Relapse rate and renal prognosis in ANCA-associated vasculitis according to long-term ANCA patterns.

Long-term observation of patients with ANCA-associated vasculitis (AAV) allows the identification of different longitudinal patterns of ANCA levels during follow-up. This study aimed to characterize these patterns and to determine their prognostic significance. All ANCA determinations performed in two university hospitals during a 2-year period were retrospectively reviewed. Patients were included in the analysis if they had high titers of anti-myeloperoxidase (anti-MPO) or anti-proteinase 3 (anti-PR3) antibodies at least once, ≥ 5 serial ANCA determinations and AAV diagnosed by biopsy or American College of Rheumatology (ACR) classification criteria. Patients' time-course ANCA patterns were classified as monophasic, remitting, recurrent or persistent. Associations between ANCA patterns and prognostic variables (relapse rate and renal outcome) were analysed by univariate and multivariate statistics. A total of 99 patients [55 with microscopic polyangiitis (MPA), 36 with granulomatosis with polyangiitis (GPA) and eight with eosinophilic granulomatosis with polyangiitis (EGPA)] were included. Median follow-up was 9 years. Among patients diagnosed with MPA or GPA, recurrent or persistent ANCA patterns were associated with a higher risk of clinical relapse [hazard ratio (HR) = 3·7, 95% confidence interval (CI) = 1·5-9·1 and HR = 2·9, 95% CI = 1·1-8·0, respectively], independently of clinical diagnosis or ANCA specificity. In patients with anti-MPO antibodies, the recurrent ANCA pattern was associated with worsening renal function [odds ratio (OR) = 5·7, 95% CI = 1·2-26·0]. Recurrent or persistent ANCA patterns are associated with a higher risk of clinical relapse. A recurrent ANCA pattern was associated with worsening renal function in anti-MPO-associated vasculitis.

Systemic activity and mortality in primary Sjögren syndrome: predicting survival using the EULAR-SS Disease Activity Index (ESSDAI) in 1045 patients.

OBJECTIVE: To score systemic activity at diagnosis and correlate baseline activity with survival in a large cohort of patients with primary Sjögren syndrome (SS). PATIENTS AND METHODS: We include 1045 consecutive patients who fulfilled the 2002 classification criteria for primary SS. The clinical and immunological characteristics and level of activity (EULAR-SS Disease Activity Index (ESSDAI) scores) were assessed at diagnosis as predictors of death using Cox proportional hazards regression analysis adjusted for age at diagnosis. The risk of death was calculated at diagnosis according to four different predictive models. RESULTS: After a mean follow-up of 117 months, 115 (11%) patients died. The adjusted standardised mortality ratio for the total cohort was 4.66 (95% CI 3.85 to 5.60), and survival rates at 5, 10, 20 and 30 years were 96%, 90%, 81% and 60%, respectively. The main baseline factors associated with overall mortality in the multivariate analysis were male gender, cryoglobulins and low C4 levels. Baseline activity in the constitutional, pulmonary and biological domains was associated with a higher risk of death. High activity in at least one ESSDAI domain (HR 2.14), a baseline ESSDAI score ≥14 (HR 1.85) and more than one laboratory predictive marker (lymphopenia, anti-La, monoclonal gammopathy, low C3, low C4 and/or cryoglobulins) (HR 2.82) were associated with overall mortality; these HRs increased threefold to 10-fold when the analysis was restricted to mortality associated with systemic disease. CONCLUSIONS: Patients with primary SS, who present at diagnosis with high systemic activity (ESSDAI ≥14) and/or predictive immunological markers (especially those with more than one), are at higher risk of death.

How are we treating our systemic patients with primary Sjögren syndrome? Analysis of 1120 patients.

