Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients.

OBJECTIVES: To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. METHODS: In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. RESULTS: 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. CONCLUSIONS: Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.

Multiple sclerosis prevalence in Malaga, Southern Spain estimated by the capture-recapture method.

BACKGROUND: Although not definitively proven, there is commonly accepted to be a latitudinal gradient in the distribution of multiple sclerosis (MS), which is more frequent in temperate zones. The European Mediterranean countries are situated in a zone of median frequency, although ever increasing figures have been noted in the last decades. OBJECTIVE: The objective of this study was to assess the current prevalence rate of MS in the province of Malaga, Southern Spain. METHODS: The capture-recapture method (CRM) uses independent sources of data and permits the number of non-registered cases of a given disease to be estimated, and by doing so, to avoid ascertainment bias. RESULTS: Use of this method showed the estimated prevalence rate of MS in the province of Malaga, Southern Spain, to be 125/10(5) (95% confidence interval: 102/10(5)-169/10(5)), higher than the figures published previously. CONCLUSIONS: Although we recognize that these data need to be confirmed in further studies and in other areas of the country using a similar method, we believe this study is the first to find such high figure of prevalence, being very similar to the figures reported in recent years in other southern European countries.

Association study of IRAK-M and SIGIRR genes with SLE in a large European-descent population.

OBJECTIVE: The aim of this study was to evaluate the relevance of genetic variants of interleukin receptor-associated kinase-M (IRAK-M) (rs11465955, rs1624395, rs1152888 and rs1370128) and single immunoglobulin IL1-1R-related molecule (SIGIRR) (rs3210908) genes in systemic lupus erythematosus (SLE) in four independent European-descent populations. METHODS: Our study population consisted of a total of 2033 SLE patients and 2357 healthy controls from Spain, Germany, Italy and Argentina. The genotyping was performed using a polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. Genetic association between the genotyped markers was determined by PLINK v1.07. RESULTS: After a meta-analysis including these four populations, a trend of association between rs11465955 (P(meta) (-analysis) = 0.06), rs1370128 (P(meta) (-analysis) = 0.07) and rs1624395 (P(meta) (-analysis) = 0.06) polymorphisms was found. However, these differences did not reach statistical significance. In addition, we did not find any association between SLE and the rs1152888 IRAK-M (P(meta) (-analysis) = 0.13) and the rs3210908 SIGIRR (P(meta) (-analysis) = 0.40) polymorphisms after the meta-analysis. No evidence of association with IRAK-M haplotypes was found. CONCLUSION: These results suggest that the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to SLE in European-descent populations.

Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases.

OBJECTIVES: To analyse the safety and efficacy of the off-label use of rituximab in patients with severe, refractory systemic autoimmune diseases. METHODS: In 2006, the Study Group on Autoimmune Diseases of the Spanish Society of Internal Medicine created the BIOGEAS project, a multicenter study devoted to collecting data on the use of biological agents in adult patients with systemic autoimmune diseases refractory to standard therapies (failure of at least two immunosuppressive agents). RESULTS: One hundred and ninety-six patients with systemic autoimmune diseases treated with rituximab have been included in the Registry (158 women and 38 men, mean age 43 years). Systemic autoimmune diseases included systemic lupus erythematosus (107 cases), inflammatory myopathies (20 cases), ANCA-related vasculitides (19 cases), Sjögren's syndrome (15 cases) and other diseases (35 cases). A therapeutic response was evaluable in 194 cases: 99 (51%) achieved a complete response, 51 (26%) a partial response and 44 (23%) were classified as non-responders. After a mean follow-up of 27.56+/-1.32 months, 44 (29%) out of the 150 responders patients relapsed. There were 40 adverse events reported in 33 (16%) of the 196 patients. The most frequent adverse events were infections, with 24 episodes being described in 19 patients. Thirteen (7%) patients died, mainly due to disease progression (7 cases) and infection (3 cases). CONCLUSIONS: Although not yet licensed for this use, rituximab is currently used to treat severe, refractory systemic autoimmune diseases, with the most favourable results being observed in Sjögren's syndrome, inflammatory myopathies, systemic lupus erythematosus and cryoglobulinemia.

[Impact of melanoma diagnosis on sun protection]. / Impacto del diagnóstico de melanoma sobre la fotoprotección.

