Mortality and cardiovascular risk in vasculitis ANCA. Importance of hypertension and renal function. Experience from southern Spain.

BACKGROUND: Cardiovascular disease (CVD) is one of the principal causes of death in antineutrophil cytoplasmic antibody-(ANCA)-associated vasculitis (AAV). OBJECTIVES: To evaluate the mortality and it's causes and CVD and its vascular risk factors (VRFs) in AAV patients in Andalusia. METHODS: A multicenter cohort of 220 AAV patients followed-up from 1979 until June 2020 was studied in Andalussia, south of Spain. The information, including socio-demographic and clinical data was recorded retrospectively through chart review. Data was analysed using Chi2, ANOVA and Cox proportional hazards regresion as uni and multivariate test with a 95% confidence interval (CI). RESULTS: During a mean ± standard deviation follow-up of 96.79 ± 75.83 months, 51 patients died and 30 presented at least one CVE. Independent prognostic factors of mortality were age (HR 1.083, p=0.001) and baseline creatinine (HR 4.41, p=0.01). Independent prognostic factors of CVE were age [hazard ratio (HR) 1.042, p=0.005] and the presence of hypertension (HTN) six months after diagnosis (HR 4.641, p=0.01). HTN, diabetes and renal failure, all of these important VRFs, are more prevalent in AAV patients than it is described in matched general population. CONCLUSIONS: Age and baseline renal function, but not CVEs, are predictors of mortality and age and early HTN are independent predictors for having a CVE. CVD screening in AAV patients is demanded.

Registry of the Spanish Network for Systemic Sclerosis: Survival, Prognostic Factors, and Causes of Death.

Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan-Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors.

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.

OBJECTIVE: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. PATIENTS AND METHODS: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. RESULTS: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. CONCLUSION: The data confirm that a LD IVCY regimen followed by AZA-the "Euro-Lupus regimen"-achieves good clinical results in the very long term.

[Comparison of high-resolution liquid chromatography versus microparticle enzyme immunoassay for the measurement of sirolimus levels in renal transplantation]. / Comparación de la cromatografía líquida de alta resolución frente al enzimoinmunoensayo de micropartículas para la determinación de sirolimus en trasplante renal.

OBJECTIVE: To compare sirolimus levels measured in whole blood using two analytical techniques: high-resolution liquid chromatography and microparticle enzyme immunoassay, and to evaluate whether hemoglobin, hematocrit, and time from kidney transplantation influence results obtained using the immune-enzymatic technique. METHOD: A retrospective, observational study in which all transplanted patients with at least one measurement of sirolimus levels using high-resolution liquid chromatography or microparticle enzyme immunoassay from October 2004 to May 2005 were consecutively included. For statistical comparisons simple linear regression, ANCOVA, intra-class correlation coefficient, and the method of agreement limits were all used. RESULTS: Ninety-one patients were assessed for a total of 307 measurements (median: 2, inter-quartile range: 1-4, range: 1-15) of sirolimus levels. The straight-line equation using the linear regression analysis was as follows: MEIA = 0.70 (95% CI: 0.39-1.01) + 1.14 (95% CI: 1.10-1.17) x HPLC/UV. The intra-class correlation coefficient between both measurements was 0.955 (95% CI 0.944-0.964). Mean overestimation using enzyme immunoassay was 24.8% +/- 19.4%. Difference in means between both measurements was 1.9 +/- 1.3 ng/mL. Agreement limits were established between -0.8 ng/mL (95% CI: -1.05; -0.55) and +4.6 ng/mL (95% CI: 4.35; 4.85). Factors such as post-transplant time, hemoglobin, and hematocrit did not influence overestimates obtained using enzyme immunoassays. These results were not influenced by non-independence in measurements. CONCLUSIONS: Despite enzyme immunoassay overestimates in establishing sirolimus levels in whole blood, its correlation with chromatography is acceptable. Added to its benefits versus chromatographic techniques, this renders enzyme immunoassay a good alternative for the measurement of sirolimus levels in whole blood.

[Experience with rituximab in the treatment of systemic erythematosus lupus]. / Experiencia con rituximab en el tratamiento de pacientes con lupus eritematoso sistémico.

OBJECTIVE: To assess the short-term effectiveness and tolerance of rituximab in patients with systemic lupus erythematous and distinct clinical manifestations. PATIENTS AND METHODS: Thirteen patients were studied. Rituximab (RTX) was indicated for refractory nephritis in 6 patients, severe thrombocytopenia in 5, aplastic anemia in 1 and peritoneal vasculitis associated with nephritis in 1. All patients received 4 weekly doses of 375 mg/m(2) of RTX. The mean length of follow-up was 12±8.5 months. Response was favorable in 9 patients: 3 with nephritis, 5 with thrombocytopenia and 1 with peritoneal vasculitis and nephritis. The mean SLE disease activity index decreased from 11 to 6.5 points. Thrombocytopenia recurred in 2 patients, who responded well to retreatment. CONCLUSIONS: The present study demonstrates that RTX is safe and effective as short-term therapy for distinct clinical manifestations associated with SLE.

