A Mathieu

Università degli studi di Cagliari, Cagliari, Sardinia, Italy

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Publications (113)453.92 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The pathogenesis of psoriatic arthritis (PsA) is still under discussion but great advances have been made in the last 2 decades that confirm the central role of tumor necrosis factor-alpha (TNF-alpha) in its inflammatory milieu. New therapeutic approaches have been proposed, and new molecules with anti-TNF-alpha activity have been chemically altered to improve their pharmacological properties. Certolizumab pegol (CZP) is a PEGylated Fc-free anti-TNF that has been shown clinically to be effective in the treatment of rheumatoid arthritis (RA), skin psoriasis, and PsA. This article summarizes available data on its clinical efficacy and safety profile in the treatment of patients with PsA.
    No preview · Article · Nov 2015 · Journal of Rheumatology Supplement
  • M Piga · L Casula · D Perra · S Sanna · A Floris · A Antonelli · A Cauli · A Mathieu
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    ABSTRACT: The objective of this paper is to evaluate hospital admissions in systemic lupus erythematosus (SLE) patients through a retrospective population-based study analyzing hospitalization data during 2001-2012 in Sardinia, an Italian region with universal health system coverage. Data on the hospital discharge records with the ICD-9-CM code for SLE (710.0) were obtained from the Department of Health and Hygiene and analyzed, mostly focusing on primary and non-primary diagnosis and Diagnosis-Related Group (DRG) code. In order to establish the significance of the annual trend for number and type of primary and non-primary discharge diagnosis, the two-tailed Cochran-Armitage test for trend was applied. In order to estimate SLE prevalence, data from administrative database and medical records were assembled. This study included 6222 hospitalizations in 1675 patients (87% women). Hospitalizations with SLE as primary diagnosis were 3782 (58.0%) and significantly decreased during the study period. The annual number of renal, hematologic and neuropsychiatric disorders as non-primary diagnosis associated with SLE remained constant; however, their percentage increased (p < 0.0001) because of a declining number of admissions for SLE without associated diagnosis and without complications. Hospitalizations with SLE as non-primary diagnosis showed a significant upward trend in number and percentage of cerebrovascular accident (p = 0.0004), acute coronary syndrome (p = 0.0004) and chronic renal failure (p = 0.0003) as underlying primary diagnosis, while complications of pregnancy, labor and childbirth (p = 0.3375), malignancies (p = 0.6608) and adverse drug reactions (p = 0.2456) did not show statistically significant changes. Infections showed an increasing trend between 2001 and 2012 but did not reach statistical significance (p = 0.0304). After correction for hospitalization (93.8%) and survival (91.1%) rates calculated over the study period, the 2012 SLE prevalence in Sardinia was estimated to be 99.3 per 100,000 inhabitants. While overall hospitalizations for SLE patients declined, those for cerebrovascular accident, acute coronary syndrome and chronic renal failure as underlying primary diagnosis increased during the study period. © The Author(s) 2015.
    No preview · Article · Jul 2015 · Lupus
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    ABSTRACT: Background Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease which is characterized by disease flares during maintenance treatment. Objectives To evaluate the incidence of flares, the possible association with clinical and serological factors and their therapeutic management in a monocentric SLE cohort. Methods Clinical and laboratory data of 143 patients with SLE, diagnosed between 1997 and 2012 according to the 1982 ACR/ARA and followed-up at the Centre of Rheumatology of the University Hospital of Cagliari, Italy, were retrospectively collected. For the purposes of the study a flare was defined and classified as severe or mild/moderate, according to a modified version of the SELENA-SLEDAI index. For each patient demographic, clinical (in agreement with the BILAG2004-index) and laboratory features as well as medication ongoing at enrolment and in the 6 months prior to the flares were recorded. Then, all these were used as covariates in the univariate statistical analysis. Results During the follow-up (5.43±4.2yr) at least one disease flare was recorded in 41 out of 143 patients (28,7%) for a total of 63 flares, with an incidence rate of 8.1 flares per 100 patient-years. 53.9% of the flare was classified as severe. Active clinical manifestations at the time of flare were: musculoskeletal (66.7%), mucocutaneous (41.3%), systemic (38.1%), hematologic (31.7%), vasculitic-vasculopathic (25.4%), kidney (22.2%), neurological (22.2%), cardio-respiratory (4.7%). At the univariate statistical analysis, the factors significantly associated with the development of flare were: level above cut off values of 7 IU/dl for Farr assay anti-dsDNA (OR: 2.66; p=0.0272) and low dose corticosteroidal monotherapy in the absence of combined treatment with immunosuppressive drugs (OR: 3.42; p=0.0080). From a sub-analysis performed on 29 flares, for which it was possible to review the anti-dsDNA changes in at least two measurements during the six months preceding flare, in 17 cases (59%) there was a rise in anti-dsDNA level greater than 20% before or concurrently of flares. As regards the therapeutic approach in 79.4% of cases the therapy with immunosuppressant or antimalarials has been modified: in the 47.6% of cases a new drug was added, in 17.5% was switched, in 15.0% the dosage was increased. Only the 30% of flares treated by modification of therapy with immunosuppressants, with or without increase of dosage of corticosteroids, was followed by another flare in the time interval of the study. Fifteen changes of therapy with immunosuppressant (with or without increase of dosage of corticosteroids) for the isolated increase in anti-DNA were recorded: only one of these cases was followed by a flare: a significant difference with the number of flares which followed the adjustement of therapy at clinical relapse (p=0,0482) was found. Conclusions In our series the increase of anti-dsDNAds antibodies (Farr assay) levels above 20% of the six-months previous values or the maintenance treatment with corticosteroidal monotherapy alone were predictors of the occurrence of flares. The study highlights the need for close follow up of anti-dsDNA antibodies levels and the importance of immunosuppressants and/or antimalarials for the maintenance therapy. