Late-onset systemic lupus erythematosus in Latin Americans: a distinct subgroup?

OBJECTIVE: To examine the characteristics of patients who developed late onset systemic lupus erythematosus (SLE) in the GLADEL (Grupo Latino Americano de Estudio del Lupus) cohort of patients with SLE. METHODS: Patients with SLE of less than two years of disease duration, seen at 34 centers of nine Latin American countries, were included. Late-onset was defined as >50 years of age at time of first SLE-related symptom. Clinical and laboratory manifestations, activity index (SLEDAI), and damage index (SLICC/ACR- DI) were ascertained at time of entry and during the course (cumulative incidence). Features were compared between the two patient groups (<50 and ≥50) using descriptive statistics and hypothesis tests. Logistic regression was performed to examine the association of late-onset lupus, adjusting for other variables. RESULTS: Of the 1480 patients included, 102 patients (6.9 %) had late-onset SLE, 87% of which were female. Patients with late-onset SLE had a shorter follow-up (3.6 vs. 4.4 years, p < 0.002) and a longer time to diagnosis (10.1 vs. 5.8 months, p < 0.001) compared to the younger onset group. Malar rash, photosensitivity, and renal involvement were less prevalent while interstitial lung disease, pleural effusions, and sicca symptoms were more frequent in the older age group (p > 0.05). In multivariable analysis, late onset was independently associated with higher odds of ocular (OR = 3.66, 95% CI = 2.15-6.23), pulmonary (OR = 2.04, 95% CI = 1.01-4.11), and cardiovascular (OR = 1.76, 95% CI = 1.04-2.98) involvement and lower odds of cutaneous involvement (OR = 0.41, 95% CI = 0.21-0.80), number of cumulative SLE criteria (OR = 0.79, 95% CI = 0.64-0.97), use of cyclophosphamide (OR = 0.47, 95% CI = 0.24-0.95), and anti-RNP antibodies (OR = 0.43, 95% CI = 0.20-0.91). A Cox regression model revealed a higher risk of dying in older onset than the younger-onset SLE (OR = 2.61, 95% CI = 1.2-5.6). CONCLUSION: Late-onset SLE in Latin Americans had a distinct disease expression compared to the younger-onset group. The disease seems to be mild with lower cumulative SLE criteria, reduced renal/mucocutaneous involvements, and less use of cyclophosphamide. Nevertheless, these patients have a higher risk of death and of ocular, pulmonary, and cardiovascular involvements.

The eighth component of human complement (C8): isolation, characterization, and hemolytic efficiency.

A method was described allowing the isolation of the eighth component of complement, C8, from human serum. C8 is an immunochemically definable, heretofore unrecognized serum protein with a molecular weight of approximately 150,000 and an electrophoretic mobility of a gamma(1)-globulin. It may be obtained with 5% yield as a 5000-fold purified, physicochemically and immunochemically homogeneous protein. Under optimal experimental conditions, a few molecules of C8 were found sufficient for lysis of a cell.

Cytotoxic effects of leukocyres triggered by complement bound to target cells.

Chromium-51-labeled chicken erythrocytes (E), treated with rabbit anti-Forssman antibody (A) and the first four (C1-4) or the first seven (C1-7) components of human complement (C), released isotope upon exposure to human leukocytes. Isotope release from EACJ-7 cells proceeded more rapidly and was more extensive than that from EACI-3 cells. Lysis of these cells was suppressed by pretreatment of leukocytes with antimycinA. Monocyte-enriched leukocyte preparations affected both types of target cell-complement intermediates, whereas purified lymphocytes lysed EACI-7 cells but not EACI-3 cells.

Validation of the Spanish, Portuguese and French versions of the Lupus Damage Index questionnaire: data from North and South America, Spain and Portugal.