INTRODUCTION: Knowledge of the dangers of sun exposure does not always lead to changes in behavior. Failure to make behavioral adjustments is of particular concern in high-risk patients. OBJECTIVES: a) To assess the impact of melanoma diagnosis on knowledge, attitudes, and behaviors relating to sun protection, and b) to identify factors that could influence sun protection behaviors. METHODS: A coded, anonymous questionnaire was given to 195 patients with a recent diagnosis of melanoma. Data were collected on clinical and demographic variables and on knowledge, attitudes, and behaviors relating to sun protection before and after diagnosis. The questionnaire also addressed patients' sense of distress and guilt following diagnosis. RESULTS: Sun protection behaviors improved following diagnosis in 66% of patients. Although 98% of patients reported having received advice on sun protection following diagnosis, 15% continued to take inadequate sun protection measures. The probability of behavioral improvement following diagnosis was 4 times greater in women than in men. The subgroup of patients whose behavior improved had worse behaviors prior to diagnosis than did those who showed no improvement. Patients who expressed distress and feelings of guilt following diagnosis were more likely to improve their sun protection behavior. Age, tumor site, intensiveness of treatment, and belief that a suntan is healthy had no significant influence on behavioral change. CONCLUSIONS: Melanoma diagnosis is associated with increased knowledge of sun protection measures and improvement in behaviors. Nevertheless, patients continue to use inadequate sun protection measures. Identification of barriers to optimal sun protection behavior may be instrumental in designing targeted educational campaigns.

Investigation of TLR5 and TLR7 as candidate genes for susceptibility to systemic lupus erythematosus.

OBJECTIVES: The aim of this study was to evaluate the relevance of genetic variants of TLR5 (rs5744168) and TLR7 (rs179008) gene in systemic lupus erythematosus (SLE) in a Spanish population. MATERIAL AND METHODS: Our study population consisted of 752 SLE patients and 1107 healthy controls. All individual were of Spanish Caucasian origin. The TLR5 and TLR7 polymorphisms were genotyped using a PCR system with pre-developed TaqMan allelic discrimination assay. RESULTS: No statistically significant differences were observed when the allele and genotype distribution of TLR5 rs5744168 and TLR7 rs179008 polymorphisms was compared between SLE patients and healthy controls. A significant increase frequency in the CC genotype of the TLR5 rs5744168 polymorphism among SLE patients without nephritis was found (93% vs. 87% in SLE patients with nephritis, p=0.03, OR=2.11 95%CI 0.93-3.51). However, this difference did not reach statistical significance in the allele frequencies (p=0.08). CONCLUSION: These results suggest that the tested variations of TLR5 and TLR7 genes do not confer a relevant role in the susceptibility or severity to SLE in the Spanish population.

[Intravenous cyclophosphamide in lupus nephritis: twenty years reducing dose]. / Ciclofosfamida intravenosa en nefritis lúpica: veinte años reduciendo dosis.

The prognosis for patients with proliferative glomerulonephritis associated with systemic lupus erythematosus has dramatically improved over recent decades. We review our experience with intermittent pulse therapy with intravenous cyclophosphamide (IC) in 97 patients (75 female) aged over 20 years. The series was divided into three groups. Group A (n=39) received monthly IC pulses (begin 1 g) for up to 24 months between 1985-1991. Group B (n=47) received monthly IC pulses (1 g) for six months with additional quarterly doses for a maximum of 18 months, depending on the therapeutic response (from 1991). From 1999, Group C (n=11) patients were treated with low-dose IC (3 g in three months) followed by azathioprine (2 mg/kg) or mycophenolate mofetil (1.5-2.0 g/day) for 12-18 months. The total IC doses (g) administered were: Group A, 15.1+/-9.0; Group B, 8.5+/-3.5; and Group C, 3.0+/-0.0. These figures show the trend progressive reduction in exposure to IC. Overall, treatment with the different IC regimens achieved satisfactory control of lupus nephritis in 76% of the patients. Comparison of the values at baseline and after 24 months showed that the serum creatinine (mg/dl) fell in Group A from 1.77+/-1.06 to 1.09+/-0.63, in Group B from 1.22+/- 0.85 to 0.95+/- 0.45, and in Group C from 0.90+/-0.23 to 1.17+/-0.54 (p<0.05). In the same period, proteinuria (g/day) fell in Group A from 6.19+/-4.31 to 0.79+/-1.76, in Group B from 4.43+/- 3.17 to 2.08+/-3.65, and in Group C from 5.43+/- 3.37 to 3.22+/-4.00 (p=0.05). There was not differences between the three groups in both variables. The adverse effects were mainly viral and bacterial infections, with no intergroup differences. Avascular osteonecrosis requiring hip replacement and early menopause were more frequent in Group A. Nine patients died, seven due to cardiovascular causes and two with infection. No differences were detected between the three groups when analyzing the overall patient survival at 5, 10 and 15 years (95%, 92%, and 84%, respectively). The likelihood of maintaining serum creatinine within normal ranges or less than twice the baseline range was similar in the three groups at 5, 10 and 15 years (92%, 72% and 66%, respectively). There were 47 episodes of relapse, with no differences between the three groups. In Summary, treatment with different regimens of intermittent IC is relatively safe and efficient to control the disease and lupus nephritis in SLE patients even with progressively smaller doses. The price paid concerned infectious complications, and bone and ovarian toxicity. New alternatives should at least maintain the same efficacy, but with fewer adverse effects and relapses.