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Preventing organ damage is a major challenge in management of Systemic Lupus Erythematosus (SLE). Few data are available on factors related to development of damage in early stages of the disease. Objectives To evaluate the early damage accrual and factors determining development and progression of damage in a prospectively followed cohort of SLE patients. Methods The Early Lupus Project comprises 8 Italian centers recruiting, from the 1st January 2012, an inception cohort of consecutive patients diagnosed with SLE. Patients were enrolled within 12 months of recognition of four or more 1997 ACR classification criteria for SLE. At study entry and then every 6 months a large panel of data was recorded. Here, we report on the development and progression of damage assessed by the SLICC/ACR Damage Index (SDI) at 6-month and 12-month of disease. Using univariate analysis, we assessed the contribution of covariates collected at baseline (demographic, serological, clinical by BILAG2004 domains, disease activity by ECLAM index and health related quality of life by visual analogic scale) in the development of damage (SDI from 0 to ≥1) and increase in pre-existing damage within 12 months from diagnosis. Stepwise regression models were fitted with covariates with p<0.1 to identify factors independently associated with prediction of damage. Results A total of 161 patients were enrolled in the Early Lupus Project inception cohort up to December 2014; 108 patients (93% Caucasians, 17 males) were eligible for this study having at least 12 months of disease. Mean age at recognition of 4 ACR criteria was 36.3±14.1 years, mean disease duration at recruitment was 2.8±4.3 months (median =1 month; interquartile range 0-3.8). At 6 months of disease, 22 (20.3%) patients had an SDI score of 1 or more (20 patients scored SDI=1; 4 patients scored SDI=2; 3 patients scored SDI≥3). At 12 months of disease, 27 (25.0%) patients had an SDI score of 1 or more and only one patient had increase in pre-existing damage. Age (p=0.01), dyslipidemia (p<0.001), number of active clinical domains according to the BILAG2004 index (p<0.01), active neuropsychiatric (p<0.01) or cardiorespiratory (p=0.02) involvement, familial history of ischemic cardiovascular events (p=0.02) registered at baseline resulted associated with development of damage. Age at diagnosis (p<0.001; OR 1.1 95% CI 1.0-1.3) and active neuropsychiatric involvement (p<0.01; OR 18.7 95% CI 3.1-110.9) were the only independent risk factors for early development of damage in this cohort. No influence of active renal involvement and medications prescribed at baseline was detected in our cohort, likely because they most contribute to development of late-onset damage. Conclusions Development of organ damage begins early in patients with SLE as effect of modifiable and non-modifiable risk factors. Addressing these since the very early stages of the disease may improve short-term outcome. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
  • M. Piga · A. Gabba · F. Figus · M. Congia · A. Cauli · A. Mathieu
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    ABSTRACT: Background The majority (70-80%) of SLE patients develop non-deforming arthritis, but in 5-15% of cases joint involvement progresses to deforming arthropathy classified as non-erosive, the so-called Jaccoud's arthropathy (JA), or erosive on X-ray, the so-called rhupus syndrome (RH). Objectives To assess the incidence of and risk factors for musculoskeletal flares and development of deforming or erosive arthropathy in SLE patients through a 5-year prospective follow-up study. Methods At baseline, 108 consecutive patients with past or present musculoskeletal involvement, fulfilling at least 4 of the 1997 ACR criteria for SLE, were recruited and underwent clinical, X-ray and ultrasound (US) examination. Visits were scheduled every 6 months or according to clinical needs. Each patient was classified as affected with RH by satisfying 1987 criteria for Rheumatoid Arthritis, with JA according to the modified Jaccoud's articular index (JAI) or with non-deforming non-erosive (NDNE) arthropathy. The occurrence of musculoskeletal flares was assessed at each visit using the musculoskeletal item of BILAG2004 index. Clinical, serological findings registered at visit preceding musculoskeletal flare and US results registered at baseline were used as covariates. Clinical and serological findings registered at baseline were used as covariates to identify risk factors related to development of hand deformities (according to JAI) and US erosions (according to the OMERACT definition), which were assessed comparing baseline versus study end findings. Stepwise logistic regression models were fitted with covariates with p<0.1 to predict outcomes; p<0.05 was considered significant. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated. Results Ninety-one patients (mean age 43.1±13.4 years; disease duration 10.7±7.3 years) completed the 5-year follow-up. In 975 clinical assessments, 25 musculoskeletal flares (8 “A” severe and 17 “B” moderate) in 17 (18.6%) patients (10 NDNE, 4 RH, 3 JA) were recorded. High level of CRP (p=0.014 OR 5.4; 95%CI 1.4-20.9) and US evidence of synovial proliferation with power-Doppler signal in joints or tendons (p=0.009 OR 9.9; 95%CI 1.6-34.8) were independently associated with risk of musculoskeletal flare; patients classified as NDNE have lower risk (p=0.008; OR 0.1 95%CI 0.01-0.56). New US erosions were detected in 18 (19.7%) patients (14 NDNE, 3 RH, 1 JA); X-ray confirmed the erosive pattern only in the 3 patients with RH. The only independent risk factor for development of new US erosion was high level of CRP (p=0.006; OR 4.4 95%CI 1.5-13.1). Development or worsening of hand deformities was detected in 7 (8.6%) patients (5 NDNE, 1 RH, 1 JA). Longer disease duration (p=0.0087; OR 1.2 95%CI 1.1-1.3), high level of CRP (p=0.031; OR 15.8 95%CI 1.2-195.2) and musculoskeletal flares during follow-up (p=0.034; OR 3.3 95%CI 1.0-10.0) were independent risk factors for development of hand deformities. Conclusions High levels of CRP and positive US power-Doppler signal identify SLE patients with higher risk for musculoskeletal flares. CRP is also a marker of erosive and deforming musculoskeletal damage accrual. Development of hand deformities was more likely in patients with higher number of musculoskeletal flares and longer disease duration. Disclosure of Interest None declared