Benefits at 3 yrs of an asthma education programme coupled with regular reinforcement.

The benefits at 3 yrs of an asthma self-management education programme coupled with educational reinforcement were assessed at follow-up visits in 63 adults with chronic asthma. Changes in asthma-related morbidity parameters, lung function and use of different classes of drugs before intervention and after 1, 2 and 3 yrs of the asthma education programme were compared using Friedman one-way analysis of variance. Improvements in the number of days off work or school, general practitioner consultations, admissions to emergency services, hospital admissions and nocturnal awakenings, as well as increases in forced expiratory volume in one second (FEV1), were significant. Comparison of data obtained at 1 yr and 2-3 yrs showed significant differences in the number of asthma-associated sleep disruptions, days off work or school and unscheduled visits to the general practitioner, as well as FEV1, but significant differences between the data obtained at 2 and 3 yrs were not observed. The percentage of patients using oral steroids had decreased significantly at 3 yrs. In adults with chronic asthma, an asthma self-management education programme coupled with educational reinforcement was effective at decreasing asthma morbidity, improving lung function and decreasing consumption of oral steroids.

Anti-ganglioside antibodies in a large cohort of European patients with systemic lupus erythematosus: clinical, serological, and HLA class II gene associations. European Concerted Action on the Immunogenetics of SLE.

OBJECTIVE: To assay anti-ganglioside antibodies (aGM1) in sera of a large cohort of European patients with systemic lupus erythematosus (SLE) to define the prevalence of these autoantibodies in SLE; to evaluate the association of aGM1 with clinical manifestations and other autoantibodies found in SLE; and to search for aGM1 association with HLA class II alleles. METHODS: Four hundred forty-eight patients with SLE were consecutively enrolled in 8 centers from 6 European countries. All sera were tested for antinuclear antibodies by immunofluorescence on HEp-2 cells as substrate, anti-dsDNA, aGM1, aCL, abeta2-glycoprotein I (abeta2-GPI) antibodies by ELISA, and antineutrophil cytoplasmic antibodies (ANCA) by immunofluorescence and by ELISA. Genomic typing for HLA class II loci was performed by polymerase chain reaction-sequence specific oligonucleotide probe method. Clinical assessment was done at the time of enrolment. RESULTS: We found 41.9% of patients with clinical signs of neuropsychiatric involvement; 15.5% of patients were positive for aGM1, 8% of the IgG isotype and 8.6% of the IgM isotype; aGM1-IgG were associated with neuropsychiatric manifestations (NPM) (RR = 3.7), with migraine (RR = 2.4), with OBS (RR = 7.3), and with peripheral neuropathy (RR = 8.5). aGM1-IgM were associated with NPM (RR = 4) and with depression (RR = 3.4). Furthermore, the genetic study showed that aGM1-IgG were associated with HLA-DQB1*0404 (RR = 7.2) while aGM1-IgM were associated with HLA-DQB1*0605 (RR = 33.3). No associations were found between aGM1 and anti-dsDNA, aCL, abeta2GP1, or ANCA. CONCLUSION: Our results show aGM1 can be found in patients with SLE. aGM1 may play a pathogenetic role for some NPM in this condition.

Anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus. Prevalence and clinical associations. European Concerted Action on the Immunogenetics of SLE.

OBJECTIVE: To test the prevalences and the clinical associations of anticardiolipin (aCL) and anti-beta2GPI (abeta2GPI) antibodies in a large series of European patients with systemic lupus erythematosus (SLE). METHODS: 574 SLE patients from 7 European countries were tested for aCL and abeta2GPI by ELISA methods. RESULTS: aCL of IgG, IgM, and IgA isotypes were detected in 22.8%, 14%, and 13.9% of the patients, respectively. IgG and IgM abeta2GPI were detected in 20% of the patients. The presence of aCL was highly associated with the presence of abeta2GPI. Medium-high titer IgG aCL and abeta2GPI were associated with thrombosis, with similar sensitivity, specificity, and positive predictive value. When present at medium-high titer, IgG aCL were associated with thrombocytopenia, IgM aCL with hemolytic anemia, and cerebrovascular accidents. IgA aCL with livedo reticularis and Raynaud's phenomenon. CONCLUSIONS: aCL, when present at medium-high titer, are as important as abeta2GPI, as a risk factor for thrombosis. Medium-high titer aCL, but not abeta2GPI, are associated with other clinical features of the antiphospholipid syndrome.

Anti-neutrophil cytoplasmic antibodies in 566 European patients with systemic lupus erythematosus: prevalence, clinical associations and correlation with other autoantibodies. European Concerted Action on the Immunogenetics of SLE.

