Clinical associations of proinflammatory cytokines, oxidative biomarkers and vitamin D levels in systemic lupus erythematosus.

Background The abnormal biological activity of cytokines plays an important role in the pathophysiology of both systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Several studies have highlighted the association of vitamin D and certain pro-inflammatory cytokines with disease activity in SLE. However, there are limited data on the association of vitamin D and antiphospholipid antibodies (aPL) with various proinflammatory biomarkers in these patients and their relative impact on clinical outcomes. Methods The serum levels of several aPL, 25-hydroxy-vitamin D, pro-inflammatory cytokines including IFNα, IL-1ß, IL-6, IL-8, IP10, sCD40L, TNFα and VEGF were measured in 312 SLE patients from the Jamaican ( n = 45) and Hopkins ( n = 267) lupus cohorts using commercial Milliplex and ELISA assays. Oxidized LDL/ß2glycoprotein antigenic complexes (oxLß2Ag) and their associated antibodies were also measured in the Jamaican cohort. Healthy controls for oxidative marker and cytokine testing were used. Results Abnormally low vitamin D levels were present in 61.4% and 73.3% of Hopkins and Jamaican SLE patients, respectively. Median concentrations of IP10, TNFα, sCD40L and VEGF were elevated in both cohorts, oxLß2Ag and IL-6 were elevated in the Jamaican cohort, and IFNα, IL-1ß and IL-8 were the same or lower in both cohorts compared to controls. IP10 and VEGF were independent predictors of disease activity, aPL, IP10 and IL-6 were independent predictors of thrombosis and IL-8, and low vitamin D were independent predictors of pregnancy morbidity despite there being no association of vitamin D with pro-inflammatory cytokines. Conclusions Our results indicate that aPL-mediated pro-inflammatory cytokine production is likely a major mechanism of thrombus development in SLE patients. We provide presumptive evidence of the role IL-8 and hypovitaminosis D play in obstetric pathology in SLE but further studies are required to characterize the subtle complexities of vitamin D's relationship with cytokine production and disease activity in these patients.

A unique antiphospholipid assay recognizing phospholipid mixture compared with criteria antiphospholipid immunoassays in lupus patients.

Background While essential for the classification of antiphospholipid syndrome (APS), anticardiolipin (aCL) assays lack specificity and anti-ß2glycoproteinI (anti-ß2GPI) assays lack sensitivity in this regard. Our aim was to perform a comparative analysis of the APhL ELISA assay (IgG/IgM) and criteria antiphospholipid (aPL) immunoassays in identifying APS-related clinical manifestations in a large group of patients with systemic lupus erythematosus (SLE). Methods Serum samples from 1178 patients from the Hopkins ( n = 543), LUMINA ( n = 588) and Jamaican SLE cohorts ( n = 47) were examined for IgG/IgM positivity in aCL (in-house), anti-ß2GPI (two commercial kits) and APhL (Louisville APL) ELISA assays. Correlation of assay positivity with clinical manifestations and sensitivity, specificity, positive and negative predictive values and likelihood ratios were evaluated. A case series analysis was also performed in patients for whom there was isolated positivity in the specific aPL assays. Results The prevalence of aCL positivity was 34.9%, anti-ß2GPI kit A was 22.6%, APhL was 11.5% and anti-ß2GPI kit B was 7.6% in the study population. Anti-ß2GPI kit B, aCL and APhL assays were correlated with venous thrombosis, while only APhL was significantly correlated with arterial thrombosis and consistently correlated with pregnancy-related morbidity. No significant correlations were noted for anti-ß2GPI kit A. Sensitivity was greatest for aCL assays followed by anti-ß2GPI kit A, APhL and anti-ß2GPI kit B, while specificity was greatest and equal for anti-ß2GPI kit B and APhL assays. Conclusions Overall, APhL antibodies, especially IgG, represent a promising biomarker for the classification of APS patients in the context of autoimmunity and in risk assessment with regards to pregnancy morbidity and thrombotic manifestations.