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Systemic lupus erythematosus (SLE) is an autoimmune disease with a high degree of variability at onset that is problematic for a correct and prompt diagnosis. We undertook this project with the purpose of collecting an inception cohort of Italian patients with recent-onset SLE, in order to obtain information on the main clinical and serological characteristics at the beginning of the disease. In this first report we describe the characteristics of this cohort at study entry. All patients with a diagnosis of SLE (1997 ACR criteria) and a disease duration less than 12 months were consecutively enrolled between 1 January 2012 and 31 December 2013 in a multicentre prospective study. Information on clinical and serological characteristics at study entry and then every six months was collected into a specific electronic database. Statistical analysis was performed by means of the Openstat program. Among 122 patients enrolled (103 F) 94.3% were Caucasians. Mean age (SD) of patients at study entry was 37.3 (14.3) years, mean age at disease onset was 34.8 (14.3) years, mean age at diagnosis was 36.9 (14.3) years, and mean disease duration was 2.9 (3.9) months. The frequency of the manifestations included in the 1997 ACR criteria was as follows: ANA 97.5%, immunologic disorders (anti-dsDNA, anti-Sm, antiphospholipid antibodies) 85.2%, arthritis 61.8%, haematologic disorders 55.7%, malar rash 31.1%, photosensitivity 29.5%, serositis 27%, renal disorders 27%, oral/nasal ulcers 11.5%, neurologic disorders 8.2%, and discoid rash 5.7%. The cumulative frequency of mucocutaneous symptoms was 77.8%. At enrolment, autoantibody frequency was: ANA 100%, anti-dsDNA 83.6%, anti-SSA 28%, anticardiolipin 24.5%, anti-nRNP 20.4%, anti-beta2GPI 17.2%, lupus anticoagulant 16.3%, anti-Sm 16%, and anti-SSB 13.1%. In this paper we describe the main clinical and serological characteristics of an Italian inception cohort of patients with recent-onset SLE. At disease onset, mucocutaneous manifestations, arthritis and haematologic manifestations were the most frequent symptoms; ANA, anti-dsDNA and complement reduction were the most frequent laboratory findings. Our data confirm that the diagnosis of SLE is a challenging one, and that SLE is a severe disease even at onset, since the majority of patients require at least a hospitalization before the diagnosis. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
    No preview · Article · May 2015 · Lupus
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    ABSTRACT: Background Ankylosing Spondylitis (AS) is a chronic inflammatory disease of the spine strongly associated with the majority of HLA-B27 alleles, with the exception of B*2709 and B*2706. Genome wide association studies (GWAS) have revealed that besides HLA-B27, other genes are involved in AS pathogenesis, such as ERAP1, an ER aminopeptidase that is implicated in peptide trimming thus influencing B27-peptide-β2microglobulin (β2m) complex stability. Several theories have been proposed to explain the B27 association with AS. Among them, the unfolded protein response (UPR) theory suggests that the tendency of B27 trimeric complex to misfold determines free heavy chain (FHC) accumulation in the endoplasmic reticulum, leading to a stress response and activation of pro-inflammatory pathways. Objectives To our knowledge this is the first ex vivo study investigating the intracellular (ic) level of FHC and β2m in peripheral blood mononuclear cells (PBMC) and the possible influence of ERAP1 allelic variance in HLA-B27 positive AS patients and healthy subjects (HSs) bearing the AS-associated (B*2705) and the non-AS-associated (B*2709) allele. Methods The ic amount of FHC and β2m in CD14+ cells from ex vivo PBMC was evaluated in 12 HLA-B*2705 patients with AS, 12 HLA-B*2705 HSs and 12 HLA-B*2709 HSs by flow cytometry analysis. HC10 (gift of Dr. Chella David) and TU99 clone (BD Biosciences, USA) monoclonal antibodies were used to detect FHC and β2m, respectively, and quantified by comparison with standard beads (antibody binding capacity ABC units, Dako Denmark). Cells were fixed and permeabilized by the Intraprep Permeabilization technique (Beakman Coulter, USA) according to standard procedure. Patients and controls were also genotyped for two ERAP1 SNPs associated with AS (rs27044 C/G and rs30187 C/T). Optimized allelic discrimination assays were purchased from Applied Biosystem (Life Technologies, Italy). Values were expressed as mean ± standard deviation. Differences between AS patients and healthy subjects were analyzed by Mann-Whitney U test. Results FHC expression in AS patients was 37486±30346 compared to B*2705 HSs 35673±16723 and B*2709 HSs 26683±10592 ABC units (p=ns). β2m quantity was also not significantly different in AS patients 174930±90441 compared to B*2705 HSs 156471±123855 and B*2709 HSs 153478±42117 ABC units (p=ns). The majority of AS patients and HSs were heterozygous for both rs27044 (C/G) and rs30187 (C/T) SNPs; the intracellular amount of FHC and β2m in the PBMC of the analysed cohorts appeared not influenced by ERAP1 allelic distribution, as shown in Fig. 1. Conclusions This study shows equal amount of FHC and β2m in the cytoplasm of B*2705 AS patients compared to B*2705 and B*2709 healthy controls, regardless of ERAP1 allelic variance. These data, therefore, do not provide support to the UPR theory in the pathogenesis of AS. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4442
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Vitamin D plays an important role in the modulation of immune system and epidemiologic data indicate low vitamin D levels in autoimmune diseases such as rheumatoid arthritis (RA), connective tissue disorders, inflammatory bowel diseases and multiple sclerosis. Several studies reported contradictory results regarding correlation between disease activity and vitamin D levels in these diseases. Objectives To assess 25-OH vitamin D concentrations in 2 independent cohorts of patients affected by inflammatory rheumatic disorders (IRD) and correlations with disease activity and disability. Methods We retrospectively analyzed 420 patients (246 RA, 100 ankylosing spondylitis (SA), 74 psoriatic arthritis (PsA) followed at Rheumatology tertiary centers in Northern France (Paris) and Southern Italy (Cagliari). All patients underwent clinical and laboratory evaluation including serum calcium and phosphorus levels, 25-OH vitamin D and parathyroid hormone (PTH). Vitamin D concentrations <30 ng/ml were considered insufficiency, while values <10 ng/ml were classified as deficiency. Disease activity was assessed by DAS 28 in RA and PsA patients, and by BASDAI and BASFI in AS patients. Results Vitamin D insufficiency and