Factors predictive of serious infections over time in systemic lupus erythematosus patients: data from a multi-ethnic, multi-national, Latin American lupus cohort.

AIM: The aim of this study was to identify factors predictive of serious infections over time in patients with systemic lupus erythematosus (SLE). METHODS: A multi-ethnic, multi-national Latin American SLE cohort was studied. Serious infection was defined as one that required hospitalization, occurred during a hospitalization or led to death. Potential predictors included were sociodemographic factors, clinical manifestations (per organ involved, lymphopenia and leukopenia, independently) and previous infections at baseline. Disease activity (SLEDAI), damage (SLICC/ACR Damage Index), non-serious infections, glucocorticoids, antimalarials (users and non-users), and immunosuppressive drugs use; the last six variables were examined as time-dependent covariates. Cox regression models were used to evaluate the predictors of serious infections using a backward elimination procedure. Univariable and multivariable analyses were performed. RESULTS: Of the 1243 patients included, 1116 (89.8%) were female. The median (interquartile range) age at diagnosis and follow-up time were 27 (20-37) years and 47.8 (17.9-68.6) months, respectively. The incidence rate of serious infections was 3.8 cases per 100 person-years. Antimalarial use (hazard ratio: 0.69; 95% confidence interval (CI): 0.48-0.99; p = 0.0440) was protective, while doses of prednisone >15 and ≤60 mg/day (hazard ratio: 4.18; 95 %CI: 1.69-10.31; p = 0.0019) and >60 mg/day (hazard ratio: 4.71; 95% CI: 1.35-16.49; p = 0.0153), use of methylprednisolone pulses (hazard ratio: 1.53; 95% CI: 1.10-2.13; p = 0.0124), increase in disease activity (hazard ratio: 1.03; 95% CI: 1.01-1.04; p = 0.0016) and damage accrual (hazard ratio: 1.22; 95% CI: 1.11-1.34; p < 0.0001) were predictive factors of serious infections. CONCLUSIONS: Over time, prednisone doses higher than 15 mg/day, use of methylprednisolone pulses, increase in disease activity and damage accrual were predictive of infections, whereas antimalarial use was protective against them in SLE patients.

Predictive factors of flares in systemic lupus erythematosus patients: data from a multiethnic Latin American cohort.

Purpose The purpose of this paper is to determine the factors predictive of flares in systemic lupus erythematosus (SLE) patients. Methods A case-control study nested within the Grupo Latino Americano De Estudio de Lupus (GLADEL) cohort was conducted. Flare was defined as an increase ≥4 points in the SLEDAI. Cases were defined as patients with at least one flare. Controls were selected by matching cases by length of follow-up. Demographic and clinical manifestations were systematically recorded by a common protocol. Glucocorticoid use was recorded as average daily dose of prednisone and antimalarial use as percentage of time on antimalarial and categorized as never (0%), rarely (>0-25%), occasionally (>25%-50%), commonly (˃50%-75%) and frequently (˃75%). Immunosuppressive drugs were recorded as used or not used. The association between demographic, clinical manifestations, therapy and flares was examined using univariable and multivariable conditional logistic regression models. Results A total of 465 cases and controls were included. Mean age at diagnosis among cases and controls was 27.5 vs 29.9 years, p = 0.003; gender and ethnic distributions were comparable among both groups and so was the baseline SLEDAI. Independent factors protective of flares identified by multivariable analysis were older age at diagnosis (OR = 0.929 per every five years, 95% CI 0.869-0.975; p = 0.004) and antimalarial use (frequently vs never, OR = 0.722, 95% CI 0.522-0.998; p = 0.049) whereas azathioprine use (OR = 1.820, 95% CI 1.309-2.531; p < 0.001) and SLEDAI post-baseline were predictive of them (OR = 1.034, 95% CI 1.005-1.064; p = 0.022). Conclusions In this large, longitudinal Latin American cohort, older age at diagnosis and more frequent antimalarial use were protective whereas azathioprine use and higher disease activity were predictive of flares.