Vitamin D levels in Jamaican patients with systemic lupus erythematosus.

Vitamin D has important effects on the immune system as it has been shown to exert antiproliferative and relative immunosuppressant effects. Low levels of this hormone may contribute to the immune activation in systemic lupus erythematosus (SLE) and other autoimmune diseases. Serum levels of 25-OH vitamin D were measured in 75 patients with SLE in Jamaica, using an enzyme-linked immunoassay. Correlations with clinical data and disease activity as determined by the BILAG index were determined. Of a total of 75 patients, 33 (44%) had vitamin D sufficiency with mean vitamin D level of 39.45 ng/ml (range, 30.35-58.16). Forty-two (56%) patients had either vitamin D deficiency or insufficiency, 30 (40%) had vitamin D insufficiency, mean 26.36 ng/ml (range, 20.26-29.88), and 12 (16%) had vitamin D deficiency, mean 16.07 ng/ml (range, 7.78-19.90). There was an overall negative relationship between the total disease activity score using the BILAG index and vitamin D levels, and this was influenced primarily by the relationship seen among the vitamin D-deficient subgroup. This was also impacted on by a patient population that was significantly skewed toward low disease activity. The negative association trended toward statistical significance. Vitamin D deficiency is prevalent among patients with SLE in Jamaica. A relationship between low serum levels of vitamin D and SLE activity may occur.

Antinuclear antibodies and HLA class II alleles in Jamaican patients with systemic lupus erythematosus.

OBJECTIVE: The relationship between human leukocyte antigens class II (HLA) and antinuclear antibodies was investigated in Jamaican patients with Systemic Lupus Erythematosus (SLE). METHODS: Samples of blood of 82 patients with SLE and 75 healthy controls were tested for antinuclear antibodies using the fluorescent antinuclear antibody (FANA) test, counterimmunoelectrophoresis (CIEP) and the Crithidia luciliae immunofluorescence test (CL-IFT). A DNA-based HLA typing method was used to determine the frequencies of alleles of HLA-DRB1, DRB3, DRB4 and DRB5 in patients and healthy controls. RESULTS: The FANA test was positive in all of the sera from patients with SLE. Anti-dsDNA antibodies were present in 49% (40/82), anti-Sm/RNP 44% (36/82) and anti-Ro/La 43% (35/82) of the sera from SLE patients. The frequency of HLA-DR4 was significantly lower in SLE patients than in healthy controls (2/82, 2% vs 15/75, 20%; RR = 0.12; p = 0.0004; CP = 0.005) but no other HLA-DRB1 SLE associations were found. A positive HLA-DR3 anti-Ro/La antibody association was found in the patients with SLE (9/21, 43% vs 5/55, 9%; odds ratio (OR) = 7.5; CP = 0.01). In contrast, possession of HLA-DR6 was negatively associated with the absence of anti-dsDNA antibodies (9/32, 28% vs 27/44, 61%; OR = 0.2; CP = 0.05). CONCLUSION: The HLA-DR6 allele is associated with the absence of antinuclear antibodies and HLA-DR3 with the presence of anti-Ro/La antibodies in Jamaican patients with SLE. However, these results and those of previous studies of Jamaican patients suggest that the HLA-DR3 association with the development of SLE reported in other populations might in fact reflect the association of HLA-DR3 with anti-Ro/La antibodies. Further investigations are needed to determine whether HLA-DRB antinuclear antibody associations define clinical subsets of SLE in Jamaican patients.