deficiency was very high: respectively 66% and 19% in RA, 76% and 10% in AS, 83% and11% in PsA. Their incidence was comparable between the two populations in RA (68% and 20% versus 62% and 18%, P = ns, respectively in the French and Italian patients), while it was significantly higher among French compared to Italian patients in AS and PsA (86% and 23% versus 61% and 0, P=0.005 and P=0.002; 89% and 20% versus 55% and 3%, P=0.002 and P=0.02, respectively in AS and PsA). Vitamin D supplementation was statistically different only in RA patients (53% versus 34%, P=0.003, respectively in French and Italian patients). In the combined populations, in RA patients, no correlation was observed between vit D and DAS score but treated patients with anti-TNF alpha agents had higher vitamin D levels (P=0.01). In SA patients low vitamin D concentrations correlated with higher BASFI (R = -0,02; P<0.05). We did not find any correlation between vitamin D levels and the other evaluated parameters. Conclusions A high incidence of vitamin D deficiency was found in IRD in the two populations, independently of geographic origin for RA, while a higher incidence was seen in French AS and PsA patients, suggesting a potential different influence of vitamin D on these diseases. By contrast, no correlations with disease activity were found except for disability index BASFI in AS patients. In our study, TNF alpha agents seem to improve vitamin D levels as well as disease activity, but it remains controversial if this is an effect linked to disease activity modulation or it directly depends from immunomodulatory properties of vitamin D. This finding encourage to perform randomized controlled studies for confirming that vitamin D supplementation could reduce the risk of autoimmunity or that it eases disease activity, although there is still not a clear consensus about the optimal circulating 25-OH vitamin D levels and the supplementation dosage for maintaining immune homeostasis. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.5038
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Some tumor-associated antigens (TAAs), apart from cancer cells, are expressed on the surface of inflammatory cells. The production of some TAAs may also be increased in some autoimmune diseases including systemic sclerosis (SSc). Objectives To assess serum carcinoembryonic antigen (CEA), CA-15.3, CA 125, CA-19.9 levels in SSc patients, and to identify any possible associations with lung involvement parameters. Methods Eighty-two SSc patients (70 females and 12 males), mean age 64±13 years (range 34-91), disease duration 6±5 years (range 1-27), were consecutively studied. None of the patients ever had any malignancies. Serum TAAs determination were considered and all patients underwent to high-resolution scan (HRCT) and pulmonary function tests (PFTs). CEA, CA 19.9, CA 15.3 and CA125 were determined by electrochemiluminescence immunoassays; the normal upper limit determined by the manufacturer, were as follows: CEA <2.5 ng/ml, CA19.9 <33 U/ml, CA 15.3 <46.5 U/ml, CA125 <21 U/ml. Results CEA was elevated in 28 (32%) of SSc patients, CA 19.9 in 7 patients (9%), CA 15.3 in 28 patients (36%), CA 125 in 6 patients (8%). Lung fibrosis at HRCT significantly associated with CEA (p<0.0003, r=0.4), CA15.3 (p<0.001, r=0.4), and CA125 (p<0.01, r=0.3) while no association was seen for CA 19.9. Forced vital capacity (FVC) significantly associated only with CA 15.3 (p=0.0001), and diffusion lung capacity for carbon monoxide (DLCO) only with CEA (p=0.04). There was an inverse correlation between CA 15.3, FVC and DLCO (r= -0.52 and r= -0.44, respectively). Conclusions The production of some TAAs may be elevated in SSc patients; CEA, CA15.3, and CA125 may have a negative prognostic role, being associated with lung fibrosis as documented by HRCT and PFTs. Further studies on higher proportion of patients could be addressed for identifying a surrogate biomarker, among TAAs, for lung involvement in SSc, to assess extent of the disease and possibly with prognostic significance. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5074
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Conventional MRI (cMRI) is a first level investigation in the diagnostic work-up of Systemic Lupus Erythematosus (SLE) patients with neuropsychiatric (NP) manifestations. Objectives To evaluate the long-term evolution of cerebral abnormalities by (cMRI) in patients with SLE. Methods Thirty patients (29F, age 53.5±11.3 yrs, disease duration 24.9±6.7 yrs) with SLE were prospectively observed and brain MRI studies (T1, T2, GRET*2 and FLAIR sequences) were obtained at baseline (MR-1 - 0.5 Tesla) and repeated after 19.4±3.7 yrs of follow-up (1.5 Tesla – MR-2). An experienced neuroradiologist analyzed the MRI comparing the following outcomes: 1) number of focal subcortical white matter hyperintensity (WMHI) lesions, 2) presence of parenchymal defects secondary to large-vessel ischemic lesions, 3) cerebral atrophy visually assessed and quantified using the Evans' index. Cumulative MRI brain damage was calculated according to a modified scoring system proposed by Petri et al (1). Each patient was assessed for the presence of NP manifestations SLE-related (NP-SLE) or unrelated (NP-nonSLE), according to criteria proposed by the Italian Study Group on NP-SLE (2). Demographic, clinical and serological data were also recorded in order to identify risk factors associated with worsening of brain MRI abnormalities. Multiple stepwise regression analysis were applied. P-values <0.05 were considered significant Results Twenty patients (66.6%) had an increased number of focal WMHI lesions whilst 8 patients (26.7%) showed a significant increase of Evans' index, defined as an increase greater than the sample mean + standard deviation. Modified Petri's score worsened in 23 patients (76.7%) and when the entire cohort was considered the difference between baseline and follow-up resulted statistically significant (MR-1: 1.3±1.5 vs. MR-2: 2.9±2.1; p<0.0001). Brain MRI showed parenchymal defects secondary to large-vessel ischemic lesions in 6 patients (20%) 4 of which were not present at baseline. Previous WMHI lesions on MRI (p=0.016; OR 231.4 and 95%CI: 2-1980) resulted as the only independent risk factor for the development of new WMHI lesions, whilst treatment with antimalarials (p=0.004; OR 0.01 and 95%CI: 0.0-0.25) was independently associated with a reduced risk. Hyperlipidemia (p=0.044; OR 10.1 and 95%CI 1.1-97.0), resulted independently associated with an increased risk to develop cortical atrophy. Finally, a cumulative steroids dose higher than 50 grams (p=0.026; OR 8.8 and 95%CI 1.2 – 61.0) was the only independent risk factor for increase in cumulative brain MRI damage. Twenty-one patients reported at least one NP event (7pts had >1 event). Fourteen patients were classified as NP-SLE and 7 as NP-nonSLE. The only independent risk factor for new NP-SLE manifestation was a previous NPSLE event (p=0.015; OR 10.2 95%CI 1.5 – 67.2) whilst higher modified Petri's score was an independent risk factor for the development of NP manifestations of any nature. Conclusions Worsening of MRI brain damage in SLE patients is related to risk factors both linked and not linked to the disease and it is associated with the risk of new NP events of any nature. References Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4488
