Luis Alberto Ramírez

Antimalarial treatment may have a time‐dependent effect on lupus survival: Data from a multinational Latin American inception cohort

OBJECTIVE To evaluate the beneficial effect of antimalarial treatment on lupus survival in a large, multiethnic, international longitudinal inception cohort. METHODS Socioeconomic and demographic characteristics, clinical manifestations, classification criteria, laboratory findings, and treatment variables were examined in patients with systemic lupus erythematosus (SLE) from the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) cohort. The diagnosis of SLE, according to the American College of Rheumatology criteria, was assessed within 2 years of cohort entry. Cause of death was classified as active disease, infection, cardiovascular complications, thrombosis, malignancy, or other cause. Patients were subdivided by antimalarial use, grouped according to those who had received antimalarial drugs for at least 6 consecutive months (user) and those who had received antimalarial drugs for <6 consecutive months or who had never received antimalarial drugs (nonuser). RESULTS Of the 1,480 patients included in the GLADEL cohort, 1,141 (77%) were considered antimalarial users, with a mean duration of drug exposure of 48.5 months (range 6-98 months). Death occurred in 89 patients (6.0%). A lower mortality rate was observed in antimalarial users compared with nonusers (4.4% versus 11.5%; P< 0.001). Seventy patients (6.1%) had received antimalarial drugs for 6-11 months, 146 (12.8%) for 1-2 years, and 925 (81.1%) for >2 years. Mortality rates among users by duration of antimalarial treatment (per 1,000 person-months of followup) were 3.85 (95% confidence interval [95% CI] 1.41-8.37), 2.7 (95% CI 1.41-4.76), and 0.54 (95% CI 0.37-0.77), respectively, while for nonusers, the mortality rate was 3.07 (95% CI 2.18-4.20) (P for trend < 0.001). After adjustment for potential confounders in a Cox regression model, antimalarial use was associated with a 38% reduction in the mortality rate (hazard ratio 0.62, 95% CI 0.39-0.99). CONCLUSION Antimalarial drugs were shown to have a protective effect, possibly in a time-dependent manner, on SLE survival. These results suggest that the use of antimalarial treatment should be recommended for patients with lupus.

Systemic lupus erythematosus in males. A study of 107 Latin American patients.

Clinical and laboratory features were analyzed in 107 Latin American male patients with systemic lupus erythematosus (SLE) who were compared with a group of 1,209 Latin American female patients with SLE to determine the presence of gender-associated differences. Males had an increased prevalence of renal disease, vascular thrombosis, and the presence of anti-dsDNA antibodies, as well as the use of moderate to high doses of corticosteroids, compared with female SLE patients. Although there was no difference in mortality from all causes, SLE-related mortality was higher in the male group. All these findings are consistent with a more severe disease in Latin American males than in female patients from the same region.

Early rheumatoid arthritis in Latin America: low socioeconomic status related to high disease activity at baseline.

To determine the influence of socioeconomic factors on disease activity in a Latin American (LA) early rheumatoid arthritis (RA) multinational inception cohort at baseline.

Association of HLA-DRB1*1602 and DRB1*1001 with Takayasu arteritis in Colombian mestizos as markers of Amerindian ancestry

We performed HLA Class I and Class II typing in 16 patients (15 women, one man) with a confirmed diagnosis of Takayasu arteritis. We did not find any of the previously described associations with HLA-B52, and/or HLA-DRB1*1301 alleles. However, in our patients, HLA-DRB1*1602 and HLA-DRB1*1001 were significantly increased. The association of Takayasu arteritis with Amerindian and Asian HLA-DRB1 alleles (DRB1*1602 and DRB1*1001) in the Colombian mestizo patients reported here, and with HLA-B*3906 previously reported in Mexicans, suggest the possibility that some HLA and disease associations are markers for ethnicity of a population carrying a disease gene which is present in an admixed population with the disease.

Takayasu arteritis in Colombia.