Impact of cognitive impairment, depression, disease activity, and disease damage on quality of life in women with systemic lupus erythematosus.

OBJECTIVES: To define the relative role of cognitive impairment, depression, disease activity, and disease damage in the decreased health-related quality of life (HRQoL) frequently observed in systemic lupus erythematosus (SLE) patients. METHOD: We studied 101 Chilean female SLE patients and applied the 12-item Medical Outcomes Study (MOS) Short Form Health Survey version 2 (SF-12v2) to assess HRQoL and the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess cognitive function. Analysis of covariance (ANCOVA) models included demographic and disease-related factors and cognitive function tests of sustained attention, memory, and executive function. RESULTS: All measures of HRQoL were lower in the 101 female SLE patients compared to the women from the Chilean general population. HRQoL was associated with the following factors: (i) depression symptoms, which were detrimental to all components of the physical and mental HRQoL scores; (ii) executive dysfunction (spatial planning), which was associated with lower scores on role limitations due to physical health problems and emotional problems, and general health perceptions; (iii) higher activity and organ damage were deleterious to role physical, bodily pain, and physical summary scores; and (iv) higher damage also impacted physical function. Impairments in sustained attention and memory did not decrease the HRQoL. CONCLUSIONS: Our results highlight the relevance of executive dysfunction to poor physical and mental health components of HRQoL in SLE together with depression, while disease activity and disease damage are associated with lower HRQoL physical components. The need for cognitive function evaluation and rehabilitation in SLE is indicated.

Anti-N-methyl-D-aspartate receptor and anti-ribosomal-P autoantibodies contribute to cognitive dysfunction in systemic lupus erythematosus.

OBJECTIVE: Autoantibodies against N-methyl-D-aspartate receptor (anti-NMDAR) and ribosomal-P (anti-P) antigens are potential pathogenic factors in the frequently observed diffuse brain dysfunctions in patients with systemic lupus erythematosus (SLE). Although studies have been conducted in this area, the role of anti-NMDAR antibodies in SLE cognitive dysfunction remains elusive. Moreover, the specific contribution of anti-P antibodies has not been reported yet. The present study attempts to clarify the contribution of anti-NMDAR and anti-P antibodies to cognitive dysfunction in SLE. METHODS: The Cambridge Neuropsychological Test Automated Battery (CANTAB) was used to assess a wide range of cognitive function areas in 133 Chilean women with SLE. ANCOVA models included autoantibodies, patient and disease features. RESULTS: Cognitive deficit was found in 20%. Higher SLEDAI-2K scores were associated with impairment in spatial memory and learning abilities, whereas both anti-NMDAR and anti-P antibodies contributed to deficits in attention and spatial planning abilities, which reflect fronto-parietal cortex dysfunctions. CONCLUSIONS: These results reveal an association of active disease together with specific circulating autoantibodies, such as anti-NMDAR and anti-P, with cognitive dysfunction in SLE patients.

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.

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.

Systemic lupus erythematosus impairs memory cognitive tests not affected by depression.

OBJECTIVE: Our aim was to assess the contribution of depression to cognitive impairment in patients with systemic lupus erythematosus (SLE). METHODS: Clinical features, education, age, and Hospital Anxiety and Depression Scale (HADS) were evaluated in 82 patients with SLE and 22 healthy controls, all Chilean women. The Cambridge Neuropsychological Test Automated Battery (CANTAB eclipseTM) assessing attention, spatial memory, and learning and executive function domains was applied. Cognitive deficit definition: a cut-off for definite impairment was defined as a score below -2 standard deviations in at least one outcome measure in two or more domains. ANCOVA with stepwise selection evaluated influences of health status (SLE or control), age, education, and HADS depression and anxiety scores on cognitive outcomes. To avoid overfitting, a shrinkage method was performed. Also, adjusted p-values for multiple comparisons were obtained. RESULTS: Cognitive deficit affected 16 (20%) patients, and no controls (p=0.039). Median HADS depression score in SLE patients was 6 (range 0-19) and in controls was 0 (0-19), p<0.001). ANCOVA and shrinkage models showed that worse cognitive performance in sustained attention and spatial working memory tests was explained by the presence of SLE but not depression, whereas depression only affected a measure of executive function (I/ED Stages completed). CONCLUSION: Depression has a limited role in cognitive impairment in SLE. Impairments in sustained attention and spatial working memory are distinctly influenced by yet-unknown disease-intrinsic factors.