OBJECTIVE: To describe how systemic disease is treated in a large cohort of Spanish patients with primary Sjögren syndrome (pSS) in daily practice, focusing on the adequacy of therapies for the level of systemic activity measured by ESSDAI score. PATIENTS AND METHODS: By December 2014, our database included 1120 consecutive patients who fulfilled the 2002 classification criteria for SS. Therapeutic schedules were classified into 4 categories: no systemic therapies, hydroxychloroquine (HCQ) and/or low dose glucocorticoids (GCS) (<20mg/day), high dose GCS (>20mg/day) and use of second-line therapies (immunosuppressive agents, intravenous immunoglobulins [IVIG] and/or rituximab [RTX]). RESULTS: There were 1048 (94%) women and 72 (6%) men , with a mean age at diagnosis of 54 years. The main drug-based therapeutic approaches for systemic pSS during follow-up were HCQ in 282 (25%) patients, GCS in 475 (42%, at doses >20mg/day in 255-23%), immunosuppressive agents in 148 (13%), IVIG in 25 (2%) and RTX in 35 (3%) patients. HCQ was associated with a lower risk of death (adjusted HR of 0.57, 95% 0.34-0.95). We classified 16 (7%) of the 255 patients treated with >20mg GCS and 21/148 (14%) treated with immunosuppressive agents as patients inadequately treated, mainly associated with articular involvement of low/moderate activity. CONCLUSION: The management of pSS should be organ-specific, using low dose GCS in patients with moderate systemic activity, limiting the use of high dose GCS and second-line therapies to refractory or potentially severe scenarios. The use of systemic therapies for dryness, chronic pain or fatigue is not warranted.

Influence of the IL17A locus in giant cell arteritis susceptibility.

OBJECTIVE: Different lines of evidence have highlighted the role of IL-17A in the inflammatory process occurring in giant cell arteritis (GCA). The aim of the present study was to assess whether the IL17A locus influences GCA susceptibility and its clinical subphenotypes. METHODS: We carried out a large meta-analysis including a total of 1266 biopsy-proven GCA patients and 3779 healthy controls from four European populations (Spain, Italy, Germany and Norway). Five IL17A polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909) were selected by tagging and genotyped using TaqMan assays. Allelic combination and dependency tests were also performed. RESULTS: In the pooled analysis, two of the five analysed polymorphisms showed evidence of association with GCA (rs2275913: PMH=1.85E-03, OR=1.17 (1.06-1.29); rs7747909: PMH=8.49E-03, OR=1.15 (1.04-1.27)). A clear trend of association was also found for the rs4711998 variant (PMH=0.059, OR=1.11 (1.00-1.23)). An independent effect of rs2275913 and rs4711998 was evident by conditional regression analysis. In addition, the haplotype harbouring the risk alleles better explained the observed association than the polymorphisms independently (likelihood p value <10(-05)). CONCLUSIONS: Polymorphisms within the IL17A locus show a novel association with GCA. This finding supports the relevant role of the Th17 cells in this vasculitis pathophysiology.

Identification of the PTPN22 functional variant R620W as susceptibility genetic factor for giant cell arteritis.

OBJECTIVE: To analyse the role of the PTPN22 and CSK genes, previously associated with autoimmunity, in the predisposition and clinical phenotypes of giant cell arteritis (GCA). METHODS: Our study population was composed of 911 patients diagnosed with biopsy-proven GCA and 8136 unaffected controls from a Spanish discovery cohort and three additional independent replication cohorts from Germany, Norway and the UK. Two functional PTPN22 polymorphisms (rs2476601/R620W and rs33996649/R263Q) and two variants of the CSK gene (rs1378942 and rs34933034) were genotyped using predesigned TaqMan assays. RESULTS: The analysis of the discovery cohort provided evidence of association of PTPN22 rs2476601/R620W with GCA (PFDR=1.06E-04, OR=1.62, CI 95% 1.29 to 2.04). The association did not appear to follow a specific GCA subphenotype. No statistically significant differences between allele frequencies for the other PTPN22 and CSK genetic variants were evident either in the case/control or in stratified case analysis. To confirm the detected PTPN22 association, three replication cohorts were genotyped, and a consistent association between the PTPN22 rs2476601/R620W variant and GCA was evident in the overall meta-analysis (PMH=2.00E-06, OR=1.51, CI 95% 1.28 to 1.79). CONCLUSIONS: Our results suggest that the PTPN22 polymorphism rs2476601/R620W plays an important role in the genetic risk to GCA.