Antinuclear antibodies and HLA class II alleles in Jamaican patients with systemic lupus erythematosus / Anticuerpos antinucleares y aleles HLA de clase II en pacientes Jamaicanos con lupus eritematoso sistémico

OBJECTIVE: The relationship between human leukocyte antigens class II (HLA) and antinuclear antibodies was investigated in Jamaican patients with Systemic Lupus Erythematosus (SLE). METHODS: Samples of blood of 82 patients with SLE and 75 healthy controls were tested for antinuclear antibodies using the fluorescent antinuclear antibody (FANA) test, counterimmunoelectrophoresis (CIEP) and the Crithidia luciliae immunofluorescence test (CL-IFT). A DNA-based HLA typing method was used to determine the frequencies of alleles of HLA-DRB1, DRB3, DRB4 and DRB5 in patients and healthy controls. RESULTS: The FANA test was positive in all of the sera from patients with SLE. Anti-dsDNA antibodies were present in 49% (40/82), anti-Sm/RNP 44% (36/82) and anti-Ro/La 43% (35/82) of the sera from SLE patients. The frequency of HLA-DR4 was significantly lower in SLE patients than in healthy controls (2/82, 2% vs 15/75, 20%; RR = 0.12; p = 0.0004; CP = 0.005) but no other HLA-DRB1 SLE associations were found. A positive HLA-DR3 anti-Ro/La antibody association was found in the patients with SLE (9/21, 43% vs 5/55, 9%; odds ratio (OR) = 7.5; CP = 0.01). In contrast, possession of HLA-DR6 was negatively associated with the absence of anti-dsDNA antibodies (9/32, 28% vs 27/44, 61%; OR = 0.2; CP = 0.05). CONCLUSION: The HLA-DR6 allele is associated with the absence of antinuclear antibodies and HLA-DR3 with the presence of anti-Ro/La antibodies in Jamaican patients with SLE. However, these results and those of previous studies of Jamaican patients suggest that the HLA-DR3 association with the development of SLE reported in other populations might in fact reflect the association of HLA-DR3 with anti-Ro/La antibodies. Further investigations are needed to determine whether HLA-DRB antinuclear antibody associations define clinical subsets of SLE in Jamaican patients.

OBJETIVO Se investigó la relación entre los antígenos de leucocito humano (human leukocyte antigens o HLAs). Clase II y los anticuerpos antinucleares en pacientes jamaicanos con lupus eritematoso sistémico (LES). MÉTODOS: Se examinaron muestras de sangre de 82 pacientes con LES y 75 controles saludables para determinar la presencia de anticuerpos antinucleares, usando la prueba del anticuerpo antinuclear fluorescente (FANA), la contrainmunoelectroforesis (CIEP) y el test de inmunofluorescencia con Crithidia luciliae (CL-IFT). Un método de tipificación HLA basado en el ADN fue usado para determinar las frecuencias de aleles de HLA-DRB1, DRB3, DRB4 y DRB5 tanto en los pacientes como en los controles saludables. RESULTADOS: La prueba FANA fue positiva en todos los sueros de pacientes con LES. Anticuerpos anti-dsADN se hallaban presentes en 49% (40/82), anti-Sm/RNP en 44% (36/82) y anti-Ro/La en 43% (35/82) de los sueros de los pacientes de LES. La frecuencia de HLA-DR4 fue significativamente más baja en los pacientes con LES que en los controles saludables (2/82, 2% vs 15/75, 20%; RR = 0.12; p = 0.0004; CP = 0.005) pero no se hallaron otras asociaciones de LES con HLA-DRB1. Se halló una asociación positiva de anticuerpos HLA-DR3 anti-Ro/La en los pacientes con LES (9/21, 43% vs 5/55, 9%; odds ratio (OR) = 7.5; CP = 0.01). En contraste con ello, la posesión de HLA-DR6m estuvo asociada negativamente con la ausencia de anticuerpos anti-dsADN (9/32, 28% vs 27/44, 61%; OR = 0.2; CP = 0.05). CONCLUSIÓN: El alele HLA-DR6 está asociado con la ausencia de anticuerpos antinucleares y el de HLA-DR3 con la presencia de anticuerpos anti-Ro/La en pacientes jamaicanos con LES. Sin embargo, estos resultados al igual que los de los previos estudios de pacientes jamaicanos, sugieren que la asociación HLA-DR3 con el desarrollo de LES reportado en otras poblaciones podría de hecho reflejar la asociación de HLA-DR3 con anticuerpos anti-Ro/La. Se requieren investigaciones ulteriores a fin de determinar si las asociaciones de anticuerpo antinuclear HLA-DRB definen subconjuntos de LES en pacientes jamaicanos.