[Interferon-beta response in multiple sclerosis associated with pre-treatment disability]. / Respuesta al interferon beta en la esclerosis multiple asociada con la discapacidad previa al tratamiento.

AIM: To study pre-treatment clinical features and influence of neutralising antibodies (NABs) in clinical response to interferon-beta (IFNB). PATIENTS AND METHODS: We analysed clinical characteristics and NABs to IFNB in 96 multiple sclerosis patients treated with IFNB. Clinical response was established by clinical criteria: = 1 relapse or an increase = 0.5 or 1 point in the Expanded Disability Status Scale (EDSS) score after one year of treatment compared with the year prior to IFNB therapy. RESULTS: Baseline clinical characteristics were similar for responders and non-responders, except for a significantly higher baseline mean EDSS score in non-responders. Time-to-first-relapse was longer and the number of patients relapse-free was higher for NAB-negative patients, but we were unable to show an association with the disability status, probably due to sample size. CONCLUSIONS: Response to IFNB was significantly associated with pre-treatment disability measured by the EDSS. The presence of NABs to IFNB presented a delayed negative effect for relapses.

Systemic lupus erythematosus: clinical and immunologic patterns of disease expression in a cohort of 1,000 patients. The European Working Party on Systemic Lupus Erythematosus.

In the present study we have analyzed the prevalence and characteristics of the most relevant clinical and immunologic features in 1,000 patients with SLE. Several differences in the expression of the disease have been observed in relation to the patients' age at onset, sex, and autoantibody serology. The childhood-onset patients more often had malar rashes (55% vs 39%) and nephropathy (28% vs 15%) as presenting manifestations. During the evolution of the disease, these patients had an increased prevalence only of malar rash (79% vs 56%) and a lower prevalence of rheumatoid factor (6% vs 19%). The older-onset patients (age 50 or older) less often showed malar rash (21% vs 42%), arthritis (52% vs 71%), and nephropathy (3% vs 17%) as the first symptom. During the evolution of their disease, these patients had a decreased prevalence of malar rash (33% vs 60%), photosensitivity (29% vs 47%), arthritis (73% vs 85%), nephropathy (22% vs 41%), thrombosis (4% vs 15%), and anti-La antibodies (6% vs 20%), but an increased prevalence of sicca syndrome (33% vs 15%). Males more often had serositis (28% vs 16%) as a first symptom, but they presented with a lower prevalence of arthritis (74% vs 85%) during the evolution of the disease. The presence of ANA, a high titer of anti-dsDNA, rheumatoid factor, anti-ENA, and antiphospholipid antibodies also distinguished additional homogeneous SLE subsets of clinical significance.

Morbidity and mortality in systemic lupus erythematosus during a 5-year period. A multicenter prospective study of 1,000 patients. European Working Party on Systemic Lupus Erythematosus.