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.

The impact of rural residency on the expression and outcome of systemic lupus erythematosus: data from a multiethnic Latin American cohort.

OBJECTIVE: The objective of this paper is to examine the role of place of residency in the expression and outcomes of systemic lupus erythematosus (SLE) in a multi-ethnic Latin American cohort. PATIENTS AND METHODS: SLE patients (< two years of diagnosis) from 34 centers constitute this cohort. Residency was dichotomized into rural and urban, cut-off: 10,000 inhabitants. Socio-demographic, clinical/laboratory and mortality rates were compared between them using descriptive tests. The influence of place of residency on disease activity at diagnosis and renal disease was examined by multivariable regression analyses. RESULTS: Of 1426 patients, 122 (8.6%) were rural residents. Their median ages (onset, diagnosis) were 23.5 and 25.5 years; 85 (69.7%) patients were Mestizos, 28 (22.9%) Caucasians and 9 (7.4%) were African-Latin Americans. Rural residents were more frequently younger at diagnosis, Mestizo and uninsured; they also had fewer years of education and lower socioeconomic status, exhibited hypertension and renal disease more frequently, and had higher levels of disease activity at diagnosis; they used methotrexate, cyclophosphamide pulses and hemodialysis more frequently than urban patients. Disease activity over time, renal damage, overall damage and the proportion of deceased patients were comparable in rural and urban patients. In multivariable analyses, rural residency was associated with high levels of disease activity at diagnosis (OR 1.65, 95% CI 1.06-2.57) and renal disease occurrence (OR 1.77, 95% CI 1.00-3.11). CONCLUSIONS: Rural residency associates with Mestizo ethnicity, lower socioeconomic status and renal disease occurrence. It also plays a role in disease activity at diagnosis and kidney involvement but not on the other end-points examined.

Common mental disorders and psychological distress in systemic lupus erythematosus are not associated with disease activity.

Psychiatric diagnosis in patients with systemic lupus erythematosus (SLE) is controversial: variations have been reported in frequency, diagnostic assays, associations with disease activity, autoantibodies, and contributing social factors. Eighty-three consecutive non-selected Chilean patients with SLE were evaluated for: (i) 26 common mental disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), using the Mini-International Neuropsychiatric Interview (MINI-plus); (ii) psychological suffering measured by Hospital Anxiety and Depression Scale (HADS); (iii) ACR 1999 neuropsychiatric (NP)SLE criteria; (iv) SLE disease activity (SLEDAI-2K); (v) cumulative damage (SLICC/ACR); and (vi) anti-ribosomal P antibodies by enzyme-linked immunoassay and immunoblot. Psychiatric diagnoses occurred in 44.6% of patients; the most frequent (21.7%) was major depressive episode (MDE). No association with lupus activity was observed in patients with a DSM-IV diagnosis or MDE or psychological suffering. ACR 1999 NPSLE criteria were present in 42.2% of patients, the majority corresponding to mood (28.9%) or anxiety disorders (15.6%). Suicidal risk was present in 9.6% of patients. Anti-ribosomal P antibodies (13.3%) were not associated with DSM-IV diagnosis. Severe psychiatric disorders in SLE are common and not associated with disease activity.

Survival of Chilean patients with systemic lupus erythematosus.