A case-control study suggests that the CCR6 locus is not involved in the susceptibility to giant cell arteritis.

OBJECTIVES: Polymorphisms of the CC chemokine receptor 6 (CCR6) gene have been recently reported to be associated with a number of autoimmune diseases. We aimed to investigate the possible influence of CCR6 rs3093024 gene variant in the susceptibility to and clinical expression of GCA. METHODS: The CCR6 polymorphism rs3093024 was genotyped in a total of 463 Spanish patients diagnosed with biopsy-proven GCA and 920 healthy controls using a TaqMan® allelic discrimination assay. PLINK software was used for the statistical analyses. RESULTS: No significant association between this CCR6 variant and GCA was observed (p=0.42, OR=0.94, CI95% 0.79-1.10). Similarly, when patients were stratified according to the specific clinical features of GCA such as polymyalgia rheumatica, visual ischaemic manifestations or irreversible occlusive disease, no statistical significant difference was detected either between the case subgroups and the control set or between GCA patients with and without the specific features of the disease. CONCLUSIONS: Our results suggest that the CCR6 rs3093024 polymorphism may not play a relevant role in the GCA pathophysiology.

Antimitochondrial antibodies in patients with chronic hepatitis C virus infection: description of 18 cases and review of the literature.

To describe the clinical and immunologic patterns of disease expression of patients with chronic hepatitis C virus (HCV) infection and positive antimitochondrial antibodies (AMA). We investigated the presence of AMA in 237 consecutive HCV patients with extrahepatic manifestations from an International Registry. AMA were detected by indirect immunofluorescence in triple rat tissue (liver, stomach and kidney), aceton-fixed criosections and FITC-conjugated rabbit anti-human immunoglobulins. We found positive AMA in 18 (8%) out of 237 HCV patients. All patients were female with a mean age at protocol inclusion of 65.8 years (ranging from 37 to 87 years). Twelve (67%) patients fulfilled classification criteria for systemic autoimmune diseases (SAD), including Sjögren's syndrome (n = 7), systemic sclerosis (n = 3) and systemic lupus erythematosus (n = 2). Fourteen (78%) of the HCV-AMA patients presented at least one of the highly suggestive characteristics of primary biliary cirrhosis (PBC): 9 (50%) had a specific M2 pattern, 6 (33%) had more than twice normal levels of alkaline phosphatase, 5 (28%) had raised IgM levels and 4 (22%) a histological pattern compatible with PBC. Five (28%) patients developed neoplasia after detection of AMA. Seven (39%) patients died, due to neoplasia (n = 4), cirrhotic complications (n = 2) and hepatopulmonary syndrome (n = 1). We describe a subset of HCV patients with positive AMA who presented a broad spectrum of clinical features, including liver, autoimmune and neoplasic manifestations. Two-thirds of these patients presented an associated SAD, mainly Sjögren's syndrome or systemic sclerosis, together with a high frequency of multiple autoantibodies and an increased prevalence of cirrhosis and neoplasia.

Systemic sclerosis developing in association with the use of interferon alpha therapy for chronic viral hepatitis.

In 1992 interferon alpha (IFNalpha) was approved by the FDA for the treatment of chronic viral hepatitis B and C. Since then IFNalpha has been implicated in the development of several autoantibodies as well as in the development or exacerbation of various autoimmune disorders. Herein, we describe a 47-year-old female who developed a limited form of systemic sclerosis (SSc) with lung involvement 6 months after the institution of IFNalpha therapy for chronic active hepatitis C. There was no family or personal history of autoimmune diseases. We speculate that the immunomodulatory effects of IFNalpha triggered the clinical manifestations of SSc in this patient. To our knowledge, this is the second case of SSc developing after therapy with IFNalpha and the first in a patient treated for chronic viral hepatitis C.

Mortality and prognostic factors in Spanish patients with systemic sclerosis.