We have previously developed and validated a self-administered questionnaire, modelled after the Systemic Lupus International Collaborating Clinics Damage Index (SDI), the Lupus Damage Index Questionnaire (LDIQ), which may allow the ascertainment of this construct in systemic lupus erythematosus (SLE) patients followed in the community and thus expand observations made about damage. We have now translated, back-translated and adapted the LDIQ to Spanish, Portuguese and French and applied it to patients followed at academic and non-academic centres in North and South America, Portugal and Spain while their physicians scored the SDI. A total of 887 patients (659 Spanish-speaking, 140 Portuguese-speaking and 80 French-speaking patients) and 40 physicians participated. Overall, patients scored all LDIQ versions higher than their physicians (total score and all domains). Infrequent manifestations had less optimal clinimetric properties but overall agreement was more than 95% for the majority of items. Higher correlations were observed among the Spanish-speaking patients than the Portuguese-speaking and French-speaking patients; further adjustments may be needed before the Portuguese and French versions of the LDIQ are applied in community-based studies. The relationship between the LDIQ and other outcome parameters is currently being investigated in a different patient sample.

[Lymphocyte imbalance in autoimmunity]. / La desregulación linfocitaria en autoinmunidad.

A subset of normal peripheral B lymphocytes expresses a T surface antigen recognized by monoclonal CD5. They form rosettes with mouse erythrocytes (MRBC). Other studies suggest that these B cells may have regulatory and helper properties. An expanded subset of lymphocytes forming MRBC was demonstrated in the peripheral blood of 31 Systemic Lupus Erythematosus (SLE) patients (14.4 +/- 2.8%) compared with normal controls (4.3 +/- 1.4%) and patients with tuberculosis (6.4 +/- 1.7%). Increased MRBC values correlated with disease severity. Investigation of cell surface antigen expression was attempted with enriched sedimented fractions using several monoclonal antibodies and immunofluorescent staining. Complete inhibition of MRBC formation was obtained with monoclonal antibodies against CD5, CD3 and CD8 while partial inhibition was observed with anti-Ia and no activity with CD4 and CD10 antibodies. Indirect evidence supports the concept that antilymphocyte antibodies cause T and B cell depletion and dysfunction. Sera from 12 patients with SLE and 28 with leprosy (LL) were analyzed for antibodies to lymphocytes in the microcytotoxicity assay: 87% of SLE and 57% of LL were positive. Lymphocytotoxic activity towards each cell type of a panel with 98 different HLA antigens was essentially the same and most sera were not specific for either T or B cells. Lymphocytotoxic sera from SLE and LL contained antibodies which inhibited MRBC formation.

[Erythrocyte CR1 receptor reactivity in patients with systemic lupus erythematosus]. / Reactividad del receptor eritrocitario CR1 en pacientes con lupus eritematoso sistémico.

Erythrocytes from 42 systemic lupus erythematosus (SLE) patients and 80 healthy volunteers were tested for the immunoadherence (CR1) receptor reactivity, observed by hemagglutination (IAHA) when incubating erythrocytes and aggregated human gamma-globulin (AHGG)-complement in appropriate proportions. Reactivity was expressed as the highest two-fold dilution of AHGG (2n) that induced hemagglutination. Erythrocytes of 15 SLE patients (35.7%) showed reactivity compared with 70 normal controls (87.5%). Both groups showed a trimodal distribution of IAHA titers in accordance with the three phenotypic groups described by other authors. Of the healthy population 72.5% belong to the intermediate reactivity mode (2(6) to 2(8)) and 64.3% of the SLE patients to the low reactivity group (negative). There was no correlation between CR1 defective expression and conventional activity parameters. This erythrocyte receptor involved in the immunocomplex clearance process, which constitutes 95% of the circulating CR1, is another factor that contributes to the pathophysiology of the disease when it is defective.

[Neutrophil-dependent inflammatory reactions in systemic lupus erythematosus]. / Reacciones inflamatorias neutrofilo-dependientes en Lupus Eritematoso Sistémico.

We studied the possible role of polymorphonuclear neutrophil (PMN) aggregation in Systemic Lupus Erythematosus (SLE) by the capacity of sera from 32 lupus patients to induce in vitro normal PMN aggregation. Neutrophil aggregating activity (NAA) in this group was significantly greater than that found in 8 inactive SLE patients and in 8 controls. In patients with SLE, there was a positive correlation between disease severity and the quantitative measure of NAA. High levels of NAA were particularly characteristic of central nervous system SLE. These data suggest that the formation of intravascular leukoaggregates may contribute to morbidity in SLE. Normal PMN increase their spontaneous superoxide anion production (0.21 nmol/min 10(7) PMN) when stimulated with sera from SLE patients. Lupus PMN also show an enhancement of 100% in superoxide production in vitro when stimulated with lupus sera. When N formyl methionine leucyl phenylalanine (FMLP) was used, lupus PMN showed an O2-production of 2.1 nmol/min 10(7) which is 5-fold the response of normal PMN stimulated by FMLP. Our results show the existence of seric factors in SLE patients that can stimulate O2-production by PMN. Lupus neutrophils show an increased response to membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive membrane stimuli such as FMLP, capable of triggering the respiratory burst. Lupus neutrophils appear more responsive to membrane stimuli. The seric and the cellular factors seem to indicate an increased rate of superoxide production by PMN in SLE patients, which can be relevant to vasculitis and tissue damage.