Environmental, genetic, and ethnic factors seem to be involved in the expression of systemic lupus erythematosus (SLE). It has been reported that SLE in the Spanish-heritage population is more common and severe than in the white population in the United States. Data on the population with SLE in South America are scarce, however. The survival of 218 Chilean patients with SLE was studied. General features of the disease were similar to those in most reports. Survival at 10 years was 79%. Prognostic factors (P < .01) were the clinical markers of renal severity, including clinical stratification of renal disease, SLE disease activity index, thrombocytopenia, thromboembolism, and the use of "megadose" corticosteroids. Multivariate analysis suggested that the disease activity index had the strongest association with outcome (P = .0007); thrombocytopenia added a marginal risk (P = .04). Renal histology was analyzed in 127 patients. Risk factors for survival were clinical renal stage, elevated serum creatinine levels, and high activity index. Chronicity index was not a risk factor. Survival curves for World Health Organization types II and III were better than for type IV (P = .06). Multivariate analysis showed that creatinine levels correlated inversely with outcome (P = .0363). Disease expression of Chilean patients with SLE was similar to that in most reports. Survival was somewhat lower than in developed countries, which may be attributable to socioeconomic and racial factors.

Clinical expression of rheumatoid arthritis in Chilean patients.

In populations such as Northern Europeans in which the HLA-DR4 subtypes DW14 and Dw4 show strong association with rheumatoid arthritis (RA), these alleles and the double allelic dose of the shared epitope are considered severity markers. The clinical expression of RA varies in different populations, which may be determined by variation in the prevalence of these markers. In the present study we analyzed the expression of RA in 112 consecutive Chilean patients and its relation to the prevalence of genetic factors, prompted by our previous observation that DR4 is weakly associated to RA in this population. Mean age was 50 +/- 14 years; 90% were seropositive and 87% were female, with a disease duration of 10 +/- 8 years. Extra-articular manifestations were found in 38% of patients, rheumatoid nodules in 27%, vasculitis in 8%, and Sjogren's syndrome in 29%. Functional capacity (ACR, 1991) I or II: 82%.15% of patients stopped working. Hand radiographs scored according to Steinbrocker in 89 patients: I, 21%; II, 15%; III, 43%; IV, 21%. In this series, patients with less formal education seemed to have more benign arthritis. In 97 controls and in 65 (56%) RA patients the presence of DRB1 alleles corresponding to DR1 and DR4 serotypes, to DR4-Dw subtypes, and homozygocity, were determined by polymerase chain reaction followed by specific oligonucleotide hybridization. The shared epitope was present in 53% of RA patients and in 30% of controls (P = .0048, odds ratio [OR] = 2.64). A double allelic dose of the epitope was present in 15% of RA patients compared with 4% of controls (P = .026, OR = 4.23). In a subgroup of 31 erosive RA patients we did not find a significant association of disease severity with the shared epitope in a single or double allelic dose. None of the DR4 subtypes that associate with RA in other populations was found significantly more prevalent in our patients. The severity of RA in our study compared with published series was intermediate between British patients with severe RA and Greek patients with milder disease. This may be due to the high prevalence of Dwl3*0403 in our population.

Autoantibodies against galectin-8: their specificity, association with lymphopenia in systemic lupus erythematosus and detection in rheumatoid arthritis and acute inflammation.

The role of autoantibodies in the pathogenesis of systemic lupus erythematosus (SLE) has not been completely defined. From more than a hundred autoantibodies described in SLE, relatively few have been associated with clinical manifestations. The glycan-binding proteins of the galectin family can modulate the immune system. Anti-galectin autoantibodies thus could have functional and/or pathogenic implications in inflammatory processes and autoimmunity. We previously reported function-blocking autoantibodies against galectin-8 (Gal-8) in SLE. Here we tested these autoantibodies against a series of other human galectins and demonstrated their specificity for Gal-8, being detectable in 23% of 78 SLE patients. Remarkably, they associated with lymphopenia (50% of 18 anti-Gal-8-positive versus 18% of 60 anti-Gal-8-negative cases, Fisher's Exact test two-tailed: P < 0.012). Lymphopenia is a common clinical manifestation in SLE, yet of unknown mechanism. In addition, six of eight patients with both lymphopenia and malar rash had anti-Gal-8 in their sera. Occurrence of these autoantibodies was not confined to SLE as we also found them in sera of patients with rheumatoid arthritis (16%) and septicemia (20%). This study thus establishes occurrence of specific anti-Gal-8 autoantibodies in autoimmune rheumatic diseases and in acute inflammation, with an apparent association to a clinical subset in SLE.