OBJECTIVE: To determine survival and mortality in a cohort of Spanish patients with scleroderma (systemic sclerosis, SSc) and to analyse whether survival is influenced by demographic, clinical or immunological variables or the extent of skin involvement. METHODS: The study included 79 patients diagnosed with SSc and taking part in a study to determine the extent of sclerosis, visceral involvement and immunological alterations. We studied the number of observed and expected deaths (the expected number being based on age- and sex-specific rates in the background population) and derived standardized mortality ratios with their 95% confidence intervals (CI). Cumulative survival after onset of the first symptom was estimated according to the Kaplan-Meier method. The Cox method was used to identify the prognostic factors. RESULTS: The mortality rate was 0.0249 deaths per person-year. Survival at 15 yr was 0.62 (95% CI 0.410-0.778). The standardized mortality ratio was 429.4% (95% CI 222-750). On crude analysis, lung involvement [forced vital capacity (FVC) <70%, pulmonary hypertension], SSc renal crisis, an active capillaroscopic pattern, pericardial effusion and age over 60 yr at diagnosis were associated with shorter survival. On multivariate analysis, only age at diagnosis over 60 yr, FVC <70% and SSc renal crisis were independent prognostic factors. CONCLUSIONS: The mortality rate associated with SSc showed a four-fold increase compared with the background population. Lung involvement and sclerodermal renal crisis were found to be independently associated with reduced survival.

Montelukast and Churg-Strauss syndrome.

Several cases of eosinophilic conditions including Churg-Strauss syndrome (CSS) have recently been reported in asthmatic patients being treated with antileukotriene receptor antagonists. One patient with CSS who experienced a clinical relapse after treatment with montelukast and two asthmatic patients who developed CSS while receiving montelukast treatment are described. In one case reduction in the dose of oral steroid preceded the onset of CSS. To our knowledge, no case of CSS relapse has previously been reported in association with leukotriene antagonists.

Morphologic capillary changes and manifestations of connective tissue diseases in patients with primary biliary cirrhosis.

The objective of this study was to investigate the presence of nailfold capillary abnormalities and extrahepatic signs of connective tissue disease in patients with primary biliary cirrhosis (PBC), as compared to patients with other chronic liver diseases. We evaluated 22 patients with PBC and 15 patients with other chronic liver diseases as a control group. Nailfold capillaroscopy was performed by two observers blinded to clinical findings using a Wild M3 stereomicroscope with an Intralux 5000 Volpi cold light lamp. We detected nailfold capillary abnormalities in 20 out of 22 (91%) PBC patients. Twelve of these 20 patients (54%) showed capillary alterations characteristic of systemic sclerosis. In the control group only two out of 15 patients (13%) presented alterations and in both cases they were a non-specific type. The presence of nailfold capillary abnormalities was significantly greater in PBC patients than in the control group (P < 0.001). Eleven out of the 22 PBC patients (50%) had extrahepatic signs of connective tissue disease and most of them were related to systemic sclerosis; patients with other chronic liver diseases did not present rheumatic manifestations (P < 0.001). In PBC patients there was a significant association between systemic sclerosis capillary pattern and rheumatic manifestations (P < 0.03). The high prevalence of nailfold capillary abnormalities characteristic of systemic sclerosis in patients with PBC and the correlation with sclerodermal manifestations suggests that this capillaroscopic finding could be a useful indicator to investigate rheumatic manifestations in these patients.

Churg-Strauss syndrome: outcome and long-term follow-up of 32 patients.