In the present study we assessed the frequency and characteristics of the main causes of morbidity and mortality in SLE during a 5-year period and analyzed the prognostic significance for morbidity and mortality of the main immunologic parameters used in clinical practice. We started in 1990 a multicenter study of 1,000 patients from 7 European countries. All had medical histories documented and underwent medical interview and routine general physical examination when entered in the study, and all were followed prospectively by the same physicians during the ensuing 5 years (1990-1995). Four hundred thirteen patients (41.3%) presented 1 or more episodes of arthritis, 264 (26.4%) had malar rash, 222 (22.2%) active nephropathy, 139 (13.9%) fever, 136 (13.6%) neurologic involvement, 132 (13.2%) Raynaud phenomenon, 129 (12.9%) serositis (pleuritis and/or pericarditis), 95 (9.5%) thrombocytopenia, and 72 (7.2%) thrombosis. Two hundred seventy patients (27%) presented infections, 113 (11.3%) hypertension, 75 (7.5%) osteoporosis, and 59 (5.9%) cytopenia due to immunosuppressive agents. Sixteen patients (1.6%) developed malignancies, with the most frequent primary localizations the uterus and the breast. Several immunologic parameters (anti-dsDNA or antiphospholipid antibodies) were found to have a predictive value for the development of SLE manifestations during the period of the study. Forty-five patients (4.5%) died; the most frequent causes of death were divided similarly among active SLE (28.9%), infections (28.9%), and thromboses (26.7%). A survival probability of 95% at 5 years was found. A lower survival probability (92%) was detected in those patients who presented at the beginning of the study with nephropathy.

Antiphospholipid, anti-beta 2-glycoprotein-I and anti-oxidized-low-density-lipoprotein antibodies in antiphospholipid syndrome.

Antiphospholipid antibodies (aPL), anti-beta 2-glycoprotein I (anti-beta 2-GPI) and anti-oxidized-low-density lipoprotein (LDL) antibodies are all implicated in the pathogenesis of antiphospholipid syndrome. To investigate whether different autoantibodies or combinations thereof produced distinct effects related to their antigenic specificities, we examined the frequencies of antiphospholipid syndrome (APS)-related features in the presence of different antibodies [aPL, beta 2-GPI, anti-oxidized low density lipoprotein (LDL)] in 125 patients with APS. Median follow-up was 72 months: 58 patients were diagnosed as primary APS and 67 as APS plus systemic lupus erythematosus (SLE). Anticardiolipin antibodies (aCL), anti-beta 2-GPI and anti-oxidized LDL antibodies were determined by ELISA; lupus anticoagulant (LA) by standard coagulometric methods. Univariate analysis showed that patients positive for anti-beta 2-GPI had a higher risk of recurrent thrombotic events (OR = 3.64, 95% CI, p = 0.01) and pregnancy loss (OR = 2.99, 95% CI, p = 0.004). Patients positive for anti-oxidized LDL antibodies had a 2.24-fold increase in the risk of arterial thrombosis (2.24, 95% CI, p = 0.03) and lower risk of thrombocytopenia (OR = 0.41 95% CI, p = 0.04). Patients positive for aCL antibodies had a higher risk of pregnancy loss (OR = 4.62 95% CI, p = 0.001). When these data were tested by multivariate logistic regression, the association between anti-beta 2-GPI and pregnancy loss and the negative association between anti-oxidized LDL antibodies and thrombocytopenia disappeared.

DQB1*0602 allele shows a strong association with multiple sclerosis in patients in Malaga, Spain.

BACKGROUND: The human leukocyte antigen (HLA) class II DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) has been associated with multiple sclerosis (MS) in all ethnic groups and very strongly in Caucasians. AIM: To investigate the possible HLA class II (DRB1, DQA1 and DQB1) associations with MS in Malaga, southern Spain. METHODS: We analysed the HLA class II sub-regions DRB1, DQA1 and DQB1 by polymerase chain reaction (PCR) and sequence-specific oligonucleotide probe hybridization (PCR/SSO) for DRB1 and DQB1 and with sequence-specific primers (PCR/SSP) for DRB1 subtypes and DQA1. Possible HLA class II associations with clinical MS characteristics were investigated in 149 subjects with and 160 without MS. RESULTS: Associations were detected between MS and the HLA class II alleles DRB1*1501 (45.6 % vs. 21.3%, p=0.001), DQA1*0102 (44% vs. 29.4%, p=0.001) and DQB1*0602 (45% vs. 20.6%, p=0.001). The DR2 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) was associated with MS (43.6 % vs. 20%, p=0.002). DQB1*0602 was the only allele that maintained an association with MS in a logistic regression model. No HLA class II alleles or genotypes were significantly associated with any clinical characteristics of MS. CONCLUSIONS: Our results confirm the positive association of the DR2 haplotype with MS, particularly the allele DQB1*0602, in the population studied. DR4 was not associated with the disease in Malaga. HLA class II alleles or haplotypes were not associated with clinical or demographic characteristics, or clinical form or severity of MS.

Azathioprine and methotrexate in multiple sclerosis.