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
  • M. Piga · E. Chessa · V. Ibba · V. Mura · A. Vacca · P. Garau · A. Gabba · G. Porru · A. Cauli · A. Mathieu
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    ABSTRACT: Background The use of biological drugs has been linked with the paradoxical development of systemic and organ specific autoimmune processes. Objectives To describe the features of biologics-induced autoimmune renal abnormalities (AIRA) through a systematic review and the analysis of 707 adult patients with inflammatory rheumatic disease (IRD) followed-up in a third level center of Rheumatology. Methods Using PubMed a systematic review was carried out according to PRISMA guidelines and included the following Mesh terms: “Arthritis, Rheumatoid” OR “Arthritis, Psoriatic” OR “Spondylitis, Ankylosing” AND “infliximab” OR “TNFR-Fc fusion protein” OR “golimumab” OR “adalimumab” OR “certolizumab pegol” OR “rituximab” OR “tocilizumab” OR “abatacept” AND “Glomerulonephritis” OR “Nephrotic Syndrome” OR “Nephrosis, Lipoid”. Last Medline was performed on the 31/08/2013. A retrospective analysis of 707 adult patients with IRD, of which 427 Rheumatoid Arthritis (RA), 168 Ankylosing Spondylitis (AS) and 112 Psoriatic Arthritis (PsA), treated with biologics between 2004 and 2013, was performed. All patients have been prospectively followed-up and have had blood tests and urine analysis at least three times per year. The aim was to identify those patients that developed biologics-induced AIRA. According to clinical manifestations and kidney histology the cases identified by systematic review and cohort analysis were classified as: A) Glomerulonephritis associated with systemic vasculitis (GNSV), B) glomerulonephritis in lupus-like syndrome (GNLS), C) other autoimmune renal disorders (OARD). Results The literature search identified 1687 articles from which 22 were considered relevant for the present study for a total of 28 case reports. The retrospective cohort analysis retrieved 3 cases. Data have been pooled. Twenty-three patients identified were on biologics treatment because RA, 4 had AS and 4 had PsA. TNF-alpha blockers were responsible for AIRA in all identified cases: 17 etanercept, 9 adalimumab and 7 infliximab. AIRA usually appeared within 12 months since the beginning of anti-TNF-alpha therapy, but 8 cases were diagnosed later. The 31 cases identified were classified as: 12 with OARD (5 membranous GN, 3 IgA nephropathy, 1 mesangial GN, 1 minimal change GN, 1 necrotizing GN, 1 not biopsied), 11 with GNSV (3 necrotizing-crescentic GN, 2 necrotizing GN, 2 pauci-immune GN, 1 Schönlein-Henoch IgA nephropathy, 3 not biopsied), 8 with GNLS (1 class III, 3 class IV, 4 not biopsied). Age at onset was younger in GNLS (38.9±13.6 years, 7 female) than in OARD (54.7±13.0 years; 6F) and GNSV (48.6±14.5 years, 6F). Better prognosis was associated with GNLS (75% complete and 25% partial resolution) and treatment with corticosteroids and immunosuppressant, whilst worse prognosis was associated with GNSV, OARD and lack of anti-TNF-alpha withdrawal. End stage renal failure was reported in 2 cases with GNSV and 1 with OARD whilst 1 dead was reported in GNSV. Conclusions Patients with IRD may suffered from biologics-induced AIRA which are apparently associated only with anti-TNF-alpha and although rare they may be life-threatening. If AIRA occur biologics must be discontinued and the patient should be treated according to clinical manifestations and biopsy findings. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4524
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Although up to 90% of patients systemic sclerosis (SSc) have been estimated to have gastrointestinal involvement, liver disease (without any cause other than SSc itself) has been reported only rarely in this disease. Liver biopsy is considered the gold standard for an accurate assessment of liver fibrosis. However, it is an invasive and expensive tool, so there has been increasing interest in non-invasive assessment evaluation of liver stiffness (LS) by transient elastography (TE) which have been recently demonstrated to be useful for the diagnosis of various grades of fibrosis in the course of chronic liver diseases. Objectives To evaluate the presence of liver fibrosis in a series of SSc patients, without any functional sign of liver disease and any cause other than SSc itself, and to identify any possible associations with demographic data, disease duration and disease phenotype. Methods Thirty-nine SSc patients (33 females and 6 males) without liver diseases, mean age 63.4±13.2 years, disease duration 10.5±8,67 years, and a sex- and age-matched control group, were consecutively studied. LS was evaluated using TE (Fibroscan; Echosens, Paris, France) and measured in kPa. We adopted 5.3 kPa as the cutoff for abnormal LS values. Results Seventeen (43.5%) SSc patients had abnormal LS values when patients were classified into two groups according to the cutoff (group A <5.3 kPa, group B >5.3 kPa); the median LS value was 4 kPa in group A and 7.1 kPa in group B. There were no significant differences between the two groups in disease duration, demographics, laboratory variables or disease characteristics. Among medications, a significant difference for patients on endothelin receptor antagonist therapy was seen in group B (P=0.02). Conclusions TE suggested, in a non-invasive fashion, liver fibrosis in 43.5% of our SSc patients, as a result of a primary hepatic involvement. LS measurement could be suggested for checking silent liver fibrosis in SSc, even in absence of abnormal liver function serological tests. However, further studies are required to investigate whether treatment regimens can influence the progression of liver fibrosis, or if they should be modified when abnormal LS values are identified. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3523
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.