OBJECTIVES: To study the clinical spectrum and evolution of Churg-Strauss syndrome in order to assess the clinicopathological features of the disease, the response to treatment and the long-term outcome. METHODS: Thirty-two patients with proven allergic and granulomatous angiitis (Churg-Strauss syndrome) and followed up at a single institution were evaluated. They were recruited between 1977 and 1999 from internal medicine departments. Data were obtained retrospectively from medical files in 15 cases and prospectively, using a standardized form, for the remaining patients. RESULTS: All patients had asthma and hypereosinophilia. The lungs, skin and peripheral nervous system were the organs most frequently involved. Antineutrophil cytoplasmic antibodies with antimyeloperoxidase specificity (MPO-ANCA) were detected in 77.8% of tested patients but they were not useful for monitoring disease activity. Extravascular granulomas were rarely seen in tissue biopsies. Forty per cent of the patients were treated with steroids alone. Immunosuppressive agents were added to the treatment when severe neurological, cardiac or gastrointestinal involvement was present. The outcome and long-term survival were good. Clinical relapse was rare after the first year of therapy. Dysaesthesiae of the distal limbs, neurophatic pain and cardiac failure were the most frequent sequelae. CONCLUSIONS: Churg-Strauss syndrome is a rare disorder characterized by hypereosinophilia and systemic vasculitis occurring in patients with asthma and allergic rhinitis. Vasculitis commonly affects the lungs, skin and peripheral nervous system. Outcome and long-term survival is usually good with steroids alone or in combination with immunosuppressive agents. The syndrome has a low mortality rate compared with other systemic vasculitides.

[Spastic paraparesias by HTLV-1: early identification of a new case. Review of the Spanish casuistics]. / Paraparesia espástica por HTLV-I: identificación temprana de un nuevo caso. Revisión de la casuística española.

This is a study of the early identification of a new case of tropical spastic paraparesis/HLTV-1-associated myelopathy in a Spanish patient not previously reported on. The patient is 48 years of age, and he has been living in Sierra Leone for the past seventeen years, where he has worked as a surgeon. On first examination, he had been suffering from symptoms of a spastic paraparesis for the previous five months. This diagnosis was confirmed using serological tests (EIA and Western-blot) on the blood and cerebrospinal fluid (CSF). We have studied the cases outlined in medical literature, paying special attention to the time elapsed between the onset of symptoms and the date on which the diagnosis was made.

Salivary and lacrimal gland dysfunction (sicca syndrome) after radioiodine therapy.

UNLABELLED: Salivary gland dysfunction has been described in patients undergoing radioiodine therapy but associated lacrimal gland dysfunction (sicca syndrome) has never been reported. We conducted a prospective cohort study with follow-up for up to 3 y in a tertiary care university center to determine the prevalence of sicca syndrome in patients after high-dose radioiodine treatment. METHODS: From January 1990 to December 1995, all patients undergoing radioiodine therapy (n = 79) with a standard dose of 925 MBq to 18.5 GBq (25-500 mCi) were interviewed using a standardized questionnaire to determine subjective ocular and oral dryness and were examined for objective lacrimal and salivary gland dysfunction. RESULTS: After radioiodine treatment, 32.9% of the patients reported subjective xerostomia and 25.3% reported subjective xerophthalmia in the first year of follow-up. Xerostomia persisted to the second year of follow-up in 20.3% of cases and was still present >3 y after the last dose of radioiodine in 15.2% of cases. Xerophthalmia persisted to the second year of follow-up in 17.7% of cases and was still present in the third year of follow-up in 13.9% of cases. Severe xerostomia occurred in 4 patients. Reduced salivary and lacrimal gland function was documented in 40 (50.6%) and 14 (17.7%) of the 79 cases, respectively, in the first year of follow-up. Objective xerostomia persisted in 13.9% of cases to the second year of follow-up and was still present in all patients >3 y after the last radioiodine application. Keratoconjunctivitis sicca persisted in 11 patients (13.9%) to the second year of follow-up but was only present in 6 patients (7.6%) >3 y after the last radioiodine application. Additionally, 28/79 patients (35.4%) who had a normal salivary gland scintigraphy previously showed reduced salivary gland function in the third year of follow-up. No significant dependence on cumulative treatment was found for objective xerostomia or xerophthalmia, but doses >11.1 GBq (300 mCi) were related to stage 3 dysfunction on salivary gland scintigraphy. CONCLUSION: Salivary and lacrimal gland dysfunction (sicca syndrome) is relatively frequent after radioiodine therapy. In most cases this is a transient side effect, but in some patients it may persist for a long period or appear late.