Evidence for the effectiveness of immunosuppressive agents in MS is scanty. There are few good quality trials; most have methodological limitations, such as a small sample size and short duration. Moreover, there is no consistency in treatment regimes, patient groups or outcome measures and the clinical benefits remain unclear. Although azathioprine appears to reduce the relapse rate in MS patients, its effect on disability progression has not been demonstrated. Methotrexate may alter the course of disease favourably in patients with progressive MS, but the evidence is again sparse.

[Normalisation and validation of the Brief Neuropsychological Battery as the reference neuropsychological test in multiple sclerosis]. / Normalizacion y validacion de la bateria neuropsicologica breve como test neuropsicologico de referencia en la esclerosis multiple.

INTRODUCTION. The current batteries such as the Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for evaluating cognitive decline in patients with multiple sclerosis are complex and time-consuming. AIM. To obtain normative values and validate a new battery. SUBJECTS AND METHODS. Four neuropsychological tests were finally included (episodic memory, the Symbol-Digit Modalities Test, a category fluency test, and the Paced Auditory Serial Addition Test). Normative values (overall and by age group) were derived by administering the battery to healthy subjects (5th percentile was the limit of normal). External validity was explored by comparison with the BRB-N. The new battery was also administered to a subsample after 4 weeks to assess reproducibility. RESULTS. To provide normative data, 1036 healthy subjects were recruited. The mean completion time was 18.5 ± 5.2 minutes. For the 229 subjects who were administered the new battery and the BRB-N, no statistically significant differences were found except for mean completion time (19 ± 4 vs 25 ± 5 minutes). In the reproducibility study, there were no significant differences except in the memory tests. CONCLUSION. The scores on the new battery and the BRB-N were strongly correlated although the shorter completion time and ease of administration could make the new battery preferable in clinical practice.

Characteristics of multiple sclerosis at onset and delay of diagnosis and treatment in Spain (the Novo Study).

Multiple sclerosis (MS) is a disease supposedly of autoimmune origin, with reactivity directed against myelin antigens. From the neuropathological point of view, MS produces inflammation, demyelination and axonal and neuronal degeneration. Inflammatory phenomena are predominant in the initial phase of the disease, followed later by neurodegenerative processes. Over the last decade, early treatment, during the most inflammatory phase of the disease, has been considered the best strategy to treat MS. Accordingly, we decided to determine the periods of delay between the first symptoms and the time to the first medical visit, the time to referral to a specialised MS unit, the delay in undertaking clinical and paraclinical tests, the diagnostic criteria used and the overall delay in diagnosis and treatment. The median time from onset of first symptoms to the first visit to a physician was 19.2 months, which represented the greatest delay. The median time between this initial medical consultation and the confirmation of the diagnosis by a specialised MS unit was 5.7 months, and the overall time from symptom onset to diagnosis was 24.9 months (2.08 years). The median time between onset of the first symptoms and the decision to give the first treatment was 2 years. The most important delay was that from symptom onset to the first medical visit, with the other delays being less. Thus, it is during this initial period that greater effort is required in order to reduce the time to diagnosis, by increasing awareness of the problem of MS among the general population and primary care physicians.

No evidence for genetic association of interferon regulatory factor 3 in systemic lupus erythematosus.

The aim of this study was to determine the potential role of three IRF3 gene polymorphisms (rs2304204, rs7251 and rs2304207) with systemic lupus erythematosus (SLE). Our study population consisted of 610 patients with SLE and 730 healthy controls. All individual were of Spanish Caucasian origin. The IRF3 polymorphisms were genotyped using a PCR system with pre-developed TaqMan allelic discrimination assay. No statistically significant differences were found when allele and genotype distribution of rs2304204, rs7251 and rs2304207 polymorphisms were compared between patients with SLE and controls [overall P values: rs7251, P = 0.06; rs2304204, P = 0.26 and rs2304207, P = 0.36, by chi-squared test on a 3 x 2 contingency table. Overall allelic P values: rs7251, P = 0.8, OR (95%CI) = 1.03 (0.87-1.22); rs2304204, P = 0.2, OR (95%CI) = 1.12 (0.93-1.34) and rs2304207, P = 0.8, OR (95%CI) = 1.02 (0.82-1.26)]. In addition, no evidence of association with haplotypes and clinical features of SLE was found. Our data suggest that the IRF3 polymorphisms do not appear to play a major role in the susceptibility or severity of SLE in a Spanish population.