CD4 TCRBV CDR3 analysis in prevalent SLE cases from two ethnic groups.

We examined CD4+ T cell TCRBV-CDR3 transcripts from 19 lupus patients and 16 controls to test the hypothesis that CD4+ TCRBV-CDR3 expression in SLE differs from normals. Within the disease group we also performed exploratory analyses to determine the association between risk of oligoclonality and HLA-DRB specificities and the duration of the CDR3 patterns. Oligoclonal patterns consistent with CDR3 restriction were three times more likely in SLE than in controls (OR = 3.7). TCRBV1, BV4, BV5.1, BV7, BV9, BV18 and BV22 gene segment CDR3 patterns of oligoclonality were seen exclusively among lupus patients. HLA-DRB3 increased the risk of oligoclonal expression in SLE. In four patients studied over time, the pattern of TCRBV-CDR3 expression was stable in a second sample obtained 6-14 months later. The increased frequency of CD4+ T cell TCRBV-CDR3 oligoclonal expression in SLE when compared to controls and the persistence of these patterns are consistent with an expanded pool of autoreactive CD4 T cells in SLE which recognize peptides derived from autoantigens. The association of HLA-DRB3 genes with increased risk of CDR3 oligoclonality among the SLE subjects is compatible with the hypothesis that molecules encoded by HLA-DRB3 may facilitate autoantigen recognition by CD4 T cells.

Photosensitivity and antinuclear antibodies in black patients with systemic lupus erythematosus.

Black patients with systemic lupus erythematosus (SLE) have a lower prevalence of photosensitivity rashes than white patients. The reasons for this are unknown, but some studies suggest a correlation between the presence of antinuclear antibodies and protection from photosensitivity. In our study, we determined serum antinuclear-antibody profiles, including anti-dsDNA, anti-Sm, anti-RNP, anti-Ro/SS-A, and anti-La/SS-B antibodies, in 91 black Jamaican patients with SLE. All 91 serum samples from SLE patients (100%) were positive in the fluorescent antinuclear-antibody test. Using the crithidia luciliae immunofluorescence test, anti-dsDNA was found in 27.5% of the samples. By a double immunodiffusion method, anti-Sm antibodies were found in 15.4%, anti-RNP in 18.7%, anti-Ro/SS-A in 9.9%, and anti-La/SS-B in 11.0%. However, no statistically significant differences were observed in the seroprevalence of these antinuclear antibodies when sera from patients of the following groups were compared: only photosensitivity rashes (n = 17), photosensitivity and other rashes (n = 23), other rashes without photosensitivity (n = 27), and patients with no skin rash of any type (n = 24). These results suggest that photosensitivity in black Jamaican patients with SLE is not associated with antinuclear-antibody specificity.

Systemic lupus erythematosus, rheumatoid arthritis and HLA phenotypes in Jamaicans.

The HLA phenotypes were investigated in 30 Jamaican patients with Systemic Lupus Erythematosus (SLE), 30 with Rheumatoid Arthritis (RA) and 40 healthy controls. HLA phenotypes were determined by the microcytoxicity technique, using commercially prepared typing trays. In this study, the HLA phenotypic associations with SLE (HLA-B14, RR 4.3: HLA-A28, RR 4.3) were not statistically significant. However, a statistically significant lack of HLA-A9 (p < 0.01; CP < 0.1) was observed in SLE patients compared to healthy controls. In RA patients, a statistically significant association was noted with HLA-A2 (RR 5.1; CP < 0.01). No HLA class II associations were noted with SLE. Class II associations with RA did not achieve statistical significance but included those previously established in other populations. The preliminary data obtained from this study indicate differences in the patterns of HLA phenotypes in Jamaican patients with SLE and RA compared to those observed in such patients elsewhere. Further studies involving larger groups of patients and typing at the serological, cellular and molecular levels are clearly warranted.