Paraparesia espástica por HTLV-I: identificación temprana de un nuevo caso. Revisión de la casuística española / Spastic paraparesias by HTLV-1: early identification of a new case. Review of the Spanish casuistics

Presentamos la identificación temprana de un nuevo caso de paraparesia espástica asociada al virus HTLV-I. El paciente, un español de 48 años, había desarrollado su actividad quirúrgica durante los últimos 17 años en Sierra Leona. Presentaba un síndrome de paraparesia espástica sin alteración esfinteriana de 5 meses de evolución. El diagnóstico se confirmó mediante la determinación de anticuerpos frente al HTLV-I en sangre y líquido cefalorraquídeo (EIA y Western blot). Hemos revisado en la bibliografía los casos descritos, prestando especial atención al tiempo transcurrido entre el inicio de los síntomas y la fecha en que se estableció el diagnóstico (AU)

No disponible

Abnormalities of erythrocyte membrane fluidity, lipid composition, and lipid peroxidation in systemic sclerosis: evidence of free radical-mediated injury.

OBJECTIVE: To elucidate whether oxidative injury occurs in systemic sclerosis (SSc) and whether it affects the erythrocyte membrane (EM) properties. METHODS: EM fluidity and lipid composition (cholesterol:phospholipid molar ratio [C:PL], fatty acid composition) were studied in 52 patients with SSc and in 53 subjects without SSc (32 with primary Raynaud's phenomenon [RP] and 21 healthy subjects [controls]). Fluidity was measured as the fluorescence anisotropy of the hydrophobic fluorescent probe DPH (1,6-diphenyl-1,3,5-hexatriene). Lipid peroxidation products were determined as thiobarbituric acid-reactive substances (TBARS). RESULTS: EM fluidity was significantly lower in SSc patients than in primary RP patients and controls (P < 0.001). The EM C:PL molar ratio was significantly higher in SSc patients than in primary RP patients and controls (P < 0.05). Levels of EM polyunsaturated n6 fatty acids (PUFA n6) were significantly lower in SSc patients than in primary RP patients and controls (P < 0.001). TBARS were significantly increased in SSc patients compared with primary RP patients and controls (P < 0.001). Multiple regression analyses indicated that the reduced EM fluidity was partly due to its greater C:PL molar ratio, lower PUFA n6 content, and higher TBARS levels. EM fluidity was lower among patients with nailfold capillary loss (P < 0.001) and digital ischemic ulcers (P < 0.05). EM lipid peroxidation products were higher among patients with pulmonary involvement (bibasal pulmonary fibrosis [P < 0.05] and reduced levels of diffusing capacity for carbon monoxide [P < 0.001]) and among patients who were positive for anti-topoisomerase I antibodies (P < 0.05) or negative for anticentromere antibodies (P < 0.001). CONCLUSION: Our findings support the idea that oxidative injury occurs in SSc and that, through lipid peroxidation, it induces structural and functional changes of the EM that may contribute to the development of the microvascular abnormalities that are seen in the disease.

[Scleroderma and pregnancy: obstetrical complications and the impact of pregnancy on the course of the disease]. / Esclerodermia y embarazo: complicaciones obstétricas y repercusión del embarazo en el curso de la enfermedad.

BACKGROUND: To describe the outcome of the pregnancy in patients with scleroderma. PATIENTS AND METHODS: Patients with scleroderma and control group were included in this retrospective study. Two groups were different in pregnant patients with scleroderma: pregnancy before scleroderma (A1) and pregnancy after scleroderma (A2). The presence of clinical problems during pregnancy and the outcome of scleroderma were collected in a questionnaire. Differences in the frequencies of complications were analyzed using the U Mann-Whitney, the chi-square or Fisher's exact test when necessary. RESULTS: The frequency of global fetal complications was increased in patients group, but there was no significantly increased frequency when variables were analyzed independently: number of births, miscarriages, fetal deaths, preterm births and low weight full term babies. There was no increased frequency of renal crisis, hypertension or eclampsia. Differences between diffuse and limited subsets were no observed. Improvement of scleroderma was seen in only 3 patients and worsening of skin thickening was experienced by 2 patients. CONCLUSIONS: The pregnant scleroderma patients are a group with high risk pregnancies and therefore well-supervised pregnancies are necessary.