Lupus in Latin-American patients: lessons from the GLADEL cohort.

The need for comprehensive published epidemiologic and clinical data from Latin American systemic lupus erythematosus (SLE) patients motivated the late Dr Alarcón-Segovia and other Latin American professionals taking care of these patients to spearhead the creation of the G: rupo L: atino A: mericano D: e E: studio del L: upus (GLADEL) cohort in 1997. This inception cohort recruited a total of 1480 multiethnic (Mestizo, African-Latin American (ALA), Caucasian and other) SLE patients diagnosed within two years from the time of enrollment from 34 Latin American centers with expertise in the diagnosis and management of this disease. In addition to the initial 2004 description of the cohort, GLADEL has contributed to improving our knowledge about the course and outcome of lupus in patients from this part of the Americas. The major findings from this cohort are highlighted in this review. They have had important clinical implications for the adequate care of SLE patients both in Latin America and worldwide where these patients may have emigrated.

Mestizos with systemic lupus erythematosus develop renal disease early while antimalarials retard its appearance: data from a Latin American cohort.

OBJECTIVES: The objective of this paper is to assess the predictors of time-to-lupus renal disease in Latin American patients. METHODS: Systemic lupus erythematosus (SLE) patients (n = 1480) from Grupo Latino Americano De Estudio de Lupus (GLADEL's) longitudinal inception cohort were studied. Endpoint was ACR renal criterion development after SLE diagnosis (prevalent cases excluded). Renal disease predictors were examined by univariable and multivariable Cox proportional hazards regression analyses. Antimalarials were considered time dependent in alternative analyses. RESULTS: Of the entire cohort, 265 patients (17.9%) developed renal disease after entering the cohort. Of them, 88 (33.2%) developed persistent proteinuria, 44 (16.6%) cellular casts and 133 (50.2%) both; 233 patients (87.9%) were women; mean (± SD) age at diagnosis was 28.0 (11.9) years; 12.2% were African-Latin Americans, 42.5% Mestizos, and 45.3% Caucasians (p = 0.0016). Mestizo ethnicity (HR 1.61, 95% CI 1.19-2.17), hypertension (HR 3.99, 95% CI 3.02-5.26) and SLEDAI at diagnosis (HR 1.04, 95% CI 1.01-1.06) were associated with a shorter time-to-renal disease occurrence; antimalarial use (HR 0.57, 95% CI 0.43-0.77), older age at onset (HR 0.90, 95% CI 0.85-0.95, for every five years) and photosensitivity (HR 0.74, 95% CI 0.56-0.98) were associated with a longer time. Alternative model results were consistent with the antimalarial protective effect (HR 0.70, 95% CI 0.50-0.99). CONCLUSIONS: Our data strongly support the fact that Mestizo patients are at increased risk of developing renal disease early while antimalarials seem to delay the appearance of this SLE manifestation. These data have important implications for the treatment of these patients regardless of their geographic location.

Massive cerebral calcifications associated with increased renal phosphate reabsorption.

Extensive bilateral cerebral cortical calcifications were demonstrated in a young patient with a history of convulsions since the age of 4 years. Initial metabolic workup showed normal serum calcium levels, hyperphosphatemia, normal renal function, low urinary calcium excretion, and normal serum immunoreactive parathyroid hormone levels. The intravenous infusion of edetate disodium (disodium EDTA) showed a normal phosphaturic and cyclic adenosine monophosphate response, ruling out the diagnosis of pseudohypoparathyroidism. The infusion of acetazolamide produced a blunted phosphaturia with almost no change in the renal phosphorus threshold, suggesting a tubular defect that allows enhanced proximal tubular reabsorption of phosphorus. Although the exact mechanisms responsible for the localized calcifications remain obscure, we suggest that an enhanced proximal tubular reabsorption of phosphorus could be involved in the pathophysiologic basis of this abnormality.

Down-regulation of immunoglobulin and IgM-rheumatoid factor synthesis by oral treatment of rheumatoid arthritis patients with a nonsteroidal antiinflammatory drug.

We examined the effect of treatment with piroxicam, a nonsteroidal antiinflammatory drug (NSAID), on immunoglobulin (Ig) and IgM-rheumatoid factor (IgM-RF) synthesis in vitro by lymphocytes of patients with rheumatoid arthritis (RA). Oral treatment with piroxicam induced a progressive decrease of spontaneous IgM-RF production by unstimulated lymphocyte cultures during 12 weeks of observation. Also, pokeweed mitogen (PWM)-driven Ig synthesis was significantly diminished and the effect on total IgM production was sustained until the end of the study. This modulation of humoral responses is consistent with the drop in RF sera level. In addition, we also showed that treatment with NSAIDs can decrease RF levels in the synovial space. NSAIDs may have a long-term beneficial effect in patients with RA due to their modulatory role of lymphocyte responses.

Abnormal immunoglobulin and rheumatoid factor synthesis by blood lymphocytes in patients with primary Sjögren's syndrome.