Occasional series: lupus around the world. The Chilean experience of systemic lupus erythematosus.

The Chilean experience with SLE began more than 40 years ago. The first series was published in 1958 with 108 patients. Lupus hair was described for the first time as a symptom that highly suggested SLE at that time. Subsequent studies have dealt with different clinical aspects of the disease. The description of silent nephropathy in SLE and inspiratory muscle dysfunction as a cause of unexplained dyspnoea have been relevant contributions to the understanding of this condition. Patient survival has improved over the last decades from 13% at 5 years in 1959 up to 87% in 1994. Reasons for this improved survival are probably related to better diagnosis and management of the severely ill patients. However, in spite of this, the incidence of infections in our patients often contributes to fatal outcome. Recently, some studies have been published related to the basic pathogenic mechanisms of this disease.

Osteoarthritis of the knee joint: an eight year prospective study.

Thirty one patients (25 women, six men, mean age 71.7 years) with established osteoarthritis (OA) of the knee were examined clinically and radiologically on two occasions, eight years apart. Four patients thought they had got better, two of whom had striking functional improvement. Seven remained the same and 20 patients got worse, two needing knee surgery and many developing severe disabilities. Most of the patients had a history of slow acquisition of OA at new joint sites, hand disease emerging as the commonest other site of involvement. Changes in symptoms, disability, and radiographs did not correlate. Three of the four patients who improved symptomatically lost range of motion at the knee and developed more severe changes on their radiographs. Chondrocalcinosis of the knee was seen in five patients, including two of those who improved.

The presence of the HLA-DRB1 shared epitope correlates with erosive disease in Chilean patients with rheumatoid arthritis.

OBJECTIVE: To assess the contribution of the HLA-DRB1 shared epitope (SE) to the radiological outcome of rheumatoid arthritis (RA) after 6 yr of follow-up in a reported series of 129 Chilean patients with established disease. METHODS: A prospective study was conducted between 1992 and 1998 using hand radiographs to assess disease outcome in a published series of patients in whom two doses of the SE were present in 20%, one dose was present in 34% and the SE was absent in 46%. At study entry, 29 of the 92 patients with hand radiographs were at Steinbrocker stages I or II (non-erosive), with a median disease duration of 2.8 yr (0.4-17). RESULTS: In 1998, 113 (87%) of the patients were alive. One hundred and eight patients underwent complete clinical evaluation. Their median age was 57 yr (range 30-81) and the median disease duration was 15 yr (6-50). We were able to study 25 of the 29 patients who had non-erosive disease at study entry in 1992. We found that 10 of 11 patients having one or two doses of the SE developed erosive disease compared with three of 14 without the SE (Yates' corrected P=0.0023, relative risk 4.24, 95% confidence interval 1.53-11.77). CONCLUSIONS: These observations support and extend the notion that the presence of the SE in one or two doses can predict the development of erosions even in RA populations in whom the SE is not as prevalent as in Caucasians.

High-dose intravenous methylprednisolone therapy associated with osteonecrosis in patients with systemic lupus erythematosus.

Osteonecrosis is related to the use of steroids in patients with systemic lupus erythematosus (SLE); its association with the use of 'pulses' of methylprednisolone (PMP) is not clear at present. In a retrospective analysis of 190 patients with SLE we found that 19% of 36 patients treated with PMP had osteonecrosis compared with 6% of 154 patients without that treatment (P < 0.04). Risk factors associated with osteonecrosis were PMP treatment, cushingoid appearance, steroid doses > or = 40 mg/day during the first month of treatment, a ratio of steroid dose in grams/year > or = 12, hematuria and proteinuria. In a stepwise regression model, when cushingoid appearance was excluded, PMP became the only significant factor (P = 0.045). We conclude that osteonecrosis can be considered a long-term complication of PMP treatment in SLE patients.