Cell-mediated cytotoxicity. Characterization of the effector cells.

Isolated human mononuclear cells were fractionated according to their membrane characteristics or physical properties. Adherent cells were depleted by filtration through glass columns; phagocytic cells were removed by iron treatment and cell subpopulations capable of forming rosettes with sheep erythrocytes (E), erythrocyte-antibody-complement (EAC) and chicken erythrocyte-antibody complexes (CEA) were separated by centrifugation of Ficoll-Hypaque gradients. The functional activity of the cell subpopulations obtained was assayed by testing PHA-induced cytoxicity (PIC), antibody-dependent cytoxicity (ADCC) and blast transformation by PHA. The results of this study demonstrate that: (1) cells reacting in PIC and ADCC assays are different, adherent and phagocytic cells being necessary for full expression of PIC and not for ADCC; (2) PHA induces direct blast transformation of purified E-RFC in the absence of PIC cytotoxic cells; (3) cell populations specifically enriched in E or EAC rosette-forming cells are not cytotoxic neither in the PHA nor in antibody mediated cytotoxic assays; (4) cells participating in ADCC can be selectively purified by centrifugation of CEA rosettes.

Antibody-dependent cell-mediated cytotoxicity in rheumatoid arthritis. Effect of rheumatoid serum fractions on normal lymphocytes.

Reduced antibody-dependent cell-mediated cytotoxicity (ADCC) was demonstrated in lymphocytes of patients with rheumatoid arthritis (RA). Rheumatoid factor (RF) positive sera inhibited ADCC of normal lymphocytes by reacting both with effector and target cells (sensitized chicken red blood cells). These sera were fractionated by specific adsorption or gradient ultracentrifugation, and isolated RF or RF negative fractions were tested for their ability to inhibit ADCC by reacting with normal human lymphocytes or target cells. RF was ineffective on normal lymphocytes but it strongly inhibited the reaction by interaction with target cells. IgG RF negative fractions of certain sera were inhibitory by direct interaction with effector cells.

La desregulación linfocitaria en autoinmunidad / Lymphocyte imbalance in autoimmunity

Una pequeña proporción de linfocitos B presente en ganglios y sangre periférica humana tiene la propiedad de formar rosetas con eritrocitos de ratón (RR) y expresar en la superficie de su membrana un antígeno de 67 Kda perteneciente a la serie T (Pan T) que es reconocido por el monoclonal CD5. Se valoró en sangre periférica de pacientes con Lupus Eritematoso Sistémico (LES) la capacidad de formar RR. Treinta y un LES tenían un valor de 14,4 + o - 2,8% que fue comparado con controles normales: 4,3 + o - 1,4 (p<0,001) y pacientes con tuberculosis activa 6,4 + o - 1,7%. La expansión de esta subpoblación en el LES correlacionó con la severidad de la enfermedad. En experimentos de inhibición obteniéndose efecto parcial con la y ninguna actividad con CD4 y CD10. Hay evidencias que apoyan el concepto de que los anticuerpos antilinfocitarios producirían disfunción y depleción específica de subpoblaciones T y B linfocitarias. Los sueros de 12 pacientes con LES y de 28 con lepra lepromatosa (LL) fueron investigados para la presencia de estos anticuerpos con el método de microcitotoxicidad. La mayoría de los sueros con LES (87%) y un 57% de los LL fueron positivos en este ensayo. No hubo diferencias en la actividad cuando se los enfrentó con un panel de 98 diferentes antígenos HLA y tampoco hubo reactividad selectiva para linfocitos T o B. En un sistema de inhibición de RR, tanto los sueros de LES como los de LL, mostraron interferencia en la formación de rosetas, lo que sugiere la presencia de...