    Full-text · Article · Feb 2014 · The Journal of Rheumatology
  • A. Cauli · G. Dessole · G. Porru · M. Piga · A. Vacca · V. Ibba · P. Garau · A. Mathieu

    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Neuropsychiatric (NP) involvement in systemic lupus erythematosus (SLE) includes a wide variety of neurologic and psychiatric manifestations whose attribution to the underlying disease is a clinical challenge. Objectives To determine the sensitivity and specificity of an attribution model (AM) applied to a large multicenter series of NP events. Methods All NP events satisfying the 1999 ACR case definition criteria occurred in a multicenter cohort of SLE patients (pts), in a timeframe of 5 years, were retrospectively analyzed. All NP events were tested by applying an arithmetical AM, firstly developed in a cohort of pts recruited in Ferrara, which included a set of 4 items selected on the basis of a literature review and by a Delphi consensus methodology during the XLVII Congress of the Italian Society of Rheumatology. The items included in the AM were the following: time of onset of NP event respect to the SLE clinical onset (before -0.5; after +0.5, concomitant +1); “minor” or not specific NP events as defined by Ainiala et al. (yes = -1; not = +0.5); opposing factors or “associations” as defined by ACR glossary (none =0; 1 = -0.5; >1 = -1); other favoring factors such as age of onset, absence of familial history for epilepsy or psychiatric disorders, abnormal serology, neuroimaging abnormalities, response to treatment, high disease activity at the time of the event (none =0, 1 =+0.5, >1=+1). According to the final score each NP event was then classified as related (≥+1), uncertain (-0.5 to +0.5) or SLE-unrelated (≤-1). The performance of the AM was estimated by its application to an external cohort of pts by the ROC curves analysis, assuming the “clinical judgment” performed by each attending team as the referral gold standard. Results 211 eligible pts were included, 91% F e 9% M, with a mean age of 33.5 yrs for a total of 430 events evaluated. Applying the AM 3 classes of values were generated: 179 events were classified as SLE related, 29 as SLE-unrelated and the remaining as uncertain events. After exclusion of uncertain events, the result obtained by the ROC curves analysis comparing the results of the AM with the clinical judgment, yielded a sensitivity of 62% and specificity of 93% when all the NP events were considered; when the analysis was restricted to first NP event only, the sensitivity raised up to 72% and specificity was 90%. Conclusions The overall performance of a new arithmetical AM was satisfactory in terms of sensitivity and specificity and allowed a proper placement in three-quarter of the NP events deemed as related and unrelated to SLE. This model can be regarded as an easy to use tool which allows a standardized approach to the complex sphere of NP involvement in SLE. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
  • A. Cauli · G. Dessole · G. Porru · M. Piga · A. Vacca · V. Ibba · P. Garau · A. Mathieu
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    ABSTRACT: Background We previously reported increased expression of cell membrane RANKL in PBMC of patients with active rheumathoid arthritis (RA) which was down-regulated by anti TNF-α treatment with adalimumab, while soluble RANKL and OPG were scarcely affected. We speculated that anti TNF-α induced down-regulation of membrane RANKL could be important in preventing articular damage in RA patients. Joint damage may also be mediated by the balance of other mediators involved in osteoclast functions such as LIGHT (TNFSF14, member of the TNF superfamily) and cathepsin-K, while osteoblast functions are influenced by DKK-1 and sclerostin, although the data available is still contrasting and the significance under debate. Objectives To investigate the impact of anti TNF-α treatment on the major soluble mediators involved in bone homeostasis in RA patients. Methods The effects of anti TNF-α therapy on bone homeostasis was studied in 15 active RA patients (DAS28 5.9±0.9) and compared with 20 healthy controls (HC); data were collected at baseline, after 6, 12 and 24 weeks. Adalimumab 40 mg was administered every other week according to guidelines, all patients experienced a satisfactory clinical response according to EULAR criteria. The serum levels of DKK-1, Sclerostin, Cathepsin-K were measured by enzyme-linked immunoassorbent assay (ELISA), all purchased from Biomedica (Vienna, Austria); LIGHT protein was detected with Quantikine ELISA (R&D System, Europe, UK) according to the manufacturer’s instruction. Values are presented as the median and interquartile range. Serum levels at different times after treatments were compared with those before therapy and HC. The significance of the results was analysed using the non parametric Mann-Whytney U-test or Wilcoxon, as appropriate, using Prism 5.0 software (GraphPadInc). P values less than 0.05 were considered significant. Results Cathepsin-K levels were found to be higher in RA patients compared to HC (9.1 IQR 45-14.3 pmol/mL) both before treatment with adalimumab (12.7 IQR 11.3-15.3 p=0.019) and at W6 (15.5 IQR 12.5-26.8 p=0.001), W12 (16.4 IQR 12.1-20.5 p=0.003), W24 (15.0 IQR 12.9-16, p=0.003). LIGHT levels were also consistently higher in the RA group compared with HC (66.0 IQR 42.6-112.0 pg/L) at baseline (96,6 IQR 65.3-179.2 p=0.03), W6 (101.6 IQR 88.7-203.1 p=0.006), W12 (150.4 IQR 88.8-192.2 p=0.003) and W24 (138.9 IQR 66-228.5 p=0.015). Sclerostin levels were higher in the untreated RA group (31.5 IQR 26.3-48.7 pmol/L) compared to HC (24.5 IQR 18.7-29.6 p=0.007). It is noteworthy that long term adalimumab treatment induced a significant reduction in sclerostin levels at W24 (19.50 IQR 14.6-29.9 p=0.002); conversely, no significant changes in DKK-1 levels were observed following adalimumab treatment at baseline (21.1 IQR 7.9-57pmol/L) compared to W6 (19.5 IQR 6.7-59.5), W12 (20.1 IQR 9.2-57.5), W24 (11.1 IQR 5.2-54.6). Conclusions The decreased levels of sclerostin following anti TNF-α treatment may reduce the inhibition of theWNT/β-catenin pathway leading to increased osteoblast activity which may balance the increased osteoclast function in RA patients (as mirrored by the persistent increase in cathepsin-K and LIGHT) and therefore contributing to the inhibition of joint damage seen in patients treated with anti-TNF-α drugs. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Pharmaco-epidemiological studies on TNF-inhibitors (TNF-I) in rheumatoid arthritis (RA) and spondyloarthritis (SpA) are providing useful data about effectiveness and safety in clinical practice. Objectives To compare drug survival in RA and SpA according to TNF-I drug using data from a multicentre Italian cohort study. Methods The patients were selected from the Monitornet database, a prospective cohort study to monitor the long-term safety of biologic therapy involving 27 rheumatology centres across Italy, supported by the Italian regulatory agency AIFA. For the purpose of these analyses we included RA or SpA patients, who started a first course infliximab (INF), etanercept (ETA) or adalimumab (ADA). Drug survival was primarily defined from start until first discontinuation (overall drug survival) and secondarily due to ineffectiveness or adverse events (AEs). A first set of analyses assessed the relationship between diagnosis and drug survival using RA as reference category, adjusting for age, gender and comorbidities. A second set of analyses stratified by diagnosis explored the relationship between TNF-I and drug survival using INF as reference category, adjusting for age, gender, comorbidities, disease duration, previous DMARDs, calendar, baseline CRP, disease activity (DAS28 or BASDAI) and severity (HAQ score or BASFI). Drug survival was analyzed using Cox proportional hazards models. Results are presented as hazard ratios (HR) and 95% confidence intervals (CI). Results 1992 RA patients (79.8% women, mean age 55.5 yrs (SD 12.3), mean disease duration 9.6 yrs (SD 8.0), mean baseline DA28 4.4 (SD 1.9), baseline HAQ 1.4 (SD 0.7), median number of previous DMARDs 2 (IQR 1-3) and 993 SpA patients (55.2% men, mean age 49.6 yrs (SD 12.5), mean disease duration 6.9 yrs (7.5), mean baseline BASDAI 4.7 (SD 2.4), mean baseline BASFI 4.6 (SD 2.5) were included in the analyses. 44.2% RA patients started ETA, 21.4% INF, 34.4% ADA, while 45.8% SpA patients ETA, 22.3% INF, 31.9% ADA. Using RA as reference, SpA patients showed a lower drug discontinuation (HR 0.92 [95%CI 0.87, 0.99]), due to a lower withdrawal for inefficacy (HR 0.90 [95%CI 0.82, 0.99]). Both in RA and in SpA, compared to INF, ETA showed a slightly better survival on treatment, also due to lower discontinuation for inefficacy (see table). Conclusions These data support a better survival on treatment for SpA over RA and for ETA as compared with INF, mainly due to lower discontinuation for ineffectiveness rather than for AEs. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Patients with inflammatory rheumatic diseases characterized by a chronic progressive course, such as Rheumatoid Arthritis (RA) and Systemic Sclerosis (SSc), develop a disability of the hand which requires an adequate assessment and therapeutic intervention through a pharmacological treatment and a proper rehabilitation program. The Re.Mo.Te. device consists of sensorized aids, allowing the execution of hand rehabilitation exercises and the extraction of relevant parameters (motion, force, pressure, speed of execution) from the analysis of several repetitions of the same movement, performed in real rehabilitation exercises typically prescribed to RA and SSs patients (1). These data are part of a larger project called Re.Mo.Te. Recovery Movement and Telemonitoring for rheumatology patients with disabilities of the hand. Objectives To validate portable device Re.Mo.Te for the evaluation of hand disability in patients with RA and SSc. Methods Ten RA patients (10F, age 56.9 ± 13.1 years) and 10 SSc patients (9F, age 56.3 ± 10.4 years) underwent an assessment of hands function through the device Re.Mo.Te. and through the measurement of: 1) Range Of Movement (ROM) of the wrists and 2) grip strength (pinch and grip) of the hand and fingers, 3) hands and fingers extension. The HAQ and the algo-functional index of Dreiser were administered to both RA and SSc patients while the Hamis test was administered exclusively to SSc patients. The Spearman’s correlation coefficient was applied to test the validity of the results obtained with the Re.Mo.Te. device and to compare them with traditional assessment; p values <0.05 were considered significant. Results All patients had a reversible hand disability (HAQ = AR: 1.5 ± 0.82; SSc: 1.4 ± 0.65 - Dreiser’s index = AR: 15.7 ± 6.0; SSc: 15.0 ± 5.7). The Spearman’s correlation coefficients between the traditional hand functional assessment and the Re.Mo.Te. device assessment were high (0.67-0.79) and statistically significant for the measurement of grip strength (p <0.0001) and overall extent (p <0.001). The ROM results showed significant correlation with the global finger extension (p <0.01) and the speed of fingers extension (p <0.001) abilities evaluated by Re.Mo.Te. Conclusions The Re.Mo.Te. device is a valuable aid for the assessment of hand disability in chronically ill subjects requiring a quantitative evaluation for the proper set up of a personalized rehabilitation program. References Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Ankylosing Spondylitis (AS) is a complex chronic inflammatory disease strongly associated with the majority of HLA-B27 alleles, with the exception