Peripheral blood B lymphocytes from patients with primary Sjögren's syndrome showed significantly higher spontaneous synthesis of IgG, IgM, and IgM rheumatoid factor in vitro, compared with B lymphocytes from healthy controls. Lymphocytes from patients also showed higher IgM rheumatoid factor production after mitogen stimulation. Patients had competent suppressor activity for IgG, but not for IgM synthesis. Pre-irradiation of T cells, but not depletion of OKT8+ cells, markedly enhanced IgG synthesis in cocultures with autologous B cells; therefore, the T lymphocyte responsible for this effect is radiosensitive and is not identified by OKT8. OKT8+ lymphocytes from patients did not suppress Ig synthesis by autologous B plus T cell cocultures. However, OKT8+ cells from normal controls down-regulated Ig synthesis by B plus T cells from patients. The abnormal proportion of helper and suppressor cells suggests that there is altered redistribution of regulatory subpopulations in peripheral blood from Sjögren's syndrome patients.

Seronegative spondyloarthropathies and HLA antigens in a Mestizo population.

HLA-A and -B antigens incidence were investigated in 100 cases of Seronegative Spondyloarthropathies and in 303 control individuals of a Venezuelan Mestizo population. Significative increased incidence of B27 was found among 69% of patients with ankylosing spondylitis and 68% with Reiter syndrome being the incidence in the control group of 2.9%. The B27 negative patients showed 40.4% positivity for Bw35, with spondylitic lesion in 12 out of 17 cases. Our results question the applicability of B27 as diagnostic criteria in the Mestizo patients bearers of a Seronegative Spondyloarthropathy and suggest the need to investigate further the role of antigens of the B locus in the pathophysiology of these clinical entities.

Multiple microcrystal deposition disease in a patient with systemic lupus erythematosus.

A 17-year-old female patient with systemic lupus erythematosus (SLE) developed chronic tophaceous gout, chondrocalcinosis and articular capsule calcification in several joints. Analysis of synovial fluid and tophi revealed the coexistence of monosodium urate, calcium pyrophosphate, hydroxyapatite, and cholesterol crystals.

Helper activity by human large granular lymphocytes in in vitro immunoglobulin synthesis.

In the present study we have examined the effect of human large granular lymphocytes (LGL) from healthy donors on Ig synthesis by autologous B lymphocytes. The results showed that this cell population has a consistent helper activity in pokeweed mitogen-activated cultures even when added at very low numbers. LGL can mediate their effect by secreting soluble helper factors capable of modulating B-cell responses as evidenced by the enhancement of IgG and IgM production by supernatants obtained from LGL cultures. Preincubation with interferon gamma further potentiated the helper activity by LGL.

Enhanced CD3-mediated T lymphocyte proliferation in patients with systemic lupus erythematosus.

Nonfractionated peripheral blood lymphocytes from patients with systemic lupus erythematosus (SLE) showed enhanced proliferative responses when stimulated via the CD3 pathway. In contrast, proliferative responses induced by phytohemagglutinin were diminished in SLE patients. Levels of CD3-induced interleukin-2 production and interleukin-2 receptor expression were comparable with normal levels. Highly purified T cells also showed augmented CD3 responses, but only in the presence of phorbol myristate acetate or a combination of phorbol myristate acetate plus calcium ionophore A23187, and not with calcium ionophore alone. The data suggest integrity of the T cell receptor/CD3 pathway for T cell activation in patients with SLE, as examined in cultures stimulated with specific anti-CD3 monoclonal antibodies rather than with multivalent lectins. An increased response via the CD3 complex could contribute to the autoimmune activity in human SLE.

Human IFN-gamma up-regulates IL-2 receptors in mitogen-activated T lymphocytes.

This study examined the role of human recombinant interferon-gamma (rIFN-gamma) in the expression of interleukin-2 receptors (IL-2R) by human T lymphocytes. rIFN-gamma enhanced total numbers of IL-2R in mitogen-activated but not resting T cells. Scatchard plot analysis indicated that rIFN-gamma increased both high- and low-affinity receptors, with a predominant effect on the latter. Phytohaemagglutinin (PHA)-activated T cells treated with IFN-gamma showed higher IL-2 binding and greater IL-2 internalization and degradation than cells treated with PHA alone. There was a corresponding increase of mitogen-driven proliferative responses, indicating an increase of functional receptors in IFN-treated cultures. IFN-gamma may influence T-cell activation and proliferation by enhancing expression of IL-2R and promoting IL-2 uptake by mitogen-activated lymphocytes.

Auricular chondritis and diffuse proliferative glomerulonephritis in primary Sjögren's syndrome.

Bilateral auricular inflammation with histological changes of relapsing polychondritis was observed in a female patient with primary Sjögren's syndrome. This was accompanied by rapidly progressive renal insufficiency due to diffuse proliferative glomerulonephritis. To our knowledge this is the first well documented case of primary Sjögren's syndrome associated with chondritis and glomerulonephritis, further emphasising the wide spectrum of extraglandular manifestations in this autoimmune disorder.