Yemil Atisha-Fregoso

Serum and Cerebrospinal Fluid Autoantibodies in Patients with Neuropsychiatric Lupus Erythematosus. Implications for Diagnosis and Pathogenesis

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-β2 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.

MCP-1, RANTES, and SDF-1 polymorphisms in Mexican patients with systemic lupus erythematosus

Chemokines and cytokines play an important role in the inflammatory development and progression of autoimmune diseases. The aim of the present study was to evaluate the role of MCP-1, SDF-1, and RANTES polymorphisms as susceptibility markers for systemic lupus erythematosus (SLE) in a group of Mexican patients. MCP-1-2518, SDF-1 G801A, and RANTES-28 polymorphisms were determined in 242 patients with SLE and 220 ethnically matched healthy controls by the polymerase chain reaction-restriction fragment length polymorphism technique. The differences between patients and healthy controls were evaluated by chi(2), Fishers exact test, and Woolf method for odds ratio. A moderately increased frequency of MCP-1-2518 A allele (p = 0.033, pC = NS) and AA genotype (p = 0.017, pC = NS) existed in SLE patients compared with healthy controls. There was a relationship between polymorphisms and some clinical and laboratory characteristics. SLE patients with and without antiphospholipid syndrome demonstrated different distribution of SDF-1 G801A genotype frequencies. On the other hand, patients with leukopenia, anti-dsDNA, and antiphospholipid autoantibodies demonstrated different MCP-1-2518 genotype distribution compared with patients without these features. Our results suggest that MCP-1 polymorphism is moderately associated with the genetic susceptibility to SLE in Mexican individuals. The polymorphisms could be related to specific clinical and laboratory characteristics in these patients.

Inflammatory profile in cerebrospinal fluid of patients with headache as a manifestation of neuropsychiatric systemic lupus erythematosus

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.

Systemic lupus erythematosus in Hispanics.

Systemic lupus erythematosus is a serious autoimmune disease that causes significant morbidity and mortality. It is also a disease for which several clinical differences among ethnic groups have been documented. Until recently, Hispanics, as separate patient cohort, had not been included in these studies. As a result, there is currently little information concerning its characteristics both at the clinical and at the molecular levels. With the currently available data, we can ascertain that this population exhibits considerable heterogeneity, in which some genetic mutations have been detected that may confer greater susceptibility and/or protection against the disease. The important differences in the clinical manifestations include a higher rate of renal complications as well as greater mortality. The latter may be due, at least in part, to lower socio-economic levels and inappropriate access to health care. However, given the limited data available that have focused on potential molecular mechanisms that may affect the Hispanic population affected with lupus, we cannot conclude that all the differences in disease outcome, complications, and severity that affect this patient population may be due to sociological factors. We conclude that more research is required to evaluate potential genetic and molecular factors that affect Hispanic lupus patients.

Refractory primary Sjögren syndrome successfully treated with bortezomib.

Primary Sjögren syndrome (PSS) is a chronic autoimmune disease characterized by sicca complex and various systemic manifestations. Although it is well accepted to use corticosteroids for the treatment of systemic manifestations, there is scarce information available regarding the use of targeted therapy for refractory cases. We describe a case of a severe PSS patient refractory to conventional treatment with a response to bortezomib, a proteasome inhibitor commonly used for the treatment of multiple myeloma. Bortezomib administration resulted in a notable improvement of the general symptoms, particularly fatigue, and a decrease in serum globulin levels as well as in serum viscosity. Hyperglobulinemic purpura disappeared, and prednisone tapering succeeded. Because of chronicity, no clinical changes were observed in sicca symptoms. As far as we know, this is the first report on the use of bortezomib in a refractory case of PSS.

Utility of Interferon-α as a Biomarker in Central Neuropsychiatric Involvement in Systemic Lupus Erythematosus

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.

Utility of Serum S100B Protein for Identification of Central Nervous System Involvement in Systemic Lupus Erythematosus

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.

An unusual multiplex systemic lupus erythematosus family with high prevalence of nephropathy, late-onset disease, and one member with disease-onset post-HIV therapy.

In the present study, we report the clinical characteristics of a unique systemic lupus erythematosus (SLE) multiplex family with 6 of its members affected by the disease, 1 of them being male. Four patients showed nephropathy, 2 of them with late-onset SLE (52 and 55-year-old), one with cutaneous and articular involvement, and another one developing lupus after 5 years undergoing highly active antiretroviral therapy (HAART) due to acquired immunodeficiency syndrome. Notwithstanding the genetic load, the fact that 2 patients showed late-onset disease, and the extreme delay of the appearance of SLE after HAART in the proband suggest that not only genetic, but other—mainly environmental—factors are necessarily required for the development of SLE.

Rheumatoid Arthritis Disease Activity Is Determinant for ABCB1 and ABCG2 Drug-Efflux Transporters Function.

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.

Clinical and Immunopathologic Profile of Mexican Patients with IgG4 Autoimmune Pancreatitis.

Autoimmune pancreatitis is part of the spectrum of IgG4-associated diseases. Its diagnostic criteria and histological subtypes have been formally proposed recently and although based on current data it has been suggested that there are differences in clinical presentation among populations, more research is needed to properly establish if this heterogeneity exists. In this paper, we describe 15 cases of autoimmune pancreatitis diagnosed at a Mexican centre of reference, all of them associated to the lymphoplasmocytic sclerosing pancreatitis variant. The mean age at the onset of symptoms was 47.5 ± 14.4 years, and 53% of patients were male. The main manifestations were weight loss (87%), obstructive jaundice (53%), and acute (27%) and chronic (27%) pancreatitis. Only 20% of patients had high IgG4 serum levels at the time of diagnosis. All patients receiving prednisone responded favourably, both in their pancreatic and extrapancreatic manifestations. Clinical manifestations of Mexican patients showed certain differences with respect to those usually reported.