of B*2706 and B*2709. GWAS studies have revealed that other genes are also involved in AS pathogenesis such as ERAP1 which is able to cleave TNFR1 and IL-1R2 cell surface receptors, supposed to play a pivotal role in AS pathogenesis. Objectives To analyze the cell surface expression of TNFR1 and IL-1R2 receptors and the possible influence of ERAP1 allelic variance. Methods The percentage of CD14 negative peripheral blood mononuclear cells (PBMC) expressing TNFR1 and IL-1R2 receptors on the cell surface was evaluated in 12 HLA-B*2705 patients with AS, 12 HLA-B*2705 healthy subjects (HC) and 12 HLA-B*2709 HC by means of flow cytometry analysis and CD120a and CD121b monoclonal antibodies, respectively. Patients and controls were genotyped for two ERAP1 SNPs associated with AS (rs27044 C/G and rs30187 C/T). Values were expressed as median percentage of positive cells (interquartile range). The differences between AS patients and HC were analyzed by Mann Whitney U-test. Results TNFR1 expression on PBMC was significantly higher in AS patients (35.5 IQR 15.9-60.4) compared to B*2705 HC (18.9 IQR 9.7-25.5, p=0.04) and B*2709 HC (13.1 IQR 9.3-21.5, p=0.02). IL-1R2 was also significantly higher in AS patients (1.5 IQR 0.6-2.5) compared to B*2705 HC (0.2 IQR 0.1-0.8, p=0.01) and B*2709 HC (0.6 IQR 0.1-1.6, p=ns). The majority of AS patients and HC were heterozygous both for rs27044 (C/G) and rs30187 (C/T); the higher numbers of TNFR1 and IL-1R2 positive cells found in AS patients compared to HC were not due to differences in the ERAP1 allelic distribution in patients and controls as shown in the figure below: Conclusions This study shows a higher expression of TNFR1 and IL-1R2 on the PBMC surface of AS patients compared to B*2705 and B*2709 regardless of ERAP1 allelic variance, underlining the important role of these two cytokines in the pathogenesis of AS. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
  • A. Vacca · P. Garau · G. Porru · S. Calvisi · V. Ibba · M. Piga · A. Floris · A. Cauli · A. Mathieu
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    ABSTRACT: Background Interstitial lung disease (ILD) is very common in systemic sclerosis (SSc) and represents the leading cause of death. Despite its toxicity, cyclophosphamide (CYC) remains one of the most effective therapy. However, limited data about optimal dosage, duration therapy and best way of administration are available. It has been suggested that a prolonged CYC regimen might be more effective than a shorter course. Objectives To evaluate safety and response to oral long-term treatment with CYC in combination with low or medium steroids dose in patients with ILD-SSc. Methods Twenty two patients with ILD-SSc treated with oral CYC, were retrospectively included in this study. A complete clinical examination, included evaluation of European disease activity score and Mesdger’ severity scale score, high-resolution (HRCT) scan, pulmonary function tests (PFTs) were performed before starting therapy, and annually therefore during 10 years of follow-up [86.6 (47.4) months]. Patients were treated with oral CYC at the dosage of 50 mg/day, for consecutive 10-15 days monthly, for a mean of 63.8 (34.2) months, in association with oral prednisone at low (<10 mg/day; n = 9) or medium (> 10 mg/day; n = 13) doses. Results The cumulative CYC dosage reached was 39 (28.7) g, (range 6-122). After the first year of therapy, differences with baseline results for diffusion lung capacity for carbon monoxide (DLCO) and forced vital capacity (FVC) were less than 15% and 10 % respectively, indicating that they remained almost stable. Moreover, in 13 patients who discontinued CYC, DLCO continued to improve more than 10% after 24 months, compared with baseline. In multivariate analysis, an improvement of more than 15% in DLCO after CYC discontinuation significantly correlated with limited cutaneous SSc, early disease, severe ILD, elevated acute phase serum proteins. HRCT documented a regression of ground glass (GG) pattern in 77% of patients. Decrease of GG was mostly detected in the first year of therapy (P < 0.01) and when GG was the predominant pattern. Disease activity estimated by European disease activity score, improved significantly after the first year (P < 0.01) and then stabilized during the follow-up. Medsger severity scale score remained overall stable. Modified Rodnan skin score remained unchanged. Ten out of 22 patients (45%) developed adverse events (reversible and no life-threathening) that require drug withdrawal in seven cases. Three patients died for not related drug causes. No side effects were reported after drug withdrawal. Conclusions Oral CYC long-term therapy seem to be as effective as the intravenous pulse route and with comparable side effects. In our series, it ameliorated and/or stabilized lung function and HRCT pattern, maintaining favorable results after long time of discontinuation. Therapy was overall well tolerated with no severe adverse events. Disclosure of Interest: None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases

Publication Stats

1k Citations
453.92 Total Impact Points

Institutions

  • 1983-2015
    • Università degli studi di Cagliari
      • • Department of Chemical and Geological Science
      • • Department of Biomedical Science
      • • Department of Environmental and Life Science
      Cagliari, Sardinia, Italy
  • 2006
    • Hospital Clínic de Barcelona
      • Servicio de Enfermedades Autoinmunes y Sistémicas
      Barcino, Catalonia, Spain
  • 2005
    • University of Naples Federico II
      • Department of Clinical Medicine and Surgery
      Napoli, Campania, Italy
  • 2000
    • Sapienza University of Rome
      • Department of Biology and Biotechnology "Charles Darwin" BBCD
      Roma, Latium, Italy
  • 1988
    • Università degli Studi di Siena
      Siena, Tuscany, Italy