Takayasu arteritis has been recognized in Colombia just recently, and so far we do not have any report concerning its presentation here. In this first report, some issues related to the presentation of the disease are indicated and compared with those found in the medical literature. No differences were found in age and sex. Most of the cases were diagnosed during an inactive phase of the disease with advanced manifestations due to vascular lesion which suggests the existence of some genetic factor influencing such a presentation, or may be the consequence of a delay in diagnosing the disease during initial and active stages due to not suspecting it. Comparing the vessels which are affected among other races and countries, we can find both differences and similarities. With the purpose of discovering the demographic, clinical, angiographic and laboratorial characteristics of Takayasu arteritis in Colombia, the present study was carried out by studying 35 clinical cases in different medical centers of the country.

Response to ODN-CpG by B Cells from patients with systemic lupus erythematosus correlates with disease activity

Different immunological alterations may condition systemic lupus erythematosus (SLE) activity. However, it is not known whether alterations in the phenotype of circulating antigen-presenting cells (APCs) and in the response to CpG oligodeoxynucleotides (ODN-CpG) correlate with disease activity. APC expression of HLA-DR, costimulatory molecules, and TLR9 expression was determined in patients with SLE, other autoimmune diseases, and healthy controls. Monocyte and B cell response to synthetic ODN-CpG sequences was also evaluated. Monocytes from patients with moderate SLE activity had higher expression of CD40 and CD86. Decreased numbers of CD19+CD80+ and BDCA-3+CD40+ cells were found in patients with severe SLE activity. In patients with moderate SLE activity, non-adherent and enriched B cell response to ODN-CpG was similar to healthy controls. Adherent and enriched B cells from patients with severe SLE activity did not increase costimulatory molecule expression or cytokine production after ODN-CpG stimulation. APCs from patients with SLE, regardless of disease activity, displayed higher percentage of TLR9+ cells, as well as increased expression of TLR9, compared to healthy controls. Results suggest that the B cell response to ODN-CpG correlates with the SLE activity, independently of TLR9 expression, indicating that alterations in B cell response in severe activity SLE may be caused by events down-stream to TLR9.

Cryptococcosis in systemic lupus erythematosus: a series of six cases

The aims of this study were to describe the clinical features of patients with systemic lupus erythematosus (SLE) who developed cryptococcal infection and ascertain their outcomes when treated with glucocorticoids and immunosuppressive agents in conjunction with long-term maintenance antifungal therapy. Six cases of cryptococcal infection in SLE were reviewed retrospectively. The mean age at the time of infection was 26.3 (11.7) years. Three patients had active SLE and all were receiving glucocorticoids [median prednisone dose of 40 (21.2—60.0) mg/day] at the time of infection diagnosis. Concomitant cytotoxic agents were used in five patients. Meningitis was the most common clinical manifestation (n = 5) and cryptococcemia was found in three cases. The patient, who developed pulmonary cryptococcosis, died from respiratory distress syndrome. All patients received induction anti-fungal therapy with amphotericin B and the five surviving patients switched to oral fluconazole indefinitely as maintenance therapy and none of them has had relapses of cryptococcal infection to last medical evaluation. As SLE patients have intrinsic abnormalities of cell-mediated immunity and receive immunosuppressive therapy, indefinite maintenance therapy with fluconazole is recommended in SLE patients with cryptococcosis. Lupus (2010) 19, 639—645.

