were 15.3 ± 8.2, 12.4 ± 8.2, and 3.8 ± 1.5, respectively. IFN-α levels in serum were higher in cNPSLE than in nonautoimmune patients (p = 0.02), but were similar to non-NPSLE and SLE-surgical groups. In CSF samples, IFN-α levels were higher in cNPSLE than in nonautoimmune patients (p = 0.03), and were nonsignificantly higher than in SLE-surgical and primary neuropsychiatric patients. Six months later, serum levels of IFN-α did not vary from baseline values despite a significant decrease in SLEDAI-2K score in cNPSLE and non-NPSLE patients. IFN-α levels in the CSF of patients with cNPSLE also remained stable. Among specific cNPSLE syndromes, CSF IFN-α levels were significantly higher among patients with acute confusional syndrome. CONCLUSION: IFN-α does not seem to represent a useful biomarker of cNPSLE syndromes; its utility in specific cNPSLE manifestations merits further investigation.
Subject(s)
Interferon-alpha/blood , Interferon-alpha/cerebrospinal fluid , Lupus Vasculitis, Central Nervous System/diagnosis , Severity of Illness Index , Adult , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Case-Control Studies , Female , Humans , Lupus Erythematosus, Systemic/blood , Lupus Erythematosus, Systemic/cerebrospinal fluid , Lupus Erythematosus, Systemic/diagnosis , Lupus Vasculitis, Central Nervous System/blood , Lupus Vasculitis, Central Nervous System/cerebrospinal fluid , Male , Middle Aged , Reproducibility of ResultsABSTRACT
Damaging interactions between antibodies and brain antigenic targets may be responsible for an expanding range of neurological disorders. In the case of systemic lupus erythematosus (SLE), patients generate autoantibodies (AAbs) that frequently bind dsDNA. Although some symptoms of SLE may arise from direct reactivity to dsDNA, much of the AAb-mediated damage originates from cross-reactivity with other antigens. We have studied lupus AAbs that bind dsDNA and cross-react with the NR2A and NR2B subunits of the NMDA receptor (NMDAR). In adult mouse models, when the blood-brain barrier is compromised, these NMDAR-reactive AAbs access the brain and elicit neuronal death with ensuing cognitive dysfunction and emotional disturbance. The cellular mechanisms that underlie these deleterious effects remain incompletely understood. Here, we show that, at low concentration, the NMDAR-reactive AAbs are positive modulators of receptor function that increase the size of NMDAR-mediated excitatory postsynaptic potentials, whereas at high concentration, the AAbs promote excitotoxicity through enhanced mitochondrial permeability transition. Other synaptic receptors are completely unaffected by the AAbs. NMDAR activation is required for producing both the synaptic and the mitochondrial effects. Our study thus reveals the mechanisms by which NMDAR-reactive AAbs trigger graded cellular alterations, which are likely to be responsible for the transient and permanent neuropsychiatric symptoms observed in patients with SLE. Our study also provides a model in which local AAb concentration determines the exact nature of the cellular response.
Subject(s)
Autoantibodies/toxicity , Brain/immunology , Brain/physiopathology , Lupus Erythematosus, Systemic/immunology , Lupus Erythematosus, Systemic/physiopathology , Lupus Vasculitis, Central Nervous System/immunology , Lupus Vasculitis, Central Nervous System/physiopathology , Neurotoxins/toxicity , Animals , Cross Reactions , Excitatory Postsynaptic Potentials , Female , Humans , In Vitro Techniques , Mice , Mice, Inbred BALB C , Mitochondrial Membrane Transport Proteins/physiology , Mitochondrial Permeability Transition Pore , Models, Immunological , Models, Neurological , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/immunologyABSTRACT
OBJECTIVE: To evaluate utility of S100B protein in serum as a marker of central nervous system involvement in systemic lupus erythematosus (SLE). METHODS: Forty patients with SLE, hospitalized because of central neuropsychiatric (cNP) manifestations (n = 36) and peripheral NP manifestations (pNP, n = 4) were studied. Patients were evaluated at hospitalization and 6 months later, including a serum and cerebrospinal fluid (CSF) sample. As controls, 4 SLE patients with septic meningitis (SLEsm), 13 surgical SLE patients (SLE surgical), 14 patients with nonautoimmune diseases, and 4 patients with primary NP syndromes were included. Serum and CSF S100B protein levels were determined by ELISA. RESULTS: At baseline, serum levels of S100B protein did not differ across SLE groups. Using an arbitrary cutoff value, positive S100B levels in serum were observed in 7 (19%), 6 (46%), and 1 patient from the cNPSLE, SLE surgical, and SLEsm groups, respectively. S100B protein levels in cNPSLE and SLE surgical patients were similar. In CSF, S100B protein levels did not differ among SLE groups, except in patients with SLEsm. Paired serum/CSF samples were obtained in 23 patients with cNPSLE at 6 months after the acute event. Overall, levels of S100B protein in serum did not change despite the decrease observed in CSF (p = 0.004). The correlation coefficient of serum and CSF S100B protein levels among all the SLE patients at baseline was poor (r = 0.23). CONCLUSION: Serum levels of S100B protein do not differentiate SLE patients with and those without central neurological manifestations.