Asymptomatic cardiac involvement in systemic lupus erythematosus.

Cardiologic and laboratory parameters were studied in 21 patients with systemic lupus erythematosus (SLE) with cardiopulmonary symptoms (CPS), 20 SLE patients without CPS and 45 age- and sex-matched healthy controls. The most frequent cardiac abnormalities in patients with CPS included pericardial effusion (24%), ventricular enlargement (20%), mitral regurgitation (19%) and tricuspid regurgitation (14%). No structural abnormalities were observed in SLE patients without CPS. Mean calculated and derived echocardiographic values in both groups of SLE patients differed significantly from those observed in normal controls (p < 0.004). Patients with CPS had significantly lower mean values of ejection fraction (p < 0.05) and fractional shortening (p < 0.03). However, the frequencies of functional abnormalities in patients with CPS did not differ significantly from those observed in patients without CPS. There were no remarkable laboratory findings in SLE patients with CPS compared to those without. The finding that some SLE patients may have functional cardiac abnormalities in the absence of CPS is an important one. It raises the question as to whether asymptomatic cardiac involvement in SLE is a separate entity or whether it heralds symptomatic cardiopulmonary involvement.

Primary antiphospholipid syndrome. A case report.

A case of the primary antiphospholipid syndrome (PAPS) in a 21-year-old Jamaican female is described. Recurrent abortions, thrombocytopenia and neurological complications as well as lupus anticoagulant positivity in the absence of features of systemic lupus erythematosus (SLE) were the main clinical findings. Diagnostic criteria, treatment and prognosis are discussed. When the antiphospholipid syndrome (APS) is present in the primary form, the diagnosis may be difficult but its recognition may prevent those vascular events which can lead to significant morbidity and foetal wastage.

Infective arthritis due to Blastocystis hominis.

A patient with rheumatoid arthritis taking prednisone developed Blastocystis hominis acute diarrhoea, which was associated with increased inflammation and effusion of the left knee. B hominis organisms were found in synovial fluid from the left knee. The patient responded dramatically to metronidazole treatment. B hominis may become disseminated in immunosuppressed patients with diarrhoea and may cause infective arthritis.

Seroepidemiologic studies of human T-cell leukemia/lymphoma virus type I in Jamaica.

The prevalence of HTLV-I antibodies was evaluated in Jamaica among persons with various malignant, infectious, autoimmune and hematologic disorders and in clinically normal persons. Results document that: (1) the prevalence of HTLV-I antibodies in this population increases with age; (2) overall, there is no significant difference in the antibody prevalence between males and females; (3) antibody-positive individuals are born in all major regions of the island and geographical variance in antibody prevalence by place of birth was not prominent; (4) there is further confirmation of the high prevalence of HTLV-I antibody-positive lymphomas in Jamaica; and (5) the prevalence of HTLV-I antibodies in hemophiliacs, patients with chronic lymphocytic leukemia (CLL), myelogenous leukemias, and patients with breast cancer is higher than in the age-matched population without malignancies, although none of these differences were statistically significant. The increased prevalence in hemophiliacs is most likely related to their frequent transfusion with blood products, but it has not yet been determined whether the prevalence in patients with other diseases is related to their diseases or other as yet undefined factors in common.

Plasma haemoglobin and complement activation in sickle cell disease.

The role of haemolysis in producing deficient complement function in homozygous sickle cell disease was studied by measuring indices of complement activation and of haemolysis in 30 asymptomatic patients. Plasma concentration of C3d (an index of increased C3 turnover) was elevated in 40% of patients, and modest decreases in serum concentration of C3 and functionally (haemolytically) active factor B were found. There was a positive correlation between C3d and plasma haemoglobin concentration (r = 0.56, p less than 0.005). Reticulocyte count and foetal haemoglobin concentration also contributed to variation in C3d, though to a lesser extent than plasma haemoglobin. Intravascular haemolysis in sickle cell disease may produce activation of complement and thus cause partial depletion of functional factor B and C3. This may reduce the immune function of the alternative pathway.