[Treatment with cyclosporine of refractory rheumatoid arthritis]. / Tratamiento con ciclosporina de la artritis reumatoídea refractaria.

Cyclosporine may be useful in the treatment of rheumatoid arthritis refractory to other immunosuppressive agents, in doses of less than 10 mg/kg/day to minimize its nephrotoxic potential, that is enhanced with prolonged use or concomitant administration of anti-inflammatory drugs. We report 15 patients aged 50 +/- 12 years with erosive rheumatoid arthritis lasting 5 +/- 4 years and refractory to other immunosuppressive agents. They were studied during one year and received cyclosporine in initial doses of 2.5 mg/kg/day that were increased to 5 mg/kg/day, assessing clinical response, blood pressure and serum creatinine. Nine patients, that received a maximal dose of 3.4 +/- 0.7 mg/kg/day during 7 +/- 4 months, improved; a 30% increase in creatinine was observed in 3, blood pressure raised in six and two had hepatic toxicity. In the six patients that did not improve, the mean treatment lapse was 4 +/- 3 months and the maximal dose achieved was 2.7 mg/kg/day; creatinine increased in one and blood pressure increased in 4. It is concluded that although the clinical response to cyclosporine was good, only 4 patients completed one year of treatment, due to the frequent secondary effects of the drug.

Novel genetic markers of rheumatoid arthritis in Chilean patients, by DR serotyping and restriction fragment length polymorphism analysis.

OBJECTIVE: The analysis of genetic markers of rheumatoid arthritis (RA) in a population in which the DR4 serotype is not strongly associated with the disease. METHODS: Chilean RA patients (56 seropositive and 22 seronegative) and 141 controls were studied by serotyping. Southern blot analysis of Bam HI restriction fragment length polymorphism (RFLP) was done in genomic DNA from 46 patients with seropositive RA, 17 patients with seronegative RA, and 45 controls, using a complementary DNA probe specific for DRB1 genes. RESULTS: The prevalence of the HLA-DR9 haplotype was strikingly higher in seropositive RA patients (21%) than in controls (3%) (Pcorr less than 0.0008, by Fisher's exact test; relative risk [RR] = 9.34). The prevalence of DR4 and DR1 haplotypes, although slightly increased, did not achieve a significant preponderance. The simultaneous presence of two Bam HI fragments (3.6 kb and 4.5 kb) was found with higher prevalence in seropositive patients (83%; RR = 9; Pcorr less than 0.00002) than in controls (36%), and seemed higher in seronegative RA patients as well (71%; RR = 4). Furthermore, its prevalence remained increased in comparisons of DR4 positive controls (36%) with DR4 positive seropositive patients (100%; RR = 67; Pcorr less than 0.0002) and DR4 positive seronegative patients (100%; RR = 36; Pcorr less than 0.006), even after excluding the DR9 positive individuals. A tendency toward higher association with DR1 seropositive RA patients (67%; RR = 12), a group with no DR4 or DR9 positive individuals, than in DR1 positive controls (14%), was also observed. CONCLUSION: The HLA-DR9 haplotype was definitively consolidated as a very strong genetic marker exclusively for seropositive RA in Chilean patients, as suggested by our previous observations. RFLP analysis showed that the simultaneous presence of 3.6-kb and 4.5-kb Bam HI fragments constituted a better RA marker than did any of the heretofore studied haplotypes. These fragments together would be linked to RA independently of the DR1, DR4, and DR9 haplotypes. The overall evidence indicates that Chilean seropositive RA patients display a genetic background that is different from that underlying RA susceptibility in other populations and suggests the existence of common, as well as distinct, genetic elements predisposing to seronegative and seropositive RA.