OBJECTIVES: To evaluate, in a cohort of 566 patients with systemic lupus erythematosus (SLE) drawn from 11 European centres: (i) the prevalence of ANCAs and their subspecificities in a large series of European SLE patients; (ii) the possible associations of ANCA with the most common clinical manifestations of the disease; and (iii) whether ANCAs correlate with some of the autoantibodies commonly found in SLE. METHODS: ANCA detection was performed by indirect immunofluorescence (IIF), and by ELISA for lactoferrin (LF), myeloperoxydase (MPO), proteinase3 (PR3) and lysozyme (LZ) subspecificities. RESULTS: The prevalence of ANCA was 16.4% (IIF). The prevalence of LF was 14.3%, LZ 4.6%, MPO 9.3%, and PR3 1.7%. Our results show that ANCA is associated with certain clinical manifestations of SLE. In particular, positive correlations were found between IIF ANCA and serositis (p = 0.026), livedo reticularis (p = 0.01), venous thrombosis (p = 0.03) and arthritis (p = 0.04), while anti-LF antibodies were associated with serositis (p = 0.05) and livedo reticularis (p < 10(-3). Nevertheless, multivariate analysis demonstrated that other autoantibodies, such as aCL and SSA/Ro, are more closely correlated than ANCA with some of the aforementioned clinical features. CONCLUSION: Our results demonstrate that ANCA are detectable in SLE sera and that some of them are associated with particular clinical manifestations. Whether ANCA plays a direct pathogenetic role in the vascular damage of SLE or only represents an epiphenomenon or a marker of disease activity remains to be elucidated.

[Importance of health education in the practice of breastfeeding]. / Importancia de la educación para la salud en la práctica de la lactancia natural.

OBJECTIVES: To find if there is a connection between health education activities (HEA), and breast-feeding (BF) and the introduction of supplementary feeding. To assess the impact of post-delivery groups on BF. DESIGN: Crossover study. SETTING: Primary care. Trinidad-Jesús Cautivo Health Centre, Málaga. PATIENTS AND OTHER PARTICIPANTS: Of the 379 children born in the district between January 1992 and December 1993, the 240 children (63.3%) monitored under the healthy child programme up to at least 6 months of age were included. MEASUREMENTS AND MAIN RESULTS: Of the 240 mothers in the sample, 107 (44.6%) received HE classes. 81.3% of the mothers who had received HE breast-fed during the first month, against 66.9% of those who did not receive HE. This difference was maintained up to the sixth month of BF. The post-delivery groups were the HE activities with most influence on BF practice. Supplementary feeding was begun before the fifth month by 34.6% of those who had not received HE, versus 21.5% of those who had received it. CONCLUSIONS: Attendance at HE classes was significantly linked to BF up to six months and to starting supplementary feeding at a later date. Post-delivery groups were the basic factor in maintaining BF for six months; ante-natal education was an influence from the third month of pregnancy.

[Class I and II HLA antigens in patients with systemic lupus erythematosus in the south of Spain]. / Antígenos HLA de clase I y II en pacientes con lupus eritematoso sistémico en el sur de España.

BACKGROUND: To establish the relation between class I and II HLA antigens, systemic lupus erythematosus (SLE), autoantibodies production, and clinical manifestations in the south of Spain (Málaga). METHODS: In a regional hospital we undertook a case-control study with a consecutive sample of 104 patients with SLE who fulfilled at least 4 criteria of ARA. Three hundred and twenty-eight local controls with no apparent pathology were included for comparison. We evaluated clinical and analytical aspects about multisystem autoimmune disease. HLA typing was serologically determined. RESULTS: Univariate analysis showed a relation between SLE and the specificities B8 (21% of patients vs 10% of controls, p = 0.005; RR = 2.3), DR3 (36% vs 20%, p = 0.0006; RR = 2.5), DRw52 (69% vs 49%, p = 0.001; RR = 2.3), and DQ2 (49% vs 36%, p = 0.0150; RR = 1.7). However, in logistic regression multivariate analysis, there was a confounding effect between DR3 and DRw52, and it could be that only this specificity, HLA-DRw52 (RR = 2.0; 95% CI: 1.1-4.0), and of lesser degree B8 (RR = 1.9; 95% CI: 0.9-4.4), are really associated with SLE. Also, in multivariate analysis, DR6 showed a negative association (5% vs 25%, p = 0.011; RR = 4.2; 95% CI: 1.5-17.2) with anti-U1RNP, while DRw52 showed a negative association with IgG-aCL (50% vs 85%, p = 0.019; RR = 0.21; 95% CI: 0.06-0.76). Furthermore, DQ2/DQ6 showed positive association with anti-SSA/Ro antibodies (50% vs 24%; p = 0.046; RR = 3.0; 95% CI: 1.0-9.0). There were also several associations between clinical manifestations and HLA. The specificities DR and DRw53 were almost always risk factors, but only DR5 was a protector for renal lesion. DRw52 and DQ specificities were always protectors when they were associated with some clinical manifestations. Isolated DR3 antigen, is not associated with any of the above-mentioned manifestations. CONCLUSIONS: The previously described relation between SLE and the antigen DR3 is confirmed, but this association could be a result of the presence of DRw52 specificity in patients, that is in linkage disequilibrium with DR3.