Subject(s)
Central Nervous System/immunology , Lupus Erythematosus, Systemic/blood , Lupus Vasculitis, Central Nervous System/blood , Nerve Growth Factors/blood , S100 Proteins/blood , Adult , Analysis of Variance , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Chi-Square Distribution , Enzyme-Linked Immunosorbent Assay , Female , Humans , Lupus Erythematosus, Systemic/cerebrospinal fluid , Lupus Erythematosus, Systemic/immunology , Lupus Vasculitis, Central Nervous System/cerebrospinal fluid , Lupus Vasculitis, Central Nervous System/immunology , Male , Nerve Growth Factors/cerebrospinal fluid , S100 Calcium Binding Protein beta Subunit , S100 Proteins/cerebrospinal fluid , Severity of Illness IndexABSTRACT
BACKGROUND: Despite the uncertainty in the diagnosis of neuropsychiatric involvement in systemic lupus erythematosus (SLE), attempts have been made to record the association of certain antibodies in serum with neuropsychiatric (NP) manifestations. We aimed to assess the behaviour and the association of serum and cerebrospinal fluid (CSF) autoantibodies with NP manifestations in SLE patients (NPSLE). METHODOLOGY/PRINCIPAL FINDINGS: Forty-seven SLE patients, hospitalized because of NP manifestations were included. They were evaluated at hospitalization and six months later, and serum and CSF samples were obtained at each evaluation. As controls, serum samples were taken from 49 non-NPSLE patients at hospitalization and six months later; serum and CSF samples were also obtained from 6 SLE patients with septic meningitis, 16 surgical SLE patients and 25 patients without autoimmune diseases. Antinuclear, anti-dsDNA, anti-ribosomal P, Anti-N-Methyl-D-Aspartate receptor (NMDAR), anti-cardiolipin, and anti-beta2 glycoprotein-I antibodies were measured. In serum, anti-ribosomal P, anti-NMDAR, and other antibodies did not differentiate among SLE groups, and the levels of all antibodies were similar among the SLE groups. Six-months later, this scenario remained unchanged and the decrease in the levels of some autoantibodies reflected a decline in disease activity, rather than a change in NPSLE. In CSF, only the presence and the levels of anti-NMDAR antibodies showed a characteristic distribution in central NPSLE and septic meningitis patients. Six months later the prevalence of most antibodies in CSF did not change, however the levels of anti-dsDNA, anti-ribosomal P, and anti-NMDAR decreased. CONCLUSION: In NPSLE, autoantibodies in serum do not reflect their behaviour in CSF. All autoantibodies were elevated in septic meningitis reflecting the global penetration of serum antibodies into the CSF in this condition. Anti-NMDAR antibodies in CSF identified patients with central NPSLE; their continued presence in CSF 6 months after neurologic symptoms raise questions regarding the conditions under which they are pathogenic.
Subject(s)
Autoantibodies/blood , Autoantibodies/cerebrospinal fluid , Lupus Erythematosus, Systemic/diagnosis , Lupus Vasculitis, Central Nervous System/cerebrospinal fluid , Lupus Vasculitis, Central Nervous System/immunology , Adult , Antibodies , Antibodies, Anticardiolipin , Antibodies, Antinuclear , Case-Control Studies , Enzyme-Linked Immunosorbent Assay , Female , Hospitalization/statistics & numerical data , Humans , Immunoglobulin G , Lupus Erythematosus, Systemic/cerebrospinal fluid , Lupus Erythematosus, Systemic/immunology , Lupus Vasculitis, Central Nervous System/diagnosis , Lupus Vasculitis, Central Nervous System/etiology , Male , Receptors, N-Methyl-D-Aspartate/immunology , Retrospective Studies , Ribosomal Proteins , Serum/immunology , Time Factors , beta 2-Glycoprotein IABSTRACT
OBJECTIVE: To assess prevention of bone mineral density (BMD) loss and durability of the response during treatment with prasterone in women with systemic lupus erythematosus (SLE) receiving chronic glucocorticoids. METHODS: 155 patients with SLE received 200 mg/day prasterone or placebo for 6 months in a double-blind phase. Subsequently, 114 patients were re-randomized to receive 200 or 100 mg/day prasterone for 12 months in an open-label phase. Primary efficacy endpoints were changes in BMD at the lumbar spine (L-spine) from baseline to Month 6 and maintenance of BMD from Month 6 to 18 for patients who received prasterone during the double-blind phase. RESULTS: In the double-blind phase, there was a trend for a small gain in BMD at the L-spine for patients who received 200 mg/day prasterone for 6 months versus a loss in the placebo group (mean +/- SD, 0.003 +/- 0.035 vs -0.005 +/- 0.053 g/cm(2), respectively; p = 0.293 between groups). In the open-label phase, there was dose-dependent increase in BMD at the L-spine at Month 18 between patients who received 200 versus 100 mg/day prasterone (p = 0.021). For patients who received 200 mg/day prasterone for 18 months, the L-spine BMD gain was 1.083 +/- 0.512% (p = 0.042). There was no overall change in BMD at the total hip over 18 months with 200 mg/day prasterone treatment. The safety profile reflected the weak androgenic properties of prasterone. CONCLUSION: This study suggests prasterone 200 mg/day may offer mild protection against bone loss in women with SLE receiving glucocorticoids. (ClinicalTrials.gov Identifiers NCT00053560 and NCT00082511).