Primary biliary cirrhosis/autoimmune hepatitis overlap syndrome developing in a patient with systemic lupus erythematosus: a case report and review of the literature

Sir, More than 80% of primary biliary cirrhosis (PBC) patients have at least one associated autoimmune condition. Among these conditions, the most frequent are Sjögren’s syndrome, scleroderma, rheumatoid arthritis and Hashimoto’s thyroiditis. The association of PBC with systemic lupus erythematosus (SLE) is rare and only a few cases have been reported. In contrast, among PBC patients the association with autoimmune hepatitis (AIH) has a prevalence of up to 9.2%. We report an unusual occurrence of PBC/AIH overlap syndrome in a SLE patient. A 50-year-old woman was diagnosed with SLE in 1986 at the age of 27 because of positive antinuclear (1:1280, homogeneous pattern) and anti-dsDNA (1:640) antibodies, malar rash, photosensitivity, non-erosive polyarthritis and lymphopenia. In 1989, urinalysis disclosed nephroticrange proteinuria (4 g/day) and microhaematuria. Diffuse proliferative lupus glomerulonephritis was confirmed by renal biopsy. Prednisolone (50mg/day) with seven monthly oral cyclophosphamide pulses (500mg each) were prescribed and then followed by eight quarterly oral cyclophosphamide pulses. Autoimmune hypothyroidism was diagnosed on the basis of high thyroid-stimulating hormone (TSH) levels (9 uUI/ml) and positive antithyroid antibodies. In March 2009, she complained of fatigue, pruritus, polyarthralgias and unquantified weight loss. Laboratory evaluations revealed: 2200/mm leukocytes, 91,000/mm platelets, and high liver enzyme levels [alkaline phosphatase (1090 U/l), g-glutamyltransferase (2116 U/l), ALT (300 U/l) and AST (232 U/l)]. Anti-mitochondrial antibodies (AMA) were positive (1:160) and anti-dsDNA and smooth-muscle antibodies (SMA) were negative. Serology for hepatitis C and B viruses was negative and serum ceruloplasmin levels were within normal limits. She had no history of alcohol consumption or hepatotoxic drug use. Abdominal ultrasonography showed a liver of micronodular aspect and splenomegaly. Upper digestive endoscopy revealed oesophageal varices. Histological features of liver biopsy revealed: portal inflammatory infiltrate consisting of lymphocytes and plasmocytes, marked loss of bile ducts, and mononuclear cell inflammatory infiltrate of the limiting plate (interface hepatitis). These findings were compatible with PBC and AIH (Figure 1). Ursodeoxycholic acid and azathioprine were started whereas prednisolone dose was increased to 30mg/day. Although abnormal liver function tests are frequent in SLE (25–50%), clinically significant liver disease is uncommon. Liver function tests abnormalities in SLE result from disease activity in 3–23% of patients, adverse drug effects, fatty infiltration, heart failure with passive liver congestion, viral hepatitis or extrahepatic disorders such as myositis. Since liver histology in most studies of SLE patients is missing, it is difficult to attribute the abnormalities in liver function to a specific disorder. In a pathologic series of SLE patients, the most typical finding was hepatic arteritis presenting features of polyarteritis nodosa (15.1%), whereas PBC was found in 2.7%. The linkage between SLE and PBC is rare. Only a few cases of SLE–PBC associations have been reported, one of them reported as AMA-negative PBC (Table 1). AMA are found in 90–95% of PBC patients and its targets are members of a family of enzymes, the 2-oxo-acid

Monocyte activation by apoptotic cells removal in systemic lupus erythematosus patients

Decreased apoptotic cells (ACs) removal has been described as relevant in systemic lupus erythematosus (SLE) pathogenesis. Binding/phagocytosis of ACs was decreased in SLE patients. Blocking experiments suggested a role for CD36 in ACs clearance in healthy controls, not observed in SLE patients. Binding/phagocytosis of ACs induced the production of IL-6, CXCL8 and CCL22 in patients and controls and IL-1β, TNF-α and CCL3 only in healthy controls. ACs clearance induced an increase in CD80 and a decrease in CD86 expression in healthy controls and atherosclerotic patients. However, SLE patients did not up-regulate CD80 expression. The number and expression of CD36 and CD163 in monocytes was not different between the groups. ACs removal induced a down-regulation of CD36 expression in adherent HLA-DR(+) cells in SLE patients but not healthy controls. The decreased binding/phagocytosis of ACs observed in SLE patients, induces a distinct immune response compared with healthy controls.

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.