[Immunogenetics of the Sjogren's syndrome in southern Spain]. / Inmunogenética del síndrome de Sjögren en el sur de España.

To establish the relation between HLA antigens, Primary Sjögren Syndrome (PSS) and autoantibodies production, in our geographical area, we undertook a case-control study with a consecutive sample of 30 patients with PSS (Fox's criteria) attending in a reference hospital. Two hundred and sixty-four local controls with no apparent pathology were included for comparison. In patients we evaluated clinical and analytical aspects about multisystem autoimmune disease. Anti-SSA/Ro and -SSB/La autoantibodies were determined by double immunodiffusion. HLA typing was serologically determined. In logistic regression multivariate analysis, there were significant association between PSS and specificities HLA-Cw7 (73% in cases, versus 35% in controls; RR = 8.0; 95% CI: 23.2-2.7), HLA-DR3 (63% vs 20%; RR = 3.4; 95% CI: 9.5-1.4) and HL-DR11 (43% vs 13%; RR = 4.1; 95% CI: 12.0-1.4). In patients, the anti-SSA/Ro autoantibodies production were associated with HLA-DR3 antigen (83% vs 25%; RR = 6./; 95% CI: 1.3-34.2). All HLA-DQ2/DQ6 heterozygotes patients (8 cases) had anti-SSA/Ro autoantibodies, versus only one half of the remainder (p = 0.029; RR = 6.3). In anti-SSA/Ro negative patients there weren't association with HLA-DR3 antigen (33% vs 20%). HLA-DR3 were associated with the presence of anti-SSB/La autoantibodies, but there wasn't signification (p = 0.081). We conclude that our patients with PSS present association with HLA-DR11 specificity, that it's a risk factor for the disease development. HLA-DR3 would determined the anti-SSA/Ro autoantibodies, and maybe also anti-SSB/La autoantibodies, production. Furthermore, HLA-DQ2/DQ6 heterozygosity would determined immune response to SSA/Ro autoantigen.

[Clinical and analytical manifestations of primary antiphospholipid antibody syndrome]. / Manifestaciones clínicas y analíticas del síndrome de anticuerpos antifosfolípido primario.

STUDY OBJECTIVE: Description of the clinical and analytical manifestations of 8 patients with Primary Antiphospholipid Syndrome (PAPS). DESIGN: Series of cases. SETTING: Patients seen in the Internal Medicine Department of a third level Medical Center in Malaga Province. PATIENTS AND INTERVENTIONS: We describe the symptoms and signs, as well as the analytical determinations that may be related with autoimmunity in 8 patients diagnosed of PAPS (Harris' Criteria). The antiphospholipid antibodies were determined by a) Biologic false-positive Venereal Disease Research Laboratory (BFP-VDRL), b) Lupus Anticoagulant (LAC): Enlargement of the activated thromboplastin partial time > 6" and Exner test, c) Anticardiolipin antibodies (aCL), IgG (UGPL/ml), IgM (UMPL/ml) by enzyme-linked immunosorbent assay (ELISA). RESULTS: Four patients were females and four males. The mean age was 35.1 +/- 13.6. None of the patients had criteria of systemic lupus erythematous. The principal clinical manifestations of the PAPS were the venous and arterial thrombotic events in different areas (7 patients); The female patient that didn't have thrombotic event presented thrombocytopenia. Only one patient had 1 abortion. The four females had livedo reticularis (LVR), associated in two of them with arterial hypertension and stroke (Sneddon syndrome). Others manifestations seen, have been, Raynaud's phenomenon, acrocyanosis, migraine, arthritis and myositis. All the patients had IgG aCL, 3 IgM aCL, 7 enlargement of the activated thromboplastin partial time and none presented VRL. Five patient had positive antinuclear antibodies (ANA), but none of them had anti- DNA, hypocomplementemia nor lymphopenia. As far as treatment goes three of the patients are anticoagulated with continuous dicoumarins . The remaining patients keep treatment with platelet antiaggregant, had a satisfactory evolution. CONCLUSIONS: This group of patients presented venous and arterial thrombotic events such as principal manifestation of the PAPS. The most sensitive test to detect antiphospholipid antibodies were the enlargement of the activated thromboplastin partial time and the aCL. It could be interest the determination of aCL in young people the present thrombotic